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10.1101/341008 | Network Reconstruction from Perturbation Time Course Data | Networks underlie much of biology from subcellular to ecological scales. Yet, understanding what experimental data are needed and how to use them for unambiguously identifying the structure of even small networks remains a broad challenge. Here, we integrate a dynamic least squares framework into established modular response analysis (DL-MRA), that specifies sufficient experimental perturbation time course data to robustly infer arbitrary two and three node networks. DL-MRA considers important network properties that current methods often struggle to capture: (i) edge sign and directionality; (ii) cycles with feedback or feedforward loops including self-regulation; (iii) dynamic network behavior; (iv) edges external to the network; and (v) robust performance with experimental noise. We evaluate the performance of and the extent to which the approach applies to cell state transition networks, intracellular signaling networks, and gene regulatory networks. Although signaling networks are often an application of network reconstruction methods, the results suggest that only under quite restricted conditions can they be robustly inferred. For gene regulatory networks, the results suggest that incomplete knockdown is often more informative than full knockout perturbation, which may change experimental strategies for gene regulatory network reconstruction. Overall, the results give a rational basis to experimental data requirements for network reconstruction and can be applied to any such problem where perturbation time course experiments are possible. | systems biology |
10.1101/341008 | Network Inference from Perturbation Time Course Data | Networks underlie much of biology from subcellular to ecological scales. Yet, understanding what experimental data are needed and how to use them for unambiguously identifying the structure of even small networks remains a broad challenge. Here, we integrate a dynamic least squares framework into established modular response analysis (DL-MRA), that specifies sufficient experimental perturbation time course data to robustly infer arbitrary two and three node networks. DL-MRA considers important network properties that current methods often struggle to capture: (i) edge sign and directionality; (ii) cycles with feedback or feedforward loops including self-regulation; (iii) dynamic network behavior; (iv) edges external to the network; and (v) robust performance with experimental noise. We evaluate the performance of and the extent to which the approach applies to cell state transition networks, intracellular signaling networks, and gene regulatory networks. Although signaling networks are often an application of network reconstruction methods, the results suggest that only under quite restricted conditions can they be robustly inferred. For gene regulatory networks, the results suggest that incomplete knockdown is often more informative than full knockout perturbation, which may change experimental strategies for gene regulatory network reconstruction. Overall, the results give a rational basis to experimental data requirements for network reconstruction and can be applied to any such problem where perturbation time course experiments are possible. | systems biology |
10.1101/342030 | Rapid adaptation of endocytosis, exocytosis and eisosomes after an acute increase in membrane tension in yeast cells | During clathrin-mediated endocytosis in eukaryotes, actin assembly is required to overcome large membrane tension and turgor pressure. However, the molecular mechanisms by which the actin machinery adapts to varying membrane tension remain unknown. In addition, how cells reduce their membrane tension when they are challenged by hypotonic shocks remains unclear. We used quantitative microscopy to demonstrate that cells rapidly reduce their membrane tension using three parallel mechanisms. In addition to using their cell wall for mechanical protection, yeast cells disassemble eisosomes to buffer moderate changes in membrane tension on a minute time scale. Meanwhile, a temporary reduction of the rate of endocytosis for 2 to 6 minutes, and an increase in the rate of exocytosis for at least 5 minutes allow cells to add large pools of membrane to the plasma membrane. We built on these results to submit the cells to abrupt increases in membrane tension and determine that the endocytic actin machinery of fission yeast cells rapidly adapts to perform clathrin-mediated endocytosis. Our study sheds light on the tight connection between membrane tension regulation, endocytosis and exocytosis. | cell biology |
10.1101/342030 | Rapid adaptation of endocytosis, exocytosis and eisosomes after an acute increase in membrane tension in yeast cells | During clathrin-mediated endocytosis in eukaryotes, actin assembly is required to overcome large membrane tension and turgor pressure. However, the molecular mechanisms by which the actin machinery adapts to varying membrane tension remain unknown. In addition, how cells reduce their membrane tension when they are challenged by hypotonic shocks remains unclear. We used quantitative microscopy to demonstrate that cells rapidly reduce their membrane tension using three parallel mechanisms. In addition to using their cell wall for mechanical protection, yeast cells disassemble eisosomes to buffer moderate changes in membrane tension on a minute time scale. Meanwhile, a temporary reduction of the rate of endocytosis for 2 to 6 minutes, and an increase in the rate of exocytosis for at least 5 minutes allow cells to add large pools of membrane to the plasma membrane. We built on these results to submit the cells to abrupt increases in membrane tension and determine that the endocytic actin machinery of fission yeast cells rapidly adapts to perform clathrin-mediated endocytosis. Our study sheds light on the tight connection between membrane tension regulation, endocytosis and exocytosis. | cell biology |
10.1101/342261 | Evolutionary forecasting of phenotypic and genetic outcomes of experimental evolution in Pseudomonas protegens | Experimental evolution with microbes is often highly repeatable under identical conditions, suggesting the possibility to predict short-term evolution. However, it is not clear to what degree evolutionary forecasts can be extended to related species in non-identical environments, which would allow testing of general predictive models and fundamental biological assumptions. To develop an extended model system for evolutionary forecasting, we used previous data and models of the genotype-to-phenotype map from the wrinkly spreader system in Pseudomonas fluorescens SBW25 to make predictions of evolutionary outcomes on different biological levels for Pseudomonas protegens Pf-5. In addition to sequence divergence (78% amino acid and 81% nucleotide identity) for the genes targeted by mutations, these species also differ in the inability of Pf-5 to make cellulose, which is the main structural basis for the adaptive phenotype in SBW25. The experimental conditions were also changed compared to the SBW25 system to test the robustness of forecasts to environmental variation. Forty-three mutants with increased ability to colonize the air-liquid interface were isolated, and the majority had reduced motility and was partly dependent on the pel exopolysaccharide as a structural component. Most (38/43) mutations are expected to disrupt negative regulation of the same three diguanylate cyclases as in SBW25, with a smaller number of mutations in promoter regions, including that of an uncharacterized polysaccharide operon. A mathematical model developed for SBW25 predicted the order of the three main pathways and the genes targeted by mutations, but differences in fitness between mutants and mutational biases also appear to influence outcomes. Mutated regions in proteins could be predicted in most cases (16/22), but parallelism at the nucleotide level was low and mutational hot spots were not conserved. This study demonstrates the potential of short-term evolutionary forecasting in experimental populations and provides testable predictions for evolutionary outcomes in other Pseudomonas species.
