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miladalsh

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processed_scinews_dataset

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections AI Remote Sensing Atmospheric Remote Sensing Biogeosciences Remote Sensing Coral Reefs Remote Sensing Discoveries in Remote Sensing Earth Observation Data Earth Observation for Emergency Management Ecological Remote Sensing Engineering Remote Sensing Environmental Remote Sensing Forest Remote Sensing Ocean Remote Sensing Remote Sensing and Geo-Spatial Science Remote Sensing Communications Remote Sensing Image Processing Remote Sensing in Agriculture and Vegetation Remote Sensing in Geology, Geomorphology and Hydrology Remote Sensing of the Water Cycle Satellite Missions for Earth and Planetary Exploration Urban Remote Sensing All Sections Special Issue All Special Issues Remote Sensing: 15th Anniversary 100 Years ISPRS - Advancing Remote Sensing Science 2nd Edition Advances in Remote Sensing for Archaeological Heritage 3D Point Clouds in Rock Mechanics Applications Accuracy Assessment of UAS Lidar Active-Passive Microwave Sensing for Earth System Parameters Advanced Communication and Networking Techniques for Remote Sensing Advanced Machine Learning and Big Data Analytics in Remote Sensing for Natural Hazards Management Advanced Machine Learning Approaches for Hyperspectral Data Analysis Advanced Radar Signal Processing and Applications Advanced Remote Sensing Methods for 3D Vegetation Mapping and Characterization Advanced Satellite-Terrestrial Networks Advanced Topics in Remote Sensing Advancement of Remote Sensing and UAS in Cartography and Visualisation Advancements in Remote Sensing and GIS in Mobile Computing and Location-Based Services Advances and Innovative Applications of Unmanned Aerial Vehicles Advances in Applications of Volunteered Geographic Information Advances in Climate and Geophysics Advances in Geographic Object-Based Image Analysis (GEOBIA) Advances in Mobile Laser Scanning and Mobile Mapping Advances in Object and Activity Detection in Remote Sensing Imagery Advances in Object and Activity Detection in Remote Sensing Imagery II Advances in Object-Based Image Analysis—Linking with Computer Vision and Machine Learning Advances in Quantitative Remote Sensing in China – In Memory of Prof. Xiaowen Li Advances in Real Aperture and Synthetic Aperture Ground-Based Interferometry Advances in Remote Sensing and Geographic Information Science and Their Uses in Geointelligence Advances in Remote Sensing Applications for the Detection of Biological Invasions Advances in Remote Sensing for Archaeological Heritage Advances in Remote Sensing in Coastal Geomorphology Advances in Remote Sensing of Agriculture Advances in Remote Sensing of Crop Water Use Estimation Advances in Remote Sensing of Forestry Advances in Remote Sensing of Wildland Fires Advances in Remote Sensing-based Disaster Monitoring and Assessment Advances in SAR: Sensors, Methodologies, and Applications Advances in Satellite Altimetry Advances in Satellite Altimetry and Its Application Advances in Synthetic Aperture Radar Remote Sensing Advances in the Remote Sensing of Terrestrial Evaporation Advances in VIIRS Data Advances of Remote Sensing in Environmental Geoscience Aerosol and Cloud Remote Sensing Airborne Laser Scanning Analysis of Remote Sensing Image Data Application of Machine Learning in Volcano Monitoring Application of Multi-Sensor Fusion Technology in Target Detection and Recognition Application of Remote Sensing in Hydrological Modeling and Watershed Management Applications and New Trends in Metrology for Radar/LiDAR-Based Systems Applications of Deep Learning in Smart Agriculture Applications of Full Waveform Lidar Applications of GNSS Reflectometry for Earth Observation Applications of Micro- and Nano-Satellites for Earth Observation Applications of Remote Sensing in Landscape Ecology in Latin America Applications of Remote Sensing in Rangelands Research Applications of Synthetic Aperture Radar (SAR) for Land Cover Analysis Approaches for Monitoring Land Degradation with Remote Sensing Archaeological Prospecting and Remote Sensing Artifacts in Remote Sensing Data Analysis: An Ecological Perspective Artificial Intelligence and Automation in Sustainable Smart Farming Artificial Neural Networks and Evolutionary Computation in Remote Sensing Assessment of Renewable Energy Resources with Remote Sensing Assimilation of Remote Sensing Data into Earth System Models Atmospheric Remote Sensing Baltic Sea Remote Sensing Big Data Analytics for Secure and Smart Environmental Services Big Earth Observation Data: From Cloud Technologies to Insights and Foresight Bistatic HF Radar Calibration and Validation of Synthetic Aperture Radar Calibration and Verification of Remote Sensing Instruments and Observations Carbon Cycle, Global Change, and Multi-Sensor Remote Sensing Cartography of the Solar System: Remote Sensing beyond Earth Celebrating the 50th Anniversary of the Moon Landing with Views of Earth from Satellite and Apollo Missions Citizen Science and Earth Observation Climate Modelling and Monitoring Using GNSS Close Range Remote Sensing Close-Range Remote Sensing by Ground Penetrating Radar Compact Polarimetric SAR Concurrent Positioning, Mapping and Perception of Multi-source Data Fusion for Smart Applications Contemporary Microwave and Radar Techniques in Remote Sensing—MIKON 2022, IRS 2022 CORINE Land Cover System: Limits and Challenges for Territorial Studies and Planning Cross-Calibration and Interoperability of Remote Sensing Instruments Cryospheric Remote Sensing Data Mining in Multi-Platform Remote Sensing Data Science in Remote Sensing Data Science, Artificial Intelligence and Remote Sensing Deep Learning for Intelligent Synthetic Aperture Radar Systems Deep Learning for Target Object Detection and Identification in Remote Sensing Data Deep Learning in Remote Sensing: Sample Datasets, Algorithms and Applications Dense Image Time Series Analysis for Ecosystem Monitoring Design and Calibration of Microwave Radiometers and Scatterometers for Remote Sensing of the Earth Designing and Managing the Next Generation of Transportation Infrastructure Digital Forest Resource Monitoring and Uncertainty Analysis Discovering A More Diverse Remote Sensing Discipline Drone-Based Ecological Conservation Earth Environment Monitoring with Advanced Spaceborne Synthetic Aperture Radar: New Architectures, Operational Modes, and Processing Techniques Earth Monitoring from A New Generation of Geostationary Satellites Earth Observation and Sustainable Development in Marine and Freshwater Systems Earth Observation for Ecosystems Monitoring in Space and Time Earth Observation for Water Resource Management in Africa Earth Observation in Planning for Sustainable Urban Development Earth Observation Technology Cluster: Innovative Sensor Systems for Advanced Land Surface Studies Earth Observation to Support Disaster Preparedness and Disaster Risk Management Earth Observation with AVHRR Data and Interconsistency Earth Observations for a Better Future Earth Earth Observations for Addressing Global Challenges Earth Observations for Geohazards Earth Observations for the Sustainable Development Ecogeomorphological Research Using Satellite Images Ecological Status and Change by Remote Sensing Environmental Research with Global Navigation Satellite System (GNSS) EO Solutions to Support Countries Implementing the SDGs ESA - NRSCC", "role": "user" }, { "content": "A research team led by Prof. Sun Xiaobing from the Anhui Institute of Optics and Fine Mechanics, Hefei Institutes of Physical Science (HFIPS), Chinese Academy of Sciences (CAS), has proposed an optimal inversion algorithm based on combined utilization of multi-band intensity and polarization information. This algorithm can meet the requirements of single-angle and multi-band polarization aerosol detection. The study was published in Remote Sensing. Aerosol optical depth (AOD) is used to characterize the extinction effect of aerosol on solar radiation, which plays an important role in remote sensing atmospheric correction and fine particulate pollution assessment. The proposed algorithm does not need prior information of the ground. It uses polarization information of short-wave infrared band to separate ground and atmospheric information, and then uses scalar information to obtain the final result. \"By decoupling the surface and atmosphere, our method can avoid inversion error and spatio-temporal matching error caused by the late updating of the surface reflectance database,\" said Prof. Sun. The researchers used the observation data of a high-precision polarization scanner (POSP) onboard the hyperspectral observation satellite (GF-5B) to verify the algorithm. \"Compared with AOD products of aerosol robotic network stations in different regions, the algorithm can retrieve AOD over different surfaces,\" said Prof. Sun. \"Another advantage is that the effectiveness of the algorithm under different pollution conditions is verified with Moderate-Resolution Imaging Spectroradiomete (MODIS) AOD products.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes ( DNAH10 and PLXND1 ). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants. Main Central body-fat distribution, as assessed by waist-to-hip ratio (WHR), is a heritable and a well-established risk factor for adverse metabolic outcomes 1 , 2 , 3 , 4 , 5 , 6 . Lower values of WHR are associated with lower risk of cardiometabolic diseases such as type 2 diabetes 7 , 8 , or differences in bone structure and gluteal muscle mass 9 . These epidemiological associations are consistent with our previously reported genome-wide association study (GWAS) results of 49 loci associated with WHR (after adjusting for body mass index, WHRadjBMI) 10 . Notably, genetic predisposition to higher WHRadjBMI is associated with increased risk of type 2 diabetes and coronary heart disease (CHD), which seems to be causal 9 . Recently, large-scale studies have identified roughly 125 common loci for multiple measures of central obesity, primarily non-coding variants of relatively modest effect 10 , 11 , 12 , 13 , 14 , 15 , 16 . Large-scale interrogation of coding and splice site variants, including both common (minor allele frequency, MAF ≥5%) and low-frequency or rare variants (LF/RV: MAF <5%), may lead to additional insights into the etiology of central obesity. Here, we identify and characterize such variants associated with WHRadjBMI using ExomeChip array genotypes. Results Protein-coding and splice site variation associations We conducted a two-stage fixed-effects meta-analysis testing additive and recessive models to detect protein-coding genetic variants that influence WHRadjBMI ( Methods and Fig. 1 ). Stage 1 included up to 228,985 variants (218,195 low-frequency or rare) in up to 344,369 individuals from 74 studies of European, South and East Asian, African and Hispanic/Latino descent individuals (Supplementary Data 1 – 3 ). Stage 2 assessed 70 suggestive ( P < 2 × 10 −6 ) stage 1 variants in two cohorts, UK Biobank (UKBB) and deCODE for a total stage 1 and 2 sample size of 476,546 (88% European). Of the 70 variants considered, two common and five low-frequency or rare were not available in stage 2 (Tables 1 and 2 and Supplementary Data 4 – 6 ). Variants are considered novel and statistically significant if they were greater than one megabase (Mb) from a previously identified WHRadjBMI SNP 10 , 11 , 12 , 13 , 14 , 15 , 16 and achieve array-wide significance ( P < 2 × 10 −7 , stage 1 and 2). Fig. 1: Summary of meta-analysis study design and workflow. Abbreviations: EUR, European, AFR, African, SAS, South Asian, EAS, East Asian and HIS, Hispanic/Latino ancestry. Full size image Table 1 Association results for combined sexes. Association results based on an additive or recessive model for coding variants that met array-wide significance ( P < 2 × 10 −7 ) in the sex-combined meta-analyses Full size table Table 2 Association results for sex-stratified analyses. Association results based on an additive or recessive model for coding variants that met array-wide significance ( P < 2 × 10 −7 ) in the sex-specific meta-analyses and reach Bonferroni corrected P value for sex heterogeneity ( P sexhet < 7.14 × 10 −4 ) Full size table In our primary meta-analysis, including all stage 1 and 2 samples, we identified 48 coding variants (16 novel) across 43 genes, 47 assuming an additive model and one under a recessive model (Table 1 and Supplementary Figs. 1 – 4 ). Due to possible heterogeneity, we also performed European-only meta-analysis. Here, four additional coding variants were significant (three novel) assuming an additive model (Table 1 and Supplementary Figs. 5 – 8 ). Of these 52 significant variants, 11 were low-frequency or rare and displayed larger effect estimates than many previously reported common variants 10 , including seven novel variants in RAPGEF3 , FGFR2, R3HDML, HIST1H1T, PCNXL3, ACVR1C and DARS2 . Variants with MAF ≤1% had effect sizes approximately three times greater than those of common variants (MAF ≥5%). Despite large sample size, we cannot rule out the possibility that additional low-frequency or rare variants with smaller effects exist (see estimated 80% power in Fig. 2 ). However, in the absence of common variants with similarly large effects, our results point to the importance of investigating LF/RVs. Fig. 2: Minor allele frequency compared to estimated effect. This scatter plot displays the relationship between MAF and the estimated effect (β) for each significant coding variant in our meta-analyses. All novel WHRadjBMI variants are highlighted in orange, and variants identified only in models that assume recessive inheritance are denoted by diamonds and only in sex-specific analyses by triangles. Eighty percent power was calculated based on the total sample size in the stage 1 and 2 meta-analysis and P = 2 × 10 −7 . Estimated effects are shown in original units (cm cm −1 ) calculated by using effect sizes in s.d. units times SD of WHR in the ARIC study (sexes combined = 0.067, men = 0.052, women = 0.080). Full size image Given established sex differences in the genetic underpinnings of WHRadjBMI 10 , 11 , we also performed sex-stratified analyses. We detected four additional novel variants that exhibit significant sex-specific effects ( P sexhet < 7.14 × 10 −4 , Methods", "role": "user" }, { "content": "A new breakthrough from the Genetic Investigation of Anthropometric Traits consortium, which includes many public health researchers from the University of North Carolina at Chapel Hill, identifies multiple genetic variants associated with how the body regulates and distributes body-fat tissue. The new findings broaden the understanding of how genes can predispose certain individuals to obesity. The GIANT Consortium is a major international collaboration of more than 275 scientists that seeks to identify genetic sites that affect human body size and shape, including height and measures of obesity. Kari E. North, professor of epidemiology at the University of North Carolina at Chapel Hill Gillings School of Global Public Health, is joint lead author of the new study, \"Protein-Coding Variants Implicate Novel Genes Related to Lipid Homeostasis 1 Contributing to Body Fat Distribution,\" published February 18 in Nature Genetics. Other co-authors from the UNC Gillings School include assistant professor Kristin Young, assistant professor Misa Graff, and postdoctoral fellow Heather Highland, all in the UNC Gillings School's department of epidemiology. Identifying the genetic variants associated with obesity is central to developing targeted interventions that can reduce the risk of chronic illnesses, such as hypertension, type 2 diabetes, and heart disease, to which obesity contributes in significant ways. Genome-wide association studies previously identified 49 loci, or positions along a chromosome where the related genetic variants are located, that predispose individuals to a higher waist-to-hip ratio, which is a way to assess body-fat distribution. Lower values of WHR are associated with lower incidence of these diseases. In this study, with a specific focus on coding variation, the team found 24 coding loci—15 common and nine rare—along the chromosomes of individuals that predispose to higher WHR. Further analysis revealed pathways and gene sets that influenced not only metabolism but also the regulation of body fat tissue, bone growth and adiponectin, a hormone that controls glucose levels and breaks down fat. The team also performed functional studies across other organisms and identified two genes that were associated with a significant increase in triglyceride levels and body fat across species. \"For the first time, we were able to examine, on a large scale, how low-frequency and rare variants influence body fat distribution,\" said Kari E. North. \"These variants are rarer in the population, but the effects they have on individuals are much larger, possibly making them more clinically relevant.\" Another major finding from this study is the importance of lipid metabolism to body­fat distribution, which could lead to a better understanding of how obesity causes downstream diseases such as Type 2 diabetes and cardiovascular disease. \"A better understanding of the genetic underpinnings of body fat distribution may lead to better treatments for obesity and the cascade of downstream diseases obesity also impacts, for example type 2 diabetes and heart disease\" North said. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Artificial photosystems are advanced by the development of conformal catalytic materials that promote desired chemical transformations, while also maintaining stability and minimizing parasitic light absorption for integration on surfaces of semiconductor light absorbers. Here, we demonstrate that multifunctional, nanoscale catalysts that enable high-performance photoelectrochemical energy conversion can be engineered by plasma-enhanced atomic layer deposition. The collective properties of tailored Co 3 O 4 /Co(OH) 2 thin films simultaneously provide high activity for water splitting, permit efficient interfacial charge transport from semiconductor substrates, and enhance durability of chemically sensitive interfaces. These films comprise compact and continuous nanocrystalline Co 3 O 4 spinel that is impervious to phase transformation and impermeable to ions, thereby providing effective protection of the underlying substrate. Moreover, a secondary phase of structurally disordered and chemically labile Co(OH) 2 is introduced to ensure a high concentration of catalytically active sites. Application of this coating to photovoltaic p + n-Si junctions yields best reported performance characteristics for crystalline Si photoanodes. Main The capture of solar energy and its conversion to storable chemical fuel by photoelectrochemical (PEC) systems provides a promising route to overcoming the current global reliance on fossil fuels 1 , 2 . In such artificial photosynthetic systems, the oxidation of water or hydroxyl ions is a requirement for providing a sufficiently abundant source of protons and electrons for sustainably driving the fuel formation reaction. However, the oxygen evolution reaction (OER) presents significant challenges in catalysis and a kinetic bottleneck for solar fuels generation. Among OER catalysts, cobalt oxides (CoO x ) have been shown to possess desirable activity over a broad range of pH values 3 . Recent breakthroughs have provided insight into the nature of catalytically active sites at the atomic scale 4 , 5 , 6 , 7 , 8 , as well as the role of dynamic structural transformations from the resting to the active states 9 , 10 , 11 . Within this context, there has been considerable interest in the development of disordered or amorphous materials that exhibit enhanced catalytic activity relative to their crystalline counterparts 12 , 13 . However, associated mechanisms of enhanced activity are only beginning to emerge. For instance, it has been shown that cobalt phosphate undergoes progressive amorphization, which results in a transition from predominantly surface-confined catalysis on crystalline surfaces to volume-active catalysis in amorphous material 10 . Likewise, Bergmann and co-workers recently demonstrated that transformation to the active phase is accompanied by reversible amorphization of a sub-nanometre-thick near-surface region of Co 3 O 4 to CoO x (OH) y (ref. 11 ). The proposed mechanisms present an intriguing picture of catalysis in dynamic materials, whereby increasing concentrations of catalytically active sites within the bulk can contribute to higher overall activity per geometric area. Although mechanistic insights are important, achieving atomic level control of structure–function relationships is essential for creating high-performance catalysts. Despite the emerging benefits of disordered or amorphous systems for OER catalysis, interfacing these materials with semiconductor light absorbers remains an outstanding challenge. For example, disordered catalyst films tend to be hydrated, and are subject to drying stress-induced cracking and delamination 14 , 15 . Such transformations introduce physical and chemical instabilities, particularly when the catalyst film is interfaced to a chemically sensitive semiconductor. In such cases, it is also necessary to form conformal coatings, while retaining optical transparency. Standard synthetic approaches for forming disordered catalysts, such as electrodeposition and other solution methods, are not well suited for achieving this combination of material properties. Here, we seek to translate catalyst design principles from solution-based synthesis approaches, in which chemically and structurally labile materials possess improved activity, to advanced vapour deposition methods capable of forming continuous and defined thin films compatible with semiconductor light absorbers. Drawing inspiration from recent studies that highlight the importance of volume transformation for increasing concentrations of OER active sites, we use plasma-enhanced atomic layer deposition (PE-ALD) to create biphasic films comprising chemically and structurally labile Co(OH) 2 on top of compact nanocrystalline Co 3 O 4 spinel layers. The presence of these two phases is important for simultaneously increasing catalytic activity and providing a stable interface to the substrate. Precise control of film thickness and conformality, afforded by PE-ALD, is crucial for creating closed films at the nanoscale, while also minimizing losses due to parasitic light absorption and eliminating traditional limitations associated with hydrated catalysts. Integration of biphasic Co 3 O 4 /Co(OH) 2 coatings with photovoltaic p + n-Si junctions yields, to the best of our knowledge, the highest photoelectrochemical activity for OER reported to date on crystalline Si. We note that sub-monolayer mixed Co 3 O 4 /Co(OH) 2 films have been previously applied to Fe 2 O 3 , resulting in considerable catalytic activity improvements 16 . Although such a coating is suitable for chemically robust light absorbers, such as haematite, it is not compatible with existing high-efficiency photoanode materials, which rapidly degrade under operational conditions. In the present work, biphasic CoO x films with defined nanocrystalline interfaces and disordered surface layers were created by PE-ALD using exposure cycles of CoCp 2 and oxygen plasma at target temperatures ranging from 40 °C to 300 °C (see Methods ) 17 , 18 . Deposition was initially performed onto the surfaces of p + -Si (0.001–0.005 Ω cm −1 ) and electrocatalytic (EC) activity for OER was evaluated under 1 M NaOH. Electrochemical properties As shown in Fig. 1a , the electrocatalytic current density is significantly increased as the deposition temperature is decreased from 300 °C to 100 °C. The dependence of activity on deposition temperature can also be seen in Fig. 1b , which shows the current density at an applied electrochemical potential of 1.8 V versus reversible hydrogen electrode (RHE), and Fig. 1c , which shows the overpotential ( η ) required to achieve current densities of 1 mA cm −2 and 10 mA cm −2 . Maximum activity is observed at a deposition temperature of approximately 100 °C. However, further decrease of the deposition temperature to", "role": "user" }, { "content": "Scientists have found a way to engineer the atomic-scale chemical properties of a water-splitting catalyst for integration with a solar cell, and the result is a big boost to the stability and efficiency of artificial photosynthesis. Led by researchers at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), the project is described in a paper published this week in the journal Nature Materials. The research comes out of the Joint Center for Artificial Photosynthesis (JCAP), a DOE Energy Innovation Hub established in 2010 to develop a cost-effective method of turning sunlight, water, and carbon dioxide into fuel. JCAP is led by the California Institute of Technology with Berkeley Lab as a major partner. The goal of this study was to strike a careful balance between the contradictory needs for efficient energy conversion and chemically sensitive electronic components to develop a viable system of artificial photosynthesis to generate clean fuel. Striking the right balance \"In order for an artificial photosystem to be viable, we need to be able to make it once, deploy it, and have it last for 20 or more years without repairing it,\" said study principal investigator Ian Sharp, head of materials integration and interface science research at JCAP. The problem is that the active chemical environments needed for artificial photosynthesis are damaging to the semiconductors used to capture solar energy and power the device. \"Good protection layers are dense and chemically inactive. That is completely at odds with the characteristics of an efficient catalyst, which helps to split water to store the energy of light in chemical bonds,\" said Sharp, who is also a staff scientist at Berkeley Lab's Chemical Sciences Division. \"The most efficient catalysts tend to be permeable and easily transform from one phase to another. These types of materials would usually be considered poor choices for protecting electronic components.\" By engineering an atomically precise film so that it can support chemical reactions without damaging sensitive semiconductors, the researchers managed to satisfy contradictory needs for artificial photosystems. \"This gets into the key aspects of our work,\" said study lead author Jinhui Yang, who conducted the work as a postdoctoral researcher at JCAP. \"We set out to turn the catalyst into a protective coating that balances these competing properties.\" Jinhui Yang performing X-ray photoelectron spectroscopy measurements, which are used to understand the chemical properties of surfaces, at the Joint Center for Artificial Photosynthesis. Credit: Robert Paz/Caltech Doing double duty The researchers knew they needed a catalyst that could not only support active and efficient chemical reactions, but one that could also provide a stable interface with the semiconductor, allow the charge generated by the absorption of light from the semiconductor to be efficiently transferred to the sites doing catalysis, and permit as much light as possible to pass through. They turned to a manufacturing technique called plasma-enhanced atomic layer deposition, performed at the Molecular Foundry at Berkeley Lab. This type of thin-film deposition is used in the semiconductor industry to manufacture integrated circuits. \"This technique gave us the level of precision we needed to create the composite film,\" said Yang. \"We were able to engineer a very thin layer to protect the sensitive semiconductor, then atomically join another active layer to carry out the catalytic reactions, all in a single process.\" The first layer of the film consisted of a nanocrystalline form of cobalt oxide that provided a stable, physically robust interface with the light-absorbing semiconductor. The other layer was a chemically reactive material made of cobalt dihydroxide. \"The design of this composite coating was inspired by recent advances in the field that have revealed how water-splitting reactions occur, at the atomic scale, on materials. In this way, mechanistic insights guide how to make systems that have the functional properties we need,\" said Sharp. Using this configuration, the researchers could run photosystems continuously for three days—potentially longer—when such systems would normally fail in mere seconds. \"A major impact of this work is to demonstrate the value of designing catalysts for integration with semiconductors,\" said Yang. \"Using a combination of spectroscopic and electrochemical methods, we showed that these films can be made compact and continuous at the nanometer scale, thus minimizing parasitic light absorption when integrated on top of photoactive semiconductors.\" The study authors noted that while this is an important milestone, there are many more steps needed before a commercially viable artificial photosystem is ready for deployment. \"In general, we need to know more about how these systems fail so we can identify areas to target for future improvement,\" said Sharp. \"Understanding degradation is an important avenue to making something that is stable for decades.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Plastic pollution is now pervasive in the Arctic, even in areas with no apparent human activity, such as the deep seafloor. In this Review, we describe the sources and impacts of Arctic plastic pollution, including plastic debris and microplastics, which have infiltrated terrestrial and aquatic systems, the cryosphere and the atmosphere. Although some pollution is from local sources — fisheries, landfills, wastewater and offshore industrial activity — distant regions are a substantial source, as plastic is carried from lower latitudes to the Arctic by ocean currents, atmospheric transport and rivers. Once in the Arctic, plastic pollution accumulates in certain areas and affects local ecosystems. Population-level information is sparse, but interactions such as entanglements and ingestion of marine debris have been recorded for mammals, seabirds, fish and invertebrates. Early evidence also suggests interactions between climate change and plastic pollution. Even if plastic emissions are halted today, fragmentation of legacy plastic will lead to an increasing microplastic burden in Arctic ecosystems, which are already under pressure from anthropogenic warming. Mitigation is urgently needed at both regional and international levels to decrease plastic production and utilization, achieve circularity and optimize solid waste management and wastewater treatment. Key points The widespread plastic pollution in the Arctic originates from both local and distant sources. Concentrations of plastic in the Arctic vary widely, with greater accumulation in certain hotspots, but are generally similar to those of more densely populated regions. Plastic has infiltrated all levels of the Arctic food web, including many endemic species, with largely unknown organismal impacts. In the fast-changing Arctic, plastic pollution adds to the effects of climate change in terms of growing sources, transport processes, potential feedback loops and ecological consequences. Mitigation of both local and distal plastic pollution is needed to prevent further ecosystem degradation. Introduction Industrial plastic production has grown rapidly since the 1950s, reaching 368 million tonnes globally per year by 2019 (ref. 1 ). Because of its low price, plastic has become one of the most widely used materials, especially in the packaging industry, and now forms an integral part of municipal waste. Every year, 19–23 million metric tonnes of mismanaged plastic waste are transferred from land-based sources to water globally 2 . As plastics are designed to be durable, they persist in the environment for long periods of time and become widely dispersed 3 , 4 . Therefore, plastic is a planetary boundary threat 5 , 6 , especially once it fragments into microplastic and nanoplastic (size ≤5 mm and ≤1 μm (ref. 7 ), respectively) due to sunlight, mechanical abrasion, biotic interaction, wave action 8 and temperature fluctuations. Plastic is also extensively used in maritime operations such as fishing, aquaculture, shipping and offshore operations, leading to substantial additional leakage into marine environments. Although millions of tonnes of plastics enter the oceans annually, it is currently unknown where in the ocean 99% of the small plastic debris ends up 9 , pointing to yet unaccounted for accumulation areas 10 . Polar regions are still perceived as pristine. However, in the past five years, high levels of plastic pollution have been found in the Arctic (Fig. 1 ). The formation of a sixth accumulation area in the Nordic Seas has been suggested by model projections 11 and is corroborated by an increase in marine debris over time 12 , 13 and comparatively high microplastic concentrations in the Arctic 14 , 15 . This evidence has prompted a Protection of the Arctic Marine Environment (PAME, Arctic Council) working group desktop study on marine litter and microplastics in the Arctic 16 to gauge the need for a Regional Action Plan, which, in turn, led to a mandate to assess the status and trends by the Arctic Monitoring and Assessment Programme 17 . Fig. 1: Overview of the pathways of plastic pollutants into the Arctic Ocean from local and distant sources. Plastic pollution can be generated by households, traffic, agriculture, wastewater treatment, landfills, illegal dumping, industry, shipyards, tourism, ships, fisheries and offshore industry, and be transported to and/or within the Arctic via the atmosphere, rivers, ocean currents, sea ice and eroding permafrost. The seafloor and sea ice are areas of plastic accumulation. The numbers in boxes refer to the abundance of plastic debris (green) or microplastics (MP, purple) in different ecosystem compartments. The ranges are based on data from 36 peer-reviewed studies reporting from 727 locations that were compiled in the database Litterbase 84 (more details on the data extraction process are provided in the Supplementary Information ). The data in each compartment were converted to common units here, but the sampling and analytical methods used in different studies varied widely, as there are currently few standardized or harmonized procedures. For example, varying size detection limits in different studies likely introduced considerable variability in the ranges shown. Figure is adapted from AWI-Infographic, CC BY 4.0 ( ). Full size image In this Review, we describe the sources of Arctic plastic debris, its distribution and its effects on Arctic biota, as well as knowledge gaps and mitigation with a broad, pan-Arctic view, complementing previous reviews focused on plastic pollution effects on Arctic biota 18 , such as seabirds 19 , or with differential geographic focuses 20 , 21 , 22 . We also discuss interactions between climate change and plastic pollution, as plastic pollution likely adds to the impacts of climate change, which has caused a three times faster increase in Arctic temperatures compared with the global average 23 . Sources of Arctic plastic debris As much of the Arctic is sparsely inhabited, relatively low local plastic pollution inputs would be expected. Yet, there are widespread observations of plastics in the region. Most model simulations and data suggest that a substantial proportion originates from the North Atlantic 9 , 24 and the North Pacific 25 , 26 (Fig. 1 ). Rivers were also suggested as a pathway of microplastic pollution in the Arctic 27 . Although the Arctic Ocean contains only ~1% of the global ocean volume, it receives >10% of", "role": "user" }, { "content": "Even the High North can't escape the global threat of plastic pollution. An international review study just released by the Alfred Wegener Institute shows the flood of plastic has reached all spheres of the Arctic. Large quantities of plastic—transported by rivers, the air and shipping–can now be found in the Arctic Ocean. High concentrations of microplastic can be found in the water, on the seafloor, remote beaches, in rivers, and even in ice and snow. The plastic is not only a burden for ecosystems; it could also worsen climate change. The study was just released in the journal Nature Reviews Earth & Environment. The numbers speak for themselves. Today, between 19 and 23 million metric tons of plastic litter per year end up in the waters of the world—that's two truckloads per minute. Since plastic is also very stable, it accumulates in the oceans, where it gradually breaks down into ever smaller pieces—from macro- to micro- and nanoplastic and can even enter the human bloodstream. And the flood of debris is bound to get worse: global plastic production is expected to double by 2045. The consequences are serious. Today, virtually all marine organisms investigated—from plankton to sperm whales—come into contact with plastic debris and microplastic. And this applies to all areas of the world's oceans—from tropical beaches to the deepest oceanic trenches. As the study published by the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) now shows, the High North is no exception. \"The Arctic is still assumed to be a largely untouched wilderness,\" says AWI expert Dr. Melanie Bergmann. \"In our review, which we jointly conducted with colleagues from Norway, Canada and the Netherlands, we show that this perception no longer reflects the reality. Our northernmost ecosystems are already particularly hard hit by climate change. This is now exacerbated by plastic pollution. And our own research has shown that the pollution continues to worsen.\" The article paints a grim picture. Although the Arctic is sparsely populated, in virtually all habitats—from beaches and the water column, to the seafloor—it shows a similar level of plastic pollution as densely populated regions around the globe. The pollution stems from both local and distant sources. Ocean currents from the Atlantic and the North Sea, and from the North Pacific over the Bering Strait, especially contribute to this. Tiny microplastic particles are also carried northward by wind. Then there are the rivers: though the Arctic Ocean makes up only one percent of the total volume of the world's oceans, it receives more than 10 percent of the global water discharge from rivers, which carry plastic into the ocean, for example, from Siberia. When seawater off the coast of Siberia freezes in the autumn, suspended microplastic becomes trapped in the ice. The Transpolar Drift transports the ice floes to Fram Strait between Greenland and Svalbard, where it melts in the summer, releasing its plastic cargo. Some of the most important local sources of pollution are municipal waste and wastewater from Arctic communities and plastic debris from ships—especially fishing vessels, whose nets and ropes pose a serious problem. Either intentionally dumped in the ocean or unintentionally lost, they account for a large share of the plastic debris in the European sector of the Arctic: On one beach on Svalbard, almost 100 percent of the plastic mass washed ashore came from fisheries according to an AWI study. \"Unfortunately, there are very few studies on the effects of the plastic on marine organisms in the Arctic,\" Bergmann explains. \"But there is evidence that the consequences there are similar to those in better-studied regions: in the Arctic, too, many animals—polar bears, seals, reindeer and seabirds—become entangled in plastic and die. In the Arctic, too, unintentionally ingested microplastic likely leads to reduced growth and reproduction, to physiological stress and inflammations in the tissues of marine animals, and even runs in the blood of humans.\" The available data on potential feedback effects between plastic debris and climate change is particularly thin. \"Here, there is an urgent need for further research,\" says the AWI expert. \"Initial studies indicate that trapped microplastic changes the characteristics of sea ice and snow.\" For example, dark particles could mean the ice absorbs more sunlight and therefore melts more rapidly. In turn, due to what is known as ice-albedo feedback this can intensify global warming. Moreover, plastic particles in the atmosphere provide condensation nuclei for clouds and rain, which means they could influence the weather and, in the long term, the climate. And last but not least, throughout their lifecycle, plastics are currently responsible for 4.5 percent of global greenhouse-gas emissions. \"Our review shows that the levels of plastic pollution in the Arctic match those of other regions around the world. This concurs with model simulations that predict an additional accumulation zone in the Arctic,\" says Bergmann. \"But the consequences might be even more serious. As climate change progresses, the Arctic is warming three times faster than the rest of the world. Consequently, the plastic flood is hitting ecosystems that are already seriously strained. \"The resolution for a global plastic treaty, passed at the UN Environment Assembly this February, is an important first step. In the course of the negotiations over the next two years, effective, legally binding measures must be adopted including reduction targets in plastic production. \"In this regard, the European countries including Germany must cut their plastic output, just as the rich Arctic States have to reduce pollution from local sources and improve the often virtually non-existent waste and wastewater management in their communities. In addition, more regulation and controls are called for—with regard to plastic debris from international shipping, and fisheries.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract G-protein-coupled receptors (GPCRs) represent one of the most important classes of drug targets. The discovery of new GCPR therapeutics would greatly benefit from the development of a generalizable high-throughput assay to directly monitor their activation or de-activation. Here we screened a variety of labels inserted into the third intracellular loop and the C-terminus of the α 2A -adrenergic receptor and used fluorescence (FRET) and bioluminescence resonance energy transfer (BRET) to monitor ligand-binding and activation dynamics. We then developed a universal intramolecular BRET receptor sensor design to quantify efficacy and potency of GPCR ligands in intact cells and real time. We demonstrate the transferability of the sensor design by cloning β 2 -adrenergic and PTH1-receptor BRET sensors and monitored their efficacy and potency. For all biosensors, the Z factors were well above 0.5 showing the suitability of such design for microtiter plate assays. This technology will aid the identification of novel types of GPCR ligands. Introduction G-protein-coupled receptors (GPCRs) constitute the largest and the most diverse group of membrane receptors in eukaryotes. They play a role in a plethora of cellular processes. Despite their functional diversity, they share a similar molecular architecture of seven transmembrane helices and a conserved mechanism of activation. Binding of agonist ligands to their cognate receptor leads to a change in the arrangement of distinct transmembrane helices, and a pronounced outward movement of helix 6 (up to 14 Å) 1 , which is then propagated to the third intracellular loop that connects helix 5 with 6, thus enabling the engagement of several downstream signaling pathways, most importantly the activation of G-proteins. We previously demonstrated that such ligand-induced conformational changes can be visualized in living cells by Förster Resonance Energy Transfer (FRET). The average distance between the third intracellular loop and the C-terminus of receptors (e.g., β 2 AR 6.2 nm) 2 is within the range addressable by FRET (2.4–7.2 nm) 3 . Therefore, tagging these conformationally sensitive sites with fluorescent donors and acceptors permits the recording of receptor activation as a change in energy transfer between these chromophores. Following this principle, a series of intramolecular FRET-based GPCR-biosensors have been generated, notably for the α 2A -adrenergic receptor (α 2A AR), employing the fluorescent proteins CFP and YFP (α 2A AR CFP/YFP ) 4 , 5 or CFP with the small Fluorescein Arsenical Hairpin Binder (FlAsH) as fluorophores 6 . These FRET-based GPCR biosensors have become widely used tools 7 and represent the most direct unbiased way to determine the effects of ligands on a given receptor. Their employment has helped to elucidate several aspects of receptor pharmacology and kinetics 8 . However, the combination of donor and acceptor fluorophores used so far suffers from a low signal-to-noise ratio and high fluorescence background which limits their use to single-cell experiments, slowing down the characterization of new pharmacological compounds as GPCR-directed therapeutics. More recently, Bioluminescence Resonance Energy Transfer (BRET) has been tested as an alternative approach to monitor the conformational change of receptors. BRET occurs between proximally situated donor–acceptor pairs (1.6–8.5 nm) 9 , but here a light emitting enzyme luciferase is used as a donor, sidestepping many of the deficiencies associated with direct illumination of the sample. Earlier attempts to generate intramolecular GPCR BRET-based biosensors employing Renilla Luciferase as a donor in combination with GFP or FlAsH as acceptor showed poor agonist-induced BRET changes 10 , 11 , 12 , 13 . Despite the many efforts in optimizing the way in which we study GPCRs and a plethora of methods to assess ligand binding or downstream signaling, the lack of a generalizable assay to monitor directly in living cells receptor activation or de-activation in a format suitable for high-throughput screening is slowing down the progress in discovering new GPCR therapeutics. In the present study, we therefore set out to permutate the well-characterized FRET-based biosensor α 2A AR CFP/YFP in order to develop a universal and versatile sensor design to reach the stringent requirements of monitoring receptor conformational dynamics in intact cells in microtiter plates. Preserving the fluorophore insertion sites in the third intracellular loop and C- terminus, we investigated whether combining different donors and acceptors would improve the transfer of energy to enable the visualization of the receptor’s conformational changes in microtiter plates. Among the 10 FRET-based and the 11 BRET-based α 2A AR biosensors generated in this study, the highest amplitude in the signals upon norepinephrine stimulation was recorded with the BRET-based α 2A AR biosensors combining NanoLuc 14 luciferase as the donor and the self-labeling protein tag Halo labeled with the HaloTag dye NanoBRET 618 as the acceptor. The EC 50 -values calculated for these BRET experiments were in line with binding affinities, demonstrating that the developed BRET biosensor α 2A AR Nluc/Halo assay faithfully reports ligand affinities. This feature was conserved also for a β 2 -adrenergic and a PTH1 receptor BRET-based biosensors. Also for these two receptors, the agonist-induced BRET changes were in line with the binding data suggesting that our receptor biosensor design is a generalizable design that may be use in lieu of the endogenous receptor to determine efficacy and potency of ligands. To assess the applicability of the biosensor design to microtiter plate and its scalability, we performed for each receptor a Z-factor analysis 15 to quantify the quality and reproducibility of the assays. For all receptors analyzed, the Z-factor was well above 0.5—which characterizes an excellent assay suitable to be used in microtiter plates. We propose that this technology will speed the characterization of new pharmacological compounds acting at GPCRs. Results Dynamic range of FRET- and BRET-based α 2A AR biosensors With the goal of generating a GPCR biosensor design to monitor receptor activation in microtiter plates, we permutated the well-characterized FRET-based biosensor α 2A AR CFP/YFP . We preserved the fluorophore insertion sites in the third intracellular loop and C-terminus (Fig. 1a ) but we substituted the original YFP with its brighter variant cpVenus or with self-labeling protein tags: SNAP (α 2A AR CFP/SNAP ; 20 kDa) 16", "role": "user" }, { "content": "Hormones and other neurotransmitters, but also drugs, act upon receptors. \"Their active substances bind to the receptors and modify the three-dimensional receptor arrangement regulating the downstream signal pathways,\" says Hannes Schihada from the Institute for Pharmacology and Toxicology at the University of Würzburg (JMU). A special case are G protein-coupled receptors (GPCR). \"About 30 percent of all authorized drugs worldwide act upon these receptors,\" explains Hannes Schihada, \"but their potential is not yet fully utilized.\" To date, it has not been possible to test the effect of millions of potential drugs on the GPCR arrangement within a very short time. \"This has been a stumbling block to the discovery of novel pharmaceutical substances and the research of still unknown GPCRs,\" says Dr. Isabella Maiellaro, who is in charge of the project together with Professor Martin Lohse. The JMU team has now developed a method that allows the determination of both activity and potency of GPCR ligands in living cells using high throughput technology. The scientists have published their results in the journal Communications Biology. What the new method can do The name of the method is BRET (bioluminescence resonance energy transfer-based sensor design). \"It can be used not only for GPCRs but for a lot of different biomolecules,\" explains Schihada. The universal sensor design now allows the exploration of receptor conformational changes in living cells with the high-throughput method. This enables a much faster pharmacological characterization by a high number of test combounds that directly act on the receptor, independently of their downstream receptor signal pathways. \"This technology can contribute to a faster and better understanding of the different levels of effectiveness of drugs and thus drive the development of novel therapeutic concepts,\" says Schihada. The study of novel receptor targets will yield a higher array to develop drugs that have less side-effects and are more efficient. Furthermore, the sensors could help to better understand what is called orphan GPCRs—GPCRs whose function and ligands are still largely unknown. \"With these findings we can lay the foundation for the treatment of severe diseases that were hitherto difficult to treat, such as Alzheimer's or multiple sclerosis,\" says the scientist. The scientists now want to expand their range of sensors suitable for high throughput. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The formation of super-Earths, the most abundant planets in the Galaxy, remains elusive. These planets have masses that typically exceed that of the Earth by a factor of a few, appear to be predominantly rocky, although often surrounded by H/He atmospheres, and frequently occur in multiples. Moreover, planets that encircle the same star tend to have similar masses and radii, whereas those belonging to different systems exhibit remarkable overall diversity. Here we advance a theoretical picture for rocky planet formation that satisfies the aforementioned constraints: building upon recent work, which has demonstrated that planetesimals can form rapidly at discrete locations in the disk, we propose that super-Earths originate inside rings of silicate-rich planetesimals at approximately ~1 au. Within the context of this picture, we show that planets grow primarily through pairwise collisions among rocky planetesimals until they achieve terminal masses that are regulated by isolation and orbital migration. We quantify our model with numerical simulations and demonstrate that our synthetic planetary systems bear a close resemblance to compact, multi-resonant progenitors of the observed population of short-period extrasolar planets. Main It has long been known that the genesis of planets begins through the coalescence of solids within protoplanetary nebulae, and models of planet formation have traditionally assumed that dust within circumstellar disks is smoothly distributed. Despite being common, this simplifying assumption may be unfounded. Several lines of evidence have recently been marshalled in support of the notion that rather than arising from a smooth gradient of solids, planetesimal formation unfolds in a small number of discrete rings 1 , 2 , 3 , 4 , 5 , 6 . In this vein, the work reported in ref. 3 has proposed that protoplanetary nebulae generally originate as decretion disks that spread radially from tenths of an au, facilitating the condensation of outward-diffusing silicate vapour into rocky dust grains at the disk’s primordial silicate sublimation line. Importantly, this process naturally leads to the formation of rocky planetesimals at a stellocentric distance comparable to the Earth’s orbital radius (as well as the generation of more distant icy bodies close to Jupiter’s present-day orbit) through gravito-hydrodynamic instabilities 7 , 8 . Such a model further yields a self-consistent explanation for the isotopic dichotomy of carbonaceous and non-carbonaceous iron meteorites, as well as the physical origins of the Solar System’s broader architecture 3 , 6 . Within the framework of the aforementioned disk model, the mass budget of silicate material that forms at the rock line is distinctively variable (Extended Data Fig. 1 ). That is, depending on the specific combination of disk viscosity and metallicity, the cumulative mass of rocky planetesimals entrained within the silicate annulus residing at an orbital radius of r ≈ 1 au can readily reach tens of Earth masses (although we note that it can also be null if the threshold for planetesimal formation through gravitational collapse is not met). Moreover, numerical modelling indicates that planetesimal formation is expected to occur over a relatively short temporal burst, such that dust is incorporated into planetary building blocks over a timescale of ~10 5 years. Adopting the ringed planetesimal formation paradigm as a platform, a key goal of our work is to consider the possibility that a typical system of extrasolar super-Earths originates within such a radially confined annulus of rocky material. As we describe below, the process of planetary conglomeration within a narrow ring of silicate-rich planetesimals naturally yields a characteristic multi- M ⊕ mass scale of the resulting planets, and the simultaneous operation of accretion and orbital migration regulates the emergence of uniformity among the growing planetary embryos (Fig. 1 ). Fig. 1: Diagram of the planet formation scenario considered in this work, in chronological order from top to bottom. In the top image, a protoplanetary nebula, represented by a yellow cone, originates from infall of gas and dust (shown with a vertical blue arrow). Viscous heating and stellar irradiation regulate the temperature of the gas, T , which in turn determines the disk’s geometric aspect ratio, h / r . Owing to strong magnetic braking, the centrifugal radius of the infalling material remains at a few tenths of an au. Driven by turbulent viscosity (which is parameterized by the Shakura–Sunayev α parameter), the disk spreads outwards to large stellocentric distances, transporting vapour and minute dust grains outwards. Silicate vapour entrained within the gas continues to be carried outwards with a velocity v r (solid blue arrows). Beyond the r ≈ 1 au silicate condensation front, however, dust grains grow and drift inwards due to the sub-Keplerian azimuthal flow of the gas, v ϕ . In the middle image, the resulting accumulation of rocky material at the silicate condensation line facilitates the formation of ~100 km planetesimals through gravito-hydrodynamic instabilities. In the bottom image, pairwise collisions among planetesimals generate multi- M ⊕ objects (brown sphere) that experience substantial orbital decay. Depletion of the local supply of solids as well as the removal of the planets from the planetesimal ring through disk-driven migration regulate the terminal planetary mass, leading to the emergence of intra-system uniformity. Full size image Results The starting point of our calculation corresponds to the epoch of large-scale planetesimal formation within a protoplanetary disk. For definitiveness, here we adopt disk conditions derived from the simulations reported in ref. 3 , although we note that for the purposes of our calculations, any ringed planetesimal formation scenario is likely to lead to similar results. Our fiducial disk model is initialized with a gas surface density of Σ 0 = 2,500 g cm −2 at 1 au, a corresponding peak dust surface density of Σ • = 500 g cm −2 and a dust-grain radius of s • = 1 mm, consistent with fragmentation-limited growth 9 . Owing primarily to viscous energy dissipation, the disk maintains an appreciable aspect ratio of scale height to orbital radius of h / r ≈ 0.05 throughout the planetesimal formation epoch. While the gas surface density is taken to dissipate exponentially with a time constant", "role": "user" }, { "content": "A new theory for how rocky planets form could explain the origin of so-called \"super-Earths\"—a class of exoplanets a few times more massive than Earth that are the most abundant type of planet in the galaxy. Further, it could explain why super-Earths within a single planetary system often wind up looking strangely similar in size, as though each system were only capable of producing a single kind of planet. \"As our observations of exoplanets have grown over the past decade, it has become clear that the standard theory of planet formation needs to be revised, starting with the fundamentals. We need a theory that can simultaneously explain the formation of the terrestrial planets in our solar system as well as the origins of self-similar systems of super-Earths, many of which appear rocky in composition,\" says Caltech professor of planetary science Konstantin Batygin, who collaborated with Alessandro Morbidelli of the Observatoire de la Côte d'Azur in France on the new theory. A paper explaining their work was published by Nature Astronomy on Jan. 12. Planetary systems begin their lifecycles as large spinning disks of gas and dust that consolidate over the course of a few million years or so. Most of the gas accretes into the star at the center of the system, while solid material slowly coalesces into asteroids, comets, planets, and moons. In our solar system, there are two distinct types of planets: the smaller rocky inner planets closest to the sun and the outer larger water- and hydrogen-rich gas giants that are farther from the sun. In an earlier study published in Nature Astronomy at the end of 2021, this dichotomy led Morbidelli, Batygin, and colleagues to suggest that planet formation in our solar system occurred in two distinct rings in the protoplanetary disk: an inner one where the small rocky planets formed and an outer one for the more massive icy planets (two of which—Jupiter and Saturn—later grew into gas giants). Super-Earths, as the name suggests, are more massive than the Earth. Some even have hydrogen atmospheres, which makes them appear almost gas giant-like. Moreover, they are often found orbiting close to their stars, suggesting that they migrated to their current location from more distant orbits. \"A few years ago we built a model where super-Earths formed in the icy part of the protoplanetary disk and migrated all the way to the inner edge of the disk, near the star,\" says Morbidelli. \"The model could explain the masses and orbits of super-Earths but predicted that all are water-rich. Recent observations, however, have demonstrated that most super-Earths are rocky, like the Earth, even if surrounded by a hydrogen atmosphere. That was the death sentence for our old model.\" Over the past five years, the story has gotten even weirder as scientists—including a team led by Andrew Howard, professor of astronomy at Caltech; Lauren Weiss, assistant professor at the University of Notre Dame; and Erik Petigura, formerly a Sagan Postdoctoral Scholar in Astronomy at Caltech and now a professor at UCLA—have studied these exoplanets and made an unusual discovery: while there exists a wide variety of types of super-Earths, all of the super-Earths within a single planetary system tend to be similar in terms of orbital spacing, size, mass, and other key features. \"Lauren discovered that within a single planetary system, super-Earths are like 'peas in a pod,'\" says Howard, who was not directly connected with the Batygin-Morbidelli paper but has reviewed it. \"You basically have a planet factory that only knows how to make planets of one mass, and it just squirts them out one after the other.\" So, what single process could have given rise to the rocky planets in our solar system but also to uniform systems of rocky super-Earths? \"The answer turns out to be related to something we figured out in 2020 but didn't realize applied to planetary formation more broadly,\" Batygin says. In a 2020 paper published in The Astrophysical Journal, Batygin and Morbidelli proposed a new theory for the formation of Jupiter's four largest moons (Io, Europa, Ganymede, and Callisto). In essence, they demonstrated that for a specific size range of dust grains, the force dragging the grains toward Jupiter and the force (or entrainment) carrying those grains in an outward flow of gas cancel each other perfectly. That balance in forces created a ring of material that constituted the solid building blocks for the subsequent formation of the moons. Further, the theory suggests that bodies would grow in the ring until they become large enough to exit the ring due to gas-driven migration. After that, they stop growing, which explains why the process produces bodies of similar sizes. In their new paper, Batygin and Morbidelli suggest that the mechanism for forming planets around stars is largely the same. In the planetary case, the large-scale concentration of solid rocky material occurs at a narrow band in the disk called the silicate sublimation line—a region where silicate vapors condense to form solid, rocky pebbles. \"If you're a dust grain, you feel considerable headwind in the disk because the gas is orbiting a bit more slowly, and you spiral toward the star; but if you're in vapor form, you simply spiral outward, together with the gas in the expanding disk. So that place where you turn from vapor into solids is where material accumulates,\" Batygin says. The new theory identifies this band as the likely site for a \"planet factory,\" that over time, can produce several similarly sized rocky planets. Moreover, as planets grow sufficiently massive, their interactions with the disk will tend to draw these worlds inward, closer to the star. Batygin and Morbidelli's theory is backed up by extensive computer modeling but began with a simple question. \"We looked at the existing model of planet formation, knowing that it does not reproduce what we see, and asked, 'What assertion are we taking for granted?'\" Batygin says. \"The trick is to look at something that everybody takes to be true but for no good reason.\" In this case, the assumption was that solid material is dispersed throughout the protoplanetary disks. By jettisoning that assumption and instead supposing that the first solid bodies form in rings, the new theory can explain different types of planetary systems with a unified framework, Batygin says. If the rocky ring contains a lot of mass, planets grow until they migrate away from the ring, resulting in a system of similar super-Earths. If the ring contains little mass, it produces a system that looks much more like our solar system's terrestrial planets. \"I'm an observer and an instrument builder, but I pay extremely close attention to the literature,\" Howard says. \"We get a regular dribble of little-but-still-important contributions. But every five years or so, someone comes out with something that creates a seismic shift in the field. This is one of those papers.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Abnormalities in synaptic inhibition play a critical role in psychiatric disorders, and accordingly, it is essential to understand the molecular mechanisms linking components of the inhibitory postsynapse to psychiatrically relevant neural circuits and behaviors. Here we study the role of IgSF9b, an adhesion protein that has been associated with affective disorders, in the amygdala anxiety circuitry. We show that deletion of IgSF9b normalizes anxiety-related behaviors and neural processing in mice lacking the synapse organizer Neuroligin-2 (Nlgn2), which was proposed to complex with IgSF9b. This normalization occurs through differential effects of Nlgn2 and IgSF9b at inhibitory synapses in the basal and centromedial amygdala (CeM), respectively. Moreover, deletion of IgSF9b in the CeM of adult Nlgn2 knockout mice has a prominent anxiolytic effect. Our data place IgSF9b as a key regulator of inhibition in the amygdala and indicate that IgSF9b-expressing synapses in the CeM may represent a target for anxiolytic therapies. Introduction Understanding the molecular basis of psychiatric disorders is one of the foremost medical challenges of our times, and substantial interest has arisen in the role of synaptic dysfunction in psychiatric pathophysiology 1 , 2 . The vast majority of corresponding studies have focused on glutamatergic, excitatory synapses, but it is becoming increasingly clear that an equally important contribution stems from abnormalities in inhibitory synaptic transmission 3 , 4 , 5 , 6 , 7 , 8 . This is particularly true for anxiety disorders, which have been linked to decreased inhibition in multiple brain regions 9 , 10 , 11 . To date however, astonishingly little is known about the molecular mechanisms by which abnormalities at inhibitory synapses contribute to the pathophysiology of anxiety disorders. A primary reason for this dearth of information is that the molecular composition of inhibitory postsynapses is only just being uncovered. In the past 5 years, the list of known inhibitory synapse organizers has expanded dramatically due to major technological advances 12 . A key question now is whether these molecules function uniformly across inhibitory synapses, or whether they display the same heterogeneity of function that is observed at the cellular level in the inhibitory network 3 , 13 . Understanding this organization will not only be essential for identifying disease mechanisms in pathological anxiety and other disorders, but may also provide a unique opportunity for uncovering selective targets for circuit-specific therapeutic interventions. A particularly interesting candidate molecule is IgSF9b, a member of the immunoglobulin superfamily of cell adhesion proteins that was recently shown to localize to inhibitory synapses in dissociated neuron cultures 14 , 15 , 16 . Variants in IgSF9b are associated with major depression and the negative symptoms of schizophrenia 17 , 18 , 19 , indicating that IgSF9b may regulate affect in human patients. IgSF9b was recently reported to act in a complex with Neuroligin-2 (Nlgn2) 14 , a member of the Neuroligin family of adhesion proteins specifically found at inhibitory synapses 12 , 20 , 21 , 22 . Loss-of-function mutations in Nlgn2 have been identified in patients with schizophrenia or pathological anxiety and autism 23 , 24 , and in mice, deletion of Nlgn2 robustly enhances anxiety-related behaviors 8 , 25 . Together, these findings raise the intriguing possibility that IgSF9b, like Nlgn2, may contribute to psychiatric pathophysiology by regulating synaptic inhibition in behaviorally relevant circuitry. To date, however, the molecular, cellular and circuitry functions of IgSF9b and its potential interactions with Nlgn2 in vivo remain completely unexplored. In the present study, we investigated the role of synaptic inhibition in anxiety by addressing two key questions: First, does IgSF9b regulate anxiety-related behavior and neural processing in the anxiety circuitry of WT and/or pathologically anxious Nlgn2 KO mice? Second, do IgSF9b and/or Nlgn2 act at specific inhibitory synapses within the anxiety circuitry and thus offer synapse-specific targets for interventions? To this end, we investigated the consequences of IgSF9b deletion and IgSF9b x Nlgn2 double deletion on anxiety-related behavior and circuits, as well as on inhibitory synapses in the amygdala, a brain region that plays a central role in the processing of anxiety information 9 , 10 , 26 , 27 . We show that IgSF9b regulates anxiety-like behaviors in Nlgn2 KO mice and that IgSF9b and Nlgn2 exert differential effects on distinct components of the amygdala inhibitory circuitry. Our data provide the first characterization of IgSF9b function in vivo and uncover a prominent anxiolytic consequence of IgSF9b deletion in Nlgn2 knockout (KO) mice, implicating IgSF9b-expressing neurons in the centromedial (CeM) amygdala as potential targets for anxiolytic therapies. Results Deletion of IgSF9b normalizes anxiety in Nlgn2 KO mice To address the role of IgSF9b in anxiety processing, we first tested whether IgSF9b deletion would alter anxiety-related behaviors and/or modulate the anxiety phenotype observed in Nlgn2 KO mice. To this end, we assessed the behavior of male adult WT, Nlgn2 single KO, IgSF9b single KO, and Nlgn2 x IgSF9b double KO mice in an open field (OF) apparatus (Fig. 1a–c ). As expected 8 , 25 , Nlgn2 KO mice spent significantly less time, traveled less distance, and made fewer entries into the anxiogenic center of the OF (Fig. 1d–g , red bars; ANOVA comparisons listed in Table 1 ; error bars represent SEM), indicative of enhanced anxiety-related behavior. Based on previous findings indicating that IgSF9b and Nlgn2 are components of the same molecular complex at inhibitory synapses 14 , we expected that deletion of IgSF9b may increase anxiety and/or exacerbate the phenotype of Nlgn2 KO mice. To our surprise, however, IgSF9b KO mice demonstrated a trend towards decreased anxiety (Fig. 1e, f , Supplementary Fig. 1d, e , blue bars). Most strikingly, the prominent anxiety phenotype of the single Nlgn2 KO mice was completely abolished in the double KO mice, with all measures unchanged from WT levels (Fig. 1 d–g, Supplementary Fig. 1 a–h, purple bars). An identical pattern of behavior was observed in female mice (Supplementary Fig. 1 i–m). Moreover, Nlgn2 KO mice spent less time, traveled less distance and made fewer entries into the anxiogenic open arms of", "role": "user" }, { "content": "Anxiety disorders are severe mental disorders in which patients suffer from intense fears and anxiety or from sudden, inexplicable panic attacks. In extreme cases, the affected individuals barely leave their homes, which can have serious consequences for their relationships with family and friends as well as for their professional lives. Scientists at the Max Planck Institute for Experimental Medicine in Göttingen have now identified a synaptic protein which, when inactivated, has an anxiolytic effect in mice. Around 10 percent of the population suffer from anxiety disorders, and current treatment options only offer effective help for a proportion of those affected. One of the changes observed in the brains of patients with anxiety disorders is an increased neuronal activity in the amygdala, a brain region that plays a key role in processing emotions such as anxiety or fear. An overactivation of the amygdala is thought to be involved in causing exaggerated anxiety. Many anxiolytic medications such as benzodiazepines presumably normalize this overactivation by strengthening the function of inhibitory synapses. Synapses are connections between nerve cells in the brain, at which information is transmitted from one nerve cell to another. At inhibitory synapses, this transmission results in a reduction in the activity of the neighbouring nerve cells. In the amygdala, for instance, this inhibits the transmission of stimuli that trigger fear and anxiety. Benzodiazepines strengthen this inhibitory effect—but unfortunately they affect not only those inhibitory synapses that transmit anxiogenic stimuli but also many other inhibitory synapses in the brain. This can lead to significant side effects such as pronounced sedation and impaired concentration. Accordingly, scientists are searching for new, more specific targets for anxiolytic medications. Mice with anxiety disorder Animal research with mice played a key role in helping the researchers in Göttingen to study anxiety disorders. Whereas healthy animals curiously investigate an empty test chamber, rodents with a pathological anxiety phenotype withdraw into a corner because they are afraid. However, when the scientists blocked the production of the recently discovered protein IgSF9b in these mice, the animals moved freely around the chamber again. IgSF9b produces a protein bridge at inhibitory synapses between two neighbouring nerve cells. \"Blocking IgSF9b in pathologically anxious mice has an anxiolytic effect and normalises anxiety behaviour in these animals. This protein could therefore be a target for pharmacological approaches to treating anxiety disorders,\" explains Olga Babaev from the Max Planck Institute for Experimental Medicine who carried out the experiments as part of her doctoral work.. An investigation of the amygdala in these animals revealed that the overactivation of the amygdala was normalized, and that this effect resulted from a strengthening of the synaptic transmission at inhibitory synapses in the amygdala. \"Our research shows that protein structures at inhibitory synapses in the centromedial amygdala, and particularly the protein IgSF9b, constitute promising new targets for potential treatments. It thus provides an important contribution toward understanding the biological causes of anxiety disorders and for the development of new anxiolytic medications,\" study leader Dilja Krueger-Burg says. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Revealing the microscopic structural and dynamic pictures of glasses is a long-standing challenge for scientists 1 , 2 . Extensive studies on the structure and relaxation dynamics of glasses have constructed the current classical picture 3 , 4 , 5 : glasses consist of some ‘soft zones’ of loosely bound atoms embedded in a tightly bound atomic matrix. Recent experiments have found an additional fast process in the relaxation spectra 6 , 7 , 8 , 9 , but the underlying physics of this process remains unclear. Here, combining extensive dynamic experiments and computer simulations, we reveal that this fast relaxation is associated with string-like diffusion of liquid-like atoms, which are inherited from the high-temperature liquids. Even at room temperature, some atoms in dense-packed metallic glasses can diffuse just as easily as they would in liquid states, with an experimentally determined viscosity as low as 10 7 Pa·s. This finding extends our current microscopic picture of glass solids and might help establish the dynamics–property relationship of glasses 4 . Main Matter can generally be classified into solid, liquid and gas states. Under extreme conditions or in specific systems, special states of matter exist that simultaneously exhibit some properties of both liquid and solid. In this case, solid matter contains rapidly diffusing, liquid-like atoms that can move fast even at low temperatures. Although it seems incredible, the existence of rapidly diffusing, liquid-like atoms in solids has been reported many times. For example, it is presumed that solid 4 He is able enter a supersolid state in which 4 He atoms can move fast and freely without any resistance 10 . In addition, a superionic state in which small/light atoms can diffuse freely while large/heavy atoms are fixed in their sublattices 11 , 12 , 13 , 14 has also been observed in materials, including ices 11 , helium–water compounds 12 , copper-based thermoelectric materials 13 and lithium-based conductors 14 , attracting growing attention in both materials science and engineering. Because glassy solids are generally recognized to be frozen liquids 2 , 4 , 5 , it is reasonable to imagine that there are more possibilities to find rapidly diffusing liquid-like atoms in glasses. In fact, a previous study of amorphous SiO 2 has even imaged liquid-like fast atoms at the edge of a two-dimensional sheet 15 . However, this fast motion was not ascribed to the amorphous nature but to the chemical-bond hierarchy 15 . Liquid-like atoms have rarely been observed in simple glasses, such as dense-packed metallic glasses (MGs). Recently, an unusual fast-relaxation process was observed in the dynamics of MGs at low temperatures where α and β relaxations are too slow to be tracked 6 , 7 , 8 , 9 . This process was regarded as the precursor of β relaxation with more localized atomic motion, probably related to certain chemical bonds, and as the initiation of plasticity in MGs. However, the underlying mechanism of this fast relaxation has yet to be elucidated. It is unclear whether such a fast relaxation in glasses is related to the liquid-like atoms. Answers to these questions may change our basic understanding of glasses. In this study we found that the fast relaxation in glasses is a continuation of the dynamics of high-temperature liquids, and its carriers are rapidly diffusing, liquid-like atoms inherited from high-temperature liquids. At room temperature (r.t.), these liquid-like atoms can diffuse rapidly with a viscosity as low as 10 7 Pa · s, which is six orders of magnetite lower than that of glasses (10 13 Pa · s) at the glass transition temperature ( T g ). Molecular dynamics (MD) simulations reveal that this fast relaxation arises from string-like diffusion of the liquid-like atoms in MGs. These findings not only clarify the mechanism of fast relaxation, but also reveal deeper insights into the nature of glasses and the glass transition. The initial clue to the existence of rapidly diffusing, liquid-like atoms in MGs comes from dynamics rather than from atomic structures. In fact, although current technology can capture the three-dimensional atomic structure of MGs 16 , it is still difficult to image the atomic motions in MGs. Dynamic spectra can provide a powerful tool to probe the features and basic properties of glasses 4 , 5 , 6 , 17 , 18 . Figure 1 shows the temperature-dependent loss modulus spectra of several typical MGs, where all samples exhibit three well-separated relaxation processes. . Figure 1a shows that in Al 85 La 10 Ni 5 MG, besides the α relaxation, a β-relaxation hump at about 470 K ( ∼ 0.83 T g ) and a distinct peak at a lower temperature of 270 K ( ∼ 0.48 T g ) occur, indicating that there are some atoms moving much faster than atoms involved in β relaxation. Combining our results and previous reports 6 , 7 , 8 , 9 , it can be concluded that this fast process is not restricted to a specific composition but is a common phenomenon in MGs. Fig. 1: Emergence of the fast-relaxation process in MGs on the dynamic mechanical spectra. a , Loss modulus E ″ at a testing frequency of 1 Hz for Al 85 La 10 Ni 5 MG, showing a distinct hump of β relaxation and a pronounced fast relaxation at temperatures far below that of β relaxation. The coloured regions provide a guide to the eye. b , Loss modulus E ″ for many other MGs, including Al 90 La 10 , Er 55 Co 20 Al 25 , La 68.5 Ni 15 Co 1.5 Al 15 , La 60 Ni 15 Al 25 , Y 68.9 Co 31.1 and (La 0.5 Ce 0.5 ) 65 Co 25 Al 10 , showing a universal fast relaxation at low temperatures. Note that both Al 85 La 10 Ni 5 and Al 90 La 10 show an obvious peak even in linear coordinates. Full size image Next, to prove that the atoms which carry fast relaxation at low", "role": "user" }, { "content": "Metallic glass is an important advanced alloy, holding promise for broad engineering applications. It appears as a solid form in many aspects, with beautiful metal appearance, exceeding elasticity, high strength, and a densely packed atomic structure. However, this all-solid notion has now been challenged. Prof. Bai Haiyang from the Institute of Physics of the Chinese Academy of Sciences (CAS) has recently shown the existence of liquid-like atoms in metallic glasses. These atoms inherit the dynamics of high-temperature liquid atoms, revealing the nature of metallic glasses as part-solid and part-liquid. Results were published in Nature Materials. Condensed matter can generally be classified into solid and liquid states. Under extreme conditions or in specific systems, matter exists in special states that simultaneously exhibit some properties of both solids and liquids. In this case, solids may contain rapidly diffusing, liquid-like atoms that can move fast even at low temperatures. For example, ice enters a \"superionic\" state under high pressure at high temperatures. In this state, H atoms can diffuse freely while O atoms are fixed in their sublattices. Such special states are also observed in Earth's inner core and in the Li-conducting materials of advanced batteries, which are drawing growing attention in science and engineering. Visualization of Liquid-like atoms in Al90La10 MG at 300K by MD simulations. Credit: Institute of Physics In this study, the researchers revealed that liquid-like atoms exist in densely packed metallic glasses. Combining extensive dynamical experiments and computer simulations, they found that when the viscosity of a liquid deviates from Arrhenius behavior, not all atoms take part in cooperative flow and subsequent solidification. In fact, some atoms can maintain liquid Arrhenius behavior even when the system is cooled down to a glass state, thus appearing as persistent liquid-like atoms that lead to fast relaxation at rather low temperatures. \"A glassy solid is essentially mostly solid and a small part liquid. Even at room temperature, liquid-like atoms in a glassy solid can diffuse just as easily as in its liquid state, with an experimentally determined viscosity as low as 107 Pa·s, while the viscosity of the solid part is larger than 1013 Pa·s,\" said Prof. Bai. These findings provide a clearer microscopic picture of glasses. This new picture can help scientists better understand how the properties of glass materials are related to their dynamics. For example, liquid-like atoms control the anelasticity of glasses and may affect their ductility. Moreover, the strong relationship between liquid-like atoms and disordered structure also has implications for studying the topological origin of fast diffusion in solids, such as superionic-state matters and ion conductors. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Multiple anthropogenic stressors cause worldwide amphibian declines. Among several poorly investigated causes is global pollution of aquatic ecosystems with endocrine disrupting compounds (EDCs). These substances interfere with the endocrine system and can affect the sexual development of vertebrates including amphibians. We test the susceptibility to an environmentally relevant contraceptive, the artificial estrogen 17α-ethinylestradiol (EE2), simultaneously in three deeply divergent systematic anuran families, a model-species, Xenopus laevis (Pipidae) and two non-models, Hyla arborea (Hylidae) and Bufo viridis (Bufonidae). Our new approach combines synchronized tadpole exposure to three EE2-concentrations (50, 500, 5,000 ng/L) in a flow-through-system and pioneers genetic and histological sexing of metamorphs in non-model anurans for EDC-studies. This novel methodology reveals striking quantitative differences in genetic-male-to-phenotypic-female sex reversal in non-model vs. model species. Our findings qualify molecular sexing in EDC-analyses as requirement to identify sex reversals and state-of-the-art approaches as mandatory to detect species-specific vulnerabilities to EDCs in amphibians. Introduction Amphibians face a global ongoing decline 1 , 2 . Anthropogenic causes such as industrial agriculture 3 , habitat destruction 4 , 5 , invasive species 6 , climate change 7 , land use 8 and infectious diseases 9 , including several forms of chytridiomycosis 10 , 11 , are among the major threats. However, the sum of multiple stressors 1 , 7 , some of which poorly known, is considered to be the true reason for the massive population declines. One potential cause represents endocrine disrupting compounds (EDCs) 12 . Besides pesticides, EDCs comprise either natural products or synthetic chemicals that mimic, enhance (an agonist), or inhibit (an antagonist) the action of hormones and in this way interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones, which are responsible for the maintenance of homeostasis, reproduction, development, and/or behavior 13 . Considerable amounts of EDCs are globally found in waste and surface waters 14 , 15 and can easily enter the body of aquatic organisms and impair their natural hormonal pathways. EDCs are well known for their negative impacts on the sexual development of aquatic organisms such as fish 16 , 17 and are suspected to cause fertility problems in humans 18 , 19 . However, their impact to non-model amphibians with aquatic larvae is not well studied, despite recent evidence for high EDC-relevance to suburban frog populations 20 . One globally relevant EDC is 17α-ethinylestradiol (EE2), a synthetically stabilized estrogen and main ingredient of many female contraceptive pills. The inert EE2 is then excreted and insufficiently eliminated by sewage plants and hence reaches aquatic ecosystems 14 . It is a main hormonal pollutant, resistant to degradation, that accumulates in sediments and biota 14 . Concentrations from 24 to 831 ng/L have been detected in European and American surface waters 21 , 22 , 23 . Such concentrations have been shown to alter behavior and somatic and sexual development in fish and amphibians 12 , 14 , 15 . Due to their semi-aquatic life cycle, often aquatic reproduction and a highly permeable skin, amphibians are especially sensitive to EDCs. Effects on development and reproduction are best examined in clawed frogs, Xenopus laevis and X. tropicalis . In these amphibian models, EE2-concentrations as low as 0.3 ng/L have been shown to affect calling behavior and mating success 24 . Higher but still environmentally relevant amounts of EE2 (29 to 840 ng/L) have been shown to affect body morphology, metamorphosis and hemoglobin catabolism 25 , 26 . Importantly, EE2 can lead to impaired sexual development as mirrored by gonad histomorphology, demonstrating that male clawed frogs ( X. laevis ) develop mixed sex (=‘intersex’, see below) gonads or even show complete phenotypic sex reversal 26 , 27 , 28 , 29 . The undifferentiated anuran gonad is bipotential and can develop into either ovary or testis 30 . Therefore, exogenous hormones can override the primary genetic sex determination signal and lead to developmental disturbances, mixed sexes or complete sex reversal. One major obstacle of studying EDC-effects in amphibians has been the mostly inaccessible information about genetic sex. In most previous EDC-studies, sex reversal had to be inferred by comparing sex ratios of control and exposed frogs, assuming a normal 1:1 proportion, which may have easily led to wrong conclusions about EDC-impacts on sex ratios. While all amphibian species investigated show genetic sex determination 31 , exhibiting either male (XX/XY) or female (ZZ/ZW) heterogamety, an extrapolated 96% of all species have microscopically indistinguishable sex chromosomes 32 , requiring molecular sexing methods. Although EDC-studies with molecular sexing were applied to the model Xenopus 26 , 33 , sex markers have become only recently available for some non-model anurans 32 , 34 , 35 , 36 , 37 , 38 and have not been used in EDC-experiments. Using a high-standard flow-through-system and the first direct experimental approach of its kind, we simultaneously exposed European tree frogs ( H. arborea ), green toads ( B. viridis ) and the well investigated but deeply diverged model-species X. laevis to EE2, applied molecular sexing followed by histological analysis and compared impacts on their sexual development. We found striking differences in the susceptibility to sex reversal between model and non-model species, showing that state-of-the-art approaches are an important prerequisite to detect species-specific vulnerabilities to EDCs in amphibians. Results Phenotypic sex reversal of genetic males Among all three anuran species, simultaneous exposure to three EE2-concentrations under flow-through-conditions resulted in different proportions of male-to-female sex reversal, ranging from 15 to 100% ( Table 1 and Fig. 1 ), which was solely revealed when comparing genetic and phenotypic sex of experimental animals. Importantly, no sex reversal occurred in control groups. While sex reversal ( Figs 1 and 2 ) was generally correlated to EE2-concentration, interspecies differences (p ≤ 0.010) between clawed frogs ( X. laevis ) and tree frogs ( H. arborea ) were found at all concentrations and between clawed frogs and green toads ( B. viridis ) at the highest concentration (5,000 ng/L; p ≤ 0.001). While EE2-treatment produced similar percentages of sex-reversed tree frogs and", "role": "user" }, { "content": "Hormonally active substances may contribute to global amphibian decline. Some compounds, for example from pharmaceuticals, occur in biologically relevant concentrations in freshwater ecosystems, and thus can affect the hormonal system and the sexual development of animals. Researchers from the IGB and the University of Wroclaw have compared the effects of the pill estrogen ethinylestradiol (EE2) in three amphibian species. The study, published in the journal Scientific Reports, shows that EE2 can lead to a complete feminization of genetic males. Without molecular establishment of the genetic sex, this has remained partly unnoticed. 17α-Ethinylestradiol (EE2) is a synthetic estrogen, which is a frequently used active ingredient of female contraceptive pills but naturally does not occur in the environment. As it is only incompletely removed in sewage treatment plants, it can reach water bodies in biologically relevant concentrations. The evolutionary biologist, Dr. Matthias Stöck, principal investigator of the study and Heisenberg-Fellow, says: \"Amphibians are almost permanently exposed to such threats. Only, if we will be able to actually access these risks, we will be able to eliminate them in the long term\". The sensitivity towards hormonally active substances, like EE2, is not the same in all amphibians, hypothesize the scientists. Some species have passed through several hundred million years of independent evolutionary history and have evolved different mechanisms of genetic sex determination. Thus, for the first time within the same experiment, the research team from the IGB and the University of Wroclaw tested the influence of EE2 on the development of three different amphibian species: In addition to the model species, the African clawed frog (Xenopus laevis), tadpoles of the European tree frog (Hyla arborea) and the European green toad (Bufo viridis) have been raised in water containing different concentrations of EE2, and compared to control groups. Tadpoles and adults of the European tree frog (Hyla arborea) may be exposed to hormonally active substances, like EE2, in their natural habitats. Credit: Christophe Dufresnes Remarkable in this experiment was that the genetic sex of all species was established using latest molecular approaches. At the same time, the researchers studied the phenotypic development of the sexual organs (gonads), i.e. the anatomical appearance and that of the tissues under the microscope. Only this comparison of genetic and phenotypic sex has allowed to completely capture the effects of EE2. \"In addition to other threats, the feminization of populations may contribute to the extinction of amphibian species\", says Matthias Stöck. The results of the study show that after exposition to EE2, in all amphibian species, a sex reversal occurred reaching from 15 to 100 percent. However, the three species exhibit different sensitivity. IGB-researcher Prof. Werner Kloas, co-author of the paper, is an internationally renowned eco-toxicologist. He says: \"EE2 is also part of our water supply and, together with other estrogen-like substances, it presents a serious risk not only for amphibians but also for humans. Our study shows that the clawed frog as model species is well-suited to study the effects of hormonally active substances in the environment. The effect established in this species, however, cannot be extrapolated to other amphibian species without caution.\" For the study, the collaboration with the University of Wroclaw in Poland was essential. The collaborator there, Prof. Maria Ogielska, declares: \"We have contributed our profound research experience from the investigation of reproduction of amphibians, namely from developmental biology, into the project\". Ph.D.-student Stephanie Tamschick says: \"Together with students, we have raised tadpoles over three months, under identical experimental conditions. It was new that we have established the genetic sex in all species, i.e. whether a tadpole was genetically male or female. In my thesis, especially by this approach, I could conclude that the feminizing effects of EE2 are so diverse among the examined frog and toad species.\" The African clawed frog (Xenopus laevis) as a model species shows high vulnerability towards the hormonally active substance EE2, an artificial Estrogen of female contraceptive pills. Credit: David Außerhofer ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis 1 , 2 . Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro , as well as enhanced tumorigenicity in murine models of primary tumour growth and pulmonary metastases. We also show that interfacial geometry modulates cell shape, adhesion through integrin α 5 β 1 , MAPK and STAT activity, and initiation of pluripotency signalling. Our results for several human cancer cell lines suggest that interfacial geometry triggers a general mechanism for the regulation of cancer-cell state. Similar to how a growing tumour can co-opt normal soluble signalling pathways 3 , our findings demonstrate how cancer can also exploit geometry to orchestrate oncogenesis. Main Cancer is a leading cause of death, primarily through the process of metastasis where malignant cells spread to distant organs 4 . It is believed that ‘tumour initiating cells’ or ‘cancer stem cells’ (herein referred to as CSCs) inherently possess the characteristics necessary for establishing metastases; however, within a tumour mass comprised of billions of cells, usually only a small percentage of cells exhibit a CSC phenotype 2 . This same population of cells is believed to be the root cause of recurrence after treatment, because most therapeutic regimens have not been optimized to target CSCs, and there have been multiple examples of CSCs being resistant to therapy 5 . Current evidence suggests wide-scale dynamic variation in the presence and function of CSCs across cancers and patients 6 . Deciphering the cues in the microenvironment that promote the CSC phenotype is a pressing need for understanding disease progression and developing therapeutics that can disrupt the processes involved for induction and survival of CSCs. Emerging evidence suggests that tumour cells may show ‘plasticity’ in response to microenvironmental cues. For example, melanoma cells have been shown to adopt a tumorigenic, CSC-like state and form new tumours after transplantation 7 . An exciting recent report showed how soft fibrin gels can promote selected growth of tumorigenic melanoma cells 8 , and further investigation demonstrated how the mechanical properties of the matrix can regulate Sox2 expression 9 . However, the canonical self-renewal transcription factors Oct4 and Nanog were not activated in these cells. The influence of matrix mechanics on cancer cell tumorigenicity has been demonstrated in several other cancers 10 . Taken together, these reports show that, in addition to the classical models underlying tumour heterogeneity, tumour cells may exhibit more plasticity than originally anticipated, and may be influenced through biophysical cues in the tumour microenvironment. Substrate stiffness is known to modulate cell behaviour 11 and gene expression 12 . Furthermore, the geometric organization of cells in tissue places them into variable regions of mechanical stress 13 , which can influence proliferation 14 , migration 15 , branching 16 , stem cell characteristics 17 , and cancer cell survival and invasiveness 18 , 19 . For example, Nelson and colleagues demonstrated how geometry can guide epithelial to mesenchymal transitions (EMT) through mechanical stress in micropatterned mammary epithelial cells 18 . In this letter we use soft hydrogel microengineering to pattern populations of tumour cells on two-dimensional (2D) and within three-dimensional (3D) hydrogels of variable stiffness, with combinations of perimeter geometric cues, to explore how biophysical parameters influence CSC characteristics and tumorigenicity ( Fig. 1a ). Figure 1: Interfacial geometry at perimeter features directs expression of CSC markers. a , Schematic depicting how extracellular matrix properties may guide tumorigenicity. b , Increasing micropattern size shows optimal curvature that guides expression of CSC markers in B16F0 cells ( N = 3, ∗ P < 0.05, Fisher’s exact test compared to glass); boxes represent 25th to 75th percentile and whiskers represent minimum–maximum. Horizontal lines and points within boxes represent the median and mean respectively for three replicates. c , Curvature influences expression of CSC molecular markers. Intensity of ABCB5 shown as fold change over the non-patterned (NP) condition ( N = 3). ( P -value from ANOVA analysis). R , pattern radius. d , Shapes controlling line width, curvature and perimeter to area ratio to explore the relationship of interfacial geometry and expression of CSC markers ( N = 3). e , Immunofluorescence heatmaps of B16F0 cells cultured in a panel of shapes with variable perimeter geometric features showing semiquantitative localization characteristics for CSC surface markers (ABCB5, CD271, CD133), slow-cycling related demethylase enzyme (JARID1B), intermediate filaments (Nestin) and transcription factors (Nanog, Oct4, Sox2). Far right column shows finite element models of perimeter stress in cellular sheets. Colour bar indicates minimum (bottom) to maximum (top) intensity. Scale bars, 50 μm. Error bars represent s.d. Full size image We prepared hydrazine-modified polyacrylamide (PA) hydrogels of different elasticity ( ∼ 1, 10, and 100 kPa) and used soft lithography to conjugate matrix proteins in various patterns with different sizes and shapes ( Supplementary Fig. 1 ). As a model system we selected the murine B16 melanoma cell lines and used putative CSC molecular markers CD271, CD133 and ABCB5 (refs 20 , 21 , 22 ). We first measured these markers in B16 melanoma cells cultured for 1, 3 and 5 days on circular patterns of different matrix elasticity and pattern size ( Supplementary Fig. 2 ). Expression of tumorigenic molecular markers strongly depended on culture duration (1–5 days) and colony size, with a maximum at the perimeter of circular islands ∼ 3,000–100,000 μm 2 . The stiffness of the underlying matrix did not exert a significant influence over the expression of CSC markers, thus we fixed the stiffness of our matrices at 10 kPa ( Fig. 1b and Supplementary Fig. 3 ). Analysis of cell morphology at these perimeter features reveals that, with decreasing pattern size, individual cells occupy longer arcs along the pattern perimeter, with larger subtended arc angles on average. This correlates", "role": "user" }, { "content": "Only a few cells in a cancerous tumor are able to break away and spread to other parts of the body, but the curve along the edge of the tumor may play a large role in activating these tumor-seeding cells, according to a new University of Illinois study. Using engineered tissue environments in various shapes and patterns, the study of skin cancer found that the more curved the cell cultures were, the more cancer cells at the edges displayed markers of stem cell characteristics - the key to spreading to other tissues. This has potential for furthering our understanding of cancer as well as developing personalized treatment plans. Led by Kristopher Kilian, a professor of materials science and engineering, and Timothy Fan, a professor of veterinary medicine, the researchers published their findings in the journal Nature Materials. \"The most dangerous part of cancer is metastasis,\" Kilian said. \"Some cells that we call cancer stem cells adopt deadly characteristics where they can travel through the bloodstream to other tissue and form new tumors. There's a need for ways to find these cells and to study them, and importantly, to develop drugs that target them, because these cancer stem cells are resistant to chemotherapy drugs that target the main tumor. This causes recurrence: The cancer comes back.\" Kilian's group specializes in tissue engineering to create models of tumors, in order to more accurately study cancer processes in a culture dish. In the new study, the researchers cultured mouse skin-cancer colonies on various 2-D and 3-D environments of different shapes and patterns to see if the tumor shape contributes to activation of cancer stem cells, and to see where in the tumor the stem cells appeared. They found that cancer stem cells seemed to appear in the highest numbers along the edges of the engineered tumor environments, particularly where there were corners and convex curves. \"It was actually quite surprising,\" Kilian said. \"Normal stem cells prefer a soft, squishy, internal position. So for cancer, everyone had assumed that the cancer stem cells were in the middle of the tumor. We found that geometric constraints, like you would have where a tumor touches healthy tissue, seem to activate these cancer stem cells at the perimeter.\" The researchers did a number of tests in their engineered environments to confirm tumor-spreading ability, such as genetic analysis. They also tested other cancer lines - human cervical, lung and prostate cancers - and found that they responded to the patterned tumor environments in the same way. Then Kilian's group teamed with Fan's group to test the skin-cancer stem cells in live mice, and found that the cells taken from the patterned environments were much more likely to cause tumors than cells taken from a conventional flat dish. \"We found that many more mice developed tumors when given the cells that we had engineered to have these stem cell characteristics, and they had a much higher incidence of metastasis in the lungs,\" Kilian said. \"In a tumor, similarly, regions that develop these kinds of shapes may activate cells that can then escape and form more tumors. This may allow surgeons to look at the perimeter of a growing tumor and use the shape to guide their assessment of which regions could be more problematic - where they need to take out more tissue around the tumor and where they may not need to take as much.\" Kilian hopes that the patterned, engineered tissue environments will give researchers a new way to find and culture cancer stem cells, which have been very elusive in conventional cultures - less than 1 percent of cells, he said. Beyond the fundamental science of finding and understanding these cancer-spreading cells, he also sees engineered tumor environments as having therapeutic applications in personalized medicine. \"You can imagine a patient has a particular tumor. You could engineer that in a dish, and using the patient's own cells, you could develop a model of their specific tumor to test out drugs,\" he said. \"If you could take a patient's cells and within days have microtumors that you could use to screen all the available drugs, then an oncologist would be able to prescribe a treatment that's tailor-made for the patient that targets both the tumor cells and these elusive cancer stem cells that currently we can't see. \"There's a lot more work to be done, but we're very excited about how a very simple materials property of a growing tumor might be a culprit of the disease spreading. We think it opens up a new avenue of investigation for drug development, guiding surgery, and understanding progression and spreading of cancer,\" Kilian said. \"Cancer is very complex, so putting it in context is key. If there is a microenvironment that provides the context for activating cells that can spread cancer, then that's important to know.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Metal halide perovskites (MHPs), emerging as innovative and promising semiconductor materials with prominent optoelectronic properties, has been pioneering a new era of light management (ranging from emission, absorption, modulation, to transmission) for next-generation optoelectronic technology. Notably, the exploration of fundamental characteristics of MHPs and their devices is the main research theme during the past decade, while in the next decade, it will be primarily critical to promote their implantation in the next-generation optoelectronics. In this review, we first retrospect the historical research milestones of MHPs and their optoelectronic devices. Thereafter, we introduce the origin of the unique optoelectronic features of MHPs, based on which we highlight the tunability of these features via regulating the phase, dimensionality, composition, and geometry of MHPs. Then, we show that owing to the convenient property control of MHPs, various optoelectronic devices with target performance can be designed. At last, we emphasize on the revolutionary applications of MHPs-based devices on the existing optoelectronic systems. This review demonstrates the key role of MHPs played in the development of modern optoelectronics, which is expected to inspire the novel research directions of MHPs and promote the widespread applications of MHPs in the next-generation optoelectronics. Peer Review reports 1 Introduction Metal halide perovskites (MHPs) have been emerging as the rising star in the field of optoelectronics during the past decade, and the state-of-the-art optoelectronic technologies based on MHPs, such as perovskite solar cells (PSCs), light emitting diodes (LEDs), photodetectors (PDs) and lasers, have been leading the prevailing paradigm owing to the intriguing optoelectronic properties of MHPs. MHPs family, taking the general formula of ABX 3 (A = CH 3 NH 3 + (MA), HC(NH 2 ) 2 + (FA), and Cs + , B = Pb 2+ , Sn 2+ , X = I − , Cl − , Br − ), possesses the merits of facile and low-cost processing and the favorable attributes of tunable optical and electronic features, providing a rich and fertile ground for the development of high-performing multifunctional optoelectronic devices and their future industrialization. The first study of optoelectronics of MHPs could be traced back to 1950s, the intensely colored crystals of CsPbX 3 (X = Cl, Br) with perovskite structure exhibits the behavior of frequency-dependent photoconductive response, implying the special electrical properties of perovskites [ 1 ]. Shortly thereafter in early 1990s, Mitzi and co-workers focused particular interest on the layered tin halide perovskites that are naturally self-assembled into quantum confinement structures (QWS) in the presence of alkylammonium cations, exhibiting obvious excitonic features and demonstrating potential application in LEDs and transistors [ 2 ], crucially with the interesting electronic properties and ability by tuning the MHP structures flexibly [ 3 , 4 , 5 ]. In the meanwhile, the first observation of light emission and lasing in (C 6 H 13 NH 3 ) 2 PbI 4 was reported in 1998 [ 6 ]. Subsequently, as the birth of first perovskite-sensitized solar cell with a power conversion efficiency (PCE) of 3.8% in 2009 [ 7 ], “perovskite fever” with a focus on solar cells application makes several milestones in PCE improvement, which has exceeded 20% since then [ 8 ]. This breakthrough process triggers the researchers’ curiosity to explore the intrinsic optoelectronic properties of MHPs, where the adjustable band gap, long carrier diffusion length, strong light absorption, low defect density and solution processability are identified [ 9 ]. In the mild-2010s, MHPs are shown to be promising for optical sources with the high optical gain and stable amplified spontaneous emission (ASE) with a threshold of 10 ± 2 μJ cm −2 at room temperature [ 10 ], and the first laser work in the field without external cavity [ 11 ] as well as the first optically pumped perovskite microcavity laser were reported shortly after [ 12 ]. In 2015, the first ASE and lasing in MHP nanocrystals of CsPbX 3 was demonstrated with low pump thresholds down to 5 ± 2 μJ cm −2 [ 13 ]. Almost the same time, the first room temperature perovskite LEDs (external quantum efficiency (EQE) ~ 0.76%) were reported by Friend and co-workers [ 14 ]. Meanwhile, the first MAPbI 3 PDs with X-ray sensitivity of 25 μC mGy air −1 cm −3 was investigated by Heiss and co-workers [ 15 ], Park and co-workers then achieved highly sensitive X-ray PDs up to 11 μC mGy air −1 cm −2 based on printable MAPbI 3 films in 2017 [ 16 ]. The next evolution of MHPs in optoelectronics comes from the revival of layered perovskites and perovskite nanocrystals (NCs) in late 2010s, and they have shown competitive photoluminescence (PL) and electroluminescence (EL) efficiency compared with bulk perovskites [ 17 ], pushing the related studies, especially of the relationships between dimensionality, size, geometry, composition, colloidal synthesis approaches and their optoelectronic properties to a new upsurge, in which the EQE of green, red, and near-infrared LEDs can be as high as 20.3%, 21.3% and 21.6% [ 18 , 19 , 20 ], respectively. Also, new breakthrough in CsPbBr 3 NCs X-ray detectors has been made with a low dose rate of 13 nGy s −1 [ 21 ]. Propelling current interest in the 2020s is that MHPs continue to exhibit new and surprising optoelectronic properties, the certified PCE for single-junction PSCs, all-perovskite tandem solar cells and hybrid tandem PSCs has been up to 25.7%, 28% and 31.3%, respectively [ 22 ], and new applications of this materials expand not only to PSCs, LEDs and PDs, but also to facilitate the integration of optoelectronic devices. Meanwhile, the challenges such as instability bottleneck has been gradually resolved. One can say that the optoelectronic properties of these materials create a host of new avenues for the scientific community to explore. Figure 1 demonstrates the representative progresses of MHPs for optoelectronics. Inspiringly, solid researches have been carried out during the course of development to disclose the unique optoelectronic features of MHPs, and their multidiscipline applications have given new momentum to the field of", "role": "user" }, { "content": "Metal halide perovskites (MHPs) have been emerging as the rising star in the field of optoelectronics during the past decade. The state-of-the-art optoelectronic technologies based on MHPs, such as perovskite solar cells (PSCs), light emitting diodes (LEDs), photodetectors (PDs) and lasers have been leading the prevailing paradigm, owing to the intriguing optoelectronic properties of MHPs. Additionally, MHPs possesses the merits of facile and low-cost processing and favorable tunable optical and electronic features, providing a rich and fertile ground for the development of high-performing multifunctional optoelectronic devices and their future industrialization. In a new paper published in eLight, a team of scientists led by Professor Wei Huang from Frontiers Science Center for Flexible Electronics, Xi'an Institute of Flexible Electronics, Northwestern Polytechnical University, China, Key Laboratory of Flexible Electronics & Institution of Advanced Materials, Nanjing Tech University, China, Key Laboratory for Organic Electronics & Information Displays, and Institute of Advanced Materials, Nanjing University of Posts and Telecommunications, and colleagues has given a panorama picture on the optoelectronic traits of MHPs and their revolutionary impact on the next-generation optoelectronics. They first review the historical research milestones of MHPs and their optoelectronic devices. Thereafter, they introduce the origin of the unique optoelectronic features of MHPs, based on which the tunability of these features via regulating the phase, dimensionality, composition, and geometry of MHPs are highlighted. Then, they show that owing to the convenient property control of MHPs, various optoelectronic devices with target performance can be designed. At last, they emphasize on the revolutionary applications of MHPs-based devices on the existing optoelectronic systems. This perspective aims at providing critical guidance for inspiring the novel research directions of MHPs to promote the widespread application of MHPs in optoelectronics. Revolutionary applications enabled by MHPs-based optoelectronic devices. Credit: He Dong, Chenxin Ran, Weiyin Gao, Mingjie Li, Yingdong Xia, Wei Huang The unique characteristics of MHPs are derived from their crystal structure and chemical composition, which allows the unprecedented flexibility to independently and synergistically tune the optoelectronic properties of MHPs, laying an important foundation for MHPs being applicable to various optoelectronic applications, including solar cells, LEDs, PDs and lasers. The reasearchers highlight the unique optoelectronic properties of MHPs: \"Of critical importance, intrinsic electronic configurations of MHPs are the direct origin of their unique optoelectronic properties, including high optical absorption, high carrier mobility, high defect tolerances, long diffusion lengths, unique ambipolar charge transport, and flexible turnability. We summarize the merits of MHPs by focusing on the fine controlling of the optoelectronic properties by regulating the structure of MHPs, including phase, dimensionality, composition, and geometry.\" \"MHPs are expected to make indispensable contribution to the advanced revolutionary technologies that could benefit [...] mankind, such as functional integration system[s], information display system[s], electronic communication system[s], and health and medical system[s],\" they add. \"Metal halide perovskites (MHPs), emerging as innovative and promising semiconductor materials with prominent optoelectronic properties, have been pioneering a new era of light management (ranging from emission, absorption, modulation, to transmission) for next-generation optoelectronic technology. Nevertheless, to promote the large-scale utilization of MHPs, there are still many technique problems to be overcome, such as stability and toxicity issues, and vast investments are required to establish the building of MHPs-based optoelectronics. Overall, one can expect that in the next decade, MHPs will be under the spotlight in the era of light,'\" the researchers forecast. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Several studies have suggested that there is a link between synaesthesia and autism but the nature of that link remains poorly characterised. The present study considers whether atypical sensory sensitivity may be a common link between the conditions. Sensory hypersensitivity (aversion to certain sounds, touch, etc., or increased ability to make sensory discriminations) and/or hyposensitivity (desire to stimulate the senses , or a reduced response to sensory stimuli are a recently introduced diagnostic feature of autism spectrum conditions (ASC). Synaesthesia is defined by unusual sensory experiences and has also been linked to a typical cortical hyper-excitability. The Glasgow Sensory Questionnaire (GSQ) was administered to synaesthetes and people with ASC. Both groups reported increased sensory sensitivity relative to controls with a large effect size. Both groups also reported a similar pattern of both increased hyper- and hypo-sensitivities across multiple senses. The AQ (Autism-Spectrum Quotient) scores were elevated in the synaesthetes, and one subscale of this measure (attention to detail) placed synaesthetes within the autistic range. A standard laboratory test of visual stress (the Pattern Glare Test), administered online, corroborated the findings of increased sensitivity to aversive visual stimuli in synaesthetes. We conclude that atypical sensory sensitivity is an important shared feature between autism and synaesthesia. Introduction People with synaesthesia have unusual experiences of the world: for example, words may evoke tastes, sequences such as months and numbers may be visualised as spatial landscapes (sequence-space synaesthesia), and graphemes (i.e., letters/numbers) may evoke colours (grapheme-colour synaesthesia). The present study focuses on grapheme-colour synaesthesia. Synaesthetic experiences tend to be percept-like in nature, occur automatically, and are triggered by inducing stimuli 1 , 2 . Synaesthesia emerges during childhood, if not before 3 , has a hereditary component 4 , and is linked to structural and functional differences in the brain 5 . It is also linked to wider cognitive differences - for example, in memory 6 and mental imagery 7 - but is not linked to global difficulties in intellectual functioning 8 . However, recent research has suggested that synaesthesia and Autism Spectrum Condition (ASC) co-occur together more than would be expected by chance. Neufeld et al . 9 and Baron-Cohen et al . 10 screened samples of patients diagnosed with autism for grapheme-colour synaesthesia (primarily) and reported prevalence rates of 17.2% and 18.9% respectively. The current prevalence estimate for grapheme-colour synaesthesia is 1–2% 11 . Hence these studies suggest a link between synaesthesia and autism. But what is the nature of that link? The present research considers this from the perspective of sensory sensitivity. Autism is a heterogeneous condition that impacts on several cognitive domains. It is unclear whether all, or only some, of these domains are related to synaesthesia. Autism entails impairments in social communication alongside unusually narrow interests and repetitive behavior (DSM-5, 2013). Contemporary models of autism also attempt to account for relative strengths as well as impairments. The empathizing-systemizing model of autism emphasizes not only the socio-cognitive difficulties in understanding others (linked to empathizing) but also an interest in and aptitude for rule-based systems (hyper-systemizing) 12 . Related, others have characterized the cognitive style of autism in terms of more local information processing that may, for instance, give them an advantage on certain perceptual tasks such as finding hidden (embedded) figures 13 . What traits relating to autism are found in studies of synaesthesia? Banissy et al . 14 administered personality questionnaires to a large group of grapheme-colour synaesthetes. Two of these assessed empathy and social functioning (the Inter-Personal Reactivity Index, IRI, and Empathy Quotient, EQ) that are known to differentiate people with autism and controls 15 , 16 . However, the synaesthetes did not score differently on any subscale in these measures. In terms of autism-related abilities and differences in cognitive style, there is more positive evidence. Mealor et al . 17 developed the Sussex Cognitive Styles Questionnaire that links together mental imagery 18 , local/global bias and systemizing. This questionnaire was given to people with grapheme-colour synaesthesia, sequence-space synaesthesia, synaesthetes with both, and controls with neither (but not to an autistic group). The presence of sequence-space synaesthesia was linked to increased systemizing, increased technical/spatial processing which also contains items from the Systemising Quotient 19 , and increased local bias which contained items from the Autism-Spectrum Quotient, AQ 20 (grapheme-colour synaesthetes tended to have scores intermediate between controls and sequence-space synaesthetes). Sequence-space synaesthesia has been linked to certain forms of savant abilities, prevalent in the autistic population, such as prodigious memorisation of dates 21 . Of course, other forms of synaesthesia may be relevant to savantism too (e.g. music visualisation). The present study considers, whether sensory sensitivity is a common facet of both synaesthesia and autism. The 2013 Diagnostic Statistical Manual (DSM-5) added the following to their list of criteria: “Hyper- or hypo-reactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).” In order to explore this feature of autism experimentally, several measures have been developed 22 , 23 , 24 . The Glasgow Sensory Questionnaire (GSQ) – used in the present study – contains items relating to seven sensory modalities (vision, hearing, taste, touch, smell, vestibular, proprioception) that tap both hypesensitivity and hyposensitivity 22 . People with high autistic traits score significantly higher than controls and, interestingly, all questions loaded on a single factor (i.e. there was no evidence of fractionation according to sensory modalities or whether hypo- or hyper-). Questionnaire measures of sensory sensitivity show no evidence of a neurotypical gender difference 22 , 24 unlike other traits related to autism that do show gender differences (with males on average tending to score lower on empathizing and higher at systemizing 12 ). Grapheme-colour synaesthetes show evidence of a hyper-excitable visual cortex as shown by reduced phosphene thresholds when the brain is stimulated using TMS (Transcranial Magnetic Stimulation) 25 . They show increased amplitude visual-evoked potentials, in EEG, for certain", "role": "user" }, { "content": "Concrete links between the symptoms of autism and synaesthesia have been discovered and clarified for the first time, according to new research by psychologists at the University of Sussex. The study, conducted by world-leading experts in both conditions at Sussex and the University of Cambridge and published in the journal Scientific Reports, found that both groups experience remarkably similar heightened sensory sensitivity, despite clear differences in communicative ability and social skills. Two previous studies had found an increased prevalence of synaesthesia in autistic subjects, suggesting that although they are not always found in conjunction, the two conditions occur together more often than would be expected by chance alone. However, this is the first study that has attempted to draw a definitive symptomatic link between the two. Synaesthesia and autism seem on the surface to be rather different things, with synaesthesia defined as a 'joining of the senses' in which music may trigger colours or words may trigger tastes, and autism defined by impaired social understanding and communication. The new research shows that both groups report heightened sensory sensitivity, such as an aversion to certain sounds and lights, as well as reporting differences in their tendency to attend to detail. However, the synaesthetes tended not to report difficulties on the traditional communicative symptoms that usually define autism. While the research shows that there are certainly links between the two conditions, these appear to be sensory rather than social. The study was led by Professor Jamie Ward, Professor of Cognitive Neuroscience and Co-Director Sussex Neuroscience group, alongside Sussex Psychology colleague, Professor Julia Simner; and Professor Simon Baron-Cohen, Professor of Developmental Psychopathology at the University of Cambridge and Director of the Autism Research Centre. Commenting on the research, Prof Ward said: \"Synaesthesia has traditionally been considered more of a gift than an impairment, whereas the opposite could often be said of autism. Our research suggests that the two have much more in common than was previously thought, and that many of the sensory traits that autistic people possess are also found in those who experience synaesthesia. \"Though further research is required, our understanding of autism in the context of synaesthetic abilities may help us unlock the secrets of some of the more positive aspects of autism, such as savantism, while also uncovering further neurological links between the two conditions.\" Another research paper by the group of researchers, looking more closely at the question of savantism in people with autism, is also due to be published soon. Reinforcing their initial research, it shows that synaesthesia tends to be particularly prevalent in people with autism who also have unexpected 'savant' abilities, such as superior abilities in arithmetic, memory and art. Prof Ward added: \"Though some theories propose a causal link between increased sensory sensitivity and impaired social functioning in people with autism, our research so far demonstrates the value of considering synaesthesia on the same spectrum as autism from a sensory point of view. We hope in future to be able to continue to explore the relationship between perceptual, cognitive and social symptoms and abilities in autistic and synaesthetic people.