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Dimerisation of APOBEC1 is dispensable for its RNA/DNA editing activity and modulates its availability The AID/APOBECs are DNA/RNA deaminases whose mutagenic activity has been linked to cancer. Among them, APOBEC1 physiologically partakes into a complex that edits a CAA codon into UAA Stop codon in the transcript of Apolipoprotein B (APOB), a protein crucial in the transport of lipids in the blood. Catalytically inactive mutants of APOBEC1 have a dominant negative effect on its activity, as they compete for the targeting of the APOB mRNA. Here we titrate APOBEC1-mediated editing in presence of catalytically inactive chimeras and mutants of APOBEC1, and we show that APOBEC1 inability to dimerise is the main determinant for its activity. This property is especially evident in an APOBEC1 mutant (L173A G227A) with increased activity on RNA despite decreased self-interaction. Moreover, dimerisation protects APOBEC1 from degradation and regulates its availability. Considering APOBEC1 capability to target DNA, we demonstrate that increased availability of the protein due to dimerisation leads to increase in the DNA damage induced by APOBEC1. These findings demonstrate that dimerisation, a property common to other APOBECs targeting DNA, might represent another layer in the regulation of this editing enzyme.
BULLET POINTSO_LIAPOBEC1 inability to dimerise is the main determinant for its activity.
C_LIO_LIDimerisation protects APOBEC1 from degradation and regulates its availability.
C_LIO_LIAlterations in the balance between monomeric and dimeric APOBEC1 increase DNA damage.
C_LI | molecular biology |
Diversity and composition of cave methanotrophic communities Methane oxidizing bacteria (methanotrophs) are a ubiquitous group of microorganisms that represent a major sink for the greenhouse gas methane (CH4). Recent studies have demonstrated that methanotrophs are abundant and contribute to CH4 dynamics in caves. However, very little is known about what controls the distribution and abundance of methanotrophs in subterranean ecosystems. Here, we report a survey of sediments collected from >20 caves in North America to elucidate the factors shaping cave methanotroph communities. Using 16S rRNA sequencing, we recovered methanotrophs from nearly all (98 %) of the samples, including cave sites where CH4 concentrations were at or below detection limits ([≤] 0.3 ppmv). We identified a core microbiome among caves that was dominated by members of the USC-{gamma} clade, which are recognized as high-affinity methanotrophs. Although methanotrophs were associated with local-scale mineralogy, their community composition did not systematically vary between the entrances and interior of caves, where CH4 concentrations varied. However, we did detect a decay in compositional similarity of methanotrophic community composition with geographic distance. This biogeographic pattern is consistent with dispersal limitation perhaps due to the insular nature of cave ecosystems. Last, the relative abundance of methanotrophs was positively correlated with cave-air CH4 concentrations--suggesting that these microorganisms contribute to CH4 flux in subterranean ecosystems.
IMPORTANCERecent observations have shown that the atmospheric greenhouse gas methane (CH4) is consumed by microorganisms (methanotrophs) in caves at rates comparable to CH4 oxidation in surface soils. Caves are abundant in karst landscapes that comprise 14 % of Earths land surface area, and therefore may be acting as a substantial CH4 sink. A detailed ecological understanding of the forces that shape methanotrophic communities in caves is lacking. We sampled cave sediments to better understand the community composition and structure of cave methanotrophs. Our results show that the members of the USC-{gamma} clade are dominant in cave communities, that the relative abundance of methanotrophs was positively correlated with CH4 concentrations in cave air, and that methanotroph relative abundance was correlated with local scale mineralogy of soils. | microbiology |
Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies.
Author SummaryOutbred Sprague Dawley rats are among the most commonly used rats for neuroscience, physiology and pharmacological research; in the year 2020, 4,188 publications contained the keyword "Sprague Dawley". Rats identified as "Sprague Dawley" are sold by several commercial vendors, including Charles River Laboratories and Harlan Sprague Dawley Inc. (now Envigo). Despite their widespread use, little is known about the genetic diversity of SD. We genotyped more than 4,000 SD rats, which we used for a genome-wide association study (GWAS) and to characterize genetic differences between SD rats from Charles River Laboratories and Harlan. Our analysis revealed extensive population structure both between and within vendors. The GWAS for Pavlovian conditioned approach (PavCA) identified a number of genome-wide significant loci for that complex behavioral trait. Our results demonstrate that, despite sharing an identical name, SD rats that are obtained from different vendors are very different. Future studies should carefully define the exact source of SD rats being used and may exploit their genetic diversity for genetic studies of complex traits. | genetics |
Nuclear envelope budding is a response to cellular stress Nuclear envelope budding (NEB) is a recently discovered alternative pathway for nucleocytoplasmic communication distinct from the movement of material through the nuclear pore complex. Through quantitative electron microscopy and tomography, we demonstrate how NEB is evolutionarily conserved from early protists to human cells. In the yeast Saccharomyces cerevisiae, NEB events occur with higher frequency during heat shock, upon exposure to arsenite or hydrogen peroxide, and when the proteasome is inhibited. Yeast cells treated with azetidine-2-carboxylic acid, a proline analogue that induces protein misfolding, display the most dramatic increase in NEB, suggesting a causal link to protein quality control. This link was further supported by both localization of ubiquitin and Hsp104 to protein aggregates and NEB events, and the evolution of these structures during heat shock. We hypothesize that NEB is part of normal cellular physiology in a vast range of species and that in S. cerevisiae NEB comprises a stress response aiding the transport of protein aggregates across the nuclear envelope.
Significance StatementA defining feature of eukaryotes is the nuclear envelope, a double lipid bilayer that serves to isolate and protect the cells genetic material. Transport of large molecules over this barrier is believed to occur almost exclusively via the nuclear pores. However, herpes virions and mega ribonucleoproteins (megaRNPs) use an alternative means of transport - via nuclear envelope budding (NEB). Here, we show NEB is a ubiquitous eukaryotic phenomenon and increases when exposed to various forms of cellular stress. NEB frequency was maximal when the cell was challenged with a drug that induces protein misfolding, indicating this transport pathway plays a role in protein quality control. These results imply that NEB is an underappreciated yet potentiallyfundamental means of nuclear transport. | cell biology |
Tension suppresses Aurora B kinase-triggered release of reconstituted kinetochore-microtubule attachments Chromosome segregation requires kinetochores to attach to microtubules from opposite spindle poles. Proper attachments come under tension and are stabilized, but defective attachments lacking tension are released, giving another chance for correct attachments to form. This error correction process requires the Aurora B kinase, which phosphorylates kinetochores to destabilize microtubule attachments. However, the mechanism by which Aurora B can distinguish kinetochore tension remains unclear because it is difficult to detect kinase-triggered detachment and manipulate kinetochore tension in vivo. To address these challenges, we developed an optical trapping-based flow assay with soluble Aurora B and reconstituted kinetochore-microtubule attachments. Strikingly, we found that tension on these attachments suppressed their Aurora B-triggered release, suggesting that tension-dependent changes in the conformation of kinetochores can regulate Aurora B activity or its outcome. Our work uncovers the basis for a key mechano-regulatory event that ensures accurate segregation and may inform studies of other mechanically regulated enzymes. | cell biology |
Human cortical dynamics during full-body heading changes The retrosplenial complex (RSC) plays a crucial role in spatial orientation by computing heading direction and translating between distinct spatial reference frames based on multi-sensory information. While invasive studies allow investigating heading computation in moving animals, established non-invasive analyses of human brain dynamics are restricted to stationary setups. To investigate the role of the RSC in heading computation of actively moving humans, we used a Mobile Brain/Body Imaging approach synchronizing electroencephalography with motion capture and virtual reality. Data from physically rotating participants were contrasted with rotations based only on visual flow. During physical rotation, varying rotation velocities were accompanied by pronounced wide frequency band synchronization in RSC, the parietal and occipital cortices. In contrast, the visual flow rotation condition was associated with pronounced alpha band desynchronization, replicating previous findings in desktop navigation studies, and notably absent during physical rotation. These results suggest an involvement of the human RSC in heading computation based on visual, vestibular, and proprioceptive input and implicate revisiting traditional findings of alpha desynchronization in areas of the navigation network during spatial orientation in movement-restricted participants. | neuroscience |
Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in flour beetles Intergenerational effects from fathers to offspring are increasingly reported from diverse organisms, but the underlying mechanisms remain speculative. Paternal trans-generational immune priming (TGIP) was demonstrated in the red flour beetle Tribolium castaneum: non-infectious bacterial exposure of fathers protects their offspring against an infectious challenge for at least two generations. Epigenetic processes, such as cytosine methylation of nucleic acids, have been proposed to enable transfer of information from fathers to offspring. Here we studied a potential role in TGIP of the Dnmt2 gene (renamed as Trdmt1 in humans), which encodes a highly conserved enzyme that methylates different RNAs, including specific cytosines of a set of tRNAs. Dnmt2 has previously been reported to be involved in intergenerational epigenetic inheritance in mice and protection against viruses in fruit flies. We first studied gene expression and found that Dnmt2 is expressed in various life history stages and tissues of T. castaneum, with high expression in the reproductive organs. RNAi-mediated knockdown of Dnmt2 in fathers was systemic, slowed down offspring larval development and increased mortality of the adult offspring upon bacterial infection. However, these effects were independent of bacterial exposure of the fathers. In conclusion, our results point towards a role of Dnmt2 for paternal effects, while elucidation of the mechanisms behind paternal TGIP needs further studies. | evolutionary biology |
An epi-evolutionary model to predict spore-producing pathogens adaptation to quantitative resistance in heterogeneous environments We model the evolutionary epidemiology of spore-producing plant pathogens in heterogeneous environments sown with several cultivars carrying quantitative resistances. The model explicitly tracks the infection-age structure and genetic composition of the pathogen population. Each strain is characterized by pathogenicity traits describing its infection efficiency and a time-varying sporulation curve taking into account lesion ageing. We first derive a general expression of the basic reproduction number [R]0 for fungal pathogens in heterogeneous environments. We show that evolutionary attractors of the model coincide with local maxima of [R]0 only if the infection efficiency is the same on all host types. We then study how three basic resistance characteristics (pathogenicity trait targeted, resistance effectiveness, and adaptation cost) in interaction with the deployment strategy (proportion of fields sown with a resistant cultivar) (i) lead to pathogen diversification at equilibrium and (ii) shape the transient dynamics from evolutionary and epidemiological perspectives. We show that quantitative resistance impacting only the sporulation curve will always lead to a monomorphic population, while dimorphism (i.e. pathogen diversification) can occur with resistance altering infection efficiency, notably with high adaptation cost and proportion of R cultivar. Accordingly, the choice of quantitative resistance genes operated by plant breeders is a driver of pathogen diversification. From an evolutionary perspective, the emergence time of the evolutionary attractor best adapted to the R cultivar tends to be shorter when the resistance impacts infection efficiency than when it impacts sporulation. In contrast, from an epidemiological perspective, the epidemiological control is always higher when the resistance impacts infection efficiency. This highlights the difficulty of defining deployment strategies of quantitative resistance maximising at the same time epidemiological and evolutionary outcomes. | evolutionary biology |
Subcutaneous neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical stroke There is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. Its level declines in muscle and other tissues postnatally. We show that levels of NT-3 in the bloodstream were low in humans with ischemia stroke relative to young healthy controls. Accordingly, we set out to determine whether subcutaneous delivery of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically feasible time frame via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke. | neuroscience |
Ratio-based sensing of two transcription factors regulates the transit to differentiation Cell state transitions are usually thought to be triggered by changes in the absolute concentrations of relevant transcription factors. In the Drosophila eye, the transcription factor Yan maintains cells in a progenitor state by repressing gene expression, while the Pointed transcription factor activates gene expression programs that promote photoreceptor specification. In this study we investigate how retinal cell state transitions are resolved by quantifying the expression dynamics of Yan and Pointed proteins. Despite extensive cell-to-cell variation in absolute concentrations of Yan and Pointed, progenitor cells maintain a relatively constant ratio of Pointed-to-Yan protein. A sustained change in the Pointed-to-Yan ratio accompanies the transition to photoreceptor fates. Genetic perturbations that disrupt the ratio produce photoreceptor specification defects, suggesting that transitions depend upon a sustained change in the ratio. A model based on the statistical physics of protein-DNA binding illustrates how ratiometric sensing could produce the changes in gene expression that underlie these cell state transitions. We propose that ratiometric control mechanisms facilitate regulation of developmental transitions by multiple transcription factors, and thereby make the transitions robust to fluctuations in absolute protein levels. | developmental biology |
Pink Cedar (Acrocarpus fraxinifolius): its prophylactic role against APAP induced organs toxicity in rats and its antiviral activity against Herpes simplex virus type 1 The possible protective effects of methanolic extract Acrocarpus fraxinifolius leaves (MEAFL) were assessed against the APAP-induced organ toxicity in male rats. Also, the content of polyphenols extracted from AFL was studied, and their relationship with antioxidant activity was investigated. MEAFL was tested for cytotoxicity on Vero cell line, with reference to IC50, and other non-toxic concentrations of all the extracts. The antiviral activity against HSV1 for all non-toxic concentrations of the extract was determined using plaque reduction assay. It was found that MEAFL showed a reduction of serum hepatic and renal cellular toxicity and cellular lipid peroxidation, as well as enhanced cellular antioxidant. Also, our results revealed that the inhibitory activity of the virus was dose dependent on the polyphenol content of the examined extract. The MIC for the MEAFL extract was determined as well as the EC50 and SI. Calculated SI showed promising value for the MEAFL, and hence can be used as therapeutic medication for HSV1. To study other possible mode of action, Vero cells were treated with the examined extracts before, during, and after virus infection to give an insight on the interference of the extract in each step in the virus life cycle. In conclusion, MEAFL showed a remarkable antioxidant effect against APAP induced organs toxicity. Also, examined extracts exhibited the antiviral activity against HSV1. | physiology |
Dual brain cortical calcium imaging reveals social interaction-specific wide-spread correlated cortical activity in mice. We employ cortical mesoscale calcium-imaging to observe brain activity in two head-fixed mice in a staged social touch-like interaction. Using a rail system, mice are brought together to a distance where macrovibrissae of each mouse make contact. Cortical signals were recorded from both mice simultaneously before, during, and after the social contact period. When the mice were together, we observed bouts of mutual whisking and cross-mouse correlated cortical activity in the vibrissae cortex. This correlated activity was specific to individual interactions as the correlations fell in trial-shuffled mouse pairs. Whisk-related global GCAMP6s signals were greater in cagemate pairs during the together period. The effects of social interaction extend outside of regions associated with mutual touch and had global synchronizing effects on cortical activity. We present an open-source platform to investigate the neurobiology of social interaction by including mechanical drawings, protocols, and software necessary for others to extend this work. | neuroscience |
RegTools: Integrated analysis of genomic and transcriptomic data for the discovery of splicing variants in cancer Somatic mutations in non-coding regions of the genome and even exonic mutations may have unidentified non-coding consequences which are often overlooked in analysis workflows. Here we present RegTools (www.regtools.org), a free, open-source software package designed to integrate analysis of somatic variant calls from genomic data with splice junctions extracted from transcriptomic data to efficiently identify variants that may cause aberrant splicing in tumors. RegTools was applied to over 9,000 tumor samples with both tumor DNA and RNA sequence data. We discovered 235,778 events where a variant significantly increased the splicing of a particular junction, across 158,200 unique variants and 131,212 unique junctions. To further characterize these somatic variants and their associated splice isoforms, we annotated them with the Variant Effect Predictor (VEP), SpliceAI, and Genotype-Tissue Expression (GTEx) junction counts and compared our results to other tools that integrate genomic and transcriptomic data. While variants associated with certain types of alternative splicing events can be identified by the aforementioned tools, the unbiased nature of Regtools has allowed us to identify novel splice variants, including previously unreported patterns of splicing disruption in cancer drivers, such as TP53, CDKN2A, and B2M, and genes not previously reported that could represent novel driver events, such RNF145. | bioinformatics |
Sensory experience controls dendritic structure and behavior by distinct pathways involving degenerins Dendrites are crucial for receiving information into neurons. Sensory experience affects the structure of these tree-like neurites, which, it is assumed, modifies neuronal function, yet the evidence is scarce, and the mechanisms are unknown. To study whether sensory experience affects dendritic morphology, we use the Caenorhabditis elegans arborized nociceptor PVD neurons, under natural mechanical stimulation induced by physical contacts between individuals. We found that mechanosensory signals induced by conspecifics affect the dendritic structure of the PVD. Moreover, developmentally isolated animals show a decrease in their ability to respond to harsh touch. The structural and behavioral plasticity following sensory deprivation are functionally independent of each other and are mediated by an array of evolutionarily conserved mechanosensory amiloride-sensitive epithelial sodium channels (degenerins). Our genetic results, supported by optogenetic, behavioral, and pharmacological evidence, suggest an activity-dependent homeostatic mechanism for dendritic structural plasticity, that in parallel controls escape response to noxious mechanosensory stimuli.
