Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 84,802 bioRxiv papers from 364,857 authors.
Most downloaded bioRxiv papers, since beginning of last month
82,661 results found. For more information, click each entry to expand.
9 downloads neuroscience
The first steps of visual processing are often described as a bank of oriented filters followed by divisive normalization. This approach has been tremendously successful at predicting contrast thresholds in simple visual displays. However, it is unclear to what extent this kind of architecture also supports processing in more complex visual tasks performed in naturally looking images. We used a deep generative image model to embed arc segments with different curvatures in naturalistic images. These images contain the target as part of the image scene, resulting in considerable appearance variation of target as well as background. Three observers localized arc targets in these images, achieving an accuracy of 74.7% correct responses on average. Data were fit by several biologically inspired models, 4 standard deep convolutional neural networks (CNN) from the computer vision literature, and by a 5-layer CNN specifically trained for this task. Four models were particularly good at predicting observer responses, (i) a bank of oriented filters, similar to complex cells in primate area V1, (ii) a bank of oriented filters followed by tuned gain control, incorporating knowledge about cortical surround interactions, (iii) a bank of oriented filters followed by local normalization, (iv) the 5-layer specifically trained CNN. A control experiment with optimized stimuli based on these four models showed that the observers’ data were best explained by model (ii) with tuned gain control. These data suggest that standard models of early vision provide good descriptions of performance in much more complex tasks than what they were designed for, while general purpose non-linear models such as convolutional neural networks do not.
9 downloads systems biology
Bacterial growth depends on numerous reactions, and yet follows surprisingly simple laws that inspired biologists for decades. Growth laws until now primarily dealt with steady-state exponential growth in constant conditions. However, bacteria in nature often face fluctuating environments, with nutritional upshifts and downshifts. We therefore ask whether there are growth laws that apply to changing environments. We derive a law for strong upshifts using an optimal resource-allocation model that was previously calibrated at steady-state growth: the post-shift growth rate equals the geometrical mean of the pre-shift growth rate and the growth rate on saturating carbon. We test this using chemostat and robotic batch culture experiments, as well as previous data from several species, and find good agreement with the model predictions. The increase in growth rate after an upshift indicates that ribosomes have spare capacity. We demonstrate theoretically that spare ribosomal capacity has the cost of slow steady-state growth, but is beneficial in fluctuating environments because it prevents large overshoots in intracellular metabolites after an upshift and allows rapid response to change. We also provide predictions for downshifts for future experimental tests. Spare capacity appears in diverse biological systems, and the present study quantifies the optimal degree of spare capacity, which rises the slower the growth rate, and suggests that it can be precisely regulated.
9 downloads genomics
Vagheesh M. Narasimhan, Raheleh Rahbari, Aylwyn Scally, Arthur Wuster, Dan Mason, Yali Xue, John Wright, Richard C. Trembath, Eamonn R Maher, David A van Heel, Adam Auton, Matthew E Hurles, Chris Tyler-Smith, Richard Durbin
Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations (DNMs) across multiple generations. Using exome sequences from 3,222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10-8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10-6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent-offspring trios, suggesting that post-zygotic mutations contribute little to the human germline mutation rate. We found frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5' CCG 3' → 5' CTG 3' context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations.
9 downloads biochemistry
Plants make hundreds of thousands of biologically active specialized metabolites varying widely in structure, biosynthesis and the processes that they influence. An increasing number of these compounds are documented to protect plants from harmful insects, pathogens, or herbivores, or mediate interactions with beneficial organisms including pollinators and nitrogen fixing microbes. Acylsugars - one class of protective compounds - are made in glandular trichomes of plants across the Solanaceae family. While most described acylsugars are acylsucroses, published examples also include acylsugars with hexose cores. The South American fruit crop Solanum quitoense (Naranjilla) produces acylsugars that contain a myo-inositol core. We identified an enzyme that acetylates triacylinositols, a function homologous to the last step in the Solanum lycopersicum acylsucrose biosynthetic pathway. Our analysis reveals parallels between S. lycopersicum acylsucrose and S. quitoense acylinositol biosynthesis, suggesting a common evolutionary origin.
