Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,521 bioRxiv papers from 264,855 authors.
Most downloaded bioRxiv papers, since beginning of last month
56,141 results found. For more information, click each entry to expand.
303 downloads neuroscience
The control of locomotion is fundamental to vertebrate animal survival. Defensive situations require an animal to rapidly decide whether to run away or suppress locomotor activity to avoid detection. While much of the neural circuitry involved in defensive action selection has been elucidated, top-down modulation of brainstem locomotor circuitry remains unclear. Here we provide evidence for the existence and functionality of a monosynaptic connection from the central amygdala (CeA) to the mesencephalic locomotor region (MLR) that inhibits locomotion in unconditioned and conditioned defensive behavior in mice. We show that locomotion stimulated by airpuff coincides with increased activity of MLR glutamatergic neurons. Using retrograde tracing and ex vivo electrophysiology, we find that the CeA makes a monosynaptic connection with the MLR. In the open field, in vivo stimulation of this projection suppressed spontaneous locomotion, whereas inhibition of this projection had no effect. However, inhibiting CeA terminals within the MLR increased both neural activity and locomotor responses to airpuff. Finally, using a conditioned avoidance paradigm known to activate CeA neurons, we find that inhibition of the CeA projection increased successful escape, whereas activating the projection reduced escape. Together these results provide evidence for a new circuit substrate influencing locomotion and defensive behaviors.
303 downloads scientific communication and education
The fairness of scholarly peer review has been challenged by evidence of disparities in publication outcomes based on author demographic characteristics. To assess this, we conducted an exploratory analysis of peer review outcomes of 23,876 initial submissions and 7,192 full submissions that were submitted to the biosciences journal eLife between 2012 and 2017. Women and authors from nations outside of North America and Europe were underrepresented both as gatekeepers (editors and peer reviewers) and authors. We found evidence of a homophilic relationship between the demographics of the gatekeepers and authors and the outcome of peer review; that is, there were higher rates of acceptance in the case of gender and country homophily. The acceptance rate for manuscripts with male last authors was seven percent, or 3.5 percentage points, greater than for female last authors (95% CI = [0.5, 6.4]); this gender inequity was greatest, at nine percent or about 4.8 percentage points (95% CI = [0.3, 9.1]), when the team of reviewers was all male; this difference was smaller and not significantly different for mixed-gender reviewer teams. Homogeny between countries of the gatekeeper and the corresponding author was also associated with higher acceptance rates for many countries. To test for the persistence of these effects after controlling for potentially confounding variables, we conducted a logistic regression including document and author metadata. Disparities in acceptance rates associated with gender and country of affiliation and the homophilic associations remained. We conclude with a discussion of mechanisms that could contribute to this effect, directions for future research, and policy implications. Code and anonymized data have been made available at https://github.com/murrayds/elife-analysis
302 downloads immunology
Stefan Jordan, Navpreet Tung, Maria Casanova-Acebes, Christie Chang, Claudia Cantoni, Dachuan Zhang, Theresa H. Wirtz, Shruti Naik, Samuel A Rose, Chad N. Brocker, Anastasiia Gainullina, Barbara B. Maier, Derek LeRoith, Frank J. Gonzalez, Felix Meissner, Jordi Ochando, Adeeb Rahman, Jerry E Chipuk, Maxim N. Artyomov, Paul S. Frenette, Laura Piccio, Marie-Luise Berres, Emily J Gallagher, Miriam Merad
Caloric restriction is known to improve inflammatory and autoimmune diseases. However, the mechanisms by which reduced caloric intake modulates inflammation are poorly understood. Here we show that short-term fasting reduced monocyte metabolic and inflammatory activity and drastically reduced the number of circulating monocytes. Regulation of peripheral monocyte numbers was dependent on dietary glucose and protein levels. Specifically, we found that activation of the low-energy sensor 5′-AMP-activated protein kinase (AMPK) in hepatocytes and suppression of systemic CCL2 production by peroxisome proliferator-activator receptor alpha (PPARα) reduced monocyte mobilization from the bone marrow. Importantly, while caloric restriction improves chronic inflammatory diseases, fasting did not compromise monocyte emergency mobilization during acute infectious inflammation and tissue repair. These results reveal that caloric intake and liver energy sensors dictate the blood and tissue immune tone and link dietary habits to inflammatory disease outcome.