Significance StatementLittle is known about how neuronal activity and sensory experience influence the structure and function of dendritic trees. Furthermore, how dendritic structures affect neuronal functions remains obscure despite their fundamental functions in neuronal sensory and synaptic activities in health and diseases. Here we show that complex dendritic trees of the nociceptive and proprioceptive PVD neuron in C. elegans display a dynamic nature where they undergo pronounced dendritic modifications during adulthood. These modifications are determined by the received sensory signals generated by conspecific worms in the plate. We revealed functions for degenerins/Epithelial sodium channels in this phenomenon, using genetic and optogenetic approaches. We found that degenerins serve to translate environmental mechanical signals into structural and functional modifications in the PVD. | neuroscience |
The best of both worlds: A new lipid complex has micelle and bicelle-like properties Bicelles have been demonstrated to be a valuable tool for studying membrane protein interactions and structure in vitro. They are distinguished by a distinct lipid bilayer that mimics the plasma membrane of cells making it more native-like than its detergent micelle counter-part. Bicelles are typically comprised of a long-chain phospholipid such as dimyristoylphosphatidylcholine (DMPC) and a short-chain phospholipid such as dihexanoylphosphatidylcholine (DHPC). When mixed together in solution DMPC-DHPC bicelles assume a discoidal structure comprised of a heterogeneous arrangement where the short-chain lipids gather around the rim of the disk and the long-chain lipids form the flat, planar, bilayer region. In this study, the nonionic surfactant, C8E5, was used to prepare mixtures with DMPC to determine if it adopts properties similar to bicelles with a q [≥] 0.5. At q [≥] 0.5, DMPC-DHPC bicelles are bilayered and DMPC is sequestered from the detergent micelle-like DHPC. Mixtures of DMPC and C8E5 were prepared at various q values, a parameter used to describe the mole ratio of DMPC to DHPC in the preparation of bicelles. Employing biophysical methods like dynamic light scattering, 31P-NMR and analytical ultracentrifugation, properties of these lipid-detergent complexes are described. Interestingly they adopted a spherical-shaped micellar structure morphology and did not assume a discoidal shape typical of bicelles at q [≥] 0.5. However, they appear to retain bilayer-like properties that may prove beneficial for in vitro biophysical studies of membrane proteins. | biophysics |
Inferring the heritability of large-scale functional networks with a multivariate ACE modeling approach Recent evidence suggests that the human functional connectome is stable at different time scales and unique. These characteristics posit the functional connectome not only as an individual marker but also as a powerful discriminatory measure characterized by high intersubject variability. Among distinct sources of intersubject variability, the long-term sources include functional patterns that emerge from genetic factors. Here, we sought to investigate the contribution of additive genetic factors to the variability of functional networks by determining the heritability of the connectivity strength in a multivariate fashion. First, we reproduced and extended the connectome fingerprinting analysis to the identification of twin pairs. Then, we estimated the heritability of functional networks by a multivariate ACE modeling approach with bootstrapping. Twin pairs were identified above chance level using connectome fingerprinting, with monozygotic twin identification accuracy equal to 57.2% on average for whole-brain connectome. Additionally, we found that a visual (0.37), the medial frontal (0.31) and the motor (0.30) functional networks were the most influenced by additive genetic factors. Our findings suggest that genetic factors not only partially determine intersubject variability of the functional connectome, such that twins can be identified using connectome fingerprinting, but also differentially influence connectivity strength in large-scale functional networks. | neuroscience |
BIN1 genetic risk factor for Alzheimer is sufficient to induce early structural tract alterations in entorhinal cortex-dentate gyrus pathway and related hippocampal multi-scale impairments Genetic factors are known to contribute to Late Onset Alzheimers disease (LOAD) but their contribution to pathophysiology, specially to prodomic phases accessible to therapeutic approaches are far to be understood.
To translate genetic risk of Alzheimers disease (AD) into mechanistic insight, we generated transgenic mouse lines that express a [~]195 kbp human BAC that includes only BIN1, a gene associated to LOAD. This model gives a modest BIN1 overexpression, dependent of the number of BAC copies. At 6 months of age, we detected impaired entorhinal cortex (EC)-hippocampal pathways with specific impairments in EC-dentate gyrus synaptic long-term potentiation, dendritic spines of granular cells and recognition episodic memory. Structural changes were quantified using MRI. Their whole-brain functional impact were analyzed using resting state fMRI with a hypoconnectivity centered on entorhinal cortex.
These early phenotype defects independent of any changes in A-beta can be instrumental in the search for new AD drug targets. | neuroscience |
Single cell variations in expression of codominant alleles A and B on RBC of AB blood group individuals. One of the key questions in biology is whether all cells of a "cell type" have more or less the same phenotype, especially with relation to non-imprinted autosomal loci. Recent studies point to differential allelic expression of autosomal genes being a prevalent phenomenon responsible to confer phenotypic variability at individual cell level. However, most studies have been carried out in actively transcribing cells. Here we display cellular mosaicism arising from differential allelic expression for the cell surface glycoprotein in the enucleated RBCs. We studied the expression of the A and B histo-blood group antigens encoded by the co-dominant alleles in individual RBCs using immunofluorescence. We assessed the relative levels of the co-dominant alleles IA and IB in 2512 RBC from 24 individuals with AB blood group using Cy3- and FITC- tagged antibodies. Quantification of individual fluorescence intensities from each cell and test of their normal distribution revealed that contrary to the general belief that all RBC in AB individuals express both antigens in comparable amounts, they segregated into 4 groups: showing normal distribution for both antigens, either antigen, and neither antigen; the deviation from normal distribution could not be correlated to maternal/paternal origin, thus appear to be stochastic. Surprisingly, very few people showed any correlation between the amounts of these two antigens on RBC. In fact, the ratio of antigen A to B in the entire set of samples spanned over 5 orders of magnitude. This variability in amount of the antigens A and/or B, combined with a lack of correlation between the amounts of these two antigens resulted in unique staining patterns for RBC, generating widespread mosaicism in the RBC population of AB blood group individuals. | genetics |
A confirmation bias in perceptual decision-making due to hierarchical approximate inference Making good decisions requires updating beliefs according to new evidence. This is a dynamical process that is prone to biases: in some cases, beliefs become entrenched and resistant to new evidence (leading to primacy effects), while in other cases, beliefs fade over time and rely primarily on later evidence (leading to recency effects). How and why either type of bias dominates in a given context is an important open question. Here, we study this question in classic perceptual decision-making tasks, where, puzzlingly, previous empirical studies differ in the kinds of biases they observe, ranging from primacy to recency, despite seemingly equivalent tasks. We present a new model, based on hierarchical approximate inference and derived from normative principles, that not only explains both primacy and recency effects in existing studies, but also predicts how the type of bias should depend on the statistics of stimuli in a given task. We verify this prediction in a novel visual discrimination task with human observers, finding that each observers temporal bias changed as the result of changing the key stimulus statistics identified by our model. By fitting an extended drift-diffusion model to our data we rule out an alternative explanation for primacy effects due to bounded integration. Taken together, our results resolve a major discrepancy among existing perceptual decision-making studies, and suggest that a key source of bias in human decision-making is approximate hierarchical inference. | animal behavior and cognition |
Inferring linguistic transmission between generations at the scale of individuals Historical linguistics strongly benefited from recent methodological advances inspired by phylogenetics. Nevertheless, no available method uses contemporaneous within-population linguistic diversity to reconstruct the history of human populations. Here, we developed an approach inspired from population genetics to perform historical linguistic inferences from linguistic data sampled at the individual scale, within a population. We built four within-population demographic models of linguistic transmission over generations, each differing by the number of teachers involved during the language acquisition and the relative roles of the teachers. We then compared the simulated data obtained with these models with real contemporaneous linguistic data sampled from Tajik speakers from Central Asia, an area known for its large within-population linguistic diversity, using approximate Bayesian computation methods. Under this statistical framework, we were able to select the models that best explained the data, and infer the best-fitting parameters under the selected models. This demonstrates the feasibility of using contemporaneous within-population linguistic diversity to infer historical features of human cultural evolution. | bioinformatics |
I knew that! Response-based Outcome Predictions and Confidence Regulate Feedback Processing and Learning Influential theories emphasize the importance of predictions in learning: we learn from feedback to the extent that it is surprising, and thus conveys new information. Here we explore the hypothesis that surprise depends not only on comparing current events to past experience, but also on online evaluation of performance via internal monitoring. Specifically, we propose that people leverage insights from response-based performance monitoring - outcome predictions and confidence - to control learning from feedback. In line with predictions from a Bayesian inference model, we find that people who are better at calibrating their confidence to the precision of their outcome predictions learn more quickly. Further in line with our proposal, EEG signatures of feedback processing are sensitive to the accuracy of, and confidence in, post-response outcome predictions. Taken together, our results suggest that online predictions and confidence serve to calibrate neural error signals to improve the efficiency of learning. | neuroscience |
A Sparse Additive Model for High-Dimensional Interactions with an Exposure Variable A conceptual paradigm for onset of a new disease is often considered to be the result of changes in entire biological networks whose states are affected by a complex interaction of genetic and environmental factors. However, when modelling a relevant phenotype as a function of high dimensional measurements, power to estimate interactions is low, the number of possible interactions could be enormous and their effects may be non-linear. In this work, we introduce a method called sail for detecting non-linear interactions with a key environmental or exposure variable in high-dimensional settings which respects the strong or weak heredity constraints. We prove that asymptotically, our method possesses the oracle property, i.e., it performs as well as if the true model were known in advance. We develop a computationally efficient fitting algorithm with automatic tuning parameter selection, which scales to high-dimensional datasets. Through an extensive simulation study, we show that sail outperforms existing penalized regression methods in terms of prediction accuracy and support recovery when there are non-linear interactions with an exposure variable. We apply sail to detect non-linear interactions between genes and a prenatal psychosocial intervention program on cognitive performance in children at 4 years of age. Results show that individuals who are genetically predisposed to lower educational attainment are those who stand to benefit the most from the intervention. Our algorithms are implemented in an R package available on CRAN (https://cran.r-project.org/package=sail). | bioinformatics |
Decoding locomotion from population neural activity in moving C. elegans The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording population calcium activity during unrestrained movement. We report that a neural population more accurately decodes locomotion than any single neuron. Relevant signals are distributed across neurons with diverse tunings to locomotion. Two distinct subpopulations are informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs. We labeled neurons AVAL and AVAR and found their activity was highly correlated with one another. They exhibited expected transients during backward locomotion, although they were not always the most informative neurons for decoding velocity. Finally, we compared population neural activity during movement and immobilization. Immobilization alters the correlation structure of neural activity and its dynamics. Some neurons previously correlated with AVA become anti-correlated and vice versa.
The activity of an animals brain contains information about that animals actions and movements. We investigated the neural representation of locomotion in the nematode C. elegans by recording brain-wide neural dynamics in freely moving animals. We report that a population of neurons more accurately decodes the animals locomotion than any single neuron. Neural signals are distributed across neurons in the population with a diversity of tuning to locomotion. Two distinct subpopulations are most informative for decoding velocity and body curvature, and different neurons activities contribute features relevant for different instances of behavioral motifs within these subpopulations. We additionally labeled the AVA neurons within our population recordings. AVAL and AVAR exhibit activity that is highly correlated with one another, and they exhibit the expected responses to locomotion, although we find that AVA is not always the most informative neuron for decoding velocity. Finally, we compared brain-wide neural activity during movement and immobilization and observe that immobilization alters the correlation structure of neural activity and its dynamics. Some neurons that were previously correlated with AVA become anti-correlated and vice versa during immobilization. We conclude that neural population codes are important for understanding neural dynamics of behavior in moving animals. | neuroscience |
Epigenome priming dictates transcription response and white matter fate upon perinatal inflammation Inflammatory insults accompanying prematurity provokes diffuse white matter injury (DWMI) which is associated with increased risk of neurodevelopmental disorders: pre-term infants have a 10 to 18-fold increased risk of developing autism spectrum disorders, compared to term infants. DWMI is due to maturation arrest in oligodendrocyte precursor cells (OPCs). Using integrated genome-wide approaches in a validated mouse perinatal model of DWMI, induced by systemic- and neuro-inflammation based on repeated interleukin-1B administrations, we show that neuroinflammation induces limited epigenomic disturbances in OPCs. In contrast, we unravel marked transcriptomic alterations of genes of the immune/inflammatory pathways, which are expressed in unstressed OPCs and physiologically downregulated along OPC maturation. Consistently, we observe that transcription factors of the inflammatory pathways occupy DNA both in unstressed and inflamed OPCs. Thus, rather than altering genome-wide chromatin accessibility, neuroinflammation takes advantage of open chromatin regions and deeply counteracts the stage-dependent downregulation of these active transcriptional programs. Therefore, our study opens new avenues for the future development of targeted approaches to protect preterm brains.
