Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 63,081 bioRxiv papers from 279,818 authors.
Most downloaded bioRxiv papers, since beginning of last month
61,451 results found. For more information, click each entry to expand.
9 downloads microbiology
Fusarium crown rot (FCR), caused by Fusarium culmorum (Wm.G.Sm) Sacc., is an important disease of wheat both in Iraq and other regions of wheat production worldwide. Changes in environmental conditions and cultural practices such as crop rotation generate stress on pathogen populations leading to the evolution of new strains that can tolerate more stressful environments. This study aims to investigate the genetic diversity among isolates of F. culmorum in Iraq. Twenty-nine samples were collected from different regions of wheat cultivation in Iraq to investigate the pathogenicity and genetic diversity of F. culmorum using the REP-PCR technique. Among the twenty-nine isolates of F. culmorum examined for pathogenicity, 96% were pathogenic to wheat at the seedling stage. The most aggressive isolate, from Baghdad, was IF 0021 at 0.890 on the FCR severity index. Three primer sets were used to assess the genotypic diversity via REP, ERIC and BOX elements. The amplicon sizes ranged from 200-800 bp for BOX-ERIC2, 110-1100 bp for ERIC-ERIC2 and 200-1300 bp for REP. In total, 410 markers were polymorphic, including 106 for BOX, 175 for ERIC and 129 for the REP. Genetic similarity was calculated by comparing markers according to minimum variance (Squared Euclidean). Clustering analysis generated two major groups, group 1 with two subgroup 1a and 1b with 5 and 12 isolates respectively, and group 2 with two subgroups 2a and 2b with 3 and 9 isolates respectively. This is the first study in this field that has been reported in Iraq.
9 downloads neuroscience
Though the fusiform is well-established as a key node in the face perception network, its role in facial expression processing remains unclear, due to competing models and discrepant findings. To help resolve this debate, we recorded from 17 subjects with intracranial electrodes implanted in face sensitive patches of the fusiform. Multivariate classification analysis showed that facial expression information is represented in fusiform activity, in the same regions that represent identity, though with a smaller effect size. Examination of the spatiotemporal dynamics revealed a functional distinction between posterior and mid-fusiform expression coding, with posterior fusiform showing an early peak of facial expression sensitivity at around 180 ms after subjects viewed a face and mid-fusiform showing a later and extended peak between 230 - 460 ms. These results support the hypothesis that the fusiform plays a role in facial expression perception and highlight a qualitative functional distinction between processing in posterior and mid-fusiform, with each contributing to temporally segregated stages of expression perception.
9 downloads genetics
Genetic interaction can be defined as a deviation of the phenotypic quantitative effect of a double gene mutation from the effect predicted from single mutations using a simple (e.g., multiplicative or linear additive) statistical model. Experimentally characterized genetic interaction networks in model organisms provide important insights into relationships between different biological functions. We describe a computational methodology allowing to systematically and quantitatively characterize a Boolean mathematical model of a biological network in terms of genetic interactions between all loss of function and gain of function mutations with respect to all model phenotypes or outputs. We use the probabilistic framework defined in MaBoSS software, based on continuous time Markov chains and stochastic simulations. In addition, we suggest several computational tools for studying the distribution of double mutants in the space of model phenotype probabilities. We demonstrate this methodology on three published models for each of which we derive the genetic interaction networks and analyze their properties. We classify the obtained interactions according to their class of epistasis, dependence on the chosen initial conditions and phenotype. The use of this methodology for validating mathematical models from experimental data and designing new experiments is discussed.
9 downloads biochemistry
The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs ER stress-dependent secretion of destabilized TTR by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition promotes the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.