302 downloads neuroscience
Background: Heterogeneity in autism spectrum disorder (ASD) has hindered the development of biomarkers, thus motivating subtyping efforts. Most subtyping studies divide ASD individuals into non-overlapping (categorical) subgroups. However, continuous inter-individual variation in ASD suggests the need for a dimensional approach. Methods: A Bayesian model was employed to decompose resting-state functional connectivity (RSFC) of ASD individuals into multiple abnormal RSFC patterns, i.e., categorical subtypes henceforth referred to as "factors". Importantly, the model allowed each individual to express one or more factors to varying degrees (dimensional subtyping). The model was applied to 306 ASD individuals (age 5.2-57 years) from two multisite repositories. Posthoc analyses associated factors with symptoms and demographics. Results: Analyses yielded three factors with dissociable whole-brain hypo/hyper RSFC patterns. Most participants expressed multiple (categorical) factors, suggestive of a mosaic of subtypes within individuals. All factors shared abnormal RSFC involving the default network, but the directionality (hypo/hyper RSFC) differed across factors. Factor 1 was associated with core ASD symptoms, while factor 2 was associated with comorbid symptoms. Older males preferentially expressed factor 3. Factors were robust across multiple control analyses and not associated with IQ, nor head motion. Conclusions: There exist at least three ASD factors with dissociable patterns of whole-brain RSFC, behaviors and demographics. Heterogeneous default network hypo/hyper RSFC across the factors might explain previously reported inconsistencies. The factors differentiated between core ASD and comorbid symptoms - a less appreciated domain of heterogeneity in ASD. These factors are co-expressed in ASD individuals with different degrees, thus reconciling categorical and dimensional perspectives of ASD heterogeneity.
302 downloads genomics
Eric V Minikel, Konrad Karczewski, Hilary C Martin, Beryl B Cummings, Nicola Whiffin, Daniel Rhodes, Jessica Alfoldi, Richard C Trembath, David A van Heel, Mark J. Daly, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Stuart L Schreiber, Daniel G. MacArthur
Naturally occurring human genetic variants predicted to cause loss of function of protein-coding genes provide an in vivo model of human gene inactivation that complements cell and model organism knockout studies. Here we investigate the application of human loss-of-function variants to assess genes as candidate drug targets, with three key findings. First, even essential genes, where loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous "knockout" humans will await sample sizes ~1,000 times those available at present. Third, automated variant annotation and filtering are powerful, but manual curation remains critical for removing artifacts and making biological inferences, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human "knockout" studies and should guide interpretation of loss-of-function variants in drug development.
302 downloads animal behavior and cognition
Habits form a crucial component of behavior. In recent years, key computational models have conceptualized habits as arising from model-free reinforcement learning (RL) mechanisms, which typically select between available actions based on the future value expected to result from each. Traditionally, however, habits have been understood as behaviors that can be triggered directly by a stimulus, without requiring the animal to evaluate expected outcomes. Here, we develop a computational model instantiating this traditional view, in which habits develop through the direct strengthening of recently taken actions rather than through the encoding of outcomes. We demonstrate that this model accounts for key behavioral manifestations of habits, including insensitivity to outcome devaluation and contingency degradation, as well as the effects of reinforcement schedule on the rate of habit formation. The model also explains the prevalent observation of perseveration in repeated-choice tasks as an additional behavioral manifestation of the habit system. We suggest that mapping habitual behaviors onto value-free mechanisms provides a parsimonious account of existing behavioral and neural data. This mapping may provide a new foundation for building robust and comprehensive models of the interaction of habits with other, more goal-directed types of behaviors and help to better guide research into the neural mechanisms underlying control of instrumental behavior more generally.
301 downloads bioinformatics
In single-cell RNA-seq (scRNA-seq) experiments, the number of individual cells has increased exponentially, and the sequencing depth of each cell has decreased significantly. As a result, analyzing scRNA-seq data requires extensive considerations of program efficiency and method selection. In order to reduce the complexity of scRNA-seq data analysis, we present scedar, a scalable Python package for scRNA-seq exploratory data analysis. The package provides a convenient and reliable interface for performing visualization, imputation of gene dropouts, detection of rare transcriptomic profiles, and clustering on large-scale scRNA-seq datasets. The analytical methods are efficient, and they also do not assume that the data follow certain statistical distributions. The package is extensible and modular, which would facilitate further development of functionalities for future requirements. The open source package is distributed under the terms of MIT license at https://pypi.org/project/scedar.