Highlights{circ} Limited epigenomic impact of inflammation on OPC maturation blockade
{circ}Major transcriptomic disturbances take advantage of a primed epigenetic landscape
{circ}Proinflammatory genes are active in OPCs and downregulated upon maturation
{circ}Neuroinflammation counteracts both this downregulation and maturation in OPCs | developmental biology |
Reorganization of thalamocortical connections in congenitally blind humans Evidence of cross-modal plasticity in blind individuals has been reported over the past decades showing that non-visual information is carried and processed by visual brain structures. This feature of the blind brain makes it a pivotal model to explore the limits and mechanisms of brain plasticity. However, despite multiple efforts, the structural underpinnings of cross-modal plasticity in congenitally blind individuals remain unclear. Using advanced neuroimaging techniques, we mapped thalamocortical connectivity and assessed cortical thickness and integrity of white matter of ten congenitally blind individuals and ten sighted controls. We hypothesized an aberrant thalamocortical pattern of connectivity taking place in the absence of visual stimuli from birth as a potential mechanism of cross-modal plasticity. In addition to the increased cortical thickness of the primary visual cortex and reduced integrity of visual white matter bundles, we observed structural connectivity changes between the thalamus and both occipital and temporal cortices. Specifically, the thalamic territory dedicated to connections with the occipital cortex was found to be smaller and displayed weaker connectivity in congenitally blind individuals, whereas the one that connects with the temporal cortex showed greater volume and stronger connectivity when compared to sighted controls. The abnormal pattern of thalamocortical connectivity included the lateral and medial geniculate nuclei and the pulvinar nucleus. For the first time in humans, a remapping of structural thalamocortical connections involving both unimodal and multimodal thalamic nuclei has been demonstrated, shedding light on the possible mechanisms of cross-modal plasticity in humans. Future studies should employ neurophysiologic approaches to explore the functional relevance of present findings. | neuroscience |
Inference of the worldwide invasion routes of the pinewood nematode Bursaphelenchus xylophilus using approximate Bayesian computation analysis AO_SCPLOWBSTRACTC_SCPLOWPopulation genetics have been greatly beneficial to improve knowledge about biological invasions. Model-based genetic inference methods, such as approximate Bayesian computation (ABC), have brought this improvement to a higher level and are now essential tools to decipher the invasion routes of any invasive species. In this paper, we performed ABC random forest analyses to shed light on the pinewood nematode (PWN) worldwide invasion routes and to identify the source of European populations. Originating from North America, this microscopic worm has been invading Asia since 1905 and Europe since 1999, causing tremendous damage on pine forests. Using microsatellite data, we demonstrated the existence of multiple introduction events in Japan (at least two involving individuals originating from the USA) and China (one involving individuals originating from the USA and one involving individuals originating from Japan). We also found that Portuguese samples had a Japanese origin. We observed some discrepancies between descriptive genetic methods and the ABC method, which are worth investigating and are discussed here. The ABC method helped clarify the worldwide history of the PWN invasion, even though the results still need to be considered with some caution because the features of the PWN and the genetic markers used probably push the ABC method to its very limits. | genetics |
Cyclic, condition-independent activity in primary motor cortex predicts corrective movement behavior Reaching movements are known to have large condition-independent neural activity and cyclic neural dynamics. A new precision center-out task was performed by rhesus macaques to test the hypothesis that cyclic, condition-independent neural activity in the primary motor cortex (M1) occurs not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with time courses and bell-shaped speed profiles similar to the initial movements. Condition-independent cyclic neural trajectories were similar and repeated for initial and each additional corrective submovement. The phase of the cyclic condition-independent neural activity predicted the time of peak movement speed more accurately than regression of instantaneous firing rate, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement.
Significance StatementDuring a precision center-out task, initial and subsequent corrective movements occur as discrete submovements with bell-shaped speed profiles. A cycle of condition-independent activity in primary motor cortex neuron populations corresponds to each submovement, such that the phase of this cyclic activity predicts the time of peak speeds--both initial and corrective. These submovements accompanied by cyclic neural activity offer important clues into how we successfully execute precise, corrective reaching movements and may have implications for optimizing control of brain-computer interfaces. | neuroscience |
Understanding population history of range expansion and environmental adaptation by visualizing gene-environment-trait associations During the history of range expansion, the populations encounter with variety of environments. They respond to the local environments by modifying the mutually interacting traits. Therefore, to understand the whole life history of the populations, it is ideal to capture the history of their range expansion with reference to the series of surrounding environments and to infer the coadaptation of the multiple traits. Toward this end, we provide an exploratory analysis based on the features of populations: site frequency spectra of populations, population-specific FST, association between genes and environments, positive selections on traits mapped on the admixture graph, and GWAS results. Correspondence analysis of genes, environments, and traits provides a birds-eye view of the history of population differentiation and range expansion and various types of environmental selections at the times. Principal component analysis of the estimated trait-specific polygenic adaptations mapped on the admixture graph enables to understand the coadaptation of multiple traits. The potential usefulness was confirmed by analyzing a public dataset of wild poplar in northwestern America. In response to the northern cold temperature and longer daylength, the populations increased the photosynthetic activity and nutrient use efficiency at the expense of the risk of pathogen invasion, and in response to warm temperature, they increased the growth. At higher altitude, they shifted the maximum activity to earlier period in spring to reduce the activity in dry summer. The R codes for our representation method and simulations of population colonization used in this study are available as supplementary script. | bioinformatics |
The molecular pH-response mechanism of the plant light-stress sensor PsbS Plants need to protect themselves from excess light, which causes photo-oxidative damage and lowers the efficiency of photosynthesis. Photosystem II subunit S (PsbS) is a pH sensor protein that plays a crucial role in plant photoprotection by detecting thylakoid lumen acidification in excess light conditions via two lumen-faced glutamates. However, how PsbS is activated under low-pH conditions is unknown. To reveal the molecular response of PsbS to low pH, we performed an NMR and infrared spectroscopic analysis of Physcomitrella patens PsbS and of the E176Q mutant in which an active glutamate has been replaced. The PsbS response mechanism at low pH involves the concerted action of repositioning of a short amphipathic helix containing E176 facing the lumen and folding of the luminal loop fragment adjacent to E71 to a 310-helix, providing clear evidence of a conformational pH switch. We propose that this concerted mechanism is a shared motif of proteins of the light-harvesting family that may control thylakoid inter-protein interactions driving photoregulatory responses. | biophysics |
Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis Background and PurposeThe extra-medical use of, and addiction to, prescription opioid analgesics is a growing health problem. To characterize how prescription opioid abuse develops, this study investigated the affective consequences of escalating prescription opioid use using intracranial self-stimulation (ICSS) reward and oxycodone intravenous self-administration (IVSA) models.
Experimental ApproachMale Wistar rats were given access to oxycodone IVSA (0.15 mg/kg/infusion, i.v.) in Short Access (ShA; 1 h) or Long Access (LgA; 12 h) sessions for 5 sessions/week followed by intermittent 60 h discontinuations from drug access, a novel explicit test of the negative reinforcement hypothesis. Separate groups were first trained in the ICSS procedure and then in oxycodone IVSA in 11 h LgA sessions.
Key ResultsRats given LgA to oxycodone escalated their responding more than ShA rats, with further significant increases observed following each 60 h discontinuation. Pre-session brain reward thresholds increased with sequential daily LgA IVSA sessions, consistent with a growing negative affective state consequent to successive daily intoxication/abstinence cycles. A 1 h oxycodone IVSA interval was sufficient to normalize these elevated reward thresholds, as was, paradoxically, a 60 h weekend abstinence. The increase in ICSS thresholds was attenuated in a group treated with the long-acting kappa opioid antagonist norBNI prior to IVSA training.
Conclusions and ImplicationsChanges in brain reward function during escalation of oxycodone self-administration are driven by an interplay between kappa opioid receptor-mediated negative affective state associated with escalated oxycodone intake and dynamic restoration of brain reward status during longer periods of abstinence. | neuroscience |
From predictive models to cognitive models: Separable behavioral processes underlying reward learning in the rat Cognitive models are a fundamental tool in computational neuroscience, embodying in software precise hypotheses about the algorithms by which the brain gives rise to behavior. The development of such models is often a hypothesis-first process, drawing on inspiration from the literature and the creativity of the individual researcher to construct a model, and afterwards testing the model against experimental data. Here, we adopt a complementary approach, in which richly characterizing and summarizing the patterns present in a dataset reveals an appropriate cognitive model, without recourse to an a priori hypothesis. We apply this approach to a large behavioral dataset from rats performing a dynamic reward learning task. The revealed model suggests that behavior in this task can be understood as a mixture of three components with different timescales: a quick-learning reward-seeking component, a slower-learning perseverative component, and a very slow "gamblers fallacy" component. | animal behavior and cognition |
Brain X chromosome inactivation is not random and can protect from paternally inherited neurodevelopmental disease. Non-random (skewed) X chromosome inactivation (XCI) in the female brain can ameliorate X-linked phenotypes, though clinical studies typically consider 80-90% skewing favoring the healthy allele as necessary for this effect1-10. Here we quantify for the first time whole-brain XCI at single-cell resolution and discover a preferential inactivation of paternal to maternal X at [~]60:40 ratio, which surprisingly impacts disease penetrance. In Fragile-X-syndrome mouse model, Fmr1-KO allele transmitted maternally in [~]60% brain cells causes phenotypes, but paternal transmission in [~]40% cells is unexpectedly tolerated. In the affected maternal Fmr1-KO(m)/+ mice, local XCI variability within distinct brain networks further determines sensory versus social manifestations, revealing a stochastic source of X-linked phenotypic diversity. Taken together, our data show that a modest [~]60% bias favoring the healthy allele is sufficient to ameliorate X-linked phenotypic penetrance, suggesting that conclusions of many clinical XCI studies using the 80-90% threshold should be re-evaluated. Furthermore, the paternal origin of the XCI bias points to a novel evolutionary mechanism acting to counter the higher rate of de novo mutations in male germiline11-16. Finally, the brain capacity to tolerate a major genetic lesion in [~]40% cells is also relevant for interpreting other neurodevelopmental genetic conditions, such as brain somatic mosaicism. | neuroscience |
Timing polymerase pausing with TV-PRO-seq: dissecting the interplay of pausing duration and location, and gene expression Transcription of many genes in metazoans is subject to polymerase pausing, which is the transient stop of transcriptionally-engaged polymerases. This is known to mainly occur in promoter proximal regions but it is not well understood. In particular, a genome-wide measurement of pausing times at high resolution has been lacking. We present here the time-variant precision nuclear run-on and sequencing (TV-PRO-seq) assay, an extension of the standard PRO-seq that allows us to estimate genome-wide pausing times at single-base resolution. Its application to human cells demonstrates that, proximal to promoters, polymerases pause more frequently but for shorter times than in other genomic regions. Pausing release by the detergent sarkosyl, previously believed to be linked to the factor NELF at the promoter proximal region only, is independent of the latter. Comparison with single-cell gene expression data reveals that the polymerase pausing times are longer in highly expressed genes, while transcriptionally noisier genes have higher pausing frequencies and slightly longer pausing times. Analyses of histone modifications suggest that the marker H3K36me3 is related to the polymerase pausing. | systems biology |
A thermodynamic chemical reaction network drove autocatalytic prebiotic peptides formation The chemical reaction networks (CRNs), which led to the transition on early Earth from geochemistry to biochemistry remain unknown. We show that under mild hydrothermal circumstances, a thermodynamic chemical reaction network including sulfite/sulfate coupled with anaerobic ammonium oxidation (Sammox), might have driven prebiotic peptides synthesis. Peptides comprise 14 proteinogenic amino acids, endowed Sammox-driven CRNs with autocatalysis. The peptides exhibit both forward and reverse catalysis, with the opposite catalytic impact in sulfite- and sulfate-fueled Sammox-driven CRNs, respectively, at both a variable temperature range and a fixed temperature, resulting in seesaw-like catalytic properties. The ratio of sulfite to sulfate switches the catalytic orientation of peptides, resulting in Sammox-driven CRNs that has both anabolic and catabolic reactions at all times. Furthermore, peptides produced from sulfite-fueled Sammox-driven CRNs could catalyze both sulfite-fueled Sammox and Anammox (nitrite reduction coupled with anaerobic ammonium oxidation) reactions. We propose that Sammox-driven CRNs were critical in the creation of life and that Anammox microorganisms that have both Sammox functions are direct descendants of Sammox-driven CRNs. | biochemistry |
Inferring causal connectivity from pairwise recordings and optogenetics To study how the brain works mechanistically, neuroscientists want to quantify causal interactions between neurons, typically requiring perturbations. When using optogenetic interventions, multiple neurons are usually perturbed which produces a confound - any of the stimulated neurons can have affected the postsynaptic neuron making it challenging to discern which of the neurons produced the causal effect. Here we show how such confounds produce large biases, and we explain how they can be reduced by combining instrumental variable (IV) and difference in differences (DiD) techniques from econometrics. The interaction between stimulation and the absolute refractory period of the neuron produces a weak, approximately random signal which can be exploited to estimate causal transmission probability. On simulated neural networks, we find that estimates using ideas from IV and DiD outperform naive techniques suggesting that methods from causal inference can be useful when studying neural interactions. | neuroscience |
In for a pound, in for a penny: How the opportunity to gain reward influences the competition for memory resources When people encounter items that they believe will help them gain reward, they later remember them better than others. A recent model of emotional memory, the emotional Context Maintenance and Retrieval model (eCMR), predicts that these effects would be stronger when stimuli that predict high and low reward can compete with each other both during encoding and retrieval. We tested this prediction in two experiments. Participants were promised {pound}1 for remembering some pictures, but only a few pence for remembering others. Their recall of the content of the pictures they saw was tested after one minute and in Experiment 2, also after 24 hours. Memory at immediate test showed effects of list composition. Recall of stimuli that predicted high reward was greater than of stimuli that predicted lower reward, but only when high- and low-reward items were studied and recalled together, not when they were studied and recalled separately. More high-reward items in mixed lists were forgotten over a 24-hour retention interval compared to items studied in other conditions, but reward did not modulate the forgetting rate, a null effect which should be replicated in a larger sample. These results confirm eCMRs predictions, although further research is required to compare that model against alternatives. | neuroscience |
Ownership, Coverage, Utilisation and Maintenance of Long-lasting insecticidal nets in Three Health Districts in Cameroon: A Cross-Sectional Study IntroductionThe Bamenda, Santa and Tiko Health Districts are in the highest malaria transmission strata of Cameroon. The purpose of this study was to explore the indicators of ownership and utilisation as well as maintenance of long-lasting insecticidal nets (LLINs) in three health districts in Cameroon.
MethodsA cross-sectional household survey involving 1,251 households was conducted in the Bamenda, Santa and Tiko Health Districts in Cameroon. A structured questionnaire was used to collect data on LLINs ownership, utilisation, and maintenance as well as demographic characteristics.