Author SummaryBiological evolution is often repeatable in the short-term suggesting the possibility of forecasting and controlling evolutionary outcomes. In addition to its fundamental importance for biology, evolutionary processes are at the core of several major societal problems, including infectious diseases, cancer and adaptation to climate change. Experimental evolution allows study of evolutionary processes in real time and seems like an ideal way to test the predictability of evolution and our ability to make forecasts. However, lack of model systems where forecasts can be extended to other species evolving under different conditions has prevented studies that first predict evolutionary outcomes followed by direct testing. We showed that a well-characterized bacterial experimental evolution system, based on biofilm formation by Pseudomonas fluorescens at the surface of static growth tubes, can be extended to the related species Pseudomonas protegens. We tested evolutionary forecasts experimentally and showed that mutations mainly appear in the predicted genes resulting in similar phenotypes. We also identified factors that we cannot yet predict, such as variation in mutation rates and differences in fitness. Finally, we make forecasts for other Pseudomonas species to be tested in future experiments. | evolutionary biology |
10.1101/344499 | KChIP4a selectively controls mesolimbic dopamine neuron inhibitory integration and learning from negative prediction errors | Midbrain dopamine (DA) neurons are essential for multiple behaviors. DA neurons that project to different regions also have unique biophysical properties, and it is thought that this diversity reflects specializations to particular computational functions. If this is true, there should be specific genetic determinants of this heterogeneity whose manipulation would lead to circumscribed impacts on behavior. We test this general hypothesis by homing in on one particular mechanism using a new transgenic model and a combination of molecular, electrophysiological, computational, and behavioral approaches. We demonstrate that KChIP4a, a singular Kv4 {beta}-subunit splice variant, determines the long hyperpolarization-rebound delays observed in nucleus accumbens core-projecting DA neurons, that this biophysical switch controls the efficacy of inhibitory inputs to pause firing and, congruently, selectively regulates learning from negative prediction errors. Our results reveal a highly specialized gene-to-behavior mechanistic chain within the DA system, illuminating how cellular diversity shapes information processing in this key neuronal population.
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org.highwire.dtl.DTLVardef@161b17aorg.highwire.dtl.DTLVardef@cad6d6org.highwire.dtl.DTLVardef@de8957org.highwire.dtl.DTLVardef@aedc6_HPS_FORMAT_FIGEXP M_FIG C_FIG | neuroscience |
10.1101/344200 | A pragmatic approach to make theoretical syntheses in ecology | Theoretical syntheses have the role of describing and guiding knowledge generation, and are usually done by enunciating the conceptual bases that guide research in a given field. In fields that develop axiomatically, the conceptual basis can be easily identified in the set of axioms guiding model building. However, ecology does not develop axiomatically but rather pragmatically, i.e., ecologists do not build models based on a predefined set of assumptions (axioms). They rather resort to any information that seems useful to learn about ecological phenomena. Therefore, a theoretical synthesis in ecology cannot rely on the enunciation of axioms; instead, it requires identifying what information and knowledge ecologists use (i.e., what they decide is useful to learn). Here we present an approach for producing theoretical syntheses based on the information/knowledge most frequently used to learn about the world. The approach consists of (i) defining a phenomenon of interest; (ii) defining a collective of scientists studying the phenomenon; (iii) surveying the scientific studies about the phenomenon published by this collective; (iv) identifying the most relevant publications used in these studies; (v) identifying how the studies refer to the most relevant publications; (vi) synthesizing what is being used by this collective to learn about the phenomenon. We implemented the approach in a case study on the phenomenon of ecological succession, defining the collective as the scientists currently studying succession. We identified three propositions that synthesize the views of the defined collective about succession. The theoretical synthesis revealed that there is no clear division between "classical" and "contemporary" succession models, and that neutral models are being used to explain successional patterns alongside with models based on niche assumptions.By implementing the pragmatic approach in a case study, we show that it can be successfully used to produce syntheses describing the conceptual bases of a field, which have the potential to guide knowledge generation. As such, these syntheses fulfil the roles ascribed to scientific theories in the epistemological literature. | ecology |
10.1101/348433 | Microbial adaptation to venom is common in snakes and spiders | Animal venoms are considered sterile sources of antimicrobial compounds with strong membrane disrupting activity against multi-drug resistant bacteria. However, bite wound infections are common in developing nations. Investigating the oral and venom microbiome of five snake and two spider species, we evidence viable microorganisms potentially unique to venom for black-necked spitting cobras (Naja nigricollis). Among these are two venom-resistant novel sequence types of Enterococcus faecalis; the genome sequence data of these isolates feature an additional 45 genes, nearly half of which improve membrane integrity. Our findings challenge the dogma of venom sterility and indicate an increased primary infection risk in the clinical management of venomous animal bite wounds.