9 downloads genomics
Luyang Zhao, Liwei Deng, Gailing Li, Huan Jin, Jinsen Cai, Huan Shang, Yan Li, Haomin Wu, Weibin Xu, Lidong Zeng, Renli Zhang, Huan Zhao, Ping Wu, Zhiliang Zhou, Jiao Zheng, Pierre Ezanno, Qin Yan, Michael Deem, Jiankui He
Third generation sequencing is a direct measurement of DNA/RNA sequences at the single molecule level without amplification. In this study, we report sequencing of the genome of the M13 virus by a new single molecule sequencing platform. Our platform detects single molecule fluorescence by the total internal reflection microscope technique, with sequencing-by-synthesis chemistry. We sequenced the genome of M13 to a depth of 316x and 100% coverage. The consensus sequence accuracy is 100%. We demonstrated that single molecule sequencing has no significant GC bias.
9 downloads neuroscience
Background: Friedreich ataxia is a recessively inherited, progressive neurological disease characterised by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of pathology in these structures. Methods: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n=20) and healthy controls (n=18) over a two-year period. Results: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Moreover, atrophy was maximal in individuals early in the disease course, while the rate of iron concentration increased with disease progression. Conclusions: Progressive dentate nuclei pathology is evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a two-year period highlights the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.
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 evolutionary biology
Evolutionary dynamics is fundamentally shaped by stochastic processes: spontaneous mutations enter populations randomly, and the fate of a mutant lineage is determined by the competition between (random) genetic drift and (deterministic) selection. In populations undergoing range expansions, fluctuations in the reproductive process and the local motion of individuals are enhanced within a small subpopulation at the edge of the population. Range expansions are typically studied in homogeneous environments, but we argue here that the fluctuations at the range edge are susceptible to small-scale environmental heterogeneities that may have a strong effect on the evolutionary dynamics of the expanding population. To show this, we tracked the dynamics of the clones of spontaneous mutations with a tunable fitness effect in bacterial colonies grown on randomly disordered surfaces. We find that environmental heterogeneity on scales much larger than an individual, but much smaller than the total population, can dramatically reduce the efficacy of selection. Time lapse microscopy and computer simulations suggest that this effect is a general consequence of a local "pinning" of the expansion front, whereby stretches of the front are slowed down on a length scale that depends on the structure of the environmental heterogeneity. This pinning focuses the range expansion into a small number of individuals with access to expansion paths, increasing the importance of chance and thus limiting the efficacy of selection.
9 downloads bioinformatics
Approximately half of proteins with experimentally determined structures can interact with other copies of themselves and assemble into homomeric complexes, the overwhelming majority of which (>96%) are symmetric. Although homomerisation is often assumed to be functionally beneficial and the result of evolutionary selection, there has been little systematic analysis of the relationship between homomer structure and function. Here, utilizing the large numbers of structures and functional annotations now available, we have investigated how proteins that assemble into different types of homomers are associated with different biological functions. We observe that homomers from different symmetry groups are significantly enriched in distinct functions, and can often provide simple physical and geometrical explanations for these associations in regards to substrate recognition or physical environment. One of the strongest associations is the tendency for metabolic enzymes to form dihedral complexes, which we suggest is closely related to allosteric regulation. We provide a physical explanation for why allostery is related to dihedral complexes: it allows for efficient propagation of conformational changes across isologous (i.e. symmetric) interfaces. Overall we demonstrate a clear relationship between protein function and homomer symmetry that has important implications for understanding protein evolution, as well as for predicting protein function and quaternary structure.