301 downloads genomics
Jimmy HW Saw, Takuro Nunoura, Miho Hirai, Yoshihiro Takaki, Rachel Parsons, Michelle Michelsen, Krista Longnecker, Elizabeth B. Kujawinski, Ramunas Stepanauskas, Zachary Landry, Craig A Carlson, Stephen J. Giovannoni
It has been hypothesized that abundant heterotrophic ocean bacterioplankton in the SAR202 clade of the phylum Chloroflexi evolved specialized metabolism for the oxidation of organic compounds that are resistant to microbial degradation via common metabolic pathways. Expansions of paralogous enzymes were reported and implicated in hypothetical metabolism involving monooxygenase and dioxygenase enzymes. In the metabolic schemes proposed, the paralogs serve the purpose of diversifying the range of organic molecules that cells can utilize. To further explore this question, we reconstructed SAR202 single amplified genomes and metagenome-assembled genomes from locations around the world, including the deepest ocean trenches. In analyses of 122 SAR202 genomes that included six subclades spanning SAR202 diversity, we observed additional evidence of paralog expansions that correlated with evolutionary history, and further evidence of metabolic specialization. Consistent with previous reports, families of flavin-dependent monooxygenases were observed mainly in the Group III SAR202, in the proposed class Monstramaria and expansions of dioxygenase enzymes were prevalent in Group IV. We found that Group I SAR202 encode expansions of racemases in the enolase superfamily, which we propose evolved for the degradation of compounds that resist biological oxidation because of chiral complexity. Supporting the conclusion that the paralog expansions indicate metabolic specialization, fragment recruitment and fluorescence in situ hybridization with phylogenetic probes showed that SAR202 subclades are indigenous to different ocean depths and geographical regions. Surprisingly, some of the subclades were abundant in surface waters and contained rhodopsin genes, altering our understanding of the ecological role of SAR202 in stratified water columns.
301 downloads biophysics
Cells maintain membrane fluidity by regulating lipid saturation, but the molecular mechanisms of this homeoviscous adaptation remain poorly understood. Here, we have reconstituted the core machinery for sensing and regulating lipid saturation in baker's yeast to directly characterize its response to defined membrane environments. Using spectroscopic techniques and in vitro ubiquitylation, we uncover a unique sensitivity of the transcriptional regulator Mga2 to the abundance, position, and configuration of double bonds in lipid acyl chains and provide unprecedented insight into the molecular rules of membrane adaptivity. Our data challenge the prevailing hypothesis that membrane viscosity serves as the measured variable for regulating lipid saturation. Rather, we show that the signaling output of Mga2 correlates with the size of a single sensor residue in the transmembrane helix, which senses the lateral pressure and/or compressibility profile in a defined region of the membrane. Our findings suggest that membrane property sensors have evolved remarkable sensitivities to highly specific aspects of membrane structure and dynamics, thus paving the way toward the development of genetically encoded reporters for such membrane properties in the future.
300 downloads evolutionary biology
Nepenthaceae is one of the largest carnivorous plant families and features ecological and morphological adaptations indicating an impressive adaptive radiation. However, investigation of evolutionary and taxonomic questions is hindered by poor phylogenetic understanding, with previous molecular studies based on limited loci and taxa. We use high-throughput sequencing with a target-capture methodology based on a 353-loci, probe set to recover sequences for 197 samples, representing 151 described or putative Nepenthes species. Phylogenetic analyses were performed using supermatrix and maximum quartet species tree approaches. Our analyses confirm five Western outlier taxa, followed by N. danseri , as successively sister to the remainder of the group. We also find mostly consistent recovery of two major Southeast Asian clades. The first contains common or widespread lowland species plus a Wallacean-New Guinean clade. Within the second clade, sects. Insignes and Tentaculatae are well supported, while geographically defined clades representing Sumatra, Indochina, Peninsular Malaysia, Palawan, Mindanao and Borneo are also consistently recovered. However, we find considerable conflicting signal at the site and locus level, and often unstable backbone relationships. A handful of Bornean taxa are inconsistently placed and require further investigation. We make further suggestions for a modified infra-generic classification of genus Nepenthes .