One Sentence SummaryIndependent bacterial colonization of cobra venom drives acquisition of genes antagonistic to venom antimicrobial peptides. | microbiology |
10.1101/348383 | The Goldilocks Effect: Female geladas in mid-sized groups have higher fitness | The cost-benefit ratio of group-living is thought to vary with group size: individuals in "optimally-sized" groups should have higher fitness than individuals in groups that are either too large or too small. However, the relationship between group size and individual fitness has been difficult to establish for long-lived species where the number of groups studied is typically quite low. Here we present evidence for optimal group size that maximizes female fitness in a population of geladas (Theropithecus gelada). Drawing on 14 years of demographic data, we found that females in small groups experienced the highest death rates, while females in mid-sized units exhibited the highest reproductive performance. This group-size effect on female reproductive performance was largely explained by variation in infant mortality (and, in particular, by infanticide from immigrant males) but not by variation in reproductive rates. Taken together, females in mid-sized units are projected to attain optimal fitness due to conspecific infanticide and, potentially, predation. Our findings provide insight into how and why group size shapes fitness in long-lived species. | evolutionary biology |
10.1101/348383 | The Goldilocks Effect: Female geladas in mid-sized groups have higher fitness | The cost-benefit ratio of group-living is thought to vary with group size: individuals in "optimally-sized" groups should have higher fitness than individuals in groups that are either too large or too small. However, the relationship between group size and individual fitness has been difficult to establish for long-lived species where the number of groups studied is typically quite low. Here we present evidence for optimal group size that maximizes female fitness in a population of geladas (Theropithecus gelada). Drawing on 14 years of demographic data, we found that females in small groups experienced the highest death rates, while females in mid-sized units exhibited the highest reproductive performance. This group-size effect on female reproductive performance was largely explained by variation in infant mortality (and, in particular, by infanticide from immigrant males) but not by variation in reproductive rates. Taken together, females in mid-sized units are projected to attain optimal fitness due to conspecific infanticide and, potentially, predation. Our findings provide insight into how and why group size shapes fitness in long-lived species. | evolutionary biology |
10.1101/348391 | Joint inference of species histories and gene flow | When populations become isolated, members of these populations can diverge genetically over time. This leads to genetic differences between these populations that increase over time if the isolation persists. This process can be counteracted by gene flow, i.e. when genes are exchanged between populations. In order to study the speciation processes when gene flow is present, isolation-with-migration methods have been developed. These methods typically assume that the ranked topology of the species history is already known. However, this is often not the case and the species tree is therefore of interest itself. For the inference of species trees, it is in turn often necessary to assume that there is no gene flow between co-existing species. This assumption, however, can lead to wrongly inferred speciation times and species tree topologies. We here introduce a new method that allows inference of the species tree while explicitly modelling the flow of genes between coexisting species. By using Markov chain Monte Carlo sampling, we co-infer the species tree alongside evolutionary parameters of interest. By using simulations, we show that our newly introduced approach is able to reliably infer the species trees and parameters of the isolation-with-migration model from genetic sequence data. We then use this approach to infer the species history of the mosquitoes from the Anopheles gambiae species complex. Accounting for gene flow when inferring the species history suggests a slightly different speciation order and gene flow than previously suggested. | evolutionary biology |
10.1101/348391 | Joint inference of species histories and gene flow | When populations become isolated, members of these populations can diverge genetically over time. This leads to genetic differences between these populations that increase over time if the isolation persists. This process can be counteracted by gene flow, i.e. when genes are exchanged between populations. In order to study the speciation processes when gene flow is present, isolation-with-migration methods have been developed. These methods typically assume that the ranked topology of the species history is already known. However, this is often not the case and the species tree is therefore of interest itself. For the inference of species trees, it is in turn often necessary to assume that there is no gene flow between co-existing species. This assumption, however, can lead to wrongly inferred speciation times and species tree topologies. We here introduce a new method that allows inference of the species tree while explicitly modelling the flow of genes between coexisting species. By using Markov chain Monte Carlo sampling, we co-infer the species tree alongside evolutionary parameters of interest. By using simulations, we show that our newly introduced approach is able to reliably infer the species trees and parameters of the isolation-with-migration model from genetic sequence data. We then use this approach to infer the species history of the mosquitoes from the Anopheles gambiae species complex. Accounting for gene flow when inferring the species history suggests a slightly different speciation order and gene flow than previously suggested. | evolutionary biology |