9 downloads bioinformatics
Motivation: In resequencing experiments, a high-throughput sequencer produces DNA-fragments (called reads) and each read is then mapped to the locus in a reference genome at which it fits best. Currently dominant read mappers (Li and Durbin, 2009; Langmead and Salzberg, 2012) are based on the Burrows-Wheeler transform (BWT). A read can be mapped correctly if it is similar enough to a substring of the reference genome. However, since the reference genome does not represent all known variations, read mapping tends to be biased towards the reference and mapping errors may thus occur. To cope with this problem, Huang et al. (2013) encoded SNPs in a BWT by the IUPAC nucleotide code (Cornish-Bowden, 1985). In a different approach, Maciuca et al. (2016) provided a 'natural encoding' of SNPs and other genetic variations in a BWT. However, their encoding resulted in a significantly increased alphabet size (the modified alphabet can have millions of new symbols, which usually implies a loss of efficiency). Moreover, the two approaches do not handle all known kinds of variation. Results: In this article, we propose a method that is able to encode many kinds of genetic variation (SNPs, MNPs, indels, duplications, transpositions, inversions, and copy-number variation) in a BWT. It takes the best of both worlds: SNPs are encoded by the IUPAC nucleotide code as in (Huang et al., 2013) and the encoding of the other kinds of genetic variation relies on the idea introduced in (Maciuca et al., 2016). In contrast to Maciuca et al. (2016), however, we use only one additional symbol. This symbol marks variant sites in a chromosome and delimits multiple variants, which are added at the end of the 'marked chromosome'. We show how the backward search algorithm, which is used in BWT-based read mappers, can be modified in such a way that it can cope with the genetic variation encoded in the BWT. We implemented our method and compared it to BWBBLE (Huang et al., 2013) and gramtools (Maciuca et al., 2016).
9 downloads bioinformatics
The phylogeny-aware alignment algorithm implemented in both PRANK and PAGAN has been found to produce highly accurate alignments for comparative sequence analysis. However, the algorithm's reliance on a guide tree during the alignment process can bias the resulting alignment rendering it unsuitable for phylogenetic inference. To overcome these issues, we have developed a new tool, Canopy, for parallelized iterative search of optimal alignment. Using Canopy, we studied the impact of the guide tree as well as the number and relative divergence of sequences on the accuracy of the alignment and inferred phylogeny. We find that PAGAN is the more robust of the two phylogeny-aware alignment methods to errors in the guide tree, but Canopy largely resolves the guide tree-related biases in PRANK. We demonstrate that, for all experimental settings tested, Canopy produces the most accurate sequence alignments and, further, that the inferred phylogenetic trees are of comparable accuracy to those obtained with the leading alternative method, SATé. Our analyses also show that, unlike traditional alignment algorithms, the phylogeny-aware algorithm effectively uses the information from denser sequence sampling and produces more accurate alignments when additional closely-related sequences are included. All methods are available for download at http://wasabiapp.org/software.
9 downloads bioinformatics
Background: DNA methylation patterns store epigenetic information in the vast majority of eukaryotic species. The relatively high costs and technical challenges associated with the detection of DNA methylation however have created a bias in the number of methylation studies towards model organisms. Consequently, it remains challenging to infer kingdom-wide general rules about the functions and evolutionary conservation of DNA methylation. Methylated cytosine is often found in specific CpN dinucleotides, and the frequency distributions of, for instance, CpG observed/expected (CpG o/e) ratios have been used to infer DNA methylation types based on higher mutability of methylated CpG. Results: Predominantly model-based approaches essentially founded on mixtures of Gaussian distributions are currently used to investigate questions related to the number and position of modes of CpG o/e ratios. These approaches require the selection of an appropriate criterion for determining the best model and will fail if empirical distributions are complex or even merely moderately skewed. We use a kernel density estimation (KDE) based technique for robust and precise characterization of complex CpN o/e distributions without a priori assumptions about the underlying distributions. Conclusions: We show that KDE delivers robust descriptions of CpN o/e distributions. For straightforward processing, we have developed a Galaxy tool, called Notos and available at the ToolShed, that calculates these ratios of input FASTA files and fits a density to their empirical distribution. Based on the estimated density the number and shape of modes of the distribution is determined, providing a rational for the prediction of the number and the types of different methylation classes. Notos is written in R and Perl.
