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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,294 bioRxiv papers from 263,837 authors.

Most downloaded bioRxiv papers, since beginning of last month

55,724 results found. For more information, click each entry to expand.

55301: Hox genes mediate the escalation of sexually antagonistic traits in water striders
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Posted to bioRxiv 03 Oct 2018

Hox genes mediate the escalation of sexually antagonistic traits in water striders
5 downloads evolutionary biology

Antonin Jean Johan Crumiere, Abderrahman Khila

Sexual conflict occurs when traits favoured in one sex impose fitness costs on the other sex. In the case of sexual conflict over mating rate, the sexes often undergo antagonistic coevolution and escalation of traits that enhance female's resistance to mating and traits that increase male's persistence. How this escalation in sexually antagonistic traits is established during ontogeny remains unclear. In the water strider Rhagovelia antilleana, male persistence traits consist of sex combs in the forelegs and multiple rows of spines and a thick femur in the rearlegs. Female resistance trait consists of a prominent spike-like projection of the pronotum. RNAi knockdown against the Hox gene Sex Combs Reduced resulted in the reduction of both the sex comb in males and the pronotum projection in females. RNAi against the Hox gene Ultrabithorax resulted in the complete loss or reduction of all persistence traits in male rearlegs. These results demonstrate that Hox genes can mediate sex-specific escalation of antagonistic traits along the body axis of both sexes.

55302: Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2
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Posted to bioRxiv 12 Dec 2018

Manganese influx and expression of ZIP8 is essential in primary myoblasts and contributes to activation of SOD2
5 downloads cell biology

Shellaina J. V. Gordon, Daniel E. Fenker, Katherine E. Vest, TERESITA PADILLA-BENAVIDES

Trace elements such as copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn) are enzyme cofactors and second messengers in cell signaling. Trace elements are emerging as key regulators of differentiation and development of mammalian tissues including blood, brain, and skeletal muscle. We previously reported an influx of Cu and dynamic expression of various metal transporters during differentiation of skeletal muscle cells. Here, we demonstrate that during differentiation of skeletal myoblasts an increase of additional trace elements such as Mn, Fe and Zn occurs. Interestingly the Mn increase is concomitant with increased Mn-dependent SOD2 levels. To better understand the Mn import pathway in skeletal muscle cells, we probed the functional relevance of the closely related proteins ZIP8 and ZIP14, which are implicated in Zn, Mn, and Fe transport. Partial depletion of ZIP8 severely impaired growth of myoblasts and led to cell death under differentiation conditions, indicating that ZIP8-mediated metal transport is essential in skeletal muscle cells. Moreover, knockdown of Zip8 impaired activity of the Mn-dependent SOD2. Growth defects were partially rescued by Mn supplementation to the medium, suggesting additional functions for ZIP8 in the skeletal muscle lineage. Knockdown of Zip14, on the other hand, had only a mild effect on myotube size, consistent with a role for ZIP14 in muscle hypertrophy. This is the first report on the functional relevance of two members of the ZIP family of metal transporters in the skeletal muscle lineage, and further supports the paradigm that trace metal transporters are critical modulators of mammalian tissue development.

55303: Spatial distribution and seasonal fluctuations of Drosophila on Santa Catalina Island with an emphasis on the repleta species group
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Posted to bioRxiv 07 Aug 2014

Spatial distribution and seasonal fluctuations of Drosophila on Santa Catalina Island with an emphasis on the repleta species group
5 downloads ecology

Joyce Y Kao, Sergey V Nuzhdin

Santa Catalina Island is a small island off the coast of southern California and for its modest size harbors several species of flies from the Drosophila genus. We performed an island-wide survey of Drosophila species to ascertain which species were endemic to the island and where they were most abundant. In doing so, we have assembled useful sampling information for researchers who wish to conduct field studies on Santa Catalina Island. From this survey, we determined that Drosophila hamatofila, Drosophila mainlandi, and Drosophila mettleri were the prominent repleta species on the island. Other repleta species encountered included Drosophila mojavensis and Drosophila wheeleri. Non-repleta species sighted on the island include Drosophila melanogaster, Drosophila pseudoobscura, Drosophila simulans, and an unknown species not seen before on the island. Additionally, we performed seasonal collections at two locations on the island and observed that species abundance and composition at these two sites vary between seasons. One of the seasonal sites was sampled in two consecutive summer seasons, which revealed that species composition had shifted between years, but relative abundances were approximately the same.