ResultsThe average number of LLINs per household was higher in the Bamenda Health District (BHD) compared to the Tiko Health District (THD) (2.5{+/-}1.4 vs 2.4{+/-}1.6) as well as the household ownership at least one LLIN (93.3% vs. 88.9%). The proportion of the defacto population with universal utilisation was higher in BHD compared to THD (13.1% vs 0.2%). In multinomial regression analysis, households in the SHD (OR = 0.4, 95% = C.I; 0.2 - 0.8, p = 6.10x10-3), were less likely to own at least one LLIN, while those in the BHD (OR = 1.3, 95% = C.I; 0.8 - 2.1, p = 0.33) were more likely to maintain LLINs compared to those in THD.
ConclusionOwnership of LLINs was low in SHD and THD in comparison to the goal of one LLIN for every two household members. Overall, LLINs coverage and accessibility was still low after the free Mass Distribution Campaigns (MDCs), making it difficult for all household members to effectively use LLINs. | epidemiology |
Healthy Choice depends on the latency and rate of information accumulation The drift diffusion model (DDM) provides a parsimonious explanation of decisions across neurobiological, psychological, and behavioral levels of analysis. Although most DDM implementations assume that only a single value guides decisions, choices often involve multiple attributes that could make separable contributions to choice. Here, we fit incentive-compatible dietary choices to a multi-attribute, time-dependent drift diffusion model (mtDDM), in which taste and health could differentially influence the evidence accumulation process. We found that these attributes shaped both the relative value signal and the latency of evidence accumulation in a manner consistent with participants idiosyncratic preferences. Moreover, by using a dietary prime, we showed how a healthy choice intervention alters mtDDM parameters that in turn predict prime-dependent choices. Our results reveal that different decision attributes make separable contributions to the strength and timing of evidence accumulation - providing new insights into the construction of interventions to alter the processes of choice. | neuroscience |
Consistency of non-cognitive skills and their relation to educational outcomes in a UK cohort Non-cognitive skills have previously been associated with a range of health and socioeconomic outcomes, though there has been considerable heterogeneity in published research. Many studies have used cross sectional data and therefore the longitudinal consistency of measures designed to capture non-cognitive skills is poorly understood. Using data from a UK cohort, we assess the consistency of non-cognitive skills over a 17-year period throughout childhood and adolescence, their genomic architecture, and their associations with socioeconomic outcomes. We find that longitudinal measurement consistency is high for behavioural and communication skills but low for other non-cognitive skills, implicating a high noise to signal ratio for many non-cognitive skills. Consistent non-zero heritability estimates and genetic correlations applied to cross-sectional measures are observed only for behavioural difficulties. When aggregating across multiple measurements, we find evidence of low heritability [Formula] for behaviour, communication, self-esteem and locus of control. We find weak correlations between aggregate measures of skills, further supporting cross-sectional measurement error in the non-cognitive measures. Associations between non-cognitive skills and educational outcomes are observed for skills measured in mid to late childhood and these are at most a third of the size of IQ-education associations. These results suggest that individual measures designed to capture non-cognitive skills may be subject to considerable measurement error and provide unreliable indicators of childrens skills. However, aggregate measures that leverage longitudinal data may more reliably identify underlying non-cognitive traits. | genetics |
Predictiveness and Reward Effects on Attention can be Explained by a Single Mechanism The authors have withdrawn their manuscript because of a failure to replicate its main empirical result. Therefore, the authors do not wish this work to be cited as a reference. If you have any questions, please contact the corresponding author. | neuroscience |
Combined use of Candida Utilis and Idesia polycarpa var. Vestita Fruit Improve the Production Performance of Laying Quail Although Idesia polycarpa oil has been wildly explored as a raw material for biodiesel, the reports studying the by-product Idesia polycarpa fruit residues (IPR) are few. This study aimed to evaluate the effect of the Idesia polycarpa fruit residues fermented feed additive (IPFF) on the egg production of laying quails. The egg production and related performances include egg quality, yolk cholesterol, yolk fatty acid, quails jejunum morphology, and relative gene expression were determined in this study. Compared to the standard diet group, birds fed the 1% IPFF showed a higher egg production (87.7% on average, 11.5% above the control; P<0.01). The yolk fatty acid composition and n6/n3 ratio were affected by IPFF or IPR. Compared to the standard diet group, the egg cholesterol content was lower in both IPFF and IPR groups, and the yolk n6/n3 ratio in the 5% IPFF group (10.3; P<0.01) was more reasonable. Meanwhile, birds under IPFF dietary supplement showed a thicker jejunum wall, higher villus, and deeper crypt than the standard diet group. In addition, the altered mRNA expression of four genes involved in cholesterol and fatty acids metabolism (SREBP-1, SREBP-2, ADGL, APOVLDL-II) in the 1% IPFF group and 5% IPR group indicated that the lipids metabolism and transportation were enhanced in the interclavicular fat pad and liver, relative to the standard diet group.
HIGHLIGHTSEgg production was higher in IPFF groups
Egg cholesterol was lower in IPFF groups
Lipid metabolism and transportation was enhanced in IPFF groups
Intestine wall was thicker in IPFF groups | microbiology |
EEG-based detection of the locus of auditory attention with convolutional neural networks In a multi-speaker scenario, the human auditory system is able to attend to one particular speaker of interest and ignore the others. It has been demonstrated that it is possible to use electroencephalography (EEG) signals to infer to which speaker someone is attending by relating the neural activity to the speech signals. However, classifying auditory attention within a short time interval remains the main challenge. We present a convolutional neural network-based approach to extract the locus of auditory attention (left/right) without knowledge of the speech envelopes. Our results show that it is possible to decode the locus of attention within 1 to 2 s, with a median accuracy of around 81%. These results are promising for neuro-steered noise suppression in hearing aids, in particular in scenarios where per-speaker envelopes are unavailable. | neuroscience |
Mismatch repair disturbs meiotic class I crossover control Sequence divergence, mediated by the anti-recombinogenic activity of mismatch repair (MMR), forms a barrier to meiotic recombination and in turn the formation of viable gametes. However, rather than MMR acting as a non-specific impediment to meiotic recombination, here we provide evidence that at regions of greater sequence divergence MMR preferentially suppresses interfering (class I) crossovers (COs). Specifically, as measured in two Saccharomyces cerevisiae hybrids containing thousands of DNA-sequence polymorphisms, removal of MMR components increases both the frequency of CO formation and the uniformity of the observed CO distribution. At fine scale, CO positions are skewed away from polymorphic regions in MMR-proficient cells, but, critically, not when members of the class I CO pathway, MSH4 or ZIP3, are inactivated. These findings suggest that class I COs are more sensitive to heteroduplex DNA arising during recombination. Simulations and analysis of Zip3 foci on meiotic chromosomes support roles for Msh2 both early and late in the class I CO maturation process. Collectively, our observations highlight an unexpected interaction between DNA sequence divergence, MMR, and meiotic class I CO control, thereby intimately linking the regulation of CO numbers and their distribution to pathways contributing to reproductive isolation and eventual speciation. | genetics |
Neural Basis Of The Sound-Symbolic Crossmodal Correspondence Between Auditory Pseudowords And Visual Shapes Sound symbolism refers to the association between the sounds of words and their meanings, often studied using the crossmodal correspondence between auditory pseudowords, e.g. takete or maluma, and pointed or rounded visual shapes, respectively. In a functional magnetic resonance imaging study, participants were presented with pseudoword-shape pairs that were sound-symbolically congruent or incongruent. We found no significant congruency effects in the blood oxygenation level-dependent (BOLD) signal when participants were attending to visual shapes. During attention to auditory pseudowords, however, we observed greater BOLD activity for incongruent compared to congruent audiovisual pairs bilaterally in the intraparietal sulcus and supramarginal gyrus, and in the left middle frontal gyrus. We compared this activity to independent functional contrasts designed to test competing explanations of sound symbolism, but found no evidence for mediation via language, and only limited evidence for accounts based on multisensory integration and a general magnitude system. Instead, we suggest that the observed incongruency effects are likely to reflect phonological processing and/or multisensory attention. These findings advance our understanding of sound-to-meaning mapping in the brain. | neuroscience |
Uncovering Network Architecture Using an Exact Statistical Input-Output Relation of a Neuron Model Using observed neuronal activity, we try to unveil hidden microcircuits. A key requirement is the knowledge of statistical input-output relation of single neurons in vivo. We use a recent exact solution of spike-timing for leaky integrate-and-fire neurons under noisy inputs balanced near threshold, and construct a framework that links synaptic type/strength, and spiking nonlinearity, with statistics of neuronal activity. The framework explains structured higher-order interactions of neurons receiving common inputs under different architectures. Comparing models prediction with an empirical dataset of monkey V1 neurons, we find that excitatory inputs to pairs explain the observed sparse activity characterized by negative triple-wise interactions, ruling out the intuitive shared inhibition. We show that the strong interactions are in general the signature of excitatory rather than inhibitory inputs whenever spontaneous activity is low. Finally, we present a guide map that can be used to reveal the hidden motifs underlying observed interactions found in empirical data. | neuroscience |
A learned embedding for efficient joint analysis of millions of mass spectra Computational methods that aim to exploit publicly available mass spectrometry repositories primarily rely on unsupervised clustering of spectra. Here, we propose to train a deep neural network in a supervised fashion based on previous assignments of peptides to spectra. The network, called "GLEAMS," learns to embed spectra into a low-dimensional space in which spectra generated by the same peptide are close to one another. We use GLEAMS as the basis for a large-scale spectrum clustering, detecting groups of unidentified, proximal spectra representing the same peptide, and we show how to use these clusters to explore the dark proteome of repeatedly observed yet consistently unidentified mass spectra. We provide a software implementation of our approach, along with a tool to quickly embed additional spectra using a pre-trained model, to facilitate large-scale analyses. | bioinformatics |
Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Schwachman-Diamond syndrome Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three unrelated Korean SDS patients that carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy (UPD) in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiological consequences. Still, the milder EFL1 variant was solely able to impair 80S ribosome assembly and induce SDS features in cell line, zebrafish, and mouse models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligo-pyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy. | genetics |
Effects of long-lasting insecticide net (LLINs) ownership/utilisation indicators on annual household malaria episodes (AHMEs) in three Health Districts in Cameroon IntroductionHousehold residents in malaria endemic areas are at high risk of multiple malaria episodes per year. This study investigated the annual household malaria episodes (AHMEs) in three health districts in Cameroon.
MethodsA community-based cross-sectional household survey using a multi-stage cluster design was conducted 2 - 3 years post campaign to assess long-lasting insecticide net (LLINs) ownership, utilisation, and maintenance as well as demographic characteristics. Multinomial regression analysis was used to identify factors associated with household LLIN ownership, utilization, and AHME.
ResultsHousehold LLINs ownership, de-facto population with universal utilisation, and AHME were respectively, 92.5%, 16.0%, and 83.4%; thus, 4 out of 25 household residents effectively used LLINs the previous night. AHME was significantly (p < 0.05) associated with age and gender (OR; 1.6, 95% C.I; 1.1 - 2.3) of household head, health district (OR; 2.8, 95% C.I; 1.1 - 7.2) and tiredness (OR; 2.6, 95% C.I; 1.0 - 6.3). LLINs ownership and insufficiency also significantly contributed to AHME. The overall average cost for the treatment of malaria was 6,399.4{+/-}4,892.8Fcfa (11.1{+/-}8.5US$).
ConclusionsThe proportion of households with at least one LLIN and those with at least one AHME were high. Findings are of concern given that average cost for the treatment of malaria represents a potentially high economic burden. The results outlined in this paper provide an important tool for the examination of the deficiencies in LLINs regular and universal utilisation. | epidemiology |
Cell fitness is an omniphenotype Moores law states that computers get faster and less expensive over time. In contrast in biopharma, there is the reverse spelling, Erooms law, which states that drug discovery is getting slower and costing more money every year. At the current pace, we estimate it costing $9.9T and it taking to the year 2574 to find drugs for less than 1% of all potentially important protein-protein interactions. Herein, we propose a solution to this problem. Borrowing from how Bitcoin works, we put forth a consensus algorithm for inexpensively and rapidly prioritizing new factors of interest (e.g., a gene or drug) in human disease research. Specifically, we argue for synthetic interaction testing in mammalian cells using cell fitness - which reflect changes in cell number that could be due many effects - as a readout to judge the potential of the new factor. That is, if we combine perturbing a known factor with perturbing the unknown factor and they produce a synergistic, i.e., multiplicative rather than additive cell fitness phenotype, this justifies proceeding with the unknown gene/drug in more complex models where the known perturbation is already validated. This recommendation is backed by the following evidence we demonstrate herein: 1) human genes currently known to be important to cell fitness involve nearly all classifications of cellular and molecular processes; 2) Nearly all human genes important in cancer - a disease defined by altered cell number - are also important in other common diseases; 3) Many drugs affect a patients condition and the fitness of their cells comparably. Taken together, these findings suggest cell fitness could be a broadly applicable phenotype for understanding gene, disease, and drug function. Measuring cell fitness is robust and requires little time and money. These are features that have long been capitalized on by pioneers using model organisms that we hope more mammalian biologists will recognize.
Short summaryCell fitness is a biological hash function that enables interoperability of biomedical data. | systems biology |
Non-random sister chromatid segregation mediates rDNA copy number maintenance in Drosophila Although considered to be exact copies of each other, sister chromatids can segregate non-randomly in some cases. For example, sister chromatids of the X and Y chromosomes segregate non-randomly during asymmetric division of male germline stem cells (GSCs) in D. melanogaster. Here we identify that the ribosomal DNA (rDNA) loci, which are located on the X and Y chromosomes, and an rDNA-binding protein, Indra, are required for non-random sister chromatid segregation (NRSS). We provide the evidence that NRSS is a mechanism by which GSCs recover rDNA copy number, which occurs through unequal sister chromatid exchange, counteracting the spontaneous copy number loss that occurs during aging. Our study reveals an unexpected role for NRSS in maintaining germline immortality through maintenance of a vulnerable genomic element, rDNA.