9 downloads cell biology
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) activate G protein-coupled receptors (GPCRs) to regulate key pathobiological processes. Here we report a novel lipid mediator GPCR cross-talk mechanism that modulates lymphatic endothelial junctional architecture in lymph nodes. LPAR1 was identified as an inducer of S1PR1/ β-arrestin coupling from a genome-wide CRISPR/ Cas9 transcriptional activation screen. LPAR1 activation induced S1PR1 β-arrestin recruitment while suppressing Gαi protein signaling. Lymphatic endothelial cells from cortical and medullary sinuses of lymph nodes which express LPAR1 and S1PR1, exhibit porous junctional architecture and constitutive S1PR1 coupling to β-arrestin which was suppressed by the LPAR1 antagonist AM095. In endothelial cells, LPAR1-activation increased trans-endothelial permeability and junctional remodeling from zipper-like structures to puncta of adhesion plaques that terminate at actin-rich stress fibers with abundant intercellular gaps. Cross-talk between LPA and S1P receptors regulates complex junctional architecture of lymphatic sinus endothelial cells, a site of high lymphocyte traffic and lymph flow.
9 downloads genetics
Boswellia serrata, an economically important indigenous tree of dry deciduous forests, provides oleoresin gum of pharmaceutical significance and excellent pulp for paper industries, but faces threat to extinction due to poor natural regeneration and commercial exploitation. 240 individuals of the species representing 12 locations of its natural distribution in central India were investigated to compare the genetic differentiation indices, QST for GBH and wood fiber length and ϕST for neutral (RAPD+ISSR) markers. The comparison for paired locations was more informative than for metapopulation. The most paired locations were either under the stabilizing selection (QST (L) < ɸST (L)) or in the genetic drift (QST(L) = ɸST (L)) whereas a relatively small number of paired locations was under the divergent selection (QS T(L) > ɸST (L)). The comparison for the metapopulation generating only a single trend of QST (P) > ɸST (P) is, therefore, misleading. For conservation, the genetically deficit locations (QST (L) < ɸST (L) and QST (L) = ɸST (L)) of B. serrata warrant for reinforcement of their genetic diversity by introduction of genotypes from other genetically divergent locations (QST (L) > ɸST (L)), which would check the fragmentation and genetic drift, resulting in reproductive vigour, natural regeneration and reverse the endangered status of the species.
9 downloads biophysics
Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally-mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Structures belonging to the TRPV, TRPM, TRPP, TRPA and TRPML subfamilies have been solved, but to date, none of the founding canonical (TRPC) structures. Here we report an electron cryo-microscopy (cryo-EM) structure of TRPC4 in its apo state to an overall resolution of 3.3 Angstrom. The structure reveals an unusually complex architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique cytosolic domain, this unique cytosolic N-terminal domain forms extensive aromatic contacts with the TRP and the C-terminal domains. The comparison of our structure with other known TRP structures provides molecular insights into TRPC4 ion selectivity and extends our knowledge of the diversity and evolution of the TRP channels.
9 downloads biochemistry
Translational repression of maternal mRNAs is an essential regulatory mechanism during early embryonic development. Repression of the Drosophila nanos mRNA, required for the formation of the anterior-posterior body axis, depends on the protein Smaug binding to two Smaug recognition elements (SREs) in the nanos 3′ UTR. In a comprehensive mass spectrometric analysis of the SRE-dependent repressor complex, we identified Smaug, Cup, Me31B, Trailer hitch, eIF4E and PABPC, in agreement with earlier data. As a novel component, the RNA-dependent ATPase Belle (DDX3) was found, and its involvement in deadenylation and repression of nanos was confirmed in vivo. Smaug, Cup and Belle bound stoichiometrically to the SREs, independently of RNA length. Binding of Me31B and Tral was also SRE-dependent, but their amounts were proportional to the length of the RNA and equimolar to each other. We suggest that ‘coating’ of the RNA by a Me31B·Tral complex may be at the core of repression.
9 downloads bioinformatics
A major challenge of data-driven biomedical research lies in the collection and representation of data provenance information to ensure reproducibility of findings. In order to communicate and reproduce multi-step analysis workflows executed on datasets that contain data for dozens or hundreds of samples, it is crucial to be able to visualize the provenance graph at different levels of aggregation. Most existing approaches are based on node-link diagrams, which do not scale to the complexity of typical data provenance graphs. In our proposed approach we reduce the complexity of the graph using hierarchical and motif-based aggregation. Based on user action and graph attributes a modular degree-of-interest (DoI) function is applied to expand parts of the graph that are relevant to the user. This interest-driven adaptive provenance visualization approach allows users to review and communicate complex multi-step analyses, which can be based on hundreds of files that are processed by numerous workflows. We integrate our approach into an analysis platform that captures extensive data provenance information and demonstrate its effectiveness by means of a biomedical usage scenario.