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Oil palm is the most productive oil crop, but its high productivity is associated with conventional management (that is, high fertilization rates and herbicide application), causing deleterious environmental impacts. Using a 2 2 factorial experiment, we assessed the effects of conventional vs reduced (equal to nutrients removed by fruit harvest) fertilization rates and herbicide vs mechanical weeding on ecosystem functions, biodiversity and profitability. Analysing across multiple ecosystem functions, mechanical weeding exhibited higher multifunctionality than herbicide treatment, although this effect was concealed when evaluating only for individual functions. Biodiversity was also enhanced, driven by 33% more plant species under mechanical weeding. Compared with conventional management, reduced fertilization and mechanical weeding increased profit by 12% and relative gross margin by 11% due to reductions in material costs, while attaining similar yields. Mechanical weeding with reduced, compensatory fertilization in mature oil palm plantations is a tenable management option for enhancing ecosystem multifunctionality and biodiversity and increasing profit, providing win–win situations. Main Oil palm production has increasingly expanded in large areas of Southeast Asia, with Indonesia currently the world’s largest producer of palm oil 1 , which also coincides with increased rates of deforestation in the country 2 . It is estimated that between 2001 and 2019, oil palm plantations were responsible for 32% of the total forest area lost in Indonesia 3 . Despite the high environmental costs, oil palm production is highly attractive because of its short-term economic returns and increasing global demand for food, fuel and cosmetics 4 . Industrial oil palm plantations (>50 ha planted area and owned by corporations 5 ) are currently estimated to account for about 60% of the total cultivated oil palm area in Indonesia 6 . Compared with smallholder farms (typically <50 ha of land and owned by individuals 5 ), the productivity of industrial oil palm plantations is ~50% higher 7 but is largely driven by high fertilizer and herbicide applications to optimize productivity 8 at the expense of other ecosystem processes. In contrast to the forests, industrial oil palm plantations tend to be structurally simplified and highly disturbed 9 , 10 , 11 and have reduced capacity to provide several ecosystem functions simultaneously (so-called ‘multifunctionality’ of ecosystems) 4 , 12 . Although various studies have addressed the deleterious effects of oil palm expansion on forest and biodiversity losses 4 , 12 , 13 , to date, there has been no holistic multiyear and spatially replicated assessment of the effect of different oil palm management strategies on ecosystem functions, biodiversity and economic productivity. Primary, experimental research studies that assess the effect of management on multiple outcomes, although presently rare, are pertinent to providing clearer oil palm management recommendations 14 because oil palm plantations are inherently complex agricultural systems. Application of fertilizer and herbicide at high frequencies are arguably the most important management activities in industrial oil palm plantations due to their effect on oil palm yield. Thus, a major leverage for a more environmentally sustainable production of palm oil is identifying optimal fertilizer application rates and weeding method to maintain sufficiently high productivity and economic profitability while minimizing associated losses of ecosystem functions and biodiversity. Fertilization contributes to maintaining high productivity levels but also represents a substantial share of management costs in industrial plantations. High fertilization rates are associated with high nutrient-leaching losses 15 and greenhouse gas (GHG) emissions 11 , 16 . Additionally, over-fertilization can have multiple deleterious effects on the soil, including reductions in soil microbial biomass 17 , pH, base cation availability 18 and notable changes in the composition of bacterial and fungal communities 19 . Economically, excess fertilization of oil palm may reduce profitability due to saturation of the yield curve despite increasing fertilizer application so that the linear increase in fertilizer costs could substantially diminish net returns 20 . This is vital to consider given global reduced availability and consequent price increase of fertilizers 21 . The effects of over-fertilization could be reduced by adjusting fertilization rates to levels that compensate only for the quantity of nutrients exported through harvest and through organic fertilization by putting back palm litter 22 and other processing by-products (for example, palm oil mill effluents and empty fruit bunches) 23 . Such a reduction in fertilization intensity may consequently promote efficient retention and recycling of soil nutrients, decrease soil acidification and the associated need for lime application and generally increase profitability due to fertilizer cost savings and hence present a more ecologically and economically attractive option. Another important management practice in industrial oil palm plantations is weed control, needed to balance the positive and potential negative effects of the understory vegetation and to facilitate access for management operations. Industrial plantations conventionally employ the use of herbicides for easy and quicker removal of the understory vegetation, but this is often complemented by mechanical weeding, for example, during rainy periods and for removing woody plants. Herbicide weed control results in lower understory vegetation diversity 24 while promoting the invasion of herbicide-resistant weeds 25 . It also reduces the habitat complexity, strongly impacting vegetation-dwelling biodiversity 26 , 27 , 28 . A more sustainable alternative could be mechanical weeding, which allows for fast regeneration of the understory vegetation due to preservation of their roots. This consequently leads to increased understory plants cover and diversity which can promote nutrient cycling 29 , 30 and enhance habitat complexity, supporting animal abundance and diversity 26 , 27 , 28 . Nevertheless, these ecologically desirable effects may have adverse economic effects as mechanical weeding requires higher labour input compared with herbicide application, which may reduce profits. Additionally, competition between oil palms and understory vegetation may put yields at risk, particularly during drought periods, given the sensitivity of fructification and fruit bunch weight to water stress 31 , 32 . In this study, we report primary data from a multidisciplinary management experiment in a state-owned industrial oil palm plantation in Jambi, Indonesia, that evaluates whether reduced management (that is, reduced fertilization rates and mechanical weeding) as an alternative to conventional management", "role": "user" }, { "content": "Oil palm trees are the most productive oil crop and global demand is increasing. However, their productivity is due to conventional management practices including high fertilizer usage and herbicide application, resulting in severe environmental damage. A new study by an international, multidisciplinary research team led by the University of Göttingen, shows that shifting to mechanical weeding and reducing fertilizer usage lead to significant increases in both ecosystem multifunctionality and profit. The scientists compared different environmental measures and economic indicators in mechanical weeding, herbicide application, and combinations of these with high and reduced fertilizer usage. Their study was published in the journal Nature Sustainability. Oil palm production has increased in Indonesia, currently the world's largest producer of palm oil, which coincides with the country's increased rate of deforestation. Although oil palm production has brought socio-economic benefits, it also causes environmental problems such as biodiversity loss, nitrate leaching and greenhouse gas emissions. The team carried out their research in plantations that were at least 16 years old, starting in 2016 in Jambi, Indonesia, with the aim of testing reduced management against conventional practices. They looked at the effects of reducing fertilizer usage to compensate for the amount of nutrients taken out with harvests of oil palm fruits, and mechanical weeding using a brush cutter. Over four years, the researchers collected data on oil palm yield, material and labor costs, animals both in the soil and above ground, diversity of ground vegetation, greenhouse gas emissions, soil fertility, and nutrient leaching. Oil palm tree plantation in Jambi province, Sumatra (Indonesia) . Credit: Oliver van Straaten \"Despite reduced fertilizer usage, the oil palm yields are similar to conventional management but profit significantly increases due to reductions in fertilizer costs. Biodiversity also significantly improves, driven by increased ground vegetation species with mechanical weeding,\" says first author Dr. Najeeb Al-Amin Iddris from the University of Göttingen's Soil Science of Tropical and Subtropical Ecosystems. As ecosystem functions tend to be interrelated, analysis was conducted across multiple ecosystem functions, known as \"multifunctionality.\" \"Mechanical weeding shows significantly higher ecosystem multifunctionality than herbicide application. It promotes fast recovery of ground vegetation and increases its species diversity, which may enhance recycling of nutrients via root uptake, and in combination with reduced fertilizer-usage decreases leaching and increases nutrient retention in the soil,\" explains Iddris. \"The study found no reduction in greenhouse gas emissions with reduced fertilizer usage and mechanical weeding during four years of this experiment. The consequences of more than 15 years of conventional management prior to the start of the experiment may have dampened the effects of reduced management,\" explains lead author Dr. Marife Corre, University of Göttingen. \"The positive effects of mechanical weeding on ecosystem multifunctionality and profit show that such smart practices can generate benefits even over a short period. Employing mechanical weeding during the early stage of establishing an oil palm plantation may reap even greater benefits,\" says Corre. \"These management practices can be easily adopted in the field and should be included as one of the criteria for production of sustainable palm oil, as set out by the Roundtable for Sustainable Palm Oil, an organization of oil palm producers, processors, manufacturers, investors, environmental groups, and social development stakeholders.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity. Main Notch is a cell-to-cell ligand–receptor signaling pathway that has a major influence on cell transcription and biology 1 , playing important roles in several diseases 2 . General Notch signaling or γ-secretase inhibitors have been used in clinics with undesired side effects, including disruption of the normal intestinal stem-cell differentiation 2 , 3 . Specific blocking antibodies are now available that target the various ligands and receptors of the Notch pathway 4 , 5 , 6 , 7 , 8 . Given the specificity of Dll4 expression in endothelial cells (ECs), targeting this ligand was initially thought to be an effective and safe strategy for specifically modulating Notch signaling and angiogenesis in disease, such as during tumor growth 6 , 7 . However, anti-Dll4 treatment was later shown to induce a loss of endothelial quiescence and vascular neoplasms, which were proposed to be the main cause of pathology in several organs 5 , 8 , 9 . This toxicity diminished the clinical appeal of Dll4/Notch blockers in cancer or cardiovascular disease settings. Here, we characterized the effect of single or compound targeting of all Notch signaling members on adult mice vascular homeostasis. High-resolution single-cell RNA sequencing (scRNA-seq) and three-dimensional (3D) confocal microscopy of adult liver vessels revealed very significant differences in the way each Notch member regulates vascular signaling, structure and single-cell states. γ-Secretase inhibitors or removal of Notch receptors did not cause substantial vascular or organ disease. Abnormal proliferating and sprouting single-cell states were generated only after Dll4 targeting. Surprisingly, suppression of these angiogenic cell states by additional genetic or pharmacological targeting was insufficient to prevent vascular and organ disease. Conceptually, our data show that the major transcriptional changes and angiogenic cell states elicited by targeting Dll4 correlate with, but do not cause, the observed vascular pathophysiology. Instead, we propose that it is the unrelated vascular structure abnormalization and malfunction that leads to organ pathology and the reported toxicity of anti-Dll4 treatment 5 , 8 . Results Notch pathway expression and signaling in adult organ ECs To elucidate the role of Notch signaling in global vascular homeostasis, we first assessed its activity in different organ vascular beds by immunodetection of the activated form of the Notch1 intracellular domain (N1ICD Val1744 ). This epitope was detected in ∼ 50% of all organ ECs (Fig. 1a,b ). Bulk RNA-seq analysis revealed that Dll4 and Notch1 are the most expressed ligand–receptor pair in quiescent vessels of most organs (Fig. 1c,d and Extended Data Fig. 1a ), and that Mfng is the most strongly expressed Notch glycosyltransferase. These enzymes are known to significantly enhance Delta ligand signaling and decrease Jagged ligand signaling 1 . Adult mice with induced deletion of Dll4 in ECs ( Dll4 iDEC - Dll4 flox/flox Cdh5-CreERT2 ) led to a significant reduction in N1ICD Val1744 and Hey1 signals in most organs’ quiescent ECs (Fig. 1e–i ). This indicates that Dll4 is the main functional ligand responsible for triggering Notch activity in most quiescent vessels. We observed compensatory upregulation of Dll1 only in lungs (Fig. 1i ). Dll4 deletion elicited remarkably different gene expression signatures among different organ vascular beds, with the adult liver endothelium presenting the most pronounced changes in gene expression (Fig. 1j,k and Extended Data Fig. 1 ). Despite significant transcriptional changes in most organs’ ECs, only the endothelium of the heart, muscle and liver showed an increase in the frequency of cycling or activated Ki67 + cells upon Dll4 deletion (Fig. 1l–n ), and these were the only organs with clear alterations in the 3D vascular architecture after the loss of Dll4–Notch signaling (Fig. 1o ). The brain underwent significant changes in gene expression (Fig. 1j,k and Extended Data Fig. 1 ), but these were not accompanied by endothelial proliferation or vascular morphological changes. Fig. 1: Dll4 deletion leads to EC activation and proliferation only in some vascular beds. a , b , Notch1 signaling activity (cleaved Val1744 N1ICD) in quiescent endothelium (DAPI + Endomucin + , abbreviated as EMCN). c , Schematic representation to illustrate the bulk RNA-seq experiment performed with adult ECs isolated by FACS. d , Heatmap with RNA-seq reads per kilobase per million mapped reads (RPKM). e , Experimental layout for the inducible deletion of Dll4 in Cdh5 + ECs ( Dll4 iDEC ) with Cdh5(PAC)-CreERT2 . f , Expression of Dll4 protein in CD31 + EMCN + vessels. g , h , Dll4 deletion significantly reduces Notch signaling activity (cleaved Val1744 N1ICD) in all quiescent vascular beds. In brain micrographs, white arrowheads indicate ECs and yellow arrowheads indicate non-ECs. Note that whereas N1ICD is maintained in non-ECs, most N1ICD signal disappears from the ECs in Dll4 iDEC brains. i , Schematic representation to illustrate the bulk RNA-seq experiment performed with adult ECs. Below, a heatmap showing the relative expression of all Notch pathway components and canonical target genes in control and Dll4 iDEC mutant ECs. j , Unsupervised hierarchical clustering showing stronger gene expression changes in Dll4 iDEC liver ECs compared with the other organs. Z -score lcpm,", "role": "user" }, { "content": "Research by scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) has demonstrated that the on-target molecular and cellular effects of medicines used to modulate the formation of new blood vessels (angiogenesis) in cardiovascular disorders and cancer are not responsible for the toxicity and vascular pathology triggered by these drugs. The study is published in Nature Cardiovascular Research. Study leader Rui Benedito commented that, \"Our results not only significantly increase our understanding of the biology of blood vessels, but will also help in the selection of the most effective and safe way to modulate angiogenesis in ischemic tissues or in cancer.\" The vascular system supplies oxygen and nutrients to the tissues and organs of the body. But the blood vessels do more than just conduct blood; they contribute actively to the physiology and homeostasis of all tissues and organs throughout life. Most blood vessels in the body are in an inactive state, which they maintain by expressing a large number of genes, including the genes of the signaling pathway mediated by Delta ligands and Notch receptors. Several drugs have been developed in recent years that either block or induce angiogenesis in cardiovascular disorders or cancer. A group of these compounds in clinical use inhibit different components of the Delta-Notch signaling pathway, which plays important roles in angiogenesis and in the maintenance of blood vessels in the inactive state. These compounds, by modulating the growth of blood vessels, efficiently block tumor growth. These compounds are also able to induce angiogenesis in ischemic tissues, thereby improving tissue regeneration and function. However, these drugs can also cause vascular injury in organs with no previous disease, including the liver and heart, and this has reduced clinical interest in their use. Until now, this vascular toxicity was thought to be due to the expression of genes that promote angiogenesis, leading to the appearance of neoplasms or tumors in the affected blood vessels. Thanks to the use of advanced genetic mouse models, high-resolution confocal microscopy, and single-cell sequencing and proteomics techniques, the team discovered that the vascular toxicity linked to these drugs is instead due to a change in the vascular architecture that impedes correct blood flow. \"Our study shows that the vascular pathology that can result from treatment with these drugs is unrelated to the expression of genes involved in angiogenesis or the appearance of neoplasms,\" said Rui Benedito. The researchers showed that these changes happen even when they blocked cell activation and the expression of angiogenesis-related genes. Therefore, explained Rui Benedito, \"although the neoplasms and the expression of genes associated with angiogenesis are associated with the change in vascular architecture, they are not the cause of this change.\" First author Macarena Fernández Chacón explained that, \"after analyzing different genes and drugs targeting blood vessels, we have found new ways to control pathological angiogenesis without significantly affecting vascular architecture in other organs, thus avoiding toxicity.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The formation of excitons in organic molecules by charge injection is an essential process in organic light-emitting diodes (OLEDs) 1 , 2 , 3 , 4 , 5 , 6 , 7 . According to a simple model based on spin statistics, the injected charges form spin-singlet (S 1 ) excitons and spin-triplet (T 1 ) excitons in a 1:3 ratio 2 , 3 , 4 . After the first report of a highly efficient OLED 2 based on phosphorescence, which is produced by the decay of T 1 excitons, more effective use of these excitons has been the primary strategy for increasing the energy efficiency of OLEDs. Another route to improving OLED energy efficiency is reduction of the operating voltage 2 , 3 , 4 , 5 , 6 . Because T 1 excitons have lower energy than S 1 excitons (owing to the exchange interaction), use of the energy difference could—in principle—enable exclusive production of T 1 excitons at low OLED operating voltages. However, a way to achieve such selective and direct formation of these excitons has not yet been established. Here we report a single-molecule investigation of electroluminescence using a scanning tunnelling microscope 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 and demonstrate a simple method of selective formation of T 1 excitons that utilizes a charged molecule. A 3,4,9,10-perylenetetracarboxylicdianhydride (PTCDA) molecule 21 , 22 , 23 , 24 , 25 adsorbed on a three-monolayer NaCl film atop Ag(111) shows both phosphorescence and fluorescence signals at high applied voltage. In contrast, only phosphorescence occurs at low applied voltage, indicating selective formation of T 1 excitons without creating their S 1 counterparts. The bias voltage dependence of the phosphorescence, combined with differential conductance measurements, reveals that spin-selective electron removal from a negatively charged PTCDA molecule is the dominant formation mechanism of T 1 excitons in this system, which can be explained by considering the exchange interaction in the charged molecule. Our findings show that the electron transport process accompanying exciton formation can be controlled by manipulating an electron spin inside a molecule. We anticipate that designing a device taking into account the exchange interaction could realize an OLED with a lower operating voltage. Main A scanning tunnelling microscope (STM) combined with an optical detection system provides atomically precise spectroscopy for investigating both optical and electron-transport processes at the nanometre scale, and has elucidated fundamental exciton physics in well defined molecular systems 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Here we applied this technique to a PTCDA molecule (Fig. 1a ) adsorbed on a three-monolayer-thick NaCl(100) film grown on a Ag(111) surface—we refer to this system as PTCDA/NaCl(3ML)/Ag(111). In an STM image of PTCDA/NaCl(3ML)/Ag(111) (Fig. 1b ), the molecules appear as double-lobed structures with a nodal plane along the long axis of the molecule 21 , 22 , 23 . The adsorption angle of PTCDA is tilted by 45° with reference to the [100] direction of the NaCl film, which is consistent with the adsorption structure 24 of PTCDA on bulk NaCl(100). Fig. 1: STM measurements of the PTCDA/NaCl(3ML)/Ag(111) system. a , Molecular structure of PTCDA (brown, C; red, O; beige, H) with long-axis direction. b , Constant-current STM image showing three PTCDA molecules on the NaCl(3ML) surface (25 nm × 25 nm, sample voltage V s = 1.0 V, tunnelling current I t = 10 pA). The directions of the long axes of the PTCDA molecules are indicated by the black double-headed arrows; white arrows indicate the [100] and [010] directions of the NaCl surface. c , The d I t /d V s spectrum of the PTCDA/NaCl(3ML)/Ag(111) system. d , STM images of PTCDA measured at the sample voltages indicated by the black arrows in c and shown at the bottom right of each image (4 nm × 4 nm, I t = 5 pA). Full size image To examine electron transport via PTCDA/NaCl(3ML)/Ag(111), we measured a differential conductance (d I t /d V s ) spectrum, where I t is the tunnelling current and V s is the sample bias voltage (Fig. 1c ). The d I t /d V s spectrum exhibits two resonant tunnelling peaks, at V s = −0.8 V and 1.1 V, and the peak onsets are at −0.5 V and 0.7 V, respectively. Double-lobed structures are observed in the STM images at both positive and negative sample voltages, and rounded structure is observed in the gap region of these peaks. The features in the d I t /d V s spectrum are similar to those in the previously reported 21 , 22 d I t /d V s spectrum of PTCDA/NaCl(2ML)/Ag(111), indicating that electron transport occurs by the same mechanism on NaCl films of different thicknesses. In the previous report 21 , 22 , PTCDA was considered to be negatively charged on NaCl(2ML)/Ag(111) owing to the high electron affinity of the molecule and the low work function of the substrate 21 , 22 , 23 . The authors 21 , 22 proposed that the lowest unoccupied molecular orbital (LUMO) was responsible for the resonant tunnelling channels observed at both positive and negative voltages. This interpretation is also valid for the PTCDA/NaCl(3ML)/Ag(111) system, and is supported by the similar double-lobed structure observed in the STM images at both voltage polarities (Fig. 1d ), which are almost identical to the spatial distribution of the LUMO determined from PTCDA/NaCl(3ML)/Au(111) (see Extended Data Figs. 1 , 2 and Methods ). In order to confirm exciton formation by charge injection, we performed scanning tunnelling luminescence (STL) measurements on PTCDA/NaCl(3ML)/Ag(111) (Fig. 2a ). The STL spectrum obtained with the tip located on a PTCDA molecule shows a broad peak ranging from 1.5 eV to 3.0 eV, and several sharp peaks at approximately 1.3 eV, 2.25 eV and 2.45 eV (Fig.", "role": "user" }, { "content": "Scientists from RIKEN and the University of California San Diego, in collaboration with international partners have found a way to significantly reduce the amount of energy required by organic light emitting diodes (OLEDs). OLEDs have attracted attention as potential replacements for liquid crystal diodes, since they offer advantages such as being flexible, thin, and not requiring backlighting. The group achieved the advance, published in Nature, by developing a new way to manipulate the \"excitons\"—pairs of electrons and holes—that are key to the transport of electrons within OLEDs. Essentially, current passing through the device creates such pairs, which then change to a lower energy level and emit visible light in the process. Normally, the excitons in OLEDs arise in two patterns, with the spins being either the same or opposite, and the ones with same spins—known technically as triplet excitons—are three times more common. However, the singlets, which are created along with the triplets, require more energy, and though they can be converted into triplets it still means that the device as a whole requires the energy to create them in the first place. In the current work, the group found a way to lower the voltage so that only triplets are formed. The work began with fundamental research to understand the basic physics behind the creation of excitons using precise single-molecule electroluminescence measurements using a scanning tunneling microscope (STM) combined with an optical detection system. They prepared a model system based on an isolated molecule of 3, 4, 9, 10-perylenetetracarboxylicdianhydride (PTCDA), an organic semiconductor, adsorbed on a metal-supported ultrathin insulating film. They used a special technique to impart a negative charge to the molecule. Then, they used the current from an STM (scanning tunneling microscope) to induce luminescence in the molecule, and monitored what type of exciton was created based on the emission spectrum. The measurements showed that at low voltage, only triplets were formed. Theoretical calculations by Kuniyuki Miwa and Michael Galperin at UC San Diego confirmed the experimental results and substantiated the mechanism. \"We believe,\" says Kensuke Kimura of the RIKEN Cluster for Pioneering Research, \"that we were able to do this thanks to a previously unknown mechanism, where electrons are selectively removed from the charged molecule depending on their spin state.\" \"It was very exciting to discover this new mechanism,\" says Yousoo Kim, leader of the Surface and Interface Science Laboratory in the RIKEN CPR, \"We believe that these findings could become a general working principle for novel OLEDs with low operating voltage.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ–DNA–PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ’s activity in replicating the human genome. Introduction Three DNA polymerases (Pols), α, δ, and ε replicate the genomic DNA in eukaryotes, with the latter two possessing the proofreading exonuclease activity required for high fidelity DNA synthesis 1 , 2 . Pol δ replicates the lagging strand and may share a role with Pol ε in replicating the leading strand 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . In contrast to the continuous leading strand synthesis, the lagging strand is synthesized discontinuously in ~200 nucleotide (nt)-long Okazaki fragments, which are then ligated to form the contiguous lagging strand 2 . Synthesis of each Okazaki fragment starts with the low fidelity Pol α synthesizing a ~30 nt RNA/DNA initiator primer. Replication factor C (RFC) then loads the homotrimeric clamp PCNA at the primer/template (P/T) junction 11 . PCNA encircles the duplex DNA and tethers Pol δ to the DNA enhancing its processivity from few nucleotides to hundreds of nucleotides per DNA binding event 12 , 13 , 14 . PCNA has also been shown to increase the nucleotide incorporation rate of Pol δ 15 . Additionally, the interaction of PCNA with Pol δ is critical for coordinating its transient replacement by other PCNA partner proteins. In the maturation of Okazaki fragments, Pol δ invades the previously synthesized Okazaki fragments to gradually displace the RNA–DNA primers for their removal by the PCNA-bound FEN1 16 . In translesion DNA synthesis, Pol δ is transiently replaced by a PCNA-bound translesion DNA polymerase to ensure the continuation of DNA replication 17 . Mammalian Pol δ consists of a catalytic subunit and three regulatory subunits (Fig. 1a ). The catalytic subunit (p125) harbours the polymerase and exonuclease activities, and a metal-binding C-terminal domain (CTD). The regulatory subunits (p50, also referred to as the B-subunit, p66 and p12) are required for optimal activity of the holoenzyme 18 and there is evidence of different context-specific subassemblies of Pol δ in vivo 19 , 20 , 21 . In particular, DNA damage or replication stress triggers the degradation of the p12 subunit, resulting in the formation of a three-subunit enzyme with an increased capacity for proofreading 20 , 21 . While mammalian Pol δ was identified more than forty years ago 22 , the architecture of this essential enzyme and its interaction with PCNA are still poorly understood. The recently published cryo-EM structure of Saccharomyces cerevisiae ( Sc ) heterotrimeric Pol δ bound to (P/T) DNA elucidated the interactions between the catalytic subunit (Pol3, homologous to human p125) and the two regulatory subunits (Pol31 and Pol32, homologous to human p50 and p66, respectively), showing a unique molecular arrangement 23 ; the p12 subunit is absent in Sc Pol δ. However, how eukaryotic Pol δ achieves processive DNA synthesis and how it cooperates with PCNA and other factors during Okazaki fragment processing remains unknown. Fig. 1: Cryo-EM structure of the processive Pol δ–DNA–PCNA complex. a Domain organization of the four subunits of human Pol δ and amino acid sequence of PCNA-interacting (PIP-box) motifs. CTD C-terminal domain, OB oligonucleotide binding domain, PDE phosphodiesterase domain. b Gold-standard Fourier shell correlation for the Cryo-EM reconstruction of the Pol δ–DNA–PCNA complex, showing the resolution estimation using the 0.143 criterion. c Cryo-EM density map of the Pol δ–DNA–PCNA complex colored by domain. d Structure of the Pol δ–DNA–PCNA complex colored by domain and sequence of the DNA primer/template substrate. The region of the substrate that was modelled is boxed. Full size image To gain insight into these molecular mechanisms, we used cryo-EM single-particle reconstruction and determined the structure of the human Pol δ heterotetramer bound to (P/T) DNA and PCNA at 3.0 Å resolution (Fig. 1b ). We show that this complex exists in alternative conformations where key interactions regulating the holoenzyme activity are lost. In addition, we present the structure of the Pol δ–DNA–PCNA–FEN1 complex at 4.0 Å resolution. We discuss these structures in the context of Pol δ function in Okazaki fragment synthesis and maturation. Results and discussion Pol δ holoenzyme architecture and interaction with PCNA We firstly reconstituted a replication-competent holoenzyme comprising Pol δ, PCNA, a 25/38 (P/T) DNA bearing a 3′-dideoxy chain terminator in the primer strand and dTTP as an incoming nucleotide. A multi-subunit system was used to optimize the coexpression of human Pol δ’s heterotetrameric complex in baculovirus-infected Sf9 insect cells. We determined the cryo-EM structure of the Pol δ–PCNA–DNA–dTTP complex at 4.1 Å resolution (Supplementary Figs. 1 , 2 ). Reconstitution of this complex in the presence of FEN1 followed by gel filtration (Supplementary Fig. 3 ) led to an analogous map albeit at higher resolution (3.0 Å; Supplementary Figs. 4 , 5 ) in which FEN1 is invisible, as well as to a 4.0 Å resolution map in which FEN1 is visible and could be modelled (see below in the text). We therefore discuss the structure of the Pol δ–PCNA–DNA–dTTP complex based on the 3.0 Å reconstruction (Fig. 1c, d ) (Supplementary Data Table 1 ). The structure has approximate dimensions of 150 Å × 130 Å × 100 Å and displays the catalytic domain of p125 on top", "role": "user" }, { "content": "The molecular machinery responsible for replicating human DNA has come into sharper focus and deepened understanding of this fundamental biological process and how it can malfunction. An international team led by researchers at KAUST has used cryo-electron micrography to study the structure of the human Pol δ-DNA-PCNA complex. During replication, the two strands in the DNA helix are unwound, and each serves as the template for a new copy. Pol δ is one of the enzymes responsible for copying one of the strands. It is tethered to the DNA by a molecule known as PCNA, forming a Pol δ-DNA-PCNA complex at the heart of replication. The team found that the catalytic core of Pol δ—the part that carries out the synthesis reaction—sits on top of PCNA and that its regulatory subunits project to the side. The DNA is threaded through a central channel in PCNA, enabling the molecule to stabilize DNA exiting the reaction area. Further analysis revealed locations in PCNA that are required for the interaction, and results showed that mutating those sites severely reduced the activity of Pol δ. Muhammad Tehseen, one of the lead authors of the study, explains that \"Professor Hamdan's lab has been systematically reconstituting and studying the activities of these proteins by single-molecule imaging, recording molecular movies of these reactions.\" Tehseen purified the molecular complex so that the team could create higher resolution static images. \"Combining the dynamic information from single-molecule imaging with static images from cryoEM is like bringing an image to life,\" he explains. The structure also clarified the role of some of the Pol δ subunits, shedding light on how it interacts with PCNA and DNA. For example, Pol δ interacts with only one monomer of PCNA, and sits in a manner that exposes the two other monomers, freeing them to interact with other proteins that act with Pol δ. One such protein is FEN1, which processes the short fragment strands of DNA, after they are synthesized by Pol δ, so that they can be stitched together to form a continuous mature strand.\" The researchers also studied the structure of the Pol δ-DNA-PCNA-FEN1 complex. The interactions they discovered support a 'toolbelt' model in which PCNA acts as a platform to which different processing enzymes bind, similar to a toolbelt with an array of tools. Working out these structures and interactions enables researchers to better understand the dynamics of DNA replication and how it goes wrong, such as mutations in Pol δ linked with tumors. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bloch oscillations (BOs) are a fundamental phenomenon by which a wave packet undergoes a periodic motion in a lattice when subjected to a force. Observed in a wide range of synthetic systems, BOs are intrinsically related to geometric and topological properties of the underlying band structure. This has established BOs as a prominent tool for the detection of Berry-phase effects, including those described by non-Abelian gauge fields. In this work, we unveil a unique topological effect that manifests in the BOs of higher-order topological insulators through the interplay of non-Abelian Berry curvature and quantized Wilson loops. It is characterized by an oscillating Hall drift synchronized with a topologically-protected inter-band beating and a multiplied Bloch period. We elucidate that the origin of this synchronization mechanism relies on the periodic quantum dynamics of Wannier centers. Our work paves the way to the experimental detection of non-Abelian topological properties through the measurement of Berry phases and center-of-mass displacements. Introduction The quest for topological quantization laws has been a central theme in the exploration of topological quantum matter 1 , 2 , which originated from the discovery of the quantum Hall effect 3 . In the last decade, the development of topological materials has led to the observation of fascinating quantized effects, including the half-integer quantum Hall effect 4 and the quantization of Faraday and Kerr rotations 5 in topological insulators 6 , 7 , as well as half-integer thermal Hall conductance in spin liquids 8 and quantum Hall states 9 . In parallel, the engineering of synthetic topological systems has allowed for the realization of quantized pumps 10 , 11 , and revealed quantized Hall drifts 12 , 13 , 14 , circular dichroism 15 , and linking numbers 16 . In this context, Bloch oscillations (BOs) 17 , 18 , 19 , 20 , 21 , 22 have emerged as a powerful tool for the detection of geometric and topological properties in synthetic lattice systems 23 , 24 , 25 , 26 , hence providing access to quantized observables. Indeed, transporting a wavepacket across the Brillouin zone (BZ) can be used to explore various geometric features of Bloch bands, including the local Berry curvature 23 and the Wilson loop of non-Abelian connections 25 . This strategy has been exploited to extract the Berry phase 27 , 28 , the Berry curvature 29 , 30 , the Chern number 12 , 13 , 14 , and quantized Wilson loops 31 in ultracold matter and photonics. The Wilson loop measurement of ref. 31 highlighted a fundamental relation between two intriguing properties of multi-band systems: the quantization of Wilson loops, a topological property related to the Wilczek-Zee connection 32 , and the existence of “multiple Bloch oscillations”, which are characterized by a multiplied Bloch period 31 , 33 , 34 , 35 , 36 , 37 , 38 , 39 . The effect investigated in ref. 31 was eventually identified as an instance of “topological Bloch oscillations”, whose general framework was proposed in ref. 40 based on the space groups of crystals and its implications on the quantization of geometric quantities (Zak phases differences). The Bloch period multiplier appears as a topological invariant, protected by crystalline symmetries, thus making multiple BOs genuinely topological. Furthermore, when a Wannier representation of the bands is possible, Zak phases correspond to the positions of charges within the unit cell, namely the Wannier centers. As a consequence, a Zak-Wannier duality allows to connect BOs to the relative phases acquired by charges within a classical point-charge picture. More recently, BOs displaying topologically protected sub-oscillations have also been found in periodically driven systems in the context of quantum walks 41 . In this work, we identify a distinct topological effect that manifests in the BOs of higher-order topological insulators (HOTIs). These newly discovered systems belong to the family of topological crystalline insulators 42 , 43 , 44 , 45 , 46 , i.e., gapped quantum systems characterized by crystal symmetries; they are characterized by quantized multipole moments in the bulk and unusual topologically protected states (e.g., corner or hinge modes) on their boundaries; see refs. 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 . Considering the prototypical Benalcazar-Bernevig-Hughes (BBH) model 47 , 48 , we unveil a phenomenon by which multiple BOs take the form of an oscillating Hall drift, accompanied with a synchronized inter-band beating, for special directions of the applied force, as summarized in Fig. 1 a. Although the Hall motion is attributed to the finite non-Abelian Berry curvature of the degenerate band structure, the inter-band beating captured by the Wilson loop is shown to be topologically protected by winding numbers. The synchronization of real-space motion and inter-band dynamics is elucidated through a quantum Rabi oscillation of Wannier centers. Finally, we observe that detached helical edge states are present on specific boundaries, compatible with the special symmetry axes associated with the topological BOs. A topological transition signaled by the sign change of the identified winding numbers and by the corresponding appearence/disapperance of these states is identified. Fig. 1: Schematics of the non-Abelian topological BOs. a The center-of-mass position \\(\\left\\langle {\\bf{r}}\\right\\rangle\\) of a gaussian wavepacket experiences a sign-changing Hall drift under the applied force F , while displaying a synchronized beating within two occupied bands. This synchronized effect, represented by the metronome, is topologically protected by the winding number w . b BBH model: a square lattice with π flux and staggered hopping amplitudes J 1 and J 2 . Vertical bonds with arrows correspond to a Peierls phase π in the hopping amplitudes. c Band structure of the model. Each band is twofold degenerate. d Brillouin zones and paths \\({\\mathcal{C}}\\) and \\(\\bar{{\\mathcal{C}}}\\) exhibiting topological BOs. Full size image Overall, our results demonstrate the rich interplay of non-Abelian gauge structures and winding numbers in the topological BOs of HOTI’s, but also establish BOs as a powerful probe for non-Abelian topological properties", "role": "user" }, { "content": "Oscillatory behaviors are ubiquitous in nature, ranging from the orbits of planets to the periodic motion of a swing. In pure crystalline systems, presenting a perfect spatially-periodic structure, the fundamental laws of quantum physics predict a remarkable and counter-intuitive oscillatory behavior: when subjected to a weak electric force, the electrons in the material do not undergo a net drift, but rather oscillate in space, a phenomenon known as Bloch oscillations. Ultracold atoms immersed in a light crystal, also known as optical lattices, are one of the many systems where Bloch oscillations have been observed. In general, the motion of particles is affected by the presence of forces, such as those generated by electromagnetic fields. In certain crystals, emergent fields reminiscent of electromagnetic fields can also exist as an intrinsic property of the material and they can potentially affect Bloch oscillations. From a mathematical point of view, these intrinsic fields can take various forms. Of particular interest are those fields represented by mathematical quantities that do not commute, namely for which the product 'a x b' is not equal to 'b x a'. These mathematical quantities, and the corresponding physical properties, are commonly called \"non-Abelian\". In nature, generalized non-Abelian forces are required to describe the weak or strong nuclear forces, whereas electromagnetism is more simply described by Abelian (commuting) ones. Writing in Nature Communications, M. Di Liberto, N. Goldman and G. Palumbo (Science Faculty, ULB) demonstrate that intrinsic non-Abelian fields can generate a novel type of Bloch oscillations in crystals. This exotic oscillatory phenomenon is characterized by a multiplication of the oscillation period, as compared to the fundamental period set by the crystal geometry. This multiplication factor has a profound origin, as it stems from the symmetries of the crystal and can be attributed to a topological invariant (a numerical quantity that is robust under small deformations of the crystal). Furthermore, these exotic Bloch oscillations are shown to be perfectly synchronized with a beating of internal states of the crystal. This work sheds new light on topological quantum matter with non-Abelian properties. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Most of the properties of the Earth–Moon system can be explained by a collision between a planetary embryo (giant impactor) and the growing Earth late in the accretion process 1 , 2 , 3 . Simulations show that most of the material that eventually aggregates to form the Moon originates from the impactor 1 , 4 , 5 . However, analysis of the terrestrial and lunar isotopic compositions show them to be highly similar 6 , 7 , 8 , 9 , 10 , 11 . In contrast, the compositions of other Solar System bodies are significantly different from those of the Earth and Moon 12 , 13 , 14 , suggesting that different Solar System bodies have distinct compositions. This challenges the giant impact scenario, because the Moon-forming impactor must then also be thought to have a composition different from that of the proto-Earth. Here we track the feeding zones of growing planets in a suite of simulations of planetary accretion 15 , to measure the composition of Moon-forming impactors. We find that different planets formed in the same simulation have distinct compositions, but the compositions of giant impactors are statistically more similar to the planets they impact. A large fraction of planet–impactor pairs have almost identical compositions. Thus, the similarity in composition between the Earth and Moon could be a natural consequence of a late giant impact. Main Successful models for Moon formation typically require a relatively low-velocity, oblique impact 1 between the proto-Earth and a planetary embryo of up to a few tenths of an Earth-mass ( M ⊕ ). Such Moon-forming impacts typically occur at the late stages of planetesimal accretion by the terrestrial planets 2 , 3 . A circum-terrestrial debris disk is formed from material ejected during these impacts. The composition of the disk, in a typical impact, is dominated by material from the impactor mantle (>60 weight per cent 1 , 4 , 5 ) with a smaller contribution (typically about 20%) from the proto-Earth. More material can be extracted from the proto-Earth when a slightly sub-Mars-sized body hits a fast-spinning planet that is later slowed down by resonances 16 . The spin should be close to the break-up velocity. Another possible channel producing such mixing of material from both the planet and impactor is the rare collision between two embryos of comparable mass, in which both masses are about half of the Earth’s mass 17 . Although these new models can potentially solve some of the composition issues raised by the giant-impact scenario, they do require ad hoc assumptions and pose several difficulties (see ref. 3 for a discussion). Here, we focus on typical giant-impact events, in which the Moon aggregates mostly from material originating from the impactor. Lunar meteorites and rock samples returned by the Apollo mission have a very similar composition to that of the Earth’s mantle, across a variety of different isotopes 6 , 7 , 8 , 9 , 10 , 11 . Combining these with the giant-impact simulation results, one can infer that the Moon-forming impactor and the Earth should have had a similar composition. This poses a fundamental difficulty with the giant-impact model for the origin of the Moon, since analysis of material from other Solar System bodies have shown them to differ significantly (>20 σ ) in composition from that of the Earth (see refs 12 and 13 , and ref. 14 for a review). This would suggest that the composition of the Moon-forming impactor should similarly have differed from that of the Earth, in contrast with the giant-impact basic prediction. Here, we analyse the results of extensive N -body simulations of terrestrial planet formation to show that the Earth–Moon composition challenge can be addressed. In particular, we show that the compositions of a large fraction, 20% to 40%, of giant impactors are consistent with being similar to that of the planets they impact. More generally, late giant impactors have compositions more similar to those of the planets they impact than do other planets in the same system, showing large differences (the probability of these two distributions of coming from the same parent distribution is between 1.3 × 10 −9 and 6.7 × 10 −8 ). To study the compositions of planets and their impactors we analysed 40 dynamical simulations (from ref. 15 , using the Mercury code 18 ) of the late stages of planetary accretion, following the formation of Jupiter and Saturn, and after all the gas in the protoplanetary disk has been dissipated and/or accreted to the gas giants (see ref. 19 for a recent review). Each simulation started from a disk of 85–90 planetary embryos and 1,000–2,000 planetesimals extending from 0.5 astronomical units (1 au is the Earth–Sun distance) to 4.5 au . Jupiter and Saturn are fully formed and have different orbits and inclinations in different sets of simulations (detailed descriptions can be found in ref. 15 and in the Methods). Within 100–200 million years, each simulation typically produced 3–4 rocky planets formed from collisions between embryos and planetesimals. Each of these planets accreted a large number of planetesimals during its evolution. All collisions were recorded and provide a map of each planet’s feeding zone (see also ref. 20 ). Assuming that the initial composition of material in the protoplanetary disk is a function of its position in the initial protoplanetary disk, one can compare the compositions of different bodies formed and evolved in the simulations. Previous studies explored the compositions of the different planets formed in similar simulations. However, the compositions of impactors on formed planets have hardly been explored. Pahlevan and Stevenson 21 analysed a single statistically limited simulation, which included a total of about 150 particles, and compared the compositions of any impactors on any planets during the simulation (not only giant impacts, due to small number statistics) to the compositions of the planets. They 21 concluded that the scatter among the compositions of the various impactors is comparable to the observed differences between the planets.", "role": "user" }, { "content": "The Moon is thought to have formed from the debris of a small planet that collided with the Earth. Since the composition of other planets in the solar system differs from that of the Earth, it was expected that the Moon's composition would also differ from that of the Earth. Surprisingly, the composition of the Earth and the Moon are very similar (no, the Moon is not made out of cheese), raising a major challenge to the \"giant impact\" origin of the Moon. A new study by researchers from the Technion and Nice University explains the origin of such compositional similarity and helps solve this conundrum The Moon has fascinated human kind since the earliest days of history. It has played a central role in the making of annual calendars in Muslim, Jewish and other cultures; and was considered one of the gods in many pagan traditions. Questions regarding the origin of the Moon, its shape and composition gave rise to myths and legends that have accompanied humanity for thousands of years, and even today many children ask themselves—and their parents—whether the Moon is made of cheese. In the modern era such millennium-old puzzles have been replaced by scientific exploration that raised no-less challenging questions, which continue to perplex us—even 40 years after man first landed on the Moon. Now, research done by Technion researchers sheds new light on the origin of the Moon and its composition. The research, published in Nature, was led by post-doctoral researcher Dr. Alessandra Mastrobuono-Battisti and her adviser Assistant Prof. Hagai Perets from the Technion, in collaboration with Dr. Sean Raymond from Nice University. \"Many models for the Moon origin were suggested by scientists, but since the 1980s the scientific community has been focusing on the most promising model—the so called 'giant impact' paradigm,\" explains Perets. \"According to this model, the Moon was formed following a collision between a small Mars-like planet (usually called Theia) and the ancient Earth. Some of the debris from the collision fell back to Earth, some was scattered far into space and the rest went into orbit around the Earth. This orbiting debris later coagulated to form a single object: the Moon.\" Based on complex simulations of such collisions, researchers have found out that most of the material that eventually forms the Moon comes from the impactor, Theia, and only a smaller fraction originates from the impacted body (in this case, the Earth). Measurements of the composition of other bodies in the solar system such as asteroids and Mars have shown that they have a very different composition from that of the Earth. Given that most of the Moon material came from another body in the solar system, it was expected that the composition of the Moon should be similarly very different from that of the Earth, according to the \"giant impact\" model. However, analysis of samples brought from the Moon by the Apollo missions showed otherwise—in terms of composition, the Earth and Moon are almost twins, their compositions are almost the same, differing by at most few parts in a million. This contradiction has cast a long shadow on the 'giant impact' model, and for some 30 years this contradiction was a major challenge to physicists grappling with the formation of the Moon. Now, Mastrobuono-Battisti, Perets and Raymond have suggested a new solution to this mystery. Simulations of the formation of planets in the solar system, showed that different planets indeed have distinct compositions, as found from the analysis of material from different planets in the solar system. Such studies have traditionally focused on studying only the compositions of the final planets. In the new research, Perets and collaborators have considered not only the planets, but also the composition of the impactors on these planets. Consequently they have discovered that in many cases, the planets and the bodies that collide with them share a very similar composition, even though they formed independently. Thus, conclude the researchers, the similarity between the Moon and Earth stems from the similarity between Theia—from which the Moon was formed—and Earth. \"It turns out that an impactor is not similar to any other random body in the solar system. The Earth and Theia appear to have shared much more similar environments during their growth than just any two unrelated bodies,\" explains Mastrobuono-Battisti. \"In other words, Theia and Earth were formed in the same region, and have therefore collected similar material. These similar living environments also led them eventually to collide; and the material ejected mostly from Theia, ultimately formed the Moon. Our results reconcile what has been perceived as a contradiction between the process whereby Moons are formed (from matter from the impacting body) and the similarity between Earth and the Moon.\" \"The Earth and the Moon might not be twins born of the same body,\" summarizes Perets, \"but they did grow up together in the same neighborhood.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure. Introduction Intracellular triglycerides are stored within lipid droplets (LD) that are juxtaposed to mitochondria in the cytoplasm 1 . This close relationship facilitates the rapid transfer of fatty acids to mitochondria, which are generated by lipolysis in response to cellular energy demands 2 . One such demand is non-shivering thermogenesis, which is mediated by brown adipose tissue (BAT) in response to cold exposure to generate heat 3 . This occurs, at least in part, when mitochondrial β-oxidation is uncoupled from oxidative phosphorylation via uncoupling protein 1. The hydrolysis of LD-derived triglycerides is initiated following the release of norepinephrine from neurons, which binds to β3 adrenergic receptors on brown adipocytes to stimulate a cell signaling cascade that activates adenylyl cyclase to generate cAMP and activate protein kinase A (PKA) 4 . In brown adipocytes, the generation of fatty acids for mitochondrial oxidation requires PKA to phosphorylate/activate perilipin, a regulatory membrane-bound protein that encircles LD. The function of perilipin is to protect triglycerides within the LD from lipolysis, and its phosphorylation by PKA allows access of cytoplasmic adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MAGL), to generate free fatty acids through sequential lipolytic steps 5 . Once fatty acids are free in the cytoplasm, they are esterified with coenzyme A (CoA) by long-chain acyl-CoA synthetase 1 (ACSL1) to form fatty acyl-CoAs, which are transported into mitochondria via carnitine palmitoyl transferase 1 and metabolized to produce heat 6 . Fatty acyl-CoA molecules can also be hydrolyzed to fatty acids in the cytoplasm by acyl-CoA thioesterase (Acot) isoforms 7 , 8 . The fatty acids generated can be utilized to make additional fatty acyl-CoAs that are transported into mitochondria or can be returned to the LD for storage. Thioesterase superfamily member 1 (Them1), which is also known as brown fat inducible thioesterase or steroidogenic acute regulatory protein-related lipid transfer (START) domain 14 (StarD14)/Acot11, plays an important role in energy homeostasis 9 , 10 . Mice with the genetic deletion of Them1 exhibit increased energy expenditure, which results in reduced weight gain when challenged with a high fat diet despite high food consumption 10 . This is attributable to increased mitochondrial fatty acid oxidation, and mechanistic studies have demonstrated that Them1 functions to suppress energy expenditure by limiting triglyceride hydrolysis in BAT, thus inhibiting the mitochondrial oxidation of LD-derived fatty acids 10 , 11 . Them1 is comprised of tandem N-terminal thioesterase domains and a C-terminal lipid-binding steroidogenic acute regulatory-related lipid transfer (START) domain. Proteomics has revealed that there are a number of BAT-selective phosphorylation sites near the N-terminus of Them1 in vivo, most notable are serine residues at (S) 15, 18, and 25 12 . Here, we show experimentally that Them1 is phosphorylated at the N-terminus after stimulation in vitro and exists in two different phosphorylation-dependent conformational states: punctate and diffuse. Punctate refers to small, highly concentrated aggregations of Them1 that localize to regions of the cytoplasm that interface with LD and mitochondria, whereas diffuse refers to homogeneously distributed Them1 across the cell cytoplasm and nucleus. We demonstrate that β-adrenergic stimulation with NE, which is used to mimic cold exposure, activates a signaling cascade that results in Them1 phosphorylation and a diffuse localization. A functional analysis revealed that Them1 in punctate form suppresses fatty acid oxidation, whereas this suppression is abrogated when it is diffusely distributed in the cell cytoplasm. Overall, these findings highlight the importance of Them1 phosphorylation in the regulation of thermogenesis in BAT and lend support for targeting Them1 for the management of obesity-related disorders. Results N-terminal serine phosphorylation of Them1 To assess the BAT-selective phosphorylation of Them1, we consulted the phosphomouse database 12 , which revealed phosphopeptides containing phosphorylation events at serine (S) 15, 18, and 25 in the N-terminus of Them1 in vivo within BAT, which are highly conserved (Supplementary Fig. 1 ). To explore the role of Them1 S-phosphorylation in regulating metabolism, cultured immortalized brown adipose cells (iBAs) from mouse BAT were used as an in vitro model. Because iBAs did not express Them1 mRNA or protein, as was the case for primary cultured brown adipocytes 11 , Them1 expression required plasmid or adenoviral transfection (Supplementary Fig. 2a–c ) to study its biochemical and physiological characteristics in vitro. To examine whether Them1 is S-phosphorylated after stimulation, we determined the aggregate abundance of phosphopeptides in the N-terminus of Them1 by mass spectrometry after stimulation with phorbol 12-myristate 13-acetate (PMA; Fig. 1a, b ) normalized to hormone-sensitive lipase as a housekeeping phosphopeptide that does not change with PMA stimulation (Supplementary Fig. 3 ). This resulted in a linear increase in phosphorylation events over time after stimulation (Fig. 1a ), with serine phosphorylation events that could be measured at S25, S27, and S31 (Fig. 1c ). Taken together, these in vivo and in vitro results suggested that stimulus-mediated S-phosphorylation within the N-terminus could control Them1 metabolic activity in BAT. Fig. 1: Regulation of Them1 phosphorylation and its subcellular localization in iBAs. a LC-MS/MS data for iBAs expressing Ad-Them1-EGFP stimulated with PMA for 0–4 h. The data are presented as normalized aggregate abundance of N-terminal phosphopeptides using hormore sensitive", "role": "user" }, { "content": "Linked to serious health problems including cancer, diabetes and cardiovascular disease, obesity affects more than a third of adults in the United States. Presently, there are few safe and effective nonsurgical therapeutic interventions available to patients with obesity. Now, a multi-disciplinary team of researchers has demonstrated that a metabolic regulatory molecule called Them1 prevents fat burning in cells by blocking access to their fuel source. Led by microscopy experts at Beth Israel Deaconess Medical Center (BIDMC) and metabolism experts at Weill Cornell Medicine and NewYork-Presbyterian, the study may contribute to the development of a new type of obesity treatment. The team's findings were published June 9 in Nature Communications. To help explain how the protein Them1 turns off heat production, BIDMC's cell biology and microscopy expert, Susan Hagen, Ph.D., associate vice-chair for research in the Department of Surgery at BIDMC, and Yue Li, Ph.D., a postdoctoral researcher in her laboratory, used light and electron microscopy to observe Them1 in action in mouse brown fat cells grown in the laboratory. \"Them1 is an interesting molecule,\" said Hagen. \"If you inhibit or block its expression, metabolism increases and that reduces body weight.\" The experiments showed that when the cells are stimulated to burn fat, a chemical modification causes Them1 molecules to spread out, or diffuse, throughout the cell. This frees the cellular powerhouses called mitochondria to efficiently turn the cell's fat stores into energy. But when the stimulation stops, Them1 molecules quickly reorganize into a structure called a biomolecular condensate. Situated between the mitochondria and the fats they use as fuel, the condensed Them1 molecules limit energy production. \"It turned out to be so incredibly interesting,\" said Hagen, who is also director of Microscopy and Histology Core Facilities at BIDMC and associate professor of surgery at Harvard Medical School. \"We asked other microscopy experts whether they had ever seen anything like the unusual images we found in resting cells. Using very sophisticated electron microscopy techniques, we were able to show—for the first time, as far as we know—what the bimolecular condensate looks like in electron microscopy.\" \"The study explains a new mechanism that regulates metabolism,\" said David Cohen, chief of the Division of Gastroenterology and Hepatology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medicine. \"Them1 hacks the energy pipeline and cuts off the fuel supply to the energy-burning mitochondria. Humans also have brown fat and produce more Them1 in cold conditions, so the findings may have exciting implications for the treatment of obesity.\" Cohen and Hagen, both members of the Harvard Digestive Diseases Center, have been collaborators since 1983. The current study—supported in part by a five-year, multi-PI grant from the National Institutes of Health—also included collaborators with expertise in structural biology from Emory University. \"This was the most fun I have ever had in science in my life,\" Hagen added. \"Including multiple primary investigators with different expertise gives you the power of doing things that you could never do on your own.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The manipulation of light–matter interactions by quantum control of atomic levels has had a profound impact on optical sciences. Such manipulation has many applications, including nonlinear optics at the few-photon level 1 , 2 , 3 , slow light 4 , 5 , lasing without inversion 6 , 7 , 8 and optical quantum information processing 9 , 10 . The critical underlying technique is electromagnetically induced transparency, in which quantum interference between transitions in multilevel atoms 11 , 12 , 13 , 14 , 15 renders an opaque medium transparent near an atomic resonance. With the advent of high-brilliance, accelerator-driven light sources such as storage rings or X-ray lasers, it has become attractive to extend the techniques of optical quantum control to the X-ray regime 16 , 17 . Here we demonstrate electromagnetically induced transparency in the regime of hard X-rays, using the 14.4-kiloelectronvolt nuclear resonance of the Mössbauer isotope iron-57 (a two-level system). We exploit cooperative emission from ensembles of the nuclei, which are embedded in a low-finesse cavity and excited by synchrotron radiation. The spatial modulation of the photonic density of states in a cavity mode leads to the coexistence of superradiant and subradiant states of nuclei, respectively located at an antinode and a node of the cavity field. This scheme causes the nuclei to behave as effective three-level systems, with two degenerate levels in the excited state (one of which can be considered metastable). The radiative coupling of the nuclear ensembles by the cavity field establishes the atomic coherence necessary for the cancellation of resonant absorption. Because this technique does not require atomic systems with a metastable level, electromagnetically induced transparency and its applications can be transferred to the regime of nuclear resonances, establishing the field of nuclear quantum optics. Main The basic requirement to observe electromagnetically induced transparency (EIT) is a three-level system represented by the ground state, |1〉, and two upper states, |2〉 and |3〉, with respective energies E 2 and E 3 > E 2 , where a strong laser field with Rabi frequency Ω C induces an atomic coherence between states |2〉 and |3〉. This leads to a Fano-type quantum interference 18 if a (weak) probe laser field is tuned across the resonant transition |1〉 → |3〉, rendering the medium almost transparent in a narrow window around the exact resonance frequency. The degree of transparency is limited by the dephasing of the atomic coherence caused by the decay of state |2〉. Thus, maximum transparency is observed if |2〉 can be considered metastable, that is, if it has a decay width, γ 2 , that is negligibly small relative to the coherent decay width, γ 3 , of the state |3〉. Quantitatively, the spectral response of an ensemble of N atoms under these conditions can be described in terms of the linear susceptibility, χ : Here Δ is the detuning of the probe field from the exact resonance and g is the atom–field coupling constant 10 . The susceptibility approaches zero at exact resonance ( Δ = 0) as γ 2 → 0. This is the phenomenon of EIT. Here we extend the concept of EIT into the regime of hard X-rays by using the Mössbauer isotope 57 Fe, which is a two-level system (neglecting the nuclear hyperfine interaction) with a transition energy of 14.4 keV and a natural linewidth of Γ 0 = 4.7 neV. It is not immediately clear how to achieve EIT without a proper nuclear three-level system. In fact, nuclear three-level systems with a metastable level together with a properly synchronized two-colour X-ray/X-ray or X-ray/light source are not available for use to establish conventional EIT schemes in the nuclear regime. Therefore, the possibility of using a single field of hard X-rays for EIT with a nuclear two-level system is highly desirable. This would open the way to exploring quantum optical concepts and nonlinear effects at very short wavelengths, which is particularly appealing in view of the X-ray laser sources in development. The key to the realization of nuclear EIT described here is cooperative emission from ensembles of Mössbauer nuclei that are properly placed in a planar cavity for hard X-rays. The physics of cooperative emission from atoms in cavities has many interesting phenomena even in the linear regime where the atom–cavity interaction can be treated in the weak-coupling limit, which is typically the case at X-ray wavelengths. Owing to the high resonant cross-section of 57 Fe, its 14.4-keV transition is a two-level system well suited to such studies. This isotope was recently used to study superradiant emission and the collective Lamb shift for a single ensemble of atoms located at an antinode of the field within a planar cavity 19 , 20 . Figure 1a shows the energy spectrum of the reflectivity of such a cavity excited in its third-order mode at a grazing angle of ϕ = 3.5 mrad. The spectrum, calculated using a transfer matrix algorithm for resonant X-ray scattering from layered media 21 , shows the superradiant enhancement of the decay width, Γ N , together with the collective Lamb shift, L N . Figure 1: Calculated reflectivity spectra of different cavity configurations. Sample geometry (top row) of planar cavities for X-rays, containing 2-nm-thick layers of 57 Fe nuclei (dark grey), and spectrally resolved reflectivity (bottom row) around the 14.4-keV nuclear resonance energy. The cavities are excited in the third-order mode under grazing angle ϕ = 3.5 mrad. The graphs in the top row show the standing wave intensity of the electromagnetic field in the cavities. a , For a single layer in the centre of the cavity, the collective decay width, Γ N , is broadened owing to superradiant enhancement and shows a shift, the collective Lamb shift L N (refs 19 , 20 ). b , If the cavity contains two 57 Fe layers placed respectively at a node and an antinode of the standing wave field, we observe a pronounced dip in the spectral response, indicative of an EIT window. c ,", "role": "user" }, { "content": "At the high-brilliance synchrotron light source PETRA III, a team of DESY scientists headed by Dr. Ralf Röhlsberger has succeeded in making atomic nuclei transparent with the help of X-ray light. At the same time they have also discovered a new way to realize an optically controlled light switch that can be used to manipulate light with light, an important ingredient for efficient future quantum computers. The research results are presented in the current edition of the scientific journal Nature. The effect of electromagnetically induced transparency (EIT) is well known from laser physics. With intense laser light of a certain wavelength it is possible to make a non-transparent material transparent for light of another wavelength. This effect is generated by a complex interaction of light with the atomic electron shell. At DESY's X-ray source PETRA III, the Helmholtz research team of Röhlsberger managed to prove for the first time that this transparency effect also exists for X-ray light, when the X-rays are directed towards atomic nuclei of the Mössbauer isotope iron-57 (which makes up 2% of naturally occurring iron). Quite remarkably, only very low light intensities are needed to observe this effect, in contrast to standard EIT experiments. How does the experiment work? The scientists positioned two thin layers of iron-57 atoms in an optical cavity, an arrangement of two parallel platinum mirrors that reflect X-ray light multiple times. The two layers of iron-57 atoms, each approximately three nanometres thick, are precisely kept in position between the two platinum mirrors by carbon, which is transparent for X-ray light of the wavelength used. This kind of sandwich with a total thickness of only 50 nanometres is irradiated under very shallow angles with an extremely thin X-ray beam from the PETRA III synchrotron light source. Within this mirror system, the light is reflected back and forth several times, generating a standing wave, a so-called resonance. When the light wavelength and the distance between both iron layers are just right in proportion, the scientists can see that the iron becomes almost transparent for the X-ray light. In order for this effect to occur, one iron layer must be located exactly in the minimum (node) of the light resonance, the other one exactly in the maximum. When the layers are shifted within the cavity, the system immediately becomes non-transparent. The scientists attribute this observation to a quantum-optical effect, caused by the interaction of atoms in the iron layers. Unlike single atoms, the atoms in an optical cavity together absorb and radiate in synchrony. In the geometry of this experiment their oscillations mutually cancel each other, as a result of which the system appears to be transparent. In contrast to previous experiments in the optical regime, only few light quanta are necessary to generate this effect. \"Our result of achieving transparency of atomic nuclei is virtually the EIT effect in the atomic nucleus,\" Röhlsberger describes the experiments. \"Undoubtedly, there is still a long way to go until the first quantum light computer becomes reality. However, with this effect, we are able to perform a completely new class of quantum-optical experiments of highest sensitivity. With the European XFEL X-ray laser, currently being built in Hamburg, there is a real chance to control X-ray light with X-ray light.\" This experiment definitely means considerable technical progress for quantum computing: apart from the basic possibility to make materials transparent with light, the intensity of light is decisive for a future technical realisation as well. Every additional quantum of light produces additional waste heat; this would be reduced by the use of the presently discovered effect. For the continuation of these experiments and the optimal utilisation of the extremely small X-ray beam size of the highly brilliant X-ray source PETRA III, a new coating facility will be installed at DESY for the production and optimisation of these optical cavities. The experiments of the DESY scientists also showed another parallel to the EIT effect: the light trapped in the optical cavity only travels with the speed of a few metres per second – normally it is nearly 300 000 kilometres per second. With further experiments, the scientists will clarify how slow the light really becomes under these circumstances, and whether it is possible to use this effect scientifically. A possible application and at the same time an important building block on the way to light-quantum computers is, for example, the storage of information with extremely slow or even stopped light pulses. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Microplastics (MP) are recognized as a growing environmental hazard and have been identified as far as the remote Polar Regions, with particularly high concentrations of microplastics in sea ice. Little is known regarding the horizontal variability of MP within sea ice and how the underlying water body affects MP composition during sea ice growth. Here we show that sea ice MP has no uniform polymer composition and that, depending on the growth region and drift paths of the sea ice, unique MP patterns can be observed in different sea ice horizons. Thus even in remote regions such as the Arctic Ocean, certain MP indicate the presence of localized sources. Increasing exploitation of Arctic resources will likely lead to a higher MP load in the Arctic sea ice and will enhance the release of MP in the areas of strong seasonal sea ice melt and the outflow gateways. Introduction Marine debris is a growing environmental concern as recent reports indicate that increasing quantities of litter disperse into secluded environments, including Polar Regions 1 , 2 , 3 and the deep ocean floor 4 . Plastic accounts for 73% of marine debris globally 5 , and it has been estimated that about 8 million tons of plastic move from land into the ocean each year 6 . However, only 1% of this has been accounted for in terms of small plastic debris 7 , highlighting that some of the major sinks of oceanic plastic litter remains to be identified. The Arctic Ocean is now in a state of rapid transition that is best exemplified by the marked reduction in age, thickness and extent of the sea ice cover 8 . The European Arctic margin is influenced by drift ice formed on the Siberian shelves and carried to the Fram Strait via the Transpolar Drift 9 . In contrast, the Fram Strait is the gateway that transports warm Atlantic water, via the West Spitsbergen Current to the Central Arctic 10 , containing an anthropogenic imprint 11 . It is well known that regions of the Arctic Ocean are highly polluted owing to local sources and long-range atmospheric input 12 . In this context sea ice has been identified early on as a major means of transport for various pollutants 13 , 14 , with north and east Greenland as well as the Laptev Sea, being especially prone to contamination from several sources 15 . A useful method to study sea ice drift pattern is by using passive microwave satellite images combined with the motions of sea ice buoys 16 , 17 , which highlight the role of sea ice, e.g. spreading oil spills 18 . Recent studies stress the changes caused by the shift to first year ice resulting in the tendency of sea ice floes to diverge from the main drift pattern 19 such as the Transpolar Drift, with complex effects on exchange processes of any contaminants between the exclusive economic zones (EEZ) of the various Arctic nations 20 . Despite the scant knowledge of Arctic ecosystems, the trend towards thinner sea ice and ice-free summers in the future has already stimulated increasing exploitation of its resources in terms of shipping, tourism, fisheries and hydrocarbon exploration 21 . Plastic degrades into smaller fragments under the influence of sunlight, temperature changes, mechanic abrasion and wave action 22 . Particles < 5 mm are called microplastics (MP) and have recently featured in a strongly growing number of studies and publications 23 . MP raise particular concerns because plastic in this size category can be taken up by a much wider range of organisms with currently largely unknown health effects on marine life and humans 24 , 25 . Over the past decade, MP were identified from numerous marine ecosystems globally 5 , including the Arctic 2 , 26 and the Southern Ocean 3 . High concentrations of MP also occur in the surface waters south-west of Svalbard 26 , but overall, MP origins, pathways and their compositional framework within Arctic sea ice remains unclear. Here, we analyzed the content and composition of MP from sea ice cores at five different locations along the Transpolar Drift to assess if sea ice is a sink and transport vector of MP. Ice cores were taken from one land-locked and four drifting ice floes to distinguish between local entrainment of MP and long-distance transport. MP composition of the cores was analyzed by focal plane array detector-based micro-fourier-transform infrared imaging 27 , 28 (Imaging FTIR) and compared to a previous study with respect to MP in Arctic sea ice cores. Analyses of discrete ice core horizons allowed us to assess the spatial variability within sea ice and to reconstruct the location of MP incorporation. By computing drift trajectories, coupled to a thermodynamic ice growth model 29 , possible source regions of MP entrainments during ice growth were identified. Results Microplastics in entire sea ice cores To quantify the MP concentration and composition we obtained ice cores during expeditions of the German research ice breaker Polarstern in spring 2014 and summer 2015 in the Fram Strait and Central Arctic (Fig. 1a , Table 1 ). The highest MP particle concentration ((1.2 ± 1.4) × 10 7 N m −3 ) was detected in an ice core taken in the pack ice of Fram Strait (core B; Fig. 1b ). The MP concentrations of all sea ice cores were highly variable with the second highest MP concentration found in the land-fast ice of the Fram Strait (core A; (4.1 ± 2.0) × 10 6 N m −3 ). The MP load of core C and E, collected north of Svalbard and in the Nansen Basin respectively, varied between (2.9 ± 2.4) × 10 6 N m −3 and (2.4 ± 1.0) × 10 6 N m −3 . The lowest concentration was found in core D (1.1 ± 0.8) × 10 6 N m −3 ; Fig. 1b ) from north of Svalbard. The values recorded in this study are", "role": "user" }, { "content": "Experts at the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) have recently found higher amounts of microplastic in Arctic sea ice than ever before. However, the majority of particles were microscopically small. Ice samples from five regions throughout the Arctic Ocean contained up to 12,000 microplastic particles per litre of sea ice. Further, the types of plastic showed a unique footprint in the ice, allowing the researchers to trace them back to possible sources. This involves the massive garbage patch in the Pacific Ocean; the high percentage of paint and nylon particles pointed to intensified shipping and fishing activities in some parts of the Arctic Ocean. The new study has just been released in the journal Nature Communications. \"During our work, we realised that more than half of the microplastic particles trapped in the ice were less than a twentieth of a millimetre wide, which means they could easily be ingested by Arctic microorganisms like ciliates, but also by copepods,\" says AWI biologist and first author Dr. Ilka Peeken. The observation is a very troubling one because, as she explains, \"No one can say for certain how harmful these tiny plastic particles are for marine life, or ultimately also for human beings.\" The AWI researcher team had gathered the ice samples in the course of three expeditions to the Arctic Ocean on board the research icebreaker Polarstern in the spring of 2014 and summer of 2015. They hail from five regions along the Transpolar Drift and the Fram Strait, which transports sea ice from the Central Arctic to the North Atlantic. Infrared spectrometer reveals heavy contamination with microparticles Microplastic refers to plastic particles, fibres, pellets and other fragments with a length, width or diameter ranging from only a few micrometres—thousandths of a millimetre—to under five millimetres. A considerable amount of microplastic is released directly into the ocean by the gradual deterioration of larger pieces of plastic. But microplastic can also be created on land—e.g., by laundering synthetic textiles or abrasion of car tires. The plastic initially floats through the air as dust, and is then blown to the ocean by the wind, or finds its way there through sewer networks. In order to determine the exact amount and distribution of microplastic in sea ice, the AWI researchers were the first to analyse the ice cores layer by layer using a Fourier transform infrared spectrometer (FTIR), a device that bombards microparticles with infrared light and uses a special mathematical method to analyse the radiation they reflect back. Depending on their makeup, the particles absorb and reflect different wavelengths, allowing every substance to be identified by its optic fingerprint. \"Using this approach, we also discovered plastic particles that were only 11 micrometres across. That's roughly one-sixth the diameter of a human hair, and also explains why we found concentrations of over 12,000 particles per litre of sea ice—which is two to three time higher than what we'd found in past measurements,\" says Gunnar Gerdts, in whose laboratory the measurements were carried out. Surprisingly, the researchers found that 67 percent of the particles detected in the ice belonged to the smallest-scale category of 50 micrometres and smaller. Germany's research icebreaker POLARSTERN above the Lomonossov Ridge in the central Arctic Ocean. Credit: Alfred-Wegener-Institut/Ruediger Stein Ice drift and the chemical fingerprint offer clues to pollutants' regions of origin The particle density and composition varied significantly from sample to sample. The researchers determined that the plastic particles were not uniformly distributed throughout the ice core. \"We traced back the journey of the ice floes we sampled and can now safely say that both the region in which the sea ice is initially formed and the water masses in which the floes drift through the Arctic while growing, have an enormous influence on the composition and layering of the encased plastic particles,\" relates Ilka Peeken. The researchers also learned that ice floes, which are driven in the Pacific water masses of the Canadian Basin, contain particularly high concentrations of polyethylene particles. Polyethylene is used in packaging material. As the experts write in their study, \"Accordingly, we assume that these fragments represent remains of the so-called Great Pacific Garbage Patch, and are pushed along the Bering Strait and into the Arctic Ocean by the Pacific inflow.\" In contrast, the scientists predominantly found particles from ship's paint and nylon waste from fishing nets in ice from the shallow marginal seas of Siberia. \"These findings suggest that both the expanding shipping and fishing activities in the Arctic are leaving their mark. The high microplastic concentrations in the sea ice can thus not only be attributed to sources outside the Arctic Ocean. Instead, they also point to local pollution in the Arctic,\" says Ilka Peeken. The researchers found a total of 17 different types of plastic in the sea ice, including packaging materials like polyethylene and polypropylene, but also paints, nylon, polyester, and cellulose acetate, the latter primarily used in the manufacture of cigarette filters. Taken together, these six materials accounted for roughly half of all the microplastic particles detected. According to Ilka Peeken, \"The sea ice binds all this plastic litter for two to a maximum of 11 years—the time it takes for ice floes from the marginal seas of Siberia or the North American Arctic to reach the Fram Strait, where they melt.\" But conversely, this also means that sea ice transports large quantities of microplastic to the waters off the northeast coast of Greenland. The researchers can't yet say whether the released plastic particles subsequently remain in the Arctic or are transported farther south; in fact, it seems likely that the plastic litter begins sinking into deeper waters relatively quickly. \"Free-floating microplastic particles are often colonised by bacteria and algae, which makes them heavier and heavier. Sometimes they clump together with algae, which makes them drift down to the seafloor much faster,\" explains AWI biologist and co-author Dr. Melanie Bergmann. The observations made by researchers at the AWI's deep-sea network HAUSGARTEN in the Fram Strait lend additional weight to this thesis. As Melanie Bergmann relates, \"We recently recorded microplastic concentrations of up to 6500 plastic particles per kilogram of seafloor; those are extremely high values.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cell cycle genes are often aberrantly expressed in cancer, but how their misexpression drives tumorigenesis mostly remains unclear. From S phase to early mitosis, EMI1 (also known as FBXO5) inhibits the anaphase-promoting complex/cyclosome, which controls cell cycle progression through the sequential degradation of various substrates. By analyzing 7403 human tumor samples, we find that EMI1 overexpression is widespread in solid tumors but not in blood cancers. In solid cancers, EMI1 overexpression is a strong prognostic marker for poor patient outcome. To investigate causality, we generated a transgenic mouse model in which we overexpressed Emi1. Emi1-overexpressing animals develop a wide variety of solid tumors, in particular adenomas and carcinomas with inflammation and lymphocyte infiltration, but not blood cancers. These tumors are significantly larger and more penetrant, abundant, proliferative and metastatic than control tumors. In addition, they are highly aneuploid with tumor cells frequently being in early mitosis and showing mitotic abnormalities, including lagging and incorrectly segregating chromosomes. We further demonstrate in vitro that even though EMI1 overexpression may cause mitotic arrest and cell death, it also promotes chromosome instability (CIN) following delayed chromosome alignment and anaphase onset. In human solid tumors, EMI1 is co-expressed with many markers for CIN and EMI1 overexpression is a stronger marker for CIN than most well-established ones. The fact that Emi1 overexpression promotes CIN and the formation of solid cancers in vivo indicates that Emi1 overexpression actively drives solid tumorigenesis. These novel mechanistic insights have important clinical implications. Introduction Cell cycle progression is regulated by the oscillation in expression and activity of various proteins, such as cyclins and cyclin-dependent kinases. 1 Proteasome-mediated protein degradation is critical in this process. The anaphase-promoting complex/cyclosome (APC/C) catalyzes the sequential proteolysis of substrates from late G 2 to early G 1 phases of the cell cycle. 2 At different stages, Cdc20 and Cdh1 act as co-factors required for APC/C activity. Several APC/C inhibitors, such as Mad2 and Emi1 (early mitotic inhibitor 1, also known as Fbxo5), compete with the APC/C for Cdc20 and Cdh1 binding, thereby stabilizing APC/C substrates. 2 In addition, Emi1 potently inhibits APC/C by blocking its catalytic site, by competitively preventing APC/C substrates from binding to APC/C co-receptors and by actively suppressing substrate mono- and polyubiquitination. 3 , 4 , 5 Emi1 is the principal inhibitor of APC/C activity from S phase to early mitosis, whereas Mad2 fulfills this role later during mitosis. 6 Defective cell cycle regulation is a hallmark of cancer. Consistently, APC/C substrates and regulators are often aberrantly expressed in tumors. 7 , 8 During mitosis, the mitotic checkpoint tightly regulates APC/C activity. It prevents precocious sister chromatid separation by ensuring that the APC/C does not prematurely target securin for degradation, thereby preventing chromosome missegregation. Thus, the aberrant expression of mitotic APC/C regulators can lead to chromosome instability (CIN), which may fuel cancer progression. The observations that CIN can promote tumorigenesis in mice and that at least two-thirds of human cancers are aneuploid indicate that CIN is an important driver of tumor evolution. 9 , 10 , 11 , 12 , 13 , 14 A number of studies have focused on unraveling the cell biological and in vivo function of Emi1 using loss-of-function and genetic ablation experiments, respectively. 5 , 15 , 16 , 17 , 18 , 19 , 20 This has provided invaluable new insights. For instance, it has become clear that Emi1-mediated stabilization of APC/C is required for mitotic progression during embryogenesis and prevents DNA re-replication and polyploidy. 16 , 17 , 18 However, it has remained unclear how Emi1 misexpression might be involved in the biology of cancer development in vivo . Here, we find that EMI1 is overexpressed in the vast majority of human solid tumors, but not blood cancers, and that this is a strong marker for poor clinical outcome. To mimic this expression status in human cancers, we generated an inducible Emi1 overexpression mouse model. We find that in vivo overexpression of Emi1 promotes CIN and the formation of a wide variety of aneuploid solid tumors due to delayed chromosome alignment followed by chromosome missegregation. This indicates that Emi1 overexpression is not a cancer-associated bystander but actively promotes CIN and tumorigenesis in vivo . Results EMI1 is overexpressed in a broad range of human cancers We assessed EMI1 mRNA expression in human cancers using 115 previously published unique expression analyses. 21 Together, EMI1 expression levels in 7403 tumor samples were compared with those in 1467 normal control samples of matched tissue type. Of the 115 studies, 102 (89%) showed that EMI1 is significantly overexpressed and 13 (11%) reported that EMI1 is underexpressed ( Figure 1a and Supplementary Table 1 ). EMI1 overexpression is observed in a range of cancers and tumor subtypes ( Figure 1b , Supplementary Table 1 and Supplementary Data set 1 ). Similarly, using the cancer genome atlas (TCGA) breast cancer data set, 22 we find that EMI1 levels are significantly increased in all four major subtypes ( P ⩽ 0.0019, t -test; Figure 1c ). Figure 1 EMI1 overexpression is a marker for poor prognosis in human solid but not blood cancers. ( a ) Fractions of 115 independent studies reporting under- and overexpression of EMI1 mRNA in cancer. Fractions are shown for all cancers and separately for solid and blood cancers. P value: Fisher’s exact test. ( b ) Box plot showing EMI1 expression levels in normal brain and glioblastoma (see also Supplementary Data set 1 for details). P value: t -test. ( c ) EMI1 expression levels in breast cancer per subtype in the TCGA data set. 22 Bottom P values compared with normal breast tissue. Top P values between groups: one-way analysis of variance Tukey’s multiple comparisons test. ^ P value<2.2 × 10 −16 . ( d ) Box plot showing reduced EMI1 expression in chronic lymphocytic leukemia (CLL) compared with normal control peripheral blood mononuclear cells (PBMCs; see Supplementary Data set 1 for details). P value: t -test. ( e ) Immunohistochemistry for EMI1 on five types of", "role": "user" }, { "content": "University of Queensland researchers have discovered a key driver in the development of most cancers, including breast, lung, liver and ovarian cancers. UQ Diamantina Institute researcher Dr Pascal Duijf said the discovery could be the foundation for improved cancer diagnosis, new treatments and better assessment of a patient's prognosis. \"My team has discovered excessively high levels of the protein EMI1 in cancer samples, including the aggressive brain cancer glioblastoma and tumours of the bone,\" Dr Duijf said. \"High levels of EMI1 promote tumour development, increase the tendency of cancer cells to spread, and change immune responses, which fuel cancer progression,\" \"This is associated with poor patient prognosis, particularly in breast cancer.\" Dr Duijf, a National Breast Cancer Foundation Career Development Fellow, said high levels of EMI1 disrupted normal cell division leading to new cells with abnormal chromosome numbers. \"This process, referred to as chromosome instability, accelerates cancer progression and allows cancer cells to become resistant to cancer therapies.\" \"Our findings indicate that high EMI1 levels are one of the strongest indicators of chromosome instability identified to date.\" Dr Duijf said the discovery was an exciting step forward. The next step was to determine whether tumours had to maintain high levels of EMI1 to survive. \"If that is the case, it could present a promising anti-cancer target,\" he said. The study is published in the Nature journal Oncogene. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Adolescents Aging Air Anthropogenic Circularity Biosafety Chemoenvironment Children's Health Climate Change Digital Health Disabilities Disaster Medicine Disease Prevention Emerging Contaminants Environment and Applied Ecology Environmental Analysis and Methods Environmental Chemistry and Technology Environmental Earth Science and Medical Geology Environmental Ecology Environmental Health Environmental Microbiology Environmental Remediation and Management Environmental Science and Engineering Exercise and Health Global Health Health Behavior, Chronic Disease and Health Promotion Health Care Sciences & Services Health Communication and Informatics Health Economics Health Informatics Health-Related Quality of Life and Well-Being Industrial Ecology Infectious Disease Epidemiology Injury Prevention and Rehabilitation Mental Health Nursing Occupational Safety and Health Oral Health Public Health Statistics and Risk Assessment Reproductive Health Skin Health Sport and Health Toxicology and Public Health Traumas Water Science and Technology Women's Health All Sections Special Issue All Special Issues 2nd Edition of Environmental Impact Assessment by Green Processes 2nd Edition of Health Literacy, Nutrition and Public Health 2nd Edition of Oral Inflammation and Chronic Autoimmune Diseases 2nd Edition of Protecting, Supporting and Promoting Appropriate Breastfeeding in the 21st Century 2nd Edition of Sleep Quality and Health-Related Outcomes 2nd Edition of Social Determinants of Health 2nd Edition of Treatment of Foot and Ankle Injury and Public Health 2nd Edition of Trends in Sustainable Buildings and Infrastructure 2nd Edition of Water Sports Implications for Training, Environment and Health 2nd Edition: Advances in Maternal and Child Healthcare 2nd Edition: Advances in Personalized Exercise Prescription for Chronic Disease Prevention and Rehabilitation 2nd Edition: Evidence-Based Nature for Human Health 2nd Edition: Movement Studies for Individuals with Visual Impairments 2nd Edition: Tobacco Smoke Exposure and Tobacco Product Use A More Sustainable and Healthier Future for All: What Works? Access, Health, Regulations, and Policy: Exploring Rural and Remote Drinking Water Supplies in North America Actions in EU MS for Combating Health Threats in the Maritime Transport Sector Active Commuting and Active Transportation Addiction Behavior Addictions and Cognitive Behavioral Therapy Approaches Addictions in Children and Adolescents Addressing Environmental Health Inequalities – Proceedings from ISEE Conference 2015 Adolescent Depression Prevention Advances in Big Data Analytics and Intelligence Advances in Earth System Science Advances in Endodontic Pain Control Advances in Environmental Biology Advances in Environmental Chemistry Advances in Environmental Economics Advances in Environmental Geotechnics Advances in Environmental Justice Advances in Environmental Modelling Advances in Environmental Neurotoxicology Advances in Environmental Sensor Networks Advances in Environmental Sustainability, Resilience, and Health Advances in Epidemiology Advances in Foot Disorders and Its Treatment Advances in Gastroenterology, Hepatology and Clinical Nutrition Advances in LGBTQ+ People's Health Advances in Mental Health, PTSD and Moral Injury Advances in Physical Diagnosis, Physiotherapy and Rehabilitation in Medicine and Dentistry Advances in Squamous Cell Cancer of the Head and Neck Advances in Substance and Drug Abuse Prevention Advances in Telehealthcare Advances in the Diagnosis and Management of Renal Diseases Advances in the Use of eHealth for Pain Management Advancing Health Equity for Sexual and Gender Minority Populations Ageing Well: The Role of Age-Friendly Environments Aging and Cognition Aging and Work Agrochemicals in the Agri-Food Chain Air Pollution and Carbon Dioxide Emissions Air Pollution Exposure and Health Risks Air Pollution Modeling Air Pollution, Climate Change, and Public Health: The Unavoidable Path towards Decarbonization Air Quality and Healthcare Associated Infections Alcohol Abuse: Newer Approaches to an Old Problem Alcohol and Drugs of Addiction, Aggression and Violence Alcohol and Health Alcohol and Public Health Alcohol Policy and Public Health Alcohol-Related Violence Alcoholism Allergic Disease Epidemiology Allergy and Environment Ambient Air Pollution and Health Vulnerability Anemia and Patients Blood Management Patient in Critical Care Animal Assisted Interventions and Activities for Health and Wellbeing Anti-cancer Activity for Cancer Prevention and Treatment Antibiotic Resistant and Pathogenic Bacteria in the Food Production Environment: Epidemiological Evolution and Control Antimicrobial Resistance Prevention and Control Antimicrobials and Antimicrobial Resistance in the Environment Application of Bio-Based Materials in Environmental Governance Application of Biostatistical Modelling in Public Health and Epidemiology Application of Robotic Devices for Neurologic Rehabilitation Application of Statistical Methods in Public Health and Medical Research Applications of Statistical and Data Science Methods in Public Health Applied Physiology and Exercise Testing in Endurance and Ultra-Endurance Sports Applying Clinical Psychology to Medical Conditions Arsenic Contamination, Bioavailability and Public Health Arsenic in Drinking Water: Current Perspectives and Future Directions Asbestos and Cancers: Exposure from Neighboring Factories and Mines, Contaminated Soil, and Slate Roofs Asbestos Exposure and Disease: An Update Asbestos Exposure and Health Impact Assessment of Public and Occupational Electromagnetic Field Exposure in New and Emerging Connectivity Exposure Scenarios Assessment, Management, and Policy-Making for Environmental Pollution Related to Land Use and Land Cover Atmospheric Change and Impact on Health Auditory Experience, Music and Voice across the Perinatal Period: Innovations in Theory, Research and Clinical practice Back and Neck Pain Bariatric Surgery: Nutritional, Metabolic and Public Health Aspects Bayesian Design in Clinical Trials Beyond Amyloid and Tau - Targeting Lipid Metabolism for Alzheimer’s Disease Biomarkers and Therapies Big Data and Mathematical Modeling in Biomedicine Biochemical and Genetics Tools for Monitoring Health and Risk of Disease Biodegradability and Environmental Sciences Biological and Agricultural Engineering Biological and Health Effects of Low Level Non-Ionising Electromagnetic Fields Biomarkers: Environmental Research and Public Health Bioprocesses for Air Pollution Control Biostatistics Reveals New Insights in Sports Science, Sports Medicine, and Health Birth Defect Prevention Blood Cells, Hematopoiesis, Molecules, Nanomedicine and Diseases Research Bone Health: Nutritional Perspectives Boredom in Health, Education and Sports Breastfeeding and Infant Health Building Related Illnesses Caffeine in the Diet: Health Implications, Safety Issues, and Molecular Mechanisms Cancer Prevention, Treatment, and Survivorship Cannabis, Cannabis-Based Products, and Cannabinoids for Medicinal Use Carbon Capture and Storage Carbon Dioxide (CO2), Emissions, Environmental and Public Health Impact Carbon Emissions and Environmental Protection Cardiac Rehabilitation in the Time of COVID-19 Cardiovascular Disease Self-Care Interventions Cardiovascular Diseases and Public Health Challenges for Health Inequalities Research during COVID-19 Pandemic Challenges in Positive Organizational", "role": "user" }, { "content": "A group of researchers, including Markus Fiedler at Blekinge Institute of Technology in Sweden has studied the phenomenon of video conference fatigue, or \"Zoom fatigue,\" and concluded that both age, gender and personality play a role in how tired you get. For example, they note that young, introvert women are affected more than others. However, there are several ways to avoid this fatigue. Markus Fiedler, researcher at Blekinge Institute of Technology, has together with other researchers in media design, media psychology and media sociology published a study on the factors behind video conference fatigue. This phenomenon, commonly known as \"Zoom fatigue\" is something that many have experienced during the pandemic, but for which there is relatively little evidence. The researchers have identified several different factors behind Zoom fatigue. \"We have found direct evidence that both age, gender and personality affect. For example, young introvert women are affected more than others. But Zoom fatigue depends on many factors, ranging from personal circumstances via the meeting's organization and technology, to the environment in which the video conference takes place,\" says Markus Fiedler. The researchers have also found a number of factors that they believe contribute to Zoom fatigue. \"We assume that both the length and the number of meetings each day play a role, as well as whether you take breaks or not between meetings. It affects whether there are delays and disturbances in pictures and speech, so that you may talk in each other's mouths, or if you have to struggle to follow the conversation. We have also seen that the environment plays a role. You may be sitting at home and ashamed to show your messy environment,\" Markus Fiedler explains. However, the researchers believe that there are some simple things you can do to reduce Zoom fatigue: Do not schedule meetings one after the otherUse simple technologyRaise your hand if you want to speak during meetingsTurn off the microphone and camera when it is not needed The researchers state that more research and evidence is needed when it comes to the contributing factors behind Zoom fatigue. They also mean that research is needed on other ways of communicating, for example, immersive experiences and technology. The study is published in the online journal International Journal of Environmental Research and Public Health. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Tibetan Plateau (TP) is a region sensitive to global climate change and has been experiencing substantial environmental changes in the past decades. Lake ice phenology (LIP) is a perceptible indicator reflecting changes of lake thermodynamics in response to global warming. Lake ice phenology over the Tibetan Plateau is however rarely observed and recorded. This research presents a dataset containing 39-year (1978–2016) lake ice phenology data of 132 lakes (each with area >40 km 2 ) over the Tibetan Plateau by combining the strengths of both remote sensing (MOD11A2, MOD10A1) and numerical modelling (air2water). Data validation shows that the ice phenology data derived by our method is highly consistent with that based on existing approaches (with R 2 > 0.75 for all phenology index and RMSE < 5d). The dataset is valuable to investigate the lake-atmosphere interactions and long-term hydrothermal change of lakes across the Tibetan Plateau. Measurement(s) lake ice phenology Technology Type(s) remote sensing and numerical modeling Background & Summary The formation and duration of ice cover for lakes in the Cryosphere plays an important role in thermodynamics of lakes. It interacts with lake water temperature and shapes aquatic ecosystems as well. Lake ice phenology (LIP, e.g., dates of freezing-up and breaking-up) are closely related to temperature variation 1 , 2 . Change of lake ice phenology in the Cryosphere is considered as one of the most reliable pieces of evidence reflecting global warming 3 , 4 , 5 . It could subsequently lead to substantial alteration in biogeochemical processes (e.g., influencing growth of plankton and causing anoxia in deep water 6 ). Research efforts on investigating changes of lake ice phenology are mainly based on ground observation, satellite observation or modelling 7 , 8 , 9 , 10 . Most of the research, however, are for lakes locating in North America or Northern Europe as there are relatively abundant in ground observations 10 . Lake ice phenology observations are not always widely available particularly for regions like the Tibetan Plateau (TP), where ground-based observation is challenging and costly. Observation from space therefore has been becoming more attractive in investigating the lake ice phenology. For instance, with stratified random sample from Sentinel-2 and PlanetScope, Pickens et al . (2021) reported that 41% of inland water area around the globe were seasonally frozen 11 . Though with uncertainties 12 from both data sources 13 , 14 , 15 and extraction methods, various satellite-based observations have shown their merits in tracking the freezing-thawing cycle of lake ice cover 16 . The most commonly used satellite data includes that from the optical sensors like Advanced Very High Resolution Radiometer (AVHRR) 17 and Moderate-resolution Imaging Spectroradiometer (MODIS) 18 , the passive microwave sensors like Scanning Multichannel Microwave Radiometer (SMMR) 3 , the Advanced Microwave Scanning Radiometer for EOS (AMSR-E) 19 and Special Sensor Microwave/Imager (SSM/I) 20 . Active microwave also shows capabilities in monitoring lake ice status based on sensors like European Remote Sensing Satellite (ERS)-1/2 synthetic aperture radar (SAR) 21 and Radarsat-1/2 SAR 22 , but the narrow swath width and the relatively low temporal resolution limited the application of the technology to monitor lake ice phenology at a daily scale and for a large area. It is also noted that the satellite-based observations of lake ice phenology mostly start from the late 1990s and could be with considerable data gaps. For example, the currently available dataset for lake ice phenology in the TP is that derived from microwave brightness temperature measured by AMSR-E, the Advanced Microwave Scanning Radiometer 2 (AMSR2) and Micro-Wave Radiation Imager (MWRI). The dataset however is limited to 51 lakes on the TP covering the period from 2002 to 2015 23 . In the literature of limnology, numerous research efforts also have been invested on developing mathematical models to reconstruct lake ice phenology for the historical period or to predict the response of lake ice phenology to a warming climate 5 , 24 . The model-based approach goes beyond reproducing data on lake ice phenology and can be used to quantify the response of lake ice phenology to climate change or climate variation. The models may cover different level of details on lake thermodynamics, subject to their research focuses 25 , 26 , 27 , 28 , 29 . It is recognized that a well simplified process-based model (like air2water 30 , 31 ) could perform as good as a more complicated model (like MINLAKE 26 , LIMNOS 27 , HIGHTSI 28 ) if the research interest is mainly on the timing of freezing and thawing of lake ice. The simplified model could be more competitive and applicable for regions with little in-situ observations (like the TP) as it requires much less data for running and calibration. The dataset herein provides complete, consistent and continuous time series (1978–2017) of reconstructed ice phenology for 132 lakes in the TP (Fig. 1 ) by combing the strengths of remote sensing and mathematical modelling forced by meteorological data. The lake surface water temperature (LSWT) derived from MODIS products (MOD11A2) 32 is applied to calibrate and validate the numerical model in reproducing the consecutive daily surface water temperature for the studied period, based on which algorithm has been developed to determine the ice phenology indices (including dates of freezing-up and breaking-up and durations). Lake ice phenology derived directly from satellite observations in this research and by other researchers is used to validate the reconstructed LIP 33 . Fig. 1 Locations of studied lakes in the Tibetan Plateau. Full size image The reconstructed LIP represents a unique dataset to investigate the long-term trends of lake ice phenology in the TP under a warming climate. The dataset can also be used for a variety of applications related to climate change, limnology, hydrology, and aquatic ecology. It is conductive to assess the impacts of climate warming on dynamics of water/heat budget and aquatic biota in lakes across the TP. Methods Figure 2 shows the general framework of our study in determining the lake ice", "role": "user" }, { "content": "Lakes on the Tibetan Plateau show a trend of later freezing-up, earlier breaking-up and thus shorten ice-covered duration since the late 1970s, according to a study by researchers from the International Research Center of Big Data for Sustainable Development Goals (CBAS) and the Aerospace Information Research Institute (AIR) of the Chinese Academy of Sciences (CAS). These findings explicitly reflect the changes in thermodynamics of lakes under a warmer climate and implicate substantial associated alteration in biogeochemical processes in this region. The study was published in Scientific Data on Dec. 2. The study was based on the lake ice phenology dataset reconstructed from remote sensing and modeling for 132 lakes over the Tibetan Plateau. Based on the reconstructed dataset, the research team also reported that for lakes from the southern to northern Tibetan Plateau, the completely ice-covered duration (CID) ranges from 15 days to 215 days. The latitude gradients of CID are 17.5 days/degree. For lakes located between 4,500 to 5,000 m, the altitude gradient of CID is estimated to be 18.9 days/hm. Ice phenology (i.e., the timing of ice-on and ice-off) records are rarely available for lakes over the Tibetan Plateau due to challenges and cost of ground-based observations. The research team developed a framework by combining the strengths of satellite-based observation and numerical modeling in reconstructing complete, consistent, and continuous time series for 132 lakes across the Tibetan Plateau for the period 1978 to 2016. The produced dataset can help to understand the response of lake thermodynamics to climate change and the subsequent hydrological and ecological impacts. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background The Daily Mile is a physical activity programme made popular by a school in Stirling, Scotland. It is promoted by the Scottish Government and is growing in popularity nationally and internationally. The aim is that each day, during class time, pupils run or walk outside for 15 min (~1 mile) at a self-selected pace. It is anecdotally reported to have a number of physiological benefits including increased physical activity, reduced sedentary behaviour, increased fitness and improved body composition. This study aimed to investigate these reports. Methods We conducted a quasi-experimental repeated measures pilot study in two primary schools in the Stirling Council area: one school with, and one without, intention to introduce the Daily Mile. Pupils at the control school followed their usual curriculum. Of the 504 children attending the schools, 391 children in primary classes 1–7 (age 4–12 years) at the baseline assessment took part. The follow-up assessment was in the same academic year. Outcomes were accelerometer-assessed average daily moderate to vigorous intensity physical activity (MVPA) and average daily sedentary behaviour, 20-m shuttle run fitness test performance and adiposity assessed by the sum of skinfolds at four sites. Valid data at both time points were collected for 118, 118, 357 and 327 children, respectively, for each outcome. Results After correction for age and gender, significant improvements were observed in the intervention school relative to the control school for MVPA, sedentary time, fitness and body composition. For MVPA, a relative increase of 9.1 min per day (95% confidence interval or 95%CI 5.1–13.2 min, standardised mean difference SMD = 0.407, p = 0.027) was observed. For sedentary time, there was a relative decrease of 18.2 min per day (10.7–25.7 min, SMD = 0.437, p = 0.017). For the shuttle run, there was a relative increase of 39.1 m (21.9–56.3, SMD = 0.236, p = 0.037). For the skinfolds, there was a relative decrease of 1.4 mm (0.8–2.0 mm, SMD = 0.246, p = 0.036). Similar results were obtained when a correction for socioeconomic groupings was included. Conclusions The findings show that in primary school children, the Daily Mile intervention is effective at increasing levels of MVPA, reducing sedentary time, increasing physical fitness and improving body composition. These findings have relevance for teachers, policymakers, public health practitioners, and health researchers. Peer Review reports Background The Daily Mile is a physical activity intervention developed at St Ninian’s Primary School (Stirling, Scotland) in 2012 [ 1 ]. The initial aim was to improve the fitness of children; although, there have since been many additional benefits anecdotally reported by children, teachers and parents [ 1 ]. These include improved physical activity, sedentary time, physical fitness, body composition, sleep, diet, concentration, well-being and obesity levels. However, no objectively measured scientific evidence has yet been gathered on the validity of these reports. The successful implementation of the Daily Mile at many schools, its continued maintenance and its increasing popularity seem to be a result of the simplicity of the activity, the autonomy given to classroom teachers over when they do it during the school day and the pupil-determined pace. Since its development, the Daily Mile has been rolled out across the country by the Scottish government [ 2 ]. It is estimated by Education Scotland that, from local authorities who responded to their query, ~ 50% of primary schools in Scotland are already doing the Daily Mile with a further 18% planning to do the Daily Mile soon (personal communication). It has also become popular in the rest of the UK with interest from the UK government [ 3 , 4 ]. Additionally, it has been introduced in the Netherlands, Belgium and parts of the USA with interest from many other countries [ 5 ], despite the lack of rigorous evidence on the efficacy of taking part. Globally, physical activity levels are low [ 6 ]. Furthermore, low physical activity levels in childhood are predictive of low physical activity levels in adulthood [ 7 ]. The World Health Organisation (WHO) considers policies and interventions to increase physical activity levels to be important in all age groups and that any potential harm of increasing physical activity is outweighed by the associated benefits [ 8 , 9 ]. In a recent accelerometer study on children (2–11 years old) from eight European countries, the proportion of children achieving 60+ minutes per day (recommended for 5–18 year olds [ 10 ]) of moderate to vigorous physical activity (MVPA) ranged from 9.5% to 34.1% in boys and from 2.0% to 14.7% in girls [ 11 ]. MVPA levels generally decline with age in both genders as sedentary time increases [ 12 ]. MVPA levels are also believed to be influenced by socioeconomic status; however, systematic reviews are unclear on the consistency of this relationship and more evidence needs to be gathered [ 13 ]. School-based physical activity interventions like the Daily Mile are appealing because they include whole classes, therefore they reach many children regardless of socioeconomic status, physical activity level or fitness level. They also break up sedentary time as they occur during lessons and have the potential to reach much larger proportions of the population than opt-in groups like sports clubs. Therefore, understanding the impact of the Daily Mile on physical activity and sedentary behaviour levels is of key importance. Overweight and obesity rates are of pandemic proportions and considered to be a key target for the WHO [ 8 ]. In Scotland, 30% of children (29% of boys and 32% of girls) aged 7–11 years were overweight or obese in 2015 [ 14 ], a figure similar to that in England [ 15 ]. At the same time, there is evidence of a decline in the performance of children in the 20-m shuttle run (an indicator of physical endurance fitness) [ 16 ]. Low fitness and low levels of physical activity in adults and children are associated with a number of risk factors for non-communicable diseases and adverse health outcomes including obesity, cardiovascular disease, diabetes, some cancers,", "role": "user" }, { "content": "Policymakers should consider introducing The Daily Mile to improve the health and fitness of schoolchildren around the world, according to new research led by the Universities of Stirling and Edinburgh. The first study of the popular Daily Mile initiative—which involves children taking a 15-minute break from class to do physical activity—has confirmed it improves fitness, body composition and activity levels in participants. The findings indicate The Daily Mile can help combat global problems such as low physical activity, high sedentary behaviour, declining fitness levels and high levels of obesity. The study was jointly led by Dr. Colin Moran and Dr. Naomi Brooks, of the University of Stirling's Faculty of Health Sciences and Sport, and Dr. Josie Booth, of the University of Edinburgh's Moray House School of Education. It also involved a number of other experts from Stirling and the University of the Highlands and Islands. Dr. Moran said: \"Our research observed positive changes in children who participated in The Daily Mile intervention, compared to our control school where the scheme was not introduced. \"It suggests that The Daily Mile is a worthwhile intervention to introduce in schools and that it should be considered for inclusion in government policy, both at home and abroad.\" The Daily Mile was founded in February 2012 by Elaine Wyllie, the then headteacher of St Ninians Primary School in Stirling, to improve the fitness of her pupils. Children are encouraged to run, jog or walk around their school grounds during a 15-minute break from class, which is in addition to normal intervals and physical education lessons. Following the scheme's success, the Scottish Government has outlined its desire for Scotland to become the first Daily Mile nation, with around half of the country's primary schools now implementing the approach. There has been interest from the UK Government and the scheme has attracted the attention of other countries, with the Netherlands, Belgium and parts of the USA among those to have already adopted the approach. The research team conducted their research at two primary schools within the Stirling Council area, with 391 pupils, aged between four and 12, participating. Each child underwent an initial assessment and then a follow-up later in the academic year. Between times, one school implemented The Daily Mile, while pupils at the other—known as the control school—followed their usual curriculum. Children wore accelerometers to record their average daily minutes of moderate to vigorous intensity physical activity (MVPA) and average daily sedentary behaviour. They also had skinfold measurements taken to check body fat, and were assessed on their performance at a multistage fitness test (known as a bleep test or shuttle run), where they ran between cones 20 metres apart between bleeps. After correcting for age and gender, the team witnessed significant improvements in the intervention school, relative to the control school. Revealing the findings of the research during a special event at St Ninians, Dr. Brooks explained: \"We observed a relative increase of 9.1 minutes per day in terms of MPVA and a relative decrease of 18.2 minutes per day in sedentary time. Children at the intervention school covered, on average, 39.1 metres more during the shuttle run, while their body composition improved too.\" There were similar results when the data was adjusted to additionally account for socioeconomic circumstances. Dr. Booth said: \"Schools can help support pupils to be more active by taking part in The Daily Mile. The benefits of an active lifestyle are wide reaching and important for education as well as for health.\" The Scottish Government's Public Health and Sport Minister, Aileen Campbell, said: \"Scotland's Daily Mile initiative is catching the imagination of the UK and beyond, and this research is even more validation of the impact it can have on people's lives. \"By taking small steps and jogging, walking or running for 15 minutes, people can make huge changes to their health and wellbeing. We want Scotland to be the first 'Daily Mile Nation', with nurseries, colleges, universities and workplaces joining over 800 primary schools and regularly taking part. \"There is great momentum behind this initiative, and I hope this research encourages even more schools and workplaces to sign up and reap the benefits of becoming more active more often.\" Elaine Wyllie, of The Daily Mile Foundation, said: \"I founded The Daily Mile as I became concerned about the lack of physical fitness displayed by pupils and wanted to find a solution. The Daily Mile started with my simple belief that it would help children lead more active lives and to encourage the development of healthy habits in their futures. \"With my pupils I saw that 15 minutes of daily activity rapidly improved pupils' fitness, health and concentration in the classroom. \"I am delighted that this new research underlines what I found and I look forward to the day when every school does The Daily Mile.\"Susan McGill, convenor of Stirling Council's Children and Young People Committee said: \"Improving children's health and wellbeing is a key priority for all schools and nurseries in Stirling. \"We are so pleased to know that an initiative started in Stirling has now been proven to have such a positive impact on the lives of so many young people.\" The paper, The Daily Mile makes primary school children more active, less sedentary and improves their fitness and body composition: a quasi-experimental pilot study, is published in BMC Medicine. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Voltage-gated K + channels function in macromolecular complexes with accessory subunits to regulate brain function. Here, we describe a peptidyl-prolyl cis - trans isomerase NIMA-interacting 1 (Pin1)-dependent mechanism that regulates the association of the A-type K + channel subunit Kv4.2 with its auxiliary subunit dipeptidyl peptidase 6 (DPP6), and thereby modulates neuronal excitability and cognitive flexibility. We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr 607 -Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex. We generated a novel mouse line harboring a knock-in Thr607 to Ala (Kv4.2TA) mutation that abolished dynamic Pin1 binding to Kv4.2. CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K + current, and reduced neuronal excitability. Behaviorally, Kv4.2TA mice displayed normal initial learning but improved reversal learning in both Morris water maze and lever press paradigms. These findings reveal a Pin1-mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility. Introduction Rapidly activating and inactivating somatodendritic voltage-gated K + (Kv) A-type currents regulate action potential (AP) repolarization and repetitive firing and prevent backpropagation into the dendrites of hippocampal pyramidal neurons 1 , 2 . Kv4.2, a member of the Shal-type family, is the prominent A-type voltage-gated potassium channel expressed in hippocampal CA1 pyramidal neuron dendrites 1 . Kv4.2’s role in controlling of dendritic excitability impacts neuronal plasticity and contributes to learning and memory 3 , 4 , 5 . Kv4.2 activity remodels synaptic NMDA receptors by regulating the relative synaptic NR2B/NR2A subunit composition ratio at hippocampal synapses 6 . Ablation of Kv4.2 in mice abolishes the gradual reduction in GluN2B/GluN2A subunit ratio during post-natal development and results in a higher proportion of silent synapses in adulthood 7 . Aberrant Kv4.2 activity is also implicated in Autism Spectrum Disorder (ASD) 8 , temporal lobe epilepsy 9 , 10 , 11 , and Fragile X syndrome 12 , 13 . Considerable evidence suggests that Kv4.2 channels function in macromolecular protein complexes with accessory subunits, including the K + channel interacting proteins (KChIP1–4) and dipeptidyl peptidases 6 and 10 (DPP6 and DPP10) 14 . DPP6 is a type II transmembrane protein that increases Kv4.2 membrane expression and single channel conductance and accelerates the inactivation and recovery from inactivation of Kv4 subunit-containing channels 15 , 16 . In CA1 hippocampal pyramidal neurons, Kv4.2-mediated currents increase in density from the soma to distal dendrites 1 . However, this gradient is abolished in DPP6 KO mice 17 . In addition to its roles in modulating multiple aspects of Kv4.2 function, DPP6 appears to regulate hippocampal synaptic development independently of Kv4.2 (ref. 18 ). Recent studies have identified DPP6 and DPP10 as genes associated with autism 19 , amyotrophic lateral sclerosis 20 , 21 and neurodegeneration 22 . Thus, the regulation of the Kv4.2-DPP6 complex may not only affect Kv4.2 channel activity but also influence Kv4.2-independent functions of DPP6. However, little is known about how the stability or composition of this complex is regulated. In the present study, we report a Pin1-dependent mechanism that regulates the composition of the Kv4.2-DPP6 complex, neuronal excitability and cognitive flexibility. Pin1 is a prolyl isomerase that selectively binds to and isomerizes phospho-Ser/Thr-Pro (pSer/Thr-Pro) bonds 23 . pSer/Thr-Pro motifs in certain proteins can exist in two sterically distinct cis and trans conformations and Pin1 specifically accelerates the cis / trans conversion to regulate post-phosphorylation signaling 23 . Mis-regulation of Pin1 plays an important role in a growing number of pathological conditions including Alzheimer disease (AD), where it may protect against age-dependent neurodegeneration 24 , 25 , 26 , 27 . We identified Pin1 as a Kv4.2 binding partner via a TAP-MS pulldown assay. Subsequent biochemical studies revealed that Pin1-Kv4.2 binding is direct and via the canonical Pin1 binding motif. Stimuli including seizure induction and exposure to enriched, novel environments increased Kv4.2 phosphorylation at the Pin1 binding site T607 by p38 MAPK in the mouse cortex and hippocampus. Using biochemical and electrophysiological techniques, we showed that Pin1 activity is required for the dissociation of the Kv4.2-DPP6 complex and this action alters neuronal excitability. To confirm these observations, we generated a mouse line containing a Kv4.2 T607A (Kv4.2TA) mutation that abolished the phosphorylation and subsequent isomerization of an important C-terminal Pin1 motif. These mutant mice phenocopied those treated with pharmacological inhibitors of Pin1, which suggests a Pin1-dependent mechanism of Kv4.2 regulation. Intriguingly, Kv4.2TA mice exhibited normal initial learning but improved reversal learning in multiple behavioral tasks, introducing Pin1 isomerase regulation of Kv4.2 as a novel mechanism impacting cognitive flexibility. Results Pin1 binds to Kv4.2 at T607 Kv4.2 accessory subunits were identified by yeast two-hybrid screens and immunopurification over a decade ago 28 , 29 . Whether there are other Kv4.2 binding proteins that modulate Kv4.2 function is unknown. Here we took advantage of recently-developed Tandem Affinity Purification (TAP) combined with mass spectrometry (MS) techniques to identify Kv4.2 binding proteins in neurons and HEK-293T cells. We purified complexes of lentivirally expressed TAP-tagged Kv4.2 in cultured hippocampal neurons (Supplementary Fig. 1a ). MS analysis showed interaction with the well-established Kv4.2 accessory subunits DPP6/10 and KChIP1-4, verifying the validity of our Kv4.2 TAP-MS screen (Supplementary Fig. 1b ). This result is similar to the proteomic analyses of Kv4.2 complex in mouse brain using Kv4.2 antibody pulldown 30 . Using the same TAP technique to purify exogenously-expressed TAP-tagged Kv4.2 from HEK-293T cells, we identified Pin1 as a Kv4.2 binding partner (Supplementary Fig. 1c-f ). As shown in the MS list, Kv4.2 has many intracellular binding partners when expressed in HEK-293T cells. However, the majority of the binding partners are protein synthesis and degradation machinery proteins (Supplementary Fig. 1c, d ). This binding was confirmed by the co-immunoprecipitation (co-IP) of endogenous Pin1 with Kv4.2 in mouse brain lysates (Fig. 1a , uncropped images of all western blots are provided in the Supplementary Information file), and immunostaining of cultured hippocampal neurons revealed that Pin1 colocalized with Kv4.2 (Fig. 1b", "role": "user" }, { "content": "Researchers at the National Institutes of Health have discovered in mice what they believe is the first known genetic mutation to improve cognitive flexibility—the ability to adapt to changing situations. The gene, KCND2, codes for a protein that regulates potassium channels, which control electrical signals that travel along neurons. The electrical signals stimulate chemical messengers that jump from neuron to neuron. The researchers were led by Dax Hoffman, Ph.D., chief of the Section on Neurophysiology at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in Nature Communications. The KCND2 protein, when modified by an enzyme, slows the generation of electrical impulses in neurons. The researchers found that altering a single base pair in the KCND2 gene enhanced the ability of the protein to dampen nerve impulses. Mice with this mutation performed better than mice without the mutation in a cognitive task. The task involved finding and swimming to a slightly submerged platform that had been moved to a new location. Mice with the mutation found the relocated platform much faster than their counterparts without the mutation. The researchers plan to investigate whether the mutation will affect neural networks in the animals' brains. They added that studying the gene and its protein may ultimately lead to insights on the nature of cognitive flexibility in people. It also may help improve understanding of epilepsy, schizophrenia, Fragile X syndrome, and autism spectrum disorder, which all have been associated with other mutations in KCND2. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Bond-selective reaction is central to heterogeneous catalysis. In heterogeneous catalysis, selectivity is found to depend on the chemical nature and morphology of the substrate. Here, however, we show a high degree of bond selectivity dependent only on adsorbate bond alignment. The system studied is the electron-induced reaction of meta-diiodobenzene physisorbed on Cu(110). Of the adsorbate’s C-I bonds, C-I aligned ‘Along’ the copper row dissociates in 99.3% of the cases giving surface reaction, whereas C-I bond aligned ‘Across’ the rows dissociates in only 0.7% of the cases. A two-electronic-state molecular dynamics model attributes reaction to an initial transition to a repulsive state of an Along C-I, followed by directed recoil of C towards a Cu atom of the same row, forming C-Cu. A similar impulse on an Across C-I gives directed C that, moving across rows, does not encounter a Cu atom and hence exhibits markedly less reaction. Introduction Bond-selective chemistry due to differences in energy barriers continues to play a major part in the understanding of thermal heterogeneous catalysis 1 , 2 . A notable advance in recent years has been the employment of selective excitation of a molecule incident or present on a surface as a means to influence the reaction probability. For vibrationally and translationally excited gaseous beams incident at metal surfaces, reactions have been reported to be mode-specific 3 , 4 , 5 , bond-selective 6 , 7 and gas-phase alignment-dependent 8 . In the case of molecules adsorbed at surfaces, electrons from scanning tunnelling microscopy (STM) have been employed to excite vibrationally or electronically the adsorbate, resulting in molecular translation 9 , 10 , 11 , rotation 11 , 12 , 13 , isomerization 14 and desorption 9 , 15 , 16 . The breaking of a selected chemical bond in the adsorbate has also been achieved by varying the electron energy 16 , 17 , 18 , 19 or, for extended adsorbates, the excitation location 19 . Here, we show a high degree of bond selectivity due to a cause that, to our knowledge, has not previously been noted, namely the directed recoil of products formed as a result of electron-induced surface reaction. The approach is quite general since directed recoil of products along what was the prior bond direction has been widely reported 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 . When the directed recoil occurs at an anisotropic surface, we find bond-selective surface reaction occurs. We show that different alignments, even of a chemically identical bond, can result in a hundred-fold alteration in reaction probability, with corresponding bond selectivity. The example given is that of an electron from an STM tip impinging on a single meta-diiodobenzene (mDIB) molecule on Cu(110) giving two orders of magnitude greater probability of breaking a carbon-iodine (C-I) bond lying ‘Along’ (AL) a Cu row than the C-I that lies ‘Across’ (AC) the rows. Molecular dynamics (MD) calculations employing an approximate anionic potential, followed by impulsive recoil across a ground potential computed by density functional theory (DFT) reproduce the observed bond selectivity, explaining it as due to directed recoil across the anisotropic surface of the Cu. Results Experiment Experiments were performed on a Cu surface held at 4.6 K. Two physisorbed states of mDIB were observed: one termed ‘Row’ 28 and the other ‘Diagonal’, the latter being the principal subject of the present report. An STM image of the Diagonal adsorption state on Cu(110) is shown in Fig. 1a , with a theoretical simulation directly below. Figure 1: Bond-selective electron-induced reaction of physisorbed mDIB on Cu(110). STM images (EXPT) and simulations (TH) show the selective dissociation of the C-I bond. ( a ) An intact physisorbed mDIB. The white cross indicates the midpoint of mDIB in the STM image. The two C-I bond directions, ‘AL’ and ‘AC’, are given by blue lines and designated as C-I(AL) and C-I(AC). ( b ) A reactive outcome as a result of the breaking of C-I(AL) in the prior mDIB reagent. ( c ) A reactive outcome for the single observed case of mDIB breaking C-I(AC). In the pictured final states (PIC), the green dashed circle indicates the Cu atom to which the IPh was bound, and the blue dashed line the direction of the broken C-I bond. All experimental STM images shown here are 25 × 17 Å 2 in size, recorded at a sample bias of +0.1 V and a tunnelling current of 0.1 nA. Full size image From the simulation, the benzene ring is located at a short-bridge site with one C-I directed along the Cu row and the other at 126° from the Cu row (measured clockwise from [1 0]), leading to the two lobes that were observed, corresponding to the two C-I bonds with I atoms located atop Cu atoms, as evident in the simulated STM image. The bond lengths of both C-I bonds in the physisorbed state were computed as ∼ 2.1 Å, and the heat of adsorption as 1.0 eV. This Diagonal adsorption state was also predicted by a computational study performed by Panosetti and Hofer 29 . The midpoint between the two lobes in Fig. 1a , EXPT, is indicated by a white cross used as the origin of the spatial distribution of the products following electron-induced reaction; see Fig. 1a–c . Electron-induced reaction of physisorbed mDIB was initiated by tunnelling electrons from the STM tip placed over the centre of the intact physisorbed reagent at a sample bias ≥+1.0 V. The experimental findings are illustrated in Fig. 1 , with, at left, sample STM images for the initial and final states of the major reaction path breaking the C-I bond AL the Cu rows, and, at the right, the minor path breaking the C-I bond directed AC the Cu rows. For 139 reactive cases, the breaking of only one of the two C-I bonds was observed, namely, the AL bond of the physisorbed mDIB, in preference to the AC bond. The bond selectivity", "role": "user" }, { "content": "Scientists at the University of Toronto have found a way to make catalysis - the use of catalysts to facilitate chemical reactions - more selective, breaking one chemical bond 100 times faster than another. The findings are described in a study published in Nature Communications. The team of researchers, led by Nobel Prize-winning chemist John Polanyi, employed a combination of experiment and theory to discover that the position of the molecule on the catalytic surface is a key factor in determining the rate at which particular bonds break. \"We found that the microscopic positioning of the molecule relative to the catalytic surface below, rendered the catalyst highly bond-specific,\" says Polanyi, University Professor in the Department of Chemistry at U of T. \"The closer the alignment of the bonds of the molecule to the rows of atoms in the catalyst, the more selective was the reaction.\" The scientists investigated a chemical reaction that involved breaking carbon-to-iodine bonds in the organic molecule iodobenzene, by means of metallic copper, a common catalyst. The reaction was initiated by an electron coming from the tip of a microscope, which attached itself to the iodobenzene. \"We observed acceleration in the reactivity of the carbon-to-iodine bonds when those bonds were aligned along rows of copper atoms in the catalyst, as compared to the bonds aligned across the copper rows,\" says Kelvin Anggara, a PhD candidate in Polanyi's research group and a lead author of the study. \"The copper surface acted more strongly on bonds that were nearby than on bonds that were further away,\" Anggara says. \"We saw 100-fold differences in reactivity between bonds pointing in specific directions on the catalyst.\" The experiment could be explained by a mathematical model developed by the researchers over the past few years, which enabled them to produce a computer-generated movie of the motions of the atoms involved in the bond-breaking at the copper surface. It was the movie that revealed the reason why the copper catalyzed the bonds along its rows in preference to bonds across the rows. \"The copper atoms along the rows were slightly closer together, by about the diameter of a single atom, than the atoms across the rows,\" says Anggara. \"This closer spacing promoted the breaking of bonds lying along the rows.\" The method is rooted in the study of chemical reactions taking place at the surface of solid materials that has guided Polanyi and his colleagues for decades. Following his receipt of the Nobel Prize in chemistry in 1986 for observing the molecular motions in chemical reactions occurring in gases, Polanyi began studying the reactions of individual molecules lying on well-defined catalytic surfaces. Polanyi says scientists are only beginning to understand how catalysis operates, and that the shift towards green chemistry makes knowing as much as possible about catalysts and how they reduce waste caused by chemical reactions more important than ever before. \"The challenge for the future will be to fabricate metal catalysts embodying atomic patterns that speed chemical reactions along pathways that lead to desired products,\" said Polanyi. \"Recent advances in the construction of surfaces, atom-by-atom, lend themselves to the fabrication of such engineered-catalysts. We're now a bit closer to that, since we begin to understand what patterns of atoms make the best catalysts.\" The findings are reported in the study \"Bond selectivity in electron-induced reaction due to directed recoil on an anisotropic substrate.\" Support for the research was provided by the Natural Sciences and Engineering Research Council of Canada, U of T NSERC General Research Fund and the Connaught International Scholarship for Doctoral Studies. Computations were performed on the SciNet HPC Consortium supercomputer at U of T. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The phylogeny of Allotheria, including Multituberculata and Haramiyida, remains unsolved and has generated contentious views on the origin and earliest evolution of mammals. Here we report three new species of a new clade, Euharamiyida, based on six well-preserved fossils from the Jurassic period of China. These fossils reveal many craniodental and postcranial features of euharamiyidans and clarify several ambiguous structures that are currently the topic of debate. Our phylogenetic analyses recognize Euharamiyida as the sister group of Multituberculata, and place Allotheria within the Mammalia. The phylogeny suggests that allotherian mammals evolved from a Late Triassic (approximately 208 million years ago) Haramiyavia -like ancestor and diversified into euharamiyidans and multituberculates with a cosmopolitan distribution, implying homologous acquisition of many craniodental and postcranial features in the two groups. Our findings also favour a Late Triassic origin of mammals in Laurasia and two independent detachment events of the middle ear bones during mammalian evolution. Main Mammalia Linnaeus, 1758 Allotheria Marsh, 1880 Euharamiyida (new clade) Shenshou lui gen. et sp. nov. Bi, Wang, Guan, Sheng and Meng Etymology. Shen , from pinyin of the Chinese word, meaning deity, divinity or cleaver; shou , from pinyin of the Chinese word for creature, animal or beast; specific name after Lu Jianhua, the collector of the holotype. Holotype. A nearly complete skeleton from an adult individual (LDNHMF2001, Lande Museum of Natural History, Tangshan, Hebei Province, China) (Figs 1a and 2d, and Extended Data Figs 1a and 2). Three specimens are referred to as the paratypes (see Supplementary Information , section A). Paratypes. Three specimens are referred to as the paratypes (see section A of Supplementary Information ). Locality and horizon. The Tiaojishan Formation, Daxishan site of Linglongta, Jianchang County, Liaoning Province, China; the locality was dated as approximately 160 million years ago (within the Oxfordian) (see Supplementary Information , section C, for age constraint). Diagnosis. Medium-sized euharamiyidan with an estimated body mass of 300 g ( Supplementary Information , section D). Dental formula I 1 -C 0 -P 2 -M 2 /I 1 -C 0 -P 1 -M 2 (I, incisor; C, canine; P, premolar; M, molar; superscript, upper teeth; subscript, lower teeth). The only pair of upper incisors (I 2 ) are in contact so that a facet is present on the medial side of each tooth; I 2 with two cusps. The mesial upper premolar (P 3 ) small (not basined) and the ultimate premolar (P 4 ) not significantly larger than upper molars. Upper molars with two main cusps in the buccal row, separated by a low ridge; three cusps in the lingual one, of which the penultimate cusp (B2) is the largest. P 4 sub-molariform with a main mesiolingual cusp (a1) and a long basined heel with two rows of cusps; M 1 with three cusps in each cusp row, M 2 with four cusps in the lingual and three in the labial row (Fig. 2d; see Supplementary Information , section A, for differential comparisons). The terminology we use to designate cusps in allotherian teeth is as follows: for upper teeth, the buccal (labial or lateral) cusp row is A, lingual row is B, cusps are numbered from the distal end; lower teeth, the lingual cusp row is a, the buccal row is b (lower case), numbering starts from the mesial (anterior) end. Eleutherodontidae Kermack et al. , 1998 Xianshou gen. nov. Wang, Meng, Bi, Guan and Sheng Etymology. Xian , from pinyin of the Chinese word meaning celestial being or immortal. Locality and horizon. Same as Shenshou . Diagnosis. Dental formula: I 2 -C 0 -P 2 -M 2 /I 1 -C 0 -P 1 -M 2 ; upper and lower molars ovoid in outline, with a shallow central basin. Differ from Sineleutherus in having three well-separated cusps of I 2 , non-molariform P 4 with a hypertrophic mesiolingual cusp (a1) and a weakly basined heel. Differ from Eleutherodon in the ovoid upper molars by absence of third row of cusps, and lack of cuspules and transverse ridges in the central basin. Differ from Shenshou and Arboroharamiya in having an extra-small I 1 , ovoid upper and lower molars, more distally positioned distobuccal cusp (A1) on P 4 and M 1 ; a hypertrophic mesiolingual cusp (a1) on lower molars (Fig. 2e, f; see Supplementary Information , section A, for differential comparisons, and Extended Data Figs 5 and 6 for additional figures). Xianshou linglong sp. nov. Wang, Meng, Bi, Guan and Sheng Etymology. linglong , from pinyin of the Chinese word, meaning ‘exquisite’, and also after the town name Linglongta where the specimen came from. Holotype. A skeleton preserved on a split slab of laminated siltstone (IVPP V16707A-B, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, Beijing, China; Figs 1b and 2e, and Extended Data Figs 1b and 5 ). Diagnosis. Estimated body mass of 83 g. I 2 with three cusps; I 3 extremely small and budlike. Upper molars with sharp cusps and stronger and sharper ridges (flutings) than those in Shenshou and X. songae ; M 1 with two main cusps at the mesial and distal end and connected by a low and sharp ridge in each cusp row; an enlarged and more distally extended distobuccal cusp (A1) on P 4 and M 1 ; P 4 enlarged with a hypertrophic mesiolingual cusp (a1) and a small talonid heel; cusp a1 of lower molar procumbent, projecting mesially beyond the crown. Xianshou songae sp. nov. Meng, Guan, Wang, Bi and Sheng Etymology. The specific name is after Rufeng Song, the collector of the holotype specimen. Holotype. A skeleton preserved partial skull, mandible, and most of the postcranial skeleton (BMNHC-PM003253, Beijing Natural History Museum, China) (Figs 1c and 2f, and Extended Data Fig. 6 ). Diagnosis. A small euharamiyidan with an estimated body mass of 40 g. Differ from X. linglong by having significantly smaller body size and in having P 4 more transversely oval, cusp A1 on P 4 and M 1 proportionally smaller and less distally extended.", "role": "user" }, { "content": "Paleontologists have described three new small squirrel-like species that place a poorly understood Mesozoic group of animals firmly in the mammal family tree. The study, led by scientists at the American Museum of Natural History and the Chinese Academy of Sciences, supports the idea that mammals—an extremely diverse group that includes egg-laying monotremes such as the platypus, marsupials such as the opossum, and placentals like humans and whales—originated at least 208 million years ago in the late Triassic, much earlier than some previous research suggests. The study is published today in the journal Nature. \"For decades, scientists have been debating whether the extinct group, called Haramiyida, belongs within or outside of Mammalia,\" said co-author Jin Meng, a curator in the Museum's Division of Paleontology. \"Previously, everything we knew about these animals was based on fragmented jaws and isolated teeth. But the new specimens we discovered are extremely well preserved. And based on these fossils, we now have a good idea of what these animals really looked like, which confirms that they are, indeed, mammals.\" The three new species—Shenshou lui, Xianshou linglong, and Xianshou songae—are described from six nearly complete 160-million-year-old fossils found in China. The animals, which researchers have placed in a new group, or clade, called Euharamiyida, likely looked similar to small squirrels. They weighed between 1 and 10 ounces and had tails and feet that indicate that they were tree dwellers. \"They were good climbers and probably spent more time than squirrels in trees,\" Meng said. \"Their hands and feet were adapted for holding branches, but not good for running on the ground.\" The members of Euharamiyida likely ate insects, nuts, and fruit with their \"strange\" teeth, which have many cusps, or raised points, on the crowns. Mammals are thought to evolve from a common ancestor that had three cusps; human molars can have up to five. But the newly discovered species had two parallel rows of cusps on each molar, with up to seven cusps on each side. How this complex tooth pattern evolved in relation to those of other mammals has puzzled scientist for many decades. This reconstruction shows arboreal mammals in a Jurassic forest. The three animals on the left side represent the three new species of euharamiyidan mammals. The other two represent a gliding species and another euharamiyidan, respectively, that were reported earlier. Credit: Zhao Chuang Despite unusual tooth patterning, the overall morphology, or physical characteristics, seen in the new haramiyidan fossils is mammalian. For example, the specimens show evidence of a typical mammalian middle ear, the area just inside the eardrum that turns vibrations in the air into ripples in the ear's fluids. The middle ears of mammals are unique in that they have three bones, as evidenced in the new fossils. However, the placement of the new species within Mammalia poses another issue: Based on the age of the Euharamiyida species and their kin, the divergence of mammals from reptiles had to have happened much earlier than some research has estimated. Instead of originating in the middle Jurassic (between 176 and 161 million years ago), mammals likely first appeared in the late Triassic (between 235 and 201 million years ago). This finding corresponds with some studies that used DNA data. The holotype specimen of Senshou lui, which represents a new species of euharamiyidan mammal. It is a nearly complete skeleton that indicates a gracile body with a tail and long fingers that were adapted for an arboreal life in Jurassic forests. Credit: ©AMNH/J. Meng \"What we're showing here is very convincing that these animals are mammals, and that we need to turn back the clock for mammal divergence,\" Meng said. \"But even more importantly, these new fossils present a new suite of characters that might help us tell many more stories about ancient mammals.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor miRNA (miR-335) produced in B cells by plasmid DNA induction (iEVs). We demonstrate that iEVs-335 efficiently and durably restored the endogenous miR-335 pool in human triple negative breast cancer cells, downregulated the expression of the miR-335 target gene SOX4 transcription factor, and markedly inhibited tumor growth in vivo . Remarkably, iEVs-335 mediated transcriptional effects that persisted in tumors after 60 days post orthotopic implantation. Genome-wide RNASeq analysis of cancer cells treated in vitro with iEVs-335 showed the regulation of a discrete number of genes only, without broad transcriptome perturbations. This new technology may be ideally suited for therapies aimed to restore tumor suppressor miRNAs in cancer cells, disrupting the oncogenic program established after escape from miRNA control. Introduction Micro-RNAs (miRNAs) are evolutionarily conserved 20–30 nucleotides that represent a large family of gene expression regulators through their ability to prevent translation of specific mRNA into protein 1 , 2 . Individual miRNAs may repress up to hundreds of transcripts 3 and can regulate diverse processes including cell growth, metabolism, immunity, inflammation, and cancer. miRNA mutations or mis-expression exist in human cancers suggesting that miRNAs can function either as tumor suppressors or oncogenes (oncomiRs) 4 , 5 . Consequently, selective miRNA restoration or oncomiR suppression represent new avenues to cancer therapy. miR-335 is implicated in the growth and metastasis of the triple negative breast cancer cell line MDA-MB-231 derivative 4175 (LM2) cell line 6 . Clinically, triple negative breast cancer patients whose primary tumors have low miR-335 expression have a shorter median time to metastatic relapse 6 . Reportedly, miR-335 inhibits tumor re-initiation but is then silenced by genetic and epigenetic mechanisms 7 . One of the targets of miR-335 is SOX4, a transcription factor involved in embryonic development and cell fate determination 8 , 9 , 10 and in epithelial to mesenchymal transition (EMT) 11 . SOX4 expression is elevated in various tumors, including lymphoma, colorectal, cervical, lung, pancreatic, and breast cancer (Human Protein Atlas portal: ). The deregulated expression of this developmental factor has been correlated with increased cancer cell proliferation, cell survival, inhibition of apoptosis, and induction of EMT 12 . Experiments in mice with conditional deletion of SOX4 in stratified epithelia showed resistance to chemical carcinogenesis leading to delayed onset and tumor size reduction 13 . Recently, we demonstrated that B cells can be reprogrammed for the enforced biogenesis and synchronous release of short noncoding (snc)RNAs 14 . sncRNAs were packaged and enriched as cargo in extracellular vesicles (EVs) induced in B cells (iEVs), with an estimate content of 3.6 copy number/iEV 15 . Here, we demonstrate that iEVs programmed to contain miR-335 cargo deliver and durably restore miR-335 to LM2 cells, modulate target mRNA expression in vitro and in vivo , and greatly reduce the growth of orthotopic LM2 tumors in immune deficient NSG mice. Interestingly, regulation was confined to a discrete number of genes, without broad transcriptome perturbations. Results A plasmid expressing miR-335 doublets in B cells At the outset, we reasoned that restoring miR-335 content in LM2 cells would be best achieved by transfecting B cells with a plasmid engineered with two miR-335 precursor stem loops 15 . The general approach and the generation of iEVs in B cells by transfection with plasmid DNA are shown in Fig. 1A . We engineered pCMVmir carrying two pre-miR-335 stem loops in tandem with a nucleotide linker (Fig. 1B ). Transfection experiments were performed in the murine myeloma cell line J558L to determine the efficiency of iEVs-335 from cells transfected with a pCMVmir coding for one or two pre-miR-335 stem loops, respectively. miR-335 relative quantification (RQ) in isolated iEVs-335 produced by J558L cells transfected with a single pre-miR-335 stem loop plasmid was modestly increased over control EVs from untransfected J558L cells. In contrast, miR-335 abundance in iEVs-335 produced by J558L cells carrying a pre-miR-335 doublet showed a nearly ~250 fold over that of cells transfected with the singlet (Fig. 1C ). Therefore, all subsequent experiments were performed using a pCMVmir carrying two pre-miR-335 stem loops. The iEVs were characterized as having an average size of 100 nm (Supplementary Fig. 1A ) and expressing CD63 and CD81 (Supplementary Fig. 1B). Negative staining by electron microscopy shows iEVs to be circular structures of ~ 100 nm diameter with a homogeneous cavity (Fig. 1D ). Because of these features iEVs have exosome like characteristics 16 . Figure 1 Experimental model and cartoon of dual miR-335 plasmid. ( A ) Schematic of experimental model involving the transfection of murine J558L B cells with pCMVmir.335, the production of induced extracellular vesicles (iEVs), and subsequent treatment on LM2 cells. ( B ) Schematic diagram of tandem hsa-mir335 stem (pre-miR) loops with an intervening spacer sequence. ( C ) Differential abundance of miR-335 in iEVs from J558L cells transfected with pCMVmir.335 containing a single or dual pre-miR-335 sequence, respectively. 10 6 J558L cells were transfected with 1 µg of plasmid DNA, and the supernatant was collected 48 hrs later. iEVs were isolated by precipitation, counted and analyzed (10 6 ) by RT-qPCR amplification using RT-specific primers for miR-335 and SnoRNA202 as a control. RQ (Relative Quantity). Results refer to the mean ± SD of a representative experiment out of three independent experiments. ( D ) Negative staining electron micrographs of iEVs-335. Magnification: Inset (6800x), Main frame 9300x. Full size image Effects of iEVs containing miR-335 on LM2 cells in vitro To establish the minimum threshold for effective miR-335 restoration in target LM2 cells, we quantified miR-335 content in LM2 cells incubated in vitro for 48 hrs with iEVs-335 over a range of iEVs:LM2 cell ratios (4 × 10 2 –10 4 iEVs: LM2 cell). The miR-335 copy number increased in a dose dependent manner, with a > 4 fold increase over untreated LM2 cells at the", "role": "user" }, { "content": "Cancer immunotherapy—efforts to better arm a patient's own immune system to attack tumors—has shown great potential for treating some cancers. Yet immunotherapy doesn't work for everyone, and some types of treatment can cause serious side effects. In a new approach, researchers at University of California San Diego School of Medicine are turning B cells, best known for producing antibodies, into factories that assemble and secrete vesicles or sacs containing microRNAs. Once internalized by cancer cells, these small pieces of genetic material dampen a gene that spurs tumor growth. In mice, breast tumors treated with this approach were fewer and significantly smaller than in untreated tumors. The study is published in the December 4 issue of Scientific Reports. \"Once further developed, we envision this method could be used in situations where other forms of immunotherapy don't work,\" said senior author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center. \"The advantages are that this type of treatment is localized, meaning potentially fewer side effects. It's long-lasting, so a patient might not need frequent injections or infusions. And it would likely work against a number of different tumor types, including breast cancer, ovarian cancer, gastric cancer, pancreatic cancer and hepatocellular carcinoma.\" MicroRNAs don't encode proteins. Instead, microRNAs bind messenger RNAs that do encode proteins, inhibiting their translation or hastening their degradation. Normal cells use microRNAs to help fine-tune which genes are dialed up or down at different times. MicroRNAs tend to be less active in cancer cells, which can allow growth-related proteins to run wild. In this study, Zanetti and team used miR-335, a microRNA that specifically dampens SOX4, a transcription factor that promotes tumor growth. They added a miR-335 precursor to B cells in the lab. Once inside, through a naturally occurring process, the cells convert the precursor into mature, active miR-335 and package it into vesicles, small, membrane-coated sacs that bud off from the cell. Each B cell can produce 100,000 miR-335-containing vesicles per day—enough to treat 10 cancer cells. To test this new system, the researchers treated human breast cancer cells with miR-335-containing vesicles or sham vesicles in the lab. Then they transplanted the cancer cells to mice. After 60 days, 100 percent (5/5) of the mice with mock-treated cancer cells had large tumors. In contrast, 44 percent (4/9) of the mice with miR-335 vesicle-treated cancer cells had tumors. On average, the tumors in the treated mice were more than 260 times smaller than those in the mock-treated mice (7.2 vs. 1,896 mm3). And the treatment was long-lasting—miR-335 levels were still elevated in the treated mice 60 days after the vesicles and cancer cells were transplanted. \"We were surprised to find that even small changes in cancer cell gene expression after miR-335 treatment were associated with specific down-regulation of molecules key to tumor growth,\" said study co-author Hannah Carter, Ph.D., assistant professor of medicine at UC San Diego School of Medicine. Other research groups and pharmaceutical companies are using tumor suppressor microRNAs therapeutically. What's new here, said researchers, is the method for producing and delivering them. According to Zanetti, this therapy could be developed in two ways. First, by first harvesting vesicles from B cells in a lab, then administering only the vesicles, as they did here, or second, by administering the B cells themselves. He says the challenge now will be to develop ways to ensure the B cells or vesicles get as close to a tumor as possible. This would be easier in some types of cancer, where the tumor is readily accessible by injection. But many cancers are difficult to access. Zanetti and colleagues are currently working to improve the delivery system, maximize efficiency and diminish side effects. \"Ideally, in the future we could test patients to see if they carry a deficiency in miR-335 and have an overabundance of SOX4,\" Zanetti said. \"Then we'd treat only those patients, cases where we know the treatment would most likely work. That's what we call personalized, or precision, medicine. We could also apply this technique to other microRNAs with other targets in cancer cells and in other cell types that surround and enable tumors.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes. Main Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer risk in more than 150 genomic regions 1 , 2 . However, the variants and genes driving these associations are mostly unknown, with fewer than 20 regions studied in detail 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Here, we aimed to fine-map all known breast cancer susceptibility regions using dense genotype data on >217,000 subjects participating in the Breast Cancer Association Consortium (BCAC) and the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). All samples were genotyped using the OncoArray 1 , 2 , 21 or the iCOGS chip 22 , 23 . Stepwise multinomial logistic regression was used to identify independent association signals in each region and to define credible causal variants (CCVs) within each signal. We found genomic features significantly overlapping the CCVs. We then used a Bayesian approach, integrating genomic features and genetic associations, to refine the set of likely causal variants and calculate their posterior probabilities. Finally, we integrated genetic and in silico epigenetic expression and chromatin conformation data to infer the likely target genes of each signal. Results Most breast cancer genomic regions contain multiple independent risk-associated signals We included 109,900 cases of breast cancer and 88,937 controls, all of European ancestry, from 75 studies in the BCAC. Genotypes (directly observed or imputed) were available for 639,118 single nucleotide polymorphisms (SNPs), deletions/insertions and copy number variants (CNVs) with a minor allele frequency (MAF) ≥ 0.1% within 152 previously defined, risk-associated regions (Supplementary Table 1 and Fig. 1 ). Multivariate logistic regression confirmed associations for 150 out of 152 regions at a significance threshold of P < 10 −4 (Supplementary Table 2a ). To determine the number of independent risk signals within each region, we applied stepwise multinomial logistic regression, deriving the association of each variant, conditional on the more significant ones, in order of statistical significance. Finally, we defined CCVs in each signal as variants with conditional P values within two orders of magnitude of the index variant 24 . We classified the evidence for each independent signal, and its CCVs, as either strong (conditional P < 10 −6 ) or moderate (10 −6 < conditional P < 10 −4 ). Fig. 1: Flowchart summarizing the study design. Logistic regression summary statistics were used to select the final set of variants to run stepwise multinomial regression. These results were meta-analyzed with CIMBA to provide the final set of strong independent signals and their CCVs. Through case-only analysis, we identified significant differences in effect sizes between ER-positive and ER-negative breast cancer and used this to classify the phenotype for each independent signal. With these strong CCVs, we ran the bio-features enrichment analysis, which identified the features to be included in the PAINTOR models, together with the OncoArray logistic regression summary statistics and the OncoArray linkage disequilibrium. Both multinomial regression CCVs and PAINTOR high-posterior-probability (PP) variants were analyzed with INQUISIT to determine high-confidence target genes. Finally, we used the set of high-confidence target genes to identify enriched pathways. iCOGS and OncoArray Cox regression was conditional on the index variants from BCAC strong signals. Full size image From the 150 genomic regions, we identified 352 independent risk signals containing 13,367 CCVs, 7,394 of which were within the 196 strong-evidence signals across 129 regions (Fig. 2a,b ). The number of signals per region ranged from 1 to 11, with 79 (53%) containing multiple signals. We noted a wide range of CCVs per signal, but in 42 signals there was only a single CCV: for these signals, the simplest hypothesis is that the CCV was causal (Fig. 2c,d and Table 1 ). Furthermore, within signals with few CCVs (<10), the mean scaled combined annotation-dependent depletion score was higher than in signals with more CCVs (13.1 versus 6.7 for CCVs in exons; P t -test = 2.7 × 10 −4 ), suggesting that these are more likely to be functional. Fig. 2: Determining independent risk signals and CCVs. a , Number of independent signals per region, identified through multinomial stepwise logistic regression. b , Signal classification as strong- or moderate-confidence signals. c , d , Number of CCVs per signal in strong- ( c ) and moderate-confidence signals ( d ), identified through multinomial stepwise logistic regression. e , Subtype classification of strong signals into ER positive, ER negative and signals equally associated with both phenotypes (ER neutral) from the BCAC analysis. f , Subtype classification from the meta-analysis of BCAC and CIMBA. Numbers in brackets show the numbers of CCVs from the meta-analysis of BCAC and CIMBA. g , Number of variants at different posterior probability thresholds. In total, 15 variants reached a posterior probability of ≥80% by at least one of the three models (ER all, ER positive or ER negative). Full size image Table 1 Signals with single CCVs and variants with a posterior probability of >80% Full size table The majority of breast tumors", "role": "user" }, { "content": "A major international study of the genetics of breast cancer has identified more than 350 DNA 'errors' that increase an individual's risk of developing the disease. The scientists involved say these errors may influence as many as 190 genes. The results, published today in the journal Nature Genetics, provide the most comprehensive map of breast cancer risk variants to date. The researchers involved, from over 450 departments and institutions worldwide, say the findings will help provide the most detailed picture yet of how differences in our DNA put some women at greater risk than others of developing the disease. The majority of the DNA is identical between individuals, but there are some differences, known as genetic variants, and these changes can have a profound effect, increasing an individual's susceptibility to disease. Our DNA—the blueprint for the human body—contains between 20,000-25,000 genes. Many of these code for proteins, the building blocks that make up the human body. Genetic variants can be located within genes, altering the protein. However, most of genetic variants are located outside genes, sometimes regulating the function of genes, turning their 'volume' up or down or even off. Finding which gene is targeted by these variants is not straightforward. Most diseases are complex, polygenetic diseases—in other words, no single genetic variant or gene causes the disease, but rather the combination of a number of them act together to increase the likelihood that an individual will develop a particular disease. Breast cancer is one such disease. Previous genome-wide association studies (GWAS), which involve comparing the DNA of patients against that of healthy controls, have found around 150 regions of the genome that clearly affect breast cancer risk. Within these regions, researchers know there are one or more genetic changes that affect the risk of developing cancer, but rarely are they able to pinpoint the specific variants or genes involved. Fine-mapping studies, such as this one, allow scientists to narrow down which variants contributing to the disease, how they might work and predict which are the genes involved. \"We know from previous studies that variants across our DNA contribute towards breast cancer risk, but only rarely have scientists have been able to identify exactly which genes are involved,\" said Dr. Laura Fachal from the Wellcome Sanger Institute. \"We need this information as it gives us a better clue to what is driving the disease and hence how we might treat or even prevent it.\" In this new study, researchers from hundreds of institutions worldwide collaborated to compare the DNA of 110,000 breast cancer patients against that of some 90,000 healthy controls. By looking in much closer detail than was previously possibly, they identified 352 risk variants. It is not yet clear exactly how many genes these target, but the researchers have identified 191 genes with reasonable confidence; less than one in five of these had been previously recognised. \"This incredible haul of newly-discovered breast cancer genes provides us with many more genes to work on, most of which have not been studied before,\" said Dr. Alison Dunning from the University of Cambridge. \"It will help us build up a much more detailed picture of how breast cancer arises and develops. But the sheer number of genes now known to play a role emphasises how complex the disease is.\" Of the newly-discovered genetic variants, a third predispose women towards developing hormone-responsive breast cancer, the type of disease found in four out of five breast cancer patients, which respond to hormonal treatments such as tamoxifen. 15% of the genetic variants predispose women to the rarer type, estrogen-receptor-negative breast cancer. The remaining genetic variants play a role in both types of breast cancer. In the majority of cases, the genetic change affected gene expression—in other words, how active a particular gene was and how much of a particular protein it created—rather than altering the type of protein itself. For instance, nine different variants regulate the same gene, the Estrogen Receptor (ESR1) gene. Many other variants affect places in the DNA where the Estrogen Receptor protein binds, and, in turn regulates other genes. This highlights the importance of the ESR1 gene and its protein product, the Estrogen Receptor, in breast cancer development. While each genetic variant only increases the risk of developing breast cancer by a very small amount, the researchers say that added together, these will allow them to 'fine tune' genetic testing and give women a much clearer picture of their genetic risk. This will then allow doctors and clinicians to provide advice on the best strategy for reducing their risk and preventing onset of the disease. Professor Doug Easton, also from the University of Cambridge, said: \"Our work would not have been possible without the help of the 200,000 volunteers who allowed us to study their DNA. It is also testament to the work of hundreds of researchers from all over the world who collaborated on this study.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The spin-transfer nano-oscillator (STNO) offers the possibility of using the transfer of spin angular momentum via spin-polarized currents to generate microwave signals. However, at present STNO microwave emission mainly relies on both large drive currents and external magnetic fields. These issues hinder the implementation of STNOs for practical applications in terms of power dissipation and size. Here, we report microwave measurements on STNOs built with MgO-based magnetic tunnel junctions having a planar polarizer and a perpendicular free layer, where microwave emission with large output power, excited at ultralow current densities and in the absence of any bias magnetic fields is observed. The measured critical current density is over one order of magnitude smaller than previously reported. These results suggest the possibility of improved integration of STNOs with complementary metal-oxide-semiconductor technology and could represent a new route for the development of the next-generation of on-chip oscillators. Introduction Oscillators are basic components of many communication, navigation and measurement systems. They provide a periodic output that can be used to generate electromagnetic energy for radiation, for high speed digital systems, clocking functions and to enable frequency up and down conversion if used as a local oscillator in communication circuits and for many other applications. There is a strong interest, driven by cost and performance, to develop improved microwave oscillators for on-chip integration and the spin-transfer nano-oscillator (STNO) is a promising candidate for this due to its combination of characteristics such as frequency tunability, nanoscale size, broad range of working temperature and relatively easy integration with complementary metal-oxide-semiconductor (CMOS) technology 1 , 2 , 3 , 4 , 5 , 6 , 7 . The STNO is not only one of the more complex non-linear dynamical systems (of great interest from fundamental point of view), but it is also important being one of the smallest auto-oscillators known in nature (hence of great interest from technological point of view). The remaining challenges that need to be addressed are the simultaneous optimization of a variety of properties, including high frequency operation, frequency tunability, narrow spectral linewidth, large output power and operation in both absence of external magnetic fields and with low applied current densities. Here, we demonstrate that the interfacial perpendicular anisotropy (IPA) between the ferromagnetic electrodes and the tunnel barrier of magnetic tunnel junctions (MTJs) employing the material combination of CoFeB/MgO is a key ingredient to improve the dynamic properties of STNOs 8 . In general, IPA can be used for the design of high efficiency spintronic devices. It permits the realization of MTJs for storage applications with high thermal stability and low switching current 8 , 9 and STNOs with very large emitted power ( i.e. > 0.95 μW delivered to a matched load) 10 . In previous studies, IPA was used to orient the magnetization of both the free and polarizer layers out of the film plane 8 , or to reduce the out-of-plane demagnetizing field ( H d ) while maintaining the orientation of both of the two magnetizations in the film plane 10 . In this work, we designed STNOs with an asymmetric MTJ consisting of an in-plane polarizer and a perpendicular free layer achieved by controlling the trade-off between IPA and H d . This orthogonal magnetic configuration is different from the one in our previous study 10 and is more efficient in order to excite large angle free layer precession (large output power) in absence of a bias magnetic field. The main objective of our experiment is to solve the key technological issues related to the integration of STNOs with CMOS technology: elimination of the need for an external magnetic bias field and reduction of drive current densities. The former goal will allow for eliminating the current lines necessary to create the magnetic field for the STNO biasing, while the latter is necessary to reduce the size of the current driving transistors (small currents allow for smaller transistors, hence making the overall oscillator smaller. For high-current oscillators, the actual size of the oscillator would be determined by the transistor size, rather than by the MTJ) and to control power dissipation. Results Spin-transfer torque oscillator The samples studied have a core magnetic stack consisting of a synthetic antiferromagnet (SAF) Co 70 Fe 30 /Ru/Co 40 Fe 40 B 20 layer and a Co 20 Fe 60 B 20 free layer (FL) separated by a MgO insulator as shown in Fig. 1a . We introduce a Cartesian coordinate system where the x-axis is the direction of the polarizer (+x), the y-axis and the z-axis are the hard in-plane and the out-of-plane axes respectively. The SAF layer is designed to have an in-plane easy axis 9 , 10 serving as a polarizer, while the Fe-rich Co 20 Fe 60 B 20 FL with a thickness of t = 1.60 ~ 1.62 nm was chosen to achieve the proper IPA, which favors the out-of-plane (perpendicular) magnetic configuration in the free layer (see Methods). Electron-beam lithography and ion milling were used to define and etch the MTJs resulting in pillar-shaped devices with nominal dimensions of 150 nm × 70 nm. The samples are different from the 50–70 nm diameter point contact spin valves with out-of-plane magnetized CoNi free layers studied in refs. 11 , 12 . A d.c. bias current is injected into the sample through a bias Tee as shown in the measurement setup in our previous work 10 , where we define the positive current I as electrons flowing from the polarizer to the free layer. A time-varying voltage produced by the oscillations of the magnetization via the tunneling magnetoresistance (TMR) effect is recorded using a 9 kHz–26.5 GHz spectrum analyzer. The measurements were carried out at room temperature. We show detailed data from a single device with free layer thickness t = 1.60 nm, however similar results have been achieved for more than 5 devices for each free layer thickness. Figure 1 Sample structure and properties. (a) Schematic of the sample layer structure consisting of an in-plane magnetized fixed (polarizer)", "role": "user" }, { "content": "By using improved magnetic materials, based on the control of interface properties of ultra-thin magnetic films, researchers from the Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences (SINANO), the University of California at Los Angeles(UCLA), and the University of Messinahave made major experimental improvements to develop a more compact, more energy-efficient generation of a mobile communication device known as spin transfer nano-oscillator (STNO). STNOs use the spin of electrons to create steady microwave oscillations needed for various applications in mobile communications, unlike current silicon-based oscillators which use their charge. The SINANO team's improved oscillator has great potential to be used in future portable electronic devices and wireless modules, systems on a chip, and for power-efficient local clock signal generation in digital systems. The STNOs are composed of two distinct magnetic layers. One layer has a fixed magnetic polar direction, while the other layer's magnetic direction can be manipulated to gyrate by passing an electric current through it. This allows the structure to produce very precise oscillating microwaves. The STNO's key advantage over existing technologies is that it can combine large tunability and low energy with nanoscale size, as well as broad working temperature ranges. Yet while STNOs are potentially superior in many respects to existing microwave oscillator technologies, their microwave signals mainly rely on both large drive currents and the application of external magnetic fields, which hinders the implementation of STNOs for practical applications in terms of power dissipation and size. By using magnetic layers with perpendicular magnetic anisotropy– similar to those used in spin-transfer torque memory – the SINANO team demonstrated large microwave signals at ultralow current densities (<5.4×105A/cm2) and in the absence of any bias magnetic fields. This eliminates the need to move large numbers of electrons through wires, and also eliminates the need for permanent magnets or conducting coils to provide the bias magnetic field, thus significantly saving both energy and space. The results are microwave oscillators that generate much less heat due to their lower current, making them more energy-efficient. \"Previously, there had been no demonstration of a spin-transfer oscillator with sufficiently high output power, low drive current density, and simultaneously without the need for an external magnetic field, hence preventing practical applications,\" said the lead researcher ZENG Zhongming, SINANO professor at the SINANO Nanofabrication Facility. \"We have realized all these requirements in a single device.\" \"The ability to excite microwave signals at ultralow current density and in zero magnetic field is exciting in nano-magnetism. This work presents a new route for the development of the next-generation of on-chip oscillators.\" said co-author G. Finocchio, who is an assistant professor at the University of Messina, Italy. \"Ultra-low-power spintronic devices have the potential to transform the electronics industry, with the most immediate example being in the area of nonvolatile magnetic memory (MRAM). This work shows that similar materials and devices may also bring nanoscale spintronic oscillators one step closer to reality,\" said Pedram Khalili, a research associate and program manager at UCLA and co-author of the paper. \"Thesedevices can be integrated with standard CMOS logic manufacturing processes, enabling a wide range of products from standalone memory and microwave components to systems on a chip.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Complex networks emerging in natural and human-made systems tend to assume small-world structure. Is there a common mechanism underlying their self-organisation? Our computational simulations show that network diffusion (traffic flow or information transfer) steers network evolution towards emergence of complex network structures. The emergence is effectuated through adaptive rewiring: progressive adaptation of structure to use, creating short-cuts where network diffusion is intensive while annihilating underused connections. With adaptive rewiring as the engine of universal small-worldness, overall diffusion rate tunes the systems’ adaptation, biasing local or global connectivity patterns. Whereas the former leads to modularity, the latter provides a preferential attachment regime. As the latter sets in, the resulting small-world structures undergo a critical shift from modular (decentralised) to centralised ones. At the transition point, network structure is hierarchical, balancing modularity and centrality - a characteristic feature found in, for instance, the human brain. Introduction Complex network structures emerge in protein 1 and ecological networks 2 , social networks 3 , the mammalian brain 4 , 5 , 6 , and the World Wide Web 7 . All these self-organising systems tend to assume small–world network (SWN) structure. SWNs may represent an optimum in that they uniquely combine the advantageous properties of clustering and connectedness that characterise, respectively, regular and random networks 8 . Optimality would explain the ubiquity of SWN structure; it does not inform us, however, whether the processes leading to it have anything in common. Here we will consider whether a single mechanism exists that has SWN structure as a universal outcome of self-organisation. In the classic Watts and Strogatz algorithm 9 , a SWN is obtained by randomly rewiring a certain proportion of edges of an initially regular network. Thereby the network largely maintains the regular clustering, while the rewiring creates shortcuts that enhance the networks connectedness. As it shows how these properties are reconciled in a very basic manner, the Watts-Strogatz rewiring algorithm has a justifiable claim to universality. However, the rewiring compromises existing order than to rather develop over time and maintain an adaptive process. Therefore the algorithm is not easily fitted to self-organising systems. In self-organising systems, we propose, network structure adapts to use - the way pedestrians define walkways in parks. Accordingly, we consider the effect of adaptive rewiring: creating shortcuts where network diffusion (traffic flow or information transfer) is intensive while annihilating underused connections. This study generalises previous work on adaptive rewiring 10 , 11 , 12 , 13 , 14 . While these studies have shown that SWN robustly emerge through rewiring according to the ongoing dynamics on the network, the claim to universality has been frustrated by need to explicitly specify the dynamics. Here we take a more general approach and replace explicit dynamics with an abstract representation of network diffusion. Heat kernels 15 capture network-specific interaction between vertices and as such they are, for the purpose of this article, a generic model of network diffusion. We study how initially random networks evolve into complex structures in response to adaptive rewiring. Rewiring is performed in adaptation to network diffusion, as represented by the heat kernel. We systematically consider different proportions of adaptive and random rewirings. In contrast with the random rewirings in the Watts-Strogatz algorithm, here, they have the function of perturbing possible equilibrium network states, akin to the Boltzmann machine 16 . In this sense, the perturbed system can be regarded as an open system according to the criteria of thermodynamics. In adaptive networks, changes to the structure generally occur at a slower rate than the network dynamics. Here, the proportion of these two rates is expressed by what we call the diffusion rate (the elapsed forward time in the network diffusion process before changes in the network structure). Low diffusion rates bias adaptive rewiring to local connectivity structures; high diffusion rates to global structures. In the latter case adaptive rewiring approaches a process of preferential attachment 17 , 18 . We will show that with progressive adaptive rewiring, SWNs always emerge from initially random networks for all nonzero diffusion rates and for almost any proportion of adaptive rewirings. Depending on diffusion rate, modular or centralised SWN structures emerge. Moreover, at the critical point of phase transition, there exists a network structure in which the two opposing properties of modularity and centrality are balanced. This characteristic is observed, for instance, in the human brain 19 , 20 , 21 . We call such a structure hierarchical. In sum, adaptation to network diffusion represents a universal mechanism for the self–organisation of a family of SWNs, including modular, centralised, and hierarchical ones. Results For each pair ( τ , p ), where τ is a heat kernel parameter, and p is the rewiring probability, 100 independently evolved networks are obtained by our adaptive rewiring algorithm (see Methods). Resulting networks are described according to measures of small-world structure, modularity, and centrality. Where appropriate, the average of such measures is taken. Small-World Structure The small-worldness index S provides a canonical measure of the degree to which a network is small-world. Here, we take a slightly modified version, in which the normalised clustering coefficient ( C ) is multiplied by the normalised global efficiency ( E ) 8 , such that S = ( C / C r ) × ( E / E r ), where C r and E r are measures of C and E for an equivalent Erdös-Rényi (ER) random network 22 . In doing so, S is also defined on disconnected networks. For random networks, S ≈ 1 and so the greater the (positive) deviation of S from one, the greater the degree of small-worldness. For comparison, we include the average small-worldness values for networks constructed by the Watts-Strogatz algorithm (100 independently constructed networks for each p = 0, 1/500, 2/500, …, 1). In Fig. 1a we observe the average small-worldness index S as a function of random rewiring probability p . Unless stated otherwise, we consider networks arising from adaptive rewiring for random rewiring probability p ∈", "role": "user" }, { "content": "It's a small world after all - and now science has explained why. A study conducted by the University of Leicester and KU Leuven, Belgium, examined how small worlds emerge spontaneously in all kinds of networks, including neuronal and social networks, giving rise to the well-known phenomenon of \"six degrees of separation\". Many systems show complex structures, of which a distinctive feature is small-world network organization. They arise in society as well as ecological and protein networks, the networks of the mammalian brain, and even human-built networks such as the Boston subway and the World Wide Web. The researchers set out to examine whether this is a coincidence that such structures are so wide-spread or is there a common mechanism driving their emergence? A study recently published in Scientific Reports by an international team of academics from the University of Leicester and KU Leuven showed that these remarkable structures are reached and maintained by the network diffusion, i.e. the traffic flow or information transfer occurring on the network. The research presents a solution to the long-standing question of why the vast majority of networks around us (WWW, brain, roads, power grid infrastructure) might have a peculiar yet common structure: small-world topology. The study showed that these structures emerge naturally in systems in which the information flow is accounted for in their evolution. Nicholas Jarman, who recently completed his PhD degree at the Department of Mathematics, and is first author of the study, said: \"Algorithms that lead to small-world networks have been known in scientific community for many decades. The Watts-Strogatz algorithm is a good example. The Watts-Strogatz algorithm, however, was never meant to address the problem of how small-world structure emerges through self-organisation. The algorithm just modifies a network that is already highly organised.\" Professor Cees van Leeuwen, who led the research at KU Leuven said: \"The network diffusion steers network evolution towards emergence of complex network structures. The emergence is effectuated through adaptive rewiring: progressive adaptation of structure to use, creating short-cuts where network diffusion is intensive while annihilating underused connections. The product of diffusion and adaptive rewiring is universally a small-world structure. The overall diffusion rate controls the system's adaptation, biasing local or global connectivity patterns, the latter providing a preferential attachment regime to adaptive rewiring. The resulting small-world structures shift accordingly between decentralised (modular) and centralised ones. At their critical transition, network structure is hierarchical, balancing modularity and centrality - a characteristic feature found in, for instance, the human brain.\" Dr Ivan Tyukin from the University of Leicester added: \"The fact that diffusion over network graph plays crucial role in keeping the system at a somewhat homeostatic equilibrium is particularly interesting. Here we were able to show that it is the diffusion process, however small or big gives rise to small-world network configurations that remain in this peculiar state over long intervals of time. At least as long as we were able to monitor the network development and continuous evolution\". Alexander Gorban, Professor in Applied Mathematics, University of Leicester commented: \"Small-world networks, in which most nodes are not neighbours of one another, but most nodes can be reached from every other node by a small number of steps, were described in mathematics and discovered in nature and human society long ago, in the middle of the previous century. The question, how these networks are developing by nature and society remained not completely solved despite of many efforts applied during last twenty years. The work of N. Jarman with co-authors discovers a new and realistic mechanism of emergence of such networks. The answer to the old question became much clearer! I am glad that the University of Leicester is a part of this exciting research.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genetic defects in myelin formation and maintenance cause leukodystrophies, a group of white matter diseases whose mechanistic underpinnings are poorly understood 1 , 2 . Hypomyelination and congenital cataract (HCC), one of these disorders, is caused by mutations in FAM126A , a gene of unknown function 3 . We show that FAM126A, also known as hyccin, regulates the synthesis of phosphatidylinositol 4-phosphate (PtdIns(4)P), a determinant of plasma membrane identity 4 , 5 , 6 . HCC patient fibroblasts exhibit reduced PtdIns(4)P levels. FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIα and its adaptors TTC7 and EFR3 (refs 5 , 7 ). A FAM126A–TTC7 co-crystal structure reveals an all-α-helical heterodimer with a large protein–protein interface and a conserved surface that may mediate binding to PI4KIIIα. Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts. We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides 8 , 9 , 10 , 11 . Our results point to a role for FAM126A in supporting myelination, an important process in development and also following acute exacerbations in multiple sclerosis 12 , 13 , 14 . Main Phosphoinositides are low-abundance anionic membrane phospholipids that play critical roles in many physiological processes 15 , 16 . At the plasma membrane, a major phosphoinositide is PtdIns(4)P, which has direct signalling roles and in addition serves as the precursor of two other plasma membrane-enriched phosphoinositides with major signalling functions in this membrane, PtdIns(4,5)P 2 and PtdIns(3,4,5)P 3 (refs 4 , 17 ). In oligodendrocytes and Schwann cells, these lipids regulate several steps in the biogenesis and maintenance of myelin, including the recruitment of myelin basic protein (MBP) to the plasma membrane by PtdIns(4,5)P 2 and the promotion of myelin growth by PtdIns(3,4,5)P 3 (refs 8 , 9 , 10 , 11 ). Phosphorylation of phosphatidylinositol (PtdIns) to generate PtdIns(4)P at the plasma membrane is mediated by PtdIns 4-kinase Type IIIα (PI4KIIIα; Stt4 in yeast) 5 , 18 , 19 . The properties, targeting mechanisms and regulation of this enzyme have only recently come into focus. Two factors required for its localization at the plasma membrane have been described 5 , 7 and structurally characterized 20 : EFR3 and TTC7 (Efr3 and Ypp1 in yeast). To identify additional regulators of PI4KIIIα, we used quantitative interaction proteomics. We immunoprecipitated either stably expressed TTC7B–GFP or GFP, followed by protease digestion and mass spectrometry analysis, to identify candidate TTC7B-binding proteins ( Fig. 1a and Supplementary Table 1 ). These experiments identified the known TTC7B interaction partners PI4KIIIα, EFR3A and EFR3B. Among the other hits, two of the most significantly enriched candidates were the paralogous FAM126A, also known as hyccin, and FAM126B, both of which were also identified in similar experiments using EFR3A–GFP or EFR3B–GFP as the bait ( Supplementary Fig. 1a ). Figure 1: FAM126 is a component of the PI4KIIIα complex. ( a ) Volcano plots of proteins associating with TTC7B–GFP versus GFP alone (top) and FAM126A–GFP versus GFP alone (bottom), from a label-free proteomics analysis of anti-GFP immunoprecipitates of HEK 293T cells stably expressing TTC7B–GFP, FAM126A–GFP or GFP alone. The logarithmic ratios of protein intensities are plotted against negative logarithmic P values of two-tailed Student’s t -test, equal variance, performed from n = 3 independent experiments. The red dashed line (significance, 0.05) separates specifically interacting proteins (top right portion of plot) from background. Selected top hits are indicated with black dots (bait is indicated in green), and all specific interactors are reported in Supplementary Table 1 . ( b ) Immunoblot analysis of PI4KIIIα complex components in anti-GFP immunoprecipitates of HEK 293T cells stably expressing TTC7B–GFP (top), FAM126A–GFP (bottom) or GFP alone. ( c ) Domain structure, evolutionary conservation and predicted extent of disordered secondary structural elements of FAM126. ( d ) Immunoblot analysis of anti-GFP immunoprecipitates from HeLa cells transfected with 3xFLAG–PI4KIIIα, TTC7B–MYC, EFR3B–HA, and the indicated GFP-tagged construct. Arrows denote specific bands and arrowheads denote nonspecific antibody bands. Unprocessed original scans of blots are shown in Supplementary Fig. 6. Full size image Mutations in FAM126A that lead to loss of the FAM126A protein cause a recessive leukoencephalopathy termed hypomyelination and congenital cataract 3 (HCC). Manifestations of this condition, which include progressive neurological impairment, mild to moderate cognitive defects, and peripheral neuropathy, stem from hypomyelination in the central and peripheral nervous systems 3 , 21 , 22 . No molecular functions or activities have been ascribed to FAM126A, and the cellular and molecular mechanisms of HCC pathogenesis are unknown. Thus, the identification of FAM126A as a potential interaction partner of TTC7 and EFR3 led us to investigate its role in PI4KIIIα complex formation and function as a first step towards understanding whether defects in phosphoinositide metabolism may cause HCC pathology. We first explored and confirmed the interaction of FAM126A with TTC7, and more generally its association with the PI4KIIIα complex, in co-immunoprecipitation/immunoblot experiments ( Fig. 1b ). Two FAM126A immunoreactive species (relative molecular masses of 58,000 ( M r 58K) and 47,000 ( M r 47K)) were enriched in TTC7B–GFP immunoprecipitates, corresponding to two predicted splice forms of FAM126A ( Supplementary Fig. 1b ). Accordingly, these two bands are absent in tissues from FAM126A knockout (KO) mice ( Supplementary Fig. 1c ). Given that the longer, M r 58K band represents the main form in mammalian brain ( Supplementary Fig. 1d ), we chose to focus on it in our subsequent studies. We then performed a reciprocal proteomics experiment using FAM126A–GFP-expressing cells to assess whether PI4KIIIα, TTC7 and EFR3 are the main interaction partners of FAM126A. Indeed, all of these proteins were the strongest hits in analogous quantitative proteomics experiments ( Fig. 1a and Supplementary Table 1 ) and were highly enriched in immunoblot analysis of FAM126A–GFP immunoprecipitates ( Fig. 1b ). Examination of the primary amino acid sequence of FAM126A revealed a", "role": "user" }, { "content": "An inherited disease of myelin marked by slow, progressive neurological impairment is caused by mutations of a gene that controls lipid metabolism, a finding that may shed insight into mechanisms to control the course of multiple sclerosis (MS), a Yale team has found. Mutations in a single gene, called FAM126A, causes a panoply of pathologies, such as developmental delay, intellectual disability, peripheral neuropathy, and muscle wasting, in addition to congenital cataracts. Until now the precise function of the gene was unknown. The labs of Yale cell biologists Pietro De Camilli and Karin Reinisch found that the protein encoded by the gene, called hyccin, helps produce a lipid crucial to formation of the myelin sheaths that surround and protect the axons of neurons throughout the nervous system. Their labs, working with other groups in the United States, Italy, and Germany, analyzed cells from patients suffering from the disease known as Hypomyelination and Congenital Cataract and found that FAM126A mutations results in the destabilization of an enzyme complex crucial to production of myelin. In MS, the course of the disease is critically dependent upon the reformation of myelin sheaths after immune system attacks then destroys them, eventually leading to the death of the neurons. The researchers hypothesize that the lipid that hyccin helps generate may play a key role in creation of myelin sheaths in normal development as well as in recovering MS patients. Postdoc Jeremy Baskin (now at Cornell) and graduate student Xudong Wu (now at Harvard) led the study in the De Camilli and Reinisch labs, respectively. The research was published Nov. 16 in the journal Nature Cell Biology. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The biosynthesis of natural products often requires eukaryotic cytochrome P450s (P450s) in combination with P450 reductase, in physical proximity, to perform electron-transfer reactions. Unfortunately, functional expression of eukaryotic P450s in bacteria remains generally difficult. Here we report an electron channelling strategy based on the application of Photorhabdus luminescens CipB scaffold protein, which allows efficient electron transfer between P450s and reductases by bringing these enzymes in close proximity. The general applicability of this electron channelling strategy is proved by developing recombinant Escherichia coli strains producing lutein, (+)-nootkatone, apigenin and l -3,4-dihydroxyphenylalanine ( l -DOPA), each of which requires P450s in its biosynthetic pathway. The production titres are then further enhanced by increasing the haem pathway flux or by optimization of the culture conditions. Remarkably, the final lutein strain produced 218.0 mg l −1 of lutein with a productivity of 5.01 mg l −1 h −1 in fed-batch fermentation under optimized culture conditions. Main Natural products have been widely used in the pharmaceutical, food, cosmetic and health industries because of their antioxidant, anti-tuberculosis, anti-inflammatory, anticancer and immunomodulatory properties 1 . Many functionally useful natural products are obtained by extraction from plants or animals, a process that is quite inefficient, with difficulties in separating target natural products from other similar metabolites 2 . Also, given the complex structures of these natural products, which feature an array of chiral or reactive functional groups, total chemical synthesis is rather difficult and costly. Such problems have motivated researchers to produce natural products by means of the fermentation of metabolically engineered microorganisms. Escherichia coli is considered to be one of the best host strains because of its high growth rate and the availability of various techniques for genetic manipulation and high cell-density culture 3 . Among many enzymes involved in the complex biosynthetic pathways of natural products, eukaryotic cytochrome P450s (P450s) are often critical enzymes in determining production efficiency, because they catalyse a range of reactions, including hydroxylation, dehydrogenation, isomerization and epoxidation. However, the expression of eukaryotic P450s in bacteria in functionally active forms has been a major challenge. In eukaryotes, membrane-associated P450s characteristically bind to the membranes of intracellular organelles, but these structures are uncommon in bacteria 4 . Furthermore, the physical distance between membrane-bound P450s and P450 reductase appears to be another critical factor in determining the reaction efficiency, because electrons generated by the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) need to be transferred from the P450 reductase to P450 4 . In a multi-step biosynthetic pathway involving competing reactions or toxic intermediates, the strategy of substrate channelling by tethering two or more enzymes in proximity has been useful in enhancing the overall reaction rates and rapidly converting metabolites to a desired product 5 , 6 , 7 . It was thus thought that electron channelling by tethering such enzymes involved in electron transfer may similarly allow more efficient electron transfers. In previous reports, electrons extracted from NADPH oxidation by P450 reductase may be immediately transferred to P450s when the enzymes are physically assembled. A recent report has highlighted the production of caffeic acid in E. coli by employing a heterotrimer-forming proliferating cell nuclear antigen scaffold system to tether bacterial P450, ferredoxin and ferredoxin reductase 8 , 9 . Another study has reported the genetic fusion of a bacterial P450 enzyme with a reductase to facilitate interaction between two enzymes 10 , 11 , 12 , 13 , 14 . These results also support the importance of an efficient electron-transfer mechanism during the production of natural products. In this Article, we describe how electron channelling is applied using the Photorhabdus luminescens CipB scaffold protein 5 , which has a relatively small size (11.29 kDa) and clusters to form a stable protein crystalline inclusion (PCI). The natural proclivity of CipB proteins to form scaffolds can be applied to assemble multiple enzymes into a functional PCI. We demonstrate the validity and universal applicability of this electron channelling strategy through four case studies, respectively producing lutein, (+)-nootkatone, apigenin and l -3,4-dihydroxyphenylalanine ( l -DOPA), all involving P450s in their biosynthetic pathways. The construction of the E. coli strains producing the four natural products is first described, followed by application of the electron channelling strategy to each strain to streamline the electron transfer between the P450s and their partner reductases. Further metabolic engineering and scale-up fermentation were also performed to increase the product titres. Results Construction of the lutein-producing E. coli strain Lutein is one of the xanthophylls that is naturally abundant in egg yolk, fruits and green leafy vegetables. Lutein exists in the macula lutea membranes of the human eye, protecting the eye against oxidative damage and excess radiation 15 . Intake of lutein reduces the risk or progression of some eye diseases, including age-related macular degeneration and cataracts 16 . It is these health benefits that has led to the increased demand for lutein. Accordingly, there has been much interest in developing metabolically engineered bacteria capable of efficiently producing lutein to replace the inefficient plant-based production system. We constructed the lutein biosynthetic pathway in E. coli , which can produce the building blocks of carotenoids—isopentenyl diphosphate (IPP) and dimethylallyl diphosphate—via the inherent 1-deoxy- d -xylulose 5-phosphate (DXP) pathway, and then convert them to farnesyl diphosphate by means of farnesyl diphosphate synthase. To complete the lutein biosynthetic pathway in E. coli , eight genes constituting the pathway from farnesyl diphosphate to lutein were introduced from heterologous hosts (Fig. 1 ). First, a biosynthetic pathway from farnesyl diphosphate to lycopene was established by employing Pantoea ananatis -derived crtE , crtB and crtI encoding geranylgeranyl pyrophosphate synthase, phytoene synthase and phytoene dehydrogenase, respectively (see Supplementary Note 1 for details of the cloning procedure). Next, a biosynthetic pathway from lycopene to lutein was established by employing the Arabidopsis thaliana -derived genes encoding lycopene ε-cyclase ( LUT2 ) 17 , lycopene β-cyclase ( LCYB ) 17 , β-carotene 3-hydroxylase ( LUT5 ) 18 , carotene ε-monooxygenase ( LUT1 ) 19 and P450 reductase 2 ( ATR2 ) 20 (Supplementary Note", "role": "user" }, { "content": "Lutein is classified as a xanthophyll chemical that is abundant in egg yolk, fruits, and vegetables. It protects the eye from oxidative damage from radiation and reduces the risk of eye diseases including macular degeneration and cataracts. Commercialized products featuring lutein are derived from the extracts of the marigold flower, which is known to harbor abundant amounts of lutein. However, the drawback of lutein production from nature is that it takes a long time to grow and harvest marigold flowers. Furthermore, it requires additional physical and chemical-based extractions with a low yield, which makes it economically unfeasible in terms of productivity. The high cost and low yield of these bioprocesses has made it difficult to readily meet the demand for lutein. These challenges inspired the metabolic engineers at KAIST, including researchers Dr. Seon Young Park, Ph.D. Candidate Hyunmin Eun, and Distinguished Professor Sang Yup Lee from the Department of Chemical and Biomolecular Engineering. The team's study was published in Nature Catalysis on August 5, 2022. This research details the ability to produce lutein from E. coli with a high yield using a cheap carbon source, glycerol, via systems metabolic engineering. The research group focused on solving the bottlenecks of the biosynthetic pathway for lutein production constructed within an individual cell. First, using systems metabolic engineering, which is an integrated technology to engineer the metabolism of a microorganism, lutein was produced when the lutein biosynthesis pathway was introduced, albeit in very small amounts. To improve the productivity of lutein production, the bottleneck enzymes within the metabolic pathway were first identified. It turned out that metabolic reactions that involve a promiscuous enzyme, an enzyme that is involved in two or more metabolic reactions, and electron-requiring cytochrome P450 enzymes are the main bottleneck steps of the pathway inhibiting lutein biosynthesis. To overcome these challenges, substrate channeling, a strategy to artificially recruit enzymes in physical proximity within the cell in order to increase the local concentrations of substrates that can be converted into products, was employed to channel more metabolic flux towards the target chemical while reducing the formation of unwanted byproducts. Furthermore, electron channeling, a strategy similar to substrate channeling but differing in terms of increasing the local concentrations of electrons required for oxidoreduction reactions mediated by P450 and its reductase partners, was applied to further streamline the metabolic flux towards lutein biosynthesis, which led to the highest titer of lutein production achieved in a bacterial host ever reported. The same electron channeling strategy was successfully applied for the production of other natural products including nootkatone and apigenin in E. coli, showcasing the general applicability of the strategy in the research field. \"It is expected that this microbial cell factory-based production of lutein will be able to replace the current plant extraction-based process,\" said Dr. Seon Young Park, the first author of the paper. She explained that another important point of the research is that integrated metabolic engineering strategies developed from this study can be generally applicable for the efficient production of other natural products useful as pharmaceuticals or nutraceuticals. \"As maintaining good health in an aging society is becoming increasingly important, we expect that the technology and strategies developed here will play pivotal roles in producing other valuable natural products of medical or nutritional importance,\" explained Distinguished Professor Sang Yup Lee. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Recurrence is frequent in pediatric ependymoma (EPN). Our longitudinal integrated analysis of 30 patient-matched repeated relapses (3.67 ± 1.76 times) over 13 years (5.8 ± 3.8) reveals stable molecular subtypes (RELA and PFA) and convergent DNA methylation reprogramming during serial relapses accompanied by increased orthotopic patient derived xenograft (PDX) (13/27) formation in the late recurrences. A set of differentially methylated CpGs (DMCs) and DNA methylation regions (DMRs) are found to persist in primary and relapse tumors (potential driver DMCs) and are acquired exclusively in the relapses (potential booster DMCs). Integrating with RNAseq reveals differentially expressed genes regulated by potential driver DMRs ( CACNA1H, SLC12A7, RARA in RELA and HSPB8, GMPR, ITGB4 in PFA) and potential booster DMRs ( PLEKHG1 in RELA and NOTCH, EPHA2, SUFU, FOXJ1 in PFA tumors). DMCs predicators of relapse are also identified in the primary tumors. This study provides a high-resolution epigenetic roadmap of serial EPN relapses and 13 orthotopic PDX models to facilitate biological and preclinical studies. Introduction Ependymoma (EPN) is the third most common malignant brain tumor of childhood, accounting for up to 12% of intracranial tumors in children. Current therapy includes maximal surgical resection and focal radiation, resulting in a 5-year overall survival (OS) and progression-free survival (PFS) of 70% and 57%, respectively 1 , 2 , 3 , 4 , 5 . However, nearly half of patients will experience late relapses 1 , 3 , 4 . Despite repeated treatment, most children with relapsed tumors eventually succumb to the disease. Ten-year OS and PFS decrease further to 50 ± 5% and 29 ± 5%, respectively 1 . The use of chemotherapeutic agents for EPN has been extensively studied for decades, however, survival benefit remains controversial 6 , 7 . In-depth understanding of the biology of EPN recurrence is needed. While it is well established that tumor location is important in EPN biology 8 , recent studies have shown that epigenetic changes mediated by DNA methylation play an important role in EPN tumorigenesis 9 , 10 , 11 as gene mutations in EPN are much less frequent than in adult cancers 9 , 10 , 11 . Indeed, non-mutational epigenetic reprogramming has recently been incorporated as an emerging hallmark of cancer 12 . Similar to several other types of pediatric cancers 13 , 14 , 15 , DNA methylation analysis has successfully subclassified pediatric EPNs into nine molecularly subgroups with distinct clinical outcomes 16 , 17 . Although oncogenic drivers have been identified for primary EPN 8 , 11 , 15 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , understanding of recurrent EPN biology is still at its infancy. One of the challenges is the difficulties of obtaining relapsed tumor tissues. Although longitudinal analysis of consecutive, serially relapsing patient tumor samples will enable the separation of serially conserved potential epigenetic driver(s) from transient alterations, it remains very difficult and requires a committed collaborative team of physicians, neuropathologist and tumor biologists. Using single recurrent EPN tumor with or without patient-matched primary tumors is a frequent approach. The second challenge lies in the reliable detection of subtle genetic/epigenetic changes. As a recent study revealed that morphological changes in recurrent EPNs was not sufficiently explained by epigenetic changes detected with 450k DNA methylation array 24 , improved DNA methylation site coverage combined with integrated analysis of gene expression patterns 9 , 10 , 25 , 26 , 27 , 28 should facilitate the discovery of genetic interactions and new therapeutic opportunities. A third challenge in studying EPN relapse is the limited availability of animal models. After the establishment of the first supratentorial EPN patient-derived orthotopic xenograft (PDOX, or orthotopic PDX) model by our group 29 , we and others have shown that direct implantation of patient tumors into the matching locations in mouse brains promoted the establishment of clinically relevant animal models that replicate histopathological features, invasive/metastasis phenotype and genetic profiles of the original patients 29 , 30 , 31 , 32 , 33 , 34 , 35 . While several genetically engineered animal models have been developed 22 , 23 , 36 , correlating tumorigenicity of patient EPN tumors during tumor progression, i.e., from diagnosis till consecutive, serial relapses of each patient, should serve as an in vivo functional assay to determine key tumorigenic drivers and identify druggable targets for EPN relapses. Here, we report a deep longitudinal analyses of DNA methylation landscape using single-base-resolution DNA methylome in a cohort of 30 patient-matched primary and serially relapsing EPN tumors together with integrated analysis of RNA-seq profiles and functional examination of PDOX tumorigenicity for this set of matched primary and relapsed EPNs. Our goal is to apply this integrated analyses and clinically relevant patient-matched PDOX mouse models from the same cohort of patients to identify the potential drivers of relapse (abnormal DNA methylation present in primary tumor and sustained in all relapsed EPNs), the potential boosters of relapse (DNA methylation newly acquired in relapsed tumors and persisted with tumor progression), and potential predictors of relapse in the primary tumors (DNA methylation in the primary tumors which predicts future/subsequent relapse). Results Maintenance of molecular subtypes during serial relapses of EPN The distinct molecular subtypes of pediatric EPN at diagnosis can impact clinical treatment 13 , 14 , 16 , 37 , 38 . While analysis of single recurrences suggested the maintenance of molecular subtypes, it remains to be determined if the molecular subtypes of EPNs will change over repeated relapses of a long period of time. Despite 50% EPN patients develop tumor recurrences 1 , 3 , 4 , relapsed tumor samples, particularly the repeated recurrences, are difficult to obtain. In our study, we collected a total of 30 serially relapsing EPN tumor samples from 10 of 110 (9.1%) pediatric patients who were followed up over 13 years. Consent to publish clinical information potentially identifying individuals was obtained. Many recurrent tumor samples were obtained after the patients were treated with chemo- and/or radiation therapies (Fig. 1A ). The time", "role": "user" }, { "content": "Investigators have identified previously unknown sets of epigenetic changes in pediatric brain tumors, which could serve as novel therapeutic targets and provide alternative treatment options for patients, according to a Northwestern Medicine study published in Nature Communications. Xiao-Nan Li, MD, Ph.D., the Rachelle and Mark Gordon Professor of Cancer Research and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was senior author of the study. Pediatric ependymoma, the third most common type of brain cancer in children, currently has a recurrence rate of 50% and most patients will eventually succumb to the disease due to poor treatment response. While the cancer is aggressive and recurrence is common, the tumors grow slower in comparison to other types of brain tumors, offering a small window for patient care teams to try different treatment strategies, including the resection of recurrent tumors. Although surgery and radiation can help prolong patient survival, more effective and long-term treatment options are urgently needed, according to Li. In the current study, Li's team performed DNA methylation sequencing together with RNA sequencing to identify epigenetic alterations using patient-matched primary and recurring ependymoma tumor tissue samples from 10 pediatric patients who had been treated with radiation and experienced cancer recurrence multiple times over a 13-year period. From this unique set of patient tumors, the investigators developed a novel panel of patient-derived orthotopic xenograft mouse models, which are critically needed for improving the understanding of tumor biology and for the testing of new therapies, according to Li. \"Ependymoma is a very interesting tumor, and unlike many other human cancers, mutations are not a major cause. In this tumor, we call the mutations 'silent' because there's not a whole lot of mutations. The changes are mostly on the epigenetics side, and that's why we focus on DNA methylation,\" said Li, who is also a professor of Pediatrics in the Division of Hematology, Oncology, and Stem Cell Transplantation. Using the xenograft models, the investigators identified three unique sets of epigenetic mutations. The first set included differentially expressed genes that were regulated by potential \"driver\" DNA methylation regions (DMRs), or genomic regions containing different DNA methylation patterns, that carried over from the primary tumors to recurring tumors. The second set contained differentially expressed genes that were regulated by potential \"booster\" DMRs, which were found only in recurring tumors. In particular, the investigators discovered that the gene PLEKHG1 was expressed in all the recurrent tumor models which, according to Li, suggests that this gene could be a potential therapeutic target. The third set of mutations identified in primary tumors were \"predictors of relapse,\" or a set of epigenetic markers that could help predict whether a tumor has a high risk of recurrence. These predictors could help providers avoid giving unnecessary treatment to patients which could lead to further complications down the road, according to Li. \"The pediatric brain is still developing, and if you treat them unnecessarily too harsh, it will delay development and decease quality of life. If there's any way we can predict and improve their quality of life, that's so important,\" Li said. Furthermore, screening these drivers and boosters could help determine potential therapeutic targets and precision medicine-based treatment strategies. \"The important things to know are that recurrent tumors and not exactly the same as primary tumors—they change a lot—and for this type of study, we need more collaboration. We need to work with as many hospitals and institutions as possible,\" Li said. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The epicardium is a mesothelial layer covering the myocardium serving as a progenitor source during cardiac development. The epicardium reactivates upon cardiac injury supporting cardiac repair and regeneration. Fine-tuned balanced signaling regulates cell plasticity and cell-fate decisions of epicardial-derived cells (EPCDs) via epicardial-to-mesenchymal transition (EMT). However, powerful tools to investigate epicardial function, including markers with pivotal roles in developmental signaling, are still lacking. Here, we recapitulated epicardiogenesis using human induced pluripotent stem cells (hiPSCs) and identified type II classical cadherin CDH18 as a biomarker defining lineage specification in human active epicardium. The loss of CDH18 led to the onset of EMT and specific differentiation towards cardiac smooth muscle cells. Furthermore, GATA4 regulated epicardial CDH18 expression. These results highlight the importance of tracing CDH18 expression in hiPSC-derived epicardial cells, providing a model for investigating epicardial function in human development and disease and enabling new possibilities for regenerative medicine. Introduction Cardiovascular diseases are the leading cause of death worldwide. The human heart is incapable of restoring itself and myocardial repair and regeneration processes are still poorly understood. In recent years the epicardium has emerged as a therapeutic target, given its ability to re-activate upon cardiac injury and promote cardiac repair 1 . The epicardium is a mesothelial layer covering the myocardium and serves as a progenitor source supporting cardiac development, repair, and regeneration 2 , 3 , 4 . Epicardiogenesis is evolutionary conserved and absolutely essential for cardiac development, with failure of epicardial formation being embryonic lethal 5 , 6 . After the formation of the proepicardium (PE), a transient cauliflower-like structure at the venous pole of the looping heart, cells of the PE migrate over and cover the looping heart tube completely, subsequently forming the epicardium. The embryonic epicardium is active, epicardial cells are proliferative and have the ability to undergo epicardial epithelial-to-mesenchymal transition (EMT). Those epicardial-derived cells (EPDCs) can proliferate and migrate, invading the underlying myocardium, where they subsequently differentiate into various cardiac cell types like vascular smooth muscle cells (SMC), cardiac fibroblasts (CF), and, to a lesser degree, endothelial cells (EC) 7 , 8 , 9 . The epicardium and EPDCs exhibit extensive developmental plasticity, which is crucial for cardiogenesis, by contributing to coronary vessel formation as well as myocardial growth and maturation 1 , 2 , 4 , 10 , 11 . During adulthood, the epicardium enters quiescence and serves as a protective layer. Only upon cardiac injury, the epicardium re-activates and contributes as a quick transient progenitor hub of derivative cells to the cardiovascular system regeneration 4 , 12 . This fact provides the epicardium with a pivotal role in mediating regenerative responses. Unlike other species, mammals lack the ability to restore the heart. Nonetheless, re-activation of the epicardium is required for cardiac scar formation as well as coronary vessel growth 13 . Not only promotes the epicardium myocardial regeneration via paracrine signaling, but it also mediates inflammatory responses 14 , 15 . Moreover, engineered patches carrying epicardial follistatin-like 1 (FSTL-1) were able to enhance cardiac regenerative responses 16 . However, despite ongoing investigation on the epicardium as a therapeutic target tissue, processes governing epicardial development, re-activation and engraftment ability are not well understood, mainly due to lacking comprehension of the fundamental biology behind the epicardium itself, including the expression dynamics of epicardial epitopes mediating tissue responses to homeostasis disruptions and cellular signaling upon cardiac damage. The epicardium coordinates a complex network of surface remodelers in order to respond to different stimuli driven by organ development and tissue repair 11 , 17 . The cell surfaceome describes the whole proteome of surface and transmembrane proteins. During tissue morphogenesis, homeostasis, and regeneration, the surfaceome, particularly surface remodelers, plays an essential role in expansion, migration, and invasion, forming complex cellular structures 18 . However, cell-surface markers defining functional epicardial cells or regulating epicardial cell-fate decisions have been difficult to identify. The cadherin family of cell–cell adhesion proteins are important for tissue morphogenesis 19 . Even though cadherins may have originated to facilitate mechanical cell-cell adhesion, their functions are pleiotropic and have evolved to be imperative for many other aspects, including cell recognition, coordinated cell movements, cell-fate decisions and the maintenance of structural tissue polarity, by controlling diverse signaling pathways 20 , 21 , 22 , 23 , 24 , 25 . In this study, we identified type II classical cadherin CDH18, formerly known as cadherin 14 (CDH14), as a specific biomarker expressed in the fetal-stage epicardium, defining cellular specification. Human pluripotent stem cells (hPSCs) 26 , 27 and their capacity to differentiate into cardiac cells allow recapitulation of epicardiogenesis in vitro 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 . Here we generated human-induced (hi)PSC-derived epicardial-like (EPI) cells. Epicardial identity was associated with sustained expression levels of key epicardial genes and retained CDH18 expression in correlation to GATA4 expression, an essential transcription factor proven to be required to form PE in vivo 37 . The loss of CDH18 expression led to the activation of cell-fate specific EMT towards SMC differentiation, confirming an important biological function of CDH18 , not only to define progressive epicardial lineage specification but also to regulate downstream signaling that drives EPDC derivation. Our study sets a basis for a reproducible model to investigate epicardial function in human cardiac development and disease, ultimately enabling new possibilities in regenerative medicine. Results Defined transcriptome of developing epicardial surfaceome revealed the enrichment of CD22 and CDH18 in late-stage populations To investigate the expression profiles of the epicardium, we compared RNA-Seq dataset of induced epicardial-like cells at day (d) 12 (Epi12) and 48 (Epi48) representing a developmental early- and late-stage respectively and investigated their relationship with the adult quiescent epicardium 28 . Whole mRNA transcriptome-based principal-component analysis (PCA) demonstrated 84.75% variance between Epi12 and Epi48 populations (Fig. 1a ), with the biggest difference observed between Epi12 and adult—quiescent—cells (Supplementary Fig. 1a, b ). The active embryonic epicardium is defined by the expression of the transcription factors Wilms’ tumor 1 (", "role": "user" }, { "content": "Heart disease remains the leading cause of death in the world. One reason is that unlike other tissues, such as bone and skin, the heart has remarkably poor regenerative capability after an injury such as a heart attack. Scientists have therefore searched for heart cells that have regenerative properties. A new study by the Yoshinori Yoshida laboratory reports the use of iPS cells to produce one such cell type, epicardial cells. The epicardium describes the most outer layer of the heart. As the heart forms, epicardial cells migrate and differentiate into different heart cells. However, after birth, the epicardium takes a quiescent state and only reactivates following injury to produce fibrosis and scarring. While this response is not ideal and fails to fully recover heart function, in some species, such as zebrafish, epicardium reactivation is a critical step for heart regeneration. In general, the epicardium of a growing fetal heart behaves differently from that of a fully formed adult heart. \"The embryonic epicardium is active. Its cells are proliferative and undergo an epithelial-to-mesenchymal transition that results in various cardiac cell types. This property is not seen in adult heart,\" said Julia Junghof, who is the first author of the study and is expected to earn her Ph.D. To study these differences, she and colleagues differentiated human iPS cells into epicardial cells. They found the protein cadherin 18 (CDH18) was expressed in only the fetal type. \"We normally rely on the expression of genes to identify epicardial cells but do not have reliable surface markers. Cadherins are best known for cell-to-cell adhesion, but they also are involved in cell-fate decisions,\" said CiRA Associate Professor Yoshinori Yoshida, who led the study. Artificially expressing genes in iPS cells is technically difficult and expensive. Using surface markers reduces the labor and cost of the experiments and also results in safer cells that can be used later for patient care. The study shows cadherin 18 (CDH18) is such a surface marker. CDH18 is better known for its role in axon development and maintenance in the nervous system, but the study showed its usefulness for identifying iPS cells that successfully differentiated into epicardial cells. Notably, while CDH18 was expressed in fetal epicardial cells, it was not expressed in adult epicardial cells, which could reflect the different regenerative properties of the heart. The loss of CDH18 expression resulted in epicardial cells losing their ability to multiply and caused an epicardial-to-mesenchymal transition that resulted in smooth muscle cells for the heart, providing new insights on how the epicardium can be activated following injury to promote heart regeneration. Thus, measuring the expression of CDH18 on differentiating iPS cells may provide an effective means for producing cells with heart regeneration ability in the lab. CiRA scientist Dr. Antonio Lucena-Cacace, a senior author of the study, added that the findings also give clues on how heart regeneration can be turned on and off in the body. \"Our findings show how regulation of the epicardial-to-mesenchymal transition affects the cell fate and regenerative responses of epicardial cells,\" he said. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract High fidelity single-shot readout of qubits is a crucial component for fault-tolerant quantum computing and scalable quantum networks. In recent years, the nitrogen-vacancy (NV) center in diamond has risen as a leading platform for the above applications. The current single-shot readout of the NV electron spin relies on resonance fluorescence method at cryogenic temperature. However, the spin-flip process interrupts the optical cycling transition, therefore, limits the readout fidelity. Here, we introduce a spin-to-charge conversion method assisted by near-infrared (NIR) light to suppress the spin-flip error. This method leverages high spin-selectivity of cryogenic resonance excitation and flexibility of photoionization. We achieve an overall fidelity > 95% for the single-shot readout of an NV center electron spin in the presence of high strain and fast spin-flip process. With further improvements, this technique has the potential to achieve spin readout fidelity exceeding the fault-tolerant threshold, and may also find applications on integrated optoelectronic devices. Introduction Resonance fluorescence method has become a commonly used method to achieve the single-shot readout of various solid-state spins such as quantum dot 1 , 2 , rare-earth ions in crystals 3 , 4 , silicon-vacancy center 5 , 6 , and nitrogen-vacancy (NV) center 7 in diamond. Under spin-selective excitation of optical cycling transition, the spin state is inferred according to collected spin-dependent fluorescence photon counts. However, the accompanying spin non-conservation processes usually limit the optical readout window for photon collection and induce the spin state flip error. This effect has become a significant obstacle for achieving high-fidelity single-shot readout, in particular, to exceed the fault-tolerant threshold 8 , 9 , 10 , 11 , 12 . A powerful method to suppress this effect is to explore optical structures for the emitters. The microstructure, such as a solid-state immersion lens, is widely used to enhance the fluorescence collection efficiency 7 , 13 , 14 , 15 , 16 . High-quality nano-cavities strongly coupled to these quantum emitters could even enhance the photon emission rate by orders of magnitude 3 , 4 , 5 , 6 . Despite these significant achievements, the practical application of such a high-quality cavity remains technically challenging. Extensive engineering works are required to obtain the high-quality cavity, place the emitter into the optimal cavity position, and tune the frequency on-demand. Besides, the fabrication process introduces unwanted strain and surface defects 17 , which may degrade the spin and optical properties 7 . Here, we demonstrate a new method to achieve a single-shot readout of NV center electron spin by combing a spin-selective photoionization process. The spin state is on-demand converted into charge state before the spin-flip relaxation becomes significant (Fig. 1 a, b). Then the charge state is measured with near unity fidelity thanks to their stability under optical illumination. The essence of this approach is to enhance the ratio of ionization rate (Γ i on ) to the spin-flip rate (Γ flip ). Fig. 1: Single-shot readout scheme based on SCC. a Energy levels used to achieve SCC. Qubit is encoded in the ground state \\(\\left|0\\right\\rangle\\) and \\(\\left|1\\right\\rangle\\) , and the \\(\\left|-1\\right\\rangle =\\left|{\\rm{AUX}}\\right\\rangle\\) state acts as the auxiliary level. The magnetic field of 585 G aligned to NV axis lifts the degeneracy between \\(\\left|-1\\right\\rangle\\) and \\(\\left|+1\\right\\rangle\\) . Note that the magnitude and direction of the magnetic field used here is not special. The coherent manipulation between \\(\\left|0\\right\\rangle\\) and \\(\\left|\\!\\pm \\!1\\right\\rangle\\) can be realized by resonant microwave, labeled by blue arrows. E y ( E 1,2 ) corresponds to the optical transition of the m S = 0 ( m S = ±1) state. The counts rate is proportional to the excited state emission rate and the fluorescence photon collection efficiency. The key part of SCC is to ionize (dark red arrow) the excited states of m S = 0 before it substantially relaxes to the ground \\(\\left|\\!\\pm \\!1\\right\\rangle\\) states through the spin-flip relaxation process (gray dashed arrow). CB is the conduction band of diamond and VB the valance band. Γ ion denotes the ionize rate, and Γ flip denotes the spin-flip rate from the E y excited state to the ground \\(\\left|\\!\\pm \\!1\\right\\rangle\\) states. A more detailed model is in Supplementary information (SI) . b A schematic diagram of SCC readout. Under the illumination of 637 nm laser, NV − keeps fluorescing stably for a long time, while NV 0 is not excited. c The excitation spectrum of the NV center used here at cryogenic temperature of 8 K. Frequency is given relative to 470.4675 THz (637.2225 nm). The non-axial strain ( δ ) induces a splitting of 2 δ = 11.8 GHz between E y and E x transitions 45 . d Spin-flip process induces the photoluminescence (PL) decay under E y excitation (5.7 nW, saturation power ~13 nW) with NV initially prepared in \\(\\left|0\\right\\rangle\\) . At the final equilibrium of PL decay curve, the NV spin is pumped into \\(\\left|\\!\\pm \\!1\\right\\rangle\\) . The solid line is the simulation according to the model described in SI , with the best-fitted spin-flip rate Γ flip = 0.75 ± 0.02 MHz. Inset: PL decay for NV initialized to \\(\\left|\\!\\pm \\!1\\right\\rangle\\) under E 1,2 excitation (4.2 nW, saturation power ~ 34 nW). From the PL decay curves, the spin initialization fidelity is estimated to be 99.7 ± 0.1% for \\(\\left|\\!\\pm \\!1\\right\\rangle\\) subspace and 99.8 ± 0.1% for \\(\\left|0\\right\\rangle\\) (SI). Full size image Results The experiments are performed on a bulk NV center inside a solid immersion lens at a cryogenic temperature of 8 K. The measurement scheme utilizes the cycling transition E y that connects excited and ground states with spin projection m S = 0 (Fig. 1 a), and the E 1,2 transition connecting states with spin projection m S = ±1. The corresponding optical transitions is shown in Fig. 1 c. The fabrication of the solid immersion lens introduced non-axial strain δ = 5.9 GHz to the NV center used. Therefore, a spin-flip rate Γ flip of 0.75 ± 0.02 MHz is observed (Fig. 1 d), much faster than previously reported 0.2", "role": "user" }, { "content": "A team led by Professor Du Jiangfeng and Professor Wang Ya from the Chinese Academy of Sciences (CAS) Key Laboratory of Microscale Magnetic Resonance of the University of Science and Technology of China put forward an innovative spin-to-charge conversion method to achieve high-fidelity readout of qubits, stepping closer towards fault-tolerant quantum computing. Quantum supremacy over classical computers has been fully exhibited in some specific problems, yet the next milestone, fault-tolerant quantum computing, still requires the accumulated logic gate error and the spin readout fidelity to exceed the fault-tolerant threshold. Du's team has resolved the first requirement in the nitrogen-vacancy (NV) center system [Nat. Commun. 6, 8748 (2015)] previously and this work targeted at high-fidelity readout of qubits. Qubit state, such as spin state, is fragile: a common readout approach may cause the flip between the 0 and 1 states for even a few photons resulting in a reading error. The readout fidelity of traditional resonance fluorescence method is strictly limited by such property. Since the spin state is difficult to measure, researchers blazed a trail to replace it with an easy-to-readout and measurable property: the charge state. They first compared the optical readout lifetime of the charge state and spin state, finding that the charge state is more stable than the spin state by five orders of magnitude. Experiment results showed that the average non-demolition charge readout fidelity reached 99.96%. Then the team adopted near-infrared (NIR) light (1064 nm) to induce the ionization of the excited spin state, transforming the spin state 0 and 1 to the \"electrically neutral\" and \"negatively charged\" charge states respectively. This process converted the spin readout to the charge readout. The results indicated that the error of traditional resonance fluorescence method reached 20.1%, while the error of this new method can be suppressed to 4.6%. The article was published in Nature Communications. This new method is compatible with tradition methods, provisioning a spin readout fidelity exceeding the fault-tolerant threshold in real applications. Thanks to the less damage of NIR light to biological tissues and other samples, this method will also effectively improve the detection efficiency of quantum sensors. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chorus waves are naturally occurring electromagnetic emissions in space and are known to produce highly energetic electrons in the hazardous radiation belt. The characteristic feature of chorus is its fast frequency chirping, whose mechanism remains a long-standing problem. While many theories agree on its nonlinear nature, they differ on whether or how the background magnetic field inhomogeneity plays a key role. Here, using observations of chorus at Mars and Earth, we report direct evidence showing that the chorus chirping rate is consistently related to the background magnetic field inhomogeneity, despite orders of magnitude difference in a key parameter quantifying the inhomogeneity at the two planets. Our results show an extreme test of a recently proposed chorus generation model and confirm the connection between the chirping rate and magnetic field inhomogeneity, opening the door to controlled plasma wave excitation in the laboratory and space. Introduction Whistler-mode chorus waves are electromagnetic emissions frequently found in space and at other planets 1 , 2 . When the electromagnetic signal of chorus is converted to an acoustic signal, these waves sound like birds chirping at dawn, hence the name. Chorus waves are known to play a dominant role in accelerating relativistic electrons in Earth’s radiation belts 3 , 4 . They have also been demonstrated to scatter electrons with energies of a few hundred eV to a few keV into the atmosphere to form diffuse and pulsating auroras 5 , 6 , 7 , playing a crucial role in the energy and mass coupling between the ionosphere and magnetosphere 8 and to be an embryonic source for plasmaspheric hiss 9 , 10 . Satellite observations show that chorus emissions are narrowband and quasi-coherent, consisting of discrete chirping elements with their central frequency changing rapidly as a function of time (i.e., chirping) 1 , 11 . The frequency chirping is not unique to whistler-mode chorus but has also been observed in electromagnetic ion cyclotron waves in space plasmas or Alfvén waves in fusion plasmas 12 , 13 . Hence there is a broad interest in understanding the fundamental physical mechanism of chorus chirping, in addition to the consensus on the importance of chorus. However, despite the early establishment of nonlinear wave–particle interactions in the generation of chorus, the theoretical mechanism of how nonlinear interactions lead to chorus chirping has been under intensive debate for over 70 years 14 , 15 , 16 , 17 , 18 . A recently proposed “Trap-Release-Amplify” (TaRA) model 19 shows that nonlinear wave–particle interactions and background magnetic field inhomogeneity work together to produce the chirping of chorus in space, unifying two different ways of estimating chorus chirping rate from previous theoretical models 14 , 16 . As a self-consistent model, electrons interact with the quasi-coherent wave packet, resulting in quasi-coherent rather than the stochastic motion of a small group of resonant electrons. The quasi-coherent motion leads to significant changes in the electron’s energy and momentum. Because the phase space density along an electron’s trajectory is constant, there is a difference between the electron’s phase space density and its neighboring at the new location, leading to the formation of phase-space structures such as phase space holes. This nonlinear interaction process results in a frequency chirping rate proportional to the wave amplitude at the equator, a conclusion verified for chorus events at Earth 20 , 21 and is widely accepted 22 , 23 . The main unique feature of the TaRA model is that it further predicts that the chirping rate is proportional to the local magnetic field inhomogeneity when the quasi-coherent phase-space structure is released from the wave packet and leads to selective amplification of new narrowband emissions. This prediction of the TaRA model is consistent with one of the previous theoretical models of chorus 14 and the statistical dependence of the chirping rate of chorus on the radial distance at Earth 24 . However, different from the nonlinear chirping rate, which is a defining feature of chorus, the dependence of the chirping rate on the magnetic field inhomogeneity is still under debate 22 . Note that the change of inhomogeneity of the background magnetic field at Earth is relatively mild. A direct experimental test with orders of magnitude variation in magnetic field inhomogeneity is not possible using wave observations only at Earth. In this work, we conduct a detailed analysis of a previously reported chorus-like emission observed by the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission 25 . Despite the vastly different magnetic field and plasma parameters, we demonstrate that the emission observed by MAVEN at Mars shares the same nonlinear nature with chorus waves at Earth and exhibits features consistent with the predictions made by the TaRA model. Results Observation MAVEN detected the wave event on 12 July 2015, and linear instability analysis confirms that the wave is of whistler mode 26 . However, linear analysis can neither confirm this event as chorus nor explain its frequency chirping, which is fundamentally nonlinear. Figure 1 a shows the trajectory of the MAVEN satellite and the magnetic field line it crosses while observing the event, whose frequency–time spectrogram is shown in Fig. 1 c. Note that Mars does not have a global magnetic field like Earth. The closed magnetic field line is part of the crustal magnetic field of Mars. As a comparison, we also show in Fig. 1 b the global magnetic field and a chorus event of Earth observed by the Van Allen Probes mission 27 (Fig. 1 d). The crustal magnetic field line at Mars encountered by MAVEN has a much smaller scale than that of typical magnetic field lines at Earth. The inhomogeneity parameter ( ξ ) of a given magnetic field line, relevant to studies of chorus, can be obtained by approximating the magnetic field strength near the equator (minimum B ) by a parabolic function; i.e., B = B 0 (1 + ξ s 2 ), where s is the distance from the equator along a field line. Using corresponding magnetic field models, we", "role": "user" }, { "content": "Chinese scientists have reproduced the observed whistler mode chorus waves on Mars using data from the Mars Atmosphere and Volatile Evolution (MAVEN) mission and compared them with phenomena on the Earth. They found that both Mars and Earth exhibit whistler mode chorus waves triggered by nonlinear processes with the key role played by background magnetic field inhomogeneity in frequency sweeping. The study, published in Nature Communications, provides crucial support for understanding chorus waves in the Martian environment and verifies the previously proposed \"Trap-Release-Amplify\" (TaRA) model under more extreme conditions. Whistler-mode chorus waves are electromagnetic wave emissions widely presented in planetary magnetospheres. When their electromagnetic signals are converted into sound, they resemble the harmonious chorus of birds in the early morning, hence the name \"chorus waves.\" Chorus waves can accelerate high-energy electrons in space through resonance, leading to a rapid increase in electron flux in Earth's radiation belts during geomagnetic storms. Additionally, they scatter high-energy electrons into the atmosphere, creating diffuse and pulsating auroras. One characteristic of chorus waves is their narrowband frequency sweeping structure. The excitation mechanism of this sweeping structure has been of great interest for decades, and scientists have proposed various theoretical models. However, there has been ongoing debate regarding why frequency sweeping occurs in chorus waves and how to calculate the sweeping frequency. One major point of contention is whether the background magnetic field inhomogeneity plays a crucial role in frequency sweeping and how it affects the sweeping phenomenon. The TaRA model, previously proposed by a team from the University of Science and Technology of China of the Chinese Academy of Sciences, is based on modern plasma physics theories and suggests that the frequency sweeping of chorus waves in the magnetosphere is the result of the combined effects of nonlinear processes and background magnetic field inhomogeneity. The model provides a corresponding formula for calculating the sweeping frequency. However, the variation in magnetic field inhomogeneity in Earth's magnetosphere is limited, making it difficult to test the TaRA model in a larger parameter space. Computer simulation of the chorus event at Mars. (a) The simulated rising-tone chorus waves obtained using the electric fields at s/de = 0.38, corresponding to the position of the observed chorus event. Color-coded is the power spectral density of the wave electric field in normalized units. The black dots and white line are the same as those in Fig. 1c. (b, c) Comparison of waveform from simulation and observation. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-38776-z There exist distinct magnetic field environments between Mars and Earth. The Earth possesses a global dipole-like magnetic field, while Mars only has localized remnant magnetization. In the remnant magnetization environment of Mars, similar chorus wave events have also been observed by the MAVEN satellite. The calculations reveal a difference of five orders of magnitude in background magnetic field inhomogeneity between Mars and Earth. By comparing wave events observed on Earth and Mars, the previously proposed TaRA model can be tested under more extreme conditions. To validate this model, in this study, scientists from the University of Science and Technology of China and the collaborators observed the particle distribution on Mars using the MAVEN satellite and combined it with the corresponding Martian crustal remnant magnetic field model. Employing a first-principles particle simulation method, scientists reproduced the observed chorus wave phenomena on Mars. Through the analysis of particle phase space distribution, they confirmed that the sweeping process of these waves is consistent with that of chorus waves on Earth, both triggered by nonlinear processes. Furthermore, scientists used two different methods provided by the TaRA model to calculate the sweeping frequency of chorus waves and compared them with the observation and simulation results. The results demonstrated a high degree of consistency between the sweeping frequencies calculated based on nonlinear processes and background magnetic field inhomogeneity, and the simulation results. These findings indicated that although Mars and Earth possess distinct magnetic and plasma environments, the observed chorus wave phenomena on Mars follow the same fundamental physical processes as those in Earth's magnetosphere. This study validated the wide applicability of the TaRA model in describing the sweeping physical processes of chorus waves under extreme conditions with a five-order difference in magnetic field inhomogeneity, which confirms the existence of chorus waves on Mars, and provides support for testing and applying the TaRA model under extreme conditions. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Deep neural networks (DNNs) hold promise for functional genomics prediction, but their generalization capability may be limited by the amount of available data. To address this, we propose EvoAug, a suite of evolution-inspired augmentations that enhance the training of genomic DNNs by increasing genetic variation. Random transformation of DNA sequences can potentially alter their function in unknown ways, so we employ a fine-tuning procedure using the original non-transformed data to preserve functional integrity. Our results demonstrate that EvoAug substantially improves the generalization and interpretability of established DNNs across prominent regulatory genomics prediction tasks, offering a robust solution for genomic DNNs. Background Uncovering cis -regulatory elements and their coordinated interactions is a major goal of regulatory genomics. Deep neural networks (DNNs) offer a promising avenue to learn these genomic features de novo through being trained to take DNA sequences as input and predict their regulatory functions as output [ 1 , 2 , 3 ]. Following training, these DNNs have been employed to score the functional effect of disease-associated variants [ 4 , 5 ]. Moreover, post hoc model interpretability methods have revealed that DNNs base their decisions on learning sequence motifs of transcription factor (TF) binding sites and dependencies with other TFs and sequence context [ 6 , 7 , 8 , 9 , 10 ]. For DNNs, generalization typically improves with more training data. However, the amount of data generated in a high-throughput functional genomics experiment is fundamentally limited by the underlying biology. For example, the extent to which certain TFs bind to DNA is constrained by the availability of high-affinity binding sites in accessible chromatin. To expand a finite dataset, data augmentations can provide additional variations on existing training data [ 11 , 12 ]. Data augmentations act as a form of regularization, guiding the learned function to be invariant to symmetries created by the data transformations [ 13 , 14 ]. This approach can help prevent a DNN from overfitting to spurious features and improve generalization [ 15 ]. The main challenge with data augmentations in genomics is quantifying how the regulatory function changes for a given transformation. With image data, basic affine transformations can translate, magnify, or rotate an image without changing its label. However, in genomics, the available neutral augmentations are reverse-complement transformation [ 16 ] and small random translations of the input sequence [ 17 , 18 ]. With the finite size of experimental data and a paucity of augmentation methods, strategies to promote generalization for genomic DNNs are limited. Here, we introduce EvoAug, an open-source PyTorch package that provides a suite of evolution-inspired data augmentations. We show that training DNNs with EvoAug leads to better generalization performance and improves efficacy with standard post hoc explanation methods, including filter interpretability and attribution analysis, across prominent regulatory genomics prediction tasks for well-established DNNs. Results and discussion Evolution-inspired data augmentations for sequence-based genomic DNNs To enhance the effectiveness of sequence-based models, data augmentations should aim to increase genetic diversity while maintaining the same biological functionality. Evolution provides a natural process to generate genetic variability, including random mutations, deletions, insertions, inversions, and translocations, among others [ 19 ]. However, these genetic changes often have functional consequences that expand phenotypic diversity and aid in natural selection. While the addition of homologous sequences to a dataset could achieve the goal of increasing sequence diversity while preserving biological function, identifying regulatory regions with similar functions throughout the genomes across species is difficult. Alternatively, synthetic perturbations that do not alter the function can be applied, but it is crucial to have prior knowledge to ensure that features such as motifs and their dependencies are not affected. Therefore, formulating new data augmentation strategies for genomics remains a significant challenge. In this study, we present a suite of evolution-based data augmentations and a two-stage training curriculum to preserve functional integrity (Fig. 1 a). In the first stage, a DNN is trained on sequences with EvoAug augmentations applied stochastically online during training, using the same training labels as the wild-type sequence. The goal is to enhance the model’s ability to learn robust representations of features, such as motifs, by exposing it to expanded (albeit synthetically generated) genetic variation. While each augmentation has the potential to disrupt core motifs in any given perturbation, we expect the overall effect to preserve motifs on average. However, the specific data augmentations employed may introduce a bias in how these motif grammars are structured. Thus, in the second stage, the DNN is fine-tuned on the original, unperturbed data to refine these features and guide the function towards the observed biology, thereby removing any bias introduced by the data augmentations (see Methods). Fig. 1 EvoAug improves generalization and interpretability of Basset models. a Schematic of evolution-inspired data augmentations (left) and the two-stage training curriculum (right). b Generalization performance (area under the precision-recall curve) for Basset models pretrained with individual and combinations of augmentations, i.e., Noise+Ins+RC (Gaussian noise, insertion, reverse-complement) and all augmentations (Gaussian noise, reverse-complement, mutation, translocation, deletion, insertion), and fine-tuned on Basset dataset. Standard represents no augmentations during training. c Comparison of the average hit rate of first-layer filters to known motifs in the JASPAR database (top) and the average q -value of the filters with matches (bottom). d Comparison of the average Pearson correlation between model predictions and experimental data from CAGI5 Challenge. b – d Each box-plot represents 5 trials with random initializations Full size image EvoAug data augmentations introduce a modeling bias to learn invariances of the (un)natural symmetries generated by the augmentations. For instance, random insertions and deletions assume that the distance between motifs is not critical, whereas random inversions and translocations promote invariances to motif strand orientation and the order of motifs, respectively. Nevertheless, the bias created by the augmentations can lead to poor generalization when the introduced bias does not accurately reflect the underlying biology. Therefore, the fine-tuning stage is critical as it provides an avenue to unlearn any biases not supported by the observed data. EvoAug improves generalization and interpretability of", "role": "user" }, { "content": "Genes make up only a small fraction of the human genome. Between them are wide sequences of DNA that direct cells when, where, and how much each gene should be used. These biological instruction manuals are known as regulatory motifs. If that sounds complex, well, it is. The instructions for gene regulation are written in a complicated code, and scientists have turned to artificial intelligence to crack it. To learn the rules of DNA regulation, they're using deep neural networks (DNNs), which excel at finding patterns in large datasets. DNNs are at the core of popular AI tools like ChatGPT. Thanks to a new tool developed by Cold Spring Harbor Laboratory Assistant Professor Peter Koo, genome-analyzing DNNs can now be trained with far more data than can be obtained through experiments alone. \"With DNNs, the mantra is the more data, the better,\" Koo says. \"We really need these models to see a diversity of genomes so they can learn robust motif signals. But in some situations, the biology itself is the limiting factor, because we can't generate more data than exists inside the cell.\" If an AI learns from too few examples, it may misinterpret how a regulatory motif impacts gene function. The problem is that some motifs are uncommon. Very few examples are found in nature. To overcome this limitation, Koo and his colleagues developed EvoAug—a new method of augmenting the data used to train DNNs. EvoAug was inspired by a dataset hiding in plain sight—evolution. The process begins by generating artificial DNA sequences that nearly match real sequences found in cells. The sequences are tweaked in the same way genetic mutations have naturally altered the genome during evolution. Next, the models are trained to recognize regulatory motifs using the new sequences, with one key assumption. It's assumed the vast majority of tweaks will not disrupt the sequences' function. Koo compares augmenting the data in this way to training image-recognition software with mirror images of the same cat. The computer learns that a backward cat pic is still a cat pic. The reality, Koo says, is that some DNA changes do disrupt function. So, EvoAug includes a second training step using only real biological data. This guides the model \"back to the biological reality of the dataset,\" Koo explains. Koo's team found that models trained with EvoAug perform better than those trained on biological data alone. As a result, scientists could soon get a better read of the regulatory DNA that write the rules of life itself. Ultimately, this could someday provide a whole new understanding of human health. The research was published in Genome Biology. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Oocytes form before birth and remain viable for several decades before fertilization 1 . Although poor oocyte quality accounts for most female fertility problems, little is known about how oocytes maintain cellular fitness, or why their quality eventually declines with age 2 . Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilization and embryo survival 3 , 4 , 5 . Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced electron transport chain. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report a physiological cell type without complex I in animals. Our findings also clarify why patients with complex-I-related hereditary mitochondrial diseases do not experience subfertility. Complex I suppression represents an evolutionarily conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes. Main Human primordial oocytes are formed during fetal development and remain dormant in the ovary for up to 50 years. Despite a long period of dormancy, oocytes retain the ability to give rise to a new organism after fertilization. Decline in oocyte fitness is a key contributor to infertility with age 2 . However, little is known about how oocytes maintain cellular fitness for decades to preserve their developmental potential, complicating efforts to understand the declining oocyte quality in ageing women. Oocytes remain metabolically active during dormancy 6 , 7 , and thus must maintain mitochondrial activity for biosynthesis of essential biomolecules 8 . Yet, mitochondria are a major source of ROS, generating them as by-products of mitochondrial oxidative metabolism. Although ROS can function as signalling molecules 9 , at high concentrations ROS promote DNA mutagenesis and are cytotoxic. Indeed, ROS levels are linked to apoptosis and reduced developmental competence in oocytes and embryos 3 , 4 , 5 . However, the mechanisms by which oocytes maintain this delicate balance between mitochondrial activity and ROS production have remained elusive. Mitochondrial ROS in early oocytes Early human oocytes can be accessed only through invasive surgery into ovaries. Therefore, biochemical investigations into oocyte biology have historically been hindered by severe sample limitations. As a consequence, mitochondrial activity in primordial oocytes remains largely unstudied. Here we overcome challenges imposed by human oocytes by utilizing an improved human oocyte isolation protocol recently developed in our laboratory 6 , which we combine with a comparative evolutionary approach using more readily available Xenopus stage I oocytes (both referred to as early oocytes hereafter; Extended Data Fig. 1a,b ). This approach allowed us to generate hypotheses using multi-species or Xenopus -alone analyses, and subsequently test those hypotheses in human oocytes. We began our studies by imaging live early human and Xenopus oocytes labelled with various mitochondrial probes that quantify ROS levels. Neither Xenopus nor human early oocytes showed any detectable ROS signal, whereas mitochondria in somatic granulosa cells surrounding the oocytes exhibited ROS and served as positive controls (Fig. 1a–c and Extended Data Fig. 1c–g ). ROS induction in oocytes also served as a positive control for live ROS probes (Extended Data Fig. 1h,i ). Fig. 1: Early oocytes have undetectable levels of ROS. a , Live-cell imaging of human and Xenopus early oocytes, both with attached granulosa cells. The ROS level was measured using MitoTracker Red CM-H 2 XRos (H2X), a reduced mitochondrial dye that does not fluoresce until it is oxidized by ROS. The boxed area is magnified in the top right image. Xenopus granulosa cells were imaged at the basal plane of the oocyte. DIC, differential interference contrast. Scale bars, 15 µm (human oocytes), 50 µm ( Xenopus oocytes), 3 µm (human granulosa cells) and 10 µm ( Xenopus granulosa cells). b , c , Quantification of the mean fluorescence intensity (MFI) of H2X in the oocyte and in the population of granulosa cells surrounding the equatorial plane of the oocyte for human ( b ) and Xenopus ( c ) oocytes. The data represent the mean ± s.e.m. of three biological replicates, shown in different colours. ** P = 0.0001 and *** P = 4.13 × 10 −11 using a two-sided Student’s t -test. d , Overnight survival of oocytes at the indicated stages of oogenesis after treatment with menadione, N -acetyl cysteine (NAC) or the combination of both (see Extended Data Fig. 1j for experimental design). At least ten oocytes were incubated per condition. The data represent the mean ± s.e.m. across four biological replicates. * P = 1.94 × 10 −9 , ** P = 3.77 × 10 −18 and *** P = 2.37 × 10 −19 compared with the untreated condition using a two-sided Student’s t -test with Šidák–Bonferroni-adjusted P values for multiple comparisons. Source data Full size image To distinguish between the possibilities that low ROS probe levels resulted from low ROS production or, alternatively, a high scavenging capacity to eliminate ROS, we treated Xenopus oocytes with menadione and assessed their survival (Extended Data Fig. 1j ). Mild treatment with menadione promotes the formation of ROS (ref. 10 ) but does not affect survival negatively in cell lines and fruit flies 11 , 12 . However, most early oocytes (78.3%) died when they were left to recover overnight after menadione treatment, in contrast to what was observed for late-stage oocytes (Fig. 1d and Extended Data Fig. 1j). Treatment with an antioxidant that quenches ROS was able to rescue oocyte survival (Fig. 1d ). These results indicate that evasion of ROS damage in oocytes involves tight control of ROS generation, rather than a higher scavenging capacity of oocytes against ROS. Mitochondrial respiration in oocytes Using dyes that sense membrane potential (tetramethylrhodamine ethyl ester", "role": "user" }, { "content": "Immature human egg cells skip a fundamental metabolic reaction thought to be essential for generating energy, according to the findings of a study by researchers at the Center for Genomic Regulation (CRG) published today in the journal Nature. By altering their metabolic activity, the cells avoid creating reactive oxygen species, harmful molecules that can accumulate, damage DNA and cause cell death. The findings explain how human egg cells remain dormant in ovaries for up to 50 years without losing their reproductive capacity. \"Humans are born with all the supply of egg cells they have in life. As humans are also the longest-lived terrestrial mammal, egg cells have to maintain pristine conditions while avoiding decades of wear-and-tear. We show this problem is solved by skipping a fundamental metabolic reaction that is also the main source of damage for the cell. As a long-term maintenance strategy, its like putting batteries on standby mode. This represents a brand new paradigm never before seen in animal cells,\" says Dr. Aida Rodriguez, postdoctoral researcher at the CRG and first author of the study. Human eggs are first formed in the ovaries during fetal development, undergoing different stages of maturation. During the early stages of this process, immature egg cells known as oocytes are put into cellular arrest, remaining dormant for up to 50 years in the ovaries. Like all other eukaryotic cells, oocytes have mitochondria—the batteries of the cell—which they use to generate energy for their needs during this period of dormancy. Using a combination of live imaging, proteomic and biochemistry techniques, the authors of the study found that mitochondria in both human and Xenopus oocytes use alternative metabolic pathways to generate energy never before seen in other animal cell types. A complex protein and enzyme known as complex I is the usual \"gatekeeper\" that initiates the reactions required to generate energy in mitochondria. This protein is fundamental, working in the cells that constitute living organisms ranging from yeast to blue whales. However, the researchers found that complex I is virtually absent in oocytes. The only other type of cell known to survive with depleted complex I levels are all the cells that make up the parasitic plant mistletoe. According to the authors of the study, the research explains why some women with mitochondrial conditions linked to complex I, such as Leber's Hereditary Optic Neuropathy, do not experience reduced fertility compared to women with conditions affecting other mitochondrial respiratory complexes. The findings could also lead to new strategies that help preserve the ovarian reserves of patients undergoing cancer treatment. \"Complex I inhibitors have previously been proposed as a cancer treatment. If these inhibitors show promise in future studies, they could potentially target cancerous cells while sparing oocytes,\" explains Dr. Elvan Böke, senior author of the study and Group Leader in the Cell & Developmental Biology program at the CRG. Oocytes are vastly different to other types of cells because they have to balance longevity with function. The researchers plan to continue this line of research and uncover the energy source oocytes use during their long dormancy in the absence of complex I, with one of the aims being to understand the effect of nutrition on female fertility. \"One in four cases of female infertility are unexplained—pointing to a huge gap of knowledge in our understanding of female reproduction. Our ambition is to discover the strategies (such as the lack of complex I) oocytes employ to stay healthy for many years in order to find out why these strategies eventually fail with advanced age,\" concludes Dr. Böke. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs. Methods The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs. Results We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model. Conclusions Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease. Background One of the most important problems in health care today is that many patients do not respond to drug treatment. According to an FDA report, this affects 38–75% of patients with common diseases [ 1 ]. This problem is closely linked to increasing costs and difficulties in drug development [ 2 ]. One important driver of this high rate of failure is suggested by genome-wide association studies (GWAS), which identify increasing numbers of genetic variants that may affect highly diverse pathways and cell types in the same disease [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. While genomic medicine has paved the way for addressing this diversity [ 15 ], the scale of the problem is indicated by single-cell RNA-sequencing (scRNA-seq) studies, which have shown altered expression of thousands of genes across many different cell types [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] . While such studies have resulted in the identification of potential novel disease mechanisms, no single-cell type, pathway, or gene has been shown to have a key regulatory role in any disease. Instead, the dispersion of multiple causal mechanisms across multiple cell types is supported by several other studies [ 6 , 8 , 9 , 24 ]. An extreme consequence of such complexity could be that a prohibitive number of drugs may be needed for effective treatment of each disease. To address this problem, we would ideally need to (1) characterize all disease-associated cell types and pathways, followed by (2) prioritization of the relatively most important. To our knowledge, neither of these two challenges has been systematically addressed. One reason is that many cell types may not be accessible in patients, and another reason lack of methods to prioritize between the cell types and pathways [ 24 ]. Here, we hypothesized that a solution to systematically investigate multicellular pathogenesis and its diagnostic and therapeutic implications could be to use scRNA-seq data to construct models of disease-associated cell types, their expression profiles, and putative interactions. We will henceforth refer to such models as multicellular disease models (MCDMs). The importance of interactions in an MCDM lies in that they link the cell types into networks. As a simplified example, if the interactions were unidirectional, they could be traced to find upstream cell types and mechanisms for therapeutic targeting. However, biological interactions are often more complex. We therefore hypothesized that network tools could be used to prioritize cell types, mechanisms, and potential drug targets. In support, methods from network science have been applied to analyze genome-wide data from different diseases [ 25 , 26 ]. We and others have used such methods to identify biomarkers and therapeutic targets based on bulk expression profiling data of individual cell types [ 12 , 27 , 28 ], as well as to develop a mathematical framework to rank network nodes [ 29 ]. A core concept is that the most interconnected nodes in a network tend to be most important. Indeed, a large body of evidence supports that such analyses can be formalized and used to find crucial nodes in a wide range of systems, ranging from proteins essential for cell survival to relevant web pages in a Google search [ 30 , 31 ]. Because many cell types are not accessible from patients, we started with a mouse disease model. We focused on a mouse model of antigen-induced arthritis (AIA), because it allows potential analysis of all cells in the target organ, joints, and adjacent lymph nodes. We used our recently developed method for translational scRNA-seq [ 32 ]. The resulting MCDMs and complementary analyses of patients with RA and 174 other diseases supported multicellular pathogenesis of great complexity. Our analyses indicate that network analyses of the MCDMs can help to prioritize cell types and genes for diagnostics and therapeutics. General applicability", "role": "user" }, { "content": "Advanced computer models of diseases can be used to improve diagnosis and treatment. The goal is to develop the models to \"digital twins\" of individual patients. Those twins may help to computationally identify and try the best medication, before actually treating a patient. The models are the result of an international study, published in the open access journal Genome Medicine. One of the greatest problems in medical care is that medication is ineffective in 40-70% of patients with common diseases. One important reason is that diseases are seldom caused by a single, easily treatable \"fault\". Instead, most diseases depend on altered interactions between thousands of genes in many different cell types. Another reason is that those interactions may differ between patients with the same diagnosis. There is a wide gap between this complexity and modern health care. An international research team aimed to bridge this gap by constructing computational disease models of the altered gene interactions across many cell types. \"Our aim is to develop those models into 'digital twins' of individual patients' diseases in order to tailor medication to each patient. Ideally, each twin will be computationally matched with and treated with thousands of drugs, before actually selecting the best drug to treat the patient\", says Dr. Mikael Benson, professor at Linköping University, Sweden, who led the study. The researchers started by developing methods to construct digital twins, using a mouse model of human rheumatoid arthritis. They used a technique, single-cell RNA sequencing, to determine all gene activity in each of thousands of individual cells from the sick mouse joints. In order to construct computer models of all the data, the researchers used network analyses. \"Networks can be used to describe and analyse most complex systems\", says Dr. Benson. \"A simple example is a soccer team, in which the players are connected into a network based on their passes. The player that exchanges passes with most other players may be most important\". Similar principles were applied to construct the mouse \"twins\", as well as to identify the most important cell type. That cell type was computationally matched with thousands of drugs. Finally, the researchers showed that the \"best\" drug could be used to treat and cure the sick mice. The study also demonstrated that it may be possible to use the computer models to diagnose disease in humans. The researchers focused on the same cell type that was used for drug identification. This cell type, T cells, plays an important role in the immune defence, and serves as a fingerprint of the whole digital twin. The researchers analysed T cells from patients with thirteen diseases, including autoimmune diseases, cardiovascular diseases and various types of cancer. The diagnostic fingerprints could be used not only to distinguish patients from healthy people, but also to distinguish most of the diseases from each other. \"Since T cells function as a sort of spy satellite, which is continuously surveying the body to discover and combat disease as early as possible, it may be possible to use this cell type for the early diagnosis of many different diseases\", says Mikael Benson. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Significant improvements to the thermoelectric figure of merit ZT have emerged in recent years, primarily due to the engineering of material composition and nanostructure in inorganic semiconductors 1 (ISCs). However, many present high- ZT materials are based on low-abundance elements that pose challenges for scale-up, as they entail high material costs in addition to brittleness and difficulty in large-area deposition. Here we demonstrate a strategy to improve ZT in conductive polymers and other organic semiconductors (OSCs) for which the base elements are earth-abundant. By minimizing total dopant volume, we show that all three parameters constituting ZT vary in a manner so that ZT increases; this stands in sharp contrast to ISCs, for which these parameters have trade-offs. Reducing dopant volume is found to be as important as optimizing carrier concentration when maximizing ZT in OSCs. Implementing this strategy with the dopant poly(styrenesulphonate) in poly(3,4-ethylenedioxythiophene), we achieve Z T = 0.42 at room temperature. Main Thermoelectric devices directly convert heat to electricity and vice versa without moving parts or working fluids, making them reliable and compact compared with conventional heat engines. OSCs offer numerous advantages over ISCs for thermoelectric applications, such as low cost, large-area deposition, high toughness and elasticity, material abundance and low weight. Furthermore, OSCs have low thermal conductivity ( κ ), which increases their energy conversion efficiency as defined by the thermoelectric figure-of-merit Z T = S 2 σ T / κ , where S is the Seebeck coefficient, σ is the electrical conductivity and T is the absolute temperature. As the material parameters constituting ZT do not suffer from the same trade-offs in OSCs as they do in ISCs (for example, OSCs do not typically obey the Wiedemann–Franz law, as the correlation between σ and κ is weak), they offer new routes to optimization of thermoelectric efficiency that remain for the most part unexplored. Doping is key to maximizing the thermoelectric power factor ( S 2 σ ), because it determines free-carrier concentration (and hence S ; ref. 2 ) and affects carrier mobility ( μ ). For OSCs, which traditionally suffer from low thermoelectric power factor, the effect of dopants on mobility is especially large, because dopants in van der Waals bonded solids can not only modify the conformation of conducting host molecules and thereby alter their carrier transport properties, but also typically increase the tunnelling distance between these molecules and hence greatly reduce the rate of thermally activated hopping. An important consequence of the weak van der Waals bonding characteristic of OSCs is that dopants often exhibit a very small ionization fraction ( b ) over a wide range of dopant concentrations 3 . The presence of a large number of non-ionized dopants can significantly reduce carrier mobility and consequently the thermoelectric power factor. This effect on S 2 σ is illustrated in Fig. 1 , where the free-carrier concentration ( n ) normalized by the host material’s total density of states ( N 0 ) is given on the horizontal axis and the ratio of total dopant volume to total host volume is given on the vertical axis. This total volume ratio is expressed as the product of the subunit (for example, monomer) volume ratio ( r )and the subunit concentration ratio ( χ ). Essentially these plots (described in more detail below) represent S 2 σ versus carrier concentration and mobility, because μ decreases exponentially with increasing r χ (ref. 4 ), and hence capture the principal properties governing S and σ = n q μ (where q is the unit charge). As in ISCs, S and σ have opposite dependences on n (for example, S ~ln( n / N 0 )), leading to a particular value of n that maximizes S 2 σ . However, the exponential dependence of μ on r χ leads to a variation in μ over typical doping concentrations in OSCs that is much larger than the variation in μ over typical doping concentrations in ISCs. Therefore, as Fig. 1 makes clear, minimizing r χ is just as important as optimizing n when maximizing S 2 σ in OSCs. Figure 1: The doping (or dedoping) trajectory required for efficient maximization of thermoelectric power factor in an OSC. a – c , Calculated 4 dependence of S 2 σ on the normalized carrier concentration ( n / N 0 ) and the ratio of total dopant volume to total host volume ( r χ ), for different degrees of carrier localization ( α / l ). S 2 σ is normalized by its maximum value as illustrated by the colour bar. d , Three-dimensional plot of normalized S 2 σ showing the steep ascent of the dedoping trajectory along both n / N 0 and r χ axes in the direction of maximum S 2 σ . e , Measured dedoping trajectory for DMSO-mixed (circles) and EG-mixed (squares) PEDOT:PSS. χ is determined by XPS data and n / N 0 is derived by fitting measured S to a numerical calculation 4 . The forbidden area occurs for n / N 0 > χ when r = 1.3. Arrows in magnified image for data indicate the direction of the dedoping process. Full size image We experimentally demonstrate the key importance of minimizing r χ for achieving high thermoelectric performance in an OSC by removing non-ionized dopant species from poly(3,4-ethylenedioxythiophene) (PEDOT) doped by poly(styrenesulphonate) (PSS). PEDOT:PSS is promising as an organic-based thermoelectric material owing to its stability in air 5 and potential for very high σ (measured over 3,000 S cm −1 ; ref. 6 ). As for other OSCs, it suffers from a small ionization fraction for the PSS dopant in pristine PEDOT:PSS (typically near 0.3 (refs 7 , 8 )) and requires a large amount of PSS to create a high carrier concentration; PEDOT:PSS mass ratios of 1:2.5 or 1:6 are typically used for high-conductivity samples 7 . Measurements of S 2 σ in PEDOT:PSS samples have yielded very low values (of the order of 1–10 μW m", "role": "user" }, { "content": "Thermoelectric materials can be used to turn waste heat into electricity or to provide refrigeration without any liquid coolants, and a research team from the University of Michigan has found a way to nearly double the efficiency of a particular class of them that's made with organic semiconductors. Organic semiconductors are carbon-rich compounds that are relatively cheap, abundant, lightweight and tough. But they haven't traditionally been considered candidate thermoelectric materials because they have been inefficient in carrying out the essential heat-to-electricity conversion process. Today's most efficient thermoelectric materials are made of relatively rare inorganic semiconductors such as bismuth, tellurium and selenium that are expensive, brittle and often toxic. Still, they manage to convert heat into electricity more than four times as efficiently as the organic semiconductors created to date. This greater efficiency is reflected in a metric known by researchers as the thermoelectric \"figure of merit.\" This metric is approximately 1 near room temperature for state-of-the-art inorganic thermoelectric materials, but only 0.25 for organic semiconductors. U-M researchers improved upon the state-of-the-art in organic semiconductors by nearly 70 percent, achieving a figure-of-merit of 0.42 in a compound known as PEDOT:PSS. \"That's about half as efficient as current inorganic semiconductors,\" said project leader Kevin Pipe, an associate professor of mechanical engineering as well as electrical engineering and computer science. Pipe is a co-author of a paper on the research published in Nature Materials on May 5, 2013. PEDOT:PSS is a mixture of two polymers: the conjugated polymer PEDOT and the polyelectrolyte PSS. It has previously been used as a transparent electrode for devices such as organic LEDs and solar cells, as well as an antistatic agent for materials such as photographic films. One of the ways scientists and engineers increase a material's capacity for conducting electricity is to add impurities to it in a process known as doping. When these added ingredients, called dopants, bond to the host material, they give it an electrical carrier. Each of these additional carriers enhances the material's electrical conductivity. In PEDOT doped by PSS, however, only small fraction of the PSS molecules actually bond to the host PEDOT; the rest of the PSS molecules do not become ionized and are inactive. The researchers found that these excess PSS molecules dramatically inhibit both the electrical conductivity and thermoelectric performance of the material. \"The trouble is that the inactive PSS molecules push the PEDOT molecules further apart, making it harder for electrons to jump between PEDOT molecules,\" Pipe said. \"While ionized PSS molecules improve electrical conductivity, non-ionized PSS molecules reduce it.\" To improve its thermoelectric efficiency, the researchers restructured the material at the nanoscale. Pipe and his team figured out how to use certain solvents to remove some of these non-ionized PSS dopant molecules from the mixture, leading to large increases in both the electrical conductivity and the thermoelectric energy conversion efficiency. This particular organic thermoelectric material would be effective at temperatures up to about 250 degrees Fahrenheit. \"Eventually this technology could allow us to create a flexible sheet—-think of Saran Wrap—-that can be rolled out or wrapped around a hot object to generate electricity or provide cooling,\" Pipe said. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Stellwagen Bank National Marine Sanctuary is located in Massachusetts Bay off the densely populated northeast coast of the United States; subsequently, the marine inhabitants of the area are exposed to elevated levels of anthropogenic underwater sound, particularly due to commercial shipping. The current study investigated the alteration of estimated effective communication spaces at three spawning locations for populations of the commercially and ecologically important fishes, Atlantic cod ( Gadus morhua ) and haddock ( Melanogrammus aeglefinus ). Both the ambient sound pressure levels and the estimated effective vocalization radii, estimated through spherical spreading models, fluctuated dramatically during the three-month recording periods. Increases in sound pressure level appeared to be largely driven by large vessel activity, and accordingly exhibited a significant positive correlation with the number of Automatic Identification System tracked vessels at the two of the three sites. The near constant high levels of low frequency sound and consequential reduction in the communication space observed at these recording sites during times of high vocalization activity raises significant concerns that communication between conspecifics may be compromised during critical biological periods. This study takes the first steps in evaluating these animals’ communication spaces and alteration of these spaces due to anthropogenic underwater sound. Introduction Sound is an efficient way to communicate in the marine environment, and animal inhabitants and people alike have developed ways to exploit this fact. Many organisms occupying the oceans actively use and produce sound. Marine mammals use sound as a primary method for communicating underwater over large distances, over shorter spatial scales fishes do the same. Marine invertebrates produce sound both actively for behavioural display purposes as well as passively due to feeding or movement. Features of ambient sound are a result of the characteristics of all of the contributing sound sources, including those composed of biological sounds such as animals vocalising (biotic), physical sounds, such as wind and water movement (geophysical or abiotic) and anthropogenic sounds such as shipping or construction (anthropogenic) 1 . Many marine organisms utilize ambient sound to navigate, choose their settlement or residence location, and to modify their daily behaviour, e.g., breeding, feeding and socializing 2 , 3 , 4 . Due to these reasons, ambient underwater sound is an important feature of marine habitats. Anthropogenic sound in certain ocean regions has increased considerably in recent decades due to various human activities such as resource acquisition, global shipping, construction, sonar, and recreational boating 1 . As ocean sound increases, so does the concern for its effects on populations of acoustic signallers, making this a topic of significant scientific research focus. Effects of anthropogenic sound exposure can be seen in the physiology and behaviour of a range of marine organisms, from invertebrates 5 , 6 to marine mammals 7 , with studies on these effects to date largely focusing on high-amplitude sources. Sound exposure can cause temporary hearing loss and threshold shifts 8 , reduction in temporal resolution ability 9 , damage and hair cell death in the inner ear 10 , 11 , and stress responses 12 . However, few studies have addressed the effects of lower-level and chronic sound exposures 13 , 14 . Fishes represent over half of all vertebrate species, and more than 800 species from greater than 100 families are known to produce sound 15 . Not surprisingly these families have evolved a large diversity of sonic organs and sound producing mechanisms 16 . This variety of mechanisms has led to the production of diverse vocalizations and acoustic characteristics between species and populations. Fish vocalizations are an important component of the marine soundscape 17 , 18 and they provide valuable information regarding the behaviour of the signaller in a variety of different contexts, such as general interactions, territorial displays, feeding, contact vocalization, and courtship interactions 19 . Fishes exhibit an array of reproductive and social behaviours and the majority of species live fairly close to the coast or in fresh water environments, consequently they are exposed to the various human activities which produce sound 20 . In addition to the increasing amount of anthropogenic sound in the marine environment, these sounds often have prominent frequencies which fall within the frequency range of acoustic communication signals, therefore, having the potential to reduce communication efficiency. One of the most widespread, yet poorly understood means in which fishes could be affected by chronic, lower-level anthropogenic sound, such as vessel sound, is through the disruption of acoustic communication by masking 21 , 22 . In this situation, the receiver experiences an increase in the threshold of detection or discrimination of the signal which could potentially lead to complete or partial loss of received signal, misinterpretation of the signal, and/or subsequently changes in the response 21 , 23 . Although there is a growing body of literature on how signallers may avoid masking from anthropogenic sound, much of the research has been conducted on terrestrial organisms and marine mammals. To date, there have been very few documented studies on the potential of anthropogenic sound to mask, disrupt or reduce acoustic communication in fishes, and fewer still on the means of avoiding masking in the presence of extraneous sound 24 , 25 . Assessing the impacts of anthropogenic sound on the ecology of fishes is not the only concern. Fish provide livelihoods to hundreds of millions of people, and is a primary source of protein for >1 billion people worldwide with growth expected for more than 9 billion by 2050 26 , which is a difficult target without strict and ongoing management. The central topographical feature within the Gerry E. Studds Stellwagen Bank National Marine Sanctuary (SBNMS), Stellwagen Bank itself, has supported high catch rates of Atlantic cod ( Gadus morhua ) and haddock ( Melanogrammus aeglefinus ) for centuries, and includes past knowledge of predicable spawning areas for cod within the sanctuary and greater Massachusetts Bay. Gulf of Maine cod stock contains genetically distinct spring- and winter-spawning subpopulations, and recent studies have highlighted waters both inshore and within the sanctuary as supporting seasonal", "role": "user" }, { "content": "NOAA scientists studying sounds made by Atlantic cod and haddock at spawning sites in the Gulf of Maine have found that vessel traffic noise is reducing the distance over which these animals can communicate with each other. As a result, daily behavior, feeding, mating, and socializing during critical biological periods for these commercially and ecologically important fish may be altered, according to a study published in Scientific Reports. Three sites in Massachusetts Bay, two inside Stellwagen Bank National Marine Sanctuary (SBNMS) and one inshore south of Cape Ann, were monitored for three months by researchers at the Northeast Fisheries Science Center (NEFSC) laboratory in Woods Hole, Mass. and at the sanctuary offices in Scituate, Mass. Vocalizations, such as Atlantic cod grunts and haddock knocks, were recorded by bottom-mounted instruments at each site during spawning in winter and spring. \"We looked at the hourly variation in ambient sound pressure levels and then estimated effective vocalization ranges at all three sites known to support spawning activity for Gulf of Maine cod and haddock stocks,\" said Jenni Stanley, a marine research scientist in the passive acoustics group at the NEFSC and SBNMS and lead author of the study. \"Both fluctuated dramatically during the study. The sound levels appear to be largely driven by large vessel activity, and we found a signification positive correlation with the number of Automatic Identification System (AIS) tracked vessels at two of the three sites.\" AIS is an automatic tracking system, used on ships and by vessel traffic services. It provides information on a vessel, such as its unique identification number, position, course and speed, which can be displayed on a shipboard radar or electronic chart display. Ambient sounds - those in the surrounding environment - include animals vocalizing, physical sounds such as wind and water movement or geological activity, and human-produced sound from ships and marine construction. Many marine animals use ambient sound to navigate, to choose where to settle, or to modify their daily behaviors including breeding, feeding and socializing. Cod grunts were present for 100 percent of the spring days and 83 percent of the winter days. Haddock knocks were present for 62 percent of the winter days within the three-month sampling period. However, ambient sound levels differed widely at the three sites, both on an hourly and daily time scale. The Atlantic cod winter spawning site, nearest the Boston shipping lanes, had the highest sound levels, while the Atlantic cod spring spawning site inshore south of Gloucester, Mass. had the lowest. Sound levels in the haddock winter spawning site, further offshore in the sanctuary, were in the middle of the range detected in the study. Study data were also used to calculate the estimated distance a fish vocalization would be heard at each of the spawning sites. The effective radius ranged widely, from roughly 4 to 70 feet, and was largely dependent on the number of tracked vessels within a 10 nautical mile radius of the recording sites. Lower-level, chronic exposure to increased ambient sound from human activities is one of the most widespread, yet poorly understood, factors that could be changing fish behavior. If they cannot hear as well as they need to, then sound signals from other fish can be lost, compromised, or misinterpreted in ways that can cause a change in behavior. Since Atlantic cod, for example, vocalize to attract mates and listen for predators, not hearing those signals could potentially reduce reproductive success and survival. \"Anthropogenic sound in certain ocean regions has increased considerably in recent decades due to various human activities such as global shipping, construction, sonar, and recreational boating,\" Stanley said. \"As ocean sound increases, so does the concern for its effects on populations of acoustic signalers, which range from invertebrates to marine mammals. We don't know if or to what extent specific species can adapt or adjust their acoustic signals to compete in this environment.\" In addition to Stanley, other researchers involved in the study were Sofie Van Parijs at the NEFSC's Woods Hole Laboratory and Leila Hatch at Stellwagen Bank National Marine Sanctuary. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electron correlations often lead to emergent orders in quantum materials, and one example is the kagome lattice materials where topological states exist in the presence of strong correlations between electrons. This arises from the features of the electronic band structure that are associated with the kagome lattice geometry: flat bands induced by destructive interference of the electronic wavefunctions, topological Dirac crossings and a pair of van Hove singularities. Various correlated electronic phases have been discovered in kagome lattice materials, including magnetism, charge density waves, nematicity and superconductivity. Recently, a charge density wave was discovered in the magnetic kagome FeGe, providing a platform for understanding the interplay between charge order and magnetism in kagome materials. Here we observe all three electronic signatures of the kagome lattice in FeGe using angle-resolved photoemission spectroscopy. The presence of van Hove singularities near the Fermi level is driven by the underlying magnetic exchange splitting. Furthermore, we show spectral evidence for the charge density wave as gaps near the Fermi level. Our observations point to the magnetic interaction-driven band modification resulting in the formation of the charge density wave and indicate an intertwined connection between the emergent magnetism and charge order in this moderately correlated kagome metal. Main In quantum materials where the energy scale of electron–electron correlations is comparable to that of the electronic kinetic energy, a range of emergent electronic phases are found 1 . Well-known systems that exhibit such rich phase diagrams include the unconventional superconductor families of cuprates 2 and iron-based superconductors 3 , 4 , where magnetic order, charge density wave (CDW) order, nematicity and superconductivity have been found in close proximity due to the entwinement of a multitude of degrees of freedom with similar energy scales, including spin, charge and orbitals. Besides engendering large quantum fluctuations that may give rise to novel phases, the intertwinement of multiple orders allows tunability of the ground state via the coupled order parameters. It is expected that, when quantum topology is realized in such a strongly correlated regime, unprecedented exotic phases are to be discovered. Recently, kagome lattices have been extensively investigated for the rich emergent physics associated with its lattice geometry in the presence of topology 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 . Among the insulators, quantum spin liquid states may exist due to the magnetic frustration 20 . Analogously, the geometric frustration for an electronic state could also cause localization as a way to quench the kinetic energy, thereby leading to a regime with narrow electronic bandwidth where electron correlation effects could be strong enough to induce emergent phases 5 , 6 . Equally importantly, the point group of the kagome lattice is that of graphene, hence the kagome lattice also shares many properties of the Dirac fermions. Therefore, kagome lattices have been intensely explored as a model system to realize topology in the presence of strong electron correlations. Among the known kagome metals, some exhibit magnetic order with ferromagnetically ordered sheets that are either ferromagnetically or antiferromagnetically stacked 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , with ordering temperatures often exceeding room temperature. Another class of recently discovered kagome materials, AV 3 Sb 5 (A = K, Rb, Cs) 17 , 18 , 19 , hosts CDW order near 100 K that may be associated with time-reversal symmetry-breaking 21 , 22 . The interpretation on the origin of these orders ranges from those initiated from a strongly interacting picture to those based on electronic instabilities from band structure 23 , 24 , 25 , 26 , 27 , 28 . For a two-dimensional (2D) kagome lattice, three key features have been identified in the electronic structure (Fig. 1d ): (1) a flat band derived from the destructive interference, (2) a Dirac crossing at the Brillouin zone (BZ) corner (K point in the inset of Fig. 1d ) and (3) a pair of Van Hove singularities (VHSs) at the BZ boundary (M point). It has been proposed that the large density of states (DOS) from the kagome flat bands could induce ferromagnetism 5 . Alternatively, at special fillings where the VHS is at the Fermi level ( E F ), interaction between the saddle points could also induce CDW order 6 , 25 , 26 , 27 . The large energy separation between the flat band and the VHSs (Fig. 1d,e ) may be one reason why CDW order and magnetic order have not been commonly observed simultaneously within one system. Efforts at tuning the ordered phases include tuning the energy location of either the flat bands or VHSs relative to the chemical potential via chemical doping 29 , hydrostatic pressure 30 and uniaxial strain 31 , all of which have demonstrated potential yet so far have resulted in decoupled order parameters of either magnetism or CDW order. Fig. 1: Crystal structure and electronic structure. a , The crystal structure of hexagonal FeGe with the unit cell shown by solid lines. Fe atoms are labelled in red and Ge atoms in grey. A-type AFM order is illustrated by red arrows denoting spin ordering of Fe atoms. b , A top view of the crystal structure to visualize the Fe kagome layer. c , A summary of the transitions as a function of temperature. d , A simplified schematic summary of AFM-induced band splitting plotted in energy ( E ) versus momentum. In the PM state, the kagome flat band appears at E F , with a Dirac crossing and a pair of VHSs well below E F . In the AFM phase, the ordered moment within each ferromagnetic layer induces exchange splitting of the spin-minority and spin-majority bands, resulting in an upshift of the blue VHS towards E F . At the onset of CDW order, a gap ( Δ CDW ) opens at the VHS band near E F", "role": "user" }, { "content": "Physicists were surprised by the 2022 discovery that electrons in magnetic iron-germanium crystals could spontaneously and collectively organize their charges into a pattern featuring a standing wave. Magnetism also arises from the collective self-organization of electron spins into ordered patterns, and those patterns rarely coexist with the patterns that produce the standing wave of electrons physicists call a charge density wave. In a study published this week in Nature Physics, Rice University physicists Ming Yi and Pengcheng Dai, and many of their collaborators from the 2022 study, present an array of experimental evidence that shows their charge density wave discovery was rarer still, a case where the magnetic and electronic orders don't simply coexist but are directly linked. \"We found magnetism subtly modifies the landscape of electron energy states in the material in a way that both promotes and prepares for the formation of the charge density wave,\" said Yi, a co-corresponding author of the study. The study was co-authored by more than a dozen researchers from Rice; Oak Ridge National Laboratory (ORNL); SLAC National Accelerator Laboratory; Lawrence Berkeley National Laboratory (LBNL); the University of Washington; the University of California, Berkeley; Israel's Weizmann Institute of Science; and China's Southern University of Science and Technology. The iron-germanium materials are kagome lattice crystals, a much-studied family of materials featuring 2D arrangements of atoms reminiscent of the weave pattern in traditional Japanese kagome baskets, which features equilateral triangles that touch at the corners. \"Kagome materials have taken the quantum materials world by storm recently,\" Yi said. \"The cool thing about this structure is that the geometry imposes interesting quantum constraints on the way the electrons are allowed to zoom around, somewhat analogous to how traffic roundabouts affect the flow of traffic and sometimes bring it to a stop.\" By nature, electrons avoid one another. One way they do this is to order their magnetic states—spins that point either up or down—in the opposite direction of their neighbors' spins. Dai, a co-corresponding study author, said, \"When put onto kagome lattices, electrons can also appear in a state where they are stuck and cannot go anywhere due to quantum interference effects.\" When electrons cannot move, the triangular arrangement produces a situation where each has three neighbors, and there is no way for electrons to collectively order all neighboring spins in opposite directions. The inherent frustration of electrons in Kagome lattice materials has long been recognized. Yi said the lattice restricts electrons in ways that \"can have a direct impact on the observable properties of the material,\" and the team was able to use that \"to probe deeper into the origins of the intertwinement of the magnetism and charge density wave\" in iron-germanium. They did so using a combination of inelastic neutron scattering experiments, which were performed at ORNL, and angle-resolved photoemission spectroscopy experiments that were performed at LBNL's Advanced Light Source and SLAC's Stanford Synchrotron Radiation Lightsource, as well in Yi's lab at Rice. \"These probes allowed us to look at what both the electrons and the lattice were doing as the charge density wave was taking shape,\" she said. Dai said the findings confirmed the team's hypothesis that charge order and magnetic order are linked in iron-germanium. \"This is one of the very few, if not of the only, known example of a kagome material where magnetism forms first, preparing the way for charges to line up,\" he said. Yi said the work shows how curiosity and basic research into natural phenomena can eventually lead to applied science. \"As physicists, we are always excited when we find materials that spontaneously form an order of some sort,\" she said. \"This means there is a chance for us to learn about the self-organizational abilities of the fundamental particles of quantum materials. Only with that kind of understanding can we one day hope to engineer materials with novel or exotic properties that we can control at will.\" Dai is the Sam and Helen Worden Professor of Physics and Astronomy. Dai and Yi are each members of the Rice Quantum Initiative and the Rice Center for Quantum Materials (RCQM). ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The accretion of volatile-rich material from the outer Solar System represents a crucial prerequisite for Earth to develop oceans and become a habitable planet 1 , 2 , 3 , 4 . However, the timing of this accretion remains controversial 5 , 6 , 7 , 8 . It has been proposed that volatile elements were added to Earth by the late accretion of a late veneer consisting of carbonaceous-chondrite-like material after core formation had ceased 6 , 9 , 10 . This view could not be reconciled with the ruthenium (Ru) isotope composition of carbonaceous chondrites 5 , 11 , which is distinct from that of the modern mantle 12 , or of any known meteorite group 5 . As a possible solution, Earth’s pre-late-veneer mantle could already have contained a fraction of Ru that was not fully extracted by core formation 13 . The presence of such pre-late-veneer Ru can only be established if its isotope composition is distinct from that of the modern mantle. Here we report the first high-precision, mass-independent Ru isotope compositions for Eoarchaean ultramafic rocks from southwest Greenland, which display a relative 100 Ru excess of 22 parts per million compared with the modern mantle value. This 100 Ru excess indicates that the source of the Eoarchaean rocks already contained a substantial fraction of Ru before the accretion of the late veneer. By 3.7 billion years ago, the mantle beneath southwest Greenland had not yet fully equilibrated with late accreted material. Otherwise, no Ru isotopic difference relative to the modern mantle would be observed. If constraints from other highly siderophile elements besides Ru are also considered 14 , the composition of the modern mantle can only be reconciled if the late veneer contained substantial amounts of carbonaceous-chondrite-like materials with their characteristic 100 Ru deficits. These data therefore relax previous constraints on the late veneer and are consistent with volatile-rich material from the outer Solar System being delivered to Earth during late accretion. Main Ruthenium is a highly siderophile element (HSE) and is therefore expected to be sequestered in the metallic core during Earth’s differentiation. Contrary to this prediction, the abundances of Ru and other HSEs in the modern mantle are higher than expected compared with metal–silicate equilibrium conditions 15 , 16 . This observation is most commonly explained by HSE replenishment of the mantle through the addition of a late veneer after core formation. Relative abundances of HSEs that are close to chondritic compositions in the mantle suggest that the late veneer must have consisted of primitive meteoritic material 17 , 18 , amounting to ~0.5% of Earth’s mass 18 . The chemical composition of the late veneer and its origin are a longstanding matter of debate, especially in the context of how and when Earth accreted its water and volatiles 3 , 6 , 9 , 10 . Previous studies debated whether significant amounts of volatile-rich carbonaceous-chondrite-like material were added by the late veneer during the final stages of Earth’s accretion 6 , 9 , 10 or had already been incorporated during earlier stages of Earth’s growth 3 , 5 , 7 , 8 , 11 . Mass-independent ruthenium isotopic variations among meteorites and Earth have provided evidence that the late veneer was derived from reduced and volatile-poor inner Solar System materials most similar to enstatite chondrites 5 , 11 , 12 , 19 . This is in contrast to constraints from the relative abundances of volatile elements such as selenium (Se), tellurium (Te) and sulfur (S) and the Se isotope composition in the silicate Earth that were used to argue for a CM or CI carbonaceous-chondrite-like late veneer composition 2 , 9 , 10 . Owing to its distinct Ru isotope composition, volatile-rich carbonaceous-chondrite-like material from the outer Solar System was excluded as possible late-veneer source material 5 , 11 , and thus the late veneer seemed unlikely to be the primary source of water and volatiles on Earth 5 , 11 . It should be noted, however, that this conclusion depends on the premise that the Ru in Earth’s mantle originates solely from the late accreted materials that were added after cessation of core formation 11 , 15 , 16 , 18 . If Earth’s pre-late-veneer mantle retained a significant fraction of Ru during metal–silicate differentiation 13 , 20 , as recently suggested, this conclusion would be invalid. Investigating Ru isotope signatures in the putative remnants of pre-late-veneer mantle would thus not only provide insights into the timescales and efficiencies of mixing the late veneer into Earth’s mantle, but also introduce constraints on the composition of the material that was added as a late veneer. To our knowledge, no unambiguous isotopic evidence for the preservation of pre-late-veneer mantle on Earth existed until now. For instance, resolvable excesses in 182 W reported for 3.8 billion-year-old (Gyr-old) Archaean rocks from Isua (Greenland) and Acasta (Canada) in conjunction with relatively low HSE abundances observed in 3.5–3.2-Gyr-old Archaean komatiites from the Pilbara Craton (Australia) and the Barberton greenstone belt (South Africa) were interpreted to reflect sluggish mixing of the late veneer into the early Archaean mantle 21 , 22 . However, it was later suggested that the mantle sources of the 3.8–3.7-Gyr-old Isua supracrustal belt (ISB) rocks, including 3.8-Gyr-old Eoarchaean peridotites from the Narssaq ultramafic body (NUB) and the south of the Isua supracrustal belt (SOISB), already had HSE abundances at about 60–100% of the modern mantle value 14 , 23 . This suggests that the late veneer was to a large extent mixed into the ambient mantle by ~3.8 billion years ago (Ga). To reconcile 182 W excesses with the presence of modern-mantle-like HSE abundances, it was proposed that a small amount of core material could have been entrained into proto-Earth’s mantle as a consequence of the Moon-forming giant impact 20 , 24 . However, 182 W anomalies could also be generated by early mantle differentiation processes during approximately the first 50 Myr of the Solar System 25 , 26 , 27 ,", "role": "user" }, { "content": "Ancient rocks from Greenland have shown that the elements necessary for the evolution of life did not come to Earth until very late in the planet's formation—much later than previously thought. An international team of geologists—led by the University of Cologne and involving UNSW scientists—have published important new findings about the origin of oceans and life on Earth: they have found evidence that a large proportion of the elements that are essential to the formation of oceans and life—such as water, carbon and nitrogen—only came to Earth very late in its history. Many scientists previously believed that these elements had already been there at the beginning of our planet's formation. However, the geological investigations published in Nature today have shown that most of the water in fact only came to Earth when its formation was almost complete. Volatile elements such as water originate from asteroids, the planetary building blocks that formed in the outer solar system. There has been a lot of discussion and controversy in the scientific community around when precisely these building blocks came to Earth. Dr. Mario Fischer-Gödde from the Institute of Geology and Mineralogy at the University of Cologne, who led the work, says we are now able to narrow down the timeframe more precisely. \"The rocks we analyzed are the oldest preserved mantle rocks. They allow us to see into the early history of the Earth as if through a window. \"We compared the composition of the oldest, approximately 3.8 billion-year-old, mantle rocks from the Archean Eon with the composition of the asteroids from which they formed, and with the composition of the Earth's mantle today.\" To understand the temporal process, the researchers determined the isotope abundances of a very rare platinum metal called ruthenium, which the Archean mantle of the Earth contained. Like a genetic fingerprint, the rare platinum metal is an indicator for the late growth phase of the Earth. \"Platinum metals like ruthenium have an extremely high tendency to combine with iron. Therefore, when the Earth formed, ruthenium must have been completely discharged into the Earth's metallic core,\" says Professor Fischer-Gödde. Professor Martin Van Kranendonk, the UNSW scientist who was part of the research, says the reason why this is of such interest relates directly to understanding the origins of life on Earth, how we humans came to be, and in fact, to whether we might be alone, or have neighbours in the universe. \"This is because the results show that Earth did not really become a habitable planet until relatively late in its accretionary history,\" he says. \"If you combine this with the evidence for very ancient life on Earth, it reveals that life got started on our planet surprisingly quickly, within only a few hundred million years. Now this might sound like a lot of time, and it is, but it is far different from what we used to think, that life took half a billion, or even a billion years to get started. \"And this gives hope for finding life on other planets that had a shorter geological history and period of 'warm and wet' conditions than Earth, because if life could get started quickly here, then perhaps it got started quickly elsewhere.\" Professor Dr. Carsten Münker, also at the University of Cologne, added: \"The fact that we are still finding traces of rare platinum metals in the Earth's mantle means that we can assume they were only added after the formation of the core was completed—they were certainly the result of later collisions of the Earth with asteroids or smaller planetesimals.\" Scientists refer to the very late building blocks of Earth, which arrived through these collisions, as the 'late veneer.\" \"Our findings suggest that water and other volatile elements such as carbon and nitrogen did indeed arrive on Earth very late in the 'late veneer' phase,\" Professor Fischer-Gödde says. The new findings are the result of collaboration among scientists from Germany, Denmark, England, Australia and Japan. The scientists are planning further field trips to India, northwestern Australia, and Greenland to investigate more rock samples. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract An important debate centres around the nature of prosociality in nonhuman primates. Chimpanzees help other individuals in some experimental settings, yet they do not readily share food. One solution to this paradox is that they are motivated to help others provided there are no competing interests. However, benefits to recipients could arise as by-products of testing. Here we report two studies that separate by-product from intended helping in chimpanzees using a GO/NO-GO paradigm. Actors in one group could help a recipient by releasing a food box, but the same action for another group prevented a recipient from being able to get food. We find no evidence for helping—chimpanzees engaged in the test regardless of the effects on their partners. Illusory prosocial behaviour could arise as a by-product of task design. Introduction The evolution of behaviour directed at improving the welfare of unrelated individuals, especially when these behaviours are costly for the actor, is an evolutionary puzzle. Although the main conundrum comes from behaviours that decrease an actor’s fitness (biological altruism), low-cost behaviours that benefit others are also an anomaly. Typically, non-kin targeted helping is explained by mutualism, reciprocity, policing and reputation which, over the long run, are likely to increase the actor’s fitness 1 . Equally puzzling are the motivations underlying prosocial acts. An act is considered prosocial if it is intended to benefit others 2 . This distinguishes genuine acts of prosociality such as helping from self-serving alternatives where benefits to others arise as incidental by-products. To understand the nature and evolutionary origins of prosocial behaviour, recent work has probed social behaviours to determine their possible underlying psychological mechanisms. More specifically, researchers have focused on whether prosocial acts are motivated to foster the welfare of others or instead have a more self-serving nature. Owing in part to their complex social life, nonhuman primates, and chimpanzees in particular, have been the focus of intense scrutiny with regard to the psychological mechanisms underlying prosocial acts. A number of candidates for prosocial behaviour have been observed in the wild. Chimpanzees risk injury by going on border patrols, come to the aid of each other in conflicts, affiliate with victims of conflicts, groom each other and share food 3 , 4 , 5 , 6 . Even more spectacular examples of potential prosocial behaviour have also been observed, such as adoption of orphans and anecdotal accounts of rescues 7 , 8 , 9 . However, it is difficult to infer intentions from observations alone, particularly anecdotes 10 . Chimpanzees and other nonhuman primates can receive immediate or delayed benefits from their actions, calling into question whether they have the goal of improving the welfare of others. Grooming can be reciprocated and can be immediately beneficial for the groomer who experiences reduced stress as well as benefits from the parasites they eat 11 , 12 , 13 , 14 . Consoled individuals do not appear to experience reduced stress but consolers benefit by receiving less redirected aggression 15 , 16 . The benefits of border patrols and coalitions, like cooperative hunting, are shared, making these mutualistic interactions. Adoptions typically come long after the orphans lost their mothers 8 . Food transfers tend to be done in response to harassment and begging (manipulation) although active transfers do occur 3 , 17 , 18 . To address the underlying motivations of apparently prosocial acts, experiments are done in captivity. The experiments fall into two types, sharing and helping. In sharing experiments, subjects typically choose between an outcome that benefits both themselves and a partner or themselves only (mutualistic preference tasks), or between an outcome that benefits a conspecific or no one (altruistic preference tasks). In tasks that involve a food delivery apparatus, chimpanzees rarely transfer food to each other even when there is no cost to doing so 19 , 20 , 21 , 22 , 23 , 24 . A token exchange paradigm involving interactions with human experimenters showed stronger evidence for prosocial preferences 25 , but overall, evidence for food transfers in chimpanzees is weak. Cooperatively breeding monkeys transfer food more often and there has been some evidence from other nonhuman primates, but results are mixed 19 , 26 , 27 , 28 , 29 , 30 , 31 . The strongest evidence for prosocial behaviour comes from experiments of instrumental aid (helping) in chimpanzees. Chimpanzees will hand objects to experimenters who reach for them and will do so in the absence of immediate food rewards, something that capuchin monkeys do not do 32 , 33 , 34 . They also help conspecifics by choosing the correct tool to access a reward 35 , releasing a door to allow conspecifics to pass through 33 and releasing food and tokens for partners 36 . The implication is that sharing and helping are fundamentally different prosocial behaviours, with the former failing to elicit prosociality in experiments due to competitive motivations for food 37 , 38 , 39 . The ability to infer goals in others—something that chimpanzees, at least, have been shown to do in other situations 40 , 41 —and the motivation to help others achieve those goals, have been suggested to have evolved far earlier than our Homo lineage 37 , 38 , 39 . An alternative interpretation is that there is no difference between the motivation to help and share in chimpanzees and that apparent prosocial behaviour might arise as a by-product of self-regarding preferences. An important feature of helping studies is that subjects might engage with the task due to stimulus enhancement (the socially influenced attraction to environmental features). Stimulus enhancement is an important mechanism for social learning in chimpanzees; observing another individual perform an action on an object can motivate the observer to act on it as well, but without imitating the actions. The same motivation that underlies social learning in chimpanzees—namely attraction to a test due to the actions of other individuals—might also drive apparent prosociality. As well, prior reward histories might also influence the results of the task", "role": "user" }, { "content": "New research into chimpanzees suggests that, when it comes to altruistically helping a fellow chimpanzee, they are 'indifferent'. The paper, published in Nature Communications, found no evidence that chimpanzees had a tendency to help others - or conversely to be spiteful - when there was no anticipated benefit to themselves. In two experiments, chimpanzees could determine whether or not a peer received access to food, and they displayed no preference for either providing access or denying access with their actions. The team, from the universities of Birmingham, Manchester and St Andrews, and the Max Planck Institute in Leipzig, argue that previous experiments that imply 'prosocial' or helpful behaviour in non-human primates were likely a by-product of task design that nudged chimpanzees into participation. Chimpanzees at the Ngamba Island Chimpanzee Sanctuary, a forested island in Uganda, participated in two studies. None of the chimpanzees were known to be closely related to each other. In the first experiment, 13 chimpanzees were split into two groups and tested with three recipient chimpanzees. They were able to see and hear one another and the equipment, including a food box containing shelled peanuts that could only be reached from the recipients' room. Recipients in the room could shake the food boxes. Sometimes shaking the box had no effect because it was locked in position by a peg in the room of the chimpanzee being tested. Other times, shaking the box allowed the recipients to get the peanuts inside. The test subjects could not get the food, but they could see what the recipients were doing. In one group (the \"go group\"), releasing the peg would unlock the food box and allow the recipients to get the peanuts. The second group of chimpanzees (the \"no go group\") saw the recipients who could get the food, but releasing the peg would lock the box and restrict the access to food. As in previous studies, the chimpanzees released the peg at high rates but this quickly declined when there was no reward for them. Importantly, there was no difference in peg release between the two groups - the chimpanzees were no more likely to release the peg to help the recipient in the go group as they were to block access to food in the no-go group. In the second experiment, 11 of the same chimpanzees were given training sessions in which they individually learned the impact of their actions on the recipients' food boxes by being able to go to the room containing the food box. This additional knowledge did not lead to a rise in peg release where food would be given to another chimpanzee, nor did it decrease peg releases when this would prevent others from eating. Dr Claudio Tennie, from the University of Birmingham, explained, \"The results of these two experiments combined demonstrate that the chimpanzees did not act in a manner that would produce benefits for others in a task where there was no perceived benefit to themselves.\" \"Indeed, given that the participants were just as likely to prevent access to food as they were to permit access, chimpanzees are no more altruistic than they are spiteful. Even after they demonstrated a clear understanding of the consequences of their actions, they remained indifferent to any effects these actions may have on others.\" Dr. Keith Jensen, from the University of Manchester, added, \"The evolution of social behaviour, and what drives individuals to act altruistically, is an important and active area of debate. Chimpanzees appear indifferent to others when it comes to giving food to others in experimental settings, yet puzzlingly, they have been shown to help humans and other chimpanzees. There has been an appealing suggestion that the roots of human altruism extend down at least as far as our common ancestor with chimpanzees. However, the results of this study challenges that view. \"Helping\" might have formerly arisen as a by-product of interesting tasks.\" \"If true, this would mean that prosocial behaviour has developed late in evolution, after our split with the other apes.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Plant-pathogenic fungi form intimate interactions with their associated bacterial microbiota during their entire life cycle. However, little is known about the structure, functions and interaction mechanisms of bacterial communities associated with fungal fruiting bodies (perithecia). Here we examined the bacterial microbiome of perithecia formed by Fusarium graminearum , the major pathogenic fungus causing Fusarium head blight in cereals. A total of 111 shared bacterial taxa were identified in the microbiome of 65 perithecium samples collected from 13 geographic locations. Within a representative culture collection, 113 isolates exhibited antagonistic activity against F. graminearum , with Pantoea agglomerans ZJU23 being the most efficient in reducing fungal growth and infectivity. Herbicolin A was identified as the key antifungal compound secreted by ZJU23. Genetic and chemical approaches led to the discovery of its biosynthetic gene cluster. Herbicolin A showed potent in vitro and in planta efficacy towards various fungal pathogens and fungicide-resistant isolates, and exerted a fungus-specific mode of action by directly binding and disrupting ergosterol-containing lipid rafts. Furthermore, herbicolin A exhibited substantially higher activity (between 5- and 141-fold higher) against the human opportunistic fungal pathogens Aspergillus fumigatus and Candida albicans in comparison with the clinically used fungicides amphotericin B and fluconazole. Its mode of action, which is distinct from that of other antifungal drugs, and its efficacy make herbicolin A a promising antifungal drug to combat devastating fungal pathogens, both in agricultural and clinical settings. Main The microbiome plays a crucial role in host development, fitness and health 1 , 2 , 3 , 4 . Numerous microbiome studies have provided insights into the composition of various microbial communities and their dynamic changes in response to exogenic factors 2 , 5 , 6 , 7 , 8 . However, autogenic factors in microbiome assembly and function are mostly overlooked, especially in terms of the importance of microbe–microbe interactions 1 . Detailed knowledge of physical and molecular interactions between different microbiome members has a high potential to aid the development of new strategies for targeted manipulations of the microbiome to improve host health 3 , 4 , 9 , 10 . In addition, the underlying interactions could also be considered in a broader sense for microbial communities of pathogenic host organisms, for example phytopathogenic fungi. Interactions between bacteria and fungi are crucial for modulating microbial communities in terms of biodiversity, ecosystem functions and host health when associated with multicellular organisms 11 . Molecular mechanisms governing inter-kingdom communication are reflected by numerous biological interactions, from antagonism to mutualism 12 . In agroecosystems, investigations of bacterial–fungal interactions are mainly focused on the suppression of pathogens 4 , 12 , 13 . Bacteria generally interfere with fungal pathogens by competition for resources and secretion of lytic enzymes or bioactive compounds (antibiosis) 14 . In most cases, the detailed modes of action of many antagonistic bacterial–fungal interactions and the involved bioactive compounds remain elusive 15 . Sometimes the underlying mechanisms have been only partially deciphered. For example, herbicolin A, which can be biosynthesized by certain Pantoea agglomerans isolates, was identified about 40 years ago as the bacterium’s most important bioactive compound against fungi and Mollicutes 16 , 17 , 18 , 19 , 20 , 21 . However, the structure of the biosynthetic gene cluster for herbicolin A as well as its mode of action remain elusive. Most phytopathogenic fungi can produce sexual structures such as perithecia that allow them to survive on infested plant debris before the next infection cycle 22 . Fusarium graminearum (Fg), the major pathogen causing Fusarium head blight (FHB) in wheat ( Triticum aestivum ), uses this strategy with high efficiency 23 . FHB epidemics not only affect global wheat production, but also contaminate grain with mycotoxins 24 . Interfering with perithecium formation to decrease the initial inoculum is a potential strategy for FHB management. Current literature mostly focuses on changes of the plant microbiome as a response to disease or contrasts healthy with diseased states 4 , 25 , 26 , 27 . The initial origin of disease-responsive microorganisms remains in most cases elusive; they might be associated with the plant host or with the pathogen itself. Similar to soil, plants and animals, fungal structures are also known to provide microhabitats for adapted bacterial communities; they can also be involved in destructive interactions with their hosts. Perithecia provide a highly specific ecological niche for bacteria that we hypothesized could play a pivotal role in disease establishment. Preliminary assessments of bacterial–fungal interactions in such microhabitats indicated antagonistic activity via emission of volatile bioactive metabolites 28 , 29 . At present, there is a lack of large-scale assessments of fungal fruiting body microbiomes and mechanistic insights into interactions between prevalent bacteria and their hosts. In this study, bacterial communities associated with Fg perithecia were profiled. Phylogenetically distinct bacteria were always detectable in perithecia from separated geographic locations in China. In parallel, representatives of 30 core microbiome members were cultured and screened for antagonistic activity. This resulted in the isolation of one highly active antagonist ( Pantoea agglomerans ZJU23) with pronounced antagonistic activity against FHB. We showed that herbicolin A (HA) secreted by ZJU23 is responsible for suppression of the phytopathogen. HA binds ergosterol and disrupts the integrity of ergosterol-containing fungal lipid rafts suppressing fungal growth, perithecium formation and virulence of Fg. Furthermore, we showed that HA has a wide antifungal spectrum including human opportunistic fungal pathogens, indicating a potential for its use in controlling fungal diseases in agricultural and clinical settings. Results Insights into perithecium-associated bacterial communities Using scanning electron microscopy, morphologically distinct bacteria were found to be embedded in or attached to the surface of Fg perithecia that were collected from geographically distant fields (Fig. 1a and Extended Data Fig. 1a ). For a detailed analysis of bacterial communities, we sampled perithecia, rice stubbles and rhizosphere soil from 13 sites within major wheat-growing regions (Fig. 1b and Supplementary Data 1 ). The bacterial community was profiled on the basis of bacterial 16S ribosomal RNA (rRNA) gene fragment sequences clustered into operational taxonomic", "role": "user" }, { "content": "Fusarium graminearum is a widespread pathogenic fungus that causes Fusarium head blight (FHB) in cereal crops worldwide, especially in wheat. Between 2000 and 2018, more than 4.5 million hectares were annually affected by FHB in China, or around 20% of the total planted area of wheat. This has resulted in annual production losses of more than 3.41 million tons. Researchers led by Prof. Bai Yang from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences, Prof. Chen Yun and Prof. Yu Yunlong at Zhejiang University, have recently found that F. graminearum perithecia provided a specific ecological niche for bacteria that could play an important role in disease establishment. Over 2,000 bacterial strains were isolated from the native microbiota of F. graminearum, and subsequently identified and screened for antagonistic activity. The researchers successfully recovered 113 isolates that showed antagonistic activity against the pathogen. One specific bacterial isolate, termed as ZJU23, was identified as Pantoea agglomerans, and had the strongest inhibitory ability against F. graminearum. Subsequently, they found that herbicolin A secreted by ZJU23 was responsible for the observed suppression of F. graminearum. Although herbicolin A was identified about four decades ago, its biosynthetic gene cluster and mode of action against fungi were not known. In this study, the researchers set out to investigate the biosynthetic gene cluster and mode of action against various fungi by combining various approaches, including transposon mutagenesis, liquid chromatography-mass spectrometry, atomic force microscopy and confocal microscopy. By comparing the metabolic profiles of ZJU23 and four deletion mutants of a potential biosynthesis gene cluster, they found that herbicolin A was synthesized by the AcbA-AcbJ cluster. They then proceeded to uncover the mode of action of herbicolin A against various fungi. It is important to note that the modes of action of cyclic lipopeptides against fungi are mostly unknown. It's surprise that herbicolin A was shown to disrupt lipid rafts by interacting with ergosterol, which resulted in the formation of abnormal cell membranes, and, ultimately, caused cell death. In addition, herbicolin A was found to inhibit the growth of Candida albicans and Aspergillus fumigatus, and was more effective than the clinical fungicides Amphotericin B and fluconazole. This provided important evidence for potential applications of herbicolin A beyond agriculture, for example in medicine. Overall, the researchers have deciphered the mechanism of the inhibitory effect of herbicolin A on fungi and identified its biosynthetic gene cluster. This could support future developments for sustainable management of Fusarium head blight worldwide. This work, titled \"Fusarium fruiting body microbiome member Pantoea agglomerans inhibits fungal pathogenesis by targeting lipid rafts,\" was published in Nature Microbiology. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the last 60 years, the diamond anvil cell (DAC) has emerged as the tool of choice in high pressure science because materials can be studied at megabar pressures using X-ray and spectroscopic probes. In contrast, the pressure range for neutron diffraction has been limited due to low neutron flux even at the strongest sources and the resulting large sample sizes. Here, we introduce a neutron DAC that enables break-out of the previously limited pressure range. Key elements are ball-bearing guides for improved mechanical stability, gem-quality synthetic diamonds with novel anvil support and improved in-seat collimation. We demonstrate a pressure record of 1.15 Mbar and crystallographic analysis at 1 Mbar on the example of nickel. Additionally, insights into the phase behavior of graphite to 0.5 Mbar are described. These technical and analytical developments will further allow structural studies on low-Z materials that are difficult to characterize by X-rays. It has been over 40 years since the ‘sound barrier’ of achieving the pressure of one megabar (= 100 GPa) was broken in a diamond anvil cell 1 and the field of high pressure research has dramatically advanced since. Conditions of the Earth’s core and lower mantle can now be simulated and many geophysical questions have been addressed 2 . Similarly, physical understanding of phase diagrams has immensely advanced and, for example, several new high pressure phases were identified in the ‘simplest’ of all materials, hydrogen (see recent review 3 ). Furthermore, new materials can now be synthesized through high pressure (and high temperature conditions) such as various nitrides 4 , 5 , 6 and, as of particular recent interest, superconducting superhydrides, for example 7 , 8 , 9 . Finally, the field continues to be highly active and multi-megabar pressures were recently achieved with sophisticated toroidal-shaped diamond anvils or double-stage techniques 10 , 11 , 12 . In common to many of these studies is the fact that in situ structure determination under pressure is performed through X-ray diffraction. While such in situ X-ray diffraction is very powerful, there are severe limitations when it comes to low-Z elements. Here, neutron diffraction has evolved as an important tool. Not only are neutrons sensitive to many low-Z elements, neutrons are also capable of distinguishing between different isotopes. As neutrons carry a magnetic moment, they also allow for the detection of magnetic Bragg diffraction. Thus, a number of very important questions in high pressure science can only be addressed by neutron diffraction. For example, for geophysics neutron diffraction can investigate the nature of water within minerals or can provide knowledge of the density and structure of the ices of water, methane, and other light compounds. Neutron diffraction is key for the understanding of phase diagrams of light elements such as hydrogen or carbon. In view of the recently discovered metal superhydrides, neutron diffraction can reveal the exact position of hydrogen in the metal matrix, thus providing important structural information. However, unlike X-ray diffraction, the relatively much lower neutron flux of existing neutron facilities required relatively large sample volumes thus limiting the pressure to a few tens of GPa. Until recently, typical maximum pressures at most user facilities were limited to \\(\\sim \\) 25 GPa when using Paris-Edinburgh cells 13 , although recently breakout studies up to 40 GPa have been reported 14 , 15 . To push for higher pressures, several iterations of neutron diamond anvil cells (DAC) have been developed over time. A major body of work commenced at the Kurchatov Institute in Moscow and was later transferred and further improved in France. There, studies up to 40 GPa on materials such as hydrogen 16 or on magnetic materials have been performed 17 . These studies however, were only able to identify a very small number of reflections, not sufficient for crystallographic analysis and full structure information. Consequently, several efforts world-wide have attempted to further the development of neutron DACs. These efforts focused on high-quality data obtained through single crystal diffraction at the Institute-Laue-Langevin 18 , 19 or the Forschungs-Neutronenquelle Heinz Maier–Leibnitz 20 as well as on higher pressure capabilities using powder diffraction at the Japan Proton Accelerator Research Complex (J-PARC) 21 , the Frank Laboratory of Neutron Physics 22 , as well as at Oak Ridge National Laboratory’s (ORNL) Spallation Neutron Source (SNS) 23 , 24 . Reaching megabar pressures in a neutron diffraction experiment is not simply done by up-scaling conventional DACs as used for X-ray diffraction. Typically, for reaching one megabar in a DAC, culet sizes of not more than \\(\\sim \\) 100 µm are used. For neutron diffraction, where the sample sizes must be much larger, the minimum culet size has been in the millimeter regime. This larger area increases the force requirement more than 10-fold to several metric tons usually supplied by a gas membrane or hydraulic press. The main problem is that such high forces induce significant shear stresses in the diamond cell body and thus in the diamond anvils and also exceeding the strength of the anvil seats resulting in frequent diamond anvil failure. Nonetheless, at the SNS efforts have been underway for over 10 years to develop megabar neutron diffraction. These efforts have centered on the high pressure diffractometer Spallation Neutrons and Pressure (SNAP) 25 . SNAP is a high-flux, medium-resolution instrument equipped with advanced neutron focusing optics and large area detectors that uses white-beam time-of-flight (TOF) neutron diffraction. This combination of white-beam TOF diffraction and large angular coverage presents advantages for high pressure studies, particularly increased Q -coverage, an ability to evaluate texture as well as an ability to handle blocked or heavily attenuated sections of the 2θ-range (since a significant portion of the full diffraction pattern can be measured at each 2θ due to the energy-dispersive nature of white-beam TOF diffraction). This allows for the use of absorbing materials in the pressure cell set-up, specifically gasket materials, without compromising the Q -range, a fact that has highly benefited DAC studies on SNAP 26 , 27 . Over time, several iterations of DACs", "role": "user" }, { "content": "For decades, scientists sought a way to apply the outstanding analytical capabilities of neutrons to materials under pressures approaching those surrounding the Earth's core. These extreme pressures can rearrange a material's atoms, potentially resulting in interesting new properties. A breakthrough resulted in 2022 when researchers at Oak Ridge National Laboratory's Spallation Neutron Source squeezed a tiny sample of material—sandwiched between two diamonds—to a record 1.2 million times the average air pressure at sea level, or approximately 1.2 megabar. But this was only the start—they still had to produce useful data from the experiments. Now those same scientists have implemented software that removes the signal interference affecting the neutrons as they pass through the diamonds before reaching the sample. The research is published in the journal Scientific Reports. \"Researchers can now perform neutron experiments beyond 1.0 megabar and extract accurate data about extraordinary atomic structures of materials,\" said Malcolm Guthrie, computational instrument scientist at ORNL's SNAP beamline. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nitrate (NO 3 − ) and nitrite (NO 2 − ) anions are often found in groundwater and surface water as contaminants globally, especially in agricultural areas due to nitrate-rich fertilizer use. One popular approach to studying the removal of nitrite/nitrate from water has been their degradation to dinitrogen via Pd-based reduction catalysis. However, little progress has been made towards understanding how the catalyst structure can improve activity. Focusing on the catalytic reduction of nitrite in this study, we report that Au NPs supporting Pd metal (\"Pd-on-Au NPs\") show catalytic activity that varies with volcano-shape dependence on Pd surface coverage. At room temperature, in CO 2 -buffered water, and under H 2 headspace, the NPs were maximally active at a Pd surface coverage of 80%, with a first-order rate constant ( k cat = 576 L g Pd −1 min −1 ) that was 15x and 7.5x higher than monometallic Pd NPs (∼4 nm; 40 L g Pd −1 min −1 ) and Pd/Al 2 O 3 (1 wt% Pd; 76 L g Pd −1 min −1 ), respectively. Accounting only for surface Pd atoms, these NPs (576 L g surface-Pd −1 min −1 ) were 3.6x and 1.6x higher than monometallic Pd NPs (160 L g surface-Pd −1 min −1 ) and Pd/Al 2 O 3 (361 L g surface-Pd −1 min −1 ). These NPs retained ∼98% of catalytic activity at a chloride concentration of 1 mM, whereas Pd/Al 2 O 3 lost ∼50%. The Pd-on-Au nanostructure is a promising approach to improve the catalytic reduction process for nitrite and, with further development, also for nitrate anions. 1. Introduction Nitrate (NO 3 − ) is found in the groundwater and surface water globally, especially in agricultural areas due to the use of nitrate rich fertilizers. 1–4 This anion, and its metabolic conversion to the nitrite anion (NO 2 − ), cause adverse human health effects, including methemoglobinemia or the ‘blue baby’ syndrome. 5 Nitrite can be also converted to carcinogenic N -nitroso compounds in the body, 6 which may result in cancer and hypertension. 7 The maximum contaminant levels (MCL) of NO 3 − and NO 2 − have been set at 10 mg N per L and 1.0 mg N per L (calculated by nitrogen weight, denoted as mg N per L), respectively, by the United States Environmental Protection Agency (US EPA). 8 For the European Union countries, the European Drinking Water Directive set concentration limits for NO 3 − and NO 2 − at 11.3 mg N per L and 0.15 mg N per L, respectively. 9 The World Health Organization guideline values of NO 3 − and NO 2 − are 11.3 mg N per L and 0.91 mg N per L. 10 Current methods to treat nitrate/nitrite contamination include ion exchange, reverse osmosis, biological denitrification, and catalytic reduction. 11–21 The EPA-approved treatment technologies for removing nitrates/nitrites in waters destined for drinking purposes are ion exchange and reverse osmosis, with the former being the most widely used. 22 The ion exchange approach removes nitrate/nitrite from water by replacing them with equivalent amount of anions such as chloride or bicarbonate ions. 11 The main disadvantage is that, after the ion exchange material is regenerated for further use by contacting with a brine solution, the resulting brine which contains the nitrate/nitrite anions must undergo further treatment prior to disposal. Reverse osmosis also results in a nitrate/nitrite-containing secondary stream that needs further treatment. The biological denitrification and catalytic reduction routes have been studied at the laboratory and pilot scales but they are not yet commercially practiced. Biological denitrification can selectively remove nitrate/nitrite from water, but it is affected by pH and the presence of other salts in water; it can generate undesired by-products; 15 and bacterial contamination of the treated water is a concern. 11 The catalytic reduction of nitrate/nitrite has received intense research interest ever since Pd-based catalysts ( e.g. , Pd–Cu, Pd–In and Pd–Sn) were shown capable of converting nitrate/nitrite to harmless nitrogen (N 2 ) using hydrogen. 23 This chemistry was first reported by Vorlop and Tacke in 1989 using supported Pd–Cu/Al 2 O 3 catalysts. 14 Vorlop and co-workers reported improved reduction activity using Pd–Sn/Al 2 O 3 and Pd–In/Al 2 O 3 catalysts. 24 The catalytic reduction of nitrate is generally accepted to occur in two stages: the reduction of NO 3 − to NO 2 − , and then reduction of NO 2 − to N 2 or NH 3 ( Scheme 1 ). 15,25–28 In greater detail, the second metal ( i.e. , Cu, In, Sn) reduces the chemisorbed NO 3 − species in the first step and the Pd then regenerates the oxidized metal via H 2 reduction (reaction (1) of Scheme 1 ). In the second stage, Pd by itself reduces chemisorbed NO 2 − species in several surface reaction steps, eventually to form N 2 (reaction (2)) or NH 3 (reaction (3)). Ammonia is an undesirable reaction product because it is a groundwater pollutant with a US EPA MCL of 0.66 mg N per L. 8 The Pd–Cu composition provides N 2 selectivity values as high as 80–95%, depending on the reaction testing conditions used. 19,29 Ammonia formation is favored at high pH values, and so N 2 selectivity is improved by operating the reaction at non-alkaline conditions, for example. 29 Scheme 1 General reaction pathway for the reduction of nitrate or nitrite anions using a Pd-based catalyst. M is a promoter metal such as Cu, In, and Sn. 27 While the compositional effects on catalytic nitrate/nitrite reduction have been amply studied, the effect of nanostructure is not well addressed yet. We have previously demonstrated that Pd catalytic activity for hydrodechlorination (a type of reduction reaction) can be varied with great control by depositing Pd metal on Au nanoparticles (to form Pd-on-Au NPs) at a pre-determined Pd surface coverage. 30–33 Motivating this work, we hypothesized that Pd-on-Au NPs catalyze nitrite reduction (the second stage of nitrate reduction)", "role": "user" }, { "content": "Chemical engineers at Rice University have found a new catalyst that can rapidly break down nitrites, a common and harmful contaminant in drinking water that often results from overuse of agricultural fertilizers. Nitrites and their more abundant cousins, nitrates, are inorganic compounds that are often found in both groundwater and surface water. The compounds are a health hazard, and the Environmental Protection Agency places strict limits on the amount of nitrates and nitrites in drinking water. While it's possible to remove nitrates and nitrites from water with filters and resins, the process can be prohibitively expensive. \"This is a big problem, particularly for agricultural communities, and there aren't really any good options for dealing with it,\" said Michael Wong, professor of chemical and biomolecular engineering at Rice and the lead researcher on the new study. \"Our group has studied engineered gold and palladium nanocatalysts for several years. We've tested these against chlorinated solvents for almost a decade, and in looking for other potential uses for these we stumbled onto some studies about palladium catalysts being used to treat nitrates and nitrites; so we decided to do a comparison.\" Catalysts are the matchmakers of the molecular world: They cause other compounds to react with one another, often by bringing them into close proximity, but the catalysts are not consumed by the reaction. In a new paper in the journal Nanoscale, Wong's team showed that engineered nanoparticles of gold and palladium were several times more efficient at breaking down nitrites than any previously studied catalysts. The particles, which were invented at Wong's Catalysis and Nanomaterials Laboratory, consist of a solid gold core that's partially covered with palladium. Many areas of the United States are at risk of contamination of drinking water by nitrates and nitrites due to overuse of agricultural fertilizers. Credit: USGS Over the past decade, Wong's team has found these gold-palladium composites have faster reaction times for breaking down chlorinated pollutants than do any other known catalysts. He said the same proved true for nitrites, for reasons that are still unknown. \"There's no chlorine in these compounds, so the chemistry is completely different,\" Wong said. \"It's not yet clear how the gold and palladium work together to boost the reaction time in nitrites and why reaction efficiency spiked when the nanoparticles had about 80 percent palladium coverage. We have several hypotheses we are testing out now. \" He said that gold-palladium nanocatalysts with the optimal formulation were about 15 times more efficient at breaking down nitrites than were pure palladium nanocatalysts, and about 7 1/2 times more efficient than catalysts made of palladium and aluminum oxide. Wong said he can envision using the gold-palladium catalysts in a small filtration unit that could be attached to a water tap, but only if the team finds a similarly efficient catalyst for breaking down nitrates, which are even more abundant pollutants than nitrites. \"Nitrites form wherever you have nitrates, which are really the root of the problem,\" Wong said. \"We're actively studying a number of candidates for degrading nitrates now, and we have some positive leads.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Protein kinase A (PKA), the main effector of cAMP in eukaryotes, is a paradigm for the mechanisms of ligand-dependent and allosteric regulation in signalling. Here we report the orthologous but cAMP-independent PKA of the protozoan Trypanosoma and identify 7-deaza-nucleosides as potent activators (EC 50 ≥ 6.5 nM) and high affinity ligands ( K D ≥ 8 nM). A co-crystal structure of trypanosome PKA with 7-cyano-7-deazainosine and molecular docking show how substitution of key amino acids in both CNB domains of the regulatory subunit and its unique C-terminal αD helix account for this ligand swap between trypanosome PKA and canonical cAMP-dependent PKAs. We propose nucleoside-related endogenous activators of Trypanosoma brucei PKA (TbPKA). The existence of eukaryotic CNB domains not associated with binding of cyclic nucleotides suggests that orphan CNB domains in other eukaryotes may bind undiscovered signalling molecules. Phosphoproteome analysis validates 7-cyano-7-deazainosine as powerful cell-permeable inducer to explore cAMP-independent PKA signalling in medically important neglected pathogens. Introduction The mechanisms of protein kinase regulation, specifically by small second messenger molecules, have been studied in great detail using protein kinase A (PKA) as a paradigm 1 . PKA, discovered 50 years ago, is present in most eukaryotes except plants, has a highly conserved structure, and is the main effector of the second messenger cAMP. Hence, the synonym cAMP-dependent protein kinase is commonly used. The inactive PKA holoenzyme is a complex of regulatory (PKAR) and catalytic (PKAC) subunits, either as R-C heterodimer or R 2 -2C heterotetramer. The R 2 homodimer is formed by an N-terminal dimerization/docking (DD) domain that also mediates sub-cellular localization via A kinase anchoring proteins (AKAPs). Two C-terminal cyclic nucleotide binding (CNB) domains cooperatively bind two molecules of cAMP, resulting in a conformational change of the R subunit that releases the active catalytic kinase subunit(s) from the inhibitory pseudo-substrate or substrate site of PKAR. The CNB domain is an ancient evolutionarily conserved domain family with >7500 members that confers ligand-dependent allosteric regulation to a diverse range of proteins 2 . In eukaryotes, CNB domains are bound and regulated by cyclic nucleotides. In bacterial transcription factors, some CNB domains can bind other ligands like heme in the case of the CO sensing transcription activator CooA 3 or chlorinated phenolic compounds in CprK, a member of the ubiquitous CRP-FNR family of transcription activators 4 . In metazoans, PKA has diverse functions ranging from metabolism and gene regulation to development, motility, and memory 5 . Many of these functions are tissue-specific and compartmentalized at the subcellular level 6 . In lower eukaryotes including fungi or apicomplexan protozoa like Plasmodium and Toxoplasma , PKA plays key roles in nutrient sensing, developmental switches, or infectivity processes 7 , 8 , 9 . Most species encode one or two PKAR isoforms and several PKAC isoforms 10 . The resulting holoenzyme isoforms differ in cell type-specificity, developmental expression, sub-cellular localization, and affinity to cAMP, thereby accounting for the pleiotropic functions of cAMP signalling. Trypanosoma brucei species are kinetoplastid parasites that infect a large variety of mammals, causing severe disease in domestic animals with important economic losses in endemic countries. The parasite is also causative of the deadly human African sleeping sickness, a neglected tropical disease 11 . Transmission is restricted to the habitat of the Tsetse fly in tropical Africa. Development of the parasite in the host and vector is a prerequisite for transmission. This developmental process can be induced by cAMP analogues 12 , 13 , 14 , although this is mediated by intracellular hydrolysis products of these analogues 15 operating via a complex network of effectors 16 . The parasite has been shown to release cAMP as a mechanism of evading the host’s innate immunity 17 . Essential roles of intracellular cAMP signalling have also been documented for cell division 12 , 18 , 19 , 20 and social motility 21 . It is therefore surprising that all attempts to detect cAMP-dependent kinase activity in African trypanosomes have failed 22 , 23 , 24 , 25 , 26 , 27 . Genes encoding three PKA catalytic subunit orthologues and one regulatory subunit orthologue have been identified in the T. brucei genome 22 , 26 , 28 , whereas alternative cAMP effectors like EPAC orthologues and cNMP-gated ion channels were not detected. By screening a genome-wide RNAi library for cAMP resistance in T. brucei , we identified a novel cAMP binding protein (CARP1) unique to kinetoplastids 29 , yet PKA was not among the hits of the screen. The catalytic subunits of T. brucei PKA are highly conserved with the presence of all 11 canonical kinase subdomains, the essential threonine in the kinase activation loop, and conserved residues implicated in mammalian PKAC’s binding to the regulatory PKAR subunits 30 . TbPKAR has a conserved C-terminal part with two CNB domains and the PKA substrate motif (RRT T V) that interacts with and inhibits PKAC. TbPKAR differs from its metazoan orthologues by an extended N-terminal domain with leucine-rich repeats (LRR) (Fig. 1a ). Some amino acid substitutions of consensus residues in the cAMP binding pockets have been noticed in sequence alignments 22 , 31 . The link between cAMP and PKA remains elusive in Trypanosoma in spite of the excellent overall conservation of the kinase. Fig. 1 PKA holoenzyme complexes in T. brucei . a Domain architecture of PKAR (top) and PKAC (bottom) orthologues from T. brucei (Tb) (TriTrypDB accessions: PKAR, Tb927.11.4610; PKAC1, Tb927.9.11100; PKAC2, Tb927.9.11030; PKAC3, Tb927.10.13010) compared to human (Hs) PKA (Uniprot accessions: PKARIα, P10644; PKACα, P17612). LRR leucine-rich repeat region, DD dimerization/docking domain, CNB cyclic nucleotide binding domain, kinase kinase domain. b Genotypes of cell lines with in situ tagged PKAC1 ( Ty1-C1 , cyan; Ty1 epitope tag in magenta) and PKAR ( R-PTP , blue; PTP-tag in black) compared to wild type (WT). The phleomycin resistance cassette ( BLE , grey) is indicated. c Two-colour fluorescent western blot analysis of the double tagged cell line ( ∆ c1/Ty1-C1 R-PTP ) using anti-PKAR and anti-PKAC1/2 (left panel, red signals), and anti-Ty1 and anti-PFR-A/C", "role": "user" }, { "content": "The unicellular parasite that causes sleeping sickness differs from other eukaryotes in the mode of regulation of an essential cellular signaling pathway. This provides a promising point of attack for drug development. Trypanosoma brucei, the insect-borne eukaryotic parasite that causes sleeping sickness in tropical Africa, is the best-known representative of a group of unicellular organisms known as kinetoplastids. Species belonging to this group are responsible for a number of potentially lethal infections in humans and other mammals, which are difficult to treat effectively. These include the trypanosome T. cruzi—the causative agent of Chagas disease, which is endemic to much of South America, while members of the related genus Leishmania attack the skin and mucous membranes. Leishmaniasis is a largely tropical disease, but is also found in Southern Europe. Research carried out by Ludwig-Maximilians-Universitaet (LMU) in Munich geneticist Professor Michael Boshart´s team with lead author Dr. Sabine Bachmaier and collaborators has now revealed that, in T. brucei, an essential intracellular signaling pathway is regulated differently from what has been established as a paradigm in eukaryotes. This discovery reveals a potential vulnerability, which could provide a promising target for new and specific therapies for infections caused by kinetoplastid parasites. The findings appear in the online journal Nature Communications. Protein kinase A (PKA) is an enzyme found in virtually all nucleated (eukaryotic) organisms apart from plants, and it plays a crucial role in cellular responses to external signals. In almost all eukaryotes, the enzymatic activity of PKA is dependent on binding of the molecule cAMP, which binds to the regulatory subunit of the protein. PKA is also essential for the survival of Kinetoplastida, as it has been shown to target cell division, cell motility and development in the group. However, all efforts to demonstrate a link between cAMP and PKA activity have failed. \"We have known for several years that the PKA found in T. brucei cannot be activated by cAMP, but there have been several contradictory reports in the published literature,\" Boshart explains. \"We have now comprehensively and conclusively verified this unexpected finding experimentally.\" To do so, the researchers developed an experimental test that allowed them to detect PKA activity in living trypanosomal cells. As in their earlier test-tube experiments, they found that there was no change in PKA activity when the intracellular level of cAMP was altered by chemical or genetic means. \"In collaboration with a chemist who works for a small company, we tested an array of chemical compounds which we had identified as possible alternative regulators of the kinase enzyme, based on our experimental data,\" Boshart says. The search identified a number of candidate molecules that were able to activate the typanosomal PKA. \"We then chose the most effective candidate from this set and optimized its performance by appropriately modifying its chemical structure,\" says Boshart. In this way, we obtained a compound that acted as a specific and highly potent activator of the enzyme.\" With the aid of 3-D structural analyses, they went on to show that the activator binds to the trypanosomal enzyme at the site in the regulatory subunit to which cAMP binds in PKAs from other eukaryotes. However, the detailed architecture of the binding pocket differs between the two proteins. The differences involve only two or three amino acid substitutions, but these changes suffice to ensure that cAMP no longer fits—while the synthetic alternatives fill the cavity neatly. With these alternative activators, Boshart and his colleagues now have useful tools at hand with which to probe the function(s) of PKA in the Kinetoplastida and identify the enzyme's target proteins. In addition, the results are of great interest from the therapeutic point of view. With appropriate modification, the parasite-specific activator could possibly be converted into an inhibitor of the trypanosome's PKA, without affecting the function of the mammalian host's enzyme. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We report webKnossos, an in-browser annotation tool for 3D electron microscopic data. webKnossos provides flight mode, a single-view egocentric reconstruction method enabling trained annotator crowds to reconstruct at a speed of 1.5 ± 0.6 mm/h for axons and 2.1 ± 0.9 mm/h for dendrites in 3D electron microscopic data from mammalian cortex. webKnossos accelerates neurite reconstruction for connectomics by 4- to 13-fold compared with current state-of-the-art tools, thus extending the range of connectomes that can realistically be mapped in the future. Main With the acceleration of 3D electron microscopic (EM) imaging of brain tissue 1 , 2 , 3 , image data sets sized tens of terabytes (TB) or even petabytes (PB) are becoming available. A cubic millimeter imaged at (15 nm) 3 voxel (vx) size corresponds to 0.3 PB of data ( Fig. 1a ); a mouse brain imaged at the same resolution corresponds to 110 PB of data. Single neurons typically extend over a large fraction of the data set ( Fig. 1a ), making it impracticable to distribute data on hard drives to large numbers of annotators who want to follow the processes of entire neurons. At the same time, data analysis in connectomics is limited by the amount of human annotation time that can be recruited for a given analysis project 4 . Thus, enabling efficient distributed 3D data annotation in PB-sized data sets, ideally in browser, is essential. Figure 1: In-browser 3D annotation of axons and dendrites for connectomics. ( a ) Sketch of mouse whole-brain 3D EM data set size (top) and 1 mm 3 of cerebral cortex (bottom) compared with the extent of a typical single pyramidal neuron (dendrites, magenta; axon, black). ( b ) Sketch of online data delivery modes using lateral prefetching in 2D (top, Google maps, CATMAID) and in 3D (bottom, webKnossos). ( c ) Comparison of data transmission when following a neurite using 2D image prefetching (black, in CATMAID) and 3D data prefetching in webKnossos (blue, ortho mode) under different bandwidth and latency conditions. Transcont, transcontinental access ( from Europe, custom CATMAID and webKnossos from South America, bottom to top). ( d ) webKnossos in-browser user interface with orthogonal viewports ( xy , yz , xz ), one 3D skeleton viewport, and the abstract tree viewer (right). ( e ) Sketch of viewing surface orientation (red) in orthogonal mode (top) and flight mode (bottom). ( f ) Flight-mode egocentric 3D image sampling on a hemisphere (top), yielding a single flight-mode data view (bottom). ( g ) Example of 3D prefetching in flight mode given flight direction and current position (gray, prefetched webKnossos cubes; red, flight-mode image surface). ( h ) Annotator speed training in ortho mode (black, n = 25 annotators) and flight mode (magenta, n = 26 annotators) on 40 neurites in cortex (randomly ordered per annotator). ( i ) Tracing speed test on 20 randomly selected cortical axons (including branches) performed by 26 annotators 8 weeks after training. Dashed line, first five neurites presented again from training. Solid line, 20 test axons. Box plots report tracing speed for these 20 test axons in ortho (black) and flight mode (magenta), reported over n = 26 annotators (left) and n = 20 axons (right); flight 1.51 ± 0.04 mm/h, ortho 0.96 ± 0.03 mm/h ( n = 520, mean ± s.e.m.). ( j ) Display of 20 test axons within data set boundary. ( k ) Illustration of tracing error measurement in one of the 20 axons—local errors (inset, less than 10-μm path length) and continuation errors (right). Black, ground truth; red, six-fold consolidated flight-mode tracing. ( l ) Tracing errors reported over tracing redundancy (using RESCOP 8 ) for 10 axons in ortho mode, flight mode and for 10 dendrites in flight mode (cyan), respectively. ( m ) same as l but only continuation errors (see k ). Dashed lines in l and m , path length corrected for each RESCOPed skeleton (see Online Methods ). ( n ) Relation between tracing speed and error rates for single-annotator reconstructions ( n = 30) of axons and dendrites (colors as in l and m ). Crosses indicate mean ± s.e.m. ( o ) same as n for continuation errors only. ( p ) Summary comparison of annotation time requirements for neurite reconstruction. Data from c , (black, webKnossos, ; red, CATMAID) and from i and n (crosses). Asterisk, annotation consumption documented in published work; pyK, consumption by experienced annotators 10 ; K, KNOSSOS annotation consumption from refs. 8 , 11 and 12 . Source data Full size image The existing in-browser annotation tool for connectomics, CATMAID 5 , 6 , uses efficient data storage and transmission in 2D image planes (comparable to Google Maps 7 ), which are sequentially browsed ( Fig. 1b ). While this approach makes data viewing and annotation seamless in the plane of imaging, 3D neurite tracing is slowed down by the time required to progress to the subsequent image plane. Under ideal high-bandwidth, low-latency connectivity conditions (like those within research institutions), this approach yields a reconstruction speed of about 470 μm/h when an expert follows an axon through 3D serial blockface EM (SBEM 1 ) data from mouse cortex ( Fig. 1c ). Under less optimal bandwidth and latency conditions (as are often experienced by student annotators at home and in mobile settings), however, reconstruction speed drops to 59–88 μm/h (measured for regular 3G connectivity and for transcontinental access, Fig. 1c ). webKnossos ( Fig. 1d , ) uses 3D data storage and transmission in small cubic packages of 32 3 vx ( Fig. 1b ). Cubic 3D image data storage using cubes of 128 3 vx is being employed in KNOSSOS 8 and pyKNOSSOS 9 , 10 , standalone data annotation applications for connectomics. We reduced 3D cube size to 32 3 vx for lag-free in-browser data transmission and for enabling the flight-mode data visualization introduced below. webKnossos enables data interaction in 3D EM images displayed in orthogonal planes ( Fig. 1d", "role": "user" }, { "content": "Scientists working in connectomics, a research field occupied with the reconstruction of neuronal networks in the brain, are aiming at completely mapping of the millions or billions of neurons found in mammalian brains. In spite of impressive advances in electron microscopy, the key bottleneck for connectomics is the amount of human labor required for the data analysis. Researchers at the Max Planck Institute for Brain Research in Frankfurt, Germany, have now developed reconstruction software that allows researchers to fly through the brain tissue at unprecedented speed. Together with the startup company scalable minds they created webKnossos, which turns researchers into brain pilots, gaining an about 10-fold speedup for data analysis in connectomics. Billions of nerve cells are working in parallel inside our brains in order to achieve behaviours as impressive as hypothesizing, predicting, detecting, thinking. These neurons form a highly complex network, in which each nerve cell communicates with about one thousand others. Signals are sent along ultrathin cables, called axons, which are sent from each neuron to its about one thousand \"followers.