One Sentence SummaryrDNA copy number maintenance by non-random sister chromatid segregation contributes to germline immortality in Drosophila | developmental biology |
A novel mechanosensitive channel controls osmoregulation, differentiation and infectivity in Trypanosoma cruzi Trypanosoma cruzi, the causative agent of Chagas disease, undergoes drastic morphological and biochemical modifications as it passes between hosts and transitions from extracellular to intracellular stages. The osmotic and mechanical aspects of these cellular transformations are not understood. Here we identify and characterize a novel mechanosensitive channel in T. cruzi (TcMscS) belonging to the superfamily of small conductance mechanosensitive channels (MscS). TcMscS is activated by membrane tension and forms a large pore permeable to anions, cations, and small osmolytes. The channel changes its location from the contractile vacuole complex in epimastigotes to the plasma membrane as the parasites develop into intracellular amastigotes. TcMscS knockout parasites show significant fitness defects, including increased cell volume, calcium dysregulation, impaired differentiation, and a dramatic decrease in infectivity. Our work provides mechanistic insights into components supporting pathogen adaptation inside the host thus opening the exploration of mechanosensation as a prerequisite of protozoan infectivity. | microbiology |
Species Tree Inference on Data with Paralogs is Accurate Using Methods Intended to Deal with Incomplete Lineage Sorting AO_SCPLOWBSTRACTC_SCPLOWMany recent phylogenetic methods have focused on accurately inferring species trees when there is gene tree discordance due to incomplete lineage sorting (ILS). For almost all of these methods, and for phylogenetic methods in general, the data for each locus is assumed to consist of orthologous, single-copy sequences. Loci that are present in more than a single copy in any of the studied genomes are excluded from the data. These steps greatly reduce the number of loci available for analysis. The question we seek to answer in this study is: What happens if one runs such species tree inference methods on data where paralogy is present, in addition to or without ILS being present? Through simulation studies and analyses of two large biological data sets, we show that running such methods on data with paralogs can still provide accurate results. We use multiple different methods, some of which are based directly on the multispecies coalescent (MSC) model, and some of which have been proven to be statistically consistent under it. We also treat the paralogous loci in multiple ways: from explicitly denoting them as paralogs, to randomly selecting one copy per species. In all cases the inferred species trees are as accurate as equivalent analyses using single-copy orthologs. Our results have significant implications for the use of ILS-aware phylogenomic analyses, demonstrating that they do not have to be restricted to single-copy loci. This will greatly increase the amount of data that can be used for phylogenetic inference. | evolutionary biology |
Neurocomputational underpinnings of expected surprise Predictive coding accounts of brain functions profoundly influence current approaches to perceptual synthesis. However, a fundamental paradox has emerged, that may be very relevant for understanding hallucinations, psychosis or cognitive inflexibility. This paradox is that in some situations surprise or prediction error related responses can decrease when predicted and yet, they can increase when we know they are predictable. This paradox is resolved by recognizing that brain responses reflect precision weighted prediction error. This then presses us to disambiguate the contributions of precision and prediction error in electrophysiology. We report, for the first time, an experimental paradigm that may be able to meet this challenge. We examined brain responses to unexpected and expected surprising sounds, assuming that the latter yield a smaller prediction error but much more amplified by a larger precision weight. Importantly, addressing this modulation requires the modelling of trial-by-trial variations of brain responses, that we reconstructed within a fronto-temporal network by combining EEG and MEG. Our results reveal an adaptive learning of surprise with larger integration of past (relevant) information in the context of expected surprises. Within the auditory hierarchy, this adaptation was found tied down to specific connections and reveals in particular and crucially precision encoding through neuronal excitability. Strikingly, these fine processes are automated as sound sequences were unattended. These findings directly speak to applications in psychiatry, where it has been suggested that a specifically impaired precision weighting is at the heart of several conditions such as schizophrenia and autism. | neuroscience |
Visual exposure enhances stimulus encoding and persistence in primary cortex The brain adapts to the sensory environment. For example, simple sensory exposure can modify the response properties of early sensory neurons. How these changes affect the overall encoding and maintenance of stimulus information across neuronal populations remains unclear. We perform parallel recordings in the primary visual cortex of anesthetized cats and find that brief, repetitive exposure to structured visual stimuli enhances stimulus encoding by decreasing the selectivity and increasing the range of the neuronal responses that persist after stimulus presentation. Low-dimensional projection methods and simple classifiers demonstrate that visual exposure increases the segregation of persistent neuronal population responses into stimulus-specific clusters. These observed refinements preserve the representational details required for stimulus reconstruction and are detectable in post-exposure spontaneous activity. Assuming response facilitation and recurrent network interactions as the core mechanisms underlying stimulus persistence, we show that the exposure-driven segregation of stimulus responses can arise through strictly local plasticity mechanisms, also in the absence of firing rate changes. Our findings provide evidence for the existence of an automatic, unguided optimization process that enhances the encoding power of neuronal populations in early visual cortex, thus potentially benefiting simple readouts at higher stages of visual processing. | neuroscience |
Sensory coding and causal impact of mouse cortex in a visual decision Correlates of sensory stimuli and motor actions are found in multiple cortical areas, but such correlates do not indicate whether these areas are causally relevant to task performance. We trained mice to discriminate visual contrast and report their decision by turning a wheel. Widefield calcium imaging and Neuropixels recordings in cortex revealed stimulus-related activity in visual (VIS) and frontal (MOs) areas, and widespread movement-related activity across the whole dorsal cortex. Optogenetic inactivation biased choices only when targeted at VIS and MOs, at times corresponding to peak stimulus decoding. A neurometric model based on summing and subtracting activity in VIS and MOs successfully described behavioral performance and predicted the effect of optogenetic inactivation. Thus, local sensory signals in visual and frontal cortex play a causal role in task performance, while widespread dorsal cortical signals correlating with movement reflect processes that do not play a causal role. | neuroscience |
Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with i the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells. | genomics |
Differential dominance of an allele of the Drosophila tbetah gene challenges standard genetic techniques The biogenic amine octopamine (OA) and its precursor tyramine (TA) are involved in controlling a plethora of different physiological and behavioral processes. The tyramine-{beta}-hydroxylase (t{beta}h) gene encodes the enzyme catalyzing the last synthesis step from TA to OA. Here, we report differential dominance (from recessive to overdominant) of the putative null t{beta}hnM18 allele in two behavioral measures in Buridans paradigm (walking speed and stripe deviation) and a proboscis extension assay in the fruit fly Drosophila melanogaster. The behavioral analysis of transgenic t{beta}h expression experiments in mutant and wild type flies as well as of OA- and TA-receptor mutants revealed a complex interaction of both aminergic systems. Our analysis suggests that the different neuronal networks responsible for the three phenotypes show differential sensitivity to t{beta}h gene expression levels. The evidence suggests that this sensitivity is brought about by a TA/OA opponent system modulating the involved neuronal circuits. This conclusion entails important implications for standard transgenic techniques, commonly used in functional genetics. | genetics |
Feedback between a retinoid-related nuclear receptor and the let-7 microRNAs controls the pace and number of molting cycles in C. elegans. Animal development requires coordination among cyclic processes, sequential cell fate specifications, and once-a-lifetime morphogenic events, but the underlying mechanisms are not well understood. C. elegans undergo four molts at regular 8-10 h intervals. The pace of the cycle is governed by PERIOD/lin-42 and other as-yet unknown factors. Cessation of the cycle in young adults is controlled by the let-7 family of microRNAs and downstream transcription factors in the heterochronic pathway. Here, we characterize a negative feedback loop between NHR-23, the worm homolog of mammalian retinoid-related orphan receptors (RORs), and the let-7 family of microRNAs that regulates both the frequency and finite number of molts. The molting cycle is decelerated in nhr-23 knockdowns, accelerated in let-7(-) mutants, and similar to wild type animals in let-7(-) nhr-23(-) double mutants. NHR-23 binds response elements (ROREs) in the let-7 promoter and activates transcription. In turn, let-7 dampens nhr-23 expression across development via a complementary let-7 binding site (LCS) in the nhr-23 3' UTR. The molecular interactions between NHR-23 and let-7 hold true for other let-7 family microRNAs. Either derepression of nhr-23 transcripts by LCS deletion or high gene dosage of nhr-23 leads to protracted behavioral quiescence and extra molts in adults. NHR-23 and let-7 also co-regulate scores of genes required for execution of the molts, including lin-42. In addition, ROREs and LCSs isolated from mammalian ROR and let-7 genes function in C. elegans, suggesting conservation of this feedback mechanism. We propose that this feedback loop unites the molting timer and the heterochronic gene regulatory network possibly by functioning as a cycle counter. | developmental biology |
Cyclic Nucleotide-Gated Ion Channel 2 modulates auxin homeostasis and signaling Cyclic Nucleotide Gated Ion Channels (CNGCs) have been firmly established as Ca2+-conducting ion channels that regulate a wide variety of physiological responses in plants. CNGC2 has been implicated in plant immunity and Ca2+ signaling due to the autoimmune phenotypes exhibited by null mutants of CNGC2. However, cngc2 mutants display additional phenotypes that are unique among autoimmune mutants, suggesting that CNGC2 has functions beyond defense and generates distinct Ca2+ signals in response to different triggers. In this study we found that cngc2 mutants showed reduced gravitropism, consistent with a defect in auxin signaling. This was mirrored in the diminished auxin response detected by the auxin reporters DR5::GUS and DII-VENUS and in a strongly impaired auxin-induced Ca2+ response. Moreover, the cngc2 mutant exhibits higher levels of the endogenous auxin indole-3-acetic acid (IAA), indicating that excess auxin in cngc2 causes its pleiotropic phenotypes. These auxin signaling defects and the autoimmunity syndrome of cngc2 could be suppressed by loss-of-function mutations in the auxin biosynthesis gene YUCCA6 (YUC6), as determined by identification of the cngc2 suppressor mutant repressor of cngc2 (rdd1) as an allele of YUC6. A loss-of-function mutation in the upstream auxin biosynthesis gene TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS (TAA1, WEAK ETHYLENE INSENSITIVE8) also suppressed the cngc2 phenotypes, further supporting the tight relationship between CNGC2 and the TAA-YUC-dependent auxin biosynthesis pathway. Taking these results together, we propose that the Ca2+ signal generated by CNGC2 is a part of the negative feedback regulation of auxin homeostasis in which CNGC2 balances cellular auxin perception by influencing auxin biosynthesis. | plant biology |
Identifying complex sequence patterns with a variable-convolutional layer effectively and efficiently Motif identification is among the most common and essential computational tasks for bioinformatics and genomics. Here we proposed a novel convolutional layer for deep neural network, named Variable Convolutional (vConv) layer, for effective motif identification in high-throughput omics data by learning kernel length from data adaptively. Empirical evaluations on DNA-protein binding and DNase footprinting cases well demonstrated that vConv-based networks have superior performance to their convolutional counterparts regardless of model complexity. Meanwhile, vConv could be readily integrated into multi-layer neural networks as an "in-place replacement" of canonical convolutional layer. All source codes are freely available on GitHub for academic usage. | bioinformatics |
Rigorous equations for isothermal titration calorimetry: theoretical and practical consequences The author has withdrawn his manuscript because:
The withdrawn preprint was about methodological aspects in Isothermal Titration Calorimetry (ITC) used to obtain thermodynamic information about reactions like A + B {rightleftarrows} C where A is initially in the cell and B injected from a syringe. The preprint considered the two possible methods in ITC:
1/ the Multiple Injection Method (MIM) making use of short-time injections separated by sufficient time to allow the reaction to reach equilibrium before a new injection.
2/ the Single Injection Method (SIM) making use of a slow continuous injection.
The first result mentioned is about a new equation linking the rate of heat evolution with the injected volume (equations 9 and 10). With this equation and with the hypothesis that there is always perfect mixing of the cell content it was concluded that an ideal titration curve (i.e. not affected by any external influence) for a simple reaction like A + B {rightleftarrows} C cannot change sign (section 3.2). This conclusion turns out to be incorrect when taking in consideration real conditions with imperfect mixing, particularly with MIM using injections often of very short duration, which prevents from reaching perfect mixing. The major problem is that this erroneous conclusion was accompanied with comparisons of the results from well-established programs, which led to the conclusion that these were in error on this point (section 3.6).
I therefore felt necessary to withdraw this preprint to avoid casting doubts unduly on these programs used extensively.
Note that many other aspects in this preprint remain correct (section 3.8). A new version of this work, limited to SIM and considering imperfect mixing, will be submitted for publication under the title: "Isothermal titration calorimetry in the single-injection mode with imperfect mixing".
If you have any questions, please contact me at dumasp@igbmc.fr or at p.dumas@unistra.fr
Sorry for the inconvenience.
Philippe Dumas
November 6, 2021 | biophysics |
Discovering footprints of evolutionary chromatin response to transposons activity: merging biophysics with bioinformatics Transposons are genome components that account for the majority of genome size in many organisms, behaving as parasitic entities and interfering with the translation mechanism. Chromatin structure influences the activity of transposons, by coordinating genome accessibility for the expression and insertion of these sequences. As a case study, we show evidences of an evolutionary response of the chromatin structure to a variation in the activity of Long Interspersed Elements (LINEs) during mammals evolution, with focus on the murine radiation and primate evolution. LINEs activity was measured using a biophysical approach for modeling LINEs as an ecosystem, where different strains of transposons might reproduce, die and compete for access to the translational machinery of the host. The model, based on the discrete stochastic processes of amplification and deactivation of LINEs copies, has been adapted to the data using Bayesian statistics to estimate its main parameters: rate of growth of transposons copy number and rate of past competition between transposons variants. This approach allows to estimate the activity of ancient LINE strains still present in the genome as deactivated components, and the possible competition among different strains. We leverage these results to highlight how the change in the chromatin structure of the murine species seems to be following an increase of LINEs activity during the appearance of the murine specific strain Lx. On the contrary, a similar response is absent in primates evolution, which follows a decrease of LINEs activity during the amplication of primate specific LIMA/LPB strains. | biophysics |
Chloroplasts alter their morphology and accumulate at the pathogen interface during infection by Phytophthora infestans Upon immune activation, chloroplasts switch off photosynthesis, produce anti-microbial compounds, and associate with the nucleus through tubular extensions called stromules. Although it is well-established that chloroplasts alter their position in response to light, little is known about the dynamics of chloroplasts movement in response to pathogen attack. Here, we report that chloroplasts accumulate at the pathogen interface during infection by the Irish potato famine pathogen Phytophthora infestans, associating with the specialized membrane that engulfs the pathogen haustorium. Chemical inhibition of actin polymerization reduces the accumulation of chloroplasts at the pathogen haustoria, suggesting this process is partially dependent on the actin cytoskeleton. However, chloroplast accumulation at haustoria does not necessarily rely on movement of the nucleus to this interface and is not affected by light conditions. Stromules are typically induced during infection, embracing haustoria and interconnecting chloroplasts, to form dynamic organelle clusters. We found that infection-triggered stromule formation relies on BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1) mediated surface immune signaling, whereas chloroplast repositioning towards haustoria does not. Consistent with the defense-related induction of stromules, effector mediated suppression of BAK1 mediated immune signaling reduced stromule formation during infection. On the other hand, immune recognition of the same effector stimulated stromules, presumably via a different pathway. These findings implicate chloroplasts in a polarized response upon pathogen attack and point to more complex functions of these organelles in plant-pathogen interactions. | plant biology |
Sequestration of RBM10 in Nuclear Bodies: Targeting Sequences and Biological Significance RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus.