9 downloads biophysics
The function of the kidney podocyte depends on its distinctive morphology. Each podocyte has finger-like projections, called foot processes, that interdigitate with the processes of neighboring cells to form the glomerular filtration barrier. The integrity of foot process interactions depends on tight spatial control of the dynamics of the underlying actin cytoskeleton, which is regulated by the GTPases, Rac1 and RhoA. To understand how spatially-specific regulation of actin filament dynamics within foot processes controls local morphology, we used a combination of 3-D microscopy and dynamical models. We experimentally determined cell-cell interactions using serial blockface scanning electron microscopy and reconstructed a 3-D spatial representation of a podocyte. We developed a minimal dynamical system for regulation of the actin cytoskeleton; using this 3-D model, we determined how spatial reaction-diffusion dynamics can dysregulate actin bundling, leading to propagation of chaotic foot process effacement. Consistent with experimental observations, our simulations predicted that hyperactive RhoA could destabilize the cytoskeleton. Our simulations showed that deleterious mechanochemical stimuli could lead to local heterogeneity of cytoskeletal dynamics resulting in the emergence of progressive and chaotic loss of foot processes. While global enhancement of Rac1 may result in stronger bundles, the spatial simulations showed that even transient local heterogeneities in polymerization could have dramatic consequences in the stability of multiple foot processes. We conclude that the podocyte morphology optimized for filtration contains intrinsic fragility whereby local imbalances in biochemical and biophysical reactions lead to morphological changes associated with glomerular pathophysiology.
9 downloads neuroscience
Ever since the discovery of acetylcholine in 1913, its role as neuromodulator has been extensively studied in a variety of model systems. These previous studies revealed that acetylcholine is of critical importance for several cognitive functions including attention, learning and memory. In spite of these previous findings, it has proven difficult to determine the amount of acetylcholine that is released during cognitive tasks with sub-second temporal resolution. One method that might be used to measure acetylcholine release is the use of an enzyme-coupled amperometric sensor, which has been suggested to measure acetylcholine with high sensitivity, selectivity and relatively high temporal resolution (< 1 second). In the present study, we have tried to adapt the technique developed in the rodent model system by Parikh and colleagues(1,2) for use in non-human primates. We aimed to measure in-vivo levels of acetylcholine in the macaque dorsolateral prefrontal cortex while the monkey performed an attention demanding curve-tracing task(3,4). We report that our attempts to measure acetylcholine using amperometry in an awake behaving macaque monkey proved difficult and tedious and that our results are inconsistent and prone to noise. In the discussion, we will outline the challenges that will need to be addressed to use this technique in non-human primates and hope that our observations inspire solutions to help future research on the role of this important neurotransmitter.
9 downloads neuroscience
Neuronal signals are usually characterized in terms of their discharge rate. However, this description is inadequate to account for the complex temporal organization of spike trains. In particular multifractality is a hallmark of the neuronal activity of the human, parkinsonian basal ganglia, which is not accounted for in most models. Here I develop a new conceptualization of neuronal activity, enabling the analysis of spike trains in terms of a velocity field. Firstly, I show that structure functions of increasing order can be used to recover the multifractal spectrum of spike trains obtained from the globus pallidus interna (GPi) of patients with Parkinson's disease. Further, I propose a neural field model to study the observed multifractality. The model describes the motion of spikes in terms of a velocity field, including a diffusive term to consider the physical properties of the electric field that is associated to neuronal activity. As the model is perturbed with colored noise, the following is observed: 1. multifractality is present for a wide range of diffusion coefficients; and 2. multifractal temporal properties are mirrored into space. These results predict that passive electric properties of neuronal activity are far more relevant to the human brain than what has been usually considered.
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