10.1101/354480 | 5' Modifications Improve Potency and Efficacy of DNA Donors for Precision Genome Editing | Nuclease-directed genome editing is a powerful tool for investigating physiology and has great promise as a therapeutic approach to correct mutations that cause disease. In its most precise form, genome editing can use cellular homology-directed repair (HDR) pathways to insert information from an exogenously supplied DNA repair template (donor) directly into a targeted genomic location. Unfortunately, particularly for long insertions, toxicity and delivery considerations associated with repair template DNA can limit HDR efficacy. Here, we explore chemical modifications to both double-stranded and single-stranded DNA-repair templates. We describe 5'-terminal modifications, including in its simplest form the incorporation of triethylene glycol (TEG) moieties, that consistently increase the frequency of precision editing in the germlines of three animal models (Caenorhabditis elegans, zebrafish, mice) and in cultured human cells. | molecular biology |
10.1101/358986 | Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes | Accurate and timely functional genome annotation is essential for translating basic pathogen research into clinically impactful advances. Here, through literature curation and structure-function inference, we systematically update the functional genome annotation of Mycobacterium tuberculosis virulent type strain H37Rv. First, we systematically curated annotations for 589 genes from 662 publications, including 282 gene products absent from leading databases. Second, we modeled 1,711 under-annotated proteins and developed a semi-automated pipeline that captured shared function between 400 protein models and structural matches of known function on protein data bank, including drug efflux proteins, metabolic enzymes, and virulence factors. In aggregate, these structure- and literature-derived annotations update 940/1,725 under-annotated H37Rv genes and generate hundreds of functional hypotheses. Retrospectively applying the annotation to a recent whole-genome transposon mutant screen provided missing function for 48% (13/27) of under-annotated genes altering antibiotic efficacy and 33% (23/69) required for persistence during mouse TB infection. Prospective application of the protein models enabled us to functionally interpret novel laboratory generated Pyrazinamide-resistant (PZA) mutants of unknown function, which implicated the emerging Coenzyme A depletion model of PZA action in the mutants PZA resistance. Our findings demonstrate the functional insight gained by integrating structural modeling and systematic literature curation, even for widely studied microorganisms. Functional annotations and protein structure models are available at https://tuberculosis.sdsu.edu/H37Rv in human- and machine-readable formats.
IMPORTANCEMycobacterium tuberculosis, the primary causative agent of tuberculosis, kills more humans than any other infectious bacteria. Yet 40% of its genome is functionally uncharacterized, leaving much about the genetic basis of its resistance to antibiotics, capacity to withstand host immunity, and basic metabolism yet undiscovered. Irregular literature curation for functional annotation contributes to this gap. We systematically curated functions from literature and structural similarity for over half of poorly characterized genes, expanding the functionally annotated Mycobacterium tuberculosis proteome. Applying this updated annotation to recent in vivo functional screens added functional information to dozens of clinically pertinent proteins described as having unknown function. Integrating the annotations with a prospective functional screen identified new mutants resistant to a first-line TB drug supporting an emerging hypothesis for its mode of action. These improvements in functional interpretation of clinically informative studies underscores the translational value of this functional knowledge. Structure-derived annotations identify hundreds of high-confidence candidates for mechanisms of antibiotic resistance, virulence factors, and basic metabolism; other functions key in clinical and basic tuberculosis research. More broadly, it provides a systematic framework for improving prokaryotic reference annotations. | genomics |
10.1101/364042 | Distracting Linguistic Information Impairs Neural Tracking of Attended Speech | Listening to speech is difficult in noisy environments, and is even harder when the interfering noise consists of intelligible speech as compared to unintelligible sounds. This suggests that the competing linguistic information interferes with the neural processing of target speech. Interference could either arise from a degradation of the neural representation of the target speech, or from increased representation of distracting speech that enters in competition with the target speech. We tested these alternative hypotheses using magnetoencephalography (MEG) while participants listened to a target clear speech in the presence of distracting noise-vocoded speech. Crucially, the distractors were initially unintelligible but became more intelligible after a short training session. Results showed that the comprehension of the target speech was poorer after training than before training. The neural tracking of target speech in the delta range (1-4 Hz) reduced in strength in the presence of a more intelligible distractor. In contrast, the neural tracking of distracting signals was not significantly modulated by intelligibility. These results suggest that the presence of distracting speech signals degrades the linguistic representation of target speech carried by delta oscillations. | neuroscience |
10.1101/365825 | Extracellular histones, a new class of inhibitory molecules of CNS axonal regeneration | Axonal regeneration in the mature CNS is limited by extracellular inhibitory factors. Triple knockout mice lacking the major myelin-associated inhibitors do not display spontaneous regeneration after injury, indicating the presence of other inhibitors. Searching for such inhibitors we have detected elevated levels of histone H3 in human cerebrospinal fluid (CSF) 24 hours after spinal cord injury. Following dorsal column lesions in mice and optic nerve crushes in rats, elevated levels of extracellular histone H3 were detected at the injury site. Similar to myelin-associated inhibitors, these extracellular histones induced growth cone collapse and inhibited neurite outgrowth. Histones mediate inhibition through the transcription factor YB-1 and Toll-like receptor 2, and these effects are independent of the Nogo receptor. Histone-mediated inhibition can be reversed by the addition of activated protein C (APC) in vitro, and APC treatment promotes axonal regeneration in the crushed optic nerve in vivo. These findings identify extracellular histones as a new class of nerve regeneration-inhibiting molecules within the injured CNS.