Note that the previous title of this manuscript was Targeting of RBM10 to S1-1 Nuclear Bodies: Targeting Sequences and its Biological Significance. | molecular biology |
Rbm10 facilitates heterochromatin assembly via the Clr6 HDAC complex Splicing factors have recently been shown to be involved in heterochromatin formation, but their role in controlling heterochromatin structure and function remains poorly understood. In this study, we identified a fission yeast homologue of human splicing factor RBM10, which has been linked to TARP syndrome. Overexpression of Rbm10 in fission yeast leads to strong global intron retention. Rbm10 also interacts with splicing factors in a pattern resembling that of human RBM10, suggesting that the function of Rbm10 as a splicing regulator is conserved. Surprisingly, our deep-sequencing data showed that deletion of Rbm10 caused only minor effect on genome-wide gene expression and splicing. However, the mutant displays severe heterochromatin defects. Further analyses indicated that the heterochromatin defects in the mutant did not result from mis-splicing of heterochromatin factors. Our proteomic data revealed that Rbm10 associates with the histone deacetylase Clr6 complex and chromatin remodelers known to be important for heterochromatin silencing. Deletion of Rbm10 results in significant reduction of Clr6 in heterochromatin. Our work together with previous findings further suggests that different splicing subunits may play distinct roles in heterochromatin regulation. | molecular biology |
A Data-Driven Transcriptional Taxonomy of Adipogenic Chemicals to Identify White and Brite Adipogens BackgroundChemicals in disparate structural classes activate specific subsets of PPAR{gamma}s transcriptional programs to generate adipocytes with distinct phenotypes.
ObjectivesOur objectives were to 1) establish a novel classification method to predict PPAR{gamma} ligands and modifying chemicals, and 2) create a taxonomy to group chemicals based on their effects on PPAR{gamma}s transcriptome and downstream metabolic functions. We tested the hypothesis that environmental adipogens highly ranked by the taxonomy, but segregated from therapeutic PPAR{gamma} ligands, would induce white but not brite adipogenesis.
Methods3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, nuclear receptor ligands known to influence adipocyte biology, potential environmental PPAR{gamma} ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by RNA-Seq and validated by RT-qPCR. A novel classification model was developed using an amended random forest procedure. A subset of environmental contaminants identified as strong PPAR{gamma} agonists were analyzed by their effects on lipid handling, mitochondrial biogenesis and cellular respiration in 3T3-L1 cells and human preadipocytes.
ResultsWe used lipid accumulation and RNA sequencing data to develop a classification system that 1) identified PPAR{gamma} agonists, and 2) sorted chemicals into likely white or brite adipogens. Expression of Cidec was the most efficacious indicator of strong PPAR{gamma} activation. Two known environmental PPAR{gamma} ligands, tetrabromobisphenol A and triphenyl phosphate, which sorted distinctly from therapeutic ligands, induced white adipocyte genes but failed to induce Pgc1a and Ucp1, and induced fatty acid uptake but not mitochondrial biogenesis in 3T3-L1 cells. Moreover, two chemicals identified as highly ranked PPAR{gamma} agonists, tonalide and quinoxyfen, induced white adipogenesis without the concomitant health-promoting characteristics of brite adipocytes in mouse and human preadipocytes.
DiscussionA novel classification procedure accurately identified environmental chemicals as PPAR{gamma} ligands distinct from known PPAR{gamma}-activating therapeutics. The computational and experimental framework has general applicability to the classification of as-yet uncharacterized chemicals. | pharmacology and toxicology |
Stimulation of phospholipase Cβ1 by Gαq promotes the assembly of stress granule proteins During adverse conditions, mammalian cells regulate protein production by sequestering the translational machinery in membrane-less organelles known as stress granules. Here, we found that activation of the G protein subunit Gq promoted the formation of particles that contained stress granule proteins through a mechanism linked to the presence of phospholipase C{beta}1 (PLC{beta}1) in the cytosol. In experiments with PC12 and A10 cells, we showed that under basal conditions, cytosolic PLC{beta}1 bound to stress granule associated proteins, including PABPC1, eIF5A, and Ago2. Knockdown of cytosolic PLC{beta}1 with siRNA or promoting its relocalization to the plasma membrane by activating Gq resulted in the formation of particles containing the stress granule markers, PABPC1, G3BP1, and Ago2. Our studies showed that the composition of these particles resemble those formed under osmotic stress and are distinct from those formed by other stresses. Our results fit a simple thermodynamic model in which cytosolic PLC{beta}1 solubilizes stress granule proteins such that its movement to activated Gq releases these particles to enable the formation of stress granules. Together, our data are suggestive of a link between Gq-coupled signals and protein translation through stress granule formation. | biochemistry |
A neuroendocrine pathway modulating osmotic stress in Drosophila Environmental factors challenge the physiological homeostasis in animals, thereby evoking stress responses. Various mechanisms have evolved to counter stress at the organism level, including regulation by neuropeptides. In recent years, much progress has been made on the mechanisms and neuropeptides that regulate responses to metabolic/nutritional stress, as well as those involved in countering osmotic and ionic stresses. Here, we identified a peptidergic pathway that links these types of regulatory functions. We uncover the neuropeptide Corazonin (Crz), previously implicated in responses to metabolic stress, as a neuroendocrine factor that inhibits the release of a diuretic hormone, CAPA, and thereby modulates the tolerance to osmotic and ionic stress. Both knockdown of Crz and acute injections of Crz peptide impact desiccation tolerance and recovery from chill-coma. Mapping of the Crz receptor (CrzR) expression identified three pairs of Capa-expressing neurons (Va neurons) in the ventral nerve cord that mediate these effects of Crz. We show that Crz acts to restore water/ion homeostasis by inhibiting release of CAPA neuropeptides via inhibition of cAMP production in Va neurons. Knockdown of CrzR in Va neurons affects CAPA signaling, and consequently increases tolerance for desiccation, ionic stress and starvation, but delays chill-coma recovery. Optogenetic activation of Va neurons stimulates excretion and simultaneous activation of Crz and CAPA-expressing neurons reduces this response, supporting the inhibitory action of Crz. Thus, Crz inhibits Va neurons to maintain osmotic and ionic homeostasis, which in turn affects stress tolerance. Earlier work demonstrated that systemic Crz signaling restores nutrient levels by promoting food search and feeding. Here we additionally propose that Crz signaling also ensures osmotic homeostasis by inhibiting release of CAPA neuropeptides and suppressing diuresis. Thus, Crz ameliorates stress-associated physiology through systemic modulation of both peptidergic neurosecretory cells and the fat body in Drosophila.
Author summaryInsects are among the largest groups of animals and have adapted to inhabit almost all environments on Earth. Their success in surviving extreme conditions stems largely from their ability to withstand environmental stress, such as desiccation and cold. However, the neural mechanisms that are responsible for coordinating responses to counter these stresses are largely unknown. To address this, we delineate a neuroendocrine axis utilizing the neuropeptides Corazonin (Crz) and CAPA, that coordinate responses to metabolic and osmotic stress. We show that Crz inhibits the release of a diuretic peptide, CAPA from a set of neurosecretory cells. CAPA in turn influences osmotic and ionic balance via actions on the Malpighian tubules (the insect analogs of the kidney) and the intestine. Taken together with earlier work, our data suggest that Crz acts to restore metabolic homeostasis at starvation and osmotic homeostasis during desiccation by inhibiting release of the diuretic hormone CAPA. Hence, this work provides a mechanistic understanding of the neuroendocrine mitigation of metabolic and osmotic stress by two peptide systems. | neuroscience |
Development and maintenance of synaptic structure is mediated by the alpha-tubulin acetyltransferase MEC-17/αTAT1 The authors have withdrawn their manuscript whilst they perform additional experiments to test some of their conclusions further. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author | cell biology |
The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here we demonstrate, through fetal, endothelial, hematopoietic and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signalling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis. | developmental biology |
Progressive domain segregation in early embryonic development and underlying correlation to genetic and epigenetic changes Chromatin undergoes drastic structural organization and epigenetic reprogramming during embryonic development. We present here a consistent view of the chromatin structural change, epigenetic reprogramming and the corresponding sequence dependence in both mouse and human embryo development. The two types of domains, identified earlier as forests and prairies, become spatially segregated during embryonic development, with the exception of zygotic genome activation (ZGA) and implantation, at which notable domain mixing occurs. Structural segregation largely coincides with DNA methylation and gene expression changes. Genes located in mixed prairie domains show proliferation and ectoderm differentiation-related function in ZGA and implantation, respectively. Chromatin of ectoderm shows the weakest and endoderm the strongest domain segregation in germ layers. This chromatin structure difference between different germ layers generally enlarges in further differentiation. The systematic chromatin structure establishment and its sequence-based segregation strongly suggest DNA sequence as a possible driving force for the establishment of chromatin 3D structures which affect profoundly the expression profile. Other possible factors correlated with/influencing chromatin structures, including temperature, germ layers, and cell cycle, were discussed for an understanding of concerted chromatin structure and epigenetic changes in development. | developmental biology |
Krüppel-like factor gene function in the ctenophore Mnemiopsis leidyi assessed by CRISPR/Cas9-mediated genome editing The Kruppel-like factor (Klf) gene family encodes for transcription factors that play an important role in the regulation of stem cell proliferation, cell differentiation, and development in bilaterians. While Klf genes have been shown to functionally specify various cell types in non-bilaterian animals, their role in early diverging animal lineages has not been assessed. Thus, the ancestral activity of these transcription factors in animal development is not well understood. The ctenophore Mnemiopsis leidyi has emerged as an important non-bilaterian model system for understanding early animal evolution. Here we characterize the expression and functional role of Klf genes during M. leidyi embryogenesis. Zygotic Klf gene function was assessed with both CRISPR/Cas9-mediated genome editing and splice-blocking morpholino oligonucleotide knockdown approaches. Abrogation of zygotic Klf expression during M. leidyi embryogenesis results in abnormal development of several organs including the pharynx, tentacle bulbs, and apical organ. Our data suggest an ancient role for Klf genes in regulating endodermal patterning, possibly through regulation of cell proliferation.
Summary StatementUsing CRISPR/Cas9 genome editing and morpholino oligonucleotide knockdown, this study shows that tissues derived from the endoderm are dependent upon Klf5 ortholog expression for proper development and patterning in the ctenophore Mnemiopsis leidyi. | developmental biology |
Cellular transformation by combined lineage conversion and oncogene expression Cancer is the most complex genetic disease known, with mutations implicated in more than 250 genes. However, it is still elusive which specific mutations found in human patients lead to tumorigenesis. Here we show that a combination of oncogenes that is characteristic of liver cancer (CTNNB1, TERT, MYC) induces senescence in human fibroblasts and primary hepatocytes. However, reprogramming fibroblasts to a liver progenitor fate, induced hepatocytes (iHeps), makes them sensitive to transformation by the same oncogenes. The transformed iHeps are highly proliferative, tumorigenic in nude mice, and bear gene expression signatures of liver cancer. These results show that tumorigenesis is triggered by a combination of three elements: the set of driver mutations, the cellular lineage, and the state of differentiation of the cells along the lineage. Our results provide direct support for the role of cell identity as a key determinant in transformation, and establish a paradigm for studying the dynamic role of oncogenic drivers in human tumorigenesis. | cancer biology |
Phosphorylation-dependent routing of RLP44 towards brassinosteroid or phytosulfokine signalling Plants rely on a complex network of cell surface receptors to integrate developmental and environmental cues into behaviour adapted to the conditions. The largest group of these receptors, leucine-rich repeat receptor-like kinases, form a complex interaction network that is modulated and extended by receptor-like proteins. This raises the question of how specific outputs can be generated when receptor proteins are engaged in a plethora of promiscuous interactions. RECEPTOR-LIKE PROTEIN 44 (RLP44) acts to promote both brassinosteroid and phytosulfokine signalling, which orchestrate a wide variety of cellular responses. However, it is unclear how these activities are coordinated. Here, we show that RLP44 is phosphorylated in its highly conserved C-terminal cytosolic tail and that this post-translational modification governs its subcellular localization. RLP44 variants in which phosphorylation is blocked enter endocytosis prematurely, leading to an almost entirely intracellular localization, whereas phospho-mimicking or ectopic phosphorylation results in preferential RLP44 localization at the plasma membrane. Phosphorylation of the C-terminus is essential for brassinosteroid-associated functions of RLP44. In contrast, RLP44s role in phytosulfokine signalling is not affected by its phospho-status. Detailed mutational analysis suggests that phospho-charge, rather than modification of individual amino acids determines routing of RLP44 to its target receptor complexes, providing a framework to understand how a common component of different receptor complexes can get specifically engaged in a particular signalling pathway. | plant biology |
Identification of sample mix-ups and mixtures in microbiome data in Diversity Outbred mice In a Diversity Outbred mouse project with genotype data on 500 mice, including 297 with microbiome data, we identified three sets of sample mix-ups (two pairs and one trio) as well as at least 15 microbiome samples that appear to be mixtures of pairs of mice. The microbiome data consisted of shotgun sequencing reads from fecal DNA, used to characterize the gut microbial communities present in these mice. These sequence reads included sufficient reads derived from the host mouse to identify the individual. A number of microbiome samples appeared to contain a mixture of DNA from two mice. We describe a method for identifying sample mix-ups in such microbiome data, as well as a method for evaluating sample mixtures in this context. | genetics |
Widespread latitudinal asymmetry in marginal population performance AimRange shifts are expected to occur when populations at one range margin perform better than those at the other margin, yet no global trend in population performances at range margins has been demonstrated empirically across a wide range of taxa and biomes. Here we test the prediction that, if impacts of ongoing climate change on population performance are widespread, then populations from the high-latitude margin (HLM) should perform as well as or better than central populations, whereas populations at low-latitude margins (LLM) populations should perform worse.
LocationGlobal
Time period1898-2020
Major taxa studiedPlants and animals
MethodsTo test our prediction, we used a meta-analysis quantifying the empirical support for asymmetry in the performance of high- and low-latitude margin populations compared to central populations. Performance estimates were derived from 51 papers involving 113 margin-centre comparisons from 54 species and 705 populations. We then related these performance differences to climatic differences among populations. We also tested whether patterns are consistent across taxonomic kingdoms (plants vs. animals) and across habitats (marine vs. terrestrial).
ResultsPopulations at margins performed significantly worse than central populations and this trend was primarily driven by the low-latitude margin. Although the difference was of small magnitude, it was largely consistent across biological kingdoms and habitats. The differences in performance were positively related to the difference in average temperatures between populations during the period 1985-2016.
Major conclusionsThe observed asymmetry in marginal population performance confirms predictions about the effects of global climate change. It indicates that changes in demographic rates in marginal populations, despite extensive short-term variation, can serve as early-warning signals of impending range shifts. | ecology |
Chemogenetic inhibition of a monosynaptic projection from the basolateral amygdala to the ventral hippocampus reduces appetitive and consummatory alcohol drinking behaviors Alcohol use disorder (AUD) and anxiety/stressor disorders frequently co-occur and this dual diagnosis represents a major health and economic problem worldwide. The basolateral amygdala (BLA) is a key brain region that is known to contribute to the etiology of both disorders. Although many studies have implicated BLA hyperexcitability in the pathogenesis of AUD and comorbid conditions, relatively little is known about the specific efferent projections from this brain region that contribute to these disorders. Recent optogenetic studies have shown that the BLA sends a strong monosynaptic excitatory projection to the ventral hippocampus (vHC) and that this circuit modulates anxiety- and fear-related behaviors. However, it is not known if this pathway influences alcohol drinking-related behaviors. Here, we employed a rodent operant drinking regimen that procedurally separates appetitive (e.g. seeking) and consummatory (e.g. intake) behaviors, chemogenetics, and brain region-specific microinjections, to determine if BLA-vHC circuitry influences alcohol drinking-related measures. We first confirmed prior optogenetic findings that silencing this circuit reduced anxiety-like behaviors on the elevated plus-maze. We then demonstrated that inhibiting the BLA-vHC pathway significantly reduced appetitive alcohol drinking-related behaviors while having no effect on consummatory measures. Sucrose seeking measures were also reduced following chemogenetic inhibition of this circuit. Taken together, these findings provide the first indication that the BLA-vHC circuit may regulate appetitive alcohol drinking-related behaviors and add to a growing body of evidence suggesting that dysregulation of this pathway may contribute to the pathophysiology of AUD and anxiety/stressor-related disorders.