300 downloads bioinformatics
High-throughput reporter assays, such as self-transcribing active regulatory region sequencing (STARR-seq), allow for unbiased and quantitative assessment of enhancers at a genome-wide level. Recent advances in STARR-seq technology have employed progressively more complex genomic libraries and increased sequencing depths, to assay larger sized regions, up to the entire human genome. These advances necessitate a reliable processing pipeline and peak-calling algorithm. Most STARR-seq studies have relied on chromatin immunoprecipitation sequencing (ChIP-seq) processing pipeline to identify peaks. However, there are key differences in STARR-seq versus ChIP-seq data: STARR-seq uses transcribed RNA to measure enhancer activity, making determining the basal transcription rate important. Furthermore, STARR-seq coverage is non-uniform, overdispersed, and often confounded by sequencing biases such as GC content and mappability. Moreover, here, we observed a clear correlation between RNA thermodynamic stability and STARR-seq readout, suggesting that STARR-seq might be sensitive to RNA secondary structure and stability. Considering these findings, we developed STARRPeaker: a negative binomial regression framework for uniformly processing STARR-seq data. We applied STARRPeaker to two whole human genome STARR-seq experiments; HepG2 and K562. Our method identifies highly reproducible and epigenetically active enhancers across replicates. Moreover, STARRPeaker outperforms other peak callers in terms of identifying known enhancers. Thus, our framework optimized for processing STARR-seq data accurately characterizes cell-type-specific enhancers, while addressing potential confounders.
300 downloads biochemistry
Homology directed repair (HDR) induced by site specific DNA double strand breaks (DSB) with CRISPR/Cas9 is a precision gene editing approach that occurs at low frequency in comparison to indel forming non homologous end joining (NHEJ). In order to obtain high HDR percentages in mammalian cells, we engineered Cas9 protein fused to a high-affinity monoavidin domain to deliver biotinylated donor DNA to a DSB site. In addition, we used the cationic polymer, polyethylenimine, to deliver Cas9 RNP-donor DNA complex into the cell. Combining these strategies improved HDR percentages of up to 90% in three tested loci (CXCR4, EMX1, and TLR) in standard HEK293 cells. Our approach offers a cost effective, simple and broadly applicable gene editing method, thereby expanding the CRISPR/Cas9 genome editing toolbox.
300 downloads bioengineering
We have engineered light-gated channelrhodopsins (ChRs) whose current strength and light sensitivity enable minimally-invasive neuronal circuit interrogation. Current ChR tools applied to the mammalian brain require intracranial surgery for transgene delivery and implantation of invasive fiber-optic cables to produce light-dependent activation of a small volume of brain tissue [~1 mm3]. To enable optogenetics for large brain volumes and without the need for invasive implants, our ChR engineering approach leverages the significant literature of ChR variants to train statistical models for the design of new, high-performance ChRs. With Gaussian Process models trained on a limited experimental set of 102 functionally characterized ChR variants, we designed high-photocurrent ChRs with unprecedented light sensitivity; three of these, ChRger1, ChRger2, and ChRger3, enable optogenetic activation of the nervous system via minimally-invasive systemic transgene delivery with rAAV-PHP.eB, which was not possible previously due to low per-cell transgene copy produced by systemic delivery. These engineered ChRs enable light-induced neuronal excitation without invasive intracranial surgery for virus delivery or fiber optic implantation, i.e. they enable minimally-invasive optogenetics.
300 downloads cell biology
Structural Maintenance of Chromosomes (SMC) complexes organize and individualize chromosomes ubiquitously, thereby contributing to their faithful segregation. Here we explore how Escherichia coli chromosome organization emerges from the action of the SMC complex MukBEF, using quantitative imaging in cells with increased MukBEF occupancy on the chromosome. We demonstrate that the E. coli chromosome is organized as series of loops around a thin axial MukBEF core whose length is ~1100 times shorter than the chromosomal DNA. The core is linear (1 μm), or circular (1.5 μm) in the absence of MatP, which displaces MukBEF from the 800 kbp replication termination region ( ter ). Our findings illustrate how MukBEF compacts the chromosome lengthwise and demonstrate how displacement of MukBEF from ter promotes MukBEF enrichment with the replication origin.
300 downloads cell biology
Endocytosis of transmembrane proteins is orchestrated by the AP2 clathrin adaptor complex. AP2 dwells in a closed, inactive state in the cytosol, but adopts an open, active conformation on the plasma membrane. Membrane-activated complexes are also phosphorylated, but the significance of this mark is debated. We recently proposed that NECAP negatively regulates AP2 by binding open and phosphorylated complexes (Beacham et al., 2018). Here, we report high-resolution cryo-EM structures of NECAP bound to phosphorylated AP2. The site of AP2 phosphorylation is directly coordinated by residues of the NECAP PHear domain that are predicted from genetic screens in C. elegans. Using membrane mimetics to generate conformationally open AP2, we find that a second domain of NECAP binds these complexes and cryo-EM reveals both domains of NECAP engaging closed, inactive AP2. Assays in vitro and in vivo confirm these domains cooperate to inactivate AP2. We propose that phosphorylation marks adaptors for inactivation.