One sentence summaryProteins typically associated with chromatin structure play an unexpected role in limiting axonal regeneration after injury. | neuroscience |
10.1101/370692 | Dispensing a synthetic green leaf volatile to two plant species in a common garden differentially alters physiological responses and herbivory | Herbivore-induced plant volatile (HIPV)-mediated eavesdropping by plants is a well-documented, inducible phenomenon that has practical agronomic applications for enhancing plant defense and pest management. However, as with any inducible phenomenon, responding to volatile cues may incur physiological and ecological costs that limit plant productivity. In a common garden experiment, we tested the hypothesis that exposure to a single HIPV would decrease herbivore damage at the cost of reduced plant growth and reproduction. Lima bean (Phaseolus lunatus) and pepper (Capsicum annuum) plants were exposed to a persistent, low-dose ([~]10ng/hour) of the green leaf volatile cis-3-hexenyl acetate (z3HAC), which is an HIPV and damage-associated volatile. z3HAC-treated pepper plants were shorter, had less aboveground and belowground biomass, and produced fewer flowers and fruits relative to controls while z3HAC-treated lima bean plants were taller and produced more leaves and flowers than did controls. Natural herbivory was reduced in z3HAC-exposed lima bean plants, but not in pepper. Cyanogenic potential, a putative direct defense mechanism in lima bean, was lower in young z3HAC-exposed leaves, suggesting a growth-defense tradeoff from z3HAC exposure alone. Plant species-specific responses to an identical volatile cue have important implications for agronomic costs and benefits of volatile-mediated inter-plant communication under field conditions. | ecology |
10.1101/373332 | The taxonomic and functional biogeographies of phytoplankton and zooplankton communities across boreal lakes | AO_SCPLOWBSTRACTC_SCPLOWStrong trophic interactions link primary producers (phytoplankton) and consumers (zooplankton) in lakes. However, the influence of such interactions on the biogeographical distribution of the taxa and functional traits of planktonic organisms in lakes has never been explicitly tested. To better understand the spatial distribution of these two major aquatic groups, we related composition across boreal lakes (104 for zooplankton and 48 for phytoplankton) in relation to a common suite of environmental and spatial factors. We then directly tested the degree of coupling in their taxonomic and functional distributions across the subset of common lakes. Although phytoplankton composition responded mainly to properties related to water quality while zooplankton composition responded more strongly to lake morphometry, we found significant coupling between their spatial distributions at taxonomic and functional levels based on a Procrustes test. This coupling was not significant after removing the effect of environmental drivers (water quality and morphometry) on the spatial distributions of the two groups. This result suggests that top-down and bottom-up effects (e.g. nutrient concentration and predation) drove trophic interactions at the landscape level. We also found a significant effect of dispersal limitation on the distribution of taxa, which could explain why coupling was stronger for taxa than for traits at the scale of this study, with a turnover of species observed between regions, but no trait turnover. Our results indicate that landscape pelagic food web responses to anthropogenic changes in ecosystem parameters should be driven by a combination of top-down and bottom-factors for taxonomic composition, but with a relative resilience in functional trait composition of lake communities. | ecology |
10.1101/373332 | The taxonomic and functional biogeographies of phytoplankton and zooplankton communities across boreal lakes | AO_SCPLOWBSTRACTC_SCPLOWStrong trophic interactions link primary producers (phytoplankton) and consumers (zooplankton) in lakes. However, the influence of such interactions on the biogeographical distribution of the taxa and functional traits of planktonic organisms in lakes has never been explicitly tested. To better understand the spatial distribution of these two major aquatic groups, we related composition across boreal lakes (104 for zooplankton and 48 for phytoplankton) in relation to a common suite of environmental and spatial factors. We then directly tested the degree of coupling in their taxonomic and functional distributions across the subset of common lakes. Although phytoplankton composition responded mainly to properties related to water quality while zooplankton composition responded more strongly to lake morphometry, we found significant coupling between their spatial distributions at taxonomic and functional levels based on a Procrustes test. This coupling was not significant after removing the effect of environmental drivers (water quality and morphometry) on the spatial distributions of the two groups. This result suggests that top-down and bottom-up effects (e.g. nutrient concentration and predation) drove trophic interactions at the landscape level. We also found a significant effect of dispersal limitation on the distribution of taxa, which could explain why coupling was stronger for taxa than for traits at the scale of this study, with a turnover of species observed between regions, but no trait turnover. Our results indicate that landscape pelagic food web responses to anthropogenic changes in ecosystem parameters should be driven by a combination of top-down and bottom-factors for taxonomic composition, but with a relative resilience in functional trait composition of lake communities. | ecology |
10.1101/380162 | Predicting subclinical psychotic-like experiences on a continuum using machine learning | Previous studies applying machine learning methods to psychosis have primarily been concerned with the binary classification of chronic schizophrenia patients and healthy controls. The aim of this study was to use electroencephalographic (EEG) data and pattern recognition to predict subclinical psychotic-like experiences on a continuum between these two extremes in otherwise healthy people. We applied two different approaches to an auditory oddball regularity learning task obtained from N = 73 participants:
O_LIA feature extraction and selection routine incorporating behavioural measures, event-related potential components and effective connectivity parameters;
C_LIO_LIRegularisation of spatiotemporal maps of event-related potentials.