\" Only thanks to recent developments in electron microscopy, researchers can aim at mapping these networks in detail. The analysis of such image data, however, is still the key bottleneck in connectomics. Most interestingly, human annotators are still outperforming even the best computer-based analysis methods today. Scientists have to combine human and machine analysis to make sense of these huge image datasets obtained from the electron microscopes. Virtual flight through the brain A research team led by Moritz Helmstaedter, director at the Max Planck Institute for Brain Research, has now found a novel highly efficient method of presenting these 3-dimenional images in-browser in such an intuitiv way that humans can fly at maximum speed along the cables in the brain. Achieving unprecedented 1,500 micrometers per hour, human annotators can still detect the branch points and tortuous paths of the axons (Boergens, Berning et al. Nature Methods, 2017). \"Think of racing at 100 mph through a curvy, hilly village\", compares Helmstaedter. Researchers think that this flight speed is the maximum humans can achieve in 3-D electron microscopic data of brain tissue – since the visualization is centered on the brain pilot, like in a plane, the steering is highly optimized for egocentric navigation. When combined with computer-based image analysis, the human part of data analysis in connectomics is now likely maximal, about 10-times faster than before. The recruiting software gives users the impression of sitting in the cockpit of an airplane. Credit: MPI f. Brain Research/ Julia Kuhl (Some Donkey) One key prerequisite for this success was the development of efficient data transmission and flight path prediction. The webKnossos software was developed in close collaboration with a computer science startup from Potsdam, Germany, called scalable minds. Over the five-year collaboration the unusual task of making gray-scale brain data usable in online data visualization was both challenging and rewarding, says Norman Rzepka, co-author of the study and one of the co-founders of the company. With human data analysis at its maximum, the researchers are now back to optimizing the computer part of the analysis – such that the precious human time is used most effectively for our scientific questions. Only when machines and humans collaborate optimally, connectomics can thrive in today's neuroscience. Flight through the brain. The \"pilot\" follows a dendrite and reaches 2,500 micrometers per hour almost effortlessly when following a dendrite. Sites of branching are indicated. Credit: MPI for Brain Research ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Neonates are protected from colonizing bacteria by antibodies secreted into maternal milk. Necrotizing enterocolitis (NEC) is a disease of neonatal preterm infants with high morbidity and mortality that is associated with intestinal inflammation driven by the microbiota 1 , 2 , 3 . The incidence of NEC is substantially lower in infants fed with maternal milk, although the mechanisms that underlie this benefit are not clear 4 , 5 , 6 . Here we show that maternal immunoglobulin A (IgA) is an important factor for protection against NEC. Analysis of IgA binding to fecal bacteria from preterm infants indicated that maternal milk was the predominant source of IgA in the first month of life and that a relative decrease in IgA-bound bacteria is associated with the development of NEC. Sequencing of IgA-bound and unbound bacteria revealed that before the onset of disease, NEC was associated with increasing domination by Enterobacteriaceae in the IgA-unbound fraction of the microbiota. Furthermore, we confirmed that IgA is critical for preventing NEC in a mouse model, in which pups that are reared by IgA-deficient mothers are susceptible to disease despite exposure to maternal milk. Our findings show that maternal IgA shapes the host–microbiota relationship of preterm neonates and that IgA in maternal milk is a critical and necessary factor for the prevention of NEC. Main NEC is associated with decreased diversity and increased numbers of Enterobacteriaceae in the intestinal microbiota; however, this is not sufficient to cause the disease 7 , 8 . Bioactive components of maternal milk, including IgA antibodies, shape the neonatal microbiota 9 , 10 , 11 , 12 . It is not known how the anti-bacterial IgA repertoire in maternal milk varies between women; however, IgA-producing B cells in the mammary glands originate in the intestine and thus may differ between mothers as a result of individualized microbiomes and infectious histories 13 , 14 , 15 . We hypothesized that differential binding of the preterm microbiota by maternal IgA is a central feature of NEC pathogenesis. To analyze immunoglobulin binding of gut bacteria in preterm infants, we stained fecal samples (Table 1 ) with anti-human IgA, IgM and IgG antibodies and measured the immunoglobulin-bound populations using flow cytometry 16 , 17 . This initial sample set contained 30 samples collected at the time of NEC diagnosis and 39 samples from age-matched controls. Surveyed across all samples, the percentage of IgA-bound bacteria was far greater than the percentages of IgM- and IgG-bound bacteria and samples from maternal-milk-fed infants contained a far greater abundance of IgA-bound (IgA + ) bacteria compared to formula-fed infants (Fig. 1a,b and Extended Data Fig. 1a,b ). Although a majority (11 out of 19) of formula-fed infants had less than 1% of their intestinal bacteria bound by IgA, some samples from formula-fed infants contained high amounts of IgA + bacteria (Fig. 1b ). Because B cells generally do not populate the intestine until about 4 weeks of age 18 , we hypothesized that fecal samples from formula-fed infants collected before this time point would not contain IgA-bound bacteria. Indeed, we found a significant temporal relationship between age and IgA binding in formula-fed infants that was not observed among maternal-milk-fed infants (Fig. 1c ). A dedicated analysis of samples from a single formula-fed preterm infant revealed no IgA + bacteria in the first 4 weeks of life, strongly indicating that maternal milk was the primary source of perinatal IgA (Extended Data Fig. 1c ). Limiting our analysis of this data set to 40 days after delivery, we found that samples from infants with NEC contained less IgA-bound bacteria than samples from age-matched controls (Fig. 1d ). However, infants with NEC in this cohort were more likely to be formula fed; additionally, their fecal samples were collected after NEC was diagnosed and treatment had been initiated with antibiotics and cessation of feeding. To eliminate the impact of these confounding variables, we selected and analyzed a prospectively collected longitudinal series of samples from 23 milk-fed preterm infants, of which 43.4% subsequently developed NEC (Table 1 ). Notably, we found that the fraction of IgA + bacteria decreased with time among infants that developed NEC, whereas IgA binding of fecal bacteria showed no relationship in controls (Fig. 1e and Extended Data Fig. 2a,b ). Thus, it appears that in infants who developed NEC, a change occurs in either the intestinal microbiota or the maternal IgA repertoire that leads to the ‘escape’ of intestinal bacteria from binding. Table 1 Study characteristics Full size table Fig. 1: IgA binding to the intestinal bacteria of preterm infants is positively correlated with maternal milk feeding and negatively correlated with the development of NEC. Flow cytometry analysis of bacterial IgA binding on fecal samples from preterm infants. a , Example of IgA staining of samples from preterm infants. b , Percentage of IgA-bound bacteria from infants fed with maternal milk fed ( n = 50) or formula ( n = 19). The box represents the number of samples with <1% IgA binding of intestinal bacteria. Two-sided Mann–Whitney U -test, data are mean ± s.e.m. c , Percentage of IgA binding was correlated by linear regression with time after delivery for infants fed with maternal milk ( n = 50) and formula ( n = 19); Pearson’s correlation coefficient. d , Percentage IgA-bound bacteria from controls ( n = 28) or infants diagnosed with NEC ( n = 23), from samples collected before DOL 40. Two-sided Mann–Whitney U -test, data are mean ± s.e.m. b – d , Samples from infants fed with maternal milk are indicated by black circles, samples from infants fed with formula are indicated by open red squares. e , Percentage IgA-bound intestinal bacteria from prospectively collected longitudinal samples of patients that will develop NEC ( n = 10 patients, n = 39 samples) and controls ( n = 13, n = 59) for each analyzed DOL. Patients are shown in different colors. Linear regression and Pearson’s correlation coefficient. Source Data Full size", "role": "user" }, { "content": "A new study from the University of Pittsburgh and UPMC Children's Hospital of Pittsburgh finds that an antibody in breastmilk is necessary to prevent necrotizing enterocolitis (NEC)—an often deadly bacterial disease of the intestine—in preterm infants. Immunoglobulin A (IgA) antibodies bind to bacteria in the gut, and, according to the study, the more bacteria that's tied up with IgA, the less likely babies are to develop NEC. Since preterm infants get IgA only from mothers' milk in their fragile first weeks of life, the authors emphasize the importance of breastmilk for these babies. The study appears today in Nature Medicine. \"It's been well known for a decade that babies who get NEC have particular bacteria—Enterobacteriaceae—in their guts, but what we found is that it's not how much Enterobacteriaceae there is, but whether it's bound to IgA that matters. And that's potentially actionable,\" said senior author Timothy Hand, Ph.D., assistant professor of pediatric infectious diseases at the R.K. Mellon Institute for Pediatric Research and Pitt's School of Medicine. The researchers looked at fecal samples from 30 preterm infants with NEC and 39 age-matched controls. Overall, breastmilk-fed babies had more IgA-bound gut bacteria than their formula-fed peers, and those who developed NEC were more likely to have been formula-fed. Tracking these infants' gut microbiomes over time, Hand's team found that for the healthy babies, Enterobacteriaceae was largely tied up by IgA, allowing diverse bacterial flora to flourish. But for the NEC infants in the days leading up to diagnosis, IgA-unbound Enterobacteriaceae was free to take over. To demonstrate causation between IgA and NEC, Hand and his team used a mouse model. \"Mice, when they're born, are equivalent in their intestinal development to a human baby born at 24 weeks,\" said lead author Kathyayini Gopalakrishna, M.D., a Ph.D. student in the Pitt Graduate School of Public Health's Department of Human Genetics, \"so they're a perfect model to study NEC in preterm infants.\" The researchers bred mice that couldn't produce IgA in their breastmilk. Pups reared on IgA-free milk were just as susceptible to NEC as their formula-fed littermates. So, breastfeeding in and of itself is not sufficient for NEC prevention. The milk must contain IgA to confer this specific benefit. But the solution for NEC may not be as simple as putting IgA into formula, Hand said. Because breastmilk has other benefits beyond IgA, donor milk is still the best option to fill the gap when breastfeeding or providing pumped maternal milk isn't an option. \"What we showed is that IgA is necessary but may not be sufficient to prevent NEC,\" Hand said. \"What we're arguing is that you might want to test the antibody content of donor milk and then target the most protective milk to the most at-risk infants.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cities are economically open systems that depend on goods and services imported from national and global markets to satisfy their material and energy requirements. Greenhouse Gas (GHG) footprints are thus a highly relevant metric for urban climate change mitigation since they not only include direct emissions from urban consumption activities, but also upstream emissions, i.e. emissions that occur along the global production chain of the goods and services purchased by local consumers. This complementary approach to territorially-focused emission accounting has added critical nuance to the debate on climate change mitigation by highlighting the responsibility of consumers in a globalized economy. Yet, city officials are largely either unaware of their upstream emissions or doubtful about their ability to count and control them. This study provides the first internationally comparable GHG footprints for four cities (Berlin, Delhi NCT, Mexico City, and New York metropolitan area) applying a consistent method that can be extended to other global cities using available data. We show that upstream emissions from urban household consumption are in the same order of magnitude as cities’ overall territorial emissions and that local policy leverage to reduce upstream emissions is larger than typically assumed. Introduction Cities worldwide strive to reduce their greenhouse gas emissions. A plethora of city networks such as the Global Covenant of Mayors for Climate & Energy, C40, International Council for Local Environmental Initiatives (ICLEI), and the Global Parliament of Mayors have emerged to foster and motivate cooperation in cutting urban GHG emissions. In 2017, 7,500 cities worldwide, representing 685 million people, were signatories of the Global Covenant of Mayors for Climate & Energy (the largest of those networks) and have declared emission reduction targets 1 . The 20 major cities in the Carbon Neutral Cities Network have pledged to become climate neutral 2 . Non-state Actor Zone for Climate Action (NAZCA), the UNFCCC online platform which tracks the climate commitments of non-state actors, lists more than 2,500 cities and many more have pledged to reduce their emissions by joining a growing number of dedicated city networks 3 . Although these initiatives increasingly recognize the inherent socio-metabolic openness of cities that inevitably leads to resource use and associated GHG emissions occurring outside the city boundaries 4 , 5 most cities still focus their reduction efforts entirely on the emissions released directly from their territory 6 . The vast majority of cities apply a perspective similar to the IPCC and OECD guidelines for national economies, where GHG emissions are attributed to the actors (households, firms, institutions) within the administrative territory on whose property or under whose legal control the emissions originate: e.g. the emissions from cement manufacturing are attributed to the cement producing company and the emissions from coal fired power plants to the electricity company. This traditional approach to allocate emissions is called territorial or production approach 4 , 7 . Figure 1a illustrates this for urban emissions. The territorial approach accounts for the direct emissions from all socio-economic actors within the city’s boundaries. There are the urban producers of goods and services and their associated transport (symbolized by a factory and a truck symbol in dark black in Fig. 1a ). There are the final consumers, typically broken down into household consumption, government consumption and fixed gross capital (investments in durable goods, e.g. public infrastructure). It is important to note that economically we distinguish between two types of actors, producers and final consumers, whereas in GHG accounting all economic actors are producers of direct emissions (symbolized by undulate lines in Fig. 1 ). Figure 1 Conceptual comparison between territorial GHG emission accounting ( a ) and the GHG footprint ( b ). Territorial emissions include the entirety of emissions that occur within the city boundary. These are direct emissions from production (goods & services, transport) and final consumption (households, government, gross fixed capital formation). Because they also include urban production for exports, territorial emissions are often indicative of the economic structure of a city (e.g. in the presence of heavy industry). The GHG footprint, instead, puts the focus on consumption within the city boundary. In this study it includes direct and upstream GHG emissions from household consumption. The former occur within the city boundary (e.g. heating and private transport), the latter may occur anywhere in the world (including within the city) and require analysing the entire supply chain of urban consumption. The GHG footprint is indicative of the consumption pattern of urban households. Full size image A consumption perspective takes a different view 7 . As the name suggests, here emissions are attributed not to the economic producer but to the economic (final) consumer of a good or service. For example, emissions are attributed to the person consuming electricity at home rather than to the power company, or to the person eating a steak, rather than to the farmer who produced it. In summary, the emissions attributable to the goods and services purchased by local final consumers but occurring along the entire production chains of the purchased goods and services are called upstream or embodied emissions. As global production chains continue to become longer and more complex, the difference between these two accounting perspectives has become considerable already at the national scale 8 . This observed separation of the geographic locations of production and consumption is even more pronounced for cities which are inherently open socio-metabolic systems. Today, urban upstream emissions often exceed those directly emitted on a city’s territory 9 , 10 . This fact limits the effectiveness of climate mitigation policies based on territorial emissions alone 11 , 12 . The reasons why current urban climate change mitigation initiatives overwhelmingly focus on territorial emissions are both pragmatic and political. Local decision makers are often unaware of the relevance of upstream emissions. The literature on upstream urban emissions is sparse and comparisons among cities are hampered by differences in methods, classifications and terminology 4 , 13 . The large number of city networks, each with different guidelines for urban emission inventories contribute to this problem", "role": "user" }, { "content": "Greenhouse gas emissions caused by urban households' purchases of goods and services from beyond city limits are much bigger than previously thought. These upstream emissions may occur anywhere in the world and are roughly equal in size to the total emissions originating from a city's own territory, a new study shows. This is not bad news but in fact offers local policy-makers more leverage to tackle climate change, the authors argue in view of the UN climate summit COP23 that just started. They calculated the first internationally comparable greenhouse gas footprints for four cities from developed and developing countries: Berlin, New York, Mexico City, and Delhi. Contrary to common beliefs, not consumer goods like computers or sneakers that people buy are most relevant, but housing and transport - sectors that cities can substantially govern. \"It turns out that the same activities that cause most local emissions of urban households - housing and transport - are also responsible for the majority of upstream emissions elsewhere along the supply chain,\" says lead-author Peter-Paul Pichler from the Potsdam Institute for Climate Impact Research (PIK). \"People often think that mayors cannot do much about climate change since their power is restricted to city limits, but their actions can have far-reaching impacts. The planned emission reductions presented so far by national governments at the UN summit are clearly insufficient to limit global warming to well below 2 degrees Celsius, the target agreed by 190 countries, therefore additional efforts are needed.\" Housing and transport cause most city emissions, locally but also upstream Cement and steel used for buildings take a huge amount of energy - typically from fossil fuels - to be produced, for instance. If a city instead chooses to foster low carbon construction materials this can drastically reduce its indirect CO2 emissions. Even things that cities are already doing can affect far-away emissions. Raising insulation standards for buildings for example certainly slashes local emissions by reducing heating fuel demand. Yet it can also turn down the need for electric cooling in summer which reduces power generation and hence greenhouse gas emissions in some power plant beyond city borders. In transport, expanding public facilities can minimize local emissions from car traffic. This reduces the number of cars that need to be built somewhere else, using loads of energy. So this is a win-win. But, again, more can be done. Cities can decide from which sources they procure the power needed to run, for instance, their subway trains or electric buses. By choosing energy from solar or wind, city governments could in fact close down far-away coal-fired power plants. Comparison of New York, Berlin, Mexico City, Delhi - applicable to cities across the world Interestingly, while the greenhouse gas footprint in the four cities that the scientists scrutinized range from 1.9 (Delhi) to 10.6 tons (New York) of CO2 equivalent per person and year, the proportions of local to upstream household emissions as well as the relative climate relevance of housing and transport turn out to be roughly the same. The international reach of upstream emissions is vast but varies. In terms of emissions, Berlin's global hinterland is largest, with more than half of its upstream emissions occurring outside of Germany, mostly in Russia, China and across the European Union. But also around 20% of Mexico City's considerably smaller upstream emissions occur outside Mexico, mainly in the US and China. \"Measuring indirect emissions of urban populations so far has often been considered to be unfeasible, at least in a way that makes it possible to compare different cities,\" says Helga Weisz, senior author of the study and a research domain co-chair at PIK. \"We show that it is possible, but you have to invest the effort to actually do it.\" Her team analyzed huge amounts of existing data on economic input and output of different regions and successfully combined these with data on emission intensity of production in a lot of different sectors. The methodology that the scientists put together is in principle applicable in any place, enabling more effective collaboration between cities to reduce greenhouse gas emission footprints. \"The power of cities, open interconnected systems of great density, to tackle climate change even in times of uncertainty on the national and international level has been underestimated by both many local decision-makers and most of the international community,\" says Weisz. \"Cities must be encouraged and enabled to focus on their full emission spectrum - local and upstream - as they continue to develop their climate mitigation plans.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9–PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation. Introduction Despite medical advances, the global burden of ischaemic heart disease is increasing 1 , 2 . Pro-inflammatory macrophage activation plays key roles in the pathogenesis of many disorders, including arterial disease 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Some pathways associated with macrophage activation may contribute to the shared mechanisms of inflammatory diseases, as demonstrated previously 11 , 12 . Despite potent therapies such as cholesterol-lowering by statins, substantial residual cardiovascular risk remains 7 , 13 , 14 , which drives the active search for novel solutions against pro-inflammatory macrophage activation. Dissecting complex and intertwined mechanisms for macrophage activation requires well-defined mechanistic models. The evidence suggests that distinct types of macrophage activation are functionally different in disease pathogenesis, a classification that has helped to assess the heterogeneity of macrophages 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . For instance, pro-inflammatory and anti-inflammatory phenotypes can oppose one another, develop in response to distinct cytokines, differ in the activating stimuli and produce different cytokines. A recently proposed nomenclature suggests that each macrophage subpopulation can be called based on a specific stimulator, for example, M(IFNγ), M(LPS), M(IL-4), M(IL-10) 21 . This established paradigm demonstrates clear relationships between classical stimuli and their respective responses—interferon gamma (IFNγ) for pro-inflammatory activation in settings such as atherosclerotic vascular disease and interleukin (IL)-4 for activation that can counter that of M(IFNγ) or M(LPS) macrophages. Hence, we used this paradigm as a starting point to explore novel regulators through global proteomics. Proteomics screening and bioinformatics in mouse and human data sets found that poly ADP-ribose polymerase 14 (PARP14), also known as ADP-ribosyltransferase diphtheria toxin-like 8 (ARTD8), and PARP9/ARTD9 both increased in M(IFNγ) and decreased in M(IL-4) cells. The network analysis associated these PARP family members with human arterial disease. Sequence similarity to the PARP catalytic domain, which transfers ADP-ribose moieties from NAD to protein acceptors, characterizes the PARP family proteins 23 . The best-characterized member, PARP1/ARTD1, represents poly-ADP-ribosylation enzymes, which processively catalyse long and branching polymers of ADP-ribose additions starting from an initial post-translational modification, commonly of glutamate. Recent evidence also validates proteins that execute mono-ADP-ribosylation as having various functions 24 . PARP14/ARTD8 is an intracellular mono-ADP-ribosyltransferase. Previous reports indicated that PARP14 enhances IL-4-induced gene expression by interacting with the cytokine-induced signal transducer and activator of transcription 6 (STAT6) in B and T cells, thereby functioning as a transcriptional co-activator 25 , 26 that may mediate this effect. A recent study reported that PARP14 regulates the stability of tissue factor mRNA in M(LPS) in mouse 27 . Less information exists regarding the molecular function of PARP9/ARTD9. Although PARP9 appears to lack catalytic activity 28 , it increases IFNγ-STAT1 signalling in B-cell lymphoma 29 . This study employed a multidisciplinary approach, including proteomics, systems biology and cell and molecular biology to explore new mechanisms for modulating the functional profile elicited after macrophage activation. Mouse and human cell lines as well as primary macrophages were used for complementary analyses of PARP14-deficient mouse and human tissues. Ultimately, the analyses led to evidence that expression of PARP14 in haematopoietic cells restrains vascular inflammation in mouse models, which are not solely regulated by either IFNγ or IL-4. Our findings suggest a novel mechanism for regulating the balance of macrophage phenotypes in vascular disease, and potentially other disorders in which macrophage activation has an impact on outcomes. Results Proteomics screening for regulators of macrophage activation We used the tandem mass tagging (TMT) quantitative proteomics to identify regulators of pro-inflammatory and non/anti-inflammatory activation in mouse RAW264.7 and human THP-1 macrophage cell lines ( Supplementary Fig. 1a–c ). In this paradigm of macrophage heterogeneity, IFNγ and IL-4 promote distinctive subpopulations 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . A pilot TMT proteomic study ( Supplementary Figs 1d and 2 ) analysed the changes in the proteomes at 0, 12 and 24 h, and observed the expected increase and decrease in STAT1 in M(IFNγ) and M(IL-4) cells, respectively, as determined by hierarchical cluster analysis ( Supplementary Fig. 2 ). Within this pilot study, we first noted that PARP14 co-clustered with STAT1 in the M(IFNγ) and M(IL-4) data ( Supplementary Fig. 2 ). To ascertain whether any changes in the M(IFNγ) and M(IL-4) proteomes were not because of cell culture conditions, we performed a second, more in-depth study that included an unstimulated macrophage control for both RAW264.7 and THP-1 experiments, and extended the stimulation period to up to 72 h, sampling six time points for a more detailed time-resolved proteomic study ( Supplementary Fig. 1d ). In this latter proteomic study, we quantified 5,137 and 5,635 proteins in RAW264.7 and THP-1 cells, respectively, across the three conditions: unstimulated control, IFNγ-stimulated macrophages and IL-4-stimulated macrophages—M(-), M(IFNγ) and M(IL-4), respectively ( Fig. 1a and Supplementary Table 1 ). An overview of the protein intensities across the three conditions revealed that the magnitude of protein abundance levels for each of the IFNγ and IL-4-stimulated RAW264.7 and THP-1 cells were generally higher than those of unstimulated cells ( Fig. 1b ), indicating that each", "role": "user" }, { "content": "Researchers at Brigham and Women's Hospital have found two new potential drug targets for treating arterial diseases such as atherosclerosis. By using proteomics to screen a vast number of molecules, the researchers identified PARP9 and PARP14 - two members of the PARP family of proteins - as regulators of macrophage activation, which has been linked to arterial disease by systems biology. Though the mechanisms that activate macrophages, a type of digestive white blood cell that targets foreign cells, remain incompletely understood, previous research shows that macrophages play an important role in the development of atherosclerosis and its thrombotic complications. Masanori Aikawa, MD, PhD, director of the Center for Interdisciplinary Cardiovascular Sciences (CICS) at the Brigham, his research fellow Hiroshi Iwata, MD, PhD, and colleagues studied atherosclerosis on the protein-level to determine which molecules were most involved in the regulation of macrophages. Once Aikawa and his colleagues narrowed down their search to these two proteins, they silenced each gene in cultured macrophages and found that tamping down PARP14 increased macrophage activation while tamping down PARP9 had the opposite effect. Aikawa founded CICS and hopes that this hypothesis-generating method can be used to streamline the lengthy process of drug development. Aikawa and CICS are using a more systematic approach which hinges on network analysis; this analysis predicts which pathways are most likely to control their studied effect so that they can prioritize these pathways. Ideally, this process would take a fraction of the time in comparison to searching through each individual pathway unaware of their likelihood of affecting their studied effect. Aikawa and his colleagues plan to augment these findings to develop targeted therapeutics for atherosclerosis and other diseases. \"Macrophage activation plays a role in not only vascular disorders but also various inflammatory and autoimmune diseases,\" said Aikawa. \"These results could provide important information about the mechanisms of these diseases and help to develop much needed new therapeutics.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although Cu/ZnO-based catalysts have been long used for the hydrogenation of CO 2 to methanol, open questions still remain regarding the role and the dynamic nature of the active sites formed at the metal-oxide interface. Here, we apply high-pressure operando spectroscopy methods to well-defined Cu and Cu 0.7 Zn 0.3 nanoparticles supported on ZnO/Al 2 O 3 , γ-Al 2 O 3 and SiO 2 to correlate their structure, composition and catalytic performance. We obtain similar activity and methanol selectivity for Cu/ZnO/Al 2 O 3 and CuZn/SiO 2 , but the methanol yield decreases with time on stream for the latter sample. Operando X-ray absorption spectroscopy data reveal the formation of reduced Zn species coexisting with ZnO on CuZn/SiO 2 . Near-ambient pressure X-ray photoelectron spectroscopy shows Zn surface segregation and the formation of a ZnO-rich shell on CuZn/SiO 2 . In this work we demonstrate the beneficial effect of Zn, even in diluted form, and highlight the influence of the oxide support and the Cu-Zn interface in the reactivity. Introduction The utilization of fossil fuels as the main energy source gives rise to serious environmental issues, including global warming caused by the continuously increasing level of atmospheric CO 2 . The hydrogenation of CO 2 is an important process to valorize CO 2 by converting it into useful chemicals and fuels, such as methanol 1 , 2 , 3 , 4 . Methanol is presently industrially synthesized from CO 2 , CO, and H 2 at pressures between 50 and 100 bar and temperatures between 200 and 300 °C using Cu/ZnO/Al 2 O 3 catalysts 5 , 6 , 7 . Although Cu/ZnO-based catalysts have been long studied, the role and the dynamic nature of the active sites that originate at the metal-oxide interface under the strongly reducing reaction conditions are still under debate. It has been shown that Cu-based catalysts containing ZnO are more active than their ZnO-free counterparts 8 and that ZnO both enhances the dispersion of the Cu nanoparticles (NPs), and acts as an electronic promoter 8 , 9 through a strong metal-support interaction 8 , 9 , 10 . This promoting effect of Zn has been attributed to the Zn being present in a number of different configurations: the formation of graphitic ZnO x layers on Cu NPs 11 , metallic Zn atoms within the Cu NP surface 12 , CuZn alloy formation 13 , Zn-decoration of stepped Cu surfaces 1 , or the formation of ZnO at the interface with Cu in single crystals 3 , 14 . A strong correlation between the Zn coverage on Cu NPs and the methanol synthesis activity was also reported 2 . Furthermore, the structure-sensitivity and size-dependent activity for this reaction were shown for Cu and CuZn-based catalysts 4 . Heterogeneous catalysts are dynamic entities and adapt their morphology and electronic structure to the chemical potential of the surrounding gaseous atmosphere 15 , 16 . Thus, for methanol synthesis catalysts, operando studies in pressure regimes that are industrially relevant (20–100 bar), as the ones discussed in the present work, are key to overcome the “pressure gap” 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , as they probe Cu and Zn under their actual working state, unraveling their active chemical and structural state. Investigations on Cu/ZnO systems revealed the presence of poorly crystalline ZnO interacting with Cu 15 , reversible changes of the Cu NP morphology depending on the reaction conditions 17 , 23 , CuZn bulk alloy formation under severe reduction conditions (600 °C in CO/H 2 ) 17 , 26 , and ZnO reduction and a stronger CuZn interaction for catalysts supported on SiO 2 19 , 20 , 21 . Interestingly, even at sub-atmospheric pressures (1–2 mbar) 27 , the dynamic behavior of these catalysts has also been corroborated with the observation of wetting/non-wetting of Cu NPs on ZnO 28 . Despite the tremendous effort dedicated to the investigation of this reaction, questions still remain on whether metallic Zn/brass is present under industrially relevant reaction conditions, its role in the reaction selectivity, and whether ZnO is needed as a part of the support, or small ZnO ensembles in direct contact with Cu within a NP can also serve to activate CO 2 . To address these questions, here we use morphologically and chemically well-defined Cu and CuZn NP catalysts that help close the materials gap between the heterogeneous industrial catalysts and the model single-crystal systems previously studied, while also addressing the pressure gap through operando spectroscopic characterization at industrially relevant high-pressure conditions. The small NP size chosen in our study allows us to investigate the changes occurring at the surface and near-surface region of the NPs by the bulk-sensitive technique X-ray absorption spectroscopy (XAS), since the fraction of atoms at the surface of Cu NPs of ca. 3 nm is ~60% 29 . In this way, we are able to shed light on the dynamic evolution of the metal NP/oxide support interface during CO 2 + CO hydrogenation. Results Model catalysts synthesis and characterization Five catalysts, designed to be analogous to the commercial Cu/ZnO/Al 2 O 3 catalyst, composed of size-controlled NPs were synthesized to investigate the different components and interactions of the industrial catalyst. Monometallic Cu NPs were deposited on (i) ZnO/Al 2 O 3 , (ii) SiO 2 , (iii) γ-Al 2 O 3 , and bimetallic Cu 0.7 Zn 0.3 NPs on (iv) SiO 2 , and (v) γ-Al 2 O 3 . The NPs were prepared following an inverse micelle encapsulation method. Figure 1a shows an atomic force microscopy (AFM) image of the Cu NPs with a mean height of 3.1 ± 0.8 nm. Similar data were obtained for the Cu 0.7 Zn 0.3 NPs (Supplementary Figure 1 ). A Cu/Zn ratio of 70/30 was chosen for the bimetallic NPs to assure sufficient promotion of Cu by Zn 4 . The powder catalysts were synthesized by incipient wetness impregnation", "role": "user" }, { "content": "The current commercial production of methanol through the hydrogenation of the green-house gas CO2 relies on a catalyst consisting of copper, zinc oxide and aluminum oxide. Even though this catalyst has been used for many decades in the chemical industry, unknowns still remain. A team of researchers from the Interface Science Department of the Fritz-Haber-Institute of the Max Planck Society, the Ruhr-University Bochum, Stanford Linear Accelerator Center (SLAC), FZ Juelich and Brookhaven National Laboratory have now elucidated the origin of intriguing catalytic activity and selectivity trends of complex nanocatalysts while at work. In particular, they shed light on the role of the oxide support and unveiled how the methanol production can be influenced by minute amounts of zinc oxide in close contact with copper. Methanol can serve as an energy source or as a raw material for the production of other chemicals, with over 60 million metric tons produced yearly. The traditional copper, zinc oxide and aluminum oxide catalyst converts synthesis gas, which is composed of H2, CO and CO2, into methanol. Though reliable, this specific catalyst's efficiency changes over time, thus affecting its longevity, as is the case with many catalysts. \"We therefore studied copper and mixed copper-zinc nanoparticles on various oxide supports to understand how they interact and evolve and unravel the role of each catalyst constituent. This knowledge will serve to improve future catalysts.\" says Núria Jiménez Divins, one of the lead authors of the study. The team investigated the catalytic process under realistic reaction conditions reproducing those applied in the industrial process, meaning high pressures (20-60 bar) and mild temperatures. This required synchrotron-generated X-ray radiation. Simon R. Bare from the Stanford Synchrotron Radiation Lightsource, who contributed to the experiments, explains: \"Reactions at such temperature and high pressures need to take place in a closed container which should also be transparent for the X-rays, which makes the measurements challenging. The special reactor design in combination with synchrotron radiation allowed us to undertake so-called operando-measurements, where we watched live what happens to the catalytic components at the industrially relevant reaction conditions.\" This allowed the researchers to follow not just the birth and death of the catalyst, but also its development and transformations leading to changes in its activity and selectivity. By combining results from microscopy, spectroscopy and catalytic measurements, the team found that some supports had a more positive influence on the performance of the catalyst than others because of how they interacted with zinc oxide, which was available in a highly dilute manner as part of Cu-Zn nanoparticles. On silicon oxide supports, zinc oxide was partially reduced to metallic zinc or gave rise to a brass alloy during the catalytic process, which over time proved to be detrimental for the methanol production. When using aluminum oxide as a support, zinc interacts strongly with the support and gets incorporated in its lattice, giving rise to a change in reaction selectivity towards dimethyl ether. \"This is an interesting finding\", says David Kordus, the other lead author of the study and Ph.D. student at the Interface Science Department at FHI. \"We know now that the choice of support material has an influence on how the active components of the catalyst behaves and dynamically adapts to the reaction conditions. Especially the oxidation state of zinc is critically influenced by this, which should be considered for future catalyst design.\" This work published in Nature Communications demonstrates that zinc oxide does not need to be available as part of the support, but that it still has a beneficial function even when available in highly dilute form as part of the nanoparticle catalyst itself. This will help elucidate the methanol synthesis catalysts better and potentially lead to an improvement of the catalyst for this important industrial process. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Greenhouse gas induced climate change is expected to lead to negative hydrological impacts for southwestern North America, including California (CA). This includes a decrease in the amount and frequency of precipitation, reductions in Sierra snow pack, and an increase in evapotranspiration, all of which imply a decline in surface water availability, and an increase in drought and stress on water resources. However, a recent study showed the importance of tropical Pacific sea surface temperature (SST) warming and an El Niño Southern Oscillation (ENSO)-like teleconnection in driving an increase in CA precipitation through the 21st century, particularly during winter (DJF). Here, we extend this prior work and show wetter (drier) CA conditions, based on several drought metrics, are associated with an El Niño (La Niña)-like SST pattern. Models that better simulate the observed ENSO-CA precipitation teleconnection also better simulate the ENSO-CA drought relationships, and yield negligible change in the risk of 21st century CA drought, primarily due to wetting during winter. Seasonally, however, CA drought risk is projected to increase during the non-winter months, particularly in the models that poorly simulate the observed teleconnection. Thus, future projections of CA drought are dependent on model fidelity of the El Niño teleconnection. As opposed to focusing on adapting to less water, models that better simulate the teleconnection imply adaptation measures focused on smoothing seasonal differences for affected agricultural, terrestrial, and aquatic systems, as well as effectively capturing enhanced winter runoff. Introduction In response to anthropogenic climate change, climate models from the Coupled Model Intercomparison Project (CMIP) version 3 and 5 indicate a likely transition to a more arid climate over many land areas, 1 resulting in increased frequency and intensity of drought. 2 , 3 Severe and widespread drought during this century are of particular concern for southwestern North America, including California (CA). 4 , 5 , 6 , 7 , 8 This drying is a consequence of reduced precipitation in the subtropics, and a poleward expansion of the subtropical dry zones. 9 , 10 , 11 , 12 , 13 Moreover, in addition to reduced precipitation, warmer temperatures will lead to an increase in evapotranspiration 3 and a decrease in mountain snow mass. 6 All of this translates into reduced surface water availability, soil moisture and runoff, 14 implying significant stress on water resources. Future drought risk in southwestern North America may even exceed that during the driest centuries of the Medieval Climate Anomaly. 15 , 16 However, despite the large body of literature suggesting an increase in drought under greenhouse gas forcing, uncertainty still remains. Overall, there is medium confidence that warming will increase the duration and intensity of droughts in some regions, including the Mediterranean, Central America and Mexico, northeast Brazil, southern Africa and central North America. 13 , 17 The only regions with a consistent increase in drought are those where precipitation decreases. 18 Furthermore, many of the above studies quantify drought using the Palmer Drought Severity Index (PDSI), which is calculated from a simple water balance model, 19 and may overestimate the increase in global drought 20 due to an oversensitivity to warmer temperatures. 21 Consistent with this uncertainty, a recent study suggests increased radiative forcing may lead to a decrease in the likelihood of CA agricultural drought. 22 This study, however, was based on a single model and did not focus on 21st century climate change. An important component of drought is precipitation, and relatively large uncertainty exists for future CA precipitation projections. 23 , 24 Relative to CMIP3, however, CMIP5 CA precipitation projections tend to yield a more consistent increase. 25 , 26 , 27 This is related to a coherent extratropical response, involving a southeastward extension of the the upper level winds in the east Pacific, 25 an increase in storm track activity, 28 and an increase in CA moisture convergence, 29 all of which promote an increase in CA precipitation. Moreover, a robust dynamical response in the tropics also exists, 27 including an increase in central/eastern tropical Pacific divergence and a poleward propagating Rossby wave, both of which are reminiscent of an El Niño-like teleconnection. Combined with warming of the tropical Pacific sea surface temperatures (SSTs), CMIP5 models that better simulate the observed El Niño-CA precipitation teleconnection yield larger, and more consistent increases in CA precipitation through the twenty-first century. 27 Using a multitude of models from the CMIP5 30 archive, we build off of prior work 27 and evaluate future CA drought risk using multiple metrics under business as usual warming. We primarily focus on annual drought to be able to compare our results to previous studies of future water availability in California and the Southwestern US from GCM simulations. 4 , 31 More importantly, the question of potential changes in seasonal versus annual (and inter-annual) drought greatly affects the feasible adaptation measures to climate change. If long-term water availability decreases, this will likely result in greater competition between agricultural, environmental, and urban users for California water and greater perennial stress on human and ecological systems. In this scenario, adaptation measures will need to focus on adapting to less water (including managing ecosystems as they transition to a drier state). If annual drought risk doesn’t change, adaptation measures can focus more on smoothing seasonal differences for affected agricultural, terrestrial, and aquatic systems as well as effectively capturing enhanced winter runoff. These two scenarios have greatly different potential losses due to climate change as well as differing adaptation costs. Results Tropical pacific sea surface temperatures and California hydrology Multiple studies 2 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 have showed that SSTs are the dominant driver of changes in precipitation and drought in many world regions over the 20th century. For CA, the dominant source of SST variations that contribute to precipitation variations is El Niño/La Niña. Observations from 1948/49 to 2014/15 show the correlation between Niño 3.4 SSTs (5S-5N; 190-240E) and CA winter (DJF) precipitation is ~0.3–0.4, which is significant at the 99%", "role": "user" }, { "content": "So here's the good news: Despite fears to the contrary, California isn't facing a year-round drought in our warming new world. However, UC Riverside Earth Sciences Professor Robert Allen's research indicates that what precipitation the state does get will be pretty much limited to the winter months—think deluge-type rainfall rather than snow—and non-winter months will be even dryer than usual, with little or no rain at all. \"It is good news,\" Allen said. \"But only relative to the alternative of no rain at all.\" Allen's latest findings build on his 2017 research that concluded global warming will bring increased winter precipitation to California through the end of this century. The findings are outlined in a paper by Allen and his co-author Ray Anderson, research soil scientist at the USDA-ARS US Salinity Lab, titled \"21st century California drought risk linked to model fidelity of the El Niño teleconnection.\" It was published September 3 in Climate and Atmospheric Science. The paper focuses on how \"greenhouse-gas-induced climate change\" will affect drought conditions in the state. The findings are based on 40 climate models that were compared to actual precipitation, soil moisture, and streamflow in the state between 1950 and 2000. Historically, about 90 percent of California's rain and snow have come during the winter months of December, January, and February, Allen said, with sporadic rain scattered over the rest of the year. But now, warming surface temperatures in the tropical Pacific Ocean are expected to amplify the rainy season by sending stormy El Niño conditions over the state in the winter. Bottom line, Allen said, the flooding and mudslides that accompanied the heavy winter rains of 2017 shouldn't be considered an aberration, but potentially California's new weather norm. The trick will be finding a way to capture excess water for dry periods, he said. \"It's all about smoothing the seasonable differences. If we can take advantage of the enhanced winter rainfall, we can hopefully get through the drying trends the rest of the year.\" Trapping that winter precipitation will be a challenge, however, especially since it's likely to come more in the form of rain than snow due to the warming climate. Historically, snow in the mountains feeds reservoirs and provides water to agriculture when it is needed in the summer, but rain will just run off unless it is captured. Allen's findings also bode ill for California's fire season. The state's new norm could mimic—or surpass—the fire season of 2017, the worst in California's history, as wet winters encourage lush spring growth that will quickly parch during the hot and dry season, becoming wildfire fuel. In fact, Allen said, these \"new norm\" projections aren't for a distant future. \"I think it's here now, so we need to start acting as quickly as possible,\" he said. \"Adaptation is incredibly important in response to climate change, and in this case it means enhancing our water storage capabilities, our reservoirs and dam structures, because things are going to become drier in the nonwinter months.\" And for ordinary citizens? This might be a great time to start investing in rain barrels. \"In Southern California, it could mean having native plants in your yard because a grass yard has to be irrigated, and that's probably not the wisest use of water,\" he said. \"It's all about living sustainably.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Species’ functional traits set the blueprint for pair-wise interactions in ecological networks. Yet, it is unknown to what extent the functional diversity of plant and animal communities controls network assembly along environmental gradients in real-world ecosystems. Here we address this question with a unique dataset of mutualistic bird–fruit, bird–flower and insect–flower interaction networks and associated functional traits of 200 plant and 282 animal species sampled along broad climate and land-use gradients on Mt. Kilimanjaro. We show that plant functional diversity is mainly limited by precipitation, while animal functional diversity is primarily limited by temperature. Furthermore, shifts in plant and animal functional diversity along the elevational gradient control the niche breadth and partitioning of the respective other trophic level. These findings reveal that climatic constraints on the functional diversity of either plants or animals determine the relative importance of bottom-up and top-down control in plant–animal interaction networks. Introduction All species are involved in mutualistic and antagonistic interactions with other species 1 . Collectively these interactions between pairs of species form complex networks that structure ecological communities 2 and maintain essential ecosystem functions, such as pollination, seed dispersal or biological control 3 . Within these networks the matching of species’ traits determines whether pairs of species are able to interact and how effective their interactions are 4 . Therefore, phenotypic traits related to species’ interactions are thought to determine the realised set of interactions within species-rich interaction networks 4 . In a broader sense, the functional traits that regulate species interactions can be viewed as coexistence traits that govern niche breadth (the diversity of a species’ interaction partners) and niche partitioning (the complementary specialisation of several species on exclusive interaction partners) in complex ecological networks and determine the ecosystem functions derived from ecological communities 4 , 5 , 6 . In theory, we would expect that species’ niche breadth and the degree of niche partitioning among species, increases with functional diversity 7 , 8 . If trait matching structures plant–animal interaction networks, the functional trait spaces of plants and animals should reciprocally control the niche breadth and partitioning of species in the respective other trophic level (Fig. 1a–c ). Hence, a reduction of functional diversity in the lower trophic level is expected to cause a reduction in niche breadth and partitioning (niche contraction and convergence) in the higher trophic level and vice versa (bottom-up and top-down control, respectively; Fig. 1d ). The convergence of interaction niches also implies that a reduction of functional diversity in one trophic level may cause increased competition for mutualistic partners in the other trophic level. The functional diversity in one trophic level may thus not only constrain the interaction niches but also the functional diversity in the other trophic level through biotic filtering and competitive exclusion 9 . Fig. 1 Potential bottom-up and top-down effects of plant and animal functional diversity on the assembly of mutualistic networks. a Example of a mutualistic bird–fruit network, in which plants and animals are ordered along two corresponding size-matching trait axes according to bill and fruit size, respectively. The grey lines represent bird–fruit interactions, which are constrained by trait matching so that the small-billed bird can only consume small fruits, whereas the large-billed bird can also consume large fruits. Trait matching determines the realised interaction niches of plants and animals (represented on the trait axis of the other trophic level). b Removal of plant species P 3 causes a loss of plant functional diversity and a contraction and convergence of the birds’ interaction niches corresponding to a reduction in niche breadth (diversity of a species’ interaction partners) and niche partitioning (complementary specialisation of several species on exclusive interaction partners; red histograms A 1 and A 2 at the top). c Likewise, removal of bird species A 2 causes a loss of animal functional diversity and a contraction and convergence of plants’ interaction niches (blue histograms P 1 and P 2 at the bottom). d Consequently, a loss of functional diversity in one trophic level should cause a reciprocal reduction in niche breadth and partitioning in the other trophic level. Note that the convergence of interaction niches also implies that a reduction of functional diversity in one trophic level may cause increased competition for mutualistic partners in the other trophic level (e.g., between A 1 and A 2 in b or between P 1 and P 2 in c ) Full size image Our framework implies that bottom-up and top-down effects may simultaneously control the assembly of plant–animal interaction networks and that abiotic constraints on either plant or animal functional diversity may determine the relative importance of bottom-up or top-down control 10 . This prediction goes beyond those from biodiversity experiments, as the latter have mainly focussed on either bottom-up or top-down effects, but have not yet assessed the relative importance and context dependence of both mechanisms simultaneously 10 , 11 , 12 . Despite a general consensus on the relevance of functional diversity for species interactions and associated ecosystem functions in real-world ecosystems 13 , 14 , 15 , it is unknown to what extent shifts in plant and animal functional diversity along environmental gradients alter the structure of species interaction networks and whether network assembly is primarily bottom-up-controlled or top-down-controlled. Here, we ask whether trait matching is a general phenomenon across mutualistic networks and whether bottom-up and top-down forces simultaneously control the assembly of these networks in real-world ecosystems. To address these two questions, we recorded a unique dataset of mutualistic bird–fruit, bird–flower and insect–flower interaction networks and associated functional traits along a 3.5 km elevational gradient (872–4396 m above sea level [a.s.l.]) of near-natural and anthropogenic habitat on the southern slopes of Mt. Kilimanjaro. The dataset comprises a total of 14,728 interactions between 200 plant and 282 animal species (99 bird and 183 insect species) sampled across the three types of mutualisms. First, we tested whether trait matching generally structured the assembly of these networks by analysing multivariate associations between plant and animal functional traits. Second, we tested", "role": "user" }, { "content": "The tropical rainforest, with its permanently wet climate, brims over with an abundance of plant species. Flowers of all sizes with shallow to deep tubes offer a wide variety of food sources to pollinators. Sunbirds, for example, developed long, down-curved beaks enabling them to reach the nectar at the bottom of long tubes. But who is the leading actor in this interplay of plants and animals? \"Ecosystems with high precipitation typically contain a wide variety of plants and show a high level of functional diversity. The higher this functional diversity, the more their animal partners are able to specialize on particular plant species. The plants therefore serve as the deciding factor for the animals' specialization,\" explains Dr. Jörg Albrecht of the Senckenberg Biodiversity and Climate Research Center, lead author of a new study regarding this topic. Albrecht and his colleagues from Germany, Switzerland and Tanzania observed and analyzed almost 15,000 interactions between plants, their pollinators and their seed dispersers over a period of five years. The study area comprised survey plots from the foothills of the Kilimanjaro up to the mountain's summit. Since 2010, an international team of scientists in the joint project \"Kilimanjaro ecosystems under global change,\" sponsored by the German Research Foundation, has been working here to find out how climate and land use affect the biological diversity on Africa's tallest mountain. Credit: Eike Lena Neuschulz However, on Kilimanjaro, it is not always the plants that make the rules. The newly published study shows that there also exist climatic conditions in which the animals set the agenda. Albrecht explains, \"Mean temperature is more important than precipitation for animal diversity. In cold climates, animal species tend to resemble each other more closely and show a lower level of functional diversity. Therefore, in cold regions, plants are not able to specialize on specific animal partners and frequently interact with the same species.\" Since the amount of precipitation and the mean temperature in many areas is expected to change due to climate change, researchers suspect that changes will also occur in the networks between plants and animals. \"Depending on how the climate will change in a particular region, either plants or animals could drive the structure of these networks in the future. A change in the flora could thus also have an impact on the animal partners of the plants,\" explains the study's senior author, Dr. Matthias Schleuning of the Senckenberg Biodiversity and Climate Research Center. According to the authors, the ability of species to adapt to new environmental conditions is not only determined by the species themselves, but also depends on the responses of their plant or animal partners. Precise predictions regarding future changes in biodiversity are essential to mitigate future environmental changes caused by climate change. \"In order to better predict how species and ecological communities will respond to global change, it is important to consider the environmental conditions together with the mutual interdependencies between species,\" says Matthias Schleuning. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We present one of the first case studies demonstrating the use of distributed acoustic sensing deployed on regional unlit fiber-optic telecommunication infrastructure (dark fiber) for broadband seismic monitoring of both near-surface soil properties and earthquake seismology. We recorded 7 months of passive seismic data on a 27 km section of dark fiber stretching from West Sacramento, CA to Woodland, CA, densely sampled at 2 m spacing. This dataset was processed to extract surface wave velocity information using ambient noise interferometry techniques; the resulting V S profiles were used to map both shallow structural profiles and groundwater depth, thus demonstrating that basin-scale variations in hydrological state could be resolved using this technique. The same array was utilized for detection of regional and teleseismic earthquakes and evaluated for long period response using records from the M8.1 Chiapas, Mexico 2017, Sep 8th event. The combination of these two sets of observations conclusively demonstrates that regionally extensive fiber-optic networks can effectively be utilized for a host of geoscience observation tasks at a combination of scale and resolution previously inaccessible. Introduction Hydrogeologic and seismological data collection are two domains for which the absence of high spatio-temporal resolution data is particularly acute, with significant impacts on our ability to characterize near-surface soil properties, groundwater systems, and seismic events. Even relatively basic subsurface hydrological parameters such as water table depths in surficial aquifers suffer from severe undersampling in both space and time. While heavily monitored basins often have a multitude of wells providing subsurface access, they are neither uniformly distributed nor frequently monitored resulting in heterogeneous datasets requiring manual quality control, curation, and analysis. The few basin-wide hydrogeological data sources, typically based on satellite remote sensing technologies, provide only surficial property estimates like soil moisture 1 , 2 , integrated strain response (e.g. InSAR 3 ), or low-resolution volumetric datasets (e.g. GRACE 4 , 5 ) which require assimilation with point measurements to provide finely resolved operational parameters 6 . Remote sensing measurements often also suffer from temporal undersampling due to satellite pass frequency. More recently, seismic ambient noise interferometry 7 has been leveraged to provide broader information on ground water storage; unfortunately limited permanent seismic networks present a challenge for these approaches. Likewise, seismological data collected using existing permanent networks often have spatial regions which suffer from significant spatial undersampling, particularly in areas distant from major plate boundaries, resulting in challenges when attempting to detect and locate small natural and induced events. The case of small magnitude induced events is particularly problematic since the basins where oil and gas production, wastewater injection, and carbon dioxide sequestration occur are often distant from historically seismogenic faults and the associated permanent seismic networks. Network sparsity increases the minimum event size for detection, results in statistical biases in the catalog, and greatly increases depth uncertainty for local events. Recent studies focusing on seismic catalog completeness in California have determined that even M2 events cannot be detected in the majority of the Sacramento and San Joaquin Basins using the existing network stations 8 . These spatio-temporal undersampling problems, for both hydrological and seismological measurements, can be remedied by re-purposing ubiquitous sensing platforms already deployed at scale. A recent example of such an approach is the utilization of smartphone accelerometers to measure strong ground motion as part of earthquake early warning applications as shown in previous studies 9 , 10 ; other examples include using social media proxies as sensors 11 or MEMS accelerometers in pervasive stationary devices such as personal computers 12 . Broader efforts to leverage networking and sensor technologies related to the Internet-of-Things (IoT) for seismology are developing but still in their infancy 13 . An alternative approach is to exploit components of the built environment to serve as distributed sensor networks. In this case we couple the use of unlit subsurface fiber-optic cables, commonly referred to as “dark fiber” since they are not utilized for data transmission, and distributed acoustic sensing (DAS) to provide such a spatially extensive sensing platform. The vast majority of fiber-optic cables in the earth’s near-surface were installed exclusively for the purpose of telecommunications. Due to high cost of fiber-optic installation, typical commercial practice is to deploy significantly more capacity, as measured by fiber count, than required; this practice, combined with advances in bandwidth available per fiber, have yielded a surplus of available fibers that remain unused. The US footprint of such unused fiber networks is massive with tens of thousands of linear kilometers of long distance fiber-optic cables available for lease or purchase in the current environment. One notable aspect of such dark fiber network components is that they tend to utilize existing “right-of-way” corridors along roads and rail connections 14 , environments rich in ambient seismic noise. Given the ubiquitous nature of installed telecom fibers, few studies have explored use of this resource for sensing applications. An early experiment explored the use of Brillouin Optical Time Domain Analysis (BOTDA) to monitor temperature over previously installed telecom fiber 15 ; however, these studies were conducted primarily to provide network integrity information rather than for environmental sensing. In a seismological context, several recent studies 16 , 17 , 18 have demonstrated the benefits of leveraging urban telecom infrastructure at a small scale. Most recently, a study in southwest Iceland 19 provided an excellent example of utilizing telecom fiber for detecting local earthquakes and measuring co-seismic strain measurement over a short transect. Distributed Acoustic Sensing (DAS) is a recently developed technique which utilizes coherent optical time-domain reflectometry to accurately measure the phase and amplitude of vibrations along an optical fiber 20 , 21 , 22 . The technique exploits changes in Rayleigh scattering induced by extensional strain; these measurements have now been quantitatively compared to point seismic recordings at both intermediate 23 and low frequencies 24 and utilized for a host of tasks including vertical seismic profiling 20 , 21 , 25 , near-surface soil property estimation 26 , 27 , 28 , 29 , 30 , surface refraction tomography 31 and earthquake seismology", "role": "user" }, { "content": "In traditional seismology, researchers studying how the earth moves in the moments before, during, and after an earthquake rely on sensors that cost tens of thousands of dollars to make and install underground. And because of the expense and labor involved, only a few seismic sensors have been installed throughout remote areas of California, making it hard to understand the impacts of future earthquakes as well as small earthquakes occurring on unmapped faults. Now researchers at the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) have figured out a way to overcome these hurdles by turning parts of a 13,000-mile-long testbed of \"dark fiber,\" unused fiber-optic cable owned by the DOE Energy Sciences Network (ESnet), into a highly sensitive seismic activity sensor that could potentially augment the performance of earthquake early warning systems currently being developed in the western United States. The study detailing the work—the first to employ a large regional network as an earthquake sensor—was published this week in Nature's Scientific Reports. Shaking up seismology with dark fiber According to Jonathan Ajo-Franklin, a staff scientist in Berkeley Lab's Earth and Environmental Sciences Area who led the study, there are approximately 10 million kilometers of fiber-optic cable around the world, and about 10 percent of that consists of dark fiber. The Ajo-Franklin group has been working toward this type of experiment for several years. In a 2017 study, they installed a fiber-optic cable in a shallow trench in Richmond, California, and demonstrated that a new sensing technology called distributed acoustic sensing (DAS) could be used for imaging of the shallow subsurface. DAS is a technology that measures seismic wavefields by shooting short laser pulses across the length of the fiber. In a follow-up study, they and a group of collaborators demonstrated for the first time that fiber-optic cables could be used as sensors for detecting earthquakes. The current study uses the same DAS technique, but instead of deploying their own fiber-optic cable, the researchers ran their experiments on a 20-mile segment of the 13,000-mile-long ESnet Dark Fiber Testbed that extends from West Sacramento to Woodland, California. \"To further verify our results from the 2017 study, we knew we would need to run the DAS tests on an actual dark fiber network,\" said Ajo-Franklin, who also heads Berkeley Lab's Geophysics Department. \"When Jonathan approached me about using our Dark Fiber Testbed, I didn't even know it was possible\" to use a network as a sensor, said Inder Monga, Executive Director of ESnet and director of the Scientific Networking Division at Berkeley Lab. \"No one had done this work before. But the possibilities were tremendous, so I said, 'Sure, let's do this!\" Chris Tracy from ESnet worked closely with the researchers to figure out the logistics of implementation. Telecommunications company CenturyLink provided fiber installation information. By coupling DAS technology with dark fiber, Berkeley Lab researchers were able to detect both local and distant earthquakes, from Berkeley to Gilroy, California, to Chiapas, Mexico. Credit: Ajo-Franklin/Berkeley Lab Because the ESnet Testbed has regional coverage, the researchers were able to monitor seismic activity and environmental noise with finer detail than previous studies. \"The coverage of the ESnet Dark Fiber Testbed provided us with subsurface images at a higher resolution and larger scale than would have been possible with a traditional sensor network,\" said co-author Verónica Rodríguez Tribaldos, a postdoctoral researcher in Ajo-Franklin's lab. \"Conventional seismic networks often employ only a few dozen sensors spaced apart by several kilometers to cover an area this large, but with the ESnet Testbed and DAS, we have 10,000 sensors in a line with a two-meter spacing. This means that with just one fiber-optic cable you can gather very detailed information about soil structure over several months.\" Digging deep for data underground After seven months of using DAS to record data through the ESnet Dark Fiber Testbed, the researchers proved that the benefits of using a commercial fiber are manifold. \"Just by listening for 40 minutes, this technology has the potential to do about 10 different things at once. We were able to pick up very low frequency waves from distant earthquakes as well as the higher frequencies generated by nearby vehicles,\" said Ajo-Franklin. The technology allowed the researchers to tell the difference between a car or moving train versus an earthquake, and to detect both local and distant earthquakes, from Berkeley to Gilroy to Chiapas, Mexico. The technology can also be used to characterize soil quality, provide information on aquifers, and be integrated into geotechnical studies, he added. With such a detailed picture of the subsurface, the technology has potential for use in time-lapse studies of soil properties, said Rodríguez Tribaldos. For example, in environmental monitoring, this tool could be used to detect long-term groundwater changes, the melting of permafrost, or the hydrological changes involved in landslide hazards. The current study's findings also suggest that researchers may no longer have to choose between data quality and cost. \"Cell phone sensors are inexpensive and tell us when a large earthquake happens nearby, but they will not be able to record the fine vibrations of the planet,\" said co-author Nate Lindsey, a UC Berkeley graduate student who led the field work and earthquake analysis for the 2017 study. \"In this study, we showed that inexpensive fiber-optics pick up those small ground motions with surprising quality.\" With 300 terabytes of raw data collected for the study, the researchers have been challenged to find ways to effectively manage and process the \"fire hose\" of seismic information. Ajo-Franklin expressed hope to one day build a seismology data portal that couples ESnet as a sensor and data transfer mechanism, with analysis and long-term data storage managed by Berkeley Lab's supercomputing facility, NERSC (National Energy Research Scientific Computing Center). Monga added that even though the Dark Fiber Testbed will soon be lit for the next generation of ESnet, dubbed \"ESnet 6,\" there may be sections that could be used for seismology. \"Although it was completely unexpected that ESnet—a transatlantic network dedicated for research—could be used as a seismic sensor, it fits perfectly within our mission,\" he said. \"At ESnet, we want to enable scientific discovery unconstrained by geography.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The distribution of seismic moment is of capital interest to evaluate earthquake hazard, in particular regarding the most extreme events. We make use of likelihood-ratio tests to compare the simple Gutenberg-Richter power-law (PL) distribution with two statistical models that incorporate an exponential tail, the so-called tapered Gutenberg-Richter (Tap) and the truncated gamma, when fitted to the global CMT earthquake catalog. Although the Tap distribution does not introduce any significant improvement of fit respect the PL, the truncated gamma does. Simulated samples of this distribution, with parameters β = 0.68 and m c = 9.15 and reshuffled in order to mimic the time occurrence of the order statistics of the empirical data, are able to explain the temporal heterogeneity of global seismicity both before and after the great Sumatra-Andaman earthquake of 2004. Introduction The Gutenberg-Richter (GR) law is not only of fundamental importance in statistical seismology 1 but also a cornerstone of non-linear geophysics 2 and complex-systems science 3 . It simply states that, for a given region, the magnitudes of earthquakes follow an exponential probability distribution. As the (scalar) seismic moment is an exponential function of magnitude, when the GR law is expressed in terms of the former variable, it translates into a power-law distribution 4 , 5 , i.e., with M seismic moment, f ( M ) its probability density, (fulfilling ), the sign “ ∝ ” denoting proportionality, and the exponent 1 + β taking values close to 1.65. This simple description provides rather good fits of available data in many cases 6 , 7 , 8 , 9 , with, remarkably, only one free parameter, β . A totally equivalent characterization of the distribution uses the survivor function (or complementary cumulative distribution), defined as for which the GR power law takes the form S ( M ) ∝ 1/ M β . The power-law distribution has important physical implications, as it suggests an origin from a critical branching process or a self-organized-critical state 3 , 10 , 11 . Nevertheless, it presents also some conceptual difficulties, due to the fact that the mean value 〈 M 〉 provided by the distribution turns out to be infinite 4 , 12 . These elementary considerations imply that the GR law cannot be naively extended to arbitrarily large values of M , and one needs to introduce additional parameters to describe the tail of the distribution, coming presumably from finite-size effects. However, a big problem is that the change from power law to a faster decay seems to take place at the highest values of M that have been observed, for which the statistics are very poor 13 . Kagan 7 has enumerated the requirements that an extension of the GR law should fulfil; in particular, he considered, among other: (i) the so called tapered (Tap) Gutenberg-Richter distribution (also called Kagan distribution 14 ), with a survivor function given by and (ii) the (left-) truncated gamma (TrG) distribution, for which the density is Note that both expressions have essentially the same functional form, but the former refers to the survivor function and the later to the density. As f ( M ) = − dS ( M )/ dM , differentiation of S tap ( M ) in (i) shows the difference between both distributions. In both cases, parameter θ represents a crossover value of seismic moment, signalling a transition from power law to exponential decay; so, θ gives the scale of the finite-size effects on the seismic moment. The corresponding value of (moment) magnitude (sometimes called corner magnitude) can be obtained from , when the seismic moment is measured in N · m 15 , 16 . Kagan 7 also argues that available seismic catalogs do not allow the reliable estimation of θ , except in the global case (or for large subsets of this case), in particular, he recommends the use of the centroid moment tensor (CMT) catalog 17 , 18 . From his analysis of global seismicity, and comparing the values of the likelihoods, Kagan 7 concludes that the tapered GR distribution gives a slightly better fit than the truncated gamma distribution, for which in addition the estimation procedure is more involving. In any case, the β −value seems to be universal (at variance with θ ), see also refs 9 , 19 and 20 . Nevertheless, the data analyzed by Kagan 7 , from 1977 to 1999, comprises a period of relatively low global seismic activity, with no event above magnitude 8.5; in contrast, the period 1950–1965 witnessed 7 of such events 21 . Starting with the great Sumatra-Andaman earthquake of 2004, and following since then with 5 more earthquakes with m ≥ 8.5 (up to the time of submitting this article), the current period seems to correspond to the past higher levels of activity. Main et al . 22 and Bell et al . 23 have re-examined the problem of the seismic moment distribution including recent global data (shallow events only). Using a Bayesian information criterion (BIC), Bell et al . 23 compare the plain GR power law with the tapered GR distribution, and conclude that, although the tapered GR gives a significantly better fit before the 2004 Sumatra event, the occurrence of this changes the balance of the BIC statistics, making the GR power law more suitable; that is, the power law is more parsimonious, or simply, is enough for describing global shallow seismicity when the recent mega-earthquakes are included in the data. Similar results have been published in ref. 24 . In the present paper we revisit the problem with more recent data, including also the truncated gamma distribution, using other statistical tools, and reaching somewhat different conclusions: when data includes periods of high seismic activity, indeed, the tapered GR distribution does not introduce any significant improvement with respect to the power law 23 , but the truncated gamma does. Data, Models and Maximum Likelihood Estimation As Main et al . 22 and Bell et al . 23 , we analyze the", "role": "user" }, { "content": "Researchers of the Mathematics Research Centre (CRM) and the UAB have developed a mathematical law to explain the size distribution of earthquakes, even in the cases of large-scale earthquakes such as those which occurred in Sumatra (2004) and in Japan (2011). The probability of an earthquake occurring exponentially decreases as its magnitude value increases. Fortunately, mild earthquakes are more probable than devastatingly large ones. This relation between probability and earthquake magnitude follows a mathematical curve called the Gutenberg-Richter law, and helps seismologists predict the probabilities of an earthquake of a specific magnitude occurring in some part of the planet. The law however lacks the necessary tools to describe extreme situations. For example, although the probability of an earthquake being of the magnitude of 12 is zero, since technically this would imply the earth breaking in half, the mathematics of the Gutenberg-Richter law do not consider impossible a 14-magnitude earthquake. \"The limitations of the law are determined by the fact that the Earth is finite, and the law describes ideal systems, in a planet with an infinite surface\", explains Isabel Serra, first author of the article, researcher at CRM and affiliate lecturer of the UAB Department of Mathematics. To overcome these shortages, researchers studied a small modification in the Gutenberg-Richter law, a term which modified the curve precisely in the area in which probabilities were the smallest. \"This modification has important practical effects when estimating the risks or evaluating possible economic losses. Preparing for a catastrophe where the losses could be, in the worst of the cases, very high in value, is not the same as not being able to calculate an estimated maximum value\", clarifies co-author Álvaro Corral, researcher at the Mathematics Research Centre and the UAB Department of Mathematics. Obtaining the mathematical curve which best fits the registered data on earthquakes is not an easy task when dealing with large tremors. From 1950 to 2003 there were only seven earthquakes measuring higher than 8.5 on the Richter scale and since 2004 there have only been six. Although we are now in a more active period following the Sumatra earthquake, there are very few cases and that makes it statistically a poorer period. Thus, the mathematical treatment of the problem becomes much more complex than when there is an abundance of data. For Corral, \"this is where the role of mathematics is fundamental to complement the research of seismologists and guarantee the accuracy of the studies\". According to the researcher, the approach currently used to analyse seismic risk is not fully correct and, in fact, there are many risk maps which are downright incorrect, \"which is what happened with the Tohoku earthquake of 2011, where the area contained an under-dimensioned risk\". \"Our approach has corrected some things, but we are still far from being able to give correct results in specific regions\", Corral continues. The mathematical expression of the law at the seismic moment, proposed by Serra and Corral, meets all the conditions needed to determine both the probability of smaller earthquakes and of large ones, by adjusting itself to the most recent and extreme cases of Tohoku, in Japan (2011) and Sumatra, in Indonesia (2004); as well as to determine negligible probabilities for earthquakes of disproportionate magnitudes. The derived Gutenberg-Richter law has also been used to begin to explore its applications in the financial world. Isabel Serra worked in this field before beginning to study earthquakes mathematically. \"The risk assessment of a firm's economic losses is a subject insurance companies take very seriously, and the behaviour is similar: the probability of suffering losses decreases in accordance with the increase in volume of losses, according to a law that is similar to that of Gutenberg-Richter, but there are limit values which these laws do not take into consideration, since no matter how big the amount, the probability of losses of that amount never results in zero\" Serra explains. \"That makes the 'expected value of losses' enormous. To solve this, changes would have to be made to the law similar to those we introduced to the law on earthquakes\". ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Alzheimer’s disease (AD) has been associated with cardiovascular and cerebrovascular risk factors (CVRFs) during middle age and later and is frequently accompanied by cerebrovascular pathology at death. An interaction between CVRFs and genetic variants might explain the pathogenesis. Genome-wide, gene by CVRF interaction analyses for AD, in 6568 patients and 8101 controls identified FMNL2 ( p = 6.6 × 10 –7 ). A significant increase in FMNL2 expression was observed in the brains of patients with brain infarcts and AD pathology and was associated with amyloid and phosphorylated tau deposition. FMNL2 was also prominent in astroglia in AD among those with cerebrovascular pathology. Amyloid toxicity in zebrafish increased fmnl2a expression in astroglia with detachment of astroglial end feet from blood vessels. Knockdown of fmnl2a prevented gliovascular remodeling, reduced microglial activity and enhanced amyloidosis. APP/PS1dE9 AD mice also displayed increased Fmnl2 expression and reduced the gliovascular contacts independent of the gliotic response. Based on this work, we propose that FMNL2 regulates pathology-dependent plasticity of the blood–brain-barrier by controlling gliovascular interactions and stimulating the clearance of extracellular aggregates. Therefore, in AD cerebrovascular risk factors promote cerebrovascular pathology which in turn, interacts with FMNL2 altering the normal astroglial-vascular mechanisms underlying the clearance of amyloid and tau increasing their deposition in brain. Working on a manuscript? Avoid the common mistakes Introduction Alzheimer’s disease (AD) affects more than 6.2 million people in the United States and approximately 24 million worldwide. Neuropathological studies indicate that in AD, the hallmark findings of neuritic plaques and neurofibrillary tangles can frequently be accompanied by varying degrees of cerebrovascular disease in up to 70% of patients [ 4 , 16 , 44 , 74 ]. Amyloid β in blood vessels, as in cerebral amyloid angiopathy, reduces cerebral blood flow and is present in most patients with AD. However, as cardio and cerebrovascular risk factors (CVRFs) increase in the elderly, accompanied by inflammation, cytokine release, endothelial dysfunction and arterial stiffening in brain [ 81 ]. Cholesterol laden macrophages accumulate in vessel walls also decreasing blood flow. The increase in atherosclerosis in the intracerebral arteries [ 55 ] and capillaries leads to microinfarcts in the hippocampus contributing to cognitive decline [ 34 ]. The relationship between CVRFs such as hypertension [ 78 ], body mass index [ 33 , 57 ], diabetes [ 22 , 59 ] and coronary heart disease [ 42 , 65 ] and AD is well known, but there has been limited mechanistic evidence directly linking these vascular risk factors in AD to the presence of ischemic microvascular pathology. Each of these vascular factors has the capacity to impair the blood–brain barrier and glio-vascular units. Arterial pulses and flow are required for glymphatic clearance of molecules including amyloid β [ 42 , 65 , 86 ]. Jagust and colleagues argued that cerebrovascular disease contributed to AD by perturbing the amyloid β pathway in addition to causing neurodegeneration [ 38 ]. However, the effects reported in epidemiological studies of the association between CVRFs and AD are inconsistent, increasing AD risk in some studies [ 86 ], but in others showing protection against AD [ 64 , 86 ]. The relationship between vascular risk factors and cerebrovascular pathology in AD could simply be the result of aging, the stage of the disease or a coincidental occurrence. An alternative explanation is that an unidentified interaction between genetic variants and vascular risk factors leading to cerebrovascular pathology in AD brain may contribute to disease pathogenesis. APOE , CLU , ABCA7 , and SORL1 , typically associated with immune mechanisms in AD, are also part of the lipid metabolism pathway providing evidence for a putative molecular relationship. In fact, ABCA7 and SORL1 have been associated with brain infarcts [ 31 ]. Using summary statistics from multiple genome-wide associations studies (GWAS), a recent study detected evidence of pleiotropy between vascular risk factors and AD [ 17 ]. Another investigation [ 88 ] found shared genetic contribution to AD and small vessel disease. Despite the possible associations between genes, vascular factors and AD, there has been no unbiased genome-wide study of genes or genetic loci to investigate the interaction between cerebrovascular risk factors, cerebrovascular pathology, and AD. Previously, we observed that the cumulative burden of vascular risk factors increased the association with AD risk [ 58 , 70 ] compared with a single risk factor. Therefore, in this investigation, a dimensionality reduction of four common cardiovascular risk factors frequently associated with cerebrovascular disease and with AD: hypertension, heart disease, diabetes, and body mass index (BMI), was employed to create a vascular risk factor burden score. To augment the sample size, we included data from five different cohorts representing different ethnic groups, facilitating the interaction analyses. Materials and methods Clinical studies Participants Participants were from the following studies: Washington Heights–Inwood Columbia Aging Project (WHICAP), Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA), the National Alzheimer’s Coordinating Center (NACC), and the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) (Table 1 ). WHICAP is a multiethnic, prospective, community-based cohort study of aging and dementia in Medicare recipients 65 years and older residing in northern Manhattan. A detailed description of the study was previously published [ 83 ]. Participants are initially recruited as nondemented elderly and were non-Hispanic white, African American or Caribbean Hispanic. A consensus diagnosis was derived for each participant by experienced clinicians based on NINCDS‐ADRDA criteria for possible, probable, or definite AD (moderate or high likelihood of neuropathological criteria for AD) [ 61 ]. Recruitment for the EFIGA began in 1998, to study the genetic architecture of AD in the Caribbean Hispanic population. Patients with familial AD were recruited and if a sibling of the proband had dementia, all other living siblings and available relatives underwent evaluation. Cases were defined as any individual meeting NINCDS-ADRDA criteria for probable or possible AD. Details of the study have previously been reported [ 90 ]. NACC collects, organizes, and maintains phenotype information from National Institute on Aging (NIA) Alzheimer’s Disease Centers (ADCs). Genetic data were", "role": "user" }, { "content": "For more than 20 years, scientists have known that people with hypertension, diabetes, high cholesterol, or obesity have a higher likelihood of developing Alzheimer's disease. The conditions can all affect the brain, damaging blood vessels and leading to strokes. But the connection between vascular disease in the brain and Alzheimer's has remained unexplained despite the intense efforts of researchers. Now, a study published in Acta Neuropathologica and led by researchers at Columbia University's Vagelos College of Physicians and Surgeons has uncovered a possible mechanism. The study found that a gene called FMNL2 links cerebrovascular disease and Alzheimer's and suggests changes in FMNL2 activity caused by cerebrovascular disease prevent the efficient clearance of toxic proteins from the brain, eventually leading to Alzheimer's disease. The finding could lead to a way to prevent Alzheimer's in people with hypertension, diabetes, obesity, or heart disease. \"Not only do we have a gene, but we have a potential mechanism,\" says senior author Richard Mayeux, MD, chair of neurology at Columbia and NewYork-Presbyterian/Columbia University Irving Medical Center. \"People have been trying to figure this out for a couple of decades, and I think we have our foot in the door now. We feel there must be other genes involved and that we've just scratched the surface.\" Mayeux and his colleagues found FMNL2 in a genome-wide hunt designed to uncover genes associated with both vascular risk factors and Alzheimer's disease. The search involved five groups of patients representing different ethnic groups. One gene, FMNL2, stood out during the analysis. But what role it could possibly play was unclear. That's when Caghan Kizil, Ph.D., a visiting associate professor at Columbia, leveraged his expertise with zebrafish as a model organism for Alzheimer's disease. FMNL2 and the blood-brain barrier \"We had this gene, FMNL2, that was lying at the interface between Alzheimer's disease in the brain and cerebrovascular risk factors,\" says Kizil. \"So we had an idea that FMNL2 might operate in the blood-brain barrier, where brain cells meet the vasculature.\" The blood-brain barrier is a semi-permeable, highly controlled border between capillaries and brain tissue that serves as a defense against disease-causing pathogens and toxins in the blood. Astrocytes, a specialized type of brain cell, compose and maintain the structure of the blood-brain barrier by forming a protective sheath around the blood vessel. This astrocyte sheath needs to loosen for the clearance of toxic amyloid—the aggregates of proteins that accumulate in the brain and lead to Alzheimer's disease. The zebrafish model confirmed the presence of FMNL2 in the astrocyte sheath, which retracted its grip on the blood vessel once toxic proteins were injected into the brain, presumably to allow for clearance. When Kizil and his colleagues blocked the function of FMNL2, this retraction did not occur, preventing clearance of amyloid from the brain. The same process was then confirmed using transgenic mice with Alzheimer's disease. The same process may also occur in the human brain. The researchers studied postmortem human brains and found increased expression of FMNL2 in people with Alzheimer's disease, along with breach of the blood-brain barrier and retraction of the astrocytes. Based on these findings, the researchers propose that FMNL2 opens the blood-brain-barrier—by controlling its astrocytes—and promotes the clearance of extracellular aggregates from the brain. And that cerebrovascular disease, by interacting with FMNL2, reduces the clearance of amyloid in the brain. The team is currently in the process of investigating other genes that could be involved in the interplay between Alzheimer's and cerebrovascular disease, which, along with FMNL2, could provide future approaches for drug development. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for mood disorders. While the mechanism of SSRI action is still unknown, SSRIs are thought to exert therapeutic effects by elevating extracellular serotonin levels in the brain, and remodel the structural and functional alterations dysregulated during depression. To determine their precise mode of action, we tested whether such neuroadaptive processes are modulated by regulation of specific gene expression programs. Here we identify a transcriptional program regulated by activator protein-1 (AP-1) complex, formed by c-Fos and c-Jun that is selectively activated prior to the onset of the chronic SSRI response. The AP-1 transcriptional program modulates the expression of key neuronal remodeling genes, including S100a10 (p11), linking neuronal plasticity to the antidepressant response. We find that AP-1 function is required for the antidepressant effect in vivo. Furthermore, we demonstrate how neurochemical pathways of BDNF and FGF2, through the MAPK, PI3K, and JNK cascades, regulate AP-1 function to mediate the beneficial effects of the antidepressant response. Here we put forth a sequential molecular network to track the antidepressant response and provide a new avenue that could be used to accelerate or potentiate antidepressant responses by triggering neuroplasticity. Introduction Major depressive disorder (MDD) is a disabling psychiatric disorder with diverse etiology, and is a leading cause of mortality and morbidity worldwide [ 1 ]. The symptoms of depression are varied, and include cognitive, motivational, emotional, and physiological changes [ 2 ]. Evidence for molecular and cellular alterations in depression includes reduction in neuroplastic properties, reduced levels of neurotrophins, and decreased neurogenesis [ 3 , 4 , 5 ]. Clinical imaging and postmortem studies indicate functional and structural alterations in the limbic brain regions, prefrontal cortex (PFC), hippocampus, and amygdala [ 4 , 6 ] in depressed patients. Many psychopharmacological agents are currently used for the treatment of depression, among which the selective serotonin reuptake inhibitors (SSRIs) are the most effective and widely prescribed [ 7 ]. However, clinical studies show that only two-thirds of patients respond to treatment, and that treatment has a delayed onset of action [ 8 ]. The therapeutic response to chronic antidepressant treatment is thought to be mediated by neuroadaptive changes in specific neuronal networks, which collectively reverses the dysregulation caused by depression [ 3 ]. There is therefore a pressing need to elucidate the identity of molecular pathways that mediate long-term treatment and antidepressant efficacy. Gene expression regulation represents a general mechanism through which mature neuronal circuits control their physiology and behavior [ 9 , 10 ]. Several transcription factors have been identified as the first responders to extracellular signals. Such factors include the immediate early genes (IEGs) such as c-Fos, FosB, Fra1, Fra2, c-Jun, Junb, Jund, Egr1, Nr4a1 , and Npas4 . These IEGs initiate and maintain gene expression profiles of crucial effector proteins, causing sustainable changes in the structure and function of mature synapses and thereby promoting behavioral plasticity. So far, among the IEGs, Creb1 and Egr1 have been previously shown to be associated with the antidepressant response [ 11 , 12 , 13 ]. Additionally, activation of cAMP, PKA, CAMK, and BDNF signaling molecules have been implicated in the chronic antidepressant response [ 14 , 15 , 16 ], likely through the regulation of physiological processes, including neuroplasticity, neuroprotection, and neurogenesis. However, how drug treatment is specifically coupled to transcription and how the signaling molecules are activated in response to chronic antidepressant administration are still unclear. Within the corticolimbic network [ 17 ], we chose to focus on the cortex, as the integral role of this brain-region in the regulation of behavior and the control of stress reactivity has been well characterized in patients and animal models [ 18 , 19 , 20 , 21 ]. Additionally, as the primary role of the serotonin-dependent function of the cortical circuit in the effective treatment of depression has been well established, studying the cortex would allow us to further delineate the molecular mechanisms regulating the complex response to antidepressants. In this study, we investigated which of the IEGs are activated in the cortex by chronic treatment with an SSRI, fluoxetine, and we elucidated the target genes regulated by these factors. Furthermore, we addressed whether the IEGs and their target genes contribute directly to the behavioral response. Our findings reveal activation of a network of molecules that are sequentially linked together to provide a robust antidepressant response. Method details Treatments, transfections, and DNA constructs For chronic drug and JNK inhibitor treatment, BALB/cJ mice (Jackson Laboratories) were housed two per cage and fluoxetine hydrochloride (Sigma) at a dose of (0.167 mg/mL) was administered in drinking water in 1% saccharine solution to mask the taste of the drug. Saccharine alone was given to the vehicle-treated animals. Mice were treated on average for 28 days and replaced with fresh solution every 3 days. On average, the fluoxetine-receiving mice drank approximately ∼ 3–4 mL a day, somewhat less compared with the control mice (that received 1% saccharine), which drank approximately ∼ 5–7 mL a day presumably due to the taste of the drug. The drinking volume of the fluoxetine-treated mice eventually normalized to that of the control mice. The fluoxetine-treated mice thus received 16–23 mg/kg/day of fluoxetine, an effective dose that is known to produce an antidepressant response in different strains of mice [ 22 ]. BALB/cJ mice were used as these mice are inherently anxious and show a robust antidepressant response. The S100a10-EGFP/Rpl10a ES691 mice of C57BL/6 background also produces a robust antidepressant response to fluoxetine treatment. For JNK inhibitor treatment in vivo, 16 mg/kg was injected intraperitoneally (i.p.) to the BALB/cJ mice on days 4, 6, 8, 10 of fluoxetine treatment to block JNK function to block c-Jun phosphorylation. For growth factor stimulation experiments in PC12/TrkB cells and primary mixed cortical neurons, growth factors BDNF (50 ng/mL) [ 23 , 24 ], FGF2 (50 ng/mL) [ 25 ], EGF (100 ng/mL) [ 26 ], IGF (100 ng/mL) [ 27 , 28 ], NGF (100 ng/mL) [ 29 ], VEGF", "role": "user" }, { "content": "Some highly effective medications also happen to be highly mysterious. Such is the case with the antidepressant drugs known as selective serotonin reuptake inhibitors, or SSRIs: They are the most common treatment for major depression and have been around for more than 40 years, yet scientists still do not know exactly how they work. Nor is it known why only two out of every three patients respond to SSRI treatment, or why it typically takes several weeks for the drugs to take effect—a significant shortcoming when you're dealing with a disabling mood disorder that can lead to impaired sleep, loss of appetite, and even suicide. New research by a team of Rockefeller scientists helps elucidate how SSRIs combat depression. Their work, published in Molecular Psychiatry, could one day make it possible to predict who will respond to SSRIs and who will not, and to reduce the amount of time it takes for the drugs to act. Brain Teasers Major depression—also known as clinical depression—is firmly rooted in biology and biochemistry. The brains of people who suffer from the disease show low levels of certain neurotransmitters, the chemical messengers that allow neurons to communicate with one another. And studies have linked depression to changes in brain volume and impaired neural circuitry. Scientists have long known that SSRIs rapidly increase the available amount of the neurotransmitter serotonin, leading to changes that go well beyond brain chemistry: Research suggests the drugs help reverse the neurological damage associated with depression by boosting the brain's innate ability to repair and remodel itself, a characteristic known as plasticity. Yet the molecular details of how SSRIs work their magic remains a mystery. Researchers in the late Paul Greengard's Laboratory of Molecular and Cellular Neuroscience set out to trace the chain of molecular events triggered by one of the most widely prescribed and effective SSRIs: fluoxetine, also known as Prozac. In particular, they wanted to see if they could tie the effects of the drug to specific changes in gene expression. Led by senior research associate Revathy Chottekalapanda, the team treated mice with fluoxetine for 28 days, then measured the animals' biochemical and behavioral responses to the drug. They conducted these experiments in a mouse strain prone to anxiety that offered several advantages including the fact that \"improvement in anxiety, in addition to depressive-like behavior, is a good measure of antidepressant drug response,\" Chottekalapanda says. Using a combination of behavioral tests and real-time RNA analysis, the researchers were able to monitor changes in the animals' behavior and gene expression as they responded to the drug. Things started to get interesting on the ninth day of treatment: The activity of a gene called c-Fos began to increase markedly, and by day 14 the mice were showing telltale behavioral changes—they were moving around more, for example, and took an interest in food even after being moved to a new environment. The timing was remarkable, Chottekalapanda says, because it aligned with well-established milestones in the treatment of human patients. \"For example, the rate of suicide drops after nine days of treatment, and people tend to feel better after two to three weeks,\" she says. As it turns out, c-Fos helps create a so-called transcription factor, AP-1, which activates specific genes by binding to their DNA. The sudden appearance of these molecules therefore raised several new questions: Which genes does AP-1 activate? What triggers the production of AP-1 in the first place? And how does this whole sequence of events ultimately beat back depression? Domino Effect Chottekalapanda and her colleagues began by analyzing the mice's cortex, a brain region previously shown to be essential for the antidepressant response, looking for changes in genes and DNA-binding proteins to which AP-1 might possibly bind. Focusing especially on the nine-day mark, they found changes in mouse genes whose human counterparts have been linked to depression and antidepressant drug response. Walking the cat backward, the team was able to identify specific molecules known as growth factors that spur the manufacture AP-1 itself, and the pathways through which they act. Taken together, these results painted a detailed picture of how fluoxetine and other SSRIs work. First, the drugs ramp up the amount of serotonin available in the brain. This triggers a molecular chain reaction that ultimately makes brain cells increase their AP-1 production—an effect that only begins to take off on day nine of treatment. AP-1 then switches on several genes that promote neuronal plasticity and remodeling, allowing the brain to reverse the neurological damage associated with depression. After two to three weeks, the regenerative effects of those changes can be seen—and felt. \"For the first time, we were able to put a number of molecular actors together at the crime scene in a time- and sequence-specific manner,\" says Chottekalapanda. To confirm their molecular model of SSRI response, Chottekalapanda and her team gave mice treated with fluoxetine an additional substance designed to block one of the pathways necessary to the production of AP-1. The results were striking: When the researchers prevented the mice from producing AP-1, the effects of the drug were severely blunted. Moreover, gene-expression analysis showed that blocking the formation of AP-1 partially reversed the activation of some of the genes responsible for the antidepressant response. One Word: Plasticity The implications of the team's findings could be far-reaching. For example, the genes that AP-1 targets could be used as biomarkers to predict whether a given patient will respond to SSRI treatment. And the cast of molecular characters involved in fluoxetine response could potentially be targeted with drugs to improve the efficacy of antidepressant treatment, perhaps even reducing the amount of time it takes for SSRIs to kick in. Towards that end, Chottekalapanda is already conducting experiments to clarify the precise reasons for the nine-day delay in AP-1 production. She would also like to know whether these molecular players are mutated or inactive in people who don't respond to SSRIs, and to discover precisely how the genes that AP-1 regulates in response to fluoxetine would promote neuronal plasticity. That last piece of the puzzle might prove to be especially important. Depression is not the only disorder that could potentially be remedied by enlisting the brain's innate healing abilities: Chottekalapanda suspects that the same plasticity-promoting pathways that are activated by antidepressants such as fluoxetine could potentially be used to treat other neurological and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. \"If we can figure out what they do, we can potentially develop treatments to reverse the damage involved not only with depression but also with other neurological disorders,\" she says. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a vasculogenic process as single cells, progressing towards a transit amplifying stage and ultimately differentiating into more mature endothelial phenotypes that comprised arterial, venous and lymphatic subtypes within the core of the tumor. Molecular profiling by RNA sequencing of purified endothelial fractions characterized EVPs as quiescent progenitors remodeling the extracellular matrix with significant paracrine activity promoting growth. Functionally, EVPs did not rely on VEGF-A signaling whereas endothelial-specific loss of Rbpj depleted the population and strongly inhibited metastasis. The understanding of endothelial heterogeneity opens new avenues for more effective anti-vascular therapies in cancer. Introduction Tumor vascularization is one of the hallmarks of cancer. It is classically proposed that for tumor progression to occur new blood vessels must form that will allow the provision of oxygen and nutrients, however these vessels also provide beneficial roles by allowing immune cells and drug delivery to inhibit tumor growth 1 . Furthermore, blood vessels have angiocrine capacity supporting directly the growth of tumors through the production of cytokines and growth factors 2 . They have also been proposed to facilitate tumor spread through the blood or lymphatic vasculature 3 . More recently, it has also been proposed that tumor vessels behaving abnormally contribute to the hypoxic environment and hence maintain tumor cells in an invasive state 4 . Beyond its detrimental role, tumor vasculature is an essential component of drug and immune cell delivery to the tumor. Overall these properties have prompted numerous attempts at normalizing abnormal blood vessel formation in the context of cancer rather than outright abrogating tumor vessels 5 Tumors are vascularized through a variety of modalities but rely predominantly on angiogenesis where VEGF family members play a crucial role. However, anti-VEGF therapy has failed in many indications to reduce tumor size, spread, or vascularization 5 . Although many of the molecular factors that drive tumor vascularization are well known and established, much less is known about the cellular origin of vessel network in tumors. In particular, it is often unclear which vascular bed or which cells are at the source of newly formed vessels in primary tumors. Past studies have proposed the existence of endothelial progenitors driving tumor vascularization 6 . Contrasting early studies, the hematopoietic, bone marrow derived, and circulating nature of this endothelial progenitors has been refuted 7 and it has been clarified that these cells are of a resident endothelial nature 8 . Although informative, many of these studies relied on single markers or cell transfers as opposed to cell fate mapping of endogenous progenitors as well as a functional rather than a marker-based definition of progenitors 9 , 10 . We have recently reported in a variety of vascular beds in mice 11 and humans 12 that the adult endothelium is heterogeneous and is composed of 3 distinct populations: an endovascular progenitor (EVP), a transit amplifying (TA), and a differentiated (D) population. In the present study, we have extensively examined the formation of tumor vasculature and show that very early upon inoculation, tumors are infiltrated by SOX18 expressing EVP cells that originate from arterial or venous but not from lymphatic beds. These EVP cells give rise to TA and D cells that form mostly venous/arterial capillaries but also lymphatics through the combined contribution of multiple clones of endothelial cells. At the functional level, only EVP cells have colony forming and transplantation capacity. The molecular characterization of EVPs shows significant differences with TA and D cells. Critically for a therapeutic perspective, anti-VEGF-A therapy did not affect EVP cells. On the other hand, conditional ablation of RBPJ, a direct protein interactor of SOX18 13 , 14 , dramatically reduced EVP cells and resulted in the abrogation of metastases providing perspectives for anti-vascular therapy of cancer by targeting the EVP population. Results Functional and molecular heterogeneity of tumor vasculature To explore the cellular origin of vessels in a growing tumor and establish the kinetics of vessel assembly, we undertook orthotopic delivery of B16-F0 melanoma cells intradermally. Cdh5-Cre ER RosaYFP mice were used to label all endothelial cells with YFP using tamoxifen injection for 5 consecutive days. Subsequently, mice were inoculated intradermally with B16-F0 tumor cells. Upon injection and development, tumors were visible from 5–7 days macroscopically and could be easily distinguished from surrounding tissues. We first examined the heterogeneity of endothelial cells based on variation in cell surface markers 11 . Dissection, single cell suspension, and analysis of tumors with minimum contamination by surrounding cells using multi-color flow cytometry allowed determining positive and negative staining for every marker using the fluorescence minus one (FMO) method (Supplementary Figure 1A ). In the absence of tamoxifen injection no YFP could be observed (not shown). Using a live gate, doublets were discounted and hematopoietic cells were identified using the lineage cocktail (Lin). Among Lin-CD34+ cells, most cells (>98%) were YFP+ demonstrating their endothelial origin (Fig. 1a ). Among these VE-cadherin expressing cells, three populations could be easily identified based on their levels of CD31 and VEGFR2 identified as EVP (CD31 lo VEGFR2 lo ), TA (CD31 int , VEGFR2 lo ), and D (CD31 hi VEGFR2 hi ) 11 . We also ensured that these Lin-CD34+ populations did not express the hematopoietic progenitor marker c-kit (Supplementary Figure 1B ). We further ensured the validity of our analysis using spontaneous melanomas developed on Tyr::Nras; Cdk4r24c 15 transgenic mice as well as in Lewis Lung Cancer (LLC) and EO771 breast cancer tumors and observed similar endothelial heterogeneity (Supplementary Figure 1C & D ). Fig. 1 Melanoma endothelium in heterogeneous. a Schematic diagram demonstrating experimental set up using vascular lineage tracing Cdh5-Cre ER RosaYFP mice. Flow cytometry plots showing", "role": "user" }, { "content": "Stopping melanoma from spreading to other parts of the body might be as simple as cutting off the blood supply to the cancer, according to researchers. Scientists from The University of Queensland's Diamantina Institute have discovered stem cells which form blood vessels in tumours, and have identified how to 'switch the cells off'. Professor Kiarash Khosrotehrani (below) said the study's findings had enormous implications for cancer patients. \"Blood vessels are vital because tumours can't grow without them – they feed the tumours and allow the cancer to spread,\" Professor Khosrotehrani said. \"If you get rid of these stem cells, then the blood vessels don't form and the tumours don't grow or spread to other locations.\" Professor Khosrotehrani said being able to block blood vessel development could be useful in treating recently diagnosed patients as it may help to prevent the cancer from spreading at an early stage. \"This idea has been around for a while, but it has proven difficult to achieve because blood vessel formation is a fundamental mechanism by which our body responds to injury,\" he said. \"Directly targeting the stem cells that form these blood vessels is a new approach that could make the difference.\" The research team will test the ability of a compound to stop these stem cells from forming blood vessels, in a study supported by National Health and Medical Research Council (NHMRC) funding. Researcher Dr. Jatin Patel said melanoma's ability to quickly spread from the skin to other parts of the body was what made it so deadly. \"We know that before tumours spread to places like lymph nodes or lungs, the body starts growing extra blood vessels in these areas – almost as if preparing special 'niches' for the cancer,\" Dr. Patel said. \"Our next study will focus on blocking the development of these niches. \"If the body doesn't prepare them, then the cancer won't grow there.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Increased inflammation associated with leaky gut is a major risk factor for morbidity and mortality in older adults; however, successful preventive and therapeutic strategies against these conditions are not available. In this study, we demonstrate that a human-origin Lactobacillus paracasei D3-5 strain (D3-5), even in the non-viable form, extends life span of Caenorhabditis elegans . In addition, feeding of heat-killed D3-5 to old mice (> 79 weeks) prevents high- fat diet-induced metabolic dysfunctions, decreases leaky gut and inflammation, and improves physical and cognitive functions. D3-5 feeding significantly increases mucin production, and proportionately, the abundance of mucin-degrading bacteria Akkermansia muciniphila also increases. Mechanistically, we show that the lipoteichoic acid (LTA), a cell wall component of D3-5, enhances mucin ( Muc2 ) expression by modulating TLR-2/p38-MAPK/NF-kB pathway, which in turn reduces age-related leaky gut and inflammation. The findings indicate that the D3-5 and its LTA can prevent/treat age-related leaky gut and inflammation. Access provided by DEAL DE / Springer Compact Clearingstelle Uni Freiburg _ Working on a manuscript? Avoid the common mistakes Introduction The world’s population is rapidly aging with a concomitant increase in aging-related comorbidities like obesity, diabetes, cardiovascular diseases, cancer, infections, and cognitive decline (Hodes et al. 2016 ; Jaul and Barron 2017 ; Tabloski 2004 ). The mechanism(s) of how aging contributes to these health ailments are still unclear, but low-grade inflammation is often found to be higher in older adults and is a major risk factor for mortality and morbidity (Franceschi and Campisi 2014 ). The pathways leading to low-grade inflammation are not completely understood, but increased gut permeability (“leaky gut”) can allow non-selective diffusion of microbial and dietary antigens from the gut lumen into the lymphatic and blood circulation, which in turn promotes inflammatory responses locally (gut mucosa) and systemically (Konig et al. 2016 ; Ulluwishewa et al. 2011 ). Thus, effective strategies to reduce leaky gut and consequent inflammation are needed. Emerging evidence suggests that detrimental perturbations in gut microbiome (dysbiosis) are associated with leaky gut, inflammation, and poor health outcomes in older adults. Gut permeability is tightly controlled by intestinal barriers including tight junction proteins and a mucus layer (Capaldo et al. 2017 ). The mucus layer functions as a physical barrier to separate gut microbes and host cells and protects from the abnormal leakage and invasion of pathogens and antigens into the circulation (Konig et al. 2016 ). The intestinal mucus layer covers the epithelial cells by making a viscoelastic gel layer, which is synthesized by goblet cells (Cornick et al. 2015 ). Intestinal goblet cells are interspersed between epithelial cells on the villi of intestinal lumen and constantly secrete mucins to form the mucus layer (Johansson 2012 ). Mucin 2 ( Muc2 ) is the major mucin secreted from intestinal goblet cells and is known to protect leaky gut and invasion of microbes (Johansson 2012 ; Vemuri et al. 2018 ). Muc2 knockout (KO) mice develop colitis with a dramatically inflammatory gut mucosa (Van der Sluis et al. 2006 ) associated with a marked decrease in mucus layer’s thickness, thereby highlighting the importance of Muc2 in maintaining gut integrity and inflammation. A thin mucus layer may allow gut microbes to invade intestinal epithelial cells and to activate inflammatory responses in immune cells (Allaire et al. 2018 ). The mucus layer’s thickness is also dramatically reduced in the gut of older adults, which is also linked with increased leaky gut and inflammation (Elderman et al. 2017 ). Given the importance of the mucus layer in protection against microbial translocation, development of gut modulators to promote gut mucin production may be beneficial to ameliorate aging-related leaky gut and inflammation. We hypothesize that probiotics can be used to modulate gut microbiome and ameliorate aging-related leaky gut and inflammation. Probiotics are live microorganisms that extend health benefits to the host/consumers upon administering in sufficient amounts (Hill et al. 2014 ). The most commonly used probiotics are non-spore-forming, gram-positive, lactic acid-producing bacteria such as specific Lactobacillus and Bifidobacterium strains that have been shown to have health-promoting effects against several human diseases (Azad et al. 2018 ; Landete et al. 2017 ; O'Toole et al. 2017 ). However, the precise mechanisms by which probiotics exert their benefits in aging remain largely unknown. Also, probiotics are thought to exert their beneficial effects as live cells; however, whether dead probiotics can also have beneficial effects is not well-known. Given the fact that commonly used probiotics like lactobacilli and bifidobacteria are Gram-positive, it has been hypothesized that bacterial molecules, such as bacterial cell wall constituents including peptidoglycan (PG) and lipoteichoic acid (LTA) and bacterial cytoplasm components including proteins and bacterial DNA, can have specific biological activities (Мokrozub et al. 2015 ). Here, we demonstrate that LTA from the cell wall of a human-origin probiotic bacterium, L. paracasei strain D3-5 (called D3-5 hereafter), exhibits potent activity to stimulate mucin production and reduces aging-related leaky gut and inflammation, which in turn improves physical and cognitive functions in older mice. Mechanistically, LTA from D3-5 stimulated Muc2 expression in goblet cells via activation of toll-like receptor 2/p38-MAPK (TLR-2/p38-MAPK)/NF-κB pathway. Our results highlight the potential of a dead probiotic strain and its cell wall-derived LTA to prevent and/or treat aging-related leaky gut and inflammation and to improve overall cognitive and physical functions in older adults. Results Dead L. paracasei D3-5 feeding extends lifespan in Caenorhabditis ( C.) elegans The onset of aging is associated with decline in muscle mass, and in physical and cognitive functions. Wild-type C. elegans N2 is a widely used animal model in several anti-aging screening studies (Mack et al. 2019 ; Tissenbaum 2015b ). In a previous study (Nagpal et al. 2018b ), we isolated six probiotic Lactobacillus strains (viz. L. plantarum SK9, L. plantarum D6-2, L. paracasei D3-5, L. paracasei D10.4, L. rhamnosus D4-4, and L. rhamnosus D7-4) from healthy infants. Here, to investigate if these strains displayed anti-aging benefits, we screened them using the wild-type C. elegans N2 (Tissenbaum 2015a ). Since longevity assay of C. elegans required addition of", "role": "user" }, { "content": "Scientists at Wake Forest School of Medicine have identified a dead probiotic that reduces age-related leaky gut in older mice. The study is published in the journal GeroScience. But what exactly is leaky gut and what does a probiotic—dead or alive—have to do with it? Some research has indicated that leaky gut, in which microbes and bacteria in the gut leak into the blood stream through holes or cracks in the intestinal lining, causes an increase in low-grade inflammation, and these conditions are common in older people. This resulting inflammation is thought to play a role in the development of many age-related diseases, such as diabetes, obesity, cancer, cardiovascular disease and decline in physical and cognitive functions. \"We know that probiotics are instrumental in maintaining a healthy gut and preventing leakage, but there isn't much data available to pinpoint which ones work and which ones don't,\" said Hariom Yadav, Ph.D., assistant professor of molecular biology at Wake Forest School of Medicine and principal investigator of the study. \"Determining the strain that is most effective at reducing leaky gut and inflammation would help us target more effective strategies to address the problem, and help explain why probiotics work for some people but not others.\" In the study, Yadav's team first screened eight strains of human-origin probiotics in roundworms, a commonly used model with a short lifespan of 11 to 20 days. They discovered that a strain of Lactobacillus paracasei (D3-5), even in the non-viable or heat-killed form, extended the roundworms' life span. They then tested their initial findings in mice. The results showed that feeding heat-killed D3-5 to older mice prevented high fat diet-induced metabolic dysfunctions, decreased leaky gut and inflammation, and improved physical and cognitive functions. \"Not only did we determine which probiotic strain was the most effective in preventing leaky gut and inflammation, we also showed that the dead version of that probiotic had the same benefits,\" Yadav said. \"This is the first-of-its kind study to show that a component (lipoteichoic acid) from the cell wall of a dead probiotic induced changes in the gut microbiome and mucin production, thereby reducing leaky gut and inflammation in elderly mice. \"We think our findings could be very useful to the food and supplement industries because dead probiotics have the potential to be more stable and have a longer shelf life than live probiotics.\" Yadav has filed a provisional patent application for D3-5. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The incorporation of impurities during the growth of nanowires from the vapour phase alters their basic properties substantially, and this process is critical in an extended range of emerging nanometre-scale technologies 1 , 2 , 3 , 4 . In particular, achieving precise control of the behaviour of group III and group V dopants has been a crucial step in the development of silicon (Si) nanowire-based devices 5 , 6 , 7 . Recently 8 , 9 , 10 , 11 it has been demonstrated that the use of aluminium (Al) as a growth catalyst, instead of the usual gold, also yields an effective p-type doping, thereby enabling a novel and efficient route to functionalizing Si nanowires. Besides the technological implications, this self-doping implies the detachment of Al from the catalyst and its injection into the growing nanowire, involving atomic-scale processes that are crucial for the fundamental understanding of the catalytic assembly of nanowires. Here we present an atomic-level, quantitative study of this phenomenon of catalyst dissolution by three-dimensional atom-by-atom mapping of individual Al-catalysed Si nanowires using highly focused ultraviolet-laser-assisted atom-probe tomography. Although the observed incorporation of the catalyst atoms into nanowires exceeds by orders of magnitude the equilibrium solid solubility 12 and solid-solution concentrations in known non-equilibrium processes 13 , 14 , the Al impurities are found to be homogeneously distributed in the nanowire and do not form precipitates or clusters. As well as the anticipated effect on the electrical properties, this kinetics-driven colossal injection also has direct implications for nanowire morphology. We discuss the observed strong deviation from equilibrium using a model of solute trapping at step edges, and identify the key growth parameters behind this phenomenon on the basis of a kinetic model of step-flow growth of nanowires. The control of this phenomenon provides opportunities to create a new class of nanoscale devices by precisely tailoring the shape and composition of metal-catalysed nanowires. Main The nanowires investigated in this study were grown on Si(111) in an ultrahigh-vacuum chemical deposition system 10 , 15 . Their growth was accomplished with Al-Si nanoparticles, which act catalytically as the energetically favoured sites for vapour-phase reactant (SiH 4 ) adsorption and (when saturated) as the nucleation sites for crystallization and one-dimensional growth 16 . The resulting nanowires are aligned along the [111] direction and display morphological characteristics that are sensitive to the growth temperature ( Supplementary Figs 1 and 2 ). Growth at the highest temperature (470 °C) yields tapered nanowires with an average height and base diameter of 475 ± 30 nm and 94 ± 8 nm, respectively ( Supplementary Fig. 1 ). Figure 1a displays a high-resolution transmission electron microscopy (TEM) micrograph of an Al-catalysed Si nanowire near the interface with the catalyst. This micrograph demonstrates that both nanowire and catalyst nanoparticle are single crystals with a coherent interface between them. However, the close atomic numbers of 13 Al and 14 Si make them indistinguishable in high-resolution TEM images of nanowires. Energy-dispersive X-ray analysis (EDX) in an aberration-corrected TEM did not find a significant Al signal in Si nanowires grown at the lowest temperature (410 °C). This indicates that the Al concentration is less than the EDX detection limit, which is typically ∼ 0.5 atomic per cent (at.%). For a rigorous analysis, we used atom-probe tomography (APT), which has a superior detection sensitivity of less than ten atomic parts per million (p.p.m.), with atomic-scale spatial resolution 17 . Pulsed evaporation of individual atoms was achieved using a focused picosecond ultraviolet (wavelength λ = 355 nm) laser. The use of a highly focused ultraviolet laser beam decreases local heating, thereby improving the detection limits and mass resolving power ( m /Δ m , where m is the mass of an isotope) 18 . Figure 1: Structure and three-dimensional map of Al-catalysed Si nanowires. a , High-resolution cross-sectional TEM image (left) displaying the interface between the catalyst particle and the nanowire. The right panel exhibits a close-up image of the interface (top), the fast Fourier transform of the image (middle), and the corresponding colour-filtered image (bottom, Al and Si regions correspond to red and blue regions, respectively) indicating that the interface is epitaxial. b , Three-dimensional APT atom-by-atom map of a nanowire grown at 410 °C. For the sake of clarity, only a limited number of atoms is displayed (2.5 × 10 4 atoms of each element). Inset, a cross-sectional TEM image of an identical Si nanowire (scale bar, 40 nm). c , Si 50 at.% isoconcentration surface of an 80-nm-long segment of a nanowire determined by analysing a three-dimensional atom-probe tomographic reconstruction: left, side view; right, top view. PowerPoint slide Full size image Figure 1b shows a three-dimensional atom-by-atom map of a single Al-catalysed Si nanowire covered by a protective nickel (Ni) layer. The inset in Fig. 1b displays a cross-sectional TEM image of an identical nanowire. Figure 1c shows two projections of an 80-nm-long segment of a Si nanowire delineated by an isoconcentration surface drawn at the 50 at.% Si level. The 50 at.% Al isoconcentration surface of the catalyst nanoparticle is displayed in Fig. 2a . Axial and radial concentration profiles of Al and Si, taken from the top 10 nm of the nanoparticle, are presented in Fig. 2b and c , respectively. Both concentration profiles demonstrate Si segregation close to the nanoparticle’s surface, possibly as a result of Si expulsion during post-growth cooling or simply due to oxidation on exposure to air. The average Si concentration measured at the core of the nanoparticle is in the range of 2.7 ± 0.9 to 3.1 ± 0.4 at.%, which is nearly twice the solubility of Si in Al at the eutectic temperature 19 . This indicates that Si solubility in Al increases in undercooled catalyst. Figure 2d displays the three-dimensional distribution of Al atoms detected in an as-grown Si nanowire. The average Al solid concentration ( ) measured for Si nanowires grown at 410 °C is ∼ (2.0 ± 0.5) × 10 20 atom cm −3 ( ∼", "role": "user" }, { "content": "Semiconductor nanowires are quasi-one-dimensional nanomaterials that have sparked a surge of interest as one of the most powerful and versatile nanotechnological building blocks with actual or potential impact on nanoelectronics, photonics, electromechanics, environmentally friendly energy conversion, biosensing, and neuro-engineering technologies. Bottom-up synthesis of nanowires through metal-catalyzed vapor phase epitaxy is a very attractive process to generate high-quality nanowires thus providing an additional degree of freedom in design of innovative devices that extend beyond what is achievable with the current technologies. In this nano-fabrication process, nanowires grow through the condensation of atoms released from a molecular vapor (called precursors) at the surface of metallic nano-droplets. Gold is broadly used to form these nano-droplets. This self-assembly of nanowires takes place spontaneously at optimal temperature and vapor pressure and can be applied to synthesize any type of semiconductor nanowires. However, to functionalize these nanomaterials a precise introduction of impurities is central to tune their electronic and optical properties. For instance, the introduction of group III and V impurities in a silicon lattice is a crucial step for optimal design and performance of silicon nanowire technologies. The accurate control of this doping process remains an outstanding challenge that is increasingly complex as a result of the relentless drive toward device miniaturization and the emergence of novel nanoscale device architectures. In a recent development, a team of scientists from Polytechnique Montréal (Canada), Northwestern University (USA), and Max Planck Institute of Microstructure Physics (Germany) led by Professor Oussama Moutanabbir has made a fascinating discovery of a novel process to precisely functionalize nanowires. By using aluminum as a catalyst instead of the canonical gold, the team demonstrated that the growth of nanowires triggers a self-doping process involving the injection of aluminum atoms thus providing an efficient route to dope nanowires without the need of post-growth processing typically used in semiconductor industry. Besides the technological implications, this self-doping implies atomic scale processes that are crucial for the fundamental understanding of the catalytic assembly of nanowires. The scientists investigated this phenomenon at the atomistic-level using the emerging technique of highly focused ultraviolet laser-assisted atom-probe tomography to achieve three-dimensional atom-by-atom maps of individual nanowires. A new predictive theory of impurity injections was also developed to describe this self-doping phenomenon, which provides myriad opportunities to create entirely new class of nanoscale devices by precisely tailoring shape and composition of nanowires. The results of their breakthrough will be published in Nature. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The two natural allotropes of carbon, diamond and graphite, are extended networks of sp 3 -hybridized and sp 2 -hybridized atoms, respectively 1 . By mixing different hybridizations and geometries of carbon, one could conceptually construct countless synthetic allotropes. Here we introduce graphullerene, a two-dimensional crystalline polymer of C 60 that bridges the gulf between molecular and extended carbon materials. Its constituent fullerene subunits arrange hexagonally in a covalently interconnected molecular sheet. We report charge-neutral, purely carbon-based macroscopic crystals that are large enough to be mechanically exfoliated to produce molecularly thin flakes with clean interfaces—a critical requirement for the creation of heterostructures and optoelectronic devices 2 . The synthesis entails growing single crystals of layered polymeric (Mg 4 C 60 ) ∞ by chemical vapour transport and subsequently removing the magnesium with dilute acid. We explore the thermal conductivity of this material and find it to be much higher than that of molecular C 60 , which is a consequence of the in-plane covalent bonding. Furthermore, imaging few-layer graphullerene flakes using transmission electron microscopy and near-field nano-photoluminescence spectroscopy reveals the existence of moiré-like superlattices 3 . More broadly, the synthesis of extended carbon structures by polymerization of molecular precursors charts a clear path to the systematic design of materials for the construction of two-dimensional heterostructures with tunable optoelectronic properties. Main C 60 fullerene, the first synthetic carbon allotrope 4 , 5 , is a geometrically closed, polycyclic polymer composed solely of carbon atoms (Fig. 1a ). This polymer is infinite in the literal sense of not having any termini, but it is obviously quite finite in being the size of a normal, albeit large, molecule. Graphene, another allotrope of elemental carbon 6 , is also a polymer of carbon atoms, but in this case, the polymerization leads to a geometrically open result: infinite, two-dimensional (2D) sheets (Fig. 1b ). Here we disclose a 2D polymer of C 60 , which we synthesize by linking C 60 molecules into layered, graphene-like hexagonal sheets (Fig. 1c ). By analogy to graphene and graphite, we have dubbed this material graphullerene, and its three-dimensional van der Waals (vdW) solid, graphullerite. Fig. 1: Carbon allotropes. a , b , C 60 fullerene, a zero-dimensional molecular cage composed of 60 carbon atoms ( a ), and graphene, consisting of a single layer of atoms ( b ), both composed of three-coordinate carbon. c , Graphullerene, a molecular sheet of carbon assembled from covalently linked C 60 fullerene superatomic building blocks. Full size image Our chemical strategy to prepare graphullerene was inspired by a recent study 7 , which used the chemical vapour transport (CVT) approach to grow single crystals of metal-doped polyfullerides. First, we grow single crystals of magnesium (Mg)-doped polyfulleride—(Mg 4 C 60 ) ∞ . These polyfullerides are obtained by pressing a pellet of C 60 and Mg powder under an inert atmosphere, sealing it in a fused silica tube under vacuum, and placing it in a horizontal furnace with a temperature gradient (Fig. 2a ). Large, black, hexagonal crystals (hundreds of micrometres in lateral dimensions), with a metallic luster, are obtained at the cold end of the tube (Fig. 2b ). Fig. 2: Synthesis and crystal structures of (Mg 4 C 60 ) ∞ . a , Schematic of the CVT technique used for the growth of (Mg 4 C 60 ) ∞ single crystals. b , Optical micrograph of a single crystal. c , Crystal structure of (Mg 4 C 60 ) ∞ showing a top view of a single layer and a side view emphasizing the stacking of the layers along the a axis. The C 60 units within each layer are much closer to one another than they are in molecular C 60 crystals 5 . The closest C···C distance between two C 60 subunits (1.573(1) Å) is roughly half of that in molecular C 60 (3.116 Å). This very close spacing between the fullerenes is a direct reflection of covalent bonding between the molecules. d , The log of the conductance ( σ ) versus temperature ( T ) for a 70-nm-thick (Mg 4 C 60 ) ∞ device. A fit to a thermally activated (Arrhenius) model is given by the dashed green line. A typical device and corresponding four-terminal measurement scheme are shown in the inset. E a , activation energy; k B , Boltzmann constant; V SD , source-drain voltage; V xx , longitudinal voltage drop. Full size image Single-crystal X-ray diffraction (SCXRD) reveals that the crystals have a layered structure, and display a quasi-hexagonal lattice, with each C 60 forming eight covalent σ bonds to six neighbours within a molecular plane. Four of these make single connections between the C 60 molecules, and each of the other two pairs doubly connects the C 60 molecules (Fig. 2c ). The synthesis yields highly reduced sheets with four Mg counterions per fullerene. The counterions are closely associated with each individual layer (Fig. 2c ), and not shared between layers; hence, the layers are only weakly bonded to each other, predominantly through vdW interactions. Single crystals of (Mg 4 C 60 ) ∞ were also grown in a recent study 8 using a similar CVT approach. We fabricated mesoscopic devices to investigate the electrical transport properties of these highly reduced polymerized fullerene sheets. We produced thin bulk flakes of (Mg 4 C 60 ) ∞ by mechanical exfoliation and deposited gold contacts using the dry-transfer and high-resolution stencil mask technique (an approximately 70-nm-thick device is shown in the inset of Fig. 2d ). (Mg 4 C 60 ) ∞ exhibits thermally activated transport along the in-plane direction (Extended Data Fig. 1 ) with an activation energy of 121 meV, as calculated from fitting an Arrhenius thermal activation model (Fig. 2d ). One of the key benefits of 2D materials prepared by mechanical exfoliation of vdW crystals is their ultra-clean surfaces without counterions or contaminants. This is critical for many applications, and in particular for the assembly of heterostructures", "role": "user" }, { "content": "Carbon in its myriad forms has long captivated the scientific community. Besides being the primary component of all organic life on earth, material forms of carbon have earned their fair share of breakthroughs. In 1996, the Nobel Prize in Chemistry went to the discoverers of fullerene, a superatomic symmetrical structure of 60 carbon atoms shaped like a soccer ball; in 2010, researchers working with an ultra-strong, atom-thin version of carbon, known as graphene, won the Nobel Prize in Physics. Today, in work published in Nature, researchers led by Columbia chemists Xavier Roy, Colin Nuckolls, and Michael Steigerwald with postdoc and first author Elena Meirzadeh have discovered a new version of carbon that sits somewhere in between fullerene and graphene: graphullerene. It's a new two-dimensional form of carbon made up of layers of linked fullerenes peeled into ultrathin thin flakes from a larger graphullerite crystal—just like how graphene is peeled from crystals of graphite (the same material found in pencils). \"It is amazing to find a new form of carbon in the year 2022,\" said Nuckolls. \"It also makes you realize that there is a whole family of materials that can be made in a similar way that will have new and unusual properties as a consequence of the information written into the superatomic building blocks.\" Meirzadeh, who synthesized the first crystals of graphullerite, referred to graphullerene as the superatomic \"cousin\" of graphene. Unlike graphene and most other two-dimensional materials that are made of repeating elements that are limited to specific bonding geometries and have specific properties as a result, graphullerene's superatomic structure makes it incredibly modular, she explained. With 60 carbon atoms in the ball to work with, fullerenes can theoretically be linked together in a number of different ways, each of which could yield different electronic, magnetic, and optical properties—this first version represents just one possible configuration, Roy said. It's a new way of thinking about structures and their properties as they grow, added Steigerwald. \"For more than 30 years, researchers have had the notion that clusters of atoms will behave differently than the larger solids that they form,\" he said. \"Here, we are making a solid out of an existing carbon superatom to see how that kind of organization will influence its properties. Would the new material behave like fullerene, or like something else?\" The team set out to bond fullerenes molecules rather than individual carbon atoms into a layered, peelable crystal, in order to study its superatomic properties in two dimensions. Meirzadeh used a high-temperature solid-state synthesis technique involving a magnesium scaffold that was later removed—a process involving acid that, after a year spent working with air-sensitive crystals inside a glovebox, was a slightly nerve-wracking final step. \"As chemists, we try things and don't always know what will happen. I thought it would fall apart, but it remained intact,\" she recalled. \"Seeing an intact, pure carbon crystal that we could then easily exfoliate and study was a great surprise.\" Once the new material was made, Meirzadeh sent samples off to collaborators at Columbia and beyond for initial imaging and characterization. The battery of tests revealed a number of intriguing electrical, optical, and thermal properties. Like graphene, graphullerene can confine and polarize light, it can accept lots of extra electrons, and it can form tunable superlattice structures; these properties make it a promising material with potential applications in new kinds of optical and electronic devices. Compared to fullerenes, graphullerite crystals are shown to have a much higher thermal conductivity, a result of the strong covalent bonds within each graphullerene sheet. Thermal conductivity helps dissipate heat, an important consideration when building devices. The work is a starting point for the team to explore the potential of graphullerene. From a chemistry perspective, they plan to tweak and tune its modular properties and introduce new structures, while collaborators will look more closely at what happens when graphullerene sheets are combined with different kinds of two-dimensional materials studied at Columbia to see what other secrets carbon conceals. \"The discoveries of both graphene and fullerenes were incredibly impactful,\" said Roy. Fullerenes, for example, are used to build organic photovoltaic cells and in medicine as contrast agents for MRI and X-ray imaging and to deliver drug therapies. The more recently discovered graphene, an extremely light yet strong material with numerous unique properties, is being actively explored for potential uses in electronics, energy applications, and more. \"Now we've combined them together into this new form of carbon. We don't know exactly what will come out of this work, but it will be very exciting to explore,\" he said. ", "role": "assistant" } ]