9 downloads developmental biology
Hox genes encode a family of transcription factors that, despite having similar in vitro DNA binding preferences, regulate distinct genetic programs along the metazoan anterior-posterior axis. To better define mechanisms of Hox specificity, we compared and contrasted the ability of abdominal Hox factors to regulate two cis-regulatory elements within the Drosophila embryo. Both the Ultrabithorax (Ubx) and Abdominal-A (Abd-A) Hox factors form cooperative complexes with the Extradenticle (Exd) and Homothorax (Hth) transcription factors to repress the distal-less leg selector gene via the DCRE, whereas only Abd-A interacts with Exd and Hth on the RhoA element to activate a rhomboid serine protease gene that stimulates Epidermal Growth Factor secretion. By swapping binding sites between these elements, we found that the RhoA Exd/Hth/Hox site configuration that mediates Abd-A specific activation can also convey transcriptional repression by both Ubx and Abd-A when placed into the DCRE, but only in one orientation. We further show that the orientation and spacing of Hox sites relative to additional transcription factor binding sites within the RhoA and DCRE elements is critical to mediate appropriate cell- and segment-specific output. These results indicate that the interaction between Hox, Exd, and Hth neither determines activation vs repression specificity nor defines Ubx vs Abd-A specificity. Instead the precise integration of Hox sites with additional TF inputs is required for accurate transcriptional output. Taken together, these studies provide new insight into the mechanisms of Hox target and regulatory specificity as well as the constraints placed on regulatory elements to convey appropriate outputs.
9 downloads neuroscience
While performing challenging perceptual tasks such as detecting a barely visible target, our perceptual reports vary across presentations of identical stimuli. How much of the neural variability that correlates with the perceptual variability is present in the primary visual cortex (V1), the first cortical processing stage of visual information? To address this question, we recorded neural population responses from V1 using voltage-sensitive dye imaging while monkeys performed a challenging reaction-time visual detection task. We found that V1 responses in the period leading to the decision correspond more closely to the monkey's report than to the visual stimulus. These results, together with a simple computational model that allows one to quantify the captured choice-related variability, suggest that most this variability is present in V1, and that areas outside of V1 contain relatively little independent choice-related variability.
9 downloads animal behavior and cognition
Teleost fishes not only communicate with well-known visual cues, but also olfactory and acoustic signals. Communicating with sound has advantages, as signals propagate fast, omnidirectionally, around obstacles, and over long distances. Heterogeneous environments might favour multimodal communication, especially in socially complex species, as combination of modalities' strengths helps overcome their individual limitations. Cichlid fishes are known to be vocal, but a recent report suggests that this is not the case for the socially complex Princess cichlid Neolamprologus pulcher from Lake Tanganyika. Here we further investigated acoustic communication in this species. Wild and captive N. pulcher produced high frequency sounds (mean: 12 kHz), when stimulated by mirror images. In laboratory experiments, N. pulcher produced distinct two-pulsed calls mostly, but not exclusively, associated with agonistic displays. Our results suggest that male N. pulcher produce more sounds at greater durations than females. Thus, we confirm that the Princess cichlid does not produce low frequency sounds, but does produce high frequency sounds, both in combination with and independent from visual displays, suggesting that sounds are not a by-product of displays. Further studies on the hearing abilities of N. pulcher are needed to clarify if the high-frequency sounds are used in intra- or inter-specific communication.
9 downloads bioinformatics
High-throughput quantification of oligodendrocyte (OL) myelination is a significant challenge that, if addressed, would facilitate the development of therapeutics to promote myelin protection and repair. Here, we established a quantitative high-throughput method to asses OL ensheathment in-vitro, combining nanofiber culture devices and automated imaging with a heuristic approach that informed the development of a deep learning analytic algorithm. The heuristic approach was developed by modeling general characteristics of OL ensheathments, while the deep learning neural network employed a UNet architecture with enhanced capacity to associate ensheathed segments with individual OLs. Reliably extracting multiple morphological parameters from individual cells, without heuristic approximations, mimics the high-level decision-making capacity of human researchers and improves the validity of the neural network. Experimental validation demonstrated that the deep learning approach matched the accuracy of expert-human measurements of the length and number of myelin segments per cell. The combined use of automated imaging and analysis reduces tedious manual labor while eliminating variability. The capacity of this technology to perform multi-parametric analyses at the level of individual cells permits the detection of nuanced cellular differences to accelerate the discovery of new insight into OL physiology.