C_LI
Using the latter approach, optimal performance was achieved using the response to frequent, predictable sounds. Features within the P50 and P200 time windows had the greatest contribution toward lower Prodromal Questionnaire (PQ) scores and the N100 time window contributed most to higher PQ scores. As a proof-of-concept, these findings demonstrate that EEG data alone are predictive of individual psychotic-like experiences in healthy people. Our findings are in keeping with the mounting evidence for altered sensory responses in schizophrenia, as well as the notion that psychosis may exist on a continuum expanding into the non-clinical population. | neuroscience |
10.1101/384024 | Individuals with ventromedial frontal damage have more unstable but still fundamentally transitive preferences | The ventromedial frontal lobes (VMF) are important for decision-making, but the precise causal role of the VMF in the decision process has not yet fully been established. Previous studies have suggested that individuals with VMF damage violate transitivity, a hallmark axiom of rational decisions. However, these prior studies cannot properly distinguish whether individuals with VMF damage are truly prone to choosing irrationally from whether their preferences are simply more variable. We had individuals with focal VMF damage, individuals with other frontal damage, and healthy controls make repeated choices across three categories - artwork, chocolate bar brands, and gambles. Using sophisticated tests of transitivity, we find that, without exception, individuals with VMF damage make rational decisions consistent with transitive preferences, even though they exhibit greater variability in their preferences. That is, the VMF is necessary for having strong and reliable preferences, but not for being a rational decision maker. VMF damage affects the noisiness with which value is assessed, but not the consistency with which value is sought. | neuroscience |
10.1101/384834 | De Novo Mutational Signature Discovery in Tumor Genomes using SparseSignatures | Cancer is the result of mutagenic processes that can be inferred from tumor genomes by analyzing rate spectra of point mutations, or "mutational signatures". Here we present SparseSignatures, a novel framework to extract signatures from somatic point mutation data. Our approach incorporates a user-specified background signature, employs regularization to reduce noise in non-background signatures, uses cross-validation to identify the number of signatures, and is scalable to large datasets. We show that SparseSignatures outperforms current state-of-the-art methods on simulated data using a variety of standard metrics. We then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms and are strongly associated with patient clinical features.
Authors SummaryCancer is a genetic disease, occurring as a result of mutagenic processes causing DNA somatic mutations in genes controlling cellular growth and division. These somatic mutations arise from processes such as defective DNA repair and environmental mutagens, which massively increase the rate of somatic variants. As a result, due to the specificity of molecular lesions caused by such processes, and the specific repair mechanisms deployed by the cell to mitigate the damage, mutagenic processes generate characteristic point mutation rate spectra which are called mutational signatures. These signatures can indicate which mutagenic processes are active in a tumor, reveal biological differences between cancer subtypes, and may be useful markers for therapeutic response. Here, we develop SparseSignatures, a novel framework for mutational signature discovery capable of both identifying the active signatures in a dataset of point mutations and calculating their exposure values, i.e., the number of mutations originating from each signature in each patient. We show that our approach outperforms current state-of-the-art methods on simulated data using a variety of standard metrics and then apply SparseSignatures to whole genome sequences of pancreatic and breast tumors, discovering well-differentiated signatures that are linked to known mutagenic mechanisms. | bioinformatics |
10.1101/385591 | GranatumX: A community engaging, modularized and flexible software environment for single-cell analysis | We present GranatumX, a next-generation software environment for single-cell data analysis. GranatumX is inspired by the interactive web tool Granatum. It enables biologists to access the latest single-cell bioinformatics methods in a web-based graphical environment. It also offers software developers the opportunity to rapidly promote their own tools with others in customizable pipelines. The architecture of GranatumX allows for easy inclusion of plugin modules, named Gboxes, that wrap around bioinformatics tools written in various programming languages and on various platforms. GranatumX can be run on the cloud or private servers and generate reproducible results. It is a community-engaging, flexible, and evolving software ecosystem for scRNA-Seq analysis, connecting developers with bench scientists. GranatumX is freely accessible at http://garmiregroup.org/granatumx/app. | bioinformatics |
10.1101/385591 | GranatumX: A community engaging, modularized and flexible webtool for single-cell analysis | We present GranatumX, a next-generation software environment for single-cell data analysis. GranatumX is inspired by the interactive web tool Granatum. It enables biologists to access the latest single-cell bioinformatics methods in a web-based graphical environment. It also offers software developers the opportunity to rapidly promote their own tools with others in customizable pipelines. The architecture of GranatumX allows for easy inclusion of plugin modules, named Gboxes, that wrap around bioinformatics tools written in various programming languages and on various platforms. GranatumX can be run on the cloud or private servers and generate reproducible results. It is a community-engaging, flexible, and evolving software ecosystem for scRNA-Seq analysis, connecting developers with bench scientists. GranatumX is freely accessible at http://garmiregroup.org/granatumx/app. | bioinformatics |
10.1101/388447 | High-quality SNPs from genic regions highlight introgression patterns among European white oaks (Quercus petraea and Q. robur). | The Src homology-2 domain containing phosphatase SHP2 is a critical regulator of signal transduction, being implicated in cell growth and differentiation. Activating mutations cause developmental disorders and act as oncogenic drivers in hematologic cancers. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as the key "allosteric switch" driving SHP2 activation. To test the putative coupling between binding cleft opening and SHP2 activation as assumed by the "allosteric switch" model, we critically reviewed structural data of SHP2 and we used extensive molecular dynamics (MD) simulation and free energy calculations of isolated N-SH2 in solution, SHP2 in solution, and SHP2 in a crystal environment. Our results demonstrate that the binding cleft in N-SH2 is constitutively flexible and open in solution, and that a closed cleft found in certain structures is a consequence of crystal contacts. The degree of opening of the binding cleft has only a negligible effect on the free energy of SHP2 activation. Instead, SHP2 activation is greatly favored by the opening of the central {beta}- sheet of N-SH2. We conclude that opening of the N-SH2 binding cleft is not the key allosteric switch triggering SHP2 activation.