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4748, 772, 8535, 6012, 13, 4802, 356, 220, 1399, 88018, 1994, 11, 279, 1176, 28367, 12782, 85274, 299, 375, 220, 19, 1174, 220, 20, 1174, 374, 264, 53584, 750, 8036, 11, 1499, 3418, 66404, 47393, 24306, 21742, 315, 12782, 33299, 320, 30035, 13, 220, 16, 64, 7609, 1115, 47393, 374, 24746, 304, 279, 24016, 5647, 315, 539, 3515, 904, 10415, 72, 11, 719, 433, 374, 14224, 5115, 35326, 304, 1694, 279, 1404, 315, 264, 4725, 11, 43169, 3544, 11, 43030, 13, 12441, 1994, 11, 2500, 85274, 299, 375, 315, 62235, 12782, 220, 21, 1174, 374, 1101, 264, 47393, 315, 12782, 33299, 11, 719, 304, 420, 1162, 11, 279, 47393, 2065, 11767, 311, 264, 53584, 750, 1825, 1121, 25, 24746, 11, 1403, 33520, 320, 17, 35, 8, 25112, 320, 30035, 13, 220, 16, 65, 7609, 5810, 584, 36333, 264, 220, 17, 35, 47393, 315, 356, 220, 1399, 1174, 902, 584, 6925, 27985, 555, 31799, 356, 220, 1399, 35715, 1139, 64241, 11, 66192, 12970, 12651, 24346, 25112, 320, 30035, 13, 220, 16, 66, 7609, 3296, 56203, 311, 66192, 323, 95273, 11, 584, 617, 42160, 420, 3769, 4876, 620, 261, 1994, 11, 323, 1202, 2380, 33520, 5355, 2761, 29614, 1147, 320, 17008, 54, 8, 6573, 11, 4876, 620, 261, 635, 13, 23966, 13, 220, 16, 25, 22208, 85274, 897, 288, 13, 264, 1174, 293, 1174, 356, 220, 1399, 88018, 1994, 11, 264, 7315, 33520, 31206, 36460, 24306, 315, 220, 1399, 12782, 33299, 320, 264, 7026, 323, 66192, 11, 31706, 315, 264, 3254, 6324, 315, 33299, 320, 293, 7026, 2225, 24306, 315, 2380, 81797, 12782, 13, 272, 1174, 12441, 620, 261, 1994, 11, 264, 31206, 11071, 315, 12782, 35105, 505, 1080, 838, 4501, 10815, 356, 220, 1399, 88018, 1994, 2307, 6756, 4857, 10215, 13, 8797, 1404, 2217, 5751, 11742, 8446, 311, 10772, 4876, 620, 261, 1994, 574, 14948, 555, 264, 3293, 4007, 220, 22, 1174, 902, 1511, 279, 11742, 68857, 414, 7710, 320, 20161, 51, 8, 5603, 311, 3139, 3254, 48473, 315, 9501, 1773, 16771, 10062, 9054, 261, 3422, 13, 5629, 11, 584, 3139, 3254, 48473, 315, 61933, 320, 44, 70, 7435, 67, 16771, 10062, 9054, 261, 579, 2345, 7, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 662, 4314, 10062, 9054, 261, 3422, 527, 12457, 555, 26422, 264, 68510, 315, 356, 220, 1399, 323, 73693, 17138, 1234, 459, 81073, 16975, 11, 66934, 433, 304, 264, 75754, 77889, 14019, 1234, 29302, 11, 323, 25012, 433, 304, 264, 16600, 55564, 449, 264, 9499, 20779, 320, 30035, 13, 220, 17, 64, 7609, 20902, 11, 3776, 11, 12651, 24346, 48473, 320, 71, 46813, 315, 19748, 442, 295, 417, 304, 45569, 15696, 705, 449, 264, 46258, 326, 5100, 11, 527, 12457, 520, 279, 9439, 842, 315, 279, 14019, 320, 30035, 13, 220, 17, 65, 7609, 23966, 13, 220, 17, 25, 24028, 13491, 323, 26110, 14726, 315, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 662, 264, 1174, 328, 82149, 315, 279, 14499, 51, 15105, 1511, 369, 279, 6650, 315, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 3254, 48473, 13, 293, 1174, 75939, 8162, 4539, 315, 264, 3254, 26110, 13, 272, 1174, 29016, 6070, 315, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 9204, 264, 1948, 1684, 315, 264, 3254, 6324, 323, 264, 3185, 1684, 82003, 279, 75172, 315, 279, 13931, 3235, 279, 264, 8183, 13, 578, 356, 220, 1399, 8316, 2949, 1855, 6324, 527, 1790, 12401, 311, 832, 2500, 1109, 814, 527, 304, 31206, 356, 220, 1399, 48473, 220, 20, 662, 578, 18585, 356, 61176, 14260, 34, 6138, 1990, 1403, 356, 220, 1399, 1207, 26726, 320, 16, 13, 22529, 7, 16, 8, 80352, 8, 374, 17715, 4376, 315, 430, 304, 31206, 356, 220, 1399, 320, 18, 13, 8027, 80352, 570, 1115, 1633, 3345, 27032, 1990, 279, 2539, 17848, 288, 374, 264, 2167, 22599, 315, 1080, 838, 306, 64186, 1990, 279, 35715, 13, 294, 1174, 578, 1515, 315, 279, 6929, 685, 320, 48823, 883, 19579, 9499, 320, 350, 883, 369, 264, 220, 2031, 5392, 76, 7716, 875, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 3756, 13, 362, 5052, 311, 264, 30945, 750, 22756, 320, 9014, 12301, 9334, 8, 1646, 374, 2728, 555, 279, 67822, 6307, 1584, 13, 362, 14595, 3756, 323, 12435, 3116, 91723, 19179, 13155, 527, 6982, 304, 279, 55959, 13, 469, 264, 1174, 15449, 4907, 26, 597, 426, 1174, 47047, 89, 18022, 6926, 26, 650, 8189, 1174, 2592, 19158, 467, 22465, 26, 650, 21578, 1174, 68102, 22465, 6068, 13, 8797, 1404, 2217, 11579, 48689, 14272, 1630, 30630, 3722, 16597, 320, 3624, 55, 37790, 8, 21667, 430, 279, 48473, 617, 264, 64241, 6070, 11, 323, 3113, 264, 48844, 2902, 327, 24346, 55372, 11, 449, 1855, 356, 220, 1399, 30164, 8223, 1080, 838, 306, 48823, 27460, 311, 4848, 36956, 2949, 264, 31206, 11277, 13, 13625, 315, 1521, 1304, 3254, 13537, 1990, 279, 356, 220, 1399, 35715, 11, 323, 1855, 315, 279, 1023, 1403, 13840, 94989, 34161, 279, 356, 220, 1399, 35715, 320, 30035, 13, 220, 17, 66, 7609, 578, 39975, 36508, 7701, 11293, 25112, 449, 3116, 73693, 5663, 919, 824, 88018, 1994, 13, 578, 5663, 919, 527, 15499, 5938, 449, 1855, 3927, 6324, 320, 30035, 13, 220, 17, 66, 7026, 323, 539, 6222, 1990, 13931, 26, 16472, 11, 279, 13931, 527, 1193, 7621, 398, 70241, 311, 1855, 1023, 11, 47904, 1555, 62627, 54, 22639, 13, 11579, 48473, 315, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 1051, 1101, 15042, 304, 264, 3293, 4007, 220, 23, 1701, 264, 4528, 14499, 51, 5603, 13, 1226, 70554, 11083, 84667, 7766, 311, 19874, 279, 20314, 7710, 6012, 315, 1521, 7701, 11293, 47393, 1534, 88018, 1994, 25112, 13, 1226, 9124, 15792, 20155, 82723, 315, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 555, 22936, 506, 8566, 7246, 323, 54568, 6761, 19015, 1701, 279, 9235, 93791, 323, 1579, 64036, 73470, 7056, 15105, 320, 276, 13489, 220, 2031, 5392, 76, 7716, 875, 3756, 374, 6982, 304, 279, 55959, 315, 23966, 13, 220, 17, 67, 7609, 320, 44, 70, 220, 19, 356, 220, 1399, 883, 12264, 252, 50829, 30945, 750, 22756, 7710, 3235, 279, 304, 90649, 5216, 320, 54290, 2956, 23966, 13, 220, 16, 883, 449, 459, 15449, 4907, 315, 220, 7994, 757, 53, 11, 439, 16997, 505, 27442, 459, 18925, 12301, 9334, 29487, 15449, 1646, 320, 30035, 13, 220, 17, 67, 7609, 3861, 315, 279, 1401, 7720, 315, 220, 17, 35, 7384, 10235, 555, 22936, 506, 8566, 7246, 315, 62627, 54, 48473, 374, 872, 24955, 92900, 27529, 2085, 5663, 919, 477, 88959, 13, 1115, 374, 9200, 369, 1690, 8522, 11, 323, 304, 4040, 369, 279, 14956, 315, 30548, 78, 47194, 128257, 198, 128256, 78191, 198, 37707, 304, 1202, 52909, 7739, 706, 1317, 6563, 55786, 279, 12624, 4029, 13, 31909, 1694, 279, 6156, 3777, 315, 682, 17808, 2324, 389, 9578, 11, 3769, 7739, 315, 12782, 617, 15662, 872, 6762, 4430, 315, 42445, 82, 13, 763, 220, 2550, 21, 11, 279, 48078, 32293, 304, 42846, 4024, 311, 279, 7142, 388, 315, 88018, 1994, 11, 264, 2307, 6756, 8045, 59402, 6070, 315, 220, 1399, 12782, 33299, 27367, 1093, 264, 22963, 5041, 26, 304, 220, 679, 15, 11, 12074, 3318, 449, 459, 24955, 96857, 11, 19670, 7716, 258, 2373, 315, 12782, 11, 3967, 439, 66192, 11, 2834, 279, 48078, 32293, 304, 28415, 13, 11450, 11, 304, 990, 4756, 304, 22037, 11, 12074, 6197, 555, 19326, 8590, 1705, 62860, 11284, 11, 40979, 452, 1983, 68978, 11, 323, 8096, 3441, 7420, 54006, 449, 1772, 5349, 323, 1176, 3229, 69675, 2206, 404, 89, 1037, 71, 617, 11352, 264, 502, 2373, 315, 12782, 430, 23874, 15038, 304, 1990, 88018, 1994, 323, 66192, 25, 4876, 620, 261, 1994, 13, 1102, 596, 264, 502, 1403, 33520, 1376, 315, 12782, 1903, 709, 315, 13931, 315, 10815, 2539, 17848, 288, 83612, 1139, 37232, 589, 258, 15792, 82723, 505, 264, 8294, 4876, 620, 261, 635, 26110, 2345, 4345, 1093, 1268, 66192, 374, 83612, 505, 48473, 315, 95273, 320, 1820, 1890, 3769, 1766, 304, 97438, 570, 330, 2181, 374, 8056, 311, 1505, 264, 502, 1376, 315, 12782, 304, 279, 1060, 220, 2366, 17, 1359, 1071, 452, 1983, 68978, 13, 330, 2181, 1101, 3727, 499, 13383, 430, 1070, 374, 264, 4459, 3070, 315, 7384, 430, 649, 387, 1903, 304, 264, 4528, 1648, 430, 690, 617, 502, 323, 19018, 6012, 439, 264, 29774, 315, 279, 2038, 5439, 1139, 279, 2307, 6756, 4857, 10215, 1210, 2206, 404, 89, 1037, 71, 11, 889, 92106, 279, 1176, 48473, 315, 4876, 620, 261, 635, 11, 14183, 311, 4876, 620, 261, 1994, 439, 279, 2307, 6756, 330, 66, 788, 258, 1, 315, 66192, 13, 27140, 66192, 323, 1455, 1023, 1403, 33520, 7384, 430, 527, 1903, 315, 40916, 5540, 430, 527, 7347, 311, 3230, 64186, 69086, 4108, 323, 617, 3230, 6012, 439, 264, 1121, 11, 4876, 620, 261, 1994, 596, 2307, 6756, 6070, 3727, 433, 17235, 44993, 11, 1364, 11497, 13, 3161, 220, 1399, 12782, 33299, 304, 279, 5041, 311, 990, 449, 11, 2539, 17848, 288, 649, 63234, 387, 10815, 3871, 304, 264, 1396, 315, 2204, 5627, 11, 1855, 315, 902, 1436, 7692, 2204, 14683, 11, 24924, 11, 323, 29393, 6012, 2345, 576, 1176, 2373, 11105, 1120, 832, 3284, 6683, 11, 11284, 1071, 13, 1102, 596, 264, 502, 1648, 315, 7422, 922, 14726, 323, 872, 6012, 439, 814, 3139, 11, 3779, 3441, 7420, 54006, 13, 330, 2520, 810, 1109, 220, 966, 1667, 11, 12074, 617, 1047, 279, 23035, 430, 28066, 315, 33299, 690, 36792, 22009, 1109, 279, 8294, 82486, 430, 814, 1376, 1359, 568, 1071, 13, 330, 8586, 11, 584, 527, 3339, 264, 6573, 704, 315, 459, 6484, 12782, 2307, 22612, 311, 1518, 1268, 430, 3169, 315, 7471, 690, 10383, 1202, 6012, 13, 19418, 279, 502, 3769, 36792, 1093, 88018, 1994, 11, 477, 1093, 2555, 775, 7673, 578, 2128, 743, 704, 311, 11049, 2539, 17848, 288, 35715, 4856, 1109, 3927, 12782, 33299, 1139, 264, 64241, 11, 58212, 481, 26110, 11, 304, 2015, 311, 4007, 1202, 2307, 6756, 6012, 304, 1403, 15696, 13, 2206, 404, 89, 1037, 71, 1511, 264, 1579, 12, 35658, 6573, 21395, 39975, 15105, 16239, 264, 61933, 85552, 430, 574, 3010, 7108, 29096, 1920, 16239, 13935, 430, 11, 1306, 264, 1060, 7543, 3318, 449, 3805, 57767, 48473, 4871, 264, 56520, 2054, 11, 574, 264, 10284, 32015, 2695, 81, 9162, 1620, 3094, 13, 330, 2170, 8590, 1705, 11, 584, 1456, 2574, 323, 1541, 956, 2744, 1440, 1148, 690, 3621, 13, 358, 3463, 433, 1053, 4498, 10980, 11, 719, 433, 14958, 35539, 1359, 1364, 32230, 13, 330, 83224, 459, 35539, 11, 10748, 12782, 26110, 430, 584, 1436, 1243, 6847, 506, 8566, 6629, 323, 4007, 574, 264, 2294, 13051, 1210, 9843, 279, 502, 3769, 574, 1903, 11, 2206, 404, 89, 1037, 71, 3288, 10688, 1022, 311, 79119, 520, 19326, 323, 7953, 369, 2926, 32758, 323, 60993, 13, 578, 11863, 315, 7177, 10675, 264, 1396, 315, 41765, 20314, 11, 29393, 11, 323, 29487, 6012, 13, 9086, 66192, 11, 4876, 620, 261, 1994, 649, 2389, 483, 323, 25685, 553, 3177, 11, 433, 649, 4287, 10283, 315, 5066, 57678, 11, 323, 433, 649, 1376, 11716, 481, 2307, 75, 32891, 14726, 26, 1521, 6012, 1304, 433, 264, 26455, 3769, 449, 4754, 8522, 304, 502, 13124, 315, 29393, 323, 14683, 7766, 13, 59813, 311, 2539, 17848, 288, 11, 4876, 620, 261, 635, 48473, 527, 6982, 311, 617, 264, 1790, 5190, 29487, 98971, 11, 264, 1121, 315, 279, 3831, 1080, 838, 306, 27460, 2949, 1855, 4876, 620, 261, 1994, 11071, 13, 66726, 98971, 8779, 93522, 349, 8798, 11, 459, 3062, 18361, 994, 4857, 7766, 13, 578, 990, 374, 264, 6041, 1486, 369, 279, 2128, 311, 13488, 279, 4754, 315, 4876, 620, 261, 1994, 13, 5659, 264, 30903, 13356, 11, 814, 3197, 311, 52143, 323, 26306, 1202, 44993, 6012, 323, 19678, 502, 14726, 11, 1418, 79119, 690, 1427, 810, 15499, 520, 1148, 8741, 994, 4876, 620, 261, 1994, 25112, 527, 11093, 449, 2204, 13124, 315, 1403, 33520, 7384, 20041, 520, 19326, 311, 1518, 1148, 1023, 24511, 12782, 20245, 1147, 13, 330, 791, 54098, 315, 2225, 66192, 323, 2539, 17848, 288, 1051, 17235, 98990, 1359, 1071, 11284, 13, 8797, 17848, 288, 11, 369, 3187, 11, 527, 1511, 311, 1977, 17808, 4604, 93591, 292, 7917, 323, 304, 16088, 439, 13168, 13307, 369, 52460, 323, 1630, 30630, 32758, 323, 311, 6493, 5623, 52312, 13, 578, 810, 6051, 11352, 66192, 11, 459, 9193, 3177, 3686, 3831, 3769, 449, 12387, 5016, 6012, 11, 374, 1694, 22815, 36131, 369, 4754, 5829, 304, 31591, 11, 4907, 8522, 11, 323, 810, 13, 330, 7184, 584, 3077, 11093, 1124, 3871, 1139, 420, 502, 1376, 315, 12782, 13, 1226, 1541, 956, 1440, 7041, 1148, 690, 2586, 704, 315, 420, 990, 11, 719, 433, 690, 387, 1633, 13548, 311, 13488, 1359, 568, 1071, 13, 220, 128257, 198 ]

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hydrofluorocarbon emissions have increased rapidly and are managed by the Kigali Amendment to the Montreal Protocol. Yet the current ambition is not consistent with the 1.5 °C Paris Agreement goal. Here, we draw on the Montreal Protocol start-and-strengthen approach to show that accelerated phase-down under the Kigali Amendment could result in additional reductions of 72% in 2050, increasing chances of staying below 1.5 °C throughout this century. Main Hydrofluorocarbon (HFC) refrigerants are factory-made chemicals produced for use in refrigeration, air-conditioning, insulating foams, fire extinguishers, solvents and aerosol propellants. Since their introduction, emissions of HFCs have grown rapidly as they are the primary replacement for ozone-depleting substances (ODSs) currently managed under the Montreal Protocol (MP) 1 , 2 , 3 . HFCs do not contain ozone-destroying chlorine or bromine atoms but are powerful GHGs and account for ~1.5% of global anthropogenic GHG emissions 2 . Without any controls, HFC emissions are expected to double by 2030 and nearly quadruple by 2050, compared to 2015 levels 3 , 4 . In 2016, HFCs were included in the Kigali Amendment (KA) to the MP—a result of an international consensus that HFCs could be most effectively controlled through the phase-down of their production and consumption under the MP (ref. 5 ), complementary to mitigation under the UN Framework Convention on Climate Change (UNFCCC). The MP process accumulated experience and expertise to ensure a fast and efficient phase-down of HFCs, which are in the same family of gases, have similar chemical properties and are used in the same sectors as the ODSs that they are replacing. The MP also uses a ‘start and strengthen’ approach wherein controlled substances are phased out in an orderly and transparent schedule which is regularly evaluated and strengthened, through amendments, as markets innovate and adjust (Extended Data Fig. 1 ; ref. 6 ). Furthermore, unlike the Paris Agreement to the UNFCCC, the MP and its amendments are legally binding for countries that ratify them. KA is a global agreement (in force since 1 January 2019) to phase-down consumption of HFCs of 80–85% by the late 2040s (Supplementary Table 1 ). Unlike previous MP amendments, which managed ODSs, the KA is primarily a climate treaty, therefore it is appropriate to evaluate the sufficiency of its ambition on the basis of its consistency with climate mitigation targets. The 2015 Paris Agreement established an ambitious target of limiting global mean temperature rise this century to well below 2 °C, preferably to 1.5 °C compared to pre-industrial levels, but did so in the context of broader international goals of sustainable development and poverty eradication. The 1.5 °C-consistent scenarios used in the IPCC Special Report on Global Warming of 1.5 °C (SR1.5) include a 75–80% reduction in HFC emissions by 2050, compared to 2010 levels 7 , along with deep and simultaneous reductions of CO 2 and all non-CO 2 climate-forcing emissions. A recent IIASA study 8 used the Greenhouse Gas and Air Pollution Interactions and Synergies (GAINS) model 9 framework to develop a range of long-term scenarios for HFC emissions under varying degrees of stringency in climate policy and assessed co-benefits in the form of electricity savings and associated reductions in GHG and air pollutant emissions. Full compliance with the KA (Fig. 1a ) is expected to achieve a 56% reduction in HFC emissions by 2050, compared to 2010 levels 8 . Hence, it will not achieve the 75–80% threshold set by 1.5 °C-consistent scenarios 7 . Full compliance with the KA phase-down schedule is estimated to avoid 0.2–0.4 °C additional warming by the end of this century 3 , 10 which is significant but insufficient to achieve a 1.5 °C-consistent pathway 7 . Despite the widely recognized success of the MP for phasing out ODSs faster 11 and at a lower cost than originally assumed, some observers question whether the HFC-reduction process under KA is taking place quickly enough to adequately address the urgency of the climate crisis 12 . Considering the role HFC mitigation plays in 1.5 °C-consistent scenarios 7 , enhancing the ambition of mitigation efforts by all parties to the MP is called for. In this study, we develop a series of alternative HFC phase-down scenarios (Fig. 1 ) consistent with the MP’s history and experience of a gradual increase in ambition. Fig. 1: HFC phase-down schedule of the Article 5 and non-Article 5 parties to the MP in KA and alternative scenarios. Article 5 parties are divided into two groups: Group 1, most of the Article 5 parties; and Group 2, Bahrain, India, Iran, Iraq, Kuwait, Oman, Pakistan, Qatar, Saudi Arabia and the United Arab Emirates. Group 2 (dashed black line) has a later freeze and phase-down steps compared with Group 1 (solid yellow line). Several non-Article 5 parties with dashed red line (Belarus, the Russian Federation, Kazakhstan, Tajikistan and Uzbekistan) have a different formulation for the calculation of baseline and have different initial phase-down steps (that is, the first two steps) from the other non-Article 5 parties with solid blue line. a , KA HFC phase-down schedules. b , Article 5 Groups 1 and 2 alignment scenario. c , 95% scenario. d , Combined scenario. e , Accelerated combined scenario. Full size image KA defines HFC phase-down schedules for four different party groups. The first group (Article 5 Group 1) includes 136 primarily developing countries that make up all Article 5 countries with the exception of ten countries characterized by high ambient air temperatures forming a second group (Article 5 Group 2) and allowed less ambitious timing of targets. Non-Article 5 countries are primarily developed countries and under KA divided into two groups with 45 countries in a first group (non-Article 5, earlier start) and five in a second group allowed to start somewhat later (non-Article 5, later start). We estimate HFC emissions (CO 2 eq using global warming potential GWP 100 from IPCC/AR5 (ref. 13 )) for all analysed scenarios (Fig. 2a ). In a pre-KA baseline, HFC emissions increase to about 4.2 GtCO 2 eq", "role": "user" }, { "content": "To have a better chance of holding global warming to 1.5 degrees Celsius, we need to accelerate the phase-down of HFC refrigerants under the Montreal Protocol. This could also reduce pollution and improve energy access. An air conditioner may freshen the atmosphere in your home, but in doing so, it is probably degrading the atmosphere of Earth. Along with other cooling technologies such as refrigerators and heat pumps, today's aircon commonly relies on chemicals called HFCs (hydrofluorocarbons), which are very powerful greenhouse gasses. HFCs have been used to replace ozone-depleting substances, and their emissions have increased rapidly in the past two decades. To meet the Paris climate goals, the world now needs to wean itself off HFCs quickly, according to a new study led by IIASA researchers published in the journal Nature Climate Change. As a bonus, this process could reduce global power consumption substantially, bringing many benefits such as lower pollution. HFCs can be replaced with various gasses that have a far lower climate impact per kilogram, including ammonia, CO2, and hydrocarbons such as propane. Indeed, a phase-down of HFCs is already required by international law. In 2016, these chemicals were brought into the Montreal Protocol, a treaty originally set up to curb ozone-depleting substances. The protocol's 2016 Kigali Amendment lays out HFC cuts for four groups of countries up to 2047, requiring consumption to fall by 80 to 85% relative to their respective baselines. The problem is that HFC emissions lag years behind consumption. They can leak out of cooling devices during manufacture and use, and when equipment is scrapped. The new study considers this lag and examines how various HFC consumption scenarios would affect future emissions, using the IIASA Greenhouse Gas and Air Pollution Interactions and Synergies (GAINS) model. The study projects that, if left uncontrolled, HFC emissions from 2019 to 2050 would have amounted to more than 92 billion tons CO2 equivalent. (Note that cumulative emissions until 2050 determines the effectiveness of HFC reduction for climate mitigation). Controlled by the Kigali Amendment, the total should be about 32 billion tons. That is however still far above the roughly 16 billion tons in SSP1‐1.9 consistent climate scenarios, in which global warming is limited to around 1.5 degrees Celsius above pre‐industrial temperatures. \"Current ambitions for HFC emissions reductions are not sufficient to meet the Paris Agreement's 1.5 degrees Celsius goal. A more ambitious target under the Kigali Amendment could still help achieve the Paris goal if countries act early,\" says Pallav Purohit, lead author on the study and a senior researcher in the Pollution Management Research Group of the IIASA Energy, Climate, and Environment Program. The Montreal protocol has a history of ratcheting up ambition, so the authors looked at various options for stronger HFC cuts. For example, in the existing Kigali Amendment, one group of developing nations is allowed to delay cuts by a few years because they have especially high ambient temperatures—so what if they were required to keep the same pace as other developing nations? This turns out to make little difference to total emissions. Or, what if all nations had to reach 95% emissions cuts by 2050, instead of 80 to 85% in 2047? Again, this barely reduces cumulative emissions to 2050, but it leaves emissions at a lower level for the rest of the century, which is more in line with 1.5 degrees Celsius scenarios. The most effective option involves all countries not only hitting 95% by 2050, but making accelerated deep cuts before that (for example, developed countries reaching 55% cuts in 2025, instead of the 35 to 40% required in the Kigali Amendment, and developing countries reaching 35% cuts in 2030, compared with 0 to 10% in the Amendment). This leads to 2050 cumulative emissions of less than 24 billion tons CO2 equivalent—much closer to the 1.5 degrees Celsius climate scenario. Better still, this early move would be an opportunity to replace old cooling equipment with more efficient hardware. This could save up to 20% of expected future global electricity consumption, which would double the climate benefits of the HFC phase-down, reduce air pollution, improve energy access and cut consumer energy bills. \"Drawing on the Montreal Protocol's start-and-strengthen approach, accelerated HFC phase-down would increase the chances of staying below 1.5 degrees Celsius,\" Purohit concludes. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The genome of the thermophilic bacterium, Aeribacillus pallidus 8, encodes the bacteriocin pallidocin. It belongs to the small class of glycocins and is posttranslationally modified, containing an S -linked glucose on a specific Cys residue. In this study, the pallidocin biosynthetic machinery is cloned and expressed in Escherichia coli to achieve its full biosynthesis and modification. It targets other thermophilic bacteria with potent activity, demonstrated by a low minimum inhibitory concentration (MIC) value. Moreover, the characterized biosynthetic machinery is employed to produce two other glycopeptides Hyp1 and Hyp2. Pallidocin and Hyp1 exhibit antibacterial activity against closely related thermophilic bacteria and some Bacillus sp. strains. Thus, heterologous expression of a glycocin biosynthetic gene cluster including an S -glycosyltransferase provides a good tool for production of hypothetical glycocins encoded by various bacterial genomes and allows rapid in vivo screening. Introduction Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are produced in all three domains of life. Part of the RiPPs overlap with a group of antibacterial peptides produced by bacteria, and this group historically is designated as bacteriocins 1 , 2 , 3 . They are active against other bacteria that are mostly closely related to the producer. These peptides exhibit considerable diversity with respect to their size, structure, mechanism of action, inhibitory spectrum, immunity mechanisms, and targeted receptors 4 . In the era of emergence of antibiotic-resistant bacteria 5 , bacteriocins have been suggested as a potential alternative to antibiotics in clinics and veterinary settings, but also as food preservatives against spoilage and pathogenic microorganisms 2 , 6 , 7 . Thermophilic bacteria have shown a great potential in biofuel production because of their higher metabolic rate and enzyme stability at elevated temperatures. Moreover, growth at high temperature facilitates recovery of volatile products, like ethanol 8 , and reduces requirement for cooling. Thermophilic fermentations are less prone to contaminations by mesophiles, although there are still risks that bioreactors will be contaminated by other thermophiles 9 , 10 . In addition, contamination by thermophiles is also a problem in production of dairy products 11 . This shows the need of discovery of new natural compounds that have activity against thermophilic bacteria. Glycocins are posttranslationally glycosylated bacteriocins. The sugar moieties are linked to the side chains of either Cys, Ser, or Thr residues. A glycocin can be regarded as being “glycoactive” when sugar moieties are essential for the antimicrobial activity 12 . Only a few glycocins have been identified and reported to date: sublancin 168, produced by Bacillus subtilis 13 ; glycocin F, produced by Lactobacillus plantarum 14 ; ASM1 (homologous to glycocin F), produced by Lb. plantarum 12 , 15 ; enterocin F4-9, produced by Enterococcus faecalis 16 and thurandacin, encoded by Bacillus thuringiensis and identified by genomic data mining and chemo-enzymatical synthesis in vitro 16 . The understanding of their mechanism of growth inhibition of target bacteria is far from complete. It is known that a specific phosphoenolpyruvate:sugar phosphotransferase system (PTS) is a factor affecting glycocin F and sublancin antibacterial activities 12 , 17 and that sublancin does not affect the integrity of the cell membrane and acts bacteriocidal 12 , 17 . In contrast, glycocin F and enterocin F4-9 have been reported to be bacteriostatic 14 , 16 . The synthetic machinery of the best-studied glycocin, sublancin, is encoded by a gene cluster containing sunA, sunS, sunT, bdbA , and bdbB genes. The precursor peptide, SunA, is modified by the S -glycosyltransferase SunS, which forms a very unusual S -linkage between the Cys residue and glucose. SunA glycosylation in vitro by SunS has been confirmed by chemo-enzymatical synthesis of mature sublancin 13 . Based on the SunT sequence similarity to bacteriocin ABC- transporters/peptidases, it is assumed that SunT cleaves the leader sequence and transports the core peptide to the outside of the cell. Two thiol-disulfide oxidoreductases, BdbA and BdbB, might be responsible for disulfide bond formation in the peptide 18 , 19 . In addition, it has been confirmed that the same gene cluster encodes the immunity protein SunI 20 . A similar genetic organization was found in gene clusters encoding the putative synthetic machineries of glycocin F 14 , thurandacin 21 and enterocin F4-9 16 . To date only two bacteriocins, i.e. geobacillin I and geobacillin II, produced by the thermophilic bacteria Geobacillus thermodenitrificans NG80-2, are well characterized 22 , 23 , 24 . Other bacteriocin-like antibacterial compounds from thermophilic microorganisms have been described in much less detail 25 , 26 , 27 , 28 , 29 , 30 , 31 . These reasons prompted us to find and to study new bacteriocins of this group. Thus, we have chosen the thermophilic Aeribacillus pallidus 8 strain that was previously isolated from soil above oil wells in Lithuania 32 . Previous studies have shown that this strain secretes an antibacterial compound that is active against other thermophilic bacteria. Unfortunately purification of this compound and identification of its amino acid sequence were not successful 32 , 33 . In this study we have identified genes in the genome of A. pallidus 8 that encode a biosynthetic machinery for a hypothetical bacteriocin (i.e. pallidocin), which belongs to the small class of glycocins. We also demonstrate the functional expression of the whole biosynthetic gene cluster of a glycocin in Gram-negative Escherichia coli , which facilitates further engineering and mechanistic studies. Following characterization of pallidocin demonstrated that it exhibits extremely strong activity against specific thermophilic bacteria, such as (Para)Geobacillus sp. and Caldibacillus sp. In addition, we identified and synthesized a variety of hypothetical glycopeptides and determined their properties by employing heterologous expression system of pallidocin. The characterized pallidocin S -glycosyltransferase PalS could be used not only for biosynthesis of hypothetical glycocins, but also for introduction of unique posttranslational modifications into other peptides with the aim to improve their bioactivities. Pallidocin is a good candidate to prevent bacterial contaminations in industrial fermentations operating under elevated temperatures. Previously, full maturation of recombinant glycocins was only reported in vitro for thurandacin and sublancin. Glycosylation and leader cleavage", "role": "user" }, { "content": "University of Groningen microbiologists and their colleagues from Lithuania have discovered a new glycocin, a small antimicrobial peptide with a sugar group attached, which is produced by a thermophilic bacterium and is stable at relatively high temperatures. They also succeeded in transferring the genes required to produce this glycocin to an E. coli bacterium. This makes it easier to produce and investigate this compound, which could potentially be used in biofuel production. These findings were published in Nature Communications on 7 March. The rise of antibiotic resistance has spurred the search for new antimicrobials. Bacteriocins—peptide toxins produced by bacteria to inhibit growth in similar or related bacterial strains—are a possible alternative to the more traditional antibiotics. Bacteriocins would also be useful to protect high-temperature fermentations mediated by thermophilic bacteria. But this would require the use of bacteriocins that are stable at higher temperatures. Mystery \"That is why we were interested to find that the thermophilic bacterium Aeribacillus palladius, isolated from the soil above an oil well in Lithuania, appeared to produce an antibacterial peptide,\" says University of Groningen Professor of Molecular Biology Oscar Kuipers. Thus far, purification and identification of the compound had not been successful. Therefore, Ph.D. student Arnoldas Kaunietis from Vilnius University spent almost two years in Kuipers' lab to solve the mystery. He is the first author on the new paper. By analyzing genomic information from the Lithuanian bacteria using BAGEL4 software developed by Anne de Jong and Auke van Heel in Kuipers' group, the researchers discovered the genes that are responsible for the production of the bacteriocin, and the final gene product was named pallidocin. The BAGEL4 software searches for gene clusters with the potential ability to produce novel antimicrobials. Sugar The antimicrobial turned out to be a glycocin belonging to a class of post-translationally modified peptides. This means that after its production, one or more functional groups are added to the peptide. In the case of glycocins, this functional group is a sugar. \"Only five other glycocins were known thus far,\" says Kuipers. In order to facilitate further research and engineering of this peptide, the genes responsible for the production of pallidocin were transferred to E. coli BL21 (DE3) bacteria. \"The expression of the genes worked well, which is a real breakthrough, as it is difficult to express a whole antimicrobial gene cluster from a gram-positive bacterial strain directly in a gram-negative bacterium and to get the product secreted.\" Biofuel After isolating pallidocin, the scientists were able to confirm that it is highly thermostable and exhibits extremely strong activity against specific thermophilic bacteria. Furthermore, by using the sequence of pallidocin biosynthesis genes in BAGEL4, two similar peptides were discovered in two different strains of Bacillus bacteria. These peptides, named Hyp1 and Hyp2, were also successfully expressed in the E. coli strain. \"This shows that the expression system works well for various glycocins; it is able to produce them in vivo,\" says Kuipers. Pallidocin might be useful in high-temperature fermentations, which are used to produce biofuels or chemical building blocks. The higher temperature makes it easier to recover volatile products such as ethanol but also reduces the risk of contamination with common bacteria. However, contamination with thermophilic bacteria is possible. \"Both pallidocin and Hyp1 appear to be active against thermophilic bacteria and some Bacillus species,\" says Kuipers. And there could be more applications: \"Contamination by thermophiles is also a problem in the food industry.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Urbanisation is increasing worldwide, and there is now ample evidence of phenotypic changes in wild organisms in response to this novel environment. Yet, the genetic changes and genomic architecture underlying these adaptations are poorly understood. Here, we genotype 192 great tits ( Parus major ) from nine European cities, each paired with an adjacent rural site, to address this major knowledge gap in our understanding of wildlife urban adaptation. We find that a combination of polygenic allele frequency shifts and recurrent selective sweeps are associated with the adaptation of great tits to urban environments. While haplotypes under selection are rarely shared across urban populations, selective sweeps occur within the same genes, mostly linked to neural function and development. Collectively, we show that urban adaptation in a widespread songbird occurs through unique and shared selective sweeps in a core-set of behaviour-linked genes. Introduction Urban development is rapidly expanding across the globe, and although urbanisation is regarded a major threat for wildlife 1 , its potential role as an evolutionary driver of adaptation has not been explored until recently 2 , 3 , 4 , 5 . Many species show phenotypic adaptations to the multiple urban challenges, such as higher levels of noise, artificial light at night, air pollution, altered food sources or habitat fragmentation 6 . These adaptations include changes in behaviour, e.g., refs. 7 , 8 , 9 , morphology and locomotion, e.g., refs. 10 , 11 , 12 , 13 or toxin tolerance 14 . Indeed, there is now evidence that the phenotypic divergence between urban and rural populations may have a genetic basis in some species 14 , 15 , in line with the finding that micro-evolutionary adaptations in natural populations can occur within short timescales, particularly in response to human activities 16 , 17 , 18 . The study of the genetic signals of adaptation could provide important insights into the magnitude of the evolutionary change induced by urbanisation on wildlife. However, the short evolutionary timescale, the dependence of evolution on local factors, and the polygenic nature of many phenotypic traits, make detecting the genomic signals of adaptation difficult 17 , 19 . The majority of studies on the genomic basis of urban adaptation have either focused on a limited number of markers and genes 3 , 20 or on a narrow geographical scale, e.g., refs. 4 , 15 , 21 , 22 , thereby limiting the inferences that can be made on the consistency of genomic responses to urbanisation 5 . Conversely, the study of multiple populations on a broad geographical scale provides a powerful framework to identify the evolutionary forces shaping the genomic responses and to test the repeatability of urban adaptation 15 , 23 , 24 . In particular, comparing across populations enables the distinction between random demographic non-adaptive processes, such as genetic drift, and signatures of natural selection, as selection might be expected to affect the same genomic regions (nucleotides or genes) and/or functional pathways across cities 23 , 25 . The current evidence on the genomic basis of urban adaptations ranges from high parallelism, involving a single or few genes 15 , 23 , to polygenic, and to putative genetic redundancy, e.g., ref. 22 . This discrepancy might be due to the variable and sometimes local urban selection pressures together with the polygenic nature of many adaptive phenotypic traits, which could lessen the likelihood for shared genetic changes at the nucleotide level 26 . In this study, we present a multi-location analysis of the evolutionary response to urbanisation, using the great tit ( Parus major ), to identify the genetic basis of urban adaptation. The great tit is a widely distributed songbird and a model species in urban, evolutionary and ecological research, e.g., refs. 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , with demonstrated phenotypic changes in response to urban environments in several populations 29 , 34 , 35 , 37 . In addition, genomic resources are well developed for this species 38 and it is known that across its European range, the species presents low genetic differentiation 21 , 39 , 40 , 41 . In order to examine genomic responses to urbanisation on a broad geographical scale, we analyse pairs of urban and rural great tit populations from nine localities across Europe (Fig. 1 and Supplementary Table 1 ). We combine several complementary approaches to: (1) detect allele frequency shifts across many loci, which will facilitate the exploration of the polygenic aspect in the adaptation to urbanisation; (2) search for selective sweeps in urban populations, which will provide information on population-specific signatures of selection; and (3) identify enriched functional pathways associated with genes putatively under selection in urban populations, which will help us to infer which particular phenotypes, known and unknown, underlie urban adaptation in great tits. Overall, the present study deepens our understanding of the evolutionary drivers and forces shaping the genomic landscape of urban adaptation on a continental scale. Fig. 1: Study sampling locations and urbanisation intensity. a Centre: map of Europe, showing the targeted cities where the sampling of great tits ( Parus major ) was carried out. Red areas indicate the main dense urban areas. The nine inset zooms flanking the central map exemplify the landscape and degree of urbanisation for each of the urban–rural sampling locations. Green shading represents canopy or green areas (i.e., vegetation cover) and roads and buildings are represented in grey. See “Methods”, Supplementary Fig. 1 and Supplementary Table 1 for more details. Map data sources: Stamen Design under CC BY 3.0 ( ); data licensed by OpenStreetMap Foundation (OSMF) under ODbL ( ). Shapefiles: Natural Earth. b Urbanisation scores (principal component, PC urb ) for all nine urban–rural pairs. In both figures, the coloured circles represent each city (in b , urban: open circles; rural: closed circles). BCN Barcelona, GLA Glasgow, GOT Gothenburg, LIS Lisbon, MAD Madrid, MAL Malmö, MIL Milan, MUC Munich, PAR Paris. Great tit illustration", "role": "user" }, { "content": "Great tits living in cities are genetically different from great tits in the countryside. Researchers made the discovery after a unique study where they examined populations of great tits in nine large European cities, including Glasgow. The researchers compared the city bird genes with the genes of their relatives in the countryside. The findings, which are published today in Nature Communications, showed that it didn't matter if the great tits lived in Barcelona, Malmö or Glasgow: in order to handle an environment created by humans, the city birds all evolved in a similar way. The European research, which was led by Lund University in collaboration with researchers at the University of Glasgow, included a study of birds from Kelvingrove Park together with birds from around the forest in the University of Glasgow's SCENE (Scottish Center for Ecology and the Natural Environment) facility, located near Loch Lomond. The researchers found that different genes linked to important biological functions regulated by serotonin, including aggression and circadian rhythms, were found to have been selected and passed on from generation to generation in the city birds. In rural populations, these behaviors are also important, however, the genes that control them do not confer the same advantage as they do in an urban environment. Caroline Isaksson, senior lecturer at Lund University, led the study together with Dr. Pablo Salmón, now a research fellow at the University of Glasgow. She said: \"This indicates that these behaviors, and cognition, are very important in order to live in urban environments with a lot of stress in the form of noise pollution, light at night, air pollution and constant proximity to people.\" Fig. 1: Study sampling locations and urbanisation intensity. From: Continent-wide genomic signatures of adaptation to urbanisation in a songbird across Europe The study is the largest carried out on how urban environments affect the genome, and thus the genetic material of the animals that live there. In total, 192 great tits were examined among populations in Malmö, Gothenburg, Madrid, Munich, Paris, Barcelona, Glasgow, Lisbon and Milan. For each urban population, the researchers had a control group of great tits living nearby, but in a rural environment. Blood samples have been taken from the birds and analyzed genetically. Dr. Pablo Salmón, from the University of Glasgow, said: \"It is surprising that cities, which from an evolutionary perspective are a recent phenomenon, are already leaving their footprint in the genome of birds.\" The researchers analyzed more than half a million single-nucleotide polymorphisms (SNPs) spread over the entire genome, and found that a handful of genes that had clearly changed in response to the urban environment. Great tits are common throughout Europe, and it has long been known that they are quite similar genetically. Despite this, researchers have now identified clear genetic differences between great tits in the city and great tits in the countryside. The study, \"Continent-wide genomic signatures of adaptation to urbanization in a songbird across Europe,\" has been published in Nature Communications. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences. Main Metastatic relapses are common in cancer patients considered disease-free after primary diagnosis and treatment 1 . Stem-like disseminated tumor cells with specialized metastatic traits adapt and survive as latent metastases in distal organs by overcoming oxidative stress, nutrient limitation, microenvironmental and immune defenses. Latent metastatic cells that persist as subclinical disease are responsible for late recurrences. Understanding the traits and vulnerabilities of these cells is critical for developing strategies to prevent metastasis 2 . Metabolic reprogramming is a hallmark of cancer that evolves during metastatic progression 3 . Nutrient availability and dependencies are likely to dictate metabolic reprogramming of disseminated cancer cells. Given that tumor cells in the primary and metastatic sites are metabolically distinct, targeting extracellular nutrient and microenvironmental driven dependencies of disseminated tumor cells is a rational approach to limit progression of metastasis 4 , 5 , 6 , 7 , 8 , 9 . Tumor cells that undergo metabolic reprogramming overcome stress imposed by the microenvironmental and persist or proliferate in distal organs 6 , 10 , 11 . However, the precise molecular processes that facilitate metabolic reprogramming in latent metastatic cells to overcome stress and persist after dissemination remain unknown. Mitochondria, the cellular energy powerhouses, are integral to stress response, as they not only support cellular bioenergetic needs but also generate metabolites that facilitate molecular and epigenomic responses. Mitochondria are dynamic organelles that undergo coordinated cycles of fusion and fission to facilitate adaptations to cellular and extracellular cues 12 . Cancer cells exploit adaptive mitochondrial dynamics to meet energy needs, regulate reactive oxygen species, reprogram cellular metabolism and survive environmental or nutrient stress 13 , 14 . In this Article, using mouse models and patient samples, we investigated how disseminated latent metastatic cells in the lipid-rich brain microenvironment meet their cellular energetic demands and persist to initiate overt metastasis. We report mitochondrial plasticity enables fatty acid oxidation (FAO) and survival of latent metastatic cells as subclinical disease. Furthermore, we demonstrate targeting mitochondrial plasticity by attenuating expression of mitochondrial fission regulator dynamin-related protein 1 (DRP1) and through pharmacologic inhibition of DRP1 using a small brain-permeable molecule suppressed growth of latent metastatic cells and reduced brain metastatic burden in preclinical models. Results Latent cells uptake FAs secreted by reactive astrocytes Cancer metastases to the central nervous system are lethal. Brain metastatic incidence in breast cancer patients varies with disease subtype and approximately 25–50% of patients with advanced stage breast cancer present with brain metastases 15 , 16 , 17 . Moreover, metachronous brain metastases are common in HER2 + (human epidermal growth factor receptor 2) and hormone receptor-positive breast cancer patients that have undergone primary therapy and considered disease-free 17 , 18 , 19 , 20 , 21 , 22 . Current treatment options for brain metastasis are limited and not curative. To understand how disseminated tumor cells persist as subclinical disease and initiate metachronous metastasis, we performed in vivo phenotypic selection in mice and isolated latent brain metastatic (Lat) cells from HCC1954 and SKBR3 HER2 + breast cancer cells 6 , 23 , 24 , 25 . Lat cells are stem cell like, immune evasive and metabolically distinct. Compared to HCC1954 HER2 + breast adenocarcinoma parental cells, brain tropic latent metastatic cells were enriched in metabolites and genes associated with fatty acid (FA) metabolism (Extended Data Fig. 1a,b Supplementary Table 1 ). Correspondingly, significant enrichment in content, namely, carnitine-conjugated FA, lauroyl- l -carnitine (carnitine 12:0) and palmitoyl- l -carnitine (carnitine 16:0), was observed in Lat cells (Extended Data Fig. 1a ). Lipidomic profiles also indicated a higher neutral FA content in Lat cells ( Fig. 1a and Supplementary Table 2 ). Cancer cells can synthesize FAs de novo or uptake them from the surrounding microenvironment 26 . However, the expression of FASN, ACC1 and phospho-ACC1 (Ser-79), enzymes associated with FA synthesis, was notably lower in Lat cells (Extended Data Fig. 1c ). Moreover, 13 C 6 -glucose tracing showed significantly low enrichment of palmitate isotopologues (Extended Data Fig. 1d and Supplementary Fig. 1a ), suggesting that Lat cells are better equipped to uptake exogenous lipids. Fig. 1: Latent cells uptake FAs secreted by reactive astrocytes. a , Heatmap showing total FA profiles of neutral lipid content generated by GC–MS in HCC1954 Pa and Lat cells ( n = 4, each group). b , IF image showing reactive astrocytes (GFAP + , magenta) surrounding Lat cells (GFP + , green) in mouse brain 5 weeks after intracardiac injection. c , IF image showing accumulation of LDs (red) in HCC1954 Pa and Lat cells (green) cultured with BODIPY-558/568-C12 labeled GFAP + reactive astrocytes (gray). Scale bar, 100 µm. d , Quantification showing average LDs in Pa and Lat cells (HCC1954 and SKBR3) cultured with BODIPY-558/568-C12 labeled astrocytes for 24 h, n = 5 each group. e , Quantification showing time-dependent increase in lipid transfer from astrocytes to HCC1954 Pa and Lat cells, n = 6, each group. Isolated astrocytes from mice pups were labeled with C12-BODIPY(2 μM) for overnight and then washed three times. Next, HCC1954 Pa and Lat cells cultured in R3F were transferred to the astrocytes cultured plates and live", "role": "user" }, { "content": "Mitochondria that power cellular activity fragment and change shape in breast cancer cells that migrate to the brain, an adaptation that appears necessary for the cells to survive, UT Southwestern Medical Center researchers report in a new study. The findings, published in Nature Cancer, could lead to new ways to prevent brain metastases, or the spread of cells from primary tumors to the brain. \"Through mitochondrial plasticity, these cancer cells undergo metabolic reprogramming that aids their survival in the brain niche that otherwise would not be available to them. Exploiting this vulnerability could offer a way to prevent brain metastases,\" said study leader Srinivas Malladi, Ph.D., Assistant Professor of Pathology at UT Southwestern and a member of the Harold C. Simmons Comprehensive Cancer Center. Metastatic cancer, which is treated as stage IV cancer, is responsible for the majority of cancer deaths. The Malladi lab focuses on understanding how cells that escape from a primary tumor can live in different locations in the body, often for years, before emerging as metastatic cancer. Using breast cancer, a disease that commonly metastasizes to the brain, as a model, Dr. Malladi and his colleagues discovered that cancer cells that migrate to the brain reprogram their metabolism to depend on fatty acids rather than carbohydrates as a main energy source. This switch is necessary to survive in the brain, which is a completely different environment, Dr. Malladi explained. But how the cells accomplish this metabolic switch was unclear. To answer this question, Dr. Malladi and his team isolated latent metastatic (Lat) cells—cancer cells that had migrated from the primary tumor but had not begun actively forming new tumors—from the brains of mouse models. They observed that these Lat cells have distinctly shaped \"punctate,\" or dot-like, mitochondria compared to the primary tumor cells with elongated tubular mitochondria. Moreover, the Lat cells readily used fatty acids. This suggested that the mitochondrial shape change or plasticity was necessary for fatty acid metabolism. Further experiments showed that the fragmentation was driven by an increase in a protein known to be involved in mitochondrial fission called dynamin-related protein 1 (DRP1). When the researchers used a genetic technique to decrease the amount of DRP1, the Lat cells' mitochondria regained their tubular shape and lost the ability to metabolize fatty acids. Similarly, when they used a chemical that inhibited DRP1, Lat cells residing in mouse brains formed fewer metastases and were significantly less likely to survive. A separate examination of metastatic tumors that formed in breast cancer patients showed that a phosphorylated form of DRP1 was elevated, suggesting that this phenomenon occurs in humans as well, Dr. Malladi said. He and his colleagues plan to test DRP1 inhibitors to determine whether they might prevent, slow, or reverse metastatic disease, an important next step toward developing a treatment. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate–adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge. Introduction Immunotherapy is providing tremendous promise in the new era of cancer treatment. Checkpoint inhibitors and adoptive T cell transfer therapy have shown improved survival in melanoma, non-small-cell lung cancer, and renal cell cancer patients 1 , 2 . However, only a fraction of patients benefit from immunotherapy, and lack of specific tumor targeting is frequently associated with immune-related toxicity. Thus, many attempts are being made to improve anticancer immunity while reducing adverse effects. In contrast to systemic immunotherapy, intratumoral injection of immunomodulators is intended to focus the immune response locally on the malignancy and tumor draining lymph nodes (TDLNs) 3 . Moreover, given the heterogeneous nature of tumor antigens (TAs), intratumoral immunotherapy may have a potential for arousing a polyclonal antitumor immune response in situ against diverse cancer targets 3 , 4 . Among various types of immunomodulators, activators of the stimulator of interferon (IFN) genes (STING) pathway to elicit antitumor immunity have recently attracted much attention 5 . Being identified as a potent STING agonist, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) functions in the cytosol to ligate STING on endoplasmic reticulum (ER) membrane to activate STING pathway and type I IFN production 6 , 7 . Recent preclinical studies involving intratumoral injection of STING agonists alone or combined with irradiation (IR) have shown its aptitude for enhancing antitumor immunity 8 , 9 , 10 . Mechanistic studies indicate that activation of STING pathway within tumor-resident antigen-presenting cells (APCs) leading to type I IFNs production is indispensable for generation of adaptive immunity against tumors 11 , 12 , 13 . Although the in situ immunotherapy approach is attractive, there are several disadvantages associated with the intratumoral injection of immunostimulants. This approach is generally limited to those accessible tumors, and becomes even more challenging if repeated injections are needed. Structurally, cGAMP contains the phosphodiester bond that is susceptible to degradation by extracellular phosphodiesterase, also the two phosphodiester bonds in cGAMP restrict its penetration through the plasma membrane. Thus, in order to achieve adequate biological activity, cGAMP is commonly used at relatively high concentrations. However, excessive intratumoral cGAMP may induce programmed death-ligand 1 (PD-L1) overexpression on tumor cells and increase tumor-infiltrating regulatory T cells (Tregs), resulting in a negative impact on antitumor immunity 10 , 14 , 15 , 16 . Importantly, several studies have shown that intratumoral immunostimulants generally induce local immune response at the injected site, but have limited effect on distant, uninjected tumor sites, implying that the local approach may be inadequate to elicit systemic immunity, or that the systemic response even if induced, may be rendered inactive when exposed to the immunosuppressive tumor microenvironment (TME) at distant naive tumor sites 3 , 10 , 17 . To overcome these limitations, we set out to develop a nanotechnological strategy that enables targeted delivery of immunostimulants to intratumoral APCs. Here, we assemble phosphatidylserine (PS) on the surface of nanoparticle-cGAMP (NP-cGAMP) because membrane-exposed PS can be recognized and engulfed by macrophages and dendritic cells through their PS receptors 18 , 19 . Because of STING located on ER membrane, it is critical to ensure intracellular delivery and subsequent release of cGAMP to cytosol while bypassing lysosome. We thus utilize calcium phosphate (CaP) to precipitate cGAMP in the liposomal core. After ingestion by APCs, in response to low endosomal pH, cGAMP is released to the cytosol and binds to STING, initiating the STING pathway. We then demonstrate that inhalation of aerosolized NP-cGAMP enables rapid distribution of NP-cGAMP to individual lesions in both lungs bearing lung metastases and subsequent uptake by APCs to stimulate STING signaling and type 1 IFNs production (Fig. 1a ). Last, we tested if inhaled NP-cGAMP can enhance radiotherapy in lung metastasis mouse models of B16-OVA melanoma and 4T1 breast carcinoma. Indeed, fractionated IR (8 Gy × 3) delivered to a lung bearing metastases combined with NP-cGAMP inhalation synergizes to control the metastases not only in the IR but also in the non-IR-treated lung. In addition to enhancing APC sensing of immunogenic IR at irradiated tumor sites and cross-presentation of TAs to prime effector T cells at TDLNs, inhaled NP-cGAMP promotes proinflammatory TME in non-irradiated tumors and facilitates recruitment of cytotoxic CD8 + T cells, which contribute to robust anticancer immunity observed in this study (Fig. 1a ). These data demonstrate that inhalation of NP-cGAMP may represent a pharmacological approach to enhance APC-mediated adaptive immune response against lung metastases. Fig. 1 Characterization of PS-coated NP-cGAMP. a Schematic of the mode of action of the inhalable NP-cGAMP for enhancing antitumor immunity against lung metastases. Inhalation of PS-coated NP-cGAMP enables targeted delivery of the STING agonist, cGAMP to APCs in both irradiated and non-irradiated lung metastases. In addition to enhancing APC maturation, innate immune sensing of immunogenic IR, and cross-presentation of tumor antigen (TA) to prime effector T cells at the irradiated tumor sites, the inhaled NP-cGAMP promotes proinflammatory response in the non-irradiated tumors and facilitates recruitment of TA-specific effector T cells to lung metastases in both lungs, which contribute to therapeutic effects on both the IR and non-IR treated tumors. b Size distribution, PDI, and surface charge of NP-cGAMP, NP labeled with DIR", "role": "user" }, { "content": "Scientists have reported a new approach to treating lung cancer with inhaled nanoparticles developed at Wake Forest School of Medicine, part of Wake Forest Baptist Health. In this proof of concept study, Dawen Zhao, M.D., Ph.D., associate professor of biomedical engineering at Wake Forest School of Medicine, used a mouse model to determine if metastatic lung tumors responded to an inhalable nanoparticle-immunotherapy system combined with the radiation therapy that is commonly used to treat lung cancer. The study is published in the current issue of Nature Communications. Lung cancer is the second most common cancer and the leading cause of cancer death among both men and women. More people die of lung cancer than of colon, breast and prostate cancers combined. Although immunotherapy is promising, it currently works in less than 20% of patients with lung cancer. Significant clinical evidence suggests that at the time of diagnosis most patients' tumors are poorly infiltrated by immune cells. This \"cold\" immune environment in tumors prevents the body's immune system from recognizing and eliminating the tumor cells. Overcoming this immunosuppressive tumor environment to attack the cancer efficiently is currently an area of great interest in the scientific community, Zhao said. Previous approaches have involved direct injection of immunomodulators into tumors to boost their immune response. However, this approach is generally limited to surface and easily-accessed tumors, and can become less effective if repeated injections are needed to sustain immune response. \"The goal of our research was to develop a novel means to convert cold tumors to hot, immune-responsive tumors,\" Zhao said. \"We wanted it to be non-invasive without needle injection, able to access multiple lung tumors at a time, and be safe for repeated use. We were hoping that this new approach would boost the body's immune system to more effectively fight lung cancer.\" The nanoparticle-immunotherapy system that Zhao and his team developed delivered immunostimulants via inhalation to a mouse model of metastatic lung cancer. The immunostimulant-loaded nanoparticle which, when deposited in the lung air sacs, were taken up by one specific type of immune cells, called antigen-presenting cells (APC). The immunostimulant, cGAMP, in the nanoparticle was then released inside the cell, where stimulation of a particular immune pathway (STING) activated the APC cell, which is a critical step to induce systemic immune response. The team also showed that combining the nanoparticle inhalation with radiation applied to a portion of one lung led to regression of tumors in both lungs and prolonged survival of the mice. In addition, the team reported that it completely eliminated lung tumors in some of the mice. Through mechanistic studies the team then confirmed that the inhalation system converted those initially cold tumors in both lungs to hot tumors favorable for robust anti-cancer immunity. Zhao's inhalable immunotherapy presents several key advantages to previous methods, especially the ability to access deep-seated lung tumors because the nanoparticulate-carrying aerosol was designed to reach all parts of the lung, and the feasibility of repeated treatment by using a non-irritating aerosol formulation. The treatment was shown to be well tolerated and safe without causing adverse immune-related distress in the mice. The Wake Forest School of Medicine researchers have filed a provisional patent application for the inhalable nanoparticle-immunotherapy system. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The membrane deforming dynamin family members MxA and MxB are large GTPases that convey resistance to a variety of infectious viruses. During viral infection, Mx proteins are known to show markedly increased expression via an interferon-responsive promoter to associate with nuclear pores. In this study we report that MxB is an inner mitochondrial membrane GTPase that plays an important role in the morphology and function of this organelle. Expression of mutant MxB or siRNA knockdown of MxB leads to fragmented mitochondria with disrupted inner membranes that are unable to maintain a proton gradient, while expelling their nucleoid-based genome into the cytoplasm. These findings implicate a dynamin family member in mitochondrial-based changes frequently observed during an interferon-based, anti-viral response. Introduction Mitochondria are dynamic organelles that undergo fission and fusion events in response to changes in metabolic needs and important cellular processes such as cell division and apoptosis 1 , 2 , 3 . Central to these alterations in mitochondrial form are the dynamin family of large GTPases, which are known to bind and remodel membranes 4 , 5 . Distinct from the conventional dynamins (Dyn1, 2, 3) that are known to support membrane scission at distinct cellular sites such as the plasma membrane 6 , the Golgi apparatus 7 , as well as endosomes 8 and autolysosomes 9 , 10 , 11 , the dynamin-related proteins have been implicated in the dynamics of both mitochondria 12 and peroxisomes 13 . Although highly conserved within the N-terminal GTPase domains, these dynamin-related proteins are only modestly conserved in the middle domain and generally lack pleckstrin binding and proline-rich domains found in the conventional family members. The mitofusins (MFN1/MFN2) are believed to support the outer mitochondrial membrane fusion and optic atrophy 1 (OPA1) has been implicated in the fusion of the inner membrane 14 , 15 , 16 , 17 . Reciprocally, dynamin-related protein 1 (DRP1) has been shown to constrict the outer mitochondrial membrane 4 with the final scission event perhaps driven by conventional Dyn2 18 . In addition to the mitochondria-associated dynamins are the myxovirus resistance GTPases (MX1/2 human and MxA/B mouse), which are <40% similar to the conventional dynamins but over 60% identical in sequence to each other. These related proteins are expressed in cells upon exposure to type 1 interferon (IFN) and convey a cellular innate immune response to a variety of different pathogenic viruses 19 , 20 , 21 , 22 , 23 , 24 including influenza, hepatitis B (MxA), and HIV-1 (MxB). We and others have found that MxA can assemble into polymers that act to deform membranes 25 , 26 and appears to reside on components of the smooth endoplasmic reticulum (ER) 25 , 27 . MxB also assembles into polymeric structures 28 and was originally found to associate with nuclear pores where it was predicted to restrict the access of a viral genome to the host transcriptional machinery 29 . MxB has been described to bind to the HIV-1 genome, while impairing its chromosomal integration 24 , 30 , 31 , and recently has been identified as a key factor behind IFN-mediated suppression of hepatitis C virus infection 32 . In this study we report that although markedly upregulated in cells treated with IFN, MxB is expressed constitutively in a variety of cell types, particularly in primary hepatocytes and hepatoma cell lines. In addition to reported localization at nuclear pores, we find that MxB is intimately associated with the inner mitochondria, where it plays an essential role in the maintenance of mitochondrial cristae and DNA stability of this organelle. Results MxB associates with mitochondria in cultured cells As the related family member MxA has been shown to convey a partial resistance to the hepatocyte-centric HBV 33 , while associating with membranous structures in hepatocytes, our goal is to compare the distribution and expression of the highly related family member MxB in hepatocyte cell lines and in the whole liver. Using several different antibodies and tagged constructs to MxB, we observe the punctate nuclear staining previously observed by others 34 , 35 , 36 . In addition to this localization, we observe a fusiform and linear staining pattern in the hepatoma cell line Hep3B and HeLa cells, using a previously published MxB antibody and exogenously expressed green fluorescent protein (GFP)/Myc-tagged constructs (Fig. 1a–d and Supplementary Fig. 1a–c ). Co-staining these cells with a variety of different organelle marker antibodies reveals that the MxB labeling represents mitochondria as confirmed by antibodies to cytochrome c oxidase 4 (CoxIV) (Fig. 1a–d and Supplementary Fig. 1a–c ). This localization is consistent when staining with three distinct MxB antibodies or expressing either GFP or Myc-tagged MxB, whereas the characteristics of labeling using these different probes varies from fine to large puncta coating the mitochondria. Fig. 1: MxB is localized to mitochondria in cultured cells. Fluorescence images of Hep3B cells or HeLa cells, stained with a polyclonal antibody (IJ-GP) to MxB ( a , c ), or expressing exogenous human MxB-GFP ( b , d ). All cells were stained for the inner mitochondrial membrane marker CoxIV. MxB is visualized as small or large puncta that align closely with mitochondrial membranes. Boxed regions provide a higher magnification for color overlays showing the alignment of MxB (green) with mitochondria (red) in both cell types. Scale bars, 10 μm. e Western blot analysis of different human tissues (Br = brain, Lng = lung, Liv = liver, LN = lymph node, SP = spleen, Tst = testis, Tns = tonsil) for endogenous MxB that appears enriched in the liver, lymph node, testis, tonsil, and pig liver. f Western blotting comparing MxB expression in HeLa cells, three different hepatocyte cell lines, and a human monocyte cell line (THP-1), as well as primary human and pig hepatocytes. Expression levels are exceptionally high in primary hepatocytes, the HepG2 and Huh7 cell lines (H3B = Hep3B, HG2 = HepG2, Hu7 = Huh7, THP = THP-1, Hu = human hepatocytes). g Western blotting of four distinct cell lines comparing endogenous", "role": "user" }, { "content": "A protein known to help cells defend against infection also regulates the form and function of mitochondria, according to a new paper in Nature Communications. The protein, one of a group called myxovirus-resistance (Mx) proteins, help cells fight infections without the use of systemic antibodies or white blood cells. The authors report that MxB, which is associated with immune response to HIV and herpes virus, is key to mitochondrial support. \"Our work provides new insights into how this dynamin MxB protein assists in fighting viral infections, which could have substantial health implications in the future,\" says Mark McNiven, Ph.D., a Mayo Clinic cell biologist and senior author. Viral infection In response to infection, a cell releases interferon and neighboring cells ramp up Mx protein production. The authors replicated previous findings that MxB blocks nuclear pores and MxB increases markedly when cells are treated with interferon. But they also show that some MxB is present in most immune tissues, such as tonsil, prior to a \"red alert\" and that it has another role. \"We were surprised to see MxB present on, and in, mitochondria,\" says Hong Cao, Ph.D., a Mayo Clinic research scientist and first author. \"That it is both induced in response to infection and vital to mitochondrial integrity is exciting, considering that HIV and herpes alter mitochondria during infection.\" Protecting the generator The authors report that during infection, MxB dynamically condenses, dissolves and reforms over time, and traced MxB's travels to the nuclear pores, as well as to the tips and along mitochondria. They also show, via a cell line that can't make MxB in response to interferon, that mitochondrial cristae are affected by MxB, as well. \"Without active MxB protein, mitochondria become nonfunctional, no longer produce energy, and kick out their DNA genome into the cytoplasm,\" says Dr. Cao. \"These cells are not happy, but may have the capacity to survive a viral infection.\" History of mitochondrial investigation The work of Dr. Cao and team builds on the findings of mitochondrial investigators at Mayo. \"Over two decades ago, our lab discovered a set of proteins that perform mechanical work to shape and pinch mitochondria,\" says Dr. McNiven. That discovery led to a variety of research initiatives across the international mitochondria field into not only basic research questions, but also into clinical areas. This work shows that mitochondrial dynamics, such as fission and fusion, are vital functions. They regulate cell death needed to retard cancer cell growth and the turnover of damaged mitochondria needed to prevent neurodegenerative disorders, and contribute to antiviral cell immunity, to name a few. The next steps, Dr. McNiven says, are to continue to investigate how MxB is targeted to and internalized by mitochondria, and how its association induces such drastic changes to biology of this organelle. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The testis produces gametes through spermatogenesis and evolves rapidly at both the morphological and molecular level in mammals 1 , 2 , 3 , 4 , 5 , 6 , probably owing to the evolutionary pressure on males to be reproductively successful 7 . However, the molecular evolution of individual spermatogenic cell types across mammals remains largely uncharacterized. Here we report evolutionary analyses of single-nucleus transcriptome data for testes from 11 species that cover the three main mammalian lineages (eutherians, marsupials and monotremes) and birds (the evolutionary outgroup), and include seven primates. We find that the rapid evolution of the testis was driven by accelerated fixation rates of gene expression changes, amino acid substitutions and new genes in late spermatogenic stages, probably facilitated by reduced pleiotropic constraints, haploid selection and transcriptionally permissive chromatin. We identify temporal expression changes of individual genes across species and conserved expression programs controlling ancestral spermatogenic processes. Genes predominantly expressed in spermatogonia (germ cells fuelling spermatogenesis) and Sertoli (somatic support) cells accumulated on X chromosomes during evolution, presumably owing to male-beneficial selective forces. Further work identified transcriptomal differences between X- and Y-bearing spermatids and uncovered that meiotic sex-chromosome inactivation (MSCI) also occurs in monotremes and hence is common to mammalian sex-chromosome systems. Thus, the mechanism of meiotic silencing of unsynapsed chromatin, which underlies MSCI, is an ancestral mammalian feature. Our study illuminates the molecular evolution of spermatogenesis and associated selective forces, and provides a resource for investigating the biology of the testis across mammals. Main The rapid evolution of the testis across mammals is probably mainly explained by positive selection associated with sperm competition, which reflects the evolutionary pressure on males to achieve reproductive success 7 . Consequently, testis sizes, sperm production rates, sperm morphologies and other cellular traits substantially vary across mammals, even between closely related species such as the great apes, due to great mating system differences, especially regarding the extent of female promiscuity 7 . The rapid evolution of the testis is reflected at the molecular level. Previous gene expression comparisons for various organs across mammals revealed that rates of evolutionary expression change are highest in the testis, probably due to frequent adaptive changes but potentially also widespread relaxation of purifying selection 1 , 2 , 3 , 4 , 5 , 6 . Consistently, genes with testis-specific expression tend to be enriched with genes whose coding sequences have been shaped by positive selection 8 . In addition, new genes that emerge during evolution tend to be predominantly expressed in the testis and thus probably also contribute to its rapid phenotypic evolution 3 , 9 . The testis also shows several other unique molecular features. First, chromatin in spermatogenic cells is massively remodelled during spermatogenesis, a process that culminates in the tight packaging of DNA around protamines in the compact sperm head 10 . This remodelling leads to widespread leaky transcription in the genome 11 , which in turn probably facilitates the initial transcription and, hence, the frequent emergence of new testis-expressed genes and alternative exons during evolution 3 , 9 , 11 , 12 . Second, the differentiation of sex chromosomes from ancestral autosomes triggered the emergence of MSCI in eutherians and marsupials 13 (therians), which led to the establishment of backup gene copies that substitute for parental genes on the X during meiosis 3 , 14 . In spite of MSCI, the X chromosome has become enriched with testis-expressed genes during evolution 3 , 15 , 16 , 17 , 18 , 19 , 20 , presumably due to sexually antagonistic selective forces favouring the fixation of male-beneficial mutations on this chromosome 21 . Finally, translational regulation of transcriptomes is widespread across spermatogenesis 6 . Previous large-scale transcriptomic investigations of testis evolution were largely limited to bulk-organ samples 1 , 2 , 3 , 4 , 5 , 6 , 19 . Recent high-throughput single-cell (sc) or single-nucleus (sn) RNA-sequencing (RNA-seq) technologies enable detailed investigations of the cellular and molecular evolution of the testis, as exemplified by two scRNA-seq comparisons between human, macaque and mouse 22 , 23 , but a comprehensive investigation of the evolution of spermatogenesis across all main mammalian lineages is lacking. Here we provide an extensive snRNA-seq resource covering testes from ten representative mammals and a bird, enabling detailed comparisons of spermatogenic cells and underlying gene expression programs within and across mammals ( ). Our evolutionary analyses of these data unveiled ancestral as well as species- and lineage-specific cellular and molecular characteristics of mammalian spermatogenesis. Spermatogenesis across 11 species We generated snRNA-seq data for testes from ten species that cover the three main mammalian lineages and include key primate species, representing all simian (anthropoid) lineages (Fig. 1a ): eutherian mammals (representatives for five of the six extant ape lineages, including humans; rhesus macaque, an Old World monkey; common marmoset, a New World monkey; and mouse), marsupials (grey short-tailed opossum) and egg-laying monotremes (platypus). Corresponding data were generated for a bird (red jungle fowl, the progenitor of domestic chicken; hereafter referred to as ‘chicken’), to be used as an evolutionary outgroup. The dataset consists of 27 libraries, with one to three biological replicates per species and a median of roughly 275 million snRNA-seq reads per library (Supplementary Table 1 ). We refined and extended existing genome annotations across all species on the basis of bulk-testis RNA-seq data (seven libraries) (Supplementary Tables 1 and 2 and Methods ), to ensure optimal read-mapping and prevent biases in cross-species analyses. After quality controls and filtering steps ( Methods ), we obtained transcriptomes for a total of 97,521 high-quality nuclei for the 11 species, with a mean of 8,866 cells per species, a median of 1,856 RNA molecules (unique molecular identifiers (UMIs)) detected per cell and low percentages of mitochondrial UMIs (Supplementary Fig. 1 and Supplementary Table 1 ). Fig. 1: snRNA profiling across ten mammals and a bird. a , Species sampled and uniform manifold approximation and projection (UMAP) of snRNA-seq datasets. UMAP of the integrated primate dataset (dashed box),", "role": "user" }, { "content": "Evolutionary pressure across male mammals to guarantee the procreation of their own offspring led to a rapid evolution of the testicle. Bioinformatic studies—conducted by an international team of researchers led by Prof. Dr. Henrik Kaessmann from the Center for Molecular Biology of Heidelberg University—show that this pressure particularly accelerated the evolution of later stages of sperm formation. The aim of these contrastive studies was, for the first time, to decode the genetic regulation of sperm formation in various species of mammals and in human beings, thereby tracing the evolution of this spermatogenesis. At the same time, the researchers were also able to detect genes whose activity had remained unchanged in the course of evolution. Spermatogenesis in the testicle is controlled by a finely coordinated, complex interplay of the activity of different genes—also known as gene expression. Hitherto the understanding of these genetic programs had been largely confined to the mouse. \"Consequently little was known about the genetic foundations that constitute the big differences in spermatogenesis across different mammals, both with regard to the number of sperm cells formed and also to their properties,\" explains Noe Mbengue, a doctoral researcher in Prof. Kaessmann's group \"Evolution of the mammalian genome.\" The Heidelberg scientists have now succeeded in defining the expression of all genes at the level of individual cells during the whole of spermatogenesis for ten different mammals. The organisms they studied represent all major groups of mammals and include humans as well as their closest relatives, great apes. To do this, the researchers used state-of-the-art single-cell genomics technologies. Based on this data they were subsequently able to trace the evolution of spermatogenesis with the aid of bioinformatic comparisons between the different mammals. According to Prof. Kaessmann, these comparative studies uncovered a time-related pattern. \"While the genetic programs in the early stages of spermatogenesis are very similar among mammals, in later stages they differ greatly; that means that the rapid evolution of the testicle is a result of major differences in cells during late spermatogenesis,\" says Dr. Florent Murat, a former postdoc in Henrik Kaessmann's research group and now a group leader at the National Research Institute for Agriculture, Food and Environment (INRAE) in Rennes (France). Further analyses by the scientists revealed genes whose activity had remained unchanged in the course of evolution. They regulate fundamental processes of sperm cell formation that are the same for all mammals. \"Hence our data also supplies valuable elements for researching fertility disorders in men,\" Prof. Kaessmann explains. Finally, the scientists' data enabled them for the first time to distinguish sperm cells that carry either an X or a Y chromosome and thus determine the sex of the offspring. With the aid of this division, the researchers succeeded in systematically studying the gene expression on these sex chromosomes. As these investigations showed, gene expression on the sex chromosomes of all male mammals is downregulated during the maturation division known as meiosis. This mechanism is presumably fundamental for preventing a disadvantageous genetic exchange between the X and Y chromosome during meiosis. The results of the study on the evolution of spermatogenesis across mammals were published in the journal Nature. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Therapeutic hypothermia (TH) enhances pulmonary surfactant performance in vivo by molecular mechanisms still unknown. Here, the interfacial structure and the composition of lung surfactant films have been analysed in vitro under TH as well as the molecular basis of its improved performance both under physiological and inhibitory conditions. The biophysical activity of a purified porcine surfactant was tested under slow and breathing-like dynamics by constrained drop surfactometry (CDS) and in the captive bubble surfactometer (CBS) at both 33 and 37 °C. Additionally, the temperature-dependent surfactant activity was also analysed upon inhibition by plasma and subsequent restoration by further surfactant supplementation. Interfacial performance was correlated with lateral structure and lipid composition of films made of native surfactant. Lipid/protein mixtures designed as models to mimic different surfactant contexts were also studied. The capability of surfactant to drastically reduce surface tension was enhanced at 33 °C. Larger DPPC-enriched domains and lower percentages of less active lipids were detected in surfactant films exposed to TH-like conditions. Surfactant resistance to plasma inhibition was boosted and restoration therapies were more effective at 33 °C. This may explain the improved respiratory outcomes observed in cooled patients with acute respiratory distress syndrome and opens new opportunities in the treatment of acute lung injury. Introduction Therapeutic hypothermia (TH) is used as an effective method to limit brain injury after certain types of cardiac arrest and perinatal asphyxia, by reducing patient body temperature from 37 to 33.5 °C 1 , 2 . Early studies also suggest some possible benefits in cooled patients suffering of acute respiratory distress syndrome (ARDS) 3 , 4 , 5 , 6 . ARDS accounts for 10% of all cases in intensive care units worldwide. Mortality remains at 30–40% and no effective treatments are available to date 7 . Primary ARDS occurs after a direct insult to the lung, whereas secondary ARDS is triggered by an extra-pulmonary pro-inflammatory event 7 , 8 , 9 . Theoretically, TH may be useful to treat primary but might be harmful in secondary ARDS 10 , 11 . Conversely, during primary ARDS the injury is at first confined to the lung, resulting in lower compliance and more severe surfactant dysfunction than in the secondary form of the syndrome 7 , 8 , 9 . During ARDS, surfactant function is impaired in several ways 12 , 13 . Protein-rich oedema fluid, high levels of cholesterol and secretory phospholipase A2 (sPLA 2 ) can all inhibit surfactant activity directly and enhance the production of reactive oxygen species (ROS). Lung surfactant is dramatically needed to reduce surface tension under the expiration-mediated shrinking of the alveolar air–liquid interface. The precise proportions of dipalmitoylphosphatidylcholine (DPPC), unsaturated phospholipids and hydrophobic surfactant proteins B (SP-B) and C (SP-C) are essential for its function in a healthy lung 12 . However, oedema proteins, such as albumin, increase in ARDS patients 14 and may compete with surfactant membranes for the air–liquid interface. The resulting interfacial steric barrier affects the in vitro surfactant adsorption and the reduction in surface tension under compression 15 . Beyond the physiological range, the drastic rise in cholesterol compared to the saturated lipid amount leads to surfactant membranes fluidification 12 . This impairs the ability of clinical and native surfactants to decrease surface tension upon breathing-like cycles 16 , 17 . Besides, methyl-β-cyclodextrin can ex vivo overcome this cholesterol-mediated inhibition in a mice model of ARDS 18 , 19 . PLA 2 targets and hydrolyses the condensed domains of phosphatidylcholine monolayers with a crumbling effect at the air–liquid interface 20 . Consistently, high levels of the secretory form of the enzyme was detected in ARDS patients along with changes in surfactant phospholipid composition and surface tension properties 21 . As a result, surfactant amount and performance are reduced and the work of breathing increases upon ARDS 13 . Interestingly, cooled animals with different types of lung failure showed better respiratory mechanics and reduced lung tissue inflammation 22 , 23 , 24 . Moreover, reports on cooled asphyxiated neonates with and without neonatal ARDS due to meconium aspiration describe an improvement in surfactant function 25 , 26 , 27 , pulmonary inflammation 27 , oxygenation and some clinical outcomes such as reduction of respiratory support and hospital stay 25 , 28 . The biological mechanisms underlying this benefit are not totally clear. DPPC turnover did not change in cooled neonates 29 , but a reduction in sPLA 2 activity has been reported 30 . However, several biophysical mechanisms may also contribute to surfactant performance under cooling. Drastic changes in body temperature leads to adaptive variations in both surfactant structure and composition to maintain proper interfacial properties in hibernating animals 31 , 32 . Besides, the surface activity of rabbit lung extracts tends to improve decreasing temperature from 40 to 15 °C 33 . It is well known that the organization and physical properties of lipid membranes, like those in lung surfactant, can be influenced by shifting temperatures towards their melting points 34 . Cooling to values below 30 °C affects lung surfactant performance in the presence of plasma compounds 35 . However, the reduction from 37 to 33 °C may have a different effect, as it is still above surfactant melting temperature (≈ 32 °C) 34 . To the best of our knowledge, no detailed in vitro studies have investigated surfactant biophysical properties under TH. Here, we analyse for the first time both the interfacial structure and the composition of lung surfactant films subjected to compression at 33 °C compared with 37 °C. We also describe enhanced surfactant function and resistance to inhibition by plasma under cooling, as a well as a more efficient restoration of function as a consequence of further surfactant supplementation. Finally, we investigate the molecular mechanisms governing this enhanced performance and propose a feasible biophysical model. Results Moderate hypothermia enhances surfactant activity in a concentration-dependent manner The activity of purified porcine surfactant (PS) was tested at different concentrations (1.5, 2.5 and 5 mg/mL) under slow (2 cycles/min) and quick (20 cycles/min)", "role": "user" }, { "content": "A tenth of all intensive care unit patients worldwide, and many critical patients with COVID-19, have acute respiratory distress syndrome (ARDS). Therapeutic hypothermia, an intentional cooling of the body, has been suggested as a way to improve ARDS. New research by Chiara Autilio and colleagues in the lab of Jesus Perez-Gil at the Complutense University of Madrid shows not only how therapeutic hypothermia works in the lungs at the molecular level, but also why it could be successfully applied to ARDS. Autilio and her colleagues' work was published in Nature Scientific Reports in January 2021 and will be presented on Tuesday, February 23 at the 65th Annual Meeting of the Biophysical Society to be held virtually. Inside our lungs, surfactant is a molecular mixture that is essential for breathing. Premature babies are sometimes born without yet having developed surfactant and require emergency surfactant replacement treatments in order to breathe. But surfactant is also inactivated and broken up in adults with lung injuries or inflammation. Because therapeutic hypothermia, a cooling of the body to about 33°C (or 91°F), has been used to improve breathing for some premature babies and for some kinds of cardiac arrest in adults, and some early studies have shown a benefit for ARDS, Autilio and colleagues wanted to know if cooling could impact surfactant. They looked at the physics of isolated surfactant in their lab, and Autilio said, \"unexpectedly, we found an improvement in surfactant activity at 33°C.\" The team found that at 33°C, the surfactant had lower surface tension, which could make it easier for oxygen to enter the lungs. They also found that the lower tension changed the activity of the molecules in the surfactant, which prevented surfactant from being disrupted by blood molecules, which can occur during lung injury. Their results indicate that \"using therapeutic hypothermia could help people with acute respiratory distress syndrome to breathe.\" There are currently clinical trials underway in other labs, testing therapeutic hypothermia as a treatment for severe breathing problems associated with COVID-19, according to Autilio. And in the Perez-Gil lab at the Complutense University, \"we are working to create a surfactant for adults, a surfactant that could work in the context of acute respiratory distress syndrome,\" says Autilio. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Music training has repeatedly been claimed to positively impact children’s cognitive skills and academic achievement (literacy and mathematics). This claim relies on the assumption that engaging in intellectually demanding activities fosters particular domain-general cognitive skills, or even general intelligence. The present meta-analytic review ( N = 6,984, k = 254, m = 54) shows that this belief is incorrect. Once the quality of study design is controlled for, the overall effect of music training programs is null ( \\( \\overline{g} \\) ≈ 0) and highly consistent across studies ( τ 2 ≈ 0). Results of Bayesian analyses employing distributional assumptions (informative priors) derived from previous research in cognitive training corroborate these conclusions. Small statistically significant overall effects are obtained only in those studies implementing no random allocation of participants and employing non-active controls ( \\( \\overline{g} \\) ≈ 0.200, p < .001). Interestingly, music training is ineffective regardless of the type of outcome measure (e.g., verbal, non-verbal, speed-related, etc.), participants’ age, and duration of training. Furthermore, we note that, beyond meta-analysis of experimental studies, a considerable amount of cross-sectional evidence indicates that engagement in music has no impact on people’s non-music cognitive skills or academic achievement. We conclude that researchers’ optimism about the benefits of music training is empirically unjustified and stems from misinterpretation of the empirical data and, possibly, confirmation bias. Working on a manuscript? Avoid the common mistakes Introduction It has been claimed that music fosters children’s cognitive skills and academic achievement. Learning to play the violin or the piano, to recognize pitches, and to keep the beat are often presented as effective cognitive enhancement tools (e.g., Jaušovec & Pahor, 2017 ). However, the idea that practicing cognitively demanding tasks may lead to domain-general cognitive enhancement is in stark contrast with empirical evidence in cognitive science and educational psychology. In fact, while human cognition has been shown to be malleable to training, transfer of skills appears to be limited to the training domain and, at best, other similar domains. It is customary to distinguish between two broad categories of transfer: near transfer and far transfer (Barnett & Ceci, 2002 ). Whereas near transfer – i.e., the transfer of skills within the same domain – is sometimes observed, far transfer – i.e., the transfer of skills across two distant domains – is rare or possibly inexistent (Melby-Lervåg, Redick, & Hulme, 2016 , Sala et al., 2019a ). Moreover, when it does occur, transfer of skills is often limited to the degree to which the two domains (source and target) share contents. For example, even transfer of skills within subspecialties of the same discipline seems to be limited. In fact, performance significantly worsens when experts engage in certain subspecialties of their field of expertise. For example, chess masters who are asked to recall or find the best move in positions coming from chess openings that do not fall into their repertoire exhibit a drastic (about 1 SD) reduction in performance (Bilalić, McLeod, & Gobet, 2009 ). This so-called curse of specificity has been recently defined as one of the fundamental particles in the standard model of human cognition (Sala & Gobet, 2019 ). Researchers involved in cognitive training do not deny that between-domain, or even within-domain, transfer is hard to trigger. Nonetheless, they claim that it is possible to induce far transfer by engaging in domain-specific cognitively demanding activities that boost domain-general cognitive skills; those skills, in turn, are supposed to generalize across many different domains (e.g., academic proficiency; Strobach & Karbach, 2016 ). At a neural level, this generalization is thought to be enabled by the activation of shared brain structures that are common to the practiced activity (e.g., music) and other core cognitive skills (e.g., fluid intelligence, working memory, and language; Moreno et al., 2011 ). In other words, domain-general cognitive enhancement and far transfer are believed to be by-products of domain-specific training (Taatgen, 2016 ). With respect to music, three main hypotheses have been formulated to explain why playing it should lead to broad cognitive benefits. To begin with, music might directly impact on general intelligence rather than on some particular cognitive skills (Schellenberg, 2004 ). This idea is consistent with the vast amount of correlational evidence showing that musicians tend to outperform non-musicians in a variety of cognitive tests. Examples include memory (Sala & Gobet, 2017a ; Talamini, Altoè, Carretti, & Grassi, 2017 ), fluid and general intelligence (Ruthsatz, Detterman, Griscom, & Cirullo, 2008 ; Schellenberg, 2006 ), attention (Saarikivi, Putkinen, Tervaniemi, & Huotilainen, 2016 ), and phonological processing (Forgeard et al., 2008 ). The same pattern of results occurs in academic skills. In fact, music skills appear to be related to better reading abilities (Anvari, Trainor, Woodside, & Levy, 2002 ), and music engagement is a predictor of overall academic achievement (Wetter, Koerner, & Schwaninger, 2009 ). Another possible link connecting music engagement and cognitive enhancement might be working memory (WM). Multimodal cognitively demanding activities are thought to strengthen WM capacity (Diamond & Ling, 2019 ; Morrison & Chein, 2011 ), which, in turn, enhances fluid intelligence and learning (Jaeggi et al., 2008 ). Music training is one such activity (Saarikivi, Huotilainen, Tervaniemi, & Putkinen, 2019 ). Simply put, the putative broad benefits of music training would stem from a boost in domain-general WM capacity rather than general intelligence. Finally, music training might positively impact on one’s sound perception and, consequently, phonological processing and even reading skills (Patel, 2011 ; Tierney & Kraus, 2013 ). This hypothesis is upheld by the fact that numerous brain structures and neural patterns are shared by music skills and language (for a review, see Jäncke, 2009 ). Interestingly, improved reading skills may also facilitate the acquisition of new skills and therefore enhance people’s IQ performance (Ritchie & Tucker-Drob, 2018 ). This further mechanism would again be consistent with the overall idea that music training conveys multiple cognitive and academic benefits. Experimental evidence The theories just described imply that music training causes cognitive enhancement and improvement in academic performance.", "role": "user" }, { "content": "Music training does not have a positive impact on children's cognitive skills, such as memory, and academic achievement, such as maths, reading or writing, according to a study published in Memory & Cognition. Previous research trials, carried out to examine a potential causal link between music training and improved cognitive and academic performance, have reached inconsistent conclusions, with some suggesting that there may be a link between music training and better cognitive and academic performance and others finding little effect. Researchers Giovanni Sala at Fujita Health University, Japan and Fernand Gobet at the London School of Economics and Political Science, UK examined existing experimental evidence regarding the impact of music training on children's non-music cognitive skills and academic achievement. The authors re-analyzed data from 54 previous studies conducted between 1986 and 2019, including a total of 6,984 children. They found that music training appeared to be ineffective at enhancing cognitive or academic skills, regardless of the type of skill (such as verbal, non-verbal, speed-related and so on), participants' age, and duration of music training. When comparing between the individual studies included in their meta-analysis, the authors found that studies with high-quality study design, such as those which used a group of active controls—children who did not learn music, but instead learned a different skill, such as dance or sports—showed no effect of music education on cognitive or academic performance. Small effects were found in studies that did not include controls or which did not randomize participants into control groups (ones that received different or no training) and intervention groups (ones that received music training). Giovanni Sala, the lead author said: \"Our study shows that the common idea that 'music makes children smarter' is incorrect. On the practical side, this means that teaching music with the sole intent of enhancing a child's cognitive or academic skills may be pointless. While the brain can be trained in such a way that if you play music, you get better at music, these benefits do not generalize in such a way that if you learn music, you also get better at maths. Researchers' optimism about the benefits of music training appears to be unjustified and may stem from misinterpretation of previous empirical data.\" Fernand Gobet, the corresponding author added: \"Music training may nonetheless be beneficial for children, for example by improving social skills or self-esteem. Certain elements of music instruction, such as arithmetical music notation could be used to facilitate learning in other disciplines.\" The authors caution that too few studies have been conducted to reach a definitive conclusion about possible positive effects of music education on non-academic or cognitive characteristics. Alternative potential avenues involving music activities may be worth exploring. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human pluripotent stem cells (hPS cells) can self-renew indefinitely, making them an attractive source for regenerative therapies. This expansion potential has been linked with the acquisition of large copy number variants that provide mutated cells with a growth advantage in culture 1 , 2 , 3 . The nature, extent and functional effects of other acquired genome sequence mutations in cultured hPS cells are not known. Here we sequence the protein-coding genes (exomes) of 140 independent human embryonic stem cell (hES cell) lines, including 26 lines prepared for potential clinical use 4 . We then apply computational strategies for identifying mutations present in a subset of cells in each hES cell line 5 . Although such mosaic mutations were generally rare, we identified five unrelated hES cell lines that carried six mutations in the TP53 gene that encodes the tumour suppressor P53. The TP53 mutations we observed are dominant negative and are the mutations most commonly seen in human cancers. We found that the TP53 mutant allelic fraction increased with passage number under standard culture conditions, suggesting that the P53 mutations confer selective advantage. We then mined published RNA sequencing data from 117 hPS cell lines, and observed another nine TP53 mutations, all resulting in coding changes in the DNA-binding domain of P53. In three lines, the allelic fraction exceeded 50%, suggesting additional selective advantage resulting from the loss of heterozygosity at the TP53 locus. As the acquisition and expansion of cancer-associated mutations in hPS cells may go unnoticed during most applications, we suggest that careful genetic characterization of hPS cells and their differentiated derivatives be carried out before clinical use. Main Somatic mutations that arise during cell proliferation and are then subject to positive selection are major causes of cancer and other diseases 6 . Acquired mutations are often present in just some of the cells in a sample, and can therefore be detected in next generation sequencing data from their presence at allelic fractions less than 50% 5 , 7 . We reasoned that the analysis of sequencing data from hES cells might reveal previously unappreciated mosaic mutations and mutation-driven expansions acquired during hES cell culture. This approach would complement previous studies describing culture-derived chromosomal-scale aneuploidies and megabase-scale copy number variants (CNVs) in hPS cells 1 , 8 , 9 . To this end, we collected and performed whole-exome sequencing (WES) of hES cell lines that were listed on the registry of hES cell lines maintained by the US National Institutes of Health (NIH) ( Fig. 1a, b ) and were able to obtain, bank and sequence 114 independent hES cell lines ( Fig. 1c–e ). We selected cell lines at low to moderate passage (P) numbers (mean P18, range P3–P37) and cultured them in a common set of growth conditions for an average of 2.7 ± 0.7 (± s.d.) passages (range 2–6 passages) before banking and sequencing ( Fig. 1f, g ). As hES-cell-derived differentiated cells are currently being evaluated in clinical trials for their safety and utility in a range of diseases such as macular degeneration 10 , we also obtained genomic DNA from an additional 26 independent hES cell lines that had been prepared under good manufacturing practice (GMP) conditions for potential clinical use ( Fig. 1a, c, e, g ). We performed WES of these 140 hES cell lines from 19 institutions to a mean read depth of 79.7 ± 0.1 (± s.e.m.) (range, 57 to 115 for UM4-6 to UM78-2) ( Fig. 1h ). Further details on cell line acquisition and selection are in Supplementary Table 1 and Methods . Figure 1: Acquisition and WES of 140 hES cell lines. a , Schematic workflow for hES cell line acquisition and sequencing. b , c , 114 hES cell lines were obtained, banked ( b ), and analysed by WES along with 26 GMP-prepared cell lines ( c ). d , 45 hES cell lines were excluded owing to use restrictions. e , 140 hES cell lines were banked and/or sequenced (see also Supplementary Table 1 and Methods ). f , HES cells were minimally cultured before banking and sequencing. g , Cumulative passage number of hES cells was moderate. h , WES coverage for sequenced hES cell lines. IRB, institutional review board; MTA, material transfer agreement; PGD, pre-implantation genetic diagnosis. PowerPoint slide Full size image To identify acquired mutations, we analysed the sequencing reads at high-quality, high-coverage heterozygous sites across the exome. To eliminate most inherited polymorphisms from consideration, we restricted this search to variants found in only 1–2 of the cell lines sequenced and in fewer than 0.01% of the individuals sampled by the Exome Aggregation Consortium (ExAC Database) 11 . The allelic fractions at which most remaining variants were represented among the sequence reads for any one hES cell DNA sample followed a binomial distribution, reflecting statistical sampling around the 50% level expected of inherited alleles ( Fig. 2a ); at a much smaller set of sites, variant alleles were present at lower fractions ( Fig. 2a, b ). We applied a statistical test to identify variants for which the observed allelic fractions were unlikely ( P < 0.01 by binomial test) to have been generated by random sampling of two equally present alleles. This search identified 263 candidate mosaic variants, of which 28 were predicted to have a damaging or disruptive effect on gene function ( Supplementary Table 2 ). Figure 2: Identification of recurrent, cancer-associated TP53 mutations in hES cells. a , Some heterozygous variants are present at low allelic fractions (boxed left) in hES cells. b , c , Likely mosaic variants ( P < 0.01, binomial test, red shading), include six mutations in TP53 ( b , Supplementary Table 3 ) that are rare in ExAC (<0.0001) ( c ). d , The four affected P53 residues are commonly mutated in human tumours. e , On a crystal structure of P53 bound to DNA, the affected residues map to the DNA binding domain and include arginine", "role": "user" }, { "content": "Regenerative medicine using human pluripotent stem cells to grow transplantable tissue outside the body carries the promise to treat a range of intractable disorders, such as diabetes and Parkinson's disease. However, a research team from the Harvard Stem Cell Institute (HSCI), Harvard Medical School (HMS), and the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard has found that as stem cell lines grow in a lab dish, they often acquire mutations in the TP53 (p53) gene, an important tumor suppressor responsible for controlling cell growth and division. Their research suggests that genetic sequencing technologies should be used to screen for mutated cells in stem cell cultures, so that cultures with mutated cells can be excluded from scientific experiments and clinical therapies. If such methods are not employed it could lead to an elevated cancer risk in those receiving transplants. The paper, published online in the journal Nature on April, 26, comes at just the right time, the researchers said, as experimental treatments using human pluripotent stem cells are ramping up across the country. \"Our results underscore the need for the field of regenerative medicine to proceed with care,\" said the study's co-corresponding author Kevin Eggan, an HSCI Principal Faculty member and the director of stem cell biology for the Stanley Center. Eggan's lab in Harvard University's Department of Stem Cell and Regenerative Biology uses human stem cells to study the mechanisms of brain disorders, including amyotrophic lateral sclerosis, intellectual disability, and schizophrenia. The research, the team said, should not discourage the pursuit of experimental treatments but instead be heeded as a call to screen rigorously all cell lines for mutations at various stages of development as well as immediately before transplantation. \"Our findings indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies,\" Eggan said. \"Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods.\" With human stem cells, researchers can recreate human tissue in the lab. This enables them to study the mechanisms by which certain genes can predispose an individual to a particular disease. Eggan has been working with Steve McCarroll, associate professor of genetics at Harvard Medical School and director of genetics at the Stanley Center, to study how genes shape the biology of neurons, which can be derived from these stem cells. McCarroll's lab recently discovered a common, precancerous condition in which a blood stem cell in the body acquires a pro-growth mutation and then outcompetes a person's normal stem cells, becoming the dominant generator of his or her blood cells. People in whom this condition has appeared are 12 times more likely to develop blood cancer later in life. The study's lead authors, Florian Merkle and Sulagna Ghosh, collaborated with Eggan and McCarroll to test whether laboratory-grown stem cells might be vulnerable to an analogous process. \"Cells in the lab, like cells in the body, acquire mutations all the time,\" said McCarroll, co-corresponding author. \"Mutations in most genes have little impact on the larger tissue or cell line. But cells with a pro-growth mutation can outcompete other cells, become very numerous, and 'take over' a tissue. We found that this process of clonal selection - the basis of cancer formation in the body - is also routinely happening in laboratories.\" To find acquired mutations, the researchers performed genetic analyses on 140 stem cell lines—26 of which were developed for therapeutic purposes using Good Manufacturing Practices, a quality control standard set by regulatory agencies in multiple countries. The remaining 114 were listed on the NIH registry of human pluripotent stem cells. \"While we expected to find some mutations in stem cell lines, we were surprised to find that about five percent of the stem cell lines we analyzed had acquired mutations in a tumor-suppressing gene called p53,\" said Merkle. Nicknamed the \"guardian of the genome,\" p53 controls cell growth and cell death. People who inherit p53 mutations develop a rare disorder called Li-Fraumeni Syndrome, which confers a near 100 percent risk of developing cancer in a wide range of tissue types. The specific mutations that the researchers observed are \"dominant negative\" mutations, meaning, when present on even one copy of P53, they are able to compromise the function of the normal protein, whose components are made from both gene copies. The exact same dominant-negative mutations are among the most commonly observed mutations in human cancers. \"These precise mutations are very familiar to cancer scientists. They are among the worst P53 mutations to have,\" said Sulagna Ghosh, a co-lead author of the study. The researchers performed a sophisticated set of DNA analyses to rule out the possibility that these mutations had been inherited rather than acquired as the cells grew in the lab. In subsequent experiments, the Harvard scientists found that p53 mutant cells outperformed and outcompeted non-mutant cells in the lab dish. In other words, a culture with a million healthy cells and one p53 mutant cell, said Eggan, could quickly become a culture of only mutant cells. \"The spectrum of tissues at risk for transformation when harboring a p53 mutation include many of those that we would like to target for repair with regenerative medicine using human pluripotent stem cells,\" said Eggan. Those organs include the pancreas, brain, blood, bone, skin, liver and lungs. However, Eggan and McCarroll emphasized that now that this phenomenon has been found, inexpensive gene-sequencing tests will allow researchers to identify and remove from the production line cell cultures with concerning mutations that might prove dangerous after transplantation. The researchers point out in their paper that screening approaches to identify these p53 mutations and others that confer cancer risk already exist and are used in cancer diagnostics. In fact, in an ongoing clinical trial that is transplanting cells derived from induced pluripotent stem cells (iPSCs), gene sequencing is used to ensure the transplanted cell products are free of dangerous mutations. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We investigated the spatiotemporal changes in strain associated with the occurrence of slow slip events (SSEs) in the subduction zones of the Japanese Islands and compared the spatial distribution of both the amount of strain accumulated for the period before and during the SSEs release using time series data from the Global Navigation Satellite System (GNSS). In this study, four SSEs were analysed: the Tokai long-term SSE (2000–2005), the Boso-Oki short-term SSE (2007), and the Bungo Channel long-term SSEs (2009–2011 and 2018–2019). As a result, we found strong negative correlations for all four dilatations before and during SSE occurrence. For these dilatations, we estimated the amount of strain released at the time of occurrence of the SSE relative to that accumulated during the period prior to the SSE. The result indicates that not all the accumulated strain before the SSEs was released when the SSEs occurred. Moreover, it is highly likely that the strain released by SSE is not only due to the strain accumulation just below the SSE occurrence region, but also due to the strain accumulation on the shallower plate boundary, which is a seismogenic zone for a future megathrust earthquake. Introduction Interplate earthquakes are considered to occur when the accumulated strain at the plate interface between a continental plate and a subducting oceanic plate exceeds a certain threshold, resulting in the release of the accumulated strain. Crustal deformation caused by the interaction between oceanic and continental plates is active in the Japanese Islands. Sagiya et al. 1 investigated the strain rates (principal strain, dilatation, and maximum shear strain) of the Japanese Islands during 1997–1999 after removing coseismic steps and found that many regions are subject to contraction. In southwestern Japan, the oceanic Philippine Sea (PHS) plate is subducting in a northwesterly direction beneath the continental Amurian plate along the Suruga Trough to the Nankai Trough (Fig. 1 ). On the plate boundary, in addition to ordinary interplate earthquakes, interplate aseismic slow slip events, known as long-term slow slip events (hereafter referred to as L-SSEs), take place in the Tokai region and the Bungo Channel at durations of several months to several years. Figure 1 Tectonic map of the study area. The black barbed lines represent the plate boundary, and the triangles indicate the direction of motion of the subducting plate with respect to the plate being subducted (Bird 28 ). The white arrows represent the velocity vectors of the Philippine Sea plate with respect to the Amurian plate (DeMets et al. 22 ). The map was created by using the Generic Mapping Tools (GMT) 27 (version: GMT4.5.7, URL link: ). Full size image L-SSEs with durations of several years have occurred in the Tokai region from 2000 to 2005 and from 2013 to 2016 and in the Bungo Channel from 1996 to 1997, 2003 to 2004, 2009 to 2011, and 2018 to 2019. Ozawa et al. 2 and Miyazaki et al. 3 reported southeastward slip as the L-SSE, which is distinct from the northwestward steady crustal movement, in the Tokai region from 2000 to 2005. Kobayashi and Hashimoto 4 found strain changes in the area east of Lake Biwa from the latter half of 2000, which is considered to be due to the L-SSE in the Tokai region. Ozawa et al. 5 , 6 , Yoshioka et al. 7 , Nakata et al. 8 , Seshimo and Yoshioka 9 , and Agata et al. 10 estimated the slip distribution of the L-SSEs in the Bungo Channel that occurred from 2009 to 2011 and from 2018 to 2019. Short-term SSEs (hereafter referred to as S-SSEs), with a duration of several tens of days, have also occurred off the Boso Peninsula, where the PHS plate is subducting beneath the North American plate along the Sagami Trough with recurrence intervals of several years. According to Ozawa et al. 11 , Hirose et al. 12 , and Fukuda 13 , displacements caused by the Boso-Oki S‒SSEs were observed in the Boso Peninsula for approximately 10 days from approximately 10 August 2007. The Boso-Oki S‒SSE was included in this study because the displacement changes identified in GNSS time series data are more distinct than those of S-SSEs in other regions, and its recurrence interval is well known (e.g., Fukuda 13 ). Although many studies on L-SSEs and S-SSEs in the Japanese Islands have been conducted, a comprehensive relationship between the accumulation and release of strain before and during the occurrence of SSEs, respectively, has yet to be conducted. Strain accumulation and release are fundamental phenomena in seismology, make it very important to investigate them. One of the major characteristics of SSEs is that the interval between the end of the previous SSE and the onset of the next SSE is well known. This makes it possible to directly compare the amount of strain accumulated before the SSE with the amount of strain released during the SSE. On the other hand, although the earthquake cycles of large earthquakes are generally considered to range from several decades to several thousand years, GNSS data are currently available for only at most 25 years. Therefore, it is difficult to know in detail the accumulation of strain during the period between earthquakes and to directly compare the amount of strain accumulated before and that released by a large earthquake. Therefore, in this study, for these SSEs, we calculated the strain fields before and during the occurrence of SSEs and investigated the relationship between the accumulation and release of strain caused by one cycle of the SSEs based on their spatial distribution and the amount of strain accumulation and release using GNSS time series data. Results The Tokai L-SSE (1 July 2000–30 June 2005), the Boso-Oki S‒SSE (9 August 2007–23 August 2007), and the two Bungo Channel L-SSEs (24 November 2009–6 February 2011 and 20 April 2018–26 May 2019) were the four SSEs analysed in this study. The former and the latter Bungo Channel L-SSE are hereafter referred to as the Bungo Channel L-SSE (1) and the", "role": "user" }, { "content": "The Japanese archipelago is actively undergoing seismic shifts due to interactions between the oceanic plate and the continental plate. At the plate boundaries located directly beneath areas of Japan (especially the Bungo Channel, Tokai and Boso-Oki regions), slow slip events (SSEs) occur, which involve gradual aseismic slipping taking place at a recurrence interval of several years. However, it is still not clear exactly how tectonic strain is accumulated and released in association with SSEs in these regions. A thorough understanding of SSEs would improve our knowledge of how megathrust earthquakes occur, leading to better forecasts. To shed some light on this, Kobe University's Kawabata Hiroki and Professor Yoshioka Shoichi (Research Center for Urban Safety and Security) used GNSS time series data to investigate the relationship between strain accumulation and release before and after the occurrence of SSEs in the Bungo Channel, Tokai and Boso-Oki regions. The results for all regions investigated revealed that not all of the accumulated strain is released when an SSE occurs. In addition, this release only occurs at the plate interface directly underneath. In contrast to this, it is highly likely that strain build-up not only happens in the SSE area but also in the shallow part of the plate boundary; in other words, the zone where a future megathrust earthquake could potentially occur. This new understanding is expected to contribute towards better earthquake forecasts in the future. These results were published in Scientific Reports. Main points An SSE is a phenomenon believed to be related to the occurrence of powerful megathrust earthquakes. Consequently, SSEs have received a lot of attention in recent years.This research study analyzed past slow slip events that occurred in the following areas of Japan: the Bungo Channel, the Tokai Region and Boso-Oki.A fundamental phenomenon that causes earthquakes is the accumulation and subsequent release of tectonic strain. Comprehensive research (that encompasses slow slip events and strain accumulation/release) is therefore considered vital to illuminate the onset mechanism behind megathrust earthquakes (such as the highly devastating Nankai Trough megathrust earthquake, which is forecasted to occur in the near future). SSEs background SSEs occur at the interface of tectonic plates, located underground below areas including the Bungo Channel, the Tokai Region and Boso-Oki. SSEs involve gradual aseismic slipping on the plate interface at a recurrence interval of several years. Plates sliding against each other in this manner is caused by the release of strain that has accumulated at the plate boundary. This movement is one of the fundamental causes of earthquakes. Many research studies have been conducted on SSEs up until now, however they tend to focus on one type. Studies have not examined different durations of SSEs across multiple regions from the perspective of strain accumulation and release. SSEs are linked to the occurrence of megathrust earthquakes. Therefore, it is vital to investigate SSE-related strain accumulation and release in order to illuminate the causal mechanism behind megathrust earthquakes. This study analyzed past SSEs that have occurred in the Bungo Channel, Tokai and Boso-Oki regions of Japan. GNSS time series data and models The researchers used GNSS time series data provided by the Geospatial Information Authority of Japan to analyze the amount and spatial distribution of strain accumulation and release before and after SSE occurrence. They analyzed the following events: a Tokai Region long-term slow slip event (L-SSE) that occurred between 2000 and 2005, a short-term slow slip event (S-SSE) that occurred in Boso-Oki in 2007, and two Bungo Channel L-SSEs that occurred in 2009-2011 and 2018-2019, respectively. These results confirmed that there was significant strain accumulation and release on the surface of the ground before and after SSE occurrence, respectively. Regardless of region, less than half of the strain accumulated beforehand was released when the SSE occurred. In addition, the researchers also created models of plate interface adhesion and slippage for the Bungo Channel L-SSEs that could explain the analysis results well. The models revealed that the impact of SSEs is not limited to where they occur but is also connected to strain accumulation at the epicenter of megathrust earthquakes in shallower areas than the plate interface. Slow slip events differ from people's typical image of an earthquake as they cannot be directly felt. However, they are intrinsically related to the occurrence of megathrust earthquakes, as indicated by this study. SSEs, especially those occurring in the Bungo Channel and Tokai regions, are considered important phenomena that could provide an early warning for earthquakes, including Tokai earthquakes and the devastating Nankai Trough megathrust earthquake (which is likely to occur in the near future). It is hoped that investigating the relationship between the strain accumulation and release that accompanies SSEs in various regions throughout the Japanese archipelago will lead to new insight into the mechanism behind megathrust earthquakes as well as the state of interplate coupling. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Climate change could pose a major challenge to efforts towards strongly increase food production over the coming decades. However, model simulations of future climate-impacts on crop yields differ substantially in the magnitude and even direction of the projected change. Combining observations of current maximum-attainable yield with climate analogues, we provide a complementary method of assessing the effect of climate change on crop yields. Strong reductions in attainable yields of major cereal crops are found across a large fraction of current cropland by 2050. These areas are vulnerable to climate change and have greatly reduced opportunity for agricultural intensification. However, the total land area, including regions not currently used for crops, climatically suitable for high attainable yields of maize, wheat and rice is similar by 2050 to the present-day. Large shifts in land-use patterns and crop choice will likely be necessary to sustain production growth rates and keep pace with demand. Introduction Between 1960 and 2000, global cereal production doubled, primarily through intensification of agriculture on current croplands and by the breeding of more productive crop varieties 1 . It is projected that global food production needs to increase by another 60–110% by 2050, to keep up with anticipated increases in human population and changes in diet 2 , 3 . Increases of this magnitude are possible through aggressive intensification in areas that are currently far below their potential 4 . However, several challenges exist relating to our ability to overcome economic, societal and environmental impediments to intensification 3 , 4 , 5 . To address these challenges effectively, and with a long-term outlook, it is necessary to understand how climate change is likely to impact the agricultural sector. Current expectations are that changes in climate over the next century will tend to decrease yields at lower latitudes and increase yields at northern latitudes 6 , 7 , but no consensus exists on the magnitude, timing and exact location of these changes. Assessments of future food production under climate change have to-date relied on synthesis of crop-climate assessments at field and/or regional scales using models which vary from highly process-based to relatively empirical in formulation 6 , 8 . Both approaches can give important insights, but suffer also from significant limitations. Empirical models implicitly capture the effects of all relevant processes over the period and location for which they were parameterized, but they are often poorly tested for the conditions likely to become the future norm under climate change 8 , 9 , and are typically limited in their spatial coverage. Process-based models account explicitly for physiological mechanisms, and can thus capture emergent behaviour under novel conditions, but generally suffer from missing processes, such as heat stress and the coupling of transpiration to leaf temperature 8 , 10 . Many research groups now develop and operate global-scale crop-climate models, but the necessary data for model development, parameterization and evaluation is often not available at this scale 11 , and in most cases, global-scale assessments fail to account for farmer adaptation to climate change 7 , 9 . As a result, these models vary strongly in both the magnitude and overall direction of their yield projections, an effect which is especially pronounced across the tropics and arid regions 7 . This uncertainty impedes understanding the scope of the societal challenge of climate change impacts on agriculture, particularly in developing countries where agriculture has larger shares in gross domestic product. Furthermore, large uncertainties in yield projections hinder our ability to assess the potential of various climate-change adaptation versus mitigation options; future changes in the productivity of different cropland areas will affect future land use, including societal decision-making on whether to, for example, reforest or intensify an area of cropland, or to extend cropland coverage 12 , 13 , 14 . We use here a data-driven approach, utilizing observation-based estimates of current maximum-attainable yield with existing technology (hereafter referred to as attainable yield, see Methods section for definition) 4 and climate analogues 15 , 16 , to assess the vulnerability of yields of the three major global cereal crops, wheat, maize and rice to climate change. Using future climate projections from five General Circulation Models (GCMs) that contributed to the Coupled Model Intercomparison Project Phase 5 (CMIP5) as part of the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC) 17 , we identify present-day analogues of future climatic conditions, across the current global cropland area, with medium- (time window of 2041–2059, henceforth mid-century) and long-term (2081–2099, henceforth end-of-century) perspectives. Analogue climates are defined based on the accumulated annual sums of growing-degree-days (GDD) and precipitation, although we also test other variable combinations and seasonal averaging periods (Methods section). We make the assumptions that, given no changes in the global cultivar pool, the attainable yields of crops are purely a function of climate, and that the most effective yield-enhancing managements available are either spatially and temporally invariant, or also a function of climate; for instance, irrigation is unlikely to be widely available in very dry climates (neglecting possible finite fossil groundwater supplies or large rivers). Based on these premises, a yield which can be attained in the present day under a given climate can also be attained in the future, under an analogous climate, but at a different location. Areas with fundamentally unsuitable soils are avoided either by restricting projection of our results to current cropland area, or by masking with soil suitability information (Methods section). Our approach is thus independent of crop modelling methodologies typically used to project future yields, although, as for crop models, the results remain subject to uncertainties in terrain and soil type, particularly at the sub-grid scale. Further, it has important added value as, in addition to considering climatic effects on crop yields, it implicitly considers adaptation of management and crop type in line with current technology available for a given climatic environment. The technique allows us to (i) assess the change in attainable crop yield across the current global cropland area for each of maize, wheat", "role": "user" }, { "content": "A team of researchers led by the University of Birmingham warns that without significant improvements in technology, global crop yields are likely to fall in the areas currently used for production of the world's three major cereal crops, forcing production to move to new areas. With a worldwide population projected to top nine billion in the next 30 years, the amount of food produced globally will need to double. A new study led by researchers from the University of Birmingham shows that much of the land currently used to grow wheat, maize and rice is vulnerable to the effects of climate change. This could lead to a major drop in productivity of these areas by 2050, along with a corresponding increase in potential productivity of many previously-unused areas, pointing to a major shift in the map of global food production. The study, published today in Nature Communications, uses a new approach combining standard climate change models with maximum land productivity data, to predict how the potential productivity of cropland is likely to change over the next 50-100 years as a result of climate change. The results show that: Nearly half of all maize produced in the world (43%), and a third of all wheat and rice (33% and 37% respectively), is grown in areas vulnerable to the effects of climate changeCroplands in tropical areas, including Sub-Saharan Africa, South America and the Eastern US, are likely to experience the most drastic reductions in their potential to grow these cropsCroplands in temperate areas, including western and central Russia and central Canada, are likely to experience an increase in yield potential, leading to many new opportunities for agriculture While the effects of climate change are usually expected to be greatest in the world's poorest areas, this study suggests that developed countries may be equally affected. Efforts to increase food production usually focus on closing the yield gap, i.e. minimising the difference between what could potentially be grown on a given area of land and what is actually harvested. Highly-developed countries already have a very small yield gap, so the negative effects of climate change on potential yield are likely to be felt more acutely in these areas. Our model shows that on many areas of land currently used to grow crops, the potential to improve yields is greatly decreased as a result of the effects of climate change,\" says lead researcher and University of Birmingham academic Dr Tom Pugh. \"But it raises an interesting opportunity for some countries in temperate areas, where the suitability of climate to grow these major crops is likely to increase over the same time period.\" The political, social and cultural effects of these major changes to the distribution of global cropland would be profound, as currently productive regions become net importers and vice versa. \"Of course, climate is just one factor when looking at the future of global agricultural practices,\" adds Pugh. \"Local factors such as soil quality and water availability also have a very important effect on crop yields in real terms. But production of the world's three major cereal crops needs to keep up with demand, and if we can't do that by making our existing land more efficient, then the only other option is to increase the amount of land that we use.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses—termed the Burden of Proof studies—designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk–outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk–outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk–outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. Main Exposure to different risk factors plays an important role in the likelihood of an individual developing or experiencing more severe outcomes from certain diseases, such as high blood pressure increasing the risk of heart disease or not having access to a safe water source increasing the risk of diarrheal diseases 1 . Understanding and quantifying the relationship between risk factor exposure and the risk of a subsequent outcome is therefore essential to set priorities for public policy, to guide public health practices, to help clinicians advise their patients and to inform personal health choices. Consequently, information on risk–outcome relationships can be used in the formulation of many types of public policies, including national recommendations on diet, occupational health rules, regulations on behavior such as smoking in public places, and guidance on appropriate levels of taxes and subsidies. As new evidence is continuously being produced and published, the systematic and comparable assessment of risk functions is a dynamic challenge. Up-to-date assessments of risk–outcome relationships are essential to, and a core component of, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) comparative risk assessment (CRA) 1 , 2 , 3 , which aims to help decision-makers understand the magnitude of different health problems. Evidence on risk–outcome relationships comes from many types of studies, including randomized controlled trials (RCTs), cohort studies, case-control studies, cross-sectional analyses, ecological studies and animal studies. Each study type has characteristic strengths and weaknesses. For example, RCTs are the most robust method for dealing with confounding but are often conducted with strict inclusion and exclusion criteria, meaning that trial participants are unlikely to be fully representative of the general population, as well as being done over relatively short durations 3 , 4 , 5 . Case-control studies are well suited for understanding the risks linked to rare outcomes but may be subject to recall bias for past exposure 6 , 7 . Animal studies are widely used in evaluating the risks of consumer products and environmental risks but may not be generalizable to humans 8 . Study design and analysis impacts causal interpretation and understanding of the results 9 . When synthesizing evidence from different studies, strong assumptions—usually that of a log-linear relationship between risk and exposure—are often made to increase the mathematical tractability of the analysis 10 , 11 , 12 . Between-study heterogeneity—that is, disagreement in study-specific inferred relationships between risk exposure and outcome—is quantified in meta-analytic summaries, and has some effect on fixed-effects variance estimates, but is not otherwise used in the overall assessments of the uncertainty in risk–outcome relationships 12 , 13 . Risk factors associated with comparatively modest increases in the hazard are often questioned because of the potential for residual confounding 14 . Given the very mixed evidence landscape, it is perhaps not surprising that there are so many controversies in the literature 15 , 16 , 17 , 18 . While evidence is often heterogeneous, the need for clear guidance has led national advisory groups and international organizations to use expert committees to evaluate the evidence and formulate recommendations. The biggest advantage of expert groups is their ability to carefully consider nuances in the available evidence, but they are inherently subjective. For instance, expert groups across subfields of health science weight types of evidence differently, and even groups of experts within the same subfield may arrive at divergent conclusions. These expert groups often use meta-analyses of the available evidence, such as those produced by the Cochrane Collaborations 19 , as an input to their deliberations. Even Cochrane Reviews, however, allow authors to use a range of methodologies and approaches to studies on risk of bias, limiting comparability across risk–outcome pairs 19 . Tools have been produced to help standardize consideration of evidence, such as Grading of Recommendations, Assessment, Development and Evaluations (GRADE 20 , 21 ), but while very helpful, they cannot be implemented algorithmically. No quantitative assessment of the evidence can or should substitute completely for expert deliberation, but a quantitative meta-analytic approach that addresses some of the issues identified by GRADE and others could be a useful input to international and national expert committee considerations. Here, we propose a complementary approach, in which we quantify the mean relationship (the risk function) between risk exposure and a disease or injury outcome, after adjusting for known biases in the existing studies. Unlike existing approaches, our approach does not force log-linearity in risk functions or make additional approximations, such as midpoint approximations for ranges or shared reference", "role": "user" }, { "content": "A new set of meta-analyses clarifies the often complex and contradictory health guidance linking certain diets, behaviors, and conditions to illness. The analyses, conducted by researchers from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington's School of Medicine, were published today in Nature Medicine. IHME analyzed the strength of the evidence for 180 pairs of risk factors and health outcomes—such as smoking and lung cancer, diet low in vegetables and type 2 diabetes, and high systolic blood pressure and ischemic heart disease. The findings are presented in an easy-to-understand star rating system showing the strength of evidence for each link. The new star rating system aims to help people make personal health decisions, inform health policy, and guide future research. \"There has been extensive research on the links between various risks and health outcomes, but findings are often very different across studies,\" explained Dr. Christopher Murray, Director of the Institute for Health Metrics and Evaluation and a lead author of the study. \"One of the goals of this new star rating system is to clear up confusion and help consumers make informed decisions about diet, exercise, and other activities that can affect their long-term health.\" In many areas, IHME found that the link between a risk factor and a health outcome was weaker than some might believe. Nearly two-thirds of the risk-outcome pairs investigated—112 out of 180—received only a one- or two-star rating. These include widely publicized pairings such as diet high in unprocessed red meat and ischemic stroke (one star). In other cases, IHME's analysis confirmed widely held consensus. Eight risk-outcome pairs received a five-star rating, including smoking and lung cancer and high systolic blood pressure and ischemic heart disease. A list of the star ratings, including a data visualization tool, can be found on IHME's website. Additional star ratings will be added in the near future. The analysis takes into account both the magnitude of risk shown by studies to date, as well as the consistency of findings between those studies. The star ratings are based on the most conservative interpretation of the available evidence, to limit the impact of error or bias in the underlying data. A one-star rating indicates that there may be no true association between the behavior or condition and the health outcome. Two stars indicates the behavior or condition is at least associated with a 0-15% change in the likelihood of a health outcome, while three stars indicates at least a 15-50% change, four stars indicates at least a 50-85% change, and five stars indicates a more than 85% change. For example, the five-star rating for smoking and lung cancer means that smoking increases the likelihood of developing or dying of lung cancer by more than 85%. At the other end of the scale, the one-star rating for red meat and ischemic stroke means that there may not be an association—in this case, because studies of this link have produced inconsistent results. Notable ratings from the study include: Credit: Institute for Health Metrics and Evaluation \"In addition to helping consumers, our analysis can guide policymakers in developing health and wellness education programs, so that they focus on the risk factors with the greatest impact on health,\" said Dr. Emmanuela Gakidou, Professor of Health Metrics Sciences at the Institute for Health Metrics and Evaluation and a lead author of the study. \"Health researchers can also use this analysis to identify areas where current evidence is weak and more definitive studies are needed.\" The IHME researchers also note that while the meta-analytical approach employed by this study should not replace expert deliberation, it can provide useful input for expert committees and advisory groups making formal health policy recommendations. IHME's analysis, which draws from the landmark Global Burden of Disease study, which marks 30 years this year, will be updated on a regular basis. As a result of constantly evolving research, the star ratings may change as more data becomes available. This is particularly the case for pairings with low star ratings due to limited or contradictory research. On the other hand, high star ratings are unlikely to change significantly because the evidence is already strong. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The expansion of brain size is accompanied by a relative enlargement of the subventricular zone during development. Epithelial-like neural stem cells divide in the ventricular zone at the ventricles of the embryonic brain, self-renew and generate basal progenitors 1 that delaminate and settle in the subventricular zone in enlarged brain regions 2 . The length of time that cells stay in the subventricular zone is essential for controlling further amplification and fate determination. Here we show that the interphase centrosome protein AKNA has a key role in this process. AKNA localizes at the subdistal appendages of the mother centriole in specific subtypes of neural stem cells, and in almost all basal progenitors. This protein is necessary and sufficient to organize centrosomal microtubules, and promote their nucleation and growth. These features of AKNA are important for mediating the delamination process in the formation of the subventricular zone. Moreover, AKNA regulates the exit from the subventricular zone, which reveals the pivotal role of centrosomal microtubule organization in enabling cells to both enter and remain in the subventricular zone. The epithelial-to-mesenchymal transition is also regulated by AKNA in other epithelial cells, demonstrating its general importance for the control of cell delamination. Main We searched the developing mouse cerebral cortex for candidate regulators of SVZ generation and expansion 3 , 4 , 5 . We chose to examine AKNA because levels of Akna mRNA correlate with the time at which the subventricular zone (SVZ) is generated (that is, low at embryonic day (E)11, high at E14 and low at E18), and because neural stem cells (NSCs) isolated at the peak of SVZ generation have higher levels of Akna when transitioning to basal progenitors 3 (Extended Data Fig. 1a, b ). To investigate the function of AKNA, we first generated monoclonal antibodies, which were validated by RNA interference (Extended Data Fig. 1c–f , Methods). Given the annotation of AKNA as an AT-hook transcription factor 6 , we were surprised to find specific immunofluorescence signals at centrosomes (Fig. 1a , Extended Data Fig. 1f–m ) in different cell types of various species (Extended Data Figs. 1 – 4 , 8 , 10 ), which was confirmed by BAC-transgenic cell lines (Extended Data Fig. 1h ) and fractionation of cell lysates (Extended Data Fig. 1n, o ). Ultrastructural analysis (Extended Data Fig. 2a–c ) showed that AKNA largely localized to the distal part of the subdistal appendages (SDAs) of the mother centriole in interphase; some AKNA was also found at the proximal ends of centrioles and along microtubules (Extended Data Fig. 2a–d , Supplementary Video 1 ). Recombinant AKNA protein decorated in vitro-reconstituted microtubules (Extended Data Fig. 2e , Supplementary Video 2 ). The centrosomal localization of AKNA is not dependent on microtubules or cargo-motors (Extended Data Fig. 2f–h ); however, it is dependent on centrioles, as AKNA is absent upon deletion of SAS4 7 (Extended Data Fig. 2i ) and the SDA protein ODF2 (Extended Data Fig. 2j, k ). AKNA localizes to the centrosome through its carboxyterminal part—a region that was omitted from its first description 6 (see Supplementary Discussion )—as AKNA(1–1080), which lacks the C-terminal 324 amino acids, is distributed in the cytoplasm but is still able to bind to microtubules (Extended Data Fig. 2l–o ). Similar to most SDA-associated proteins 8 , AKNA dissociates from centrosomes during M-phase without proteolytic degradation (Extended Data Figs. 1 h panel 2 , 3a, b ) and reassembles at the centrosomes during late telophase and early G1 phase (Supplementary Video 3 ); this dissociation and reassembly is regulated by phosphorylation (Extended Data Fig. 3c, d ). Thus, AKNA is a novel integral component of centrosomal SDAs and binding to microtubules, which raises the question of what its role is during development. Fig. 1: AKNA is a centrosome component that regulates NSC delamination. a , Immunostaining of E14 cortex (CTX) cells, showing AKNA at the mother centriole together with ODF2 (distal and subdistal appendages) and GT335 (cilia and centrioles) ( n = 4). b , E14 cortex sections showing AKNA + subsets of centrosomes. Pericentrin + (PCNT + )AKNA + centrosomes (blue arrows) at the ventricular zone (VZ) (panel 3); many AKNA + centrosomes in the SVZ and intermediate zone (IZ) (panel 2); and most centrosomes AKNA − (red arrows) in the cortical plate (CP) (panel 1). V, ventricle. n = 12. c , d , g , h , Confocal micrographs illustrating binning and the distribution of control ( c , g ), Akna shRNA no. 1 (shAkna 1) ( d ), electroporated GFP + cells at 2 d.p.e. and AKNA overexpression (OE) at 1 d.p.e. ( h ). e , f , i , j , Quantifications as indicated in panels. e , i , Mean ± s.e.m. as transparent band in the same colour. f , j , Box plots show median, quartiles (box) and range (whiskers). e , Control shRNA, n = 6; Akna shRNA no. 1, n = 5; Akna shRNA no. 2 (shAkna 2), n = 5 embryos. * P ≤ 0.05, ** P ≤ 0.01 (exact P values (from top to bottom) 0.00796, 0.00432, 0.00865, 0.02217, 0.03174, 0.01731, 0.00432, 0.00865 and 0.00865). f , Control shRNA, n = 5; Akna shRNA no. 2, n = 5 embryos. NS, not significant, ** P ≤ 0.01 (exact P values (from left to right) 0.00793, 0.30952 and 0.00793). i , GFP (control), n = 9; AKNA overexpression, n = 11; AKNA(1–1080), n = 4 embryos. ** P ≤ 0.01, *** P ≤ 0.001 (exact P values (from top to bottom) 0.00779, 0.00147 and 0.00008). j , GFP (control), n = 4; AKNA overexpression, n = 4 embryos. NS, not significant, * P ≤ 0.05 (exact P values (from left to right), 0.02857, 0.48571 and 0.02857). e , f , i , j , Two-sided Mann–Whitney U test. Scale bars, 2.5 μm ( a ), 20 μm ( b ), 50 μm ( c , d , g , h ). Source data Full", "role": "user" }, { "content": "The use of stem cells to repair organs is one of the foremost goals of modern regenerative medicine. Scientists at Helmholtz Zentrum München and Ludwig Maximilian University of Munich (LMU) have discovered that the protein Akna plays a key role in this process. It controls, for example, the behavior of neural stem cells via a mechanism that may also be involved in the formation of metastases. The study was published in the renowned journal Nature. The research team led by Prof. Dr. Magdalena Götz, director of the Institute for Stem Cell Research (ISF) at Helmholtz Zentrum München and Chair of Physiological Genomics of the LMU Biomedical Center, wanted to identify the factors that regulate the maintenance or differentiation of neural stem cells. To this end, the scientists isolated neural stem cells, which either self-renew and generate additional neural stem cells or differentiate. \"We found that the Akna protein is present in higher concentrations in stem cells that generate neurons,\" explains ISF researcher German Camargo Ortega, first author of the study together with Dr. Sven Falk. \"Our experiments showed that low levels of the Akna protein cause stem cells to remain in the stem cell niche, whereas higher levels stimulate them to detach from the niche, thus promoting differentiation,\" the author continues. The scientists were surprised to discover the position of the protein − namely at the centrosome, an organelle in the cell's interior that acts as chief architect for the organization of the cytoskeleton and regulates cell division. \"We discovered that an incorrect sequence was originally published for this protein,\" Sven Falk reports. \"However, our work clearly showed that Akna is located directly at the centrosome.\" The researchers were able to show that Akna recruits and anchors microtubules at the centrosome. This weakens the connections to neighboring cells, and promotes detachment and migration from the stem cell niche. Akna (here in magenta) is a novel centrosome component regulating the interaction with the cytoskeleton. Credit: Helmholtz Zentrum München \"Our experiments show that this function also plays an important role in a process known as epithelial-to-mesenchymal transition, or EMT for short,\" explains the study leader Magdalena Götz. \"In this process, cells detach from a cluster, proliferate and begin to migrate. This occurs, for example when stem cells migrate to form new neurons, but it can also be harmful in disease, for example when cancer cells leave a tumor to form metastases elsewhere in the body. \"The novel mechanism that we identified by studying the function of Akna therefore appears to play a key role in a broad range of medically relevant processes.\" In the next step, the research team plans to investigate the role of Akna in other stem cells and in the immune system. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Despite the fact that children can draw on their memories to make novel inferences, it is unknown whether they do so through the same neural mechanisms as adults. We measured memory reinstatement as participants aged 7–30 years learned new, related information. While adults brought memories to mind throughout learning, adolescents did so only transiently, and children not at all. Analysis of trial-wise variability in reactivation showed that discrepant neural mechanisms—and in particular, what we interpret as suppression of interfering memories during learning in early adolescence—are nevertheless beneficial for later inference at each developmental stage. These results suggest that while adults build integrated memories well-suited to informing inference directly, children and adolescents instead must rely on separate memories to be individually referenced at the time of inference decisions. Main Young adults reactivate memories when they encounter new related experiences. Such reactivation can facilitate memory integration, whereby related events experienced at different times are stored as overlapping memory traces 1 , 2 , 3 . Memory integration thus promotes forming links between memories that extend knowledge beyond direct observation. Memory integration in adults relies on hippocampus (HPC) and medial prefrontal cortex (PFC) 2 , 4 , 5 , 6 , 7 and has been shown to benefit behaviours such as inferential reasoning, which requires simultaneous consideration of multiple memories 3 . For example, when asked to derive a relationship that has not been directly observed but must be inferred across several prior events, adults benefit from having previously connected (or integrated) their memories at encoding 5 , 6 , 8 , 9 , 10 . However, inferential reasoning can also be accomplished via an alternative mechanism in which memories for the original experiences are stored separately to be later recombined 11 , 12 , 13 when making the inference itself. Such a retrieval-based mechanism depends on memories for the individual events but importantly does not rely on them having been integrated at encoding. It has been suggested that young children’s inference ability 14 , 15 arises predominantly from a retrieval-based mechanism. For example, children struggle disproportionately with reasoning given their memory performance 16 , 17 , and they are insensitive to manipulations designed to promote integration during encoding 18 . Both of these findings are consistent with the idea that reasoning during childhood relies primarily on operations engaged during inference itself. Given that inferential reasoning is a predictor of academic success 19 , 20 and the real possibility that children approach it in a fundamentally different way, it is crucial that we understand the neural mechanisms supporting its improvement throughout development. We suggest that how memories for related experiences are formed will depend on both (1) the refinement of HPC-based mechanisms that support the ability to flexibly reactivate neocortical representations of related memories during new learning 21 , 22 and (2) the frontal mechanisms available to mediate conflict among reactivated memories, the results of which will ultimately influence how memories are formed in HPC 23 , 24 , 25 . Importantly, we suggest that reactivation is a necessary but not sufficient condition for memory integration to occur, as additional mechanisms must be engaged after memory reactivation to ultimately link related memories according to their overlapping features. Our overarching hypothesis is that, developmentally speaking, reactivation and integration will emerge in succession, paralleling the maturation of HPC 26 , 27 , 28 , 29 , 30 and its PFC connections 31 , 32 , respectively. As such, there will be a period—specifically, adolescence—during which individuals reactivate but do not integrate. Both HPC and PFC along with their interconnecting pathways show a protracted developmental trajectory continuing into (at least) adolescence 26 , 27 , 31 , with PFC being particularly late to mature 33 . We suggest that the emergence of the first step necessary for an adult-like integration mechanism—namely, memory reactivation during new encoding—would therefore require that HPC retrieval is flexible enough to allow for the reinstatement of related memories during a similar but not identical (that is, partially overlapping) new experience 34 , 35 . Such flexible retrieval may not mature until around 10 years of age 25 , 36 , thereby preventing any top-down influence on HPC codes and leaving inference in children to be carried out entirely to the time of decision itself. Along with the maturation of HPC retrieval mechanisms is expected to come a greater likelihood of memory reinstatement in adolescence; and yet, we suggest that such reactivation will nevertheless continue to have a different behavioural consequence than it does in adults. In particular, we suggest that reactivation of past memories in adolescence may yield memory competition that is resolved by suppression and an ultimate de-emphasis of the relationships among memories. We suggest that such a phenomenon in our task may be due to the combined influence of at least two factors. First, there is general maturation of top-down control networks during adolescence that has been linked to improvements in higher-order cognitive abilities 37 , 38 , 39 , 40 . Some have even observed that adolescence may be a peak period for top-down control of memory behaviours, with adolescents showing enhanced engagement of lateral PFC relative to adults 41 . Such increased control of memory among adolescents in our task may correspond to an enhanced tendency to suppress related, interfering memories 25 , 32 . Consistent with this idea, past work in rodents has highlighted adolescence as a unique time during which previous memories are suppressed during new, similar experiences 42 , 43 . Second, there are developmental changes in the HPC 26 , 27 , 28 , 29 , 30 that may lead to differences in memory representation. In terms of overall memory quality, adolescence is associated with increases in precision 44 , 45 , greater richness of episodic detail 46 and enhancements in recollective quality 47 —all potentially attributable to changes in HPC encoding 41 , 48 , 49 , 50 , 51 , 52 . Given these findings, we expect that adolescents will be", "role": "user" }, { "content": "A new study of brain activity patterns in people doing a memory task finds that the way we make inferences—finding hidden connections between different experiences—changes dramatically as we age. The study's findings might one day lead to personalized learning strategies based on a person's cognitive and brain development. The researchers found that whereas adults build integrated memories with inferences already baked in, children and adolescents create separate memories that they later compare to make inferences on the fly. \"How adults structure knowledge is not necessarily optimal for children, because adult strategies might require brain machinery that is not fully mature in children,\" said Alison Preston, professor of neuroscience and psychology and senior author of the study published today in the journal Nature Human Behaviour. She co-led the study with first author Margaret Schlichting, formerly a doctoral student in Preston's lab and currently assistant professor of psychology at the University of Toronto. To understand the distinction between how adults and children make inferences, imagine visiting a day care center. In the morning, you see a child arriving with one adult, but in the afternoon that child leaves with a different adult. You might infer that the two grown-ups are the child's parents and are a couple, and your second memory would include both the second person you saw and information from your earlier experience in order to make an inference about how the two adults—whom you didn't actually see together—might relate to each other. This new study finds that a child who has the same experiences isn't likely to make the same kind of inference that an adult would during the second experience. The two memories are less connected. If you ask your child to infer who that child's parents are, your child can still do it; he or she just has to retrieve the two distinct memories and then reason about how each adult might be related. The neural machinery of children and adults differs, and the strategy that children use may be optimal for the way their brains are wired before key memory systems in the hippocampus and prefrontal cortex fully mature, the researchers believe. That difference could keep children from recalling past memories during new learning and limit their ability to connect events. \"In the absence of a mature memory system, the best thing a child can do is lay down accurate, non-overlapping memory traces,\" Preston said. \"From those accurate memory traces, children can later bring them to mind to promote inferences about their connections.\" Hannah Roome (right) and Nicole Varga prepare a study participant for an fMRI brain scan. Credit: Vivian Abagiu/University of Texas at Austin The researchers asked 87 subjects, ages 7 to 30, to look at pairs of images while lying in an fMRI (functional magnetic resonance imaging) scanner, which measures brain activity by detecting small changes in blood flow with images that, as in the day care example above, provide opportunities to infer relationships between objects that had not appeared together. The researchers found that the strategy adolescents used for making inferences was different from both that of young children and adults. Going back to the example of the parents at the day care, when an adolescent stores a memory of the second grown-up with the child, the adolescent suppresses the earlier memory involving the first one. Each memory becomes even more distinct than with younger children, and there are even fewer automatic inferences about how the two adults relate. \"Teenagers may have learning strategies that are tuned to explore the world more so than exploiting what they already know,\" Preston said. This and other lessons from the study could inform strategies for improving teaching and learning at various ages. \"From a brain maturation perspective, different people are going to be at different places,\" Preston said, \"and we can devise learning strategies that take advantage of the neural machinery that an individual has at hand, no matter if they are 7 years old or 70 years old.\" The study's other authors are Katharine Guarino at Loyola University Chicago and Hannah Roome of UT Austin. This work was supported by the National Institutes of Health and by the Canada Foundation for Innovation. Preston holds the Dr. A. Wilson Nolle and Sir Raghunath P. Mahendroo Professorship in Neuroscience. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Effective use of agricultural residual biomass may be beneficial for both local and global ecosystems. Recently, biochar has received attention as a soil enhancer and its effects on plant growth and soil microbiota have been investigated. However, there is little information on how the physical, chemical and biological properties of soil amended with biochar are affected. In this study, we evaluated the effects of the incorporation of torrefied plant biomass on physical and structural properties, elemental profiles, initial plant growth and metabolic and microbial dynamics in aridisol from Botswana. Hemicellulose in the biomass was degraded while cellulose and lignin were not, owing to the relatively low-temperature treatment in the torrefaction preparation. Water retentivity and mineral availability for plants were improved in soils with torrefied biomass. Furthermore, fertilization with 3% and 5% of torrefied biomass enhanced initial plant growth and elemental uptake. Although the metabolic and microbial dynamics of the control soil were dominantly associated with a C1 metabolism, those of the 3% and 5% torrefied biomass soils were dominantly associated with an organic acid metabolism. Torrefied biomass was shown to be an effective soil amendment by enhancing water retentivity, structural stability and plant growth and controlling soil metabolites and microbiota. Introduction In African dryland landscapes, improving nutrient-poor soils is important for increasing agricultural productivity, particularly because a significant population growth is expected in this region over the next 100 years. In the Republic of Botswana in southern Africa, Jatropha curcas L. has received attention as a biomass resource 1 , 2 although has exhibited unsatisfactory growth due to the arid climate, chilling injury and oligotrophic soil conditions (aridisols) 3 , 4 . Therefore, methods of soil amendment are expected to promote its agricultural production in nonfarming lands. In dryland ecosystems, such as arid African landscapes, termites, which build termite mounds, play a key role in soil amelioration 5 . Their effects may be artificially achieved through soil amendment using charcoal-like soil enhancers 6 , 7 . Charcoal has a porous structure and harbors soil microbes 8 that play roles in soil enrichment. Activated charcoal has been reported to increase nutrients, reduce nutrient leaching, enhance nutrient uptake and increase crop production 9 , 10 . Recently, biochar, which is made from post-harvest biomass residues, has been studied for its use to amend soils in various African countries 11 , 12 . Torrefied biomass, which is a kind of biochar made at low temperature under anaerobic conditions, is made by the torrefaction of plant biomass derived from grasses and/or woods. Torrefied biomass revealed isothermal pyrolyzed biomass at relatively low temperature ranges of 200 °C–300 °C 13 , 14 . The treatment evaporates the internal water from the biomass with an economic use of energy 15 ; therefore, this type of biochar exploits this resource of carbon-rich material. Watanabe et al. characterized torrefied Jatropha biomass components and they suggest that detoxification of phorbol ester by thermal degradation renders it suitable as a soil amendment 16 . The beneficial effects of biochar on plant growth and soil microbiota have also been investigated 12 , 13 , 17 , 18 . For example, Anders et al. 19 reported that biochar enhanced the positive correlation between nutrients and microbiota more in nutrient-poor soils than in nutrient-rich soils. Fox et al. 20 also reported that soil amended with biochar enhanced the microbially mediated nutrient mobilization of S and P resulting in an improvement in plant growth. However, the relationship between the metabolites and microbiota has not been evaluated in soil amended with biochar. A soil study focused on the humic substance or microbial properties in forest soils using nuclear magnetic resonance (NMR) 21 , 22 . However, a comprehensive approach based on physical, chemical and biological viewpoints was greatly anticipated to evaluate the effects of biochar on soil amendment. We had evaluated various soil properties, such as plant degrading abilities, using some analytical strategies and compared NMR and other meta-analytical methods 23 , 24 . In this study, we focused on torrefied biomass and evaluated the soil amendment effects of this biomass in an aridisol from Botswana. We evaluated water retentivity, chemical components, effect on plant growth and metabolic and microbial variations in the soil ( Fig. 1 ). Figure 1 Schematic representation of this study. Effects of soil amendment with torrefied biomass were evaluated using three steps: (1) characterization of Jatropha curcas pyrolysis profiles, (2) evaluation of soil physical and chemical properties and (3) evaluation of plant growth ability using J. curcas seedlings. Full size image Results and Discussion Torrefication profile of J. curcas To prepare the torrefied biomass, the thermal degradation profile of J. curcas was characterized by thermogravimetric (TG)-differential thermal analysis (DTA), attenuated total reflectance (ATR)-Fourier transform infrared (FTIR), grain size distribution and 1 H- 13 C heteronuclear single quantum coherence (HSQC) NMR spectra ( Figs S1–S4 ). Dehydration occurred at approximately 70 °C and degradation of the hemicellulose components at approximately 160 °C–280 °C ( Fig. S1 ). The torrefied biomass bonds, revealed by the vibration of the benzene C–H bond, the syringyl C–O vibration and cellulose and hemicellulose C–H deformations that were known to cleave under a fast pyrolysis treatment 25 , were broken between 240 °C and 250 °C ( Fig. S2; Table S1 ). The grain size of torrefied biomass was over 1,400, 710, 355 and 106 μm or smaller and the ratios were 11.40%, 25.30%, 28.45%, 23.06% and 11.79%, respectively ( Fig. S3 ). The chemical component comparison of raw and 240 °C torrefied biomass showed that some signals such as adipate, d -fructose and l -glutamine disappeared, but many saccharide signals such as maltodextrin remained ( Fig. S4; Table S2 ). Because denaturation of the supramolecular structures with the remaining main components such as cellulose at 240 °C may be able to provide adsorption of water and nutrient elements during incorporation into soil for plant growth, the torrefication temperature in these experiments was set at 240 °C. In addition, major toxic compounds (the profiles were already characterized", "role": "user" }, { "content": "Researchers at the RIKEN Center for Sustainable Resource Science in Japan have shown that torrefied biomass can improve the quality of poor soil found in arid regions. Published in Scientific Reports, the study showed that adding torrefied biomass to poor soil from Botswana increased water retention in the soil as well as —the amount of plant growth. When high temperatures and the absence of oxygen are used to bring about the decomposition of biomass residue from agricultural products such as grains, the result is a charcoal-rich substance called biochar. Torrefied biomass—sometimes called bio-coal—is a type of biochar made at relatively lower temperatures that has recently received attention as a pretreatment method for biomass utilization. In order to characterize the biological properties of soil treated with biochar, the team incorporated torrefied plant residual biomass from the biodiesel crop Jatropha curcas into aridisol, a type of soil found in arid regions such as Botswana, and compared several soil properties with samples that had not been treated. Explained team leader Jun Kikuchi, \"Jatropha is a potential biomass resource for dryland African landscapes, but the poor climate and soil conditions have limited its production. Our study shows that treating the poor soil with torrefied biomass improves a variety of factors that ultimately lead to greater plant growth.\" An important quality of good soil is its ability to retain water. Tests showed that water retention increased with the percentage of torrefied biomass, with 5% biomass yielding a soil that contained about 5% more water than the control soil. A good soil also remains structurally sound deeper in the ground where pressure from above is higher. Soil treated with 5% torrefied biomass showed significantly higher levels of compression stress than the control soil, and significantly shorter relaxation time—the time needed for it to relax back into its normal shape after being compressed. After finding that the torrefied biomass retained more water, the team tested the chemical properties of the soils. They found that levels of potassium, phosphorous, and sulfur were higher in the soil treated with torrefied biomass, as was the availability of potassium, sodium, and phosphorous—three elements regularly take up from the soil by plants. When they tested how well plants grew in the different soils, they found that plants grown in the torrefied biomass had thicker stems, much longer roots, and were heavier that those grown in the untreated soil. The plants grown in torrefied biomass also took up more potassium than controls and less manganese, an element known to inhibit plant growth. Other important features of soil are its metabolic and microbial components. Some compounds produced by the degradation and break down of cellulose are known to promote plant growth. The researchers found that levels of these organic acids, such as lactate and acetate, were higher in the treated soil, again supporting the idea that torrefied biomass can enhance soil fertilization. The treated soil also showed higher levels of Devosia sp. And Opitutus sp., bacteria that use lactate as a carbon source. This indicated that the soil metabolites available in the treated soil allowed for a different microbial environment that presumably acted to enhance plant growth. \"Our next step,\" says Kikuchi, \"is to elucidate the complicated reactions between symbiotic microbiota and plants for effective growth in nutrient-poor environments.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma. Main Controlling the tissue exposure of drugs remains the most persistent challenge of modern cancer therapies and the holy grail of drug delivery 1 , 2 , 3 , 4 . By exploiting features such as size, shape, composition and release kinetics, nanocarriers can enhance the therapeutic indexes of drugs by increasing their exposure in diseased sites and/or avoiding major sites of toxicity 1 , 3 , 4 . The development of nanomedicine combination therapies represents a frontier of modern cancer treatment 5 , 6 , 7 , 8 , 9 , 10 . Although recent pioneering advancements in cancer biology have greatly improved the ability to identify and predict synthetic lethalities of drug combinations, the clinical translation of such combinations suffers from fundamental barriers 5 , 6 , 7 , 8 , 9 . For instance, due to the distinct physical properties of dissimilar drugs, combinations of those drugs that are synergistic in vitro may not accumulate in target tissues/cells in vivo 6 , 7 , 8 , 9 , 10 . Due to this disconnect, many clinical combination therapies are empirically derived based on the maximum tolerated dose (MTD) of each component drug rather than rational synergies 6 , 7 , 8 . Combination therapies present an exciting nanomedicine opportunity wherein multiple drugs that are pharmacologically different may be delivered to the same tissue/cell in precise ratios to empower their synergistic mechanisms. For example, Vyxeos (CPX-351), a clinically successful liposomal formulation of 5:1 cytarabine:daunorubicin, maintained a synergistic drug ratio (from 5:1 to 9:1) in the blood compartment over 24 h post-injection, whereas the free drugs exhibited a 1,923:1 ratio 15 min post-injection 11 , 12 . Although strategies for incorporating mixtures of structurally dissimilar drugs through encapsulation, chemical conjugation and/or self-assembly have been extensively studied, nanocarriers that simultaneously achieve controlled drug ratios, multidrug release kinetics and/or sequential release for two or more drugs remain rare 5 , 6 , 7 , 8 , 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 . Moreover, due to differences in cell uptake pathways, rates of cellular internalization and/or drug release kinetics, multidrug nanocarriers could exhibit synergistic ratios that are distinct from their free-drug counterparts, necessitating the identification of optimal ratios in the nanocarrier context. Given that most nanocarriers rely on supramolecular interactions between the drugs, vehicle and/or surfactant(s), which depend on the physical properties of the drugs, exchanging one drug for another may result in changes to the physical properties of the final nanocarrier. It is, thus, difficult to make multiple single-drug nanocarriers and multidrug nanocarriers with varying drug ratios but otherwise identical properties. Hence, in combination nanocarriers employed to date, the synergistic drug ratios exemplified for the free drugs are typically translated directly to the nanocarriers, without considering the possibility that these ratios may no longer be optimal 11 , 12 . Moreover, it remains unknown whether multidrug nanocarriers have fundamental advantages over mixtures of single-drug nanocarriers. Here we introduce a nanocarrier design that allows us to address these questions in the context of the second-most common haematologic malignancy in the United States—multiple myeloma (MM)—which remains incurable in most patients 21 . Our approach leverages ‘bottlebrush prodrugs’ (BPDs) comprising the clinically relevant three-drug combination of a proteasome inhibitor (PI) bortezomib (Btz), an immunomodulatory drug pomalidomide (Pom) and a corticosteroid dexamethasone (Dex). This drug combination is able to overcome resistance to the front line and standard-of-care regimen of lenalidomide (Len)/Btz/Dex as Pom allows for higher target-binding affinity compared to Len (refs. 22 , 23 , 24 , 25 ). In spite of the empirical derivation of this combination in the clinic, it offers prolonged progression-free survival in Len-refractory patients (17.8 versus 9.5 months) as well as in non-Len-refractory patients (22.0 versus 12.0 months); moreover, it improves the overall survival rates in both settings (85.90% versus 50.80% and 95.37% versus 60.00%, respectively) 26 . Nevertheless, the combination suffers from substantial drawbacks that primarily arise from off-tissue toxicities, poor stability and the development of Btz resistance. Although several examples of nanoparticle-based Btz formulations have been reported as monotherapies 27 , 28 , 29 , 30 , 31 , so far they have shown only minor improvements over free Btz in terms of efficacy 32 , 33 . By contrast, combination nanomedicines for MM are exceptionally rare, and nanocarriers incorporating the clinical combination of Btz, Pom and Dex have not been reported 32 , 33 , 34 , 35 , 36 , 37 , 38 . Moreover, no examples of more than two drug combination therapies with systematically optimized synergistic ratios have been demonstrated in any disease context. Here we show that (1) synergies between free drugs identified in vitro do not necessarily translate to BPDs and (2) BPDs bearing a statistical mixture of drugs in a synergistic ratio are more effective than a mixture of three different physically equivalent single-drug BPDs administered at the same ratio. The latter finding", "role": "user" }, { "content": "Treating cancer with combinations of drugs can be more effective than using a single drug. However, figuring out the optimal combination of drugs, and making sure that all of the drugs reach the right place, can be challenging. To help address those challenges, MIT chemists have designed a bottlebrush-shaped nanoparticle that can be loaded with multiple drugs, in ratios that can be easily controlled. Using these particles, the researchers were able to calculate and then deliver the optimal ratio of three cancer drugs used to treat multiple myeloma. \"There's a lot of interest in finding synergistic combination therapies for cancer, meaning that they leverage some underlying mechanism of the cancer cell that allows them to kill more effectively, but oftentimes we don't know what that right ratio will be,\" says Jeremiah Johnson, an MIT professor of chemistry and one of the senior authors of the study. In a study of mice, the researchers showed that nanoparticles carrying three drugs in the synergistic ratio they identified shrank tumors much more than when the three drugs were given at the same ratio but untethered to a particle. This nanoparticle platform could potentially be deployed to deliver drug combinations against a variety of cancers, the researchers say. Irene Ghobrial, a professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, and P. Peter Ghoroghchian, president of Ceptur Therapeutics and a former MIT Koch Institute Clinical Investigator, are also senior authors of the paper, which appears today in Nature Nanotechnology. Alexandre Detappe, an assistant professor at the Strasbourg Europe Cancer Institute, and Hung Nguyen Ph.D. '19 are the paper's lead authors. Controlled ratio Using nanoparticles to deliver cancer drugs allows the drugs to accumulate at the tumor site and reduces toxic side effects because the particles protect the drugs from being released prematurely. However, only a handful of nanoparticle drug formulations have received FDA approval to treat cancer, and only one of these particles carries more than one drug. For several years, Johnson's lab has been working on polymer nanoparticles designed to carry multiple drugs. In the new study, the research team focused on a bottlebrush-shaped particle. To make the particles, drug molecules are inactivated by binding to polymer building blocks and then mixed together in a specific ratio for polymerization. This forms chains that extend from a central backbone, giving the molecule a bottlebrush-like structure with inactivated drugs—prodrugs—along the bottlebrush backbone. Cleavage of the linker that holds the drug to the backbone release the active agent. \"If we want to make a bottlebrush that has two drugs or three drugs or any number of drugs in it, we simply need to synthesize those different drug conjugated monomers, mix them together, and polymerize them. The resulting bottlebrushes have exactly the same size and shape as the bottlebrush that only has one drug, but now they have a distribution of two, three, or however many drugs you want within them,\" Johnson says. In this study, the researchers first tested particles carrying just one drug: bortezomib, which is used to treat multiple myeloma, a cancer that affects a type of B cells known as plasma cells. Bortezomib is a proteasome inhibitor, a type of drug that prevents cancer cells from breaking down the excess proteins they produce. Accumulation of these proteins eventually causes the tumor cells to die. When bortezomib is given on its own, the drug tends accumulate in red blood cells, which have high proteasome concentrations. However, when the researchers gave their bottlebrush prodrug version of the drug to mice, they found that the particles accumulated primarily in plasma cells because the bottlebrush structure protects the drug from being released right away, allowing it to circulate long enough to reach its target. Synergistic combinations Using the bottlebrush particles, the researchers were also able to analyze many different drug combinations to evaluate which were the most effective. Currently, researchers test potential drug combinations by exposing cancer cells in a lab dish to different concentrations of multiple drugs, but those results often don't translate to patients because each drug is distributed and absorbed differently inside the human body. \"If you inject three drugs into the body, the likelihood that the correct ratio of those drugs will arrive at the cancer cell at the same time can be very low. The drugs have different properties that cause them to go to different places, and that hinders the translation of these identified synergistic drug ratios quite immensely,\" Johnson says. However, delivering all three drugs together in one particle could potentially overcome that obstacle and make it easier to deliver synergistic ratios. Because of the ease of creating bottlebrush particles with varying concentrations of drugs, the researchers were able to compare particles carrying different ratios of bortezomib and two other drugs used to treat multiple myeloma: an immunostimulatory drug called pomalidomide, and dexamethasone, an anti-inflammatory drug. Exposing these particles to cancer cells in a lab dish revealed combinations that were synergistic, but these combinations were different from the synergistic ratios that had been identified using drugs not bound to the bottlebrush. \"What that tells us is that whenever you are trying to develop a synergistic drug combination that you ultimately plan to administer in a nanoparticle, you should measure synergy in the context of the nanoparticle,\" Johnson says. \"If you measure it for the drugs alone, and then try to make a nanoparticle with that ratio, you can't guarantee it will be as effective.\" New combinations In tests in two mouse models of multiple myeloma, the researchers found that three-drug bottlebrushes with a synergistic ratio significantly inhibited tumor growth compared to the free drugs given at the same ratio and to mixtures of three different single-drug bottlebrushes. They also discovered that their bortezomib-only bottlebrushes were very effective at slowing tumor growth when given in higher doses. Although it is approved for blood cancers such as multiple myeloma, bortezomib has never been approved for solid tumors due to its limited therapeutic window and bioavailability. \"We were happy to see that the bortezomib bottlebrush prodrug on its own was an excellent drug, displaying improved efficacy and safety compared to bortezomib, and that has led us to pursue trying to bring this molecule to the clinic as a next-generation proteasome inhibitor,\" Johnson says. \"It has completely different properties than bortezomib and gives you the ability to have a wider therapeutic index to treat cancers that bortezomib has not been used in before.\" Johnson, Nguyen, and Yivan Jiang Ph.D. '19 have founded a company called Window Therapeutics, which is working on further developing these particles for testing in clinical trials. The company also hopes to explore other drug combinations that could be used against other types of cancer. Johnson's lab is also working on using these particles to deliver therapeutic antibodies along with drugs, as well as combining them with larger particles that could deliver messenger RNA along with drug molecules. \"The versatility of this platform gives us endless opportunities to create new combinations,\" he says. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Crustose coralline red algae (CCA) play a key role in the consolidation of many modern tropical coral reefs. It is unclear, however, if their function as reef consolidators was equally pronounced in the geological past. Using a comprehensive database on ancient reefs, we show a strong correlation between the presence of CCA and the formation of true coral reefs throughout the last 150 Ma. We investigated if repeated breakdowns in the potential capacity of CCA to spur reef development were associated with sea level, ocean temperature, CO 2 concentration, CCA species diversity, and/or the evolution of major herbivore groups. Model results show that the correlation between the occurrence of CCA and the development of true coral reefs increased with CCA diversity and cooler ocean temperatures while the diversification of herbivores had a transient negative effect. The evolution of novel herbivore groups compromised the interaction between CCA and true reef growth at least three times in the investigated time interval. These crises have been overcome by morphological adaptations of CCA. Introduction Coral reefs support the biologically most diverse marine ecosystems and have done so over substantial parts of earth history, starting in the Late Triassic, when scleractinian corals became prolific reef builders 1 . Mitigating the threats to modern coral reef ecosystems will thus benefit from a better understanding of the underlying causes in the rise and fall of ancient coral reefs 2 . Reefs, broadly defined as laterally confined limestone “structures built by the growth or metabolic activity of sessile benthic aquatic organisms” 3 comprise a large array of constructional styles and biota, and grew in a variety of environments. The concept of ‘true reefs’ in ancient reefs derives from the constructional style and environment of recent tropical, shallow-water coral reefs. True reefs with a syndepositional relief and a rigid framework constructed by skeletal organisms are known since Cambrian times 4 but occur alongside other reef types such as reef mounds, mud mounds and biostromes. There is a significant increase of both the relative and absolute abundance of true reefs over the Phanerozoic 5 . This trend may be caused by intrinsic (biological) factors as there are few significant correlations with earth system parameters such as temperature, sea level, or oceans chemistry 5 . Although hypothesized to play a major role 6 , the relative importance of biotic interactions in reef evolution is still poorly known. The evolution of crustose coralline red algae (Subclass Corallinophycidae Le Gall and Saunders 7 , hereafter referred to as ‘CCA’) may underline such interactions in an exemplary fashion. CCA play a key role in the construction of many modern coral reefs 8 , 9 , 10 in several regards: CCA are not only primary producers and contributors of calcareous sediment but also often act as consolidators and binders of coral reefs. The algae can form a distinct ridge providing a surf-resistant reef crest and bind loose sediment 11 . Even though there are examples of true reefs that grow successful without this CCA ridge under wave-exposure 12 , 13 , CCA are still considered as ‘the glue that holds coral reefs together’ 9 in many cases. Another key factor for the success of modern coral reefs are grazing organisms such as echinoids and parrot fish, because they remove fleshy algae from the reef surface 14 , 15 . The evolution of grazers also led to an increased feeding pressure on CCA, followed by adaptive strategies of the CCA 16 . It seems plausible that this development also impacted a potential capacity of CCA to facilitate coral reef formation in the geological past. However, this hypothesis has not been assessed quantitatively until now. There are hints for a long-term positive interaction between corals and CCA over geological timescales 17 . However, a finer temporal and taxonomic resolution and the inclusion of environmental parameters may explain if and why a potential importance of CCA for reef development varies over time. Using data from the PaleoReefsDatabase (PARED), a comprehensive compendium of geological and paleontological data of Phanerozoic reef sites as described previously 18 , 19 , 20 , we evaluate the role of CCA in coral reef development at the level of geological stages from the Early Cretaceous to the Pleistocene while considering additional factors such as ocean temperature and chemistry as well as interactions with relevant groups of grazing organisms. We test three hypotheses: (1) The probability of true reef formation is correlated with the presence of CCA reef cementers; (2) the capacity of CCA to reinforce coral reefs is linked to various oceanographic and ecological parameters; (3) the diversification of grazing organisms led to transient crises in the capacity of CCA to support true reef formation. Additionally, we highlight alternative explanations for the correlation between CCA occurrences and the formation of true reefs. This includes the impact of herbivore radiation on corals rather than on CCA directly and ecological niches for CCA provided by increased reef growth. Results The general hypothesis that the occurrence of true reefs is strongly correlated with CCA as secondary reef builders is supported by the linear regression model (Fig. 1 ). Regression residuals are not auto-correlated suggesting that no further data treatment is required. (Supporting Information Fig. S1 ). Figure 1 Role of CCA as secondary reef builders. Linear regression model between proportions of true reefs and proportions of coral reefs with CCA as secondary reef builders indicating a significant correlation between CCA cementation and true reef development. Full size image The temporal patterns of the investigated variables, proportions of true CCA-reefs, sea level, ocean temperature, CO 2 concentration, species diversity of CCA, and the origin and diversification patterns of the grazer clades echinoids and parrot fish are visualized in Fig. 2 . Four transient crises are evident, one between the Turonian and the Campanian, one in the Paleocene (Selandian–Thanetian), one in the Miocene (Serravallian), and the youngest one in the Pliocene (Zanclean–Piacenzian). Figure 2 Temporal patterns of true CCA-reef formation and potentially influencing parameters. Patterns of investigated variables,", "role": "user" }, { "content": "Coral reefs are hotspots of biodiversity. As they can withstand heavy storms, they offer many species a safe home, and at the same time, they protect densely populated coastal regions as they level out storm-driven waves. However, how can these reefs that are made up of often very fragile coral be so stable? A team of researchers from Friedrich-Alexander Universität Erlangen-Nürnberg (FAU) and the University of Bayreuth have now discovered that a very specific type of 'cement' is responsible for this—by forming a hard calcareous skeleton, coralline red algae stabilize the reefs, and have been doing so for at least 150 million years. The wide variety of life they support is immediately apparent on images of tropical coral reefs. Their three-dimensional scaffolding provides a habitat for a large number of species. However, the skeletons of the coral are often so fragile that they would not be able to withstand heavy storms by themselves. Even if scientists have long suspected that coralline red algae provide support to reefs with their calcareous skeletons, this is the first time that this link has been proven. Coralline red algae have been supporting coral reefs for at least 150 million years The researchers from FAU and the University of Bayreuth were able to prove this supporting function by analyzing more than 700 fossilized reefs from 150 million years of the Earth's history. \"The coralline red algae form a calcareous skeleton and cement the coral reefs together,\" explains Dr. Sebastian Teichert from the Chair of Palaeoenvironmental Research at FAU. \"However, several crises over the course of millions of years have limited their capacity to do so.\" Successful adaptive strategies against plant grazers These crises include the evolution of plant grazing marine animals such as sea urchins and parrot fishes who have repeatedly decimated populations of coralline red algae over the course of time. The algae, however, developed defense mechanisms such as special growth forms in order to defend themselves against their attackers. \"The algae have adapted so well that they now even benefit from these plant grazers,\" says Teichert. \"They rid the coralline red algae of damaging growth such as green algae, allowing it to grow unhindered.\" This means coralline red algae are more successful at supporting coral reefs today than ever before in the Earth's history. The extent to which climate change affects the supporting role of coralline red algae is not yet known. Any deterioration to their living conditions would not only affect the coral and other inhabitants of reefs, but also humans, as coral reefs level out storm-driven waves and make an important contribution to coastal protection. They also provide a nursery habitat for several fish and shellfish which are an important source of food. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the past century, many of the world’s major rivers have been modified for the purposes of flood mitigation, power generation and commercial navigation 1 . Engineering modifications to the Mississippi River system have altered the river’s sediment levels and channel morphology 2 , but the influence of these modifications on flood hazard is debated 3 , 4 , 5 . Detecting and attributing changes in river discharge is challenging because instrumental streamflow records are often too short to evaluate the range of natural hydrological variability before the establishment of flood mitigation infrastructure. Here we show that multi-decadal trends of flood hazard on the lower Mississippi River are strongly modulated by dynamical modes of climate variability, particularly the El Niño–Southern Oscillation and the Atlantic Multidecadal Oscillation, but that the artificial channelization (confinement to a straightened channel) has greatly amplified flood magnitudes over the past century. Our results, based on a multi-proxy reconstruction of flood frequency and magnitude spanning the past 500 years, reveal that the magnitude of the 100-year flood (a flood with a 1 per cent chance of being exceeded in any year) has increased by 20 per cent over those five centuries, with about 75 per cent of this increase attributed to river engineering. We conclude that the interaction of human alterations to the Mississippi River system with dynamical modes of climate variability has elevated the current flood hazard to levels that are unprecedented within the past five centuries. Main Flooding of the lower Mississippi River in the spring of 2011 was among the largest discharge events since systematic measurements began in the late nineteenth century, and it caused US$3.2 billion in agricultural losses and damages to infrastructure 6 . This and other recent flood events on the Mississippi River—including those in 2016 and 2017—have repeatedly, although controversially, been attributed to an aggressive campaign of river engineering designed and implemented over the past 150 years 3 , 4 , 5 . Federally mandated efforts to reduce the impacts of flooding began in the late nineteenth century and initially relied almost exclusively on the use of artificial levees, but this strategy was revised in the wake of a particularly devastating flood in the spring of 1927 that overwhelmed the levee system 7 . The current flood management system—the Mississippi River & Tributaries Project (MR&T)—includes a series of spillways that can be opened to relieve pressure on an enlarged levee system, as well as an artificially shortened and straightened main channel that is held in place by concrete retaining walls (revetments) and isolated from most of its natural floodplain 2 , 6 , 7 . Although these modifications are credited with protecting communities and croplands within the floodplain from inundation, artificial channelization has altered the relationship between discharge and river stage 3 , 4 and accelerated the rate of land loss in the Mississippi River delta 8 , necessitating additional investments in flood mitigation infrastructure and coastal restoration 9 . Although fluvial processes are sensitive to flood mitigation infrastructure, climate variability can also shape the dynamics of continental drainage networks, particularly over decadal to centennial timescales that are difficult to detect using short observational records 10 , 11 . Precipitation and soil water storage over the Mississippi River basin are influenced by climate variability driven by sea-surface-temperature anomalies in both the Pacific and Atlantic Oceans 12 , 13 . Yet establishing the natural controls on discharge extremes of the lower Mississippi has proved challenging because gauging-station measurements record a limited range of variability, particularly before major investments were made in river engineering. As a result, analyses of historical streamflow records disagree over the role that dynamical modes of climate variability play in modulating the discharge 12 , 14 , 15 . To plan flood mitigation and other infrastructure projects, it is critical to understand the climate controls on the discharge of the lower Mississippi River, but the short length of the instrumental record limits our ability to evaluate the range of natural hydrological variability from observational data alone. Recent advances in palaeoflood hydrology could extend the instrumental record back in time to diagnose the controls on the discharge of large alluvial rivers such as the lower Mississippi. Traditional approaches in palaeoflood hydrology, which include the use of slackwater deposits as flood event indices 16 , are of limited use on the low-relief landscapes that characterize the Mississippi River alluvial plain. One new approach uses the sedimentary archives held in floodplain lakes, which act as sediment traps during overbank floods, to develop continuous, quantitative and event-scale records of past flood frequency and magnitude 17 , 18 . Parallel work in dendrochronology demonstrates that when trees are inundated by floodwaters they exhibit anatomical anomalies in that year’s growth ring such that they provide a precise chronology of flood events that occurred during the growing season 19 . Together, these methodological advances provide an opportunity to evaluate interannual to multi-decadal scale trends in flood frequency and magnitude on a large alluvial river such as the lower Mississippi, before and during the era of river engineering. Here we analyse records of individual overbank flood events derived from sedimentary and tree-ring archives from the lower Mississippi River’s floodplain ( Fig. 1 ). We collected sediment cores from the in-filling thalwegs of three oxbow lakes, Lake Mary (MRY), False River Lake (FLR) and Lake Saint John (STJ), that formed by neck cut-offs of the lower Mississippi River in ad 1776, ad 1722 and roughly ad 1500, respectively 20 ( Extended Data Figs 1 , 2 , 3 ). In these sedimentary archives, we identified individual flood events by using grain-size analysis, bulk geochemistry (from X-ray fluorescence scanning, XRF) and radiography; developed age–depth models constrained by multiple independent chronological controls ( Extended Data Figs 4 , 5 , 6 ); and estimated flood magnitudes from a linear model that relates the coarse grain-size component to the discharge of historical flood events 18 ( Extended Data Fig. 7 ; see Methods for details). We also include tree-ring", "role": "user" }, { "content": "A new study has revealed for the first time the last 500-year flood history of the Mississippi River. It shows a dramatic rise in the size and frequency of extreme floods in the past century—mostly due to projects to straighten, channelize, and bound the river with artificial levees. The new research, led by scientists at Woods Hole Oceanographic Institution (WHOI), also uncovered a clear pattern over the centuries linking flooding on the Mississippi with natural fluctuations of Pacific and Atlantic Ocean water temperatures. This newly recovered long-term record provides a historical context that spotlights how more recent river engineering has intensified flooding to unprecedented levels. \"The floods that we've had over the last century are bigger than anything we've seen in the last 500 years,\" said Sam Muñoz, a former postdoctoral scholar at WHOI and the lead author of the study, published April 5, 2018, in the journal Nature. The research shows that in the past 150 years, the magnitude of the 100-year flood—a flood that has a 1 percent chance of occurring in any given year—has increased by about 20 percent. The research team found that about three-quarters of that elevated flood hazard can be attributed to human modifications of the river and its basin. \"There's been a longstanding question about the extent to which all the changes we have made to the Mississippi River—one of the most engineered rivers in the world—have altered the probability of really large floods,\" said Muñoz, now an assistant professor at Northeastern University. To answer that question, the scientists used a technique that WHOI paleoclimatologist Jeff Donnelly pioneered in the coastal ocean to track the history of hurricanes: extracting long cores of bottom sediment from lakes and marshes. \"It's sort of the equivalent of sticking a straw in a milkshake, putting your thumb over the top, and pulling it out,\" said Donnelly, a co-lead on the study. In this case, the \"straw\" was a 30-foot-long aluminum tube deployed from a small pontoon boat, and the \"milkshake\" was the mud, sand, and silt at the bottom of three oxbow lakes adjacent to the Mississippi River. During large floods, faster moving water from the river channel stirs up larger-grained sediments and flows into the usually disconnected lakes, carrying sediments and debris along with it. The material from the river is caught in the lakes and eventually sinks. It forms a layer on the bottom that is subsequently buried over time. The layers are telltale clues of past floods. The deeper the cores, the further back in time the scientists can reach. The grain size in the layers provides clues to the size of the floods. The larger the flood, the more energy is generated by the river water, and the larger the grains that get deposited in the lakes, said WHOI geoscientist Liviu Giosan, another lead member of the research team. By analyzing grain size and flood size for known flood events—for example, the Great Mississippi River flood of 1927—Muñoz could estimate the sizes of previously unknown floods represented in the sediment cores. To find out when those floods had occurred, the team used isotopes of lead, cesium, and carbon to date the coarse sediment layers. Zhixiong Shen of Coastal Carolina University used a technique called optically-stimulated luminescence—which determines a material's age by analyzing when it was last exposed to sunlight. Matthew Therrell of the University of Alabama used annual tree rings to reconstruct a detailed record of more recent regional flooding. Combining these methods, the team traced the history of floods back over 500 years—about 350 years further back in time than the oldest written flood records. Next, they compared what they found to records of naturally oscillating climate cycles that affect sea surface temperatures in the Atlantic and Pacific, such as the El Niño-Southern Oscillation (ENSO). They found that the Mississippi's flood cycles corresponded with ocean and climate cycles. In particular, El Niño events bring more storms and rainfall to central North America, which saturates the ground around the Mississippi. One phase of the Atlantic Ocean oscillation brings extreme rainfall over the Mississippi basin. When the two coincide, flooding is more likely. \"We're able for the first time to really parse out how the natural variability of the climate system influences flooding, and then how people have modified that,\" Muñoz said. The sediment data also showed that the natural rhythm of flooding caused by ocean changes was greatly amplified by major federally-funded river engineering projects that began after 1928 to facilitate commercial navigation on the river and to protect communities and cropland from floods. The societal benefits of river engineering should be weighed against the risks that more large floods pose to agriculture, infrastructure, and communities, the scientists said. In addition, big floods sweep more pollutants and fertilizers into the Gulf of Mexico, causing oxygen-depleted \"dead zones.\" Giosan says restoring more natural flood patterns to the river and allowing sediments to flow onto the floodplain during floods would help rebuild the drowning Mississippi delta, whose planned restoration is projected to cost tens of billions of dollars. According to the team, the next steps will be to dig deeper into the river sediments to extend the flood record even further back in time and to apply this new method to understand what drives flooding on other major rivers systems around the world. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Analysis of molecular aberrations across multiple cancer types, known as pan-cancer analysis, identifies commonalities and differences in key biological processes that are dysregulated in cancer cells from diverse lineages. Pan-cancer analyses have been performed for adult 1 , 2 , 3 , 4 but not paediatric cancers, which commonly occur in developing mesodermic rather than adult epithelial tissues 5 . Here we present a pan-cancer study of somatic alterations, including single nucleotide variants, small insertions or deletions, structural variations, copy number alterations, gene fusions and internal tandem duplications in 1,699 paediatric leukaemias and solid tumours across six histotypes, with whole-genome, whole-exome and transcriptome sequencing data processed under a uniform analytical framework. We report 142 driver genes in paediatric cancers, of which only 45% match those found in adult pan-cancer studies; copy number alterations and structural variants constituted the majority (62%) of events. Eleven genome-wide mutational signatures were identified, including one attributed to ultraviolet-light exposure in eight aneuploid leukaemias. Transcription of the mutant allele was detectable for 34% of protein-coding mutations, and 20% exhibited allele-specific expression. These data provide a comprehensive genomic architecture for paediatric cancers and emphasize the need for paediatric cancer-specific development of precision therapies. Main Paired tumour and normal samples from 1,699 patients with paediatric cancers enrolled in Children’s Oncology Group clinical trials were analysed, including 689 B-lineage acute lymphoblastic leukaemias (B-ALL), 267 T-lineage ALLs (T-ALL), 210 acute myeloid leukaemias (AML), 316 neuroblastomas (NBL), 128 Wilms tumours and 89 osteosarcomas ( Extended Data Fig. 1a–c ). All tumour specimens were obtained at initial diagnosis, and 98.5% of patients were 20 years of age or younger (see Methods, Extended Data Fig. 1d ). The median somatic mutation rate ranged from 0.17 per million bases (Mb) in AML and Wilms tumours to 0.79 in osteosarcomas ( Fig. 1a, b ), lower than the 1–10 per Mb found in common adult cancers 6 . Genome-wide analysis (see Methods) identified 11 mutational signatures (T-1 through T-11; Fig. 1c–e and Supplementary Table 1a–c ). Signatures T-1 through T-9 corresponded to known COSMIC signatures 7 , whereas T-10 and T-11 were novel but enriched in mutations with a low (<0.3) mutant allele fraction (MAF). Figure 1: Somatic mutation rate and signature. Sample size of each histotype is shown in parentheses. Mutation rate using non-coding SNVs from WGS ( a ) and coding SNVs from WGS and WES ( b ). Red line, median. a and b are scaled to the total number of samples with WGS ( n = 651), WGS or WES ( n = 1,639), respectively. c , Mutational signatures identified from WGS and T-ALL WES data and their contribution in each histotype. d , Mutation spectrum of representative samples in each histotype. Hypermutators (three s.d. above mean rate of corresponding histotype) are labelled with an asterisk. e , Mean and s.d. of MAF of each signature in each histotype. PowerPoint slide Full size image Signatures T-1 and T-4 (clock-like endogenous mutational processes) were present in all samples and contributed to large proportions of all mutations in T-ALL (97%), AML (63%), B-ALL (36%), and Wilms tumours (28%). T-2 and T-7 (APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like)) were highly enriched in B-ALLs with ETV6-RUNX1 fusions (15-fold and 9-fold enrichment for T-2 and T-7, respectively; Supplementary Table 1e ). T-3 (homologous recombination deficiency) was present in many childhood cancers, including osteosarcomas (18 of 19), NBLs (59 of 137), Wilms tumours (28 of 81), and B-ALL (47 of 218). T-8 (8-oxoguanine DNA damage) was present in a small proportion (4.5–12%) of AML, B-ALL, osteosarcoma, and Wilms tumour samples. T-8 was also present in many (36%) NBL samples and was associated with age at diagnosis ( Supplementary Table 1d ). T-9 (DNA repair deficiency) was present in two B-ALLs, including one (sample PARJSR) with a somatic MSH6 frameshift mutation. T-2, T-3, T-5, T-7, T-8, and T-9 were enriched among the 39 samples with elevated mutation rates in each histotype ( Fig. 1d ). The T-5 ultraviolet-light (UV)-exposure signature was unexpectedly present in eight B-ALL samples ( Extended Data Fig. 2a–c ). Although its mutation rate in B-ALL, ranging from 0.06 to 0.72 per Mb, was 100-fold lower than the average rate in adult (15.8 per Mb) 8 and paediatric (14.4 per Mb) 9 skin cancer, T-5 exhibited other features associated with UV-related DNA damage. Specifically, CC>TT dinucleotide mutations were enriched 110-fold in these eight B-ALL samples when compared with other samples ( P = 1.07 × 10 −7 ), which is consistent with pyrimidine dimer formation. Moreover, transcriptional strand bias in T-5 indicated that photodimer formation contributed to cytosine damage. The validity of T-5 was further confirmed by analysis of the mutation clonality, cross-platform concordance, genomic distribution and mutation spectrum of each sample (see Methods, Extended Data Fig. 2d–i ), indicating that UV exposure or other mutational processes 10 , 11 may contribute to paediatric leukemogenesis. Notably, all T-5 B-ALLs had aneuploid genomes ( P = 3 × 10 −5 ; two-sided binomial test; cohort frequency 24%) without any oncogenic fusions. By analysing the enrichment 12 , 13 of somatic alterations within each histotype or the pan-cancer cohort (see Methods), we identified 142 significantly mutated driver genes ( Fig. 2a , Supplementary Table 2 , Extended Data Fig. 3a ). Somatic alterations in CDKN2A , which were predominantly deletions, occurred at the highest frequency, affecting 207 of 267 (78%) T-ALLs, 91 of 218 (42%) B-ALLs and 2 of 19 (11%) osteosarcomas ( Extended Data Fig. 3b ). More than half (73) of the driver genes were specific to a single histotype, such as TAL1 for T-ALL and ALK for NBL ( Extended Data Fig. 3c ). Genes that were mutated in both leukaemias and the three solid tumour histotypes accounted for only 17% of driver genes ( Extended Data Fig. 3e ), of which some genes had various types of somatic alteration. For example, STAG2 , a known driver gene for Ewing’s sarcoma 14 and adult AML 15 , exhibited five different types", "role": "user" }, { "content": "Researchers have determined that children and adults with cancer usually have different mutated genes driving their disease, which suggests they would likely benefit from different therapies. The finding, from a collaborative study led by St. Jude Children's Research Hospital, underscores the need to develop precision medicines for pediatric cancer. The research, along with a companion study led by scientists at the Hopp Children's Cancer Center at NCT Heidelberg (KiTZ) and the German Cancer Research Center, Heidelberg, appears as an advance online publication today in the scientific journal Nature. The findings from the back-to-back papers provide the most comprehensive analysis yet of the genomic landscape of childhood cancer across multiple subtypes. The results will help guide clinical and laboratory research to improve understanding, diagnosis and treatment of pediatric cancer patients worldwide, including the estimated 15,780 children and adolescents diagnosed annually in the U.S. Rather than focusing on a single tumor type, the St. Jude—led study evaluated data generated by members of the Therapeutic Applicable Research to Generate Effective Treatments (TARGET) program. The study was funded in part by the National Cancer Institute of the National Institutes of Health. The scientists evaluated six cancer subtypes using three different, next-generation sequencing approaches. The researchers compared somatic genetic mutations—genomic changes found in cancer cells but not in normal cells—and their impact on key biological processes in tumor and normal tissues of 1,699 pediatric cancer patients. The approach, called pan-cancer analysis, revealed that only 45 percent of the mutated genes \"driving\" cancer in children are the same as the genes \"driving\" cancer in adults. \"This shows for the first time that pediatric and adult cancers frequently arise from different genes with different mutations,\" said corresponding author Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology. The first authors are Xiaotu Ma, Ph.D., and Yu Liu, Ph.D., both members of her laboratory. \"The results really bring home the message that pediatric cancer patients are not small adults and their disease should not be treated as if that were the case,\" Zhang said. \"Better treatments and more sensitive diagnostic tests require understanding the biology driving pediatric cancer. These results provide a better roadmap for researchers working in the laboratory and the clinic.\" Treatment advances have pushed cure rates for pediatric cancer to better than 80 percent, but cancer remains the leading cause of death by disease in U.S. children ages 1 to 19. Treatments often involve major life-long side effects, including the risk of second cancers. The Genomic Architecture of Pediatric Cancers The analysis included patients enrolled in the clinical trials of the Children's Oncology Group, a clinical research cooperative. The patients had acute lymphoblastic leukemia, both B and T-cell ALL; acute myeloid leukemia; the bone cancer osteosarcoma; the kidney cancer called Wilms tumor; and neuroblastoma, a tumor of the sympathetic nervous system. Unlike a previously published adult pan-cancer analysis, which focused primarily on coding sequence mutations, the St. Jude team analyzed variations in DNA copies and chromosomal rearrangements. The data were from whole genome sequencing of the complete DNA of patients' tumor and normal tissue. Transcriptome sequencing was also performed. That provided a snapshot of gene expression in cells. The analysis also included the first comprehensive evaluation of quantitative and qualitative expression of mutant versus wild-type alleles in multiple cancer subtypes. The sequencing data was provided by the National Cancer Institute's TARGET initiative. TARGET was launched to understand the genetic changes that underlie pediatric cancer. The intention of the program was to use the data by the research community to improve the precision oncology treatment of pediatric cancers. For this study, Zhang and her colleagues processed the sequencing data using a uniform analytic framework. \"Looking across tumor types helps to identify really important mutations in pediatric cancer and understand the pathways involved,\" she said. Genomic Alterations Revealed For example, the analysis identified unexpected patterns of mutations, or mutational signatures, in eight of the 689 patients with B-ALL. The patients' DNA had a mutational signature consistent with exposure to ultraviolet light, which was previously observed exclusively in skin cancers. The patients also shared another genomic abnormality—too many or too few chromosomes. \"This finding suggests that exposure to ultraviolet light may be a previously unrecognized environmental factor that increases the risk for developing leukemia in some children,\" said co-author Ludmil Alexandrov, Ph.D., of the University of California, San Diego. In addition, the analysis revealed that rather than point mutations in DNA, a majority (62 percent) of the mutations driving pediatric cancer were copy-number alterations and structural variations. Copy-number alterations leave patients with too many or too few copies of particular genes. Structural variations involve gene rearrangements. \"This shows that as genomics moves into the clinic, diagnostic testing for pediatric patients must include copy-number changes and structural variations,\" Zhang said. Data Being Shared Zhang and several other St. Jude scientists are also co-authors of a study led by investigators at the German Cancer Research Center. That study included whole genome and whole exome data from 914 pediatric cancer patients with blood, central nervous system and solid tumors. The sequencing data came from the St. Jude Children's Research Hospital—Washington University Pediatric Cancer Genome Project and other sources. The Pediatric Cancer Genome Project, which began in 2010, sequenced the genomes of more than 800 children and adolescents with some of the least-understood and most difficult-to-treat cancers. Researchers worldwide can explore somatic mutation data used for both pediatric pan-cancer studies through the St. Jude interactive ProteinPaint portal. The information, including the genes, mutations and cellular pathways underlying a variety of pediatric cancers, is an unmatched resource for pediatric cancer research going forward. The TARGET initiative somatic variants used in the analysis are available at the NCI TARTGET Data Matrix, and the sequencing data will be available at the NCI's Genomic Data Commons. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1 /2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL. Introduction Recent evidence implicates DNA repair and the genome integrity checkpoints as major barriers whose deregulation is largely responsible for the enhanced genetic instability of cancer cells 1 . The CHK2 kinase is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks (DSBs). DNA DSBs induce the activation of ATM (ataxia telangiectasia mutated), which subsequently phosphorylates CHK2 on threonine 68 (ref. 2 ). Phosphorylation of CHK2 induces CHK2 dimerization, which is required for CHK2 activity. Once dimerized, CHK2 is further activated by autophosphorylation in trans at residues 383, 387, 546 and 516 (ref. 2 ). CHK2 phosphorylates a range of proteins involved in cell cycle control and apoptosis including cdc25A, cdc25C, Mdmx, p53, BRCA1, PML, E2F1, and phosphatase 2A (ref. 2 ). CHK2 also mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes 3 . Cells derived from CHK2-deficient mice exhibit defects in their ability to delay entry into S phase, sustain a G2 cell cycle arrest, and undergo apoptosis in response to DNA damage 4 . It is newly reported that CHK2, independent of p53 and DNA damage, is required for proper progression of mitosis, and for the maintenance of chromosomal stability in human somatic cells 5 . CHK2 can also protect genome integrity by promoting apoptosis through interacting with a number of other substrates. Inhibition of CHK2 by transfection of a dominant-negative CHK2 mutant or a chemical inhibitor, debromohymenialdesine, stabilizes centrosomes, maintains high cyclin B1 levels, and allows for a prolonged activation of Cdk1 (ref. 6 ). Under these conditions, multinuclear HeLa syncytia do not arrest at the G2/M boundary and rather enter mitosis and subsequently die during the metaphase of the cell cycle 6 . Therefore, inhibition of CHK2 can sensitize proliferating cells to chemotherapy-induced apoptosis. The first indication of the role of CHK2 in cancer came from a study that reported the presence of germline mutations in CHK2 in families with Li-Fraumeni Syndrome 7 . It has been subsequently shown that defects of CHK2 occur in subsets of diverse sporadic malignancies and predispose to several types of hereditary carcinomas 8 . However, there is increasing evidence that CHK2 is a cancer susceptibility gene, but not a tumour suppressor gene in the classical sense 9 , 10 . CHK2 is aberrantly and constitutively activated in invasive urinary bladder carcinomas, and the putative proapoptotic checkpoint signalling can be disabled by inactivation of CHK2 and/or p53 tumour suppressors in subsets of these tumours 8 . More than 50% of CHK2 was phosphorylated at Thr68 in surgically resected lung and breast tumour specimens from otherwise untreated patients 11 . Targeting of CHK2 with small interfering RNA prevents survivin release from the mitochondria and enhanced apoptosis following induction of DNA damage by ionizing radiation (IR) or doxorubicin and inhibits the growth of resistant in vivo tumours. Expression of a dominant negative CHK2 potentiates cytotoxicity in HCT116 colon carcinoma cells to doxorubicin 9 . These findings suggested that activated CHK2 manifests both tumour-suppressor functions as well as the capacity to promote tumour and cell survival 9 , 12 . Relatively little is known about the contribution of CHK2 or the efficacy of CHK2 inhibitor in diffuse large B-cell lymphoma (DLBCL). The extracellular signal-regulated kinases 1 and 2 (ERK1/2) regulate cell proliferation and survival. Deregulation of ERK signalling is associated with genomic instability and cancer 13 . In earlier work, we showed that ERK inhibition induced the apoptosis of human DLBCL cells and has marked antitumour activity in human DLBCL xenograft models, implying the potential role of targeting ERK in the therapy of DLBCL 14 . It was shown that disruption of ERK1/2 activation by pharmacologic MEK1/2 inhibitors results in a dramatic increase in apoptosis of hematopoietic malignant cells 15 , 16 . Considering that there is little data on CHK2 and ERK signalling in lymphoid malignancies, in this study, we explored the molecular mechanisms underlying the functional interaction between ERK2 and CHK2. Furthermore, we investigated the potential therapeutic efficacy of combining ERK and CHK2 inhibitors in a pre-clinical model of DLBCL. We report here that the interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2 and that concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in human DLBCL. Results ERK1/2 and CHK2 are highly expressed in human DLBCL To examine the expression of both ERK1/2 and CHK2 in human DLBCL, we performed immunohistochemistry analysis to evaluate the ERK1/2 and CHK2 protein levels on 50 primary DLBCL specimens and 24 reactive lymph nodes. The expression of ERK1/2 and CHK2 was examined in the adjacent slides from the same sample. The DLBCL was further classified into germinal centre B-cell (GCB) and activated B-cell (ABC) subtypes, according to well-accepted immunohistochemistry-based algorithms 17 , 18 . Based on the criteria defined in the Methods, the specimens were divided into three staining groups: negative, low and high. As summarized in Table 1 , ERK1/2 levels are markedly elevated in 98% of all the DLBCL and 100% of the GCB subtype DLBCL samples as compared with the normal GCB cells of the reactive lymph nodes", "role": "user" }, { "content": "Researchers at the University of Maryland School of Medicine have discovered a novel interaction between two proteins involved in regulating cell growth that could provide possible new drug targets for treating diffuse large B-cell lymphoma, the most common type of non-Hodgkin's lymphoma. In a study published online in Nature Communications, the scientists report that they have found a complex molecular and functional relationship between ERK (extracellular signal-regulated kinase), a protein that helps to regulate cell proliferation and survival, and CHK2 (checkpoint kinase 2), a protein that is involved in the cellular DNA damage response. They also demonstrated, for the first time, elevated levels of both proteins in diffuse large B-cell lymphoma cells, compared to non-cancerous cells. Ronald B. Gartenhaus, M.D., associate professor of medicine at the University of Maryland School of Medicine and the senior author, says researchers found that CHK2 appears to regulate the activity of ERK, although the exact mechanism is not clear. \"The two proteins physically interact, which was not known before, and we may be able to use this interaction for therapeutic advantage. We found that treating human B-cell lymphoma cells with both an ERK inhibitor inhibitor and a CHK2 inhibitor killed substantially more cancer cells than treating the cells with either drug alone,\" he says. \"Based on our findings, we believe that a combination therapy targeting both ERK and CHK2 could offer a potential new approach to treating diffuse large B-cell lymphoma,\" says Dr. Gartenhaus, who is co-leader of the Program in Molecular and Structural Biology at the University of Maryland Marlene and Stewart Greenebaum Cancer Center. The drugs used to inhibit ERK and CHK2 caused the cancer cells to die through a process called apoptosis, or programmed cell death. Human cells normally self-destruct in a controlled manner, but cancer cells lose this ability and consequently grow uncontrollably. E. Albert Reece, M.D., Ph.D., M.B.A., vice president of medical affairs at the University of Maryland and dean of the University of Maryland School of Medicine, says, \"This is a very important discovery that may ultimately benefit patients with diffuse large B-cell lymphoma, a common hematological malignancy that can be difficult to treat. These findings provide valuable new insight into the molecular make-up of this cancer that may lead to new targeted drug therapies.\" Lymphoma is a cancer that originates in the lymphocytes (a type of white blood cell) of the immune system. Diffuse large B-cell lymphoma is a fast-growing, aggressive form of non-Hodgkin's lymphoma. It accounts for about 30 to 35 percent of all non-Hodgkin's lymphomas, and about 25,000 new cases are diagnosed each year. Non-Hodgkin's lymphomas usually are treated with several types of chemotherapy – cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) – and a biological therapy, such as the monoclonal antibody rituximab (Rituxan). Radiation therapy may be used on occasion, and bone marrow or stem cell transplantation may also be a treatment option. Dr. Gartenhaus says researchers hope the study findings will help to develop new therapies that will be effective and well-tolerated by patients. \"We believe it is important to identify drugs that can improve the efficacy and reduce the toxicity of standard anti-lymphoma therapy,\" he says. The new research showed that using compounds to inhibit ERK and CHK2 did not cause any significant damage to normal cells or tissue examined in the lab, according to Bojie Dai, Ph.D., a postdoctoral fellow at the University of Maryland School of Medicine and the lead author. \"We hope that new therapies directed at these two proteins would have modest side effects because they would target only the lymphoma cells,\" Dr. Dai says. Dr. Gartenhaus says that researchers don't know yet whether the interaction between ERK and CHK2 occurs in other types of lymphoma. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to > 99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired. Introduction Hematopoietic stem cell transplantation (HSCT) is a powerful treatment modality that enables replacement of host hematopoietic stem cells (HSCs) with HSCs from a healthy donor or genetically improved/corrected HSCs from the patient 1 . This procedure often results in life-long benefits and can curatively treat many malignant and non-malignant blood and immune diseases. Hence >1,000,000 patients have been transplanted in the last 60+ years for a wide range of blood and immune diseases, including leukemias, hemoglobinopathies, metabolic diseases, immunodeficiencies, and even HIV 2 . HSCT has also been demonstrated to be a beneficial treatment for autoimmune diseases 3 , and, with modern gene-modification techniques such as lentiviral transduction and ZFN, TALEN, or CRISPR/Cas9 gene editing, HSCT application may be expanded to an even wider range of diseases 4 . However, despite its broad curative potential, HSCT is currently mainly restricted to otherwise incurable malignant diseases and it is estimated that <25% of patients that could benefit from HSCT undergo transplantation 5 . This is largely due to undesirable morbidity/mortality from cytotoxic chemotherapy and irradiation-based conditioning currently necessary to enable donor HSC engraftment and the risks associated with graft versus host disease (GvHD). Due to their non-specific nature, classic conditioning regimens lead to both detrimental short-term and long-term complications including multi-organ damage, mucositis, need for frequent red blood cell and platelet transfusions, infertility, and secondary malignancies 6 , 7 . Additionally, these agents result in profound and prolonged immune ablation, which predisposes patients to serious and sometimes fatal opportunistic infections necessitating extended hospitalizations and exposure to toxic side effects of anti-infective agents 8 . Although much work has led to the development of reduced intensity conditioning (RIC) methods, which use lower dose combination chemotherapy with or without low dose irradiation, patients still experience many of these debilitating side effects 9 . Eliminating such harsh conditioning regimens would dramatically improve HSCT and expand its use, especially when combined with gene therapy or gene editing where the native hematopoietic system can be repaired without the need for allogeneic transplantation which carries GvHD and immune suppression risk. Traditionally, conditioning involves total body irradiation (TBI) and/or various chemotherapy prior to HSCT. These agents have been thought essential to make “space” in host bone marrow (BM) for donor HSC engraftment 10 , but they are non-specific and induce significant collateral damage. We previously demonstrated in immunodeficient mice that host HSC competition specifically limits donor HSC engraftment 11 , 12 . Subsequently, we showed that host HSCs in this model could be depleted using an antagonistic anti-murine CD117 monoclonal antibody (ACK2), resulting in an effective, safe, alternative single-agent conditioning approach enabling high donor HSC engraftment 11 . However, this naked antibody conditioning approach only functions as a stand-alone agent in certain disease models; such as immune deficiency 11 , 13 and Fanconi anemia 14 . In other settings, it has been found necessary to combine ACK2 with agents such as low-dose irradiation 15 or CD47 antagonism 13 to increase potency, making clinical translation of this approach challenging. We have recently shown that an alternative antibody-based approach to transplant conditioning is through use of CD45.1 or CD45.2 antibodies conjugated to the drug saporin 16 . Saporin is a ribosome-inactivating protein with potent cell-cycle-independent cytotoxic activity 17 . Unlike other toxins, it lacks a general cell entry domain and on its own is non-toxic. It can be targeted to specific cell types by coupling to antibodies directed to various cell-surface antigens and it is believed that upon receptor-mediated internalization, saporin is released intracellularly halting protein synthesis and inducing cell death 17 . As CD45 is present on most hematopoietic cells, including HSCs, we found CD45-antibody-drug-conjugates (CD45-ADCs) to be effective conditioning agents in various syngeneic immunocompetent mouse models 16 . However, as CD45 is also present on all lymphocytes, CD45-ADCs lead to profound lymphodepletion 16 and therefore likely will maintain opportunistic infection susceptibility. Therefore, if this approach is translated, it may be suited for HSCT contexts where immune depletion is required (e.g. allotransplant and autoimmune disease treatment), but is likely to be suboptimal for other applications. For settings such as autologous gene therapy, an improved solution in which HSCs can be specifically depleted while maintaining intact immunity would be optimal. Here, we show that CD117 antibody-drug-conjugates (CD117-ADCs) effectively and specifically deplete host HSCs in vivo with minimal toxicity. This allows safe and highly efficient transplantation of immunocompetent mice with whole bone marrow (WBM) or purified HSCs, whereas downstream effector cells are spared due to a lack of CD117 expression, thereby leading to the preservation of immunity. Results CD117-ADC potently depletes endogenous HSCs We created a single-agent antibody-drug-conjugate targeting the antigen CD117 (c-kit), which is a critical hematopoietic stem and progenitor cell receptor for the cytokine stem cell factor (SCF) 18 . Within the hematopoietic compartment, CD117 expression is largely restricted to HSCs and proximal multi-potent and oligopotent progenitors, though it is also expressed on some downstream hematopoietic effector cells such as mast cells and rare cells of other tissues 19 . The CD117-ADC was prepared by combining biotinylated anti-CD117 antibody (clone 2B8) with streptavidin–saporin (Fig. 1a ).", "role": "user" }, { "content": "Blood stem cell transplants—also known as bone-marrow transplants—can cure many blood, immune, autoimmune, and metabolic disorders, from leukemia to sickle-cell disease. But to make sure the healthy blood cells \"take,\" doctors first have to deplete the patient's own, defective blood stem cells using intensive chemotherapy or whole-body radiation. This wipes out the patient's immune system, raising the risk of infection and often causing serious side effects, including anemia, infertility, secondary cancers, organ damage, and even death. \"We know that stem cell transplants can cure dozens of blood disorders, including exciting progress with treating autoimmunity,\" said Professor David Scadden, co-director of the Harvard Stem Cell Institute and director of the Center for Regenerative Medicine at Massachusetts General Hospital. \"Yet they are rarely used beyond treating blood cancers because of the extreme rigors the patients must endure.\" New research led by Scadden and his colleagues at Harvard University has demonstrated in mice an effective alternative to this toxic pretreatment. Published in Nature Communications, the findings pave the way for clinical studies that will show whether the method would work in humans, making blood stem cell transplants safer and available to more patients. \"If the principles demonstrated in these studies translate to the clinic, they open the possibility of expanding stem cell transplantation to many more patients who we know would benefit if only it were made more tolerable,\" said Derrick Rossi, co-senior author of the paper. A promising antibody Previous research showed that a certain antibody blocks a receptor called CD117, which is carried mainly by blood-forming stem cells. When mice with genetically deficient immune systems were treated with the antibody, it selectively targeted those cells to die, making chemotherapy and radiation unnecessary. On its own, the antibody wasn't enough. Clinical trials with a human version of this antibody are now underway in patients with a rare disease called severe combined immunodeficiency. Building on this knowledge, the scientists identified an antibody that targets CD117, but is internalized by cells. Realizing that this could allow them to deliver a toxin directly—and selectively—into stem cells that have CD117, they attached it to a drug called saporin. Saporin, which has already been used in cancer patients, inhibits ribosomes, the protein-building structure in all cells. The team hoped that the combination would effectively kill blood-forming stem cells, and only those cells, by stopping their ability to make important proteins. It did. The Nature Communications study showed that a single dose of the antibody-drug combination eliminated more than 99 percent of blood-forming stem cells in mice. This allowed transplanted stem cells to take up residence in the recipient animals, effectively replacing their damaged blood and immune systems. The combination targeted the recipients' stem cells without harming other kinds of blood cells, and without causing clinically significant side effects. The animals' immune cell functions were preserved and responded effectively to pathogens. \"We theorized it would be effective, but were both reassured and excited when it worked so well,\" said first author Agnieszka Czechowicz of Boston Children's Hospital, who was also deeply involved in previous CD117 studies. Future research will evaluate the safety and efficacy of the antibody-drug combination, and explore other promising combinations. Magenta Therapeutics of Cambridge has licensed this technology and is working toward developing and testing the approach in patients. The company presented preclinical data on anti-CD117 and other antibody-drug conjugates at the American Society of Hematology meeting in December 2018. \"Collectively, these results are transformative for the field of transplant research. They open up the possibility of transplanting safely and effectively, without putting patients through toxic treatments,\" said Rahul Palchaudhuri of Harvard's Department of Stem Cell and Regenerative Biology, who was co-first author on the paper. \"If this approach works in people, we can make a difference for patients suffering from many different diseases,\" said Scadden. \"Patient conversations with their doctors would be more about benefit and cure and less about risk and suffering. That is our goal.