9 downloads physiology
Considerable evidence demonstrates that the vestibular system contributes to regulating sympathetic nerve activity and blood pressure. Initial studies in decerebrate animals showed that presumed pre-sympathetic neurons in the rostral ventrolateral medulla (RVLM) respond to small-amplitude (<10°) rotations of the body, as in other brain areas that process vestibular signals, despite the fact that such movements do not appreciably affect blood distribution in the body. However, a subsequent experiment in conscious animals showed that few RVLM neurons respond to small-amplitude movements. This study tested the hypothesis that vestibular inputs to RVLM neurons are modulated in conscious animals, such that vestibulosympathetic responses are only elicited when changes in body position are large enough to require changes in sympathetic nerve activity. The activity of approximately a third of RVLM neurons whose firing rate was related to the cardiac cycle, and thus likely received baroreceptor inputs, responded to vestibular inputs elicited by 40° head-up tilts in conscious cats, but not during 10° sinusoidal rotations in the pitch plane that affected the activity of neurons in brain regions providing inputs to the RVLM. These data suggest the existence of brain circuitry that suppresses vestibular influences on the activity of RVLM neurons and the sympathetic nervous system unless these inputs are physiologically warranted. We also determined that RVLM activity is not altered prior to tilts when a light cue is provided signaling the movement. The simplest interpretation of this findings is that feedforward cardiovascular responses are associated with active movement such as occurs during exercise, but not passive movements that require cardiovascular adjustments.
9 downloads biochemistry
The malarial pathogen Plasmodium falciparum (Pf) is a member of the Apicomplexa, which independently evolved a highly specific lactate dehydrogenase (LDH) from an ancestral malate dehydrogenase (MDH) via a five-residue insertion in a key active site loop. PfLDH is widely considered an attractive drug target due to its unique active site. Apicomplexan loop conservation suggests that a particular insertion sequence was required to evolve LDH specificity, and we previously showed (Boucher 2014) that a tryptophan in the insertion, W107f, is essential for activity and specificity. However, the roles of other residues in the loop are currently unknown. Here we show that PfLDH activity is remarkably resilient to radical perturbations of both loop identity and length. Thus, alternative insertions could have evolved LDH specificity as long as they contained a tryptophan in the proper location. PfLDH therefore has high potential to develop resistance to drugs that target its distinctive active site.
9 downloads microbiology
Lindsey E. Bazzone, Michael King, Christopher R. MacKay, Pyae P. Kyawe, Paul Meraner, Daniel Lindstrom, Joselyn Rojas-Quintero, Caroline A. Owen, Jennifer P. Wang, Abraham L. Brass, Evelyn A Kurt-Jones, Robert W. Finberg
Encephalomyocarditis virus (EMCV) is a picornavirus that produces lytic infections in murine and human cells. Employing a genome-wide CRISPR-Cas9 knockout screen to find host factors required for EMCV infection, we identified a role for ADAM9 in EMCV infection. CRISPR-mediated deletion of ADAM9 in multiple human cell lines rendered the cells highly resistant to EMCV infection and cell death. Primary fibroblasts from ADAM9 KO mice were also strongly resistant to EMCV infection and cell death. In contrast, ADAM9 KO and WT cells were equally susceptible to infection with other viruses, including the picornavirus Coxsackie virus B. ADAM9 KO cells failed to produce viral progeny when incubated with EMCV. However, bypassing EMCV entry into cells through delivery of viral RNA directly to the cytosol yielded infectious EMCV virions from ADAM9 KO cells, suggesting that ADAM9 is not required for EMCV replication post-entry. These findings establish that ADAM9 is required for the early stage of EMCV infection, likely for virus entry or viral genome delivery to the cytosol.
9 downloads bioinformatics
High-throughput biological data -- such as mass spectrometry-based proteomics data -- suffer from systematic non-biological variance, which is introduced by systematic errors such as batch effects. This hinders the estimation of 'real' biological signals and, thus, decreases the power of statistical tests and biases the identification of differentially expressed sample classes. To remove such unintended variation, while retaining the biological signal of interest, the analysis workflows for mass spectrometry-based quantification typically comprises normalization steps prior to the statistical analysis of the data. Several normalization methods, such as quantile normalization, have originally been developed for microarray data. However, unlike microarray data, proteomics data may contain features, in the form of protein intensities, that are consistently highly abundant across experimental conditions and, hence, are encountered in the tails of the protein intensity distribution. If such proteins are present, statistical inferences of the intensity profiles of the normalized features are impeded through the increased number of false positive findings due to the biased estimation of the variance of the data. Thus, we developed a, freely available, novel approach: 'tail-robust quantile normalization'. It extends the traditional quantile normalization to preserve the biological signals of features in the tails of the distribution over experimental conditions and to account for sample-dependent missing values. ### Competing Interest Statement The authors have declared no competing interest.