Significance StatementSHP2 is a multi-domain protein, playing an important role in up-regulating cellular processes such as cell survival, proliferation, and programmed cell death. SHP2 mutations cause developmental disorders and were found in many cancer types, including neuroblastoma, breast cancer, and leukemia. In healthy cells, SHP2 mainly takes an autoinhibited, inactive form, and SHP2 is activated upon binding of phosphopeptides to the N-SH2 domain. For the past two decades, the widening of the binding cleft upon peptide binding has been considered as the key event driving SHP2 activation. Here, by analyzing crystallographic data and molecular simulations, we demonstrate that the binding cleft in N-SH2 is, instead, already open and accessible in solution, and its degree of opening does not influence SHP2 activation. | evolutionary biology |
10.1101/388447 | High-quality SNPs from genic regions highlight introgression patterns among European white oaks (Quercus petraea and Q. robur). | The Src homology-2 domain containing phosphatase SHP2 is a critical regulator of signal transduction, being implicated in cell growth and differentiation. Activating mutations cause developmental disorders and act as oncogenic drivers in hematologic cancers. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as the key "allosteric switch" driving SHP2 activation. To test the putative coupling between binding cleft opening and SHP2 activation as assumed by the "allosteric switch" model, we critically reviewed structural data of SHP2 and we used extensive molecular dynamics (MD) simulation and free energy calculations of isolated N-SH2 in solution, SHP2 in solution, and SHP2 in a crystal environment. Our results demonstrate that the binding cleft in N-SH2 is constitutively flexible and open in solution, and that a closed cleft found in certain structures is a consequence of crystal contacts. The degree of opening of the binding cleft has only a negligible effect on the free energy of SHP2 activation. Instead, SHP2 activation is greatly favored by the opening of the central {beta}- sheet of N-SH2. We conclude that opening of the N-SH2 binding cleft is not the key allosteric switch triggering SHP2 activation.
Significance StatementSHP2 is a multi-domain protein, playing an important role in up-regulating cellular processes such as cell survival, proliferation, and programmed cell death. SHP2 mutations cause developmental disorders and were found in many cancer types, including neuroblastoma, breast cancer, and leukemia. In healthy cells, SHP2 mainly takes an autoinhibited, inactive form, and SHP2 is activated upon binding of phosphopeptides to the N-SH2 domain. For the past two decades, the widening of the binding cleft upon peptide binding has been considered as the key event driving SHP2 activation. Here, by analyzing crystallographic data and molecular simulations, we demonstrate that the binding cleft in N-SH2 is, instead, already open and accessible in solution, and its degree of opening does not influence SHP2 activation. | evolutionary biology |
10.1101/391896 | Eye movements during text reading align with the rate of speech production | Across languages, the speech signal is characterized by a predominant modulation of the amplitude spectrum between about 4.3-5.5Hz, reflecting the production and processing of linguistic information chunks (syllables, words) every [~]200ms. Interestingly, [~]200ms is also the typical duration of eye fixations during reading. Prompted by this observation, we demonstrate that German readers sample written text at [~]5Hz. A subsequent meta-analysis with 142 studies from 14 languages replicates this result, but also shows that sampling frequencies vary across languages between 3.9Hz and 5.2Hz, and that this variation systematically depends on the complexity of the writing systems (character-based vs. alphabetic systems, orthographic transparency). Finally, we demonstrate empirically a positive correlation between speech spectrum and eye-movement sampling in low-skilled readers. Based on this convergent evidence, we propose that during reading, our brains linguistic processing systems imprint a preferred processing rate, i.e., the rate of spoken language production and perception, onto the oculomotor system. | neuroscience |
10.1101/386920 | Basal ganglia and cortical control of thalamic rebound spikes | Movement-related decreases in firing rate have been observed in basal ganglia output neurons. They may transmit motor signals to the thalamus, but the effect of these firing rate decreases on downstream neurons in the motor thalamus is not known. One possibility is that they lead to thalamic post-inhibitory rebound spikes. However, it has also been argued that the physiological conditions permitting rebound spiking are pathological, and primarily present in Parkinsons disease. As in Parkinsons disease neural activity becomes pathologically correlated, we investigated the impact of correlations in basal ganglia output on the transmission of motor signals using a Hodgkin-Huxley model of thalamocortical neurons. We found that such correlations disrupt the transmission of motor signals via rebound spikes by decreasing the signal-to-noise ratio and increasing the trial-to-trial variability. We further examined the role of sensory responses in basal ganglia output neurons and the effect of cortical excitation of motor thalamus in modulating rebound spiking. Interestingly, both could either promote or suppress the generation of rebound spikes depending on their timing relative to the motor signal. Finally, we determined parameter regimes, such as levels of excitation, under which rebound spiking is feasible in the model, and confirmed that the conditions for rebound spiking are primarily given in pathological regimes. However, we also identified specific conditions in the model that would allow rebound spiking to occur in healthy animals in a small subset of thalamic neurons. Overall, our model provides novel insights into differences between normal and pathological transmission of motor signals. | neuroscience |