299 downloads neuroscience
Loren L Looger, Jonathan S. Marvin, Yoshiteru Shimoda, Vincent Magloire, Marco Leite, Takashi Kawashima, Thomas P. Jensen, Erika L Knott, Ondrej Novak, Kaspar Podgorski, Nancy J Leidenheimer, Dmitri A. Rusakov, Misha B Ahrens, Dimitri M Kullmann
Current techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR (maximum DeltaF/F ~ 2.5, Kd ~ 9 micromolar, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of: (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.
298 downloads bioengineering
Three-dimensional (3D) brain organoids derived from human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), have become a powerful system to study early development events and to model human disease. Cerebral organoids are generally produced in static culture or in a culture vessel with active mixing, and the two most widely used systems for mixing are a large spinning flask and a miniaturized multi-well spinning bioreactor (also known as Spin Omega (SpinΩ). The SpinΩ provides a system that is amenable to drug testing, has increased throughput and reproducibility, and utilizes less culture media. However, technical limitations of this system include poor stability of select components and an elevated risk of contamination due to the inability to sterilize the device preassembled. Here, we report a new design of the miniaturized bioreactor system, which we term Spinfinity (Spin∞) that overcomes these concerns to permit long-term experiments.
298 downloads genomics
Synergistic interactions between gene functions drive cellular complexity. However, the combinatorial explosion of possible genetic interactions (GIs) has necessitated the use of scalar interaction readouts (e.g. growth) that conflate diverse outcomes. Here we present an analytical framework for interpreting manifolds constructed from high-dimensional interaction phenotypes. We applied this framework to rich phenotypes obtained by Perturb-seq (single-cell RNA-seq pooled CRISPR screens) profiling of strong GIs mined from a growth-based, gain-of-function GI map. Exploration of this manifold enabled ordering of regulatory pathways, principled classification of GIs (e.g. identifying true suppressors), and mechanistic elucidation of synthetic lethal interactions, including an unexpected synergy between CBL and CNN1 driving erythroid differentiation. Finally, we apply recommender system machine learning to predict interactions, facilitating exploration of vastly larger GI manifolds.
298 downloads animal behavior and cognition
Fabrice de Chaumont, Elodie Ey, Nicolas Torquet, Thibault Lagache, Stephane Dallongeville, Albane Imbert, Thierry Legou, Anne-Marie Le Sourd, Philippe Faure, Thomas Bourgeron, Jean-Christophe Olivo-Marin
Preclinical studies of psychiatric disorders require the use of animal models to investigate the impact of environmental factors or genetic mutations on complex traits such as decision-making and social interactions. Here, we present a real-time method for behavior analysis of mice housed in groups that couples computer vision, machine learning and Triggered-RFID identification to track and monitor animals over several days in enriched environments. The system extracts a thorough list of individual and collective behavioral traits and provides a unique phenotypic profile for each animal. On mouse models, we study the impact of mutations of genes Shank2 and Shank3 involved in autism. Characterization and integration of data from behavioral profiles of mutated female mice reveals distinctive activity levels and involvement in complex social configuration.
297 downloads biochemistry
Bacteria possess an array of defenses against foreign invaders, including diverse nucleases that target and destroy the genome of an invading bacteriophage or foreign DNA element. A recently-described bacteriophage immunity pathway employs a cGAS/DncV-like nucleotidyltransferase to produce a cyclic tri-AMP second messenger, which activates the DNA endonuclease effector NucC. Here, we show that NucC is related to restriction enzymes but uniquely assembles into a homotrimer in solution. cAAA binding in a conserved allosteric pocket promotes assembly of two NucC trimers into a homohexamer competent for double-strand DNA cleavage. We propose that NucC mediates bacteriophage immunity either through global activation, causing altruistic cell death and abortive infection, or through local activation and targeted phage genome destruction. Finally, we identify NucC homologs in type III CRISPR-Cas systems, where they likely function as accessory nucleases activated by cyclic oligoadenylate second messengers synthesized by these systems' effector complexes.
- Top preprints of 2018
- Paper search
- Author leaderboards
- Overall metrics
- The API
- Email newsletter
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!