HIGHLIGHTSO_LIThe basolateral amygdala sends a monosynaptic glutamatergic projection to the ventral hippocampus
C_LIO_LIInhibiting this circuit reduces anxiety-like behaviors in male Long Evans rats
C_LIO_LIInhibition of this pathway also decreases operant alcohol seeking-related behaviors
C_LI | neuroscience |
Thunor: Visualization and Analysis of High-Throughput Dose-response Datasets High-throughput cell proliferation assays to quantify drug-response are becoming increasingly common and powerful with the emergence of improved automation and multi-time point analysis methods. However, pipelines for analysis of these datasets that provide reproducible, efficient, and interactive visualization and interpretation are sorely lacking. To address this need, we introduce Thunor, an open-source software platform to manage, analyze, and visualize large, dose-dependent cell proliferation datasets. Thunor supports both end-point and time-based proliferation assays as input. It provides a simple, user-friendly interface with interactive plots and publication-quality images of cell proliferation time courses, dose-response curves, and derived dose-response metrics, e.g. IC50, including across datasets or grouped by tags. Tags are categorical labels for cell lines and drugs, used for aggregation, visualization, and statistical analysis, e.g. cell line mutation or drug class/target pathway. A graphical plate map tool is included to facilitate plate annotation with cell lines, drugs, and concentrations upon data upload. Datasets can be shared with other users via point-and-click access control. We demonstrate the utility of Thunor to examine and gain insight from two large drug response datasets: a large, publicly available cell viability database and an in-house, high-throughput proliferation rate dataset. Thunor is available from www.thunor.net. | pharmacology and toxicology |
High-pass filtering artifacts in multivariate classification of neural time series data 0.BackgroundTraditionally, EEG/MEG data are high-pass filtered and baseline-corrected to remove slow drifts. Minor deleterious effects of high-pass filtering in traditional time-series analysis have been well-documented, including temporal displacements. However, its effects on time-resolved multivariate pattern classification analyses (MVPA) are largely unknown.
New MethodTo prevent potential displacement effects, we extend an alternative method of removing slow drift noise - robust detrending - with a procedure in which we mask out all cortical events from each trial. We refer to this method as trial-masked robust detrending.
ResultsIn both real and simulated EEG data of a working memory experiment, we show that both high-pass filtering and standard robust detrending create artifacts that result in the displacement of multivariate patterns into activity silent periods, particularly apparent in temporal generalization analyses, and especially in combination with baseline correction. We show that trial-masked robust detrending is free from such displacements.
Comparison with Existing Method(s)Temporal displacement may emerge even with modest filter cut-off settings such as 0.05 Hz, and even in regular robust detrending. However, trial-masked robust detrending results in artifact-free decoding without displacements. Baseline correction may unwittingly obfuscate spurious decoding effects and displace them to the rest of the trial.
ConclusionsDecoding analyses benefits from trial-masked robust detrending, without the unwanted side effects introduced by filtering or regular robust detrending. However, for sufficiently clean data sets and sufficiently strong signals, no filtering or detrending at all may work adequately. Implications for other types of data are discussed, followed by a number of recommendations. | neuroscience |
The HIV-1 ribonucleoprotein dynamically regulates its condensate behavior and drives acceleration of protease activity through membraneless granular phase separation A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase separated molecular sponges, stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ~2400 Gag and ~120 GagPol by viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules. | molecular biology |
Long-term potentiation in neurogliaform cells modulates excitation-inhibition balance in the temporoammonic pathway Apical dendrites of pyramidal neurons integrate information from higher-order cortex and thalamus, and gate signaling and plasticity at proximal synapses. In the hippocampus, neurogliaform cells and other interneurons located within stratum lacunosum-moleculare mediate powerful inhibition of CA1 pyramidal neuron distal dendrites. Is the recruitment of such inhibition itself subject to use-dependent plasticity, and if so, what induction rules apply? Here we show that interneurons in mouse stratum lacunosum-moleculare exhibit Hebbian NMDA receptor-dependent long-term potentiation (LTP). Such plasticity can be induced by selective optogenetic stimulation of afferent fibers in the temporoammonic pathway from the entorhinal cortex, but not by equivalent stimulation of afferents from the thalamic nucleus reuniens. We further show that theta-burst patterns of afferent firing induces LTP in neurogliaform interneurons identified using neuron-derived neurotrophic factor (Ndnf)-Cre mice. Theta-burst activity of entorhinal cortex afferents led to an increase in disynaptic feed-forward inhibition, but not monosynaptic excitation, of CA1 pyramidal neurons. Activity-dependent synaptic plasticity of neurogliaform cells in stratum lacunosum-moleculare thus alters the excitation-inhibition balance at entorhinal cortex inputs to the apical dendrites of pyramidal neurons, implying a dynamic role for these interneurons in gating CA1 dendritic computations.
Significance statementElectrogenic phenomena in distal dendrites of principal neurons in the hippocampus have a major role in gating synaptic plasticity at afferent synapses on proximal dendrites. Apical dendrites also receive powerful feed-forward inhibition mediated in large part by neurogliaform neurons. Here we show that theta-burst activity in afferents from the entorhinal cortex induces Hebbian long-term potentiation at excitatory synapses recruiting these GABAergic cells. Such LTP increases disynaptic inhibition of principal neurons, thus shifting the excitation-inhibition balance in the temporoammonic pathway in favor of inhibition, with implications for computations and learning rules in proximal dendrites. | neuroscience |
Individual tree-crown detection in RGB imagery using semi-supervised deep learning neural networks Remote sensing can transform the speed, scale, and cost of biodiversity and forestry surveys. Data acquisition currently outpaces the ability to identify individual organisms in high resolution imagery. We outline an approach for identifying tree-crowns in RGB imagery while using a semi-supervised deep learning detection network. Individual crown delineation has been a long-standing challenge in remote sensing and available algorithms produce mixed results. We show that deep learning models can leverage existing Light Detection and Ranging (LIDAR)-based unsupervised delineation to generate trees that are used for training an initial RGB crown detection model. Despite limitations in the original unsupervised detection approach, this noisy training data may contain information from which the neural network can learn initial tree features. We then refine the initial model using a small number of higher-quality hand-annotated RGB images. We validate our proposed approach while using an open-canopy site in the National Ecological Observation Network. Our results show that a model using 434,551 self-generated trees with the addition of 2848 hand-annotated trees yields accurate predictions in natural landscapes. Using an intersection-over-union threshold of 0.5, the full model had an average tree crown recall of 0.69, with a precision of 0.61 for the visually-annotated data. The model had an average tree detection rate of 0.82 for the field collected stems. The addition of a small number of hand-annotated trees improved the performance over the initial self-supervised model. This semi-supervised deep learning approach demonstrates that remote sensing can overcome a lack of labeled training data by generating noisy data for initial training using unsupervised methods and retraining the resulting models with high quality labeled data. | ecology |
Multi-omic analyses reveal a role for mammalian CIC in cell cycle regulation and mitotic fidelity CIC encodes a transcriptional repressor that is inactivated by loss-of-function mutations in several cancer types, indicating that it may function as a tumor suppressor. Recent studies have indicated that CIC may regulate cell cycle genes in humans; however, a systematic investigation of this proposed role has not yet been reported. Here, we used single-cell RNA sequencing to show that inactivation of CIC in human cell lines correlated with transcriptional dysregulation of genes involved in cell cycle control. We also mapped CICs protein-protein and genetic interaction networks, identifying interactions between CIC and members of the Switch/Sucrose Non-Fermenting (SWI/SNF) complex as well as revealing novel candidate interactions between CIC and cell cycle regulators. We further showed that CIC loss was associated with an increased frequency of mitotic defects in human cell lines and in a mouse model. Our study thus positions CIC as a cell cycle regulator and indicates that CIC loss can lead to mitotic errors, consistent with CICs emerging role as a tumor suppressor of relevance in several cancer contexts. | cancer biology |
Network Inference with Granger Causality Ensembles on Single-Cell Transcriptomic Data Advances in single-cell transcriptomics enable measuring the gene expression of individual cells, allowing cells to be ordered by their state in a dynamic biological process. Many algorithms assign pseudotimes to each cell, representing the progress along the biological process. Ordering the expression data according to such pseudotimes can be valuable for understanding the underlying regulator-gene interactions in a biological process, such as differentiation. However, the distribution of cells sampled along a transitional process, and hence that of the pseudotimes assigned to them, is not uniform. This prevents using many standard mathematical methods for analyzing the ordered gene expression states. We present Single-cell Inference of Networks using Granger Ensembles (SINGE), an algorithm for gene regulatory network inference from single-cell gene expression data. Given ordered single-cell data, SINGE uses kernel-based Granger Causality regression, which smooths the irregular pseudotimes and missing expression values. It then aggregates the predictions from an ensemble of regression analyses with a modified Borda count to compile a ranked list of candidate interactions between transcriptional regulators and their target genes. In two mouse embryonic stem cell differentiation case studies, SINGE outperforms other contemporary algorithms for gene network reconstruction. However, a more detailed examination reveals caveats about transcriptional network reconstruction with single-cell RNA-seq data. Network inference methods, including SINGE, may have near random performance for predicting the targets of many individual regulators even if the overall performance is good. In addition, including uninformative pseudotime values can hurt the performance of network reconstruction methods. A MATLAB implementation of SINGE is available at https://github.com/gitter-lab/SINGE. | bioinformatics |
Multiple sources of Shh are critical for the generation and scaling of ventral spinal cord oligodendrocyte precursor populations. Graded Sonic Hedgehog (Shh) signaling emanating from notochord and floorplate patterns the early neural tube. Soon thereafter, Shh signaling strength within the ventricular zone becomes dis-contiguous and discontinuous along the ventral to dorsal axis suggesting a distribution of Shh that cannot be achieved by diffusion alone. Here we discover that sequential activation of Shh expression by ventricular zone derivatives is critical for counteracting a precocious exhaustion of the Olig2 precursor cell population of the pMN domain at the end of motor neuron genesis and during the subsequent phase of ventral oligodendrocyte precursor production. Selective expression of Shh by motor neurons of the lateral motor column at the beginning of oligodendrogenesis ensures a more yielding pMN domain at limb levels compared to thoracic levels. Thus, patterned expression of Shh by ventricular zone derivatives including earlier born neurons contributes to the scaling of the spinal cord along the anterior - posterior axis by regulating the activity of a select ventricular zone precursor domain at later stages of development. | developmental biology |
Microbial metabolism and adaptations in Atribacteria-dominated methane hydrate sediments Gas hydrates harbor gigatons of natural gas, yet their microbiomes remain understudied. We bioprospected 16S rRNA amplicons, metagenomes, and metaproteomes from methane hydrate-bearing sediments under Hydrate Ridge (offshore Oregon, USA, ODP Site 1244, 2-69 mbsf) for novel microbial metabolic and biosynthetic potential. Atribacteria sequences generally increased in relative sequence abundance with increasing sediment depth. Most Atribacteria ASVs belonged to JS-1-Genus 1 and clustered with other sequences from gas hydrate-bearing sediments. We recovered 21 metagenome-assembled genomic bins spanning three geochemical zones in the sediment core: the sulfate-methane transition zone, metal (iron/manganese) reduction zone, and gas hydrate stability zone. We found evidence for bacterial fermentation as a source of acetate for aceticlastic methanogenesis and as a driver of iron reduction in the metal reduction zone. In multiple zones, we identified a Ni-Fe hydrogenase-Na+/H+ antiporter supercomplex (Hun) in Atribacteria and Firmicutes bins and in other deep subsurface bacteria and cultured hyperthermophiles from the Thermotogae phylum. Atribacteria expressed tripartite ATP-independent (TRAP) transporters downstream from a novel regulator (AtiR). Atribacteria also possessed adaptations to survive extreme conditions (e.g., high salt brines, high pressure, and cold temperatures) including the ability to synthesize the osmolyte di-myo-inositol-phosphate as well as expression of K+-stimulated pyrophosphatase and capsule proteins.
Originality-Significance StatementThis work provides insights into the metabolism and adaptations of microbes that are ubiquitous and abundant in methane-rich ecosystems. Our findings suggest that bacterial fermentation is a source of acetate for aceticlastic methanogenesis and a driver of iron reduction in the metal reduction zone. Atribacteria, the most abundant phylum in gas hydrate-bearing sediments, possess multiple strategies to cope with environmental stress. | microbiology |
A Stomata Classification and Detection System in Microscope Images of Maize Cultivars Research on stomata, i.e., morphological structures of plants, has increased in popularity in the last years. These structures (pores) are in charge of the interaction between the internal plant system and the environment, working on different processes such as photosynthesis and transpiration stream. Besides, a better understanding of the pore mechanism plays a significant role when exploring the evolution process, as well as the behavior of plants. Although the study of stomata in dicots species of plants has advanced considerably in the past years, there is little information about stomata of cereal grasses. Also, automated detection of these structures have been considered in the literature, but some gaps are still uncovered. This fact is motivated by high morphological variation of stomata and the presence of noise from the image acquisition step. In this work, we propose a new methodology for automatic stomata classification and a new detection system in microscope images for maize cultivars. We have achieved an approximated accuracy of 97.1% in the identification of stomata regions using classifiers based on deep learning features, which figures out as a nearly perfect classification system. | plant biology |
A scalar Poincare map for struggling in Xenopus tadpoles Short-term synaptic plasticity is widely found in many areas of the central nervous system. In particular, it is believed that synaptic depression can act as a mechanism to allow simple networks to generate a range of different firing patterns. The locomotor circuit of hatchling Xenopus tadpoles produces two types of behaviours: swimming and the slower, stronger struggling movement that is associated with rhythmic bends of the whole body. Struggling is accompanied by anti-phase bursts in neurons on each side of the spinal cord and is believed to be governed by a short-term synaptic depression of commissural inhibition. To better understand burst generation in struggling, we study a minimal network of two neurons coupled through depressing inhibitory synapses. Depending on the strength of the synaptic conductance between the two neurons, such a network can produce symmetric n - n anti-phase bursts, where neurons fire n spikes in alternation, with the period of such solutions increasing with the strength of the synaptic conductance. Relying on the timescale disparity in the model, we reduce the eight-dimensional network equations to a fully explicit scalar Poincare burst map. This map tracks the state of synaptic depression from one burst to the next, and captures the complex bursting dynamics of the network. Fixed points of this map are associated with stable burst solutions of the full network model, and are created through fold bifurcations of maps. We derive conditions that describe period increment bifurcations between stable n - n and (n + 1) - (n + 1) bursts, producing a full bifurcation diagram of the burst cycle period. Predictions of the Poincare map fit excellently with numerical simulations of the full network model, and allow the study of parameter sensitivity for rhythm generation. | neuroscience |
Protein appetite drives macronutrient-related differences in ventral tegmental area neural activity Control of protein intake is essential for numerous biological processes as several amino acids cannot be synthesized de novo, however, its neurobiological substrates are still poorly understood. In the present study, we combined in vivo fiber photometry with nutrient-conditioned flavor in a rat model of protein appetite to record neuronal activity in the ventral tegmental area (VTA), a central brain region for the control of food-related processes. In adult male rats, protein restriction increased preference for casein (protein) over maltodextrin (carbohydrate). Moreover, protein consumption was associated with a greater VTA response relative to carbohydrate. After initial nutrient preference, a switch from a normal balanced diet to protein restriction induced rapid development of protein preference but required extensive exposure to macronutrient solutions to induce greater VTA responses to casein. Furthermore, prior protein restriction induced long-lasting food preference and VTA responses. This study reveals that VTA circuits are involved in protein appetite in times of need, a crucial process for all animals to acquire an adequate amount of protein in their diet.