10.1101/396036 | Reduction in CD11c+ microglia correlates with clinical progression in chronic experimental autoimmune demyelination | Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease with high variability of clinical symptoms. In most cases MS appears as a relapsing-remitting disease course that at a later stage transitions into irreversible progressive decline of neurologic function. The mechanisms underlying MS progression remain poorly understood. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS. Here we demonstrate that mice that develop mild EAE after immunization with myelin oligodendrocyte glycoprotein 35-55 are prone to undergo clinical progression around 30 days after EAE induction. EAE progression was associated with reduction in CD11c+ microglia and dispersed coalescent parenchymal infiltration. We found sex-dependent differences mediated by p38 signaling, a key regulator of inflammation. Selective reduction of CD11c+ microglia in female mice with CD11c-promoter driven p38 knockout (KO) correlated with increased rate of EAE progression. In protected animals, we found CD11c+ microglia forming contacts with astrocyte processes at the glia limitans and immune cells retained within perivascular spaces. Together, our study provides evidence on the protective role of CD11c+ microglia in controlling CNS immune cell parenchymal infiltration in autoimmune demyelination. | neuroscience |
10.1101/410803 | 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 |
10.1101/410803 | 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 |
10.1101/412213 | 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 |
10.1101/412924 | 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 |
10.1101/413153 | 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 |
10.1101/415992 | 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 |
10.1101/417972 | 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 |
10.1101/422063 | 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 |
10.1101/422063 | Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red 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 |
10.1101/423467 | 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 |
10.1101/427864 | 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 |
10.1101/430744 | 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 |
10.1101/432328 | 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 |
10.1101/432328 | 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 |
10.1101/432328 | 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 |
10.1101/432328 | 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 |
10.1101/430306 | 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 |
10.1101/436634 | 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 |
10.1101/436634 | 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 |
10.1101/436758 | 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 |
10.1101/437327 | 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 |
10.1101/437335 | 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 |
10.1101/437228 | 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 |
10.1101/437228 | 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 |
10.1101/439083 | 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 |
10.1101/440321 | 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 |
10.1101/441246 | 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 |
10.1101/442822 | 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 |
10.1101/445304 | 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 |
10.1101/445643 | 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 |
10.1101/411702 | 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 |
10.1101/449009 | 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 |
10.1101/452326 | 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 |
10.1101/452326 | 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 |
10.1101/453746 | 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 |
10.1101/453746 | 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 |
10.1101/453746 | 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 |
10.1101/452581 | 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 |
10.1101/452581 | Exploratory analysis of multiple traits co-adaptations in the population history | 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 |
10.1101/457614 | 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 |
10.1101/460048 | 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 |
10.1101/461129 | 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 |
10.1101/458992 | 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 |
10.1101/461442 | 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 |
10.1101/461707 | 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 |
10.1101/463760 | 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 |
10.1101/464388 | 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 |
10.1101/464388 | 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 |
10.1101/464388 | 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 |
10.1101/465005 | 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 |
10.1101/465005 | 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 |
10.1101/465393 | 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 |
10.1101/470682 | 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 |
10.1101/469809 | 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 |
10.1101/471201 | 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 |
10.1101/475673 | 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 |
10.1101/480418 | 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 |
10.1101/478347 | 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 |
10.1101/479956 | 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 |
10.1101/483263 | 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 |
10.1101/483263 | 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 |
10.1101/483362 | 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 |
10.1101/483362 | Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-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 |
10.1101/483362 | Somatic uniparental disomy mitigates the most damaging EFL1 allele combination in Shwachman-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 |
10.1101/488445 | 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 |
10.1101/487157 | 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 |
10.1101/487157 | 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 |
10.1101/487157 | 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 |
10.1101/498352 | 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 |
10.1101/498352 | 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 |
10.1101/498469 | 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 |