9 downloads epidemiology
Background: Shanghai is one of the biggest cities which have the highest number of entry travelers from all over the world. The HIV?human immunodeficiency virus? infection status of this population can reflect global trends of HIV prevalence to a certain extent. Methods:A retrospective cohort study was conducted to reveal the prevalence and characteristics of HIV-1 infection among entry travelers who applied to residency in Shanghai. The HIV-1 infection rate was estimated based on the detection of HIV-1 antibody. Results:Among 50830 entry travelers who applied to residency in Shanghai?2005-2016?, 245 were determined HIV-1 positive with an infection rate of 0.48%. The detection rate of HIV was significantly higher in male (P<0.0001). Those aged 18-30 years, 31-40 years and >40years accounted for 34.3%,39.6% and 26.1% respectively of the infected population. Although there was no trend of increase in HIV-1 prevalence rates (Cochran-Armitage Z =2.543, P =0.111),proportions of individuals infected through homosexual transmission increased over the study period (Cochran-Armitage Z =5.41, P<0.001), while the proportions infected through heterosexual(Cochran-Armitage Z=3.38, P=0.001). Conclusion: The rate and characteristics of HIV-1 infection among foreign applicant to residency in Shanghai were revealed in the study. The results could provide the necessary epidemiological data for monitoring the HIV-1 epidemic among entry international travelers and to further contribute to the establishment of relevant policies and regulations for HIV control and prevention.
9 downloads bioinformatics
Current methods used to analyze real-time quantitative polymerase chain reaction (qPCR) data exhibit systematic deviations from the assumed model over the progression of the reaction. Slight variations in the amount of the initial target molecule or in early amplifications are likely responsible for these deviations. Commonly-used 4- and 5-parameter sigmoidal models appear to be particularly susceptible to this issue, often displaying patterns of autocorrelation in the residuals. The presence of this phenomenon, even for technical replicates, suggests that these parametric models may be misspecified. Specifically, they do not account for the sequential dependent nature of qPCR fluorescence measurements. We demonstrate that a Smooth Transition Autoregressive (STAR) model addresses this limitation by explicitly modeling the dependence between cycles and the gradual transition between amplification regimes. In summary, application of a STAR model to qPCR amplification data improves model fit and reduces autocorrelation in the residuals.
9 downloads immunology
Histone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1lf/fMb1 Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection, germinal centers failed to form in Dot1lf/fCd23 Cre/+ mice. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Dot1l deletion significantly attenuated the formation of class-switched antibody-secreting cells in both T-dependent and T-independent responses. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.
9 downloads genomics
Microalgal Chlorella has been demonstrated to process wastewater efficiently from piggery industry, yet optimization through genetic engineering of such a bio-treatment is currently challenging, largely due to the limited data and knowledge in genomics. In this study, we first investigated the differential growth rates among three wastewater-processing Chlorella strains: Chlorella sorokiniana BD09, Chlorella sorokiniana BD08 and Chlorella sp. Dachan, and the previously published Chlorella sorokiniana UTEX 1602, showing us that BD09 maintains the best tolerance in synthetic wastewater. We then performed genome sequencing and analysis, resulting in a high-quality assembly for each genome with scaffold N50 >2 Mb and genomic completeness ≥ 91%, as well as genome annotation with 9,668, 10,240, 9,821 high-confidence gene models predicted for BD09, BD08, and Dachan, respectively. Comparative genomics study unravels that metabolic pathways, which are involved in nitrogen and phosphorus assimilation, were enriched in the faster-growing strains. We found that gene structural variation and genomic rearrangement might contribute to differential capabilities in wastewater tolerance among the strains, as indicated by gene copy number variation, domain reshuffling of orthologs involved, as well as a ~1 Mb-length chromosomal inversion we observed in BD08 and Dachan. In addition, we speculated that an associated bacterium, Microbacterium chocolatum, which was identified within Dachan, play a possible role in synergizing nutrient removal. Our three newly sequenced Chlorella genomes provide a fundamental foundation to understand the molecular basis of abiotic stress tolerance in wastewater treatment, which is essential for future genetic engineering and strain improvement.
9 downloads bioinformatics
Metadata curation has become increasingly important for biological discovery and biomedical research because a large amount of heterogeneous biological data is currently freely available. To facilitate efficient metadata curation, we developed an easy-to-use web-based curation application, GEOMetaCuration, for curating the metadata of Gene Expression Omnibus datasets. It can eliminate mechanical operations that consume precious curation time and can help coordinate curation efforts among multiple curators. It improves the curation process by introducing various features that are critical to metadata curation, such as a back-end curation management system and a curator-friendly front-end. The application is based on a commonly used web development framework of Python/Django and is open-sourced under the GNU General Public License V3. GEOMetaCuration is expected to benefit the biocuration community and to contribute to computational generation of biological insights using large-scale biological data. An example use case can be found at the demo website: http://geometacuration.yubiolab.org. Source code URL: https://bitbucket.com/yubiolab/GEOMetaCuration.