Significance StatementAcquiring insufficient protein in ones diet has severe consequences for health and ultimately will lead to death. In addition, a low level of dietary protein has been proposed as a driver of obesity as it can leverage up intake of fat and carbohydrate. However, much remains unknown about the role of the brain in ensuring adequate intake of protein. Here, we show that in a state of protein restriction a key node in brain reward circuitry, the ventral tegmental area, is activated more strongly during consumption of protein than carbohydrate. Moreover, although rats behavior changed to reflect new protein status, patterns of neural activity were more persistent and only loosely linked to protein status. | neuroscience |
Dot1L-dependent H3K79 methylation facilitates histone variant H2A.Z exchange at DNA double strand breaks and is required for high fidelity, homology-directed DNA repair In eukaryotic cells, the homology-directed repair (HDR) and non-homologous end joining (NHEJ) pathways are required for the repair of DNA double strand breaks (DSB). The high-fidelity HDR pathway is particularly important for maintenance of genomic stability. In mammals, histone post-translational modifications and histone variant exchange into nucleosomes at sites of DSB generate an open chromatin state necessary for repair to take place. However, the specific contributions of histone modifications to histone variant exchange at DSB sites and the influence of these changes on the DNA repair process and genome stability are incompletely understood. Here we show that Dot1L-catalyzed methylation of H3 histone on lysine 79 (H3K79) is required for efficient HDR of DSB. In cells with DNA DSB either lacking Dot1L or expressing a methylation-dead Dot1L, there is altered kinetics of DNA repair factor recruitment, markedly decreased H2A.Z incorporation at DSB sites, and a specific and profound reduction in HDR, which results in significant genomic instability. These findings demonstrate a new role for Dot1L, identifying it as a critical regulator of the DNA repair process and a steward of genomic integrity. | molecular biology |
Optical measurement of voltage sensing by endogenous ion channel A primary goal of molecular physiology is to understand how conformational changes of proteins affect the function of cells, tissues, and organisms. Here, we describe an imaging method for measuring the conformational changes of the voltage sensors of endogenous ion channel proteins within live tissue, without genetic modification. We synthesized GxTX-594, a variant of the peptidyl tarantula toxin guangxitoxin-1E, conjugated to a fluorophore optimal for two-photon excitation imaging through light-scattering tissue. GxTX-594 targets the voltage sensors of Kv2 proteins, which form potassium channels and plasma membrane-endoplasmic reticulum junctions. GxTX-594 dynamically labels Kv2 proteins on cell surfaces in response to voltage stimulation. To interpret dynamic changes in labeling intensity, we developed a statistical thermodynamic model that relates the conformational changes of Kv2 voltage sensors to labeling intensity. We used two-photon excitation imaging of rat brain slices to image Kv2 proteins in neurons. This imaging method enabled identification of conformational changes of endogenous Kv2 voltage sensors in tissue. | biophysics |
BLight: Efficient exact associative structure for k-mers MotivationA plethora of methods and applications share the fundamental need to associate information to words for high throughput sequence analysis. Doing so for billions of k-mers is commonly a scalability problem, as exact associative indexes can be memory expensive. Recent works take advantage of overlaps between k-mers to leverage this challenge. Yet existing data structures are either unable to associate information to k-mers or are not lightweight enough.
ResultsWe present BLight, a static and exact data structure able to associate unique identifiers to k-mers and determine their membership in a set without false positive, that scales to huge k-mer sets with a low memory cost. This index combines an extremely compact representation along with very fast queries. Besides, its construction is efficient and needs no additional memory. Our implementation achieves to index the k-mers from the human genome using 8GB of RAM (23 bits per k-mer) within 10 minutes and the k-mers from the large axolotl genome using 63 GB of memory (27 bits per k-mer) within 76 minutes. Furthermore, while being memory efficient, the index provides a very high throughput: 1.4 million queries per second on a single CPU or 16.1 million using 12 cores. Finally, we also present how BLight can practically represent metagenomic and transcriptomic sequencing data to highlight its wide applicative range.
AvailabilityWe wrote the BLight index as an open source C++ library under the AGPL3 license available at github.com/Malfoy/BLight. It is designed as a user-friendly library and comes along with code usage samples. | bioinformatics |
Work Flows for Cellular Epidemiology, From Conception to Translation The authors have withdrawn their manuscript after issues with the cell viability validation (Fig. 8) were found. In the interest of furthering science and ensuring that clinical decisions are based on best practices and evidence, the issue is described in more detail in the peer-reviewed, published paper: https://www.frontiersin.org/articles/10.3389/fphys.2021.647603/full
Knothe Tate ML, Srikantha A, Wojek C, Zeidler D (2021) Connectomics of Bone to Brain-- Probing Physical Renderings of Cellular Experience, Frontiers in Physiology 12: 1018, doi: 10.3389/fphys.2021.647603
As noted in that published work: "Osteocyte coordinates can be extracted from the YOLO classified image set, enabling high throughput analyses of massive datasets, which in the future could include other cellular inhabitants of tissues including blood cells, immune cells, chondrocytes, etc. While the method shows great promise for automated detection of cells, the greatest limitation of the method is the definition of appropriate and unbiased classifiers. The definition of osteocytes as pyknotic and viable based on the number of cell processes was shown to be flawed in a parallel study testing the assumption using biochemical based viability measures (Anastopolous and Knothe Tate, 2021)."
Therefore, the authors do not wish this work to be cited as reference for the project.
If you have any questions, please contact the corresponding author. | physiology |
Maize brace root mechanics vary by whorl, genotype, and reproductive stage Root lodging is responsible for significant crop losses world-wide. During root lodging, roots fail by breaking, buckling, or pulling out of the ground. In maize, above-ground roots, called brace roots, have been shown to reduce root lodging susceptibility. However, the underlying structural-functional properties of brace roots that prevent root lodging are poorly defined. In this study, we quantified structural mechanical properties, geometry, and bending moduli for brace roots from different whorls, genotypes, and reproductive stages. Using 3-point bend tests, we show that brace root mechanics are variable by whorl, genotype, and reproductive stage. Generally, we find that within each genotype and reproductive stage, the brace roots from the whorl closest to the ground had higher structural mechanical properties and a lower bending modulus than brace roots from the second whorl. There was additional variation between genotypes and reproductive stages. Specifically, genotypes with higher structural mechanical properties also had a higher bending modulus, and senesced brace roots had lower structural mechanical properties than hydrated brace roots. Collectively these results highlight the importance of considering whorl-of-origin, genotype, and reproductive stage for quantification of brace root mechanics, which is important for mitigating crop loss due to root mechanical failure. | plant biology |
Urinary glucocorticoids in harbour seal (Phoca vitulina) pups during rehabilitation The glucocorticoid (GC) hormone cortisol is often measured in animals to indicate their welfare and stress levels. However, the levels of other naturally occurring GCs are usually overlooked. We aimed to investigate whether aspects of the care and conditions of harbour seal (Phoca vitulina) pups in rehabilitation centres are reflected in urinary concentrations of four endogenous GCs. Urine samples were collected non-invasively from pups taken in as "orphans" at five different rehabilitation centres: three on the Irish Sea and two in the southern North Sea. Concentrations of urinary cortisol, cortisone, prednisolone and prednisone were analysed by mass spectrometry. Urinary concentrations of endogenous prednisolone and prednisone occurred in similar magnitude to cortisol, for the first time in any mammal species. The levels of all GC concentrations decreased as pups gained mass, but the most significant effect was for prednisone. Pups with mass less than 11kg, i.e. healthy average birth mass, had significantly higher levels of prednisone (but not of the other GCs) than pups of 11kg or more. Cortisol, cortisone and prednisolone concentrations were slightly higher for pups without access to water than those with water; however, we found no significant effect of social group on GC levels. Based on these findings, we tentatively suggest that the GCs may be elevated in harbour seal pups during rehabilitation in response to some physiological factors deviating from the norm of free-living pups. Our findings highlight the importance of measuring other GCs, in addition to cortisol, for understanding stressors affecting the welfare of seal pup in rehabilitation. | zoology |
The pharmacodynamic inoculum effect from the perspective of bacterial population modeling SynopsisO_ST_ABSBackgroundC_ST_ABSThe quantitative determination of the effects of antimicrobials is essential for our understanding of pharmacodynamics and for their rational clinical application. However, common pharmacodynamic measures of antimicrobial efficacy, such as the MIC and the pharmacodynamic function, fail to capture the observed dependence of efficacy on the bacterial population size -- a phenomenon called inoculum effect.
ObjectivesWe aimed to assess the relationship between bacterial inoculum size and pharmacodynamic parameters, and to determine the consequences of the inoculum effect on bacterial population dynamics under treatment with antimicrobials.
MethodsWe used the mathematical multi-hit model to quantify the effect of the inoculum on the pharmacodynamic parameters. The model describes antimicrobial action mechanistically, which allowed us to test various hypotheses concerning the mechanistic basis of the inoculum effect.
ResultsOur model showed that the inoculum effect can arise from the binding dynamics of antimicrobial molecules to bacterial targets alone and does not require enzymatic degradation of antimicrobials. With enzymatic degradation, however, the inoculum effect is more pronounced. We propose to include the inoculum effect when measuring antimicrobial efficacy, i. e. to extend the pharmacodynamic function with the inoculum effect. This extended pharmacodynamic function mimiced simple long-term population dynamics well. More complex scenarios were only captured with the mechanism-based multi-hit model. In simulations with competing antimicrobial-sensitive and -resistant bacteria, neglecting the inoculum effect lead to an overestimation of the competitive ability of the resistant strain.
ConclusionsOur work emphasizes that the pharmacodynamic function -- and in general any efficacy measure, e.g. the MIC -- should include information about the inoculum size on which it is based, and ideally account for the inoculum effect. | pharmacology and toxicology |
Opposing steroid signals modulate protein homeostasis through deep changes in fat metabolism in Caenorhabditis elegans Protein homeostasis is crucial for viability of all organisms, and mutations that enhance protein aggregation cause different human pathologies, including polyglutamine (polyQ) diseases, such as some spinocerebellar ataxias or Huntington disease. Here, we report that neuronal Stomatin-like protein UNC-1 protects against aggregation of prone-to-aggregate proteins, like polyQs, -synuclein and {beta}-amyloid, in C. elegans. UNC-1, in IL2 neurons, antagonizes the function of the cytosolic sulfotransferase SSU-1 in neurohormonal signalling from ASJ neurons. The target of this hormone is the nuclear hormone receptor NHR-1, which acts cell-autonomously to protect from aggregation in muscles. A second nuclear hormone receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses reveal deep changes in the expression of genes involved in fat metabolism, in unc-1 mutants, which are regulated by NHR-1. This suggest that fat metabolism changes, controlled by neurohormonal signalling, contributes to modulate protein homeostasis. | genetics |
Traces of transposable element in genome dark matter co-opted by flowering gene regulation networks. AO_SCPLOWBSTRACTC_SCPLOWTransposable elements (TEs) are mobile, repetitive DNA sequences that make the largest contribution to genome bulk. They thus contribute to the so-called "dark matter of the genome", the part of the genome in which nothing is immediately recognizable as biologically functional.
We developed a new method, based on k-mers, to identify degenerate TE sequences. With this new algorithm, we detect up to 10% of the A. thaliana genome as derived from as yet unidentified TEs, bringing the proportion of the genome known to be derived from TEs up to 50%. A significant proportion of these sequences overlapped conserved non-coding sequences identified in crucifers and rosids, and transcription factor binding sites. They are overrepresented in some gene regulation networks, such as the flowering gene network, suggesting a functional role for these sequences that have been conserved for more than 100 million years, since the spread of flowering plants in the Cretaceous. | genomics |
Rabies virus with a destabilization domain added to its nucleoprotein spreads between neurons only if the domain is removed Monosynaptic tracing using rabies virus is an important technique in neuroscience, allowing brain-wide labeling of neurons directly presynaptic to a targeted neuronal population. A 2017 article reported development of a noncytotoxic version - a major advance - based on attenuating the rabies virus by addition of a destabilization domain to the C-terminus of a viral protein. However, this modification did not appear to hinder the ability of the virus to spread between neurons. We analyzed two viruses provided by the authors and show here that both were mutants that had lost the intended modification, explaining the papers paradoxical results. We then made a virus that actually did have the intended modification and found that it did not spread under the conditions described in the original paper - namely, without an exogenous protease being expressed in order to remove the destabilization domain - but that it did spread, albeit with relatively low efficiency, if the protease was supplied. We conclude that the new approach is not robust but that it may become a viable technique given further optimization and validation.
SIGNIFICANCE STATEMENTRabies virus, which spreads between synaptically connected neurons, has been one of the primary tools used by neuroscientists to reveal the organization of the brain. A new modification to rabies virus was recently reported to allow the mapping of connected neurons without adverse effects on the cells health, unlike earlier versions. Here we show that the conclusions of that study were probably incorrect and based on having used viruses that had lost the intended modification because of mutations. We also show that a rabies virus that does retain the intended modification does not spread between neurons under the conditions reported previously; however, it does spread between neurons under different conditions, suggesting that the approach may be successful if refined further. | neuroscience |
Dynamically Linking Influenza Virus Infection Kinetics, Lung Injury, Inflammation, and Disease Severity Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. Here, we established dynamical connections between viral loads, infected cells, CD8+ T cell-mediated clearance, lung injury, inflammation, and disease severity using an integrative model-experiment exchange. The model was validated through CD8 depletion and whole lung histomorphometry, which showed that the infected area matched the model-predicted infected cell dynamics and that the resolved area paralleled the relative CD8 dynamics. Inflammation could further be predicted by the infected cell dynamics, and additional analyses revealed nonlinear relations between lung injury, inflammation, and disease severity. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy. | systems biology |