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In animal embryos, transcription is mostly silent for several cell divisions, until the release of the first major wave of embryonic transcripts through so-called zygotic genome activation (ZGA) 1 . Maternally provided ZGA-triggering factors have been identified in Drosophila melanogaster and Danio rerio 2 , 3 , but their mammalian homologs are still undefined. Here, we provide evidence that the DUX family of transcription factors 4 , 5 is essential to this process in mice and potentially in humans. First, human DUX4 and mouse Dux are both expressed before ZGA in their respective species. Second, both orthologous proteins bind the promoters of ZGA-associated genes and activate their transcription. Third, Dux knockout in mouse embryonic stem cells (mESCs) prevents the cells from cycling through a 2-cell-like state. Finally, zygotic depletion of Dux leads to impaired early embryonic development and defective ZGA. We conclude that DUX-family proteins are key inducers of zygotic genome activation in placental mammals. Main Dux genes encode double-homeodomain proteins and are conserved throughout placental mammals 4 , 5 . Human DUX4 , the intronless product of an ancestral DUXC , is nested within the D4Z4 macrosatellite repeat of chromosome 4 as an array of 10 to 100 units (ref. 6 ). DUX4 , DUXC , and Dux genes from other placental mammals display the same repetitive structure: DUX4 from primates and Afrotheria and DUXC from cows and other Laurasiatheria localize at telomeric or pericentromeric regions, and mouse Du x tandem repeats lie adjacent to a mouse-specific chromosomal fusion point that resembles a subtelomeric structure 4 , 5 . Overexpression-inducing mutations in DUX4 are associated with facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy 7 , 8 , and forced DUX4 production in human primary myoblasts leads to upregulation of genes active during early embryonic development 9 . On the basis of this premise, we analyzed publicly available RNA-seq data sets corresponding to this period, focusing on DUX4 and the 100 genes most upregulated in DUX4 -overexpressing muscle cells 10 , 11 ( Fig. 1a and Supplementary Table 1 ). DUX4 RNA was detected from the oocyte to 4-cell (4C) stages, whereas transcripts from putative DUX4 targets emerged on average at the 2-cell (2C) stage and peaked at the 8-cell (8C) stage, as previously defined for human ZGA 12 . Transcripts upregulated in DUX4 -overexpressing muscle cells 11 were also enriched at the 8C stage ( Supplementary Fig. 1a,b ), and after clustering of genes according to their patterns of early embryonic expression ( Fig. 1b ), we delineated (i) 1,517 genes whose transcript expression was already detected in oocytes, plateaued up to 4C and abruptly decreased afterward (maternal gene cluster); (ii) 94 genes and 124 genes whose expression started at 2C and peaked at 4C and 8C, respectively, before rapidly decreasing, a pattern consistent with that of early-ZGA genes (2C–4C and 2C–8C gene clusters); and (iii) 1,352 genes expressed only from 4C, peaking at 8C, and then progressively decreasing, as expected for late-ZGA genes (4C–8C gene cluster). Only the two early-ZGA clusters (2C–4C and 2C–8C) were highly enriched in genes upregulated in DUX4 -overexpressing myoblasts ( Fig. 1c and Supplementary Fig. 1c ). Figure 1: DUX4 promotes transcription of genes expressed during early ZGA. ( a ) Comparative expression during early human embryonic development of DUX4 (red) and the top 100 genes upregulated after DUX4 overexpression in human primary myoblasts (blue; solid line, average; dashed lines, 95% confidence interval around the mean). Oo, oocyte; Zy, zygote; Mo, morula; Bl, blastocyst. ( b ) Cluster of genes differentially expressed during early embryonic development were selected from the previously identified subsets of genes ( Supplementary Fig. 1a ) on the basis of high expression at 4C (top) and 8C (bottom). Blue solid and dotted lines delineate the mean and 95% confidence interval, respectively. ( c ) Expression of genes from each cluster illustrated in b , after ectopic expression of DUX4 in human primary myoblasts. Lower parts of the panels depict the fold change in expression of genes within these clusters, all randomly distributed along the y axes, with kernel density plotted in the upper part. Full size image It is technically challenging to reliably analyze chromatin from the very low number of cells that make up an early embryo, but chromatin immunoprecipitation (ChIP)–seq data obtained in DUX4-overexpressing human embryonic stem cells (hESCs) ( Fig. 2a,b and Supplementary Fig. 2 ) and myoblasts 9 ( Supplementary Fig. 3 ) showed a marked enrichment of the transcription factor around the annotated transcription start site (TSS) regions of early-ZGA genes (2C–4C and 2C–8C clusters) but not zygotic (maternal) and late-ZGA (4C–8C) genes. Interestingly, several genes were bound not on their annotated TSSs, but on neighboring sequences, and their transcription was found to start near this DUX4-binding site ( Supplementary Fig. 4 ). DUX4 has been demonstrated to drive expression of many of its target genes from alternative promoters 11 . After examining publicly available single-cell RNA-seq data quantifying the far 5′ ends of transcripts (TFEs) in early human development 13 , we found that the TFEs of 24 out of 31 early-ZGA genes overlapped with DUX4-binding sites ( Fig. 2c,d and Supplementary Fig. 3c,d ). DUX4 was also recruited to several groups of transposable elements (TEs), notably endogenous retroviruses such as HERVL, MER11B, and MER11C, whose expression increased at ZGA ( Supplementary Fig. 2b,c ). Furthermore, DUX4 overexpression in hESCs led to early-ZGA-gene induction, as previously observed in myoblasts 11 ( Fig. 2e ). Figure 2: DUX4 binds TSSs of genes expressed during early ZGA and activates their expression in hESCs. ( a ) Average coverage normalized for sequencing depth of the ChIP–seq signal of DUX4 (blue) overexpressed in hESCs in a window of 5 kb from the annotated TSSs of genes belonging to the 2C–4C and 2C–8C clusters from Figure 1b . Total input is represented in gray (line, average; shading, s.e.m.). ( b ) Fraction of genes belonging to each cluster from Figure 1b with a DUX4", "role": "user" }, { "content": "The formation of a human embryo starts with the fertilization of the oocyte by the sperm cell. This yields the zygote, the primordial cell that carries one copy each of the maternal and paternal genomes. However, this genetic information starts being expressed only after the zygote divides a couple of times. But what triggers this process, called \"zygotic genome activation\", was unknown until now. EPFL scientists have just found that members of the DUX family of proteins are responsible for igniting the gene expression program of the nascent embryo. Published in Nature Genetics, this discovery is a milestone for developmental biology. Alberto de Iaco, a postdoc in the lab of Didier Trono at EPFL, drew upon a seemingly irrelevant study of patients suffering from a form of muscular dystrophy where mutations lead to the production in muscle cells of a protein called DUX4, which is normally detected only at the earliest stage of human embryonic development. De Iaco also found that when DUX4 is forcibly produced in muscle cells, it turns on a whole set of genes that are expressed during zygotic genome activation. This was what first suggested that DUX4 could be the key regulator of this seminal event. To confirm this, the researchers analyzed publicly available data to determine what components of the human genome are expressed during the first few days of embryonic development. They found that DUX4 is one of the very first genes expressed at this stage, releasing a high concentration of its protein product just before zygotic genome activation. In line with this lead, the scientists could show that the DUX4 protein binds to the regulatory region of genes that are induced during zygotic genome activation, stimulating their expression. Next, they looked at mouse embryonic stem cells, which contain the mouse version of the DUX4 gene (called simply DUX). When in culture, a small fraction of these cells exhibit a any given time the gene expression pattern of 2-cell stage embryos, before cycling back to the features of more advanced embryonic cells. But when the EPFL researchers deleted the DUX gene, this process stopped, the appearance of the 2-cell stage-like subpopulation was suppressed. The final piece of evidence came when the EPFL scientists removed the DUX gene from fertilized mouse oocytes using CRISPR/Cas9 genome editing. This prevented zygotic genome activation altogether, and precluded the growth of embryos beyond the first couple of cell divisions. The study points to DUX4, and by extension the DUX family of proteins, as the master regulator responsible for kick-starting genome expression at the earliest stage of embryonic life in humans, mouse and probably all placental mammals. \"An old enigma is solved,\" says Didier Trono. \"The study sheds light on what triggers the genetic program that ultimately makes us what we are. It can also help us understand certain cases of infertility and perhaps guide the development of new treatments for DUX-related muscle dystrophies\". He and his team are now curious about what could unleash, in the first few hours of our embryonic life, the ephemeral yet so crucial production of this master regulator. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract X-ray Fluorescence (XRF) microscopy is a growing approach for imaging the trace element concentration, distribution, and speciation in biological cells at the nanoscale. Moreover, three-dimensional nanotomography provides the added advantage of imaging subcellular structure and chemical identity in three dimensions without the need for staining or sectioning of cells. To date, technical challenges in X-ray optics, sample preparation, and detection sensitivity have limited the use of XRF nanotomography in this area. Here, XRF nanotomography was used to image the elemental distribution in individual E . coli bacterial cells using a sub-15 nm beam at the Hard X-ray Nanoprobe beamline (HXN, 3-ID) at NSLS-II. These measurements were simultaneously combined with ptychography to image structural components of the cells. The cells were embedded in small (3–20 µm) sodium chloride crystals, which provided a non-aqueous matrix to retain the three-dimensional structure of the E . coli while collecting data at room temperature. Results showed a generally uniform distribution of calcium in the cells, but an inhomogeneous zinc distribution, most notably with concentrated regions of zinc at the polar ends of the cells. This work demonstrates that simultaneous two-dimensional ptychography and XRF nanotomography can be performed with a sub-15 nm beam size on unfrozen biological cells to co-localize elemental distribution and nanostructure simultaneously. Introduction Trace elements are essential for carrying out biochemical reactions and act as structural components in cells. The appreciation of the important roles that trace elements, especially metals, play in cell metabolism has resulted in an increase in the number of studies in this area 1 , 2 , 3 , 4 , 5 . However, to truly understand the functions of trace elements in cells and tissues, the distribution within a cell must be imaged and quantified in the native cellular environment, which has proven to be difficult. Hard XRF microscopy is a well-suited microanalytical technique for assessing the elemental distribution in a wide range of materials including whole cells and tissues 6 , 7 , 8 . In XRF microscopy, multiple elements can be mapped simultaneously, which provides precise elemental co-localization and speciation. High detection sensitivity down to sub-parts-per-million has been demonstrated in biological studies 9 , 10 . To understand the functions of trace elements in biological cells, the X-ray probe must resolve subcellular compartments on the sub-micron to nanometer scale such as mammalian nuclei, mitochondria, and cell membranes, which measure ~6 μm, ~1 μm and ~10 nm, respectively 11 . In prokaryotic cells such as E . coli (1 μm × 3 μm), the outer and inner cell membranes are each ~10–15 nm wide, while ribosomes are about 20 nm in size 12 . Nanoscale imaging with X-rays requires high-resolution nano-focusing optics like Kirkpatrick-Baez mirrors 13 , 14 , 15 and Fresnel zone plate optics 16 . A more sophisticated, higher-resolving, nano-focusing approach is to use Multilayer Laue Lenses (MLLs) 17 , 18 , 19 , incorporated into a specialized X-ray microscope located at a beamline with infrastructure for good vibration isolation and thermal stability 20 , 21 , 22 . It is well-accepted that X-ray imaging of living biological specimens can be a challenge due to radiation-induced damage, so cells are frequently imaged in the fixed/dried or frozen-hydrated state 23 . While fixed/dried cells are least subject to radiation damage from water hydrolysis and free radical production, the subcellular structure can be compromised, especially at the nanoscale. Frozen-hydrated cells represent the most natural state of the cell while reducing the effects of radiation damage; however, this method requires the cells to be flash frozen, e.g. with a plunge freezer, and imaged in a cryostage. Since optical configurations of nanotomography instruments with MLLs 21 have very short working distances and rotation constraints, integration of a cryostage is a significant technical challenge. In addition, since the trace elements are typically micro- to nanomolar in concentration, sensitive detectors with a large solid angle situated close to the sample are required for quantification, further increasing technical complexity. Whereas two-dimensional XRF microscopy is the most straightforward approach for imaging cells and tissues, these two-dimensional data can be ambiguous when imaging three-dimensional objects, e.g. when aiming to differentiate between elements located on the surface of a cell from those distributed throughout the cell. At present, only a few three-dimensional XRF tomography studies from whole biological specimens have been reported. Kim et al . have studied the role of the vacuolar iron uptake transporter in the uptake and distribution of iron in the Arabidopsis seed, which was performed at 12 μm spatial resolution 24 . More recently, de Jonge et al . performed three-dimensional XRF tomography of a whole diatom, Cyclotella meneghiniana , at 400 nm spatial resolution using 150 nm voxels over a 15 μm field of view 9 . This work elegantly showed the distribution of several species including silicon and zinc within the organelles including the siliceous frustule, a diatom’s cell wall. Most surprising was the detection of Fe and Mn rings in the cell wall that would not have been detectable using only two-dimensional projections. To date, XRF nanotomography has been limited by sub-micron spatial resolution and weak absorption contrast in biological cells, inhibiting its ability to distinguish the ultra-structures of cell organelles 25 . In contrast, coherent diffraction imaging techniques, such as ptychography, can be used to image the fine structural components in samples 26 but cannot determine the distribution of trace elements. However, by combining XRF nanotomography and ptychography, it is possible to obtain complementary data on elemental and structural composition, respectively, at the nanoscale from biological cells 8 , 27 . The results described here represent a combination of two-dimensional ptychography and XRF nanotomography performed on E . coli cells using a MLL microscope with a sub-15 nm focused beam. Methods Cell culture LB media (10 mL) was inoculated with a single colony of BL21 (DE3) E . coli cells and the culture grown at 37 °C with shaking to an OD of 0.6–0.8. Cells were harvested in 1 mL aliquots via centrifugation at 3,500", "role": "user" }, { "content": "Scientists at the National Synchrotron Light Source II (NSLS-II)—a U.S. Department of Energy (DOE) Office of Science User Facility at DOE's Brookhaven National Laboratory—have used ultrabright x-rays to image single bacteria with higher spatial resolution than ever before. Their work, published in Scientific Reports, demonstrates an X-ray imaging technique, called X-ray fluorescence microscopy (XRF), as an effective approach to produce 3-D images of small biological samples. \"For the very first time, we used nanoscale XRF to image bacteria down to the resolution of a cell membrane,\" said Lisa Miller, a scientist at NSLS-II and a co-author of the paper. \"Imaging cells at the level of the membrane is critical for understanding the cell's role in various diseases and developing advanced medical treatments.\" The record-breaking resolution of the X-ray images was made possible by the advanced capabilities of the Hard X-ray Nanoprobe (HXN) beamline, an experimental station at NSLS-II with novel nanofocusing optics and exceptional stability. \"HXN is the first XRF beamline to generate a 3-D image with this kind of resolution,\" Miller said. While other imaging techniques, such as electron microscopy, can image the structure of a cell membrane with very high resolution, these techniques are unable to provide chemical information on the cell. At HXN, the researchers could produce 3-D chemical maps of their samples, identifying where trace elements are found throughout the cell. \"At HXN, we take an image of a sample at one angle, rotate the sample to the next angle, take another image, and so on,\" said Tiffany Victor, lead author of the study and a scientist at NSLS-II. \"Each image shows the chemical profile of the sample at that orientation. Then, we can merge those profiles together to create a 3-D image.\" XRF images show the zinc (B), calcium (C), chlorine (D) distributions in the single bacteria. XRF image E shows all three elements in the cell. Image A shows bacteria embedded in sodium chloride crystals. Credit: Brookhaven National Laboratory Miller added, \"Obtaining an XRF 3-D image is like comparing a regular X-ray you can get at the doctor's office to a CT scan.\" The images produced by HXN revealed that two trace elements, calcium and zinc, had unique spatial distributions in the bacterial cell. \"We believe the zinc is associated with the ribosomes in the bacteria,\" Victor said. \"Bacteria don't have a lot of cellular organelles, unlike a eukaryotic (complex) cell that has mitochondria, a nucleus, and many other organelles. So, it's not the most exciting sample to image, but it's a nice model system that demonstrates the imaging technique superbly.\" Yong Chu, who is the lead beamline scientist at HXN, says the imaging technique is also applicable to many other areas of research. \"This 3-D chemical imaging or fluorescence nanotomography technique is gaining popularity in other scientific fields,\" Chu said. \"For example, we can visualize how the internal structure of a battery is transforming while it is being charged and discharged.\" A 3-D view of the single bacteria produced through XRF. Credit: Brookhaven National Laboratory In addition to breaking the technical barriers on X-ray imaging resolution with this technique, the researchers developed a new method for imaging the bacteria at room temperature during the X-ray measurements. \"Ideally, XRF imaging should be performed on frozen biological samples that are cryo-preserved to prevent radiation damage and to obtain a more physiologically relevant understanding of cellular processes,\" Victor said. \"Because of the space constraints in HXN's sample chamber, we weren't able to study the sample using a cryostage. Instead, we embedded the cells in small sodium chloride crystals and imaged the cells at room temperature. The sodium chloride crystals maintained the rod-like shape of the cells, and they made the cells easier to locate, reducing the run time of our experiments.\" The researchers say that demonstrating the efficacy of the X-ray imaging technique, as well as the sample preparation method, was the first step in a larger project to image trace elements in other biological cells at the nanoscale. The team is particularly interested in copper's role in neuron death in Alzheimer's disease. \"Trace elements like iron, copper, and zinc are nutritionally essential, but they can also play a role in disease,\" Miller said. \"We're seeking to understand the subcellular location and function of metal-containing proteins in the disease process to help develop effective therapies.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. Our understanding of how selective effects of individual mutations are distributed across ages is however poor. Established evolutionary theories assume that mutations causing aging have negative late-life effects, coupled to either positive or neutral effects early in life. New theory now suggests evolution of aging may also result from deleterious mutations with increasing negative effects with age, a possibility that has not yet been empirically explored. Results To directly test how the effects of deleterious mutations are distributed across ages, we separately measure age-specific effects on fecundity for each of 20 mutations in Drosophila melanogaster . We find that deleterious mutations in general have a negative effect that increases with age and that the rate of increase depends on how deleterious a mutation is early in life. Conclusions Our findings suggest that aging does not exclusively depend on genetic variants assumed by the established evolutionary theories of aging. Instead, aging can result from deleterious mutations with negative effects that amplify with age. If increasing negative effect with age is a general property of deleterious mutations, the proportion of mutations with the capacity to contribute towards aging may be considerably larger than previously believed. Background Aging is the decline in physiological function with age, which results in a gradual decrease in survival and/or reproductive performance [ 1 , 2 , 3 , 4 ]. Aging affects many organisms and studies have shown that it has a genetic basis (reviewed in [ 5 ]). Theory suggests that aging evolves because the strength of selection declines with age [ 6 , 7 , 8 , 9 , 10 , 11 ], in combination with mutations with age-specific effects on performance. Two main evolutionary/genetic theories of aging have been proposed based on this idea. They both suggest that aging results from mutations with late acting deleterious effects, while they differ in that Mutation Accumulation (MA; [ 8 ]) assumes aging mutations to be neutral early in life whereas antagonistic pleiotropy (AP; [ 9 ]) assumes them to be beneficial. The AP and MA theories of aging have both been tested extensively, and evidence in favor of each has been found in the laboratory as well as in the wild (AP, e.g., [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ], MA, e.g., [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]). The two theories make contrasting predictions about how early and late life performances are associated with one another. While AP predicts a negative association, the initial formulation of the MA theory, based on mutations with effects spanning very short age intervals, predicts no association [ 2 , 30 ]. These predictions stand in sharp contrast to the positive pleiotropy often observed between early and late life performance (e.g., [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]). Charlesworth [ 43 ] later extended the MA theory to also encompass mutations with effects spanning several (up to all) adult age classes, a modification which allows for positive pleiotropy under MA. Alternatively, aging can be reconciled with positive pleiotropy if variation in aging, at least within populations, is primarily caused by deleterious mutations with increasing negative effects with age. This possibility is also logically appealing, since from a biological perspective it is difficult to imagine a genetic architecture where mutations have deleterious effects exclusively confined to specific adult age classes. Aging through mutations with gradually increasing negative effects has rarely been considered (see discussions in [ 30 , 33 , 44 , 45 ]), but is predicted by recent theory [ 46 , 47 ]. The genetics of aging has primarily been studied using experimental evolution and quantitative genetics. These approaches have provided a general understanding of how genetic variants collectively contribute to aging, but provide limited information on the age-specific effects of individual mutations [ 48 ]. QTL studies and GWAS partly circumvent this limitation (e.g., [ 18 , 28 , 49 , 50 , 51 ]), but can generally only detect signals from mutations with large effects segregating at appreciable frequencies. To learn more about how the selective effect of individual deleterious mutations is distributed over age classes, we here measure the effect on female fecundity across adult life for 20 mutations in Drosophila melanogaster . From an evolutionary perspective, aging concerns both the elevation of mortality and the reduction in reproductive performance with age. Studying the latter however has several experimental advantages: as the same individuals can be measured at several time points, it provides a general measure of somatic condition, and experimental effort can be focused to key ages. Our results show that 16 of the 20 tested mutations have a negative effect on fecundity and that the negative effect increases with age for 14 of these 16. Increasing negative effects with age could hence be an inherent property of deleterious mutations, causing most deleterious mutations to contribute towards aging. Results To test if deleterious mutations have an increasing negative effect with advancing age, we independently introgressed 20 dominant mutations ( Bl[1] , Bsb[1] , bw[D] , Dfd[1] , Dr[1] , Frd[1] , Gl[1] , H[2] , Ki[1] , Kr[If-1] , L[rm] , Ly[1] , nw[B] , Pin[1] , Pri[1] , Pu[2] , Rap1[1] , Sb[1] , sna[Sco] , wg[Sp-1] ) by backcrossing for ≥ 11 generations into our outbred Drosophila melanogaster base population (Dahomey). To test for age-specific effects on reproductive performance, we then estimated the fecundity of 500–550 females of each mutation when expressed in the heterozygous state in young (day 5), middle-aged (day 19), and moderately old (day 33) individuals and compared this to the fecundity of 500–550 paired", "role": "user" }, { "content": "The number of mutations that can contribute to aging may be significantly higher than previously believed, according to new research on fruit flies. The study by scientists at Linköping University, Sweden, supports a new theory about the type of mutation that can lie behind aging. The results have been published in BMC Biology. We live, we age and we die. Many functions of our bodies deteriorate slowly but surely as we age, and eventually an organism dies. This thought may not be very encouraging, but most of us have probably accepted that this is the fate of all living creatures—death is part of life. However, those who study evolutionary biology find it far from clear why this is the case. \"The evolution of aging is, in a manner of speaking, a paradox. Evolution causes continuous adaptation in organisms, but even so it has not resulted in them ceasing to age,\" says Urban Friberg, senior lecturer in the Department of Physics, Chemistry and Biology at Linköping University and leader of the study. Nearly 70 years ago, evolutionary biologists proposed two theories concerning two different types of mutation that contribute to aging. Both of these mutations have a detrimental effect as the organism becomes older—which leads to aging—while they are either advantageous or neutral early in life. Researchers have, however, not been able to determine which of the two types of mutation contributes most to aging, despite experimental studies. A new theory was proposed a few years ago suggesting that aging is caused by mutations with a detrimental effect early in life, and whose negative effects increase with age. Those who support this hypothesis believe that many of the mutations that arise have negative effects right from the start, compared with the normal variant of a gene. Martin Iinatti Brengdahl, PhD student at Linköping University, examining fruit flies in a microscope. Credit: Magnus Johansson/Linköping University The study now published describes experiments to test the theory of mutations that have a detrimental effect throughout life and contribute to aging. The authors used one of the most well-studied animals in the world, namely the fruit fly, or Drosophila melanogaster. They tested 20 different mutations that they had placed into the genetic material of the flies. For each individual mutation, they studied a group of flies with the mutation and a control group without it. Each mutation had a specific, visible effect, which made it easy to follow, such as a somewhat different appearance of the wings or a different shape of the eyes. As an organism ages, the probability that an individual dies increases, and its ability to reproduce falls. The researchers determined the fertility of the fruit flies and used it as a measure of aging. They counted the number of eggs laid by each female early in life, after two weeks, and finally after a further two weeks (which is a ripe old age for a fruit fly!). The researchers wanted to see whether the difference between flies with the mutations and the control group changed as they aged. The results support the theory they were testing. Most of the mutations had a negative effect on the fertility of the fruit flies early in life, and most of them also caused reproductive aging to occur more rapidly. \"The results suggest that mutations that are detrimental early in life can also contribute to aging. Thus it may be that mutations that bring on aging are significantly more common than we previously believed,\" says Martin Iinatti Brengdahl, doctoral student in the Department of Physics, Chemistry and Biology and principal author of the study. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We introduce Air Learning, an open-source simulator, and a gym environment for deep reinforcement learning research on resource-constrained aerial robots. Equipped with domain randomization, Air Learning exposes a UAV agent to a diverse set of challenging scenarios. We seed the toolset with point-to-point obstacle avoidance tasks in three different environments and Deep Q Networks (DQN) and Proximal Policy Optimization (PPO) trainers. Air Learning assesses the policies’ performance under various quality-of-flight (QoF) metrics, such as the energy consumed, endurance, and the average trajectory length, on resource-constrained embedded platforms like a Raspberry Pi. We find that the trajectories on an embedded Ras-Pi are vastly different from those predicted on a high-end desktop system, resulting in up to \\(40\\%\\) longer trajectories in one of the environments. To understand the source of such discrepancies, we use Air Learning to artificially degrade high-end desktop performance to mimic what happens on a low-end embedded system. We then propose a mitigation technique that uses the hardware-in-the-loop to determine the latency distribution of running the policy on the target platform (onboard compute on aerial robot). A randomly sampled latency from the latency distribution is then added as an artificial delay within the training loop. Training the policy with artificial delays allows us to minimize the hardware gap (discrepancy in the flight time metric reduced from 37.73% to 0.5%). Thus, Air Learning with hardware-in-the-loop characterizes those differences and exposes how the onboard compute’s choice affects the aerial robot’s performance. We also conduct reliability studies to assess the effect of sensor failures on the learned policies. All put together, Air Learning enables a broad class of deep RL research on UAVs. The source code is available at: . Working on a manuscript? Avoid the common mistakes 1 Introduction Deep Reinforcement Learning (RL) has shown promising results in domains like sensorimotor control for cars (Bojarski et al., 2016 ), indoor robots (Chiang et al., 2019 ), as well as UAVs (Gandhi et al., 2017 ; Sadeghi & Levine, 2016 ). Deep RL’s ability to adapt and learn with minimum apriori knowledge makes them attractive for use in complex systems (Kretchmar, 2000 ). Unmanned Aerial Vehicles (UAVs) serve as a great platform for advancing state of the art for deep RL research. UAVs have practical applications, such as search and rescue (Waharte & Trigoni, 2010 ), package delivery (Faust et al., 2017 ; Goodchild & Toy, 2018 ), construction inspection (Peng et al., 2017 ). Compared to other robots such as self-driving cars, robotic arm, they are vastly cheap to prototype and build, which makes them truly scalable. Footnote 1 Also, UAVs have fairly diverse control requirements. Targeting low-level UAV control (e.g. attitude control) requires continuous control (e.g., angular velocities) whereas, targeting high-level tasks such as point-to-point navigation can use discrete control. Last but not least, at deployment time they must be a fully autonomous system, running onboard computationally- and energy-constrained computing hardware. But despite the promise of deep RL, there are several practical challenges in adopting reinforcement learning for the UAV navigation task as shown in Fig. 1 . Broadly, the problems can be grouped into four main categories: (1) environment simulator, (2) learning algorithms, (3) policy architecture, and (4) deployment on resource-constrained UAVs. To address these challenges, the boundaries between reinforcement learning algorithms, robotics control, and the underlying hardware must soften. The figure illustrates the cross-layer, and interdisciplinary nature of the field, spanning from environment modeling to the underlying system. Each layer, in isolation, has a complex design space that needs to be explored for optimization. In addition, there are interactions across the layers that are also important to consider (e.g., policy size on a power-constrained mobile or embedded computing system). Hence, there is a need for a platform that can aid interdisciplinary research. More specifically, we need a research platform that can benchmark each of the layers individually (for depth), as well as end-to-end execution for capturing the interactions across the layers (for breadth). Fig. 1 Aerial robotics is a cross-layer, interdisciplinary field. Designing an autonomous aerial robot to perform a task involves interactions between various boundaries, spanning from environment modeling down to the choice of hardware for the onboard compute Full size image In this paper, we present Air Learning (Sect. 4 )—an open source deep RL research simulation suite and benchmark for autonomous UAVs. As a simulation suite of tools, Air Learning provides a scalable and cost-effective applied reinforcement learning research. It augments existing frameworks such as AirSim (Shah et al., 2017 ) with capabilities that make it suitable for deep RL experimentation. As a gym, Air Learning enables RL research for resource constrained systems. Air Learning addresses the simulator level challenge, by providing domain randomization. We develop a configurable environment generator with a range of knobs to generate different environments with varying difficulty levels. The knobs (randomly) tune the number of static and dynamic obstacles, their speed (if relevant), texture and color, arena size, etc. In the context of our benchmarking autonomous UAV navigation task, the knobs help the learning algorithms generalize well without overfiting to a specific instance of an environment. Footnote 2 Air Learning addresses the learning challenges (RL algorithm, policy design, and reward optimization) by exposing the environment generator as an OpenAI gym (Brockman et al., 2016 ) interface and integrating it with Baselines (Hill et al., 2018 ), which has high-quality implementations of the state-of-the-art RL algorithms. We provide templates which the researchers can use for building multi-modal input policies based on Keras/Tensorflow. And as a DRL benchmark, the OpenAI gym interface enables easy addition of new deep RL algorithms. At the point of writing this paper, we provide two different reinforcement learning algorithms Deep Q-Networks (DQN) (Mnih et al., 2013 ) and Proximal Policy Optimization (PPO) (Schulman et al., 2017 ). DQN is an off-policy, discrete action RL algorithm, and PPO is an on-policy, continuous action control of UAVs. Both come ready with curriculum learning (Bengio et al., 2009 ) support. To address the resource-constrained challenge early on in the", "role": "user" }, { "content": "Roboticists worldwide have been trying to develop autonomous unmanned aerial vehicles (UAVs) that could be deployed during search and rescue missions or that could be used to map geographical areas and for source-seeking. To operate autonomously, however, drones should be able to move safely and efficiently in their environment. In recent years, reinforcement learning (RL) algorithms have achieved highly promising results in enabling greater autonomy in robots. However, most existing RL techniques primarily focus on the algorithm's design without considering its actual implications. As a result, when the algorithms are applied on real UAVs, their performance can be different or disappointing. For instance, as many drones have limited onboard computing capabilities, RL algorithms trained in simulations can take longer to make predictions when they are applied on real robots. These longer computation times can make a UAV slower and less responsive, which could in turn affect the outcome of a mission or result in accidents and collisions. Researchers at Harvard University and Google Research recently developed Air Learning, an open-source simulator and gym environment where researchers can train RL algorithms for UAV navigation. This unique environment, introduced in a paper published in Springer Link's Special Issue on Reinforcement Learning for Real Life, could help to improve the performance of autonomous UAVs in real-world settings. \"To achieve true autonomy in UAVs, there is a need to look at system-level aspects such as the choice of the onboard computer,\" Srivatsan Krishnan, one of the researchers who carried out the study, told TechXplore. \"Therefore, the primary objective of our study was to provide the foundational blocks that will allow researchers to evaluate these autonomy algorithms holistically.\" In Air Learning, UAV agents can be exposed to and trained on challenging navigation scenarios. More specifically, they can be trained on point-to-point obstacle avoidance tasks in three key environments, using two training techniques called deep Q networks (DQN) and proximal policy optimization (PPO) algorithms. \"Air Learning provides foundational building blocks to design and evaluate autonomy algorithms in a holistic fashion,\" Krishnan said. \"It provides OpenAI gym-compatible environment generators that will allow researchers to train several reinforcement learning algorithms and neural network-based policies.\" On the platform developed by Krishnan and his colleagues, researchers can assess the performance of the algorithms they developed under various quality-of-flight (QoF) metrics. For instance, they can assess the energy consumed by drones when using their algorithms, as well as their endurance and average trajectory length when utilizing resource-constrained hardware, such as a Raspberry Pi. \"Once their algorithms are designed, researchers can use the hardware-in-the-loop to plug in an embedded computer and evaluate how the autonomy algorithm performs as if it's running on an actual UAV with that onboard computer,\" Krishnan said. \"Using these techniques, various system-level performance bottlenecks can be identified early on in the design process.\" When running tests on Air Learning, the researchers found that there usually is a discrepancy between predicted performances and the actual functioning of onboard computers. This discrepancy can affect the overall performance of UAVs, potentially affecting their deployment, mission outcomes and safety. \"Though we specifically focus on UAVs, we believe that the methodologies we used can be applied to other autonomous systems, such as self-driving cars,\" Krishnan said. \"Given these onboard computers are the brain of the autonomous systems, there is a lack of systematic methodology on how to design them. To design onboard computers efficiently, we first need to understand the performance bottlenecks, and Air Learning provides the foundational blocks to understand what the performance bottlenecks are.\" In the future, Air Learning could prove to be a valuable platform for the evaluation of RL algorithms designed to enable the autonomous operation of UAVs and other robotic systems. Krishnan and his colleagues are now using the platform they created to tackle a variety of research problems, ranging from the development of drones designed to complete specific missions to the creation of specialized onboard computers. \"Reinforcement learning is known to be notoriously slow to train,\" Krishnan said. \"People generally speed up RL training by throwing more computing resources, which can be expensive and lower entry barriers for many researchers. Our work QuaRL (Quantized reinforcement learning) uses quantization to speed up RL training and inference. We used Air Learning to show the real-world application of QuaRL in deploying larger RL policies on memory-constrained UAVs.\" Onboard computers act as the \"brains\" of autonomous systems, thus they should be able to efficiently run a variety of algorithms. Designing these computers, however, can be highly expensive and lacks a systematic design methodology. In their next studies, therefore, Krishnan and his colleagues also plan to explore how they could automate the design of onboard computers for autonomous UAVs, to lower their cost and maximize UAV performance. \"We already used Air Learning to train and test several navigation policies for different deployment scenarios,\" Krishnan said. \"In addition, as part of our research on autonomous applications, we created a fully autonomous UAV to seek light sources. The work used Air Learning to train and deploy a light-seeking policy to run on a tiny microcontroller-powered UAV.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination. Main Induction of HIV-1 envelope (Env) broadly neutralizing antibodies (BnAbs) is a key goal of HIV-1 vaccine development. BnAbs can target conserved regions that include conformational glycans, the gp41 membrane proximal region, the V1/V2 region, glycan-associated C3/V3 on gp120, and the CD4-binding site 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 . Most mature BnAbs have one or more unusual features (long third complementarity-determining region of the heavy chain (HCDR), polyreactivity for non-HIV-1 antigens, and high levels of somatic mutations), suggesting substantial barriers to their elicitation 4 , 10 , 11 , 12 , 13 . In particular, CD4-binding site BnAbs have extremely high levels of somatic mutation, suggesting complex or prolonged maturation pathways 4 , 5 , 6 , 7 . Moreover, it has been difficult to find Env proteins that bind with high affinity to BnAb germline or unmutated common ancestors (UCAs), a trait that would be desirable for candidate immunogens for induction of BnAbs 7 , 14 , 15 , 16 , 17 , 18 . Although it has been shown that Env proteins bind to UCAs of BnAbs targeting the gp41 membrane proximal region 16 , 19 , and to UCAs of some V1/V2 BnAbs 20 , so far, heterologous Env proteins have not been identified that bind the UCAs of CD4-binding site BnAb lineages 7 , 18 , 21 , 22 , 23 , although they should exist 21 . Eighty per cent of heterosexual HIV-1 infections are established by one transmitted/founder virus 24 . The initial neutralizing antibody response to this virus arises approximately 3 months after transmission and is strain-specific 25 , 26 . The antibody response to the transmitted/founder virus drives viral escape, such that virus mutants become resistant to neutralization by autologous plasma 25 , 26 . This antibody–virus race leads to poor or restricted specificities of neutralizing antibodies in ∼ 80% of patients; however in ∼ 20% of patients, evolved variants of the transmitted/founder virus induce antibodies with considerable neutralization breadth, such as BnAbs 2 , 20 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . There are several potential molecular routes by which antibodies to HIV-1 may evolve, and indeed, types of antibody with different neutralizing specificities may follow different routes 6 , 11 , 15 , 34 . Because the initial autologous neutralizing antibody response is specific for the transmitted/founder virus 31 , some transmitted/founder Env proteins might be predisposed to binding the germ line or UCA of the observed BnAb in those rare patients that make BnAbs. Thus, although neutralizing breadth generally is not observed until chronic infection, a precise understanding of the interaction between virus evolution and maturing BnAb lineages in early infection may provide insight into events that ultimately lead to BnAb development. BnAbs studied so far have only been isolated from individuals who were sampled during chronic infection 1 , 3 , 4 , 5 , 6 , 7 , 20 , 27 , 29 . Thus, the evolutionary trajectories of virus and antibody from the time of virus transmission to the development of broad neutralization remain unknown. We and others have proposed vaccine strategies that begin by targeting UCAs, the putative naive B-cell receptors of BnAbs with relevant Env immunogens to trigger antibody lineages with potential ultimately to develop breadth 6 , 11 , 13 , 14 , 15 , 16 , 18 , 19 , 21 . This would be followed by vaccination with Env proteins specifically selected to stimulate somatic mutation pathways that give rise to BnAbs. Both aspects of this strategy have proved challenging owing to a lack of knowledge of specific Env proteins capable of interacting with UCAs and early intermediate antibodies of BnAbs. Here we report the isolation of the CH103 CD4-binding site BnAb clonal lineage from an African patient, CH505, who was followed from acute HIV-1 infection to BnAb development. We show that the CH103 BnAb lineage is less mutated than most other CD4-binding site BnAbs, and may be first detectable as early as 14 weeks after HIV-1 infection. Early autologous neutralization by antibodies in this lineage triggered virus escape, but rapid and extensive Env evolution in and near the epitope region preceded the acquisition of plasma antibody neutralization breadth defined as neutralization of heterologous viruses. Analysis of the co-crystal structure of the CH103 Fab fragment and a gp120 core demonstrated a new loop-binding mode of antibody neutralization. Isolation of the CH103 BnAb lineage The CH505 donor was enrolled in the CHAVI001 acute HIV-1 infection cohort 35 approximately 4 weeks after HIV-1 infection ( Supplementary Fig. 1 ) and followed for more than 3 years. Single genome amplification of 53 plasma viral Env gp160 RNAs 24 from 4 weeks after transmission identified a single clade C transmitted/founder virus. Serological analysis demonstrated the development of autologous neutralizing antibodies at 14 weeks, CD4-binding site antibodies that bound to a recombinant Env protein (resurfaced stabilized core 3 (RSC3)) 5 at 53 weeks, and evolution", "role": "user" }, { "content": "By tracking the very earliest days of one person's robust immune response to HIV, researchers have charted a new route for developing a long-sought vaccine that could boost the body's ability to neutralize the virus. The research team, led by Barton F. Haynes, M.D., director of the Duke Human Vaccine Institute, and John Mascola, M.D., acting director of the NIH Vaccine Research Center, have for the first time described the co-evolution of antibodies and virus in a person with HIV whose immune system mounted a broad attack against the pathogen. Findings are published April 3, 2013, in the journal Nature. Most vaccines work by inducing this antibody response, but the HIV virus has proved to be a difficult vaccine target. When HIV antibodies are produced, they typically have a limited range, and the virus changes rapidly to escape harm, leading to an arms race that the virus usually wins. The current research was aided by new technologies that can detect early infection and track the subsequent immune response and virus evolution. It fills gaps in knowledge that have impeded development of an effective vaccine for a virus that has killed more than 30 million people worldwide. \"This project could only have been carried out by a multidisciplinary team working closely together,\" said Haynes, who led the work as a project of the Duke Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) consortium, which is funded by the National Institute of Allergy and Infectious Diseases. \"For the first time, we have mapped not only the evolutionary pathway of the antibody, but also the evolutionary pathway of the virus, defining the sequence of events involved that induce the broadly neutralizing antibodies.\" The evolution of the viral protein (green) from 14 weeks through 100 weeks post-transmission is compared to the maturation of the human antibody. Credit: Los Alamos National Laboratory The key to this finding was a person in Africa whose HIV infection was detected so early that the virus had not yet mutated to avoid the immune assault. The individual also exhibited a fortuitous trait that occurs in only about 20 percent of people infected with HIV – an immune system that produces broadly neutralizing antibodies. These immune weapons attack vulnerable sites of the virus that are conserved despite mutations. In identifying the early viral infection, the team found the outer envelope, the viral surface glycoprotein, which triggered the start of the broadly neutralizing antibody development. By tracking the precise virus and antibody pathways involved, the Duke CHAVI-ID and NIH teams now have a detailed road map for development of a potential vaccine, which involves immunogens with an outer envelope specifically selected to stimulate the production of broadly neutralizing antibodies. \"The next step is to use that information to make sequential viral envelopes and test them as experimental vaccines,\" Haynes said. \"This is a process of discovery and we've come a long way with regard to understanding what the problem has been.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Interactions between biomolecules underlie all cellular processes and ultimately control cell fate. Perturbation of native interactions through mutation, changes in expression levels or external stimuli leads to altered cellular physiology and can result in either disease or therapeutic effects 1 , 2 . Mapping these interactions and determining how they respond to stimulus is the genesis of many drug development efforts, leading to new therapeutic targets and improvements in human health 1 . However, in the complex environment of the nucleus, it is challenging to determine protein–protein interactions owing to low abundance, transient or multivalent binding and a lack of technologies that are able to interrogate these interactions without disrupting the protein-binding surface under study 3 . Here, we describe a method for the traceless incorporation of iridium-photosensitizers into the nuclear micro-environment using engineered split inteins. These Ir-catalysts can activate diazirine warheads through Dexter energy transfer to form reactive carbenes within an approximately 10 nm radius, cross-linking with proteins in the immediate micro-environment (a process termed µMap) for analysis using quantitative chemoproteomics 4 . We show that this nanoscale proximity-labelling method can reveal the critical changes in interactomes in the presence of cancer-associated mutations, as well as treatment with small-molecule inhibitors. µMap improves our fundamental understanding of nuclear protein–protein interactions and, in doing so, is expected to have a significant effect on the field of epigenetic drug discovery in both academia and industry. Main Mapping protein–protein interactions (PPIs) is central to our understanding of cellular biology 5 . The enormous challenges associated with this undertaking are magnified in the nucleus in which transient and multivalent interactions, fine-tuned by posttranslational modifications (PTMs), combine to choreograph DNA-templated processes such as transcription 6 . Perturbations to these regulatory mechanisms often lead to disease 7 , for example, somatic mutations that alter the composition and activity of chromatin-associated protein complexes are implicated in many human cancers and developmental disorders 8 , 9 , 10 . Moreover, recent studies have shown that histone proteins are themselves frequently mutated in cancers 11 , 12 , 13 . Understanding how these mutations lead to, or perpetuate, disease is the focus of intense investigation 11 , 12 , 13 , work that necessitates accurate comparative mapping of chromatin-associated PPI networks as a function of altered cell states 1 . The elucidation of nuclear PPIs has typically been performed by immunoprecipitation–mass spectrometry (IP–MS) workflows, in which antibodies recognizing selected proteins are used to enrich their target along with direct interactors 14 . However, IP–MS approaches rely on nuclear lysates as input, which may not be ideal for every system 15 , 16 , especially when the interactions are transient in nature (for example, driven by posttranslational modification) or require multiprotein complexes that bridge native chromatin 17 , 18 , 19 . This has fuelled the development of chemoproteomics approaches such as those based on photocrosslinking 20 , 21 or proximity-labelling 22 , 23 , 24 technologies that seek to capture PPIs in a native-like environment. Despite these ongoing advances, no single method exists to map chromatin interactomes in a general and unbiased manner and particularly to discern how such interactions are affected by perturbations such as mutation or drug treatment (Fig. 1a ). To address this need we considered the union of technologies recently disclosed by our two laboratories, µMap 4 and in nucleo protein trans -splicing 20 , to enable a traceless, short-range proximity-labelling method that can be readily deployed to any nuclear protein target. Protein trans -splicing using ultrafast split inteins facilitates the installation of iridium (Ir)-photocatalysts onto the N or C termini of target proteins. On irradiation with blue light-emitting diodes (LEDs) in the presence of a biotin–diazirine probe, localized carbene generation (through Dexter energy transfer from photoexcited iridium to aryl diazirines) allows interactomes to be determined, specifically those within about 10 nm of the iridium-centred photocatalyst (Fig. 1b ). Fig. 1: Development of a catalytic labelling platform using inteins. a , Chromatin interactomes can be perturbed through mutation leading to oncogenic phenotypes. Epigenetic drugs alter the chromatin interactome for therapeutic benefit. b , Cartoon showing strategy for nuclear photo-proximity labelling. Ir-photocatalysts can be incorporated into nuclear proteins via protein trans -splicing. The N-terminal fragment of Cfa N is fused to a target nuclear protein, whereas Cfa C is linked to the photocatalyst. In nucleo splicing provides Ir-conjugated nuclear proteins. Following excitation under blue light irradiation, the photocatalyst activates diazirines (to form carbenes via loss of molecular nitrogen) through a process called Dexter energy transfer. These carbenes are then poised to insert into neighbouring proteins that can be enriched using streptavidin beads. Comparative chemoproteomic analysis reveals how a given perturbation (for example, a mutation or drug treatment) affects local interactomes, providing insights into the mechanistic basis for disease or therapy. The mock volcano plot in Fig. 1 was created using BioRender . Full size image Our proposed workflow offers distinct advantages for the elucidation of subtly perturbed chromatin interactomes through mutation or ligand binding. Principally, the short radius afforded by this technology limits labelling to the close vicinity of a designated chromatin factor or nucleosome, only identifying proteins that are affected by a particular mutation or pharmacological intervention. This is critically important, given the structural and functional heterogeneity of chromatin 25 . Furthermore, the incorporation of the µMap catalyst is designed to be almost traceless and its small size is expected to minimize disruption to the native environment (for example, in comparison to fusion proteins), allowing the study of modifications that only minimally change the native interactome. We began our studies by preparing an Ir-conjugated intein fragment (complementary C-terminal fragment Cfa C -Ir), using a combination of solid-phase peptide synthesis and click chemistry (Fig. 2a,b ). We next fused the N-terminal fragment of the engineered Cfa split intein (Cfa N ) 26 , 27 to the C terminus of histone H3.1. For analytical convenience, we also included HA and FLAG epitope tags flanking the intein (Fig. 2c ). We then treated nuclei isolated from these", "role": "user" }, { "content": "Studying the microbiology of any entity, be it a molecule or a dolphin, ideally means putting a spotlight as close to the source material as possible. That can be especially challenging when you're investigating the Rube Goldberg environment of a cell's nucleus. But in research published this week in Nature, Princeton chemists from the Muir Lab and the MacMillan Lab used two marquee technologies to shine a light right where they wanted it. In the process, they discovered critical, unexpected changes in interactions surrounding a DNA-protein complex called chromatin—essentially, an architecture that allows for the compaction of DNA—in the presence of genetic mutations widely associated with cancer. Interactions between biomolecules control every biological function. Mapping their activity leads to a deeper understanding of cell fate. So researchers paired the strengths of µMap, the MacMillan Lab's proximity-labeling system introduced three years ago, with in nucleo protein trans-splicing, a protein engineering technology introduced in 2016 and optimized since by the Muir Lab. \"The whole point of µMap is to understand biology, broadly defined, in ways that you couldn't beforehand, because µMap gives you such incredibly precise information. This research is an example of doing precisely that,\" said David MacMillan, the James S. McDonnell Distinguished University Professor of Chemistry and a recipient of the 2021 Nobel Prize in Chemistry. \"With this research, we saw that the biology is happening because of these mutations,\" he said. \"It was impossible to see that before, so we were driving in the dark. It's another piece in this whole wall, a brick of what µMap's going to be able to do. It's still just the beginning, but this is a true collaboration.\" The combination of these technologies allowed researchers to tether an iridium photocatalyst to a protein of interest to study these minute interactions and how they change in the presence of mutations—all without impacting the complex microenvironment within the cell nucleus. The photocatalyst highlighted a radius of focus just one nucleosome wide, allowing researchers to peer into this microenvironment with unprecedented specificity. \"So many things in biology and disease come down to how chromatin moves and changes,\" said Ciaran Seath, a former postdoc in the MacMillan Lab and co-lead author on the paper with Antony Burton, a former postdoc in the Muir Lab. \"Viruses, aging, cancers, all the things we looked at, change how chromatin can move and react. We figured, if you could watch that, you could learn about all of these different problems in a modular way. \"Sometimes you can't see or predict all the other things that are likely to happen in the machine of the nucleus. Now that we have paired these tools, we can measure these unforeseen consequences. It's like touching a point on a spider's web,\" he said. \"You can see the whole thing move.\" Burton added, \"What the synergy of these technologies gets you, in a minimally perturbative way, is the ability to install a small catalyst onto a protein of interest and then map what's nearby. We were able to illuminate protein interactions and complex, downstream effects at a level of detail that is very hard to do with other methods. \"Most importantly, we can chart how these change as a function of mutation or drug treatment, presenting opportunities for academic and industrial application.\" The research was authored by Seath, now an assistant professor of chemistry at the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology in Jupiter, Florida; Burton, now a senior scientist in chemical biology at AstraZeneca in Boston, Massachusetts; and senior scientists Thomas Muir, the Van Zandt Williams Jr. Class of 1965 Professor, and MacMillan. Advancing the field of epigenetics The research has important implications for epigenetics, the branch of biology that explores changes in gene expression. At the heart of epigenetics are histone proteins, which package DNA and restrict access to the genome, thereby playing a key role in regulating transcription. Recently, mutations to these histone proteins have been discovered and linked to a wide range of cancers. \"One of the things we looked at was adding a mutation that occurs in a histone that's linked to cancer,\" said Muir. \"What we wanted to know is, what happens when that mutation is present; what can no longer be recruited, what's no longer in the neighborhood, what new things are brought in that shouldn't normally be there? \"We were able to use these technologies to find all sort of things that get changed when we put this mutation on the chromatin, things related to gene regulation,\" he added. \"We were able to infer mechanistic insights that relate to how genes get misregulated with a mutation.\" Beginning their research three years ago, the team hypothesized that the mutation associated with cancer precipitates some sort of loss of function. Biomolecules find chromatin and bind with it to leave a transcriptional mark. Researchers believed that the mutation blocked some of that action, thus leading to cell dysfunction. Their hypothesis was borne out with this research, which generated molecular detail on how a tiny change in the genome can lead to major impacts. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The selection of peptides for presentation at the surface of most nucleated cells by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response in vertebrates. However, the mechanisms of the rapid selection of high affinity peptides by MHC I from amongst thousands of mostly low affinity peptides are not well understood. We developed computational systems models encoding distinct mechanistic hypotheses for two molecules, HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405), which differ by a single residue yet lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We used in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We used molecular dynamics simulations to show that peptide selector function correlates with protein plasticity and confirmed this experimentally by altering the plasticity of MHC I with a single point mutation, which altered in vivo selector function in a predictable way. Finally, we investigated the mechanisms by which the co-factor tapasin influences MHC I plasticity. We propose that tapasin modulates MHC I plasticity by dynamically coupling the peptide binding region and α 3 domain of MHC I allosterically, resulting in enhanced peptide selector function. Introduction Peptides bound to Major histocompatibility complex class I (MHC I) molecules are displayed at the surface of most nucleated cells in jawed vertebrates for surveillance by cytotoxic T-lymphocytes (CTL) 1 , 2 , 3 . In transformed or diseased cells, peptides derived from viral or aberrantly expressed proteins are presented alongside peptides derived from native proteins. This is possible because MHC I has degenerate specificity: each molecule can bind a range of peptides of different lengths and sequences. In selecting peptides and presenting them at the cell surface, MHC I provides CTLs with a sample of the internal cell proteome. This property makes MHC I an attractive target for the development of immunotherapies that exploit the CTL response. Examples include therapies that modulate the overall cell surface presentation of peptides by MHC I, or that target MHC I at the cell surface with specific peptide vaccines to make cells more, or less, visible to CTLs. The selection of peptides by MHC I occurs in the endoplasmic reticulum (ER) and is modulated by a multi-protein complex into which the MHC I:β 2 m heterodimer is recruited. This peptide loading complex comprises of the peptide Transporter associated with Antigen Presentation (TAP), which transports peptides into the ER, chaperone proteins calreticulin and ERp57 and an MHC I-specific cofactor tapasin (reviewed in 4 ). Incorporation of MHC I molecules into the peptide loading complex locates them in close proximity to the peptide supply. Here, MHC I interacts with cofactor molecules to preferentially select peptides of high affinity from the large intracellular pool of many potential peptides of largely lower affinity 5 , 6 . Selection of high affinity peptides confers stability and immunogenicity to MHC I 7 , 8 and is one of the most important factors in establishing the specificity and intensity of a CTL response 9 . We refer to the peptide selector function of MHC I as its ability to preferentially select higher affinity peptides over lower affinity ones. This in turn profoundly influences the downstream MHC I function of presenting peptides to CTLs. MHC I molecules are highly polymorphic, but have a common tertiary structure ( Fig. 1 ) consisting of: the polymorphic heavy chain, monomorphic β 2 -microglobulin (β 2 m) and a peptide of generally 8–10 amino acids in length, non-covalently bound into a peptide binding groove. Intrinsic differences in the peptide selector function of different allelic variants of MHC I molecules become most apparent when the co-factor molecule tapasin is non-functional or absent. This is because tapasin masks these intrinsic differences by preferentially enhancing the selector function of MHC I molecules that are inefficient at selecting high affinity peptides 10 , 11 . When tapasin is absent, differences in the primary sequence of MHC I are sufficient to alter peptide selector function 12 . For example, two human alleles HLA-B*35:01 and HLA-B*52:01 differ by 12 residues in their primary sequence. In the absence of tapasin, HLA-B*35:01 molecules are expressed at a high level at the cell surface, whilst HLA-B*52:01 molecules are only observed at low levels 13 . Remarkably, even a single amino acid difference can alter the intrinsic peptide selector function of MHC I: HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405) differ by a single residue at position 116 ( Fig. 1A ), yet they lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides in the absence tapasin 10 . In tapasin-deficient cells, B*4402 is poor at sampling the peptidome and as a consequence is degraded in the endoplasmic reticulum (ER), while B*4405 is able to effectively select high affinity peptides and present them at the cell surface. Figure 1 Structure of the MHC I molecule (A) Ribbon representation of the MHC I molecule HLA-B*44:05 and its three components: a polymorphic heavy chain (yellow), non-covalently bound invariant β 2 m (yellow) and peptide (red). The polymorphic residue 116 between B*4402 and B*4405 is shown in blue (B) Comparison of B*4402 (PDB: 1M6O, green) and B*4405 (PDB: 1SYV, blue) structures. RMSD between them of 0.3 Å. (C) Combined ribbon and surface representation of the MHC I molecule peptide binding groove. Full size image These observations of allelic differences in intrinsic MHC I peptide selector function imply that tapasin normalizes the peptide selector function of MHC I alleles. However, a mechanistic explanation for how tapasin achieves this is lacking. Furthermore, despite there being many crystal structures of MHC I, the structural basis for intrinsic differences in selector function between MHC I alleles remains unknown. Importantly, what is not revealed by X-ray crystallography is the formation of a MHC I peptide complex and the significance or otherwise of the processes involved. For example, the structures of B*4402 and B*4405 reveal highly similar peptide bound conformations with a RMSD of 0.3 Å between", "role": "user" }, { "content": "New research has uncovered an important mechanism in the drive to understand immunological processes that protect us against infection, allergy and cancer. Researchers from Medicine, Chemistry and Biological Sciences in the University's Institute for Life Science (IfLS) have been collaborating with Microsoft Research UK to investigate the function of the antigen-presenting protein MHC1. Their research, which started more than a decade ago and has been part-funded by Cancer Research UK, has explored the pliability of the protein and how its ability to shape-shift dictates its function. Principal Investigator Tim Elliott, Professor of Experimental Oncology and Deputy Director for the IfLS, said: \"This protein acts as a molecular interface between your body and your immune system. It alerts your immune system to the fact that the body has been infected by a virus or invaded by cancer, and guides white blood cells to kill them. What we have discovered is that it can only perform these vital functions if it is allowed to \"wriggle\" in a particular way. We also discovered that, because it is a pliable molecule, different parts of the protein communicate with one another - if we touch it in one place, the function in a distant part of the molecule changes. These findings are of real interest to both immunologists who are developing new immunotherapies for diseases and biology as a whole. They have generated real interest in the healthcare industry.\" The team's discoveries could have a major impact on the future of medical treatment and in the long term could see the development of cancer immunotherapies and vaccines against infection. It could also help to reduce allergies such as contact hypersensitivity by understanding how the additives used in healthcare products are detected by the immune system. The results of the study were recently published in the journal Scientific Reports and have led to the award of significant industry funding from the consumer goods giant Unilever. It has awarded the team £700,000 to work in collaboration with its scientists to continue exploring ways to minimise allergic reactions, involving MHC1, to additives in healthcare products. Professor Elliott said: \"This is fantastic news. It is a strong indication of the quality of our research that consumer companies such as Unilever are interested in the fundamental science that we are exploring and can see the potential applications for industry even if they are still a long way ahead. By bringing together different disciplines under the umbrella of the IfLS we are making a step change in the way we solve biological problems.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Tissue-resident memory T (T RM ) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens 1 , 2 , 3 , 4 . However, the biological pathways that enable the long-term survival of T RM cells are obscure 4 , 5 . Here we show that mouse CD8 + T RM cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 ( Fabp4 / Fabp5 ) impairs exogenous free fatty acid (FFA) uptake by CD8 + T RM cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T CM ) cells in lymph nodes. In vitro , CD8 + T RM cells, but not CD8 + T CM cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4 / Fabp5 double-knockout CD8 + T RM cells. The persistence of CD8 + T RM cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo . Moreover, skin CD8 + T RM cells that lacked Fabp4 / Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4 / Fabp5 double-knockout CD8 + T RM cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8 + T RM cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8 + T RM cells, and suggest that CD8 + T RM cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity. Main Memory T cells protect the host through rapid recall responses to pathogens. A population of memory T cells that is vital for host defence, T RM cells, has recently been characterized 1 , 2 , 3 , 4 . T RM cells reside in epithelial barrier tissues and persist for long periods of time at the interface between host and environment 3 , 4 . Upon re-infection, CD8 + T RM cells provide a rapid antigen-specific immune response, creating an inflammatory and antiviral microenvironment that facilitates pathogen elimination 6 , 7 , 8 , 9 . Although previous studies have yielded clues 10 , 11 , 12 , 13 , little is known about the molecular program that regulates the long-term survival of these cells. To answer this question, we first evaluated skin T RM cell maturation by comparing gene expression patterns at different time points after infection. OT-I transgenic mouse T cells were transferred into recipient mice one day before immunization with a recombinant VACV that expresses chicken ovalbumin peptide (amino acids 257–264) under the control of an early gene promoter (rVACV OVA ) 14 . OT-I cells were readily found in the skin at day 5 after infection and reached their maximum level at day 10, before beginning to decrease in numbers ( Extended Data Fig. 1a ). Skin-infiltrating OT-I cells were sorted at different time points after infection and were analysed by transcriptional profiling. Principal-component analysis showed that transcriptomes of skin-infiltrating T cells clustered tightly from day 25 to day 90 after infection, suggesting that mouse skin CD8 + T RM cell maturation is largely completed by day 25 after infection ( Fig. 1a ). Transcriptomes of T RM cells are distinct from those of T CM cells and effector memory T (T EM ) cells ( Fig. 1a, b and Extended Data Fig. 1b ), consistent with previous reports 11 , 12 , 13 . Next, we directly compared T RM cells (day 30) and T CM cells ( Fig. 1c ). Notably, genes encoding FABP4 and FABP5 were among the most strongly upregulated genes in T RM cells, as was the gene that encodes CD36, a lipid-scavenger cell-surface receptor 15 ( Fig. 1c ). Quantitative real-time PCR (qPCR) confirmed the increased gene expression of Fabp4 and Fabp5 in CD8 + T RM cells ( Fig. 1d, e and Extended Data Fig. 1c ). Immunofluorescence staining of the skin showed expression of FABP4 and FABP5 in skin CD8 + T RM cells ( Fig. 1f ). To extend these observations to other peripheral tissues, mice with transferred OT-I cells were infected with VACV OVA by intratracheal infection and gene expression of Fabp4 and Fabp5 was measured 30 days later in lung CD8 + T RM cells. Consistently, increased Fabp4 and Fabp5 gene expression was observed ( Extended Data Fig. 1d ). Figure 1: Skin CD8 + T RM cells show increased expression of FABP4 and FABP5. a , Principal-component analysis (PCA) of gene-expression data for CD8 + T cell subtypes. Each time point represents an individual experiment wherein mRNA was pooled from 15–20 mice from 3–4 independent biological groups (5 mice per group). Numbered dots are for skin T cells derived after infection for the indicated number of days. b , Pearson correlation coefficients among CD8 + T cell subtypes. c , Heatmap of differentially expressed genes selected from a pair-wise comparison between OT-I T RM (day 30) and T CM cells. d , qPCR analysis of Fabp4 and Fabp5 expression in T N , T CM , T EM and T RM cells (day 30). e , qPCR analysis of Fabp4 and Fabp5 gene expression in skin CD103 − and CD103 + T RM cells (day 30). f , Immunofluorescence staining of FABP4 (top) and FABP5 (bottom) in OT-I T RM cells 30 days after infection. Scale bar, 20 μm. g , qPCR analysis of Pparg expression in T N , T CM , T EM and T RM", "role": "user" }, { "content": "The capacity for memory isn't exclusive to the brain. The immune system, with its sprawling network of diverse cell types, can recall the pathogens it meets, helping it to swiftly neutralize those intruders upon future encounters. For the last several years, BWH's Thomas Kupper, MD, Chair of the Department of Dermatology, and his colleagues have been studying a unique kind of immune memory cell, known as a tissue-resident memory T (TRM) cell. Discovered more than 10 years ago by Rachael Clark, MD, PhD (also in BWH Dermatology), these cells live in peripheral tissues, like the skin, gut and joints, and are thought to be a key source of the immune system's protective memory. Although much remains to be learned about the biology of these specialized memory T-cells, dysfunctional TRM cells are strongly implicated in autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease and other conditions. To uncover the key genetic signals that guide the development of TRM cells, Kupper and his colleagues, led by postdoctoral fellow Youdong Pan, PhD, took an unbiased approach. They measured the level of gene activity for every gene in the genome as the cells developed in mice. That led the team to a remarkable finding, reported in a recent issue of the journal Nature: genes involved in lipid metabolism are highly active in TRM cells, roughly 20- to 30-fold more active than in other types of T-cells. Among these genes are two key mediators of lipid uptake, fatty-acid-binding proteins 4 and 5 (Fabp4 and Fabp5). Kupper and his colleagues teamed up with Gökhan Hotamisligil, PhD, an expert in lipid biology and metabolism at the Harvard T. H. Chan School of Public Health, to further dissect the roles of Fabp4 and Fabp5 in TRM cells. They found that TRM cells that lack both genes show a striking defect in their ability to import lipids. (Cells lacking just one of the genes are unaffected, likely because the two genes are highly related and perform overlapping functions.) Moreover, these Fabp4- and Fabp5-deficient TRM cells are significantly compromised both in their ability to protect against infection and their long-term survival in peripheral tissues. Based on his team's recent work, Kupper says the picture that is emerging of TRM cells highlights a unique dependence on fatty acids and other lipids as an energy source. Other types of T-cells can also metabolize lipids, but they cannot take them up from the environment, as TRM cells can. This could become an important Achilles' heel for investigators to target in the future. Drugs aimed at inhibiting lipid uptake could enable the selective removal of TRM cells from tissues, while leaving other types of T-cells intact. Current therapies for autoimmune disease are fairly broad in their activity—quieting down many types of immune cells, including TRM cells. But they work transiently, likely because TRM cells remain in place. \"I think the real potential pay off of this story is to try and use this new information therapeutically,\" said Kupper. \"While there are treatments for autoimmune diseases that impact pathogenic tissue-resident memory T-cells, none are able to effectively remove the cells from tissues. We've identified the first plausible mechanism for doing just that.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Physical systems differing in their microscopic details often display strikingly similar behaviour when probed at macroscopic scales. Those universal properties, largely determining their physical characteristics, are revealed by the powerful renormalization group (RG) procedure, which systematically retains ‘slow’ degrees of freedom and integrates out the rest. However, the important degrees of freedom may be difficult to identify. Here we demonstrate a machine-learning algorithm capable of identifying the relevant degrees of freedom and executing RG steps iteratively without any prior knowledge about the system. We introduce an artificial neural network based on a model-independent, information-theoretic characterization of a real-space RG procedure, which performs this task. We apply the algorithm to classical statistical physics problems in one and two dimensions. We demonstrate RG flow and extract the Ising critical exponent. Our results demonstrate that machine-learning techniques can extract abstract physical concepts and consequently become an integral part of theory- and model-building. Main Machine learning has been captivating public attention lately due to groundbreaking advances in automated translation, image and speech recognition 1 , game-playing 2 and achieving super-human performance in tasks in which humans excelled while more traditional algorithmic approaches struggled 3 . The applications of those techniques in physics are very recent, initially leveraging the trademark prowess of machine learning in classification and pattern recognition and applying them to classify phases of matter 4 , 5 , 6 , 7 , 8 , study amorphous materials 9 , 10 , or exploiting the neural networks’ potential as efficient nonlinear approximators of arbitrary functions 11 , 12 to introduce a new numerical simulation method for quantum systems 13 , 14 . However, the exciting possibility of employing machine learning not as a numerical simulator, or a hypothesis tester, but as an integral part of the physical reasoning process is still largely unexplored and, given the staggering pace of progress in the field of artificial intelligence, of fundamental importance and promise. The renormalization group (RG) approach has been one of the conceptually most profound tools of theoretical physics since its inception. It underlies the seminal work on critical phenomena 15 , and the discovery of asymptotic freedom in quantum chromodynamics 16 , and of the Kosterlitz–Thouless phase transition 17 , 18 . The RG is not a monolith, but rather a conceptual framework comprising different techniques: real-space RG 19 , functional RG 20 and density matrix RG 21 , among others. While all of those schemes differ quite substantially in their details, style and applicability, there is an underlying physical intuition that encompasses all of them—the essence of RG lies in identifying the ‘relevant’ degrees of freedom and integrating out the ‘irrelevant’ ones iteratively, thereby arriving at a universal, low-energy effective theory. However potent the RG idea, those relevant degrees of freedom need to be identified first 22 , 23 . This is often a challenging conceptual step, particularly for strongly interacting systems, and may involve a sequence of mathematical mappings to models, whose behaviour is better understood 24 , 25 . Here we introduce an artificial neural network algorithm iteratively identifying the physically relevant degrees of freedom in a spatial region and performing an RG coarse-graining step. The input data are samples of the system configurations drawn from a Boltzmann distribution; no further knowledge about the microscopic details of the system is provided. The internal parameters of the network, which ultimately encode the degrees of freedom of interest at each step, are optimized (‘learned’, in neural network parlance) by a training algorithm based on evaluating real-space mutual information (RSMI) between spatially separated regions. We validate our approach by studying the Ising and dimer models of classical statistical physics in two dimensions. We obtain the RG flow and extract the Ising critical exponent. The robustness of the RSMI algorithm to physically irrelevant noise is demonstrated. The identification of the important degrees of freedom, and the ability to execute a real-space RG procedure 19 , has not only quantitative but also conceptual significance: it allows one to gain insights into the correct way of thinking about the problem at hand, raising the prospect that machine-learning techniques may augment the scientific inquiry in a fundamental fashion. The RSMI algorithm Before going into more detail, let us provide a bird’s eye view of our method and results. We begin by phrasing the problem in probabilistic/information-theoretic terms, a language also used in refs 26 , 27 , 28 , 29 , 30 . To this end, we consider a small ‘visible’ spatial area \\({\\mathscr{V}}\\) , which together with its environment \\({\\mathscr{E}}\\) forms the system \\({\\mathscr{X}}\\) , and we define a particular conditional probability distribution \\({P}_{{\\rm{\\Lambda }}}({\\mathscr{H}}| {\\mathscr{V}})\\) , which describes how the relevant degrees of freedom \\({\\mathscr{H}}\\) (‘dubbed hiddens’) in \\({\\mathscr{V}}\\) depend on both \\({\\mathscr{V}}\\) and \\({\\mathscr{E}}\\) . We then show that the sought-after conditional probability distribution is found by an algorithm maximizing an information-theoretic quantity, the mutual information, and that this algorithm lends itself to a natural implementation using artificial neural networks. We describe how RG is practically performed by coarse-graining with respect to \\({P}_{{\\rm{\\Lambda }}}({\\mathscr{H}}| {\\mathscr{V}})\\) and iterating the procedure. Finally, we provide a verification of our claims by considering two paradigmatic models of statistical physics: the Ising model—for which the RG procedure yields the famous Kadanoff block spins—and the dimer model, whose relevant degrees of freedom are much less trivial. We reconstruct the RG flow of the Ising model and extract the critical exponent. Consider then a classical system of local degrees of freedom \\({\\mathscr{X}}=\\left\\{{x}_{1},\\ldots ,{x}_{N}\\right\\}\\equiv \\left\\{{x}_{i}\\right\\}\\) , defined by a Hamiltonian energy function H ({ x i }) and associated statistical probabilities \\(P({\\mathscr{X}})\\propto {{\\rm{e}}}^{-\\beta {\\rm{H}}\\left(\\left\\{{x}_{i}\\right\\}\\right)}\\) , where β is the inverse temperature. Alternatively (and sufficiently for our purposes), the system is given by Monte Carlo samples of the equilibrium distribution \\(P({\\mathscr{X}})\\) . We denote a small spatial region of interest by \\({\\mathscr{V}}\\equiv \\left\\{{v}_{i}\\right\\}\\) and the remainder of the system by \\({\\mathscr{E}}\\equiv \\left\\{{e}_{i}\\right\\}\\) , so that \\({\\mathscr{X}}=({\\mathscr{V}},{\\mathscr{E}})\\) . We adopt a probabilistic point of view, and treat \\({\\mathscr{X}},{\\mathscr{E}}\\) and so on as random", "role": "user" }, { "content": "Two physicists at ETH Zurich and the Hebrew University of Jerusalem have developed a novel machine-learning algorithm that analyses large data sets describing a physical system and extract from them the essential information needed to understand the underlying physics. Over the past decade, machine learning has enabled groundbreaking advances in computer vision, speech recognition and translation. More recently, machine learning has also been applied to physics problems, typically for the classification of physical phases and the numerical simulation of ground states. Maciej Koch-Janusz, a researcher at the Institute for Theoretical Physics at ETH Zurich, Switzerland, and Zohar Ringel of the Hebrew University of Jerusalem, Israel, have now explored the exciting possibility of harnessing machine learning not as a numerical simulator or a \"hypothesis tester,\" but as an integral part of the physical reasoning process. One important step in understanding a physical system consisting of a large number of entities—for example, the atoms making up a magnetic material—is to identify among the many degrees of freedom of the system those that are most relevant for its physical behaviour. This is traditionally a step that relies heavily on human intuition and experience. But now, Koch-Janusz and Ringel demonstrate a machine-learning algorithm based on an artificial neural network that is capable of doing just that, as they report in the journal Nature Physics. Their algorithm takes data about a physical system without any prior knowledge about it and extracts those degrees of freedom that are most relevant to describe the system. Technically speaking, the machine performs one of the crucial steps of one of the conceptually most profound tools of modern theoretical physics, the so-called renormalization group. The algorithm of Koch-Janusz and Ringel provides a qualitatively new approach: the internal data representations discovered by suitably designed machine-learning systems are often considered to be obscure, but the results yielded by their algorithm provide fundamental physical insight, reflecting the underlying structure of physical system. This raises the prospect of employing machine learning in science in a collaborative fashion, combining the power of machines to distil information from vast data sets with human creativity and background knowledge. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Test anxiety may be better thought of as a biopsychosocial process affecting academic performance during the days leading up to an exam, rather than a static appraisal of attitudes related to test taking. This was a passive observational study following students 2 days before a midterm exam and was designed to test the Sleep Anxiety Performance Process (SAPP) model in the context of a psychology statistics exam. Methods Undergraduates ( N = 167) enrolled in a statistics class, January–November 2015. Participants completed an electronic battery of measures and Sleep Mood Study Diaries (SMS) during the mornings, 2 days before a statistics exam. Instructors confirmed exam scores. Results A path model showed a reciprocal bi-directional relationship between Sleep Quality and restfulness (Q&R) and test anxiety 2 days before a scheduled exam, with test anxiety measured in the morning, before the exam predicting exam performance. Prior exam performance, being a non-native English speaker (ESL), and class performance motivation also predicted exam performance. Conclusions These data support the SAPP model’s premise that that sleep and anxiety feed one another, as a reciprocal process, that collectively impairs academic performance, with direct effects on academic performance, but with implications for overall student health. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Test anxiety has been defined as the emotional, physiological, and behavioral responses in the anticipation of negative evaluation from an upcoming test or exam [ 1 ]. Between 10 and 40% of students experience test anxiety and students with higher levels of test anxiety perform more poorly on tests and have lower Grade Point Averages (GPA: the accumulated average of point values assigned to final letter grades, typically ranging from 1 to 4, with an A = 4 points, a B = 3, etc.) [ 2 ]. However, consequences of test anxiety extend beyond the classroom and are correlated with poor health behaviors, including dysregulated sleep patterns and poor sleep quality [ 3 ]. Given the well-known bi-directional relationship between sleep and anxiety [ 4 ], it would be important to understand the specific pathways by which anxiety and sleep predicts exam performance and potentially unfold over the course of the several days prior to an exam. Characteristics of the relationship between test-taking and anxiety have been well documented. Although trait anxiety is related to test anxiety and GPA [ 5 ], state and test-specific anxiety measured immediately before an exam have been shown to have stronger relationships to performance than do more distal measures of state anxiety [ 6 , 7 ]. In one particularly well-designed study, researchers assessed trait anxiety, state anxiety, and statistics specific anxiety. Measured 2 weeks before the exam, trait anxiety was related to statistics specific anxiety and state anxiety. However, performance was predicted by attitudes about math and interest in the class, statistics specific anxiety, and state anxiety measured proximal to the test [ 6 ]. Test anxiety varies across time [ 7 ], across classes, and attitudes about subject matter are important. In particular, statistics classes are associated with high levels of anxiety [ 1 , 8 ], especially for female students [ 9 ], and class performance has been shown to be driven both by attitudes about the specific class and anxiety [ 6 ]. Although most test anxiety studies have only examined the relationship between test anxiety and performance, extant research suggests that sleep is related to both academic performance and anxiety. For instance, sleep deprivation has been found to compromise a broad array of memory processes [ 10 ]. Average sleep duration, sleep habits, and chronotype have been found to predict GPA [ 11 , 12 , 13 , 14 ] and medical students’ exam scores [ 15 ]. In an illustrative study, end of the semester undergraduate course performance was predicted by prior academic performance, study habits, chronotype, sleep duration, and sleep quality [ 16 ]. In any study of exam anxiety, it would be important to measure both anxiety and sleep as sleep problems such as insomnia and anxiety are highly correlated [ 17 ]. State and trait anxiety have documented relationships to shorter total sleep time and disrupted sleep [ 18 , 19 ], longer sleep onset latencies, more Wake Time after Sleep Onset (WASO [ 20 ]), and there is evidence of a bidirectional relationship between poor sleep and anxiety [ 4 ]. A few studies have examined exam-related anxiety, sleep, and exam performance. Among college students, test anxiety was related to sleep duration and quality the night before an exam, but only test anxiety predicted actual exam performance [ 18 ]. Stress (a construct related to anxiety) was found to increase, and sleep quality (but not duration) was found to decrease in the week before an exam period [ 21 ]. Stress and sleep duration were related to academic performance among medical students [ 22 , 23 ]. During the month before a high-stakes exam, stress increased and sleep duration decreased; however, the individual relationship of stress and sleep disruption were not examined [ 22 ]. Collectively, these studies indicate that anxiety (and stress) and poor sleep (shorter duration and poor quality) go hand in hand. However, the temporal relationship between sleep disruption and anxiety has not yet been explicitly examined. The Present Study Test anxiety is a serious academic problem for college students. However, the bidirectional relationship between sleep and anxiety suggests that it would be important to examine the temporal relationship between sleep (duration and quality) and test anxiety as predictors of academic performance. Because there is an abundance of research documenting a reciprocal relationship between sleep problems such as insomnia and anxiety, we proposed that the effects of test anxiety on academic performance would unfold as a reciprocal process, across several days, as represented by the Sleep Anxiety Performance Process (SAPP) model. Moreover, given the relationship of sleep problems to decrements in memory, we predicted that sleep would mediate the relationship between", "role": "user" }, { "content": "College students across the country struggle with a vicious cycle: Test anxiety triggers poor sleep, which in turn reduces performance on the tests that caused the anxiety in the first place. New research from the University of Kansas just published in the International Journal of Behavioral Medicine is shedding light on this biopsychosocial process that can lead to poor grades, withdrawal from classes and even students who drop out. Indeed, about 40% of freshman don't return to their universities for a second year in the United States. \"We were interested in finding out what predicted students' performance in statistics classes—stats classes are usually the most dreaded undergrad class,\" said lead author Nancy Hamilton, professor of psychology at KU. \"It can be a particular problem that can be a sticking point for a lot of students. I'm interested in sleep, and sleep and anxiety are related. So, we wanted to find out what the relationship was between sleep, anxiety and test performance to find the correlation and how it unfolds over time.\" Hamilton and graduate student co-authors Ronald Freche and Ian Carroll and undergraduates Yichi Zhang and Gabriella Zeller surveyed the sleep quality, anxiety levels and test scores for 167 students enrolled in a statistics class at KU. Participants completed an electronic battery of measures and filled out Sleep Mood Study Diaries during the mornings in the days before a statistics exam. Instructors confirmed exam scores. The study showed \"sleep and anxiety feed one another\" and can hurt academic performance predictably. \"We looked at test anxiety to determine whether that did predict who passed, and it was a predictor,\" Hamilton said. \"It was a predictor even after controlling for students' past performance and increased the likelihood of students failing in class. When you look at students who are especially anxious, it was almost a five-point difference in their score over students who had average levels of anxiety. This is not small potatoes. It's the difference between a C-minus abd a D. It's the difference between a B-plus and an A-minus. It's real.\" Beyond falling grades, a student's overall health could suffer when test anxiety and poor sleep reinforce each other. \"Studies have shown students tend to cope with anxiety through health behaviors,\" Hamilton said. \"Students may use more caffeine to combat sleep problems associated with anxiety, and caffeine can actually enhance sleep problems, specifically if you're using caffeine in the afternoon or in the evening. Students sometimes self-medicate for anxiety by using alcohol or other sedating drugs. Those are things that we know are related.\" Hamilton said universities could do more to communicate to students the prevalence of test anxiety and provide them with resources. \"What would be really helpful for a university to do is to talk about testing anxiety and to talk about the fact that it's very common and that there are things that can be done for students who have test anxiety,\" she said. \"A university can also talk to instructors about doing things that they can do to help minimize the effect of testing anxiety.\" According to Hamilton, instructors are hindered by the phenomenon as well: Anxiety and associated sleep problems actually distort instructors' ability to measure student knowledge in a given subject. \"As an instructor, my goal when I'm writing a test is to assess how much a student understands,\" she said. \"So having a psychological or an emotional problem gets in the way of that. It actually impedes my ability to effectively assess learning. It's noise. It's unrelated to what they understand and what they know. So, I think it behooves all of us to see if we can figure out ways to help students minimize the effects of anxiety on their performance.\" The KU researcher said testing itself isn't the problem and suggested an increase in regular tests might reduce anxiety through regular exposure. However, she said a few small changes to how tests are administered also could calm student anxiety. \"In classes that use performance-based measures like math or statistics, classes that tend to really induce a lot of anxiety for some students, encouraging those students to take five minutes right before an exam to physically write about what they're anxious about can help—that's cheap, that's easy,\" Hamilton said. \"Also, eliminating a time limit on a test can help. There's just really nothing to be gained by telling students, 'You have an hour to complete a test and what you don't get done you just don't get done.' That's really not assessing what a student can do—it's only assessing what a student can do quickly.\" Hamilton said going forward she'd like research into the link between test anxiety and poor sleep broadened to include a more diverse group of students and also to include its influence on remote learning. \"The students in this study were mostly middle-class, Caucasian students,\" she said. \"So, I hesitate to say these results would generalize necessarily to universities that have a more heterogeneous student body. I also would hesitate to say how this would generalize into our current Zoom environment. I don't know how that shakes out because the demands of doing exams online are likely to be very different.\" ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The hygroscopic deformation of pine cones, featured by opening and closing their scales depending on the environmental humidity, is a well-known stimuli-responsive model system for artificial actuators. However, it has not been noted that the deformation of pine cones is an ultra-slow process. Here, we reveal that vascular bundles with unique parallelly arranged spring/square microtubular heterostructures dominate the hygroscopic movement, characterized as ultra-slow motion with the outer sclereids. The spring microtubes give a much larger hygroscopic deformation than that of the square microtubes along the longitudinal axis direction, which bends the vascular bundles and consequently drives the scales to move. The outer sclereids with good water retention enable the vascular-bundle-triggered deformation to proceed ultra-slowly. Drawing inspiration, we developed soft actuators enabling controllable yet unperceivable motion. The motion velocity is almost two orders of magnitude lower than that of the same-class actuators reported, which made the as-developed soft actuators applicable in camouflage and reconnaissance. Main Stimuli-responsive deformation is an important seed dispersal strategy for many natural organisms 1 , 2 , 3 , 4 , 5 , 6 , and clarifying the underlying mechanisms has become increasingly non-trivial for designing stimuli-responsive materials 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . The pine cone, a typical natural organism with hygroscopic deformation character, has gained a good reputation as a bionic model for constructing artificial actuators 15 , 16 , 17 , 18 , 19 , 20 . Specifically, the pine cone is capable of humidity-responsive geometric reshaping, characterized by reversible opening and closing of the scales by alternately decreasing and increasing the environmental humidity (Fig. 1a and Supplementary Fig. 1 ). However, it has not been noted that the hygroscopic deformation of the pine cone is an ultra-slow process, with a velocity (normalized by the thickness) 21 much lower than that of other hygroscopic plant organisms such as wheat awn and seed capsules. To be noticed, such ultra-slow motion also proceeds rather steadily with a large amplitude (Fig. 1b and Supplementary Table 1 ) 2 , 5 , 22 , 23 . Therefore, the pine cone opens only in a long-term dry environment, which is beneficial to the long-distance dispersal of seeds from the parent tree by wind and animals 24 . Fig. 1: The typical slow hygroscopic geometric reshaping of a pine cone and its hierarchical components of scale, skin, skeleton and VB. a , Opening process of a waterlogged pine cone. The waterlogged pine cone gradually opened over time at 35 °C with a RH of 30–40% and took over 24 hours to reach the fully open state. b , Summary of the deformation velocity and capability of various hygroscopic plant organisms, where the pine cone scale (stars) exhibits the smallest thickness-normalized velocity (brown symbols) while still having quite a large deformability (green symbols). c , Optical images of front and side views of the samples: the whole scale, skin, skeleton and VB. d , The humidity-responsive reversible bending of the whole scale, skin, skeleton and VB. Top, optical images showing the dynamic processes. Bottom, the deformation of wet samples in air versus time, characterized by the change of the distance l between the tip (point P 1 ) and the tail (point O) of the sample and the tilt angle θ of the tip–tail line (brown line) relative to the horizontal axis (black dashed arrow; upper left). All samples are almost straight with the largest l 0 and θ (90°) at the wet state. The solid line in the lower plot represents mean values, and the shaded region represents the standard deviation from three repeated experiments. e , The deformation capability characterized by Δ l / l 0 and Δ θ and the velocity characterized by (Δ l / l 0 )/Δ t and Δ θ/ Δ t of the scale, skin, skeleton and VB. The data in e are presented as mean ± standard deviation (s.d.) of n = 3 measurements. Source data Full size image Numerous efforts have been made to explore the bending mechanism of the pine cone scale 1 , 25 , 26 , 27 , 28 , 29 , 30 . As reported by Shaw 25 , the opening of pine cones is caused by a larger shrinkage of the bast tissues (sclereids) than that of the vascular tissues in the scale. Further, the difference in the hygroscopic expansion was found to be controlled by the microfibril orientation in these two tissue cells 1 , 26 , 27 . The microfibrils in vascular tissues are oriented towards the long axis of the cell and constrain the cell deformation, while the microfibrils in sclereid cells are perpendicular to the cell’s long axis, which endow the cell with a larger expansion rate and lower stiffness along this long axis. For a long time, the hygroscopic movement of the pine cone has been ascribed to the uneven hygroscopic expansion of vascular bundles (VBs) and sclereids in the scale 1 , 30 . Recently, some researchers observed that the VBs and sclereids can deform separately 28 , 29 ; however, the bending mechanism of the VBs and their contributions to the bending of the whole scale remain unexplored. Here, we report that the hygroscopic deformation of the pine cone is an ultra-slow process dominated by VBs with a unique spring/square ( ○ /□) microtube heterostructure. As environmental humidity changes, spring microtubes give a larger deformation than do square microtubes, which drives the hygroscopic deformation of the VBs. With VBs imbedded in the sclereids with good water retention, the pine cone scale exhibits a much lower deformation velocity than other plant tissues, by at least one order of magnitude. Drawing inspiration, we fabricated actuators whose motion is almost unperceivable due to the rather low motion velocity of 10 –5 BL s –1 where BL is body length, which is two orders of magnitude lower than that of other reported humidity-driven actuators (around 10 –3 to 10 –1 BL s –1", "role": "user" }, { "content": "In a study recently published in Nature Materials, Prof. Wang Shutao from the Technical Institute of Physics and Chemistry (TICP) of the Chinese Academy of Sciences (CAS) and Prof. Liu Huan from Beihang University revealed the secret of ultra-slow motion of pine cones and developed mimicking actuators enabling unperceivable motion. Responsive actuators have attracted extensive attention by virtue of their great potential applications in flexible robotics, sensors, energy conversion and other fields. Pine cones are a well-known bionic model for constructing artificial actuators. However, little attention has been paid to the fact that the hygroscopic motion of pine cones is an ultra-slow process. Hygroscopic deformation has long been attributed to the uneven hygroscopic expansion of vascular bundles (VBs) and sclereids, controlled by their different microfibril orientations. The mechanism cannot explain the observation that VBs themselves are capable of reversible hygroscopic motion. Therefore, the mechanism of ultra-slow motion in pine cones has long been unclear. In this work, the researchers revealed that VBs are composed of unique parallelly arranged spring/square microtubes forming heterostructures. The spring microtubes show much larger hygroscopic deformation than do square microtubes along the longitudinal axis direction. This deformation bends the VBs and consequently drives the scales to move as humidity changes. Pine-cone-inspired actuators with unperceivable motions. Credit: TICP In addition, the soft outer sclereids, which have good water retention, slow down the VB-triggered motion without compromising motion amplitude. Drawing inspiration from this observation, the researchers prepared one-dimensional (1D) heterostructured spring/square pillars filled with a hygroscopic polymer to mimic the skin in the scales, which increases the water diffusion path and decreases the overall expansion velocity. With the spring/square pillars as basic units, they developed soft actuators enabling controllable yet unperceivable motion, which is two orders of magnitude slower than motion enabled by other reported actuators. \"This study offers deep insight into understanding the well-known hygroscopic deformation of the pine cone and other plant tissues capable of moving, but also into developing stimuli-responsive actuators that enable motion to proceed extremely slowly and unperceivably,\" said Prof. Wang. They envision such actuators enabling ultra-slow motion for use in various camouflage and reconnaissance applications, according to Prof. Liu. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci ( IQCK , ACE , ADAM10 , ADAMTS1 , and WWOX ), two of which ( ADAM10 , ACE ) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. Main Our previous work identified 19 genome-wide-significant common variant signals in addition to APOE that influence risk for LOAD (onset age > 65 years) 1 . These signals, combined with ‘subthreshold’ common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 3 . To search for additional signals, we conducted a GWAS meta-analysis of non-Hispanic Whites (NHW) by using a larger Stage 1 discovery sample (17 new, 46 total datasets; n = 21,982 cases, 41,944 cognitively normal controls) from our group, the International Genomics of Alzheimer’s Project (IGAP) (composed of four consortia: Alzheimer Disease Genetics Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), The European Alzheimer’s Disease Initiative (EADI), and Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES) (Supplementary Tables 1 and 2 , and Supplementary Note ). To sample both common and rare variants (minor allele frequency (MAF) ≥ 0.01 and MAF < 0.01, respectively), we imputed the discovery datasets by using a 1,000 Genomes reference panel consisting of 36,648,992 single-nucleotide polymorphisms (SNPs), 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis. Genotype dosages were analyzed within each dataset, and then combined with meta-analysis (Supplementary Fig. 1 and Supplementary Tables 1– 3). Results Meta-analysis of Alzheimer’s disease GWAS The Stage 1 discovery meta-analysis produced 12 loci with genome-wide significance ( P ≤ 5 × 10 −8 ) (Table 1 ), all of which are previously described 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Genomic inflation factors ( λ ) were slightly inflated ( λ median = 1.05; λ regression = 1.09; see Supplementary Figure 2 for a quantile–quantile (QQ) plot); however, univariate linkage disequilibrium score (LDSC) regression 12 , 13 estimates indicated that the majority of this inflation was due to a polygenic signal, with the intercept being close to 1 (1.026, s.e.m. = 0.006). The observed heritability ( h 2 ) of LOAD was estimated at 0.071 (0.011) using LDSC. Stage 1 meta-analysis was first followed by Stage 2, using the I-select chip we previously developed in Lambert et al. 1 (including 11,632 variants, n = 18,845; Supplementary Table 4 ) and finally Stage 3A ( n = 11,666) or Stage 3B ( n = 30,511) (for variants in regions not well captured in the I-select chip) (see Supplementary Figure 1 for the workflow). The final sample was 35,274 clinical and autopsy-documented Alzheimer’s disease cases and 59,163 controls. Table 1 Summary of discovery Stage 1, Stage 2 and overall meta-analyses results for identified loci reaching genome-wide significance after Stages 1 and 2 Full size table Meta-analysis of Stages 1 and 2 produced 21 genome-wide-significant associations ( P ≤ 5 × 10 −8 ) (Table 1 and Fig. 1 ), 18 of which were previously reported as genome-wide significant in Lambert et al. 1 . Three other signals were not initially described in the initial IGAP GWAS: the rare R47H TREM2 coding variant previously reported by others 7 , 8 , 14 ; ECHDC3 (rs7920721; NC_000010.10 : g.11720308A>G), which was recently identified as a potential genome-wide-significant Alzheimer’s disease risk locus in several studies 15 , 16 , 17 , and ACE (rs138190086; NC_000017.10 : g.61538148G>A) (Supplementary Figs. 3 and 4 ). In addition, seven signals showed suggestive association with P < 5 × 10 −7 (closest genes: ADAM10 , ADAMTS1 , ADAMTS20 , IQCK , MIR142/TSPOAP1-AS1 , NDUFAF6 , and SPPL2A ) (Supplementary Figs. 5 – 11 ). Stage 3A and meta-analysis of all three stages for these nine signals (excluding the TREM2 signal; see Supplementary Table 5 for the variant list) identified five genome-wide-significant loci. In addition to ECHDC3 , this included four new genome-wide Alzheimer’s disease risk signals at IQCK , ADAMTS1 , ACE , and ADAM10 (Table 2 ) . ACE and ADAM10 were previously reported as Alzheimer’s disease candidate genes 18 , 19 , 20 , 21 , 22 but were not replicated in some subsequent studies 23 , 24 , 25 . A recent GWAS using family history of Alzheimer’s disease or dementia as a proxy 26 also identified these two risk loci, suggesting that while use of proxy Alzheimer’s disease/dementia cases introduces less sensitivity and specificity for true Alzheimer’s disease signals overall in comparison to clinically diagnosed Alzheimer’s disease, proxy studies can identify disease-relevant associations. Two of the four other signals approached genome-wide significance: miR142/TSPOAP1-AS1 ( P = 5.3 × 10 −8 ) and NDUFAF6 ( P = 9.2 × 10 −8 ) (Table 2 ). Stage 3A also extended the analysis of two loci ( NME8 and MEF2C ) that were previously genome-wide significant in our 2013 meta-analysis. These loci were not genome-wide significant in our current study and will deserve", "role": "user" }, { "content": "Analysis of genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer's disease, and confirmed 20 known others. An international team of researchers also reports for the first time that mutations in genes specific to tau, a hallmark protein of Alzheimer's disease, may play an earlier role in the development of the disease than originally thought. These new findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are \"genetic hubs\" that are an important part of the disease process. The study, which was funded in part by the National Institute on Aging (NIA) and other components of the National Institutes of Health, follows results from 2013. It will be published online February 28, 2019 in the journal Nature Genetics. \"This continuing collaborative research into the genetic underpinnings of Alzheimer's is allowing us to dig deeper into the complexities of this devastating disease,\" said Richard J. Hodes, M.D., director of the NIA. \"The size of this study provides additional clarity on the genes to prioritize as we continue to better understand and target ways to treat and prevent Alzheimer's.\" The researchers, members of the International Genomic Alzheimer's Project (IGAP), analyzed both rare and common gene variants in 94,437 individuals with late onset Alzheimer's disease, the most common form of dementia in older adults. IGAP is made up of four consortia in the United States and Europe that have been working together since 2011 on genome-wide association studies (GWAS) involving thousands of DNA samples and shared datasets. GWAS are aimed at detecting variations in the genome that are associated with Alzheimer's. Understanding genetic variants is helping researchers define the molecular mechanisms that influence disease onset and progression. In addition to confirming the known association of 20 genes with risk of Alzheimer's and identifying five additional Alzheimer's-associated genes, these genes were analyzed to see what cellular pathways might be implicated in the disease process. The pathway analysis implicated the immune system, lipid metabolism and amyloid precursor protein (APP) metabolism. Mutations in the APP gene have been shown to be directly related to early onset Alzheimer's. The present study, done in late onset Alzheimer's subjects, suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer's and with late onset Alzheimer's. In addition, for the first time, the study implicated a genetic link to tau binding proteins. Taken together, data suggest that therapies developed by studying subjects with early-onset disease could also be applied to the late-onset form of Alzheimer's. The research was led by an international team of experts including Brian Kunkle, Ph.D. and Margaret Pericak-Vance, Ph.D., from the Miller School of Medicine's John P. Hussman Institute for Human Genomics at the University of Miami, and Benjamin Grenier-Boley, Ph.D. and Jean-Charles Lambert, Ph.D., from INSERM, Lille, France. Once the functions of the five genes newly associated with Alzheimer's—IQCK, ACE, ADAM10, ADAMTS1 and WWOX—are understood and examined in conjunction with the functions of the 20 known genes, researchers will be in a better position to identify where the genetic hubs of Alzheimer's are clustering. Armed with these findings, researchers can look more deeply into these genetic hubs to reveal disease mechanisms and potential drug targets. A key to these discoveries was the sample size, the largest to date for this kind of Alzheimer's study. A large sample is especially important to find rare genes that might be involved with a disease. \"Having more and more samples in GWAS data sets is like adding more and more pixels to a photograph—it helps researchers see details that they otherwise wouldn't and helps them decide where to focus further study,\" explained Marilyn Miller, Ph.D., director of the Genetics of Alzheimer's Disease program in the Division of Neuroscience at NIA. \"If the genes only appear in one out of ten thousand people, you need to find several samples containing those genes for results to be statistically significant.\" Miller also emphasized the collaborative resources that made these discoveries possible. In addition to IGAP, the study resulted from open data sharing and coordination among the Alzheimer's Disease Research Centers (funded under a variety of awards), the National Alzheimer's Coordinating Center, the NIA Genetics of Alzheimer's Disease Data Storage Site, the National Cell Repository for Alzheimer's Disease, Alzheimer's Disease Genetics Consortium, the CHARGE Consortium, and the Late-onset Alzheimer's Disease Family Study. ", "role": "assistant" } ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the early 1930’s, Fermi wrote two papers in which he introduced the concepts of “scattering length” and “pseudopotential.” Since that time, these terms have become universally associated with low energy scattering phenomena. Even though the two papers are very different—one in atomic physics, the other in neutron physics—a simple figure underlies both. The figure appears many times in Fermi’s work. We review how the two papers came about and briefly discuss modern developments of the work that Fermi initiated with these two remarkable papers. Working on a manuscript? Avoid the common mistakes 1 Introduction Close to ninety years ago Fermi wrote papers defining two terms now universally used to describe scattering processes: “scattering length” and “pseudopotential.” The papers discussed phenomena that could hardly be more different. The 1934 paper [ 9 ] focused on atomic spectroscopy, explaining the puzzling pressure shift of spectral lines in highly excited alkali metal atoms [ 1 ]. The 1936 paper [ 11 ] focused on the scattering of thermal neutrons from free protons and from protons bound in materials. But as Segre notes, p706, in his commentaries to Fermi’s collected papers [ 13 ] “Fermi had a great insight for discerning analogies in phenomena which were completely unrelated.” Both papers do indeed have a common feature: a drawing, almost a sketch, of a radial wave function inside and outside a potential well. A version of the figure appears thirteen times in the collected works, six times in his nuclear physics notes [ 12 ] and became, as Segre notes further “… a sort of trademark in many of his (Fermi’s) later theoretical studies.” In our paper here, we discuss the history of these two papers, the way the figure was utilized by Fermi, and how his thinking evolved between the first and the second publications. We think it is a useful exercise to go back and be reminded of the creative processes of one of the twentieth century’s most innovative physicists. While both papers were first written in Italian, the second was subsequently translated into English [ 13 ] and is better known, to the extent that often the neutron paper is cited as the genesis of the idea of the pseudopotential. But primacy of the original ideas does lie with the first paper from atomic physics. The methodology he developed there for analyzing spectroscopic data continued to be cited into the 1980’s [ 20 ]. And interestingly, most of the applications today of the pseudopotential concept lie in the field of atom–atom interactions in ultracold systems. During this period, Fermi also wrote his primary papers [ 10 ] explaining beta decay. CN Yang relates [ 28 ] that Wigner considered this to be Fermi’s most important contribution to physics. The figure does not appear there of course. But it does have a feature these other two papers have: squeezing what you do not know into an increasingly smaller volume—eventually a delta-function—and characterizing your lack of knowledge by a single number, \\(G_F\\) in beta decay, the scattering length a , for low energy scattering processes. 2 Fermi’s paper of 1934 The goal of the paper was to explain shifts to higher energy of alkali metal absorption spectral lines due to the interaction with “foreign” neutral atoms. Of particular interest were transitions from very high lying levels, for example, 3S–30P in sodium. Simple Bohr model scaling puts the radius of the valence electron orbit at ~ 500 Å. At a gas pressure of one atmosphere, the electron can then collide with of order 13,000 foreign atoms in the atom volume. At this excitation energy, the valence electron is barely bound, with kinetic energy ~ 0.015 eV and de Broglie wavelength ~ 100 Å. Atomic spectroscopy was a strength of Fermi’s colleagues at Rome. In late 1933, Amaldi and Segre [ 1 ] had investigated pressure broadening of sodium spectral lines due to “perturber” atoms and had found puzzling results. They had expected the foreign gas to destroy the high terms of the absorption series, spreading the lines out so they were no longer clearly visible. That did not happen. Furthermore, they expected the spectral lines to always shift to the red. That did not happen either. In argon, the lines did shift red. But in nitrogen, they did not shift at all, and in hydrogen and helium, they shifted blue. The shift to the red was based on the idea that the foreign gas atoms would be polarized by the residual field + e of the core of the alkali metal atom (Z protons, Z-1 electrons). This would lower the energy of the outer electron to account for the energy stored in the polarization electric field. A classical analogy would be a capacitor consisting of two spherical shells, with a dielectric consisting of foreign gas atoms in between the two shells. The energy is \\(U=\\frac{1}{2}{Q}^{2}/C\\) and with Q fixed as C increases by a factor k , the dielectric constant, the energy U of the system goes down. Fermi introduced his own version of the polarization model. Taking advantage of a calculation by his colleague Wick [ 27 ], he confirmed that while the polarization shift had about the right magnitude, the effect was always to the red, lower in energy. Footnote 1 With the failure of the polarization model, Fermi then proceeded to look for an alternate explanation, this time focusing on the behavior of the valence electron as it travels slowly in its orbit. Denoting R as the magnitude of the distance of the electron from the core of the alkali atom, and r as the magnitude of the distance of the electron from the perturbing neutral atom, he writes the Schrodinger equation for the wave function of the electron as: $${\\nabla }^{2} \\psi \\left(r\\right)+\\left(\\frac{8{\\pi }^{2}m}{{h}^{2}}\\right)\\left(\\epsilon -U\\left(R\\right)\\right) \\psi \\left(r\\right)-\\left(\\frac{8{\\pi }^{2}m}{{h}^{2}}\\right)\\sum_{i}{V}_{i}{\\psi} \\left(r\\right)\\,\\,\\hbox{=}\\,\\,0$$ (1) Here, \\(V_i(r)\\) is the potential well due to perturber atom i , and U ( R ) is the weak and slowly varying coulomb attraction of the alkali atom", "role": "user" }, { "content": "One way to better understand an atom is to shoot a particle at it and infer the atom's properties based on how the particle bounces off it. In the mid-1930s, the physicist Enrico Fermi showed that one measurable number—the scattering length—illuminated everything that could be known about an electron scattering off an atom, or a neutron scattering off a nucleus. In a new paper in EPJ Historical Perspectives on Contemporary Physics, Chris Gould from North Carolina State University in Raleigh, U.S., explains how Fermi's simple sketch of a radial wave function laid the groundwork for a better understanding of low energy scattering phenomena, and led in turn to the concept of the pseudopotential, widely used in many areas of physics, including ultracold atom research and studies of qubits in realizations of quantum computers. In Fermi's atomic physics paper, published in 1934, his sketch of a radial wave function—the value of a wave function at some distance from a scatterer—was the clue that led him to understand a puzzling result in atomic spectroscopy. In his neutron physics paper, published in 1936, Fermi went in a different direction, employing the scattering length concept to introduce a new idea—the pseudopotential, a potential well with a radius of zero—to correctly predict how a neutron scatters in paraffin. Gould concludes that Fermi's extraordinary intuition enabled the physicist to apply concepts to seemingly unrelated areas, and to develop ideas that impact the world of quantum physics to this day. ", "role": "assistant" } ]

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