9 downloads molecular biology
Many eukaryotic protein-coding genes give rise to alternative mRNA isoforms with identical protein-coding capacities but which differ in the extents of their 3' untranslated regions (3'UTRs), due to the usage of alternative sites of pre-mRNA cleavage and polyadenylation. By governing the presence of regulatory 3'UTR sequences, this type of alternative polyadenylation (APA) can significantly influence the stability, localisation and translation efficiency of mRNA. Though a variety of molecular mechanisms for APA have been proposed, previous studies have identified a pivotal role for the multi-subunit cleavage factor I (CFIm) in this process in mammals. Here we show that, in line with previous reports, depletion of the CFIm 68 kDa subunit (CFIm68) by CRISPR/Cas9-mediated gene disruption in HEK293 cells leads to a shift towards the use of promoter-proximal poly(A) sites. Using these cells as the basis for a complementation assay, we show that CFIm68 lacking its arginine/serine-rich (RS) domain retains the ability to form a nuclear complex with other CFIm subunits, but selectively lacks the capacity to restore polyadenylation at promoter-distal sites. In addition, nanoparticle-mediated analysis indicates that the RS domain is extensively phosphorylated in vivo. Overall, these results suggest that the CFIm68 RS domain makes a key regulatory contribution to APA.
9 downloads neuroscience
Imitation and perspective taking are core features of non-verbal social interactions. We imitate one another to signal a desire to affiliate and consider others' points of view to better understand their perspective. Prior research suggests that a relationship exists between prosocial behaviour and imitation. For example, priming prosocial behaviours has been shown to increase imitative tendencies in automatic imitation tasks. Despite its importance during social interactions, far less is known about how perspective taking might relate to either prosociality or imitation. The current study investigates the relationship between imitation and perspective taking by testing the extent to which these skills are similarly modulated by prosocial priming. Across all experimental groups, a surprising ceiling effect emerged in the perspective taking task (the Director's Task), which prevented the investigation prosocial priming on perspective taking. A comparison of other studies using the Director's Task shows wide variability in accuracy scores across studies and is suggestive of low task reliability. In addition, despite using a high-power design, and contrary to three previous studies, no effect of prosocial prime on imitation was observed. Meta-analysing all studies to date suggests that the effects of prosocial primes on imitation are variable and could be small. The current study, therefore, offers caution when using the Director's Task as a measure of perspective taking with adult populations, as it shows high variability across studies and may suffer from a ceiling effect. In addition, the results question the size and robustness of prosocial priming effects on automatic imitation. More generally, by reporting null results we hope to minimise publication bias and by meta-analysing results as studies emerge and making data freely available, we hope to move towards a more cumulative science of social cognition.
9 downloads genetics
Harm-Jan Westra, Marta Martinez Bonet, Suna Onengut, Annette Lee, Yang Luo, Nick Teslovich, Jane Worthington, Javier Martin, Tom Huizinga, Lars Klareskog, Solbritt Rantapaa-Dahlqvist, Wei-Min Chen, Aaron R. Quinlan, John A Todd, Stephen Eyre, Peter A. Nigrovic, Peter K. Gregersen, Stephen S. Rich, Soumya Raychaudhuri
We fine-mapped 76 rheumatoid arthritis (RA) and type 1 diabetes (T1D) loci outside of the MHC. After sequencing 799 1kb regulatory (H3K4me3) regions within these loci in 568 individuals, we observed accurate imputation for 89% of common variants. We fine-mapped these loci in RA (11,475 cases, 15,870 controls), T1D (9,334 cases and 11,111 controls) and combined datasets. We reduced the number of potential causal variants to ≤5 in 8 RA and 11 T1D loci. We identified causal missense variants in five loci (DNASE1L3, SIRPG, PTPN22, SH2B3 and TYK2) and likely causal non coding variants in six loci (MEG3, TNFAIP3, CD28/CTLA4, ANKRD55, IL2RA, REL/PUS10). Functional analysis confirmed allele specific binding and differential enhancer activity for three variants: the CD28/CTLA4 rs117701653 SNP, the TNFAIP3 rs35926684 indel, and the MEG3 rs34552516 indel. This study demonstrates the potential for dense genotyping and imputation to pinpoint missense and non-coding causal alleles.
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