55304: The Abnormal Oswald Ripening of Protein Nanofiber in Myofibrillar Protein Solution
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Posted to bioRxiv 28 Feb 2019

The Abnormal Oswald Ripening of Protein Nanofiber in Myofibrillar Protein Solution
5 downloads biophysics

Fuge Niu, Rui Zhang, Jiamei Fan, Weichun Pan

In solutions of myofibrillar protein extracted from giant squid (Dosidicus gigas), the size-coarsening process of protein nanofiber is complex. At high temperature (25°C), nanofiber keeps growth but with two distinguishable patterns, slow rate at the initial stage with t0.2 and the fast one at the late stage with t2.3. The intersection of these two slopes is around 300 min. Meanwhile, protein concentration in solution enhances as well. These behaviors contradict to the prediction of Ostwald ripening. Thus, we call this process as abnormal. These abnormal behaviors come from the conformation change of some types of constitution protein molecules with chemical potential reduction when they dissolve from nanofiber to solution. On the other hand, low temperature (10°C) depresses this size growth. This observation suggests that temperature regulates protein molecule conformation change in nanofiber. The consequence of this abnormal Ostwald ripening process is that all protein molecules in nanofiber are redistributed. Protein molecules with the absence of conformation change in dissolution accumulate in nanofiber to cause it growing, while the rest concentrates in solution.

55305: The effect of pre-analytical conditions on blood metabolomics in epidemiological studies
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Posted to bioRxiv 08 Jan 2019

The effect of pre-analytical conditions on blood metabolomics in epidemiological studies
5 downloads epidemiology

Diana L Santos Ferreira, Hannah J Maple, Matt Goodwin, Judith S Brand, Vikki Yip, Josine L. Min, Alix Groom, Debbie A Lawlor, Susan Ring

Background: Serum and plasma are commonly used biofluids for large-scale metabolomic-epidemiology studies. Their metabolomic profile is susceptible to changes due to variability in pre-analytical conditions and the impact of this is unclear. Methods: Participant-matched EDTA-plasma and serum samples were collected from 37 non-fasting volunteers and profiled using a targeted nuclear magnetic resonance (NMR) metabolomics platform (N=151 traits). Metabolic concentrations were compared between reference (pre-storage: 4C, 1.5h; post-storage: no sample preparation or NMR-analysis delays) and four, pre-storage, blood processing conditions, where samples were incubated at (i) 4C, 24h; (ii) 4C, 48h; (iii) 21C, 24h; (iv) 21C, 48h, before centrifugation; and two, post-storage, sample processing conditions in which samples (i) thawed overnight, then left for 24h before addition of sodium buffer followed by immediate NMR analysis; (ii) thawed overnight, addition of sodium buffer, then left for 24h before profiling. Linear regression models with random-intercepts were used to assess the impact of these six pre-analytical conditions on EDTA-plasma/serum metabolome. Results: Fatty acids, beta-hydroxybutyrate, glycoprotein-acetyls and most lipid-related traits, in serum and plasma, were robust to the tested pre and post-storage conditions. Pre-storage conditions impacted concentrations of glycolysis metabolites, acetate, albumin and amino-acids by levels that could potentially bias research results (up to 1.4SD difference compared with reference). Post-storage conditions affected histidine, phenylalanine and LDL-particle-size, with differences up to 1.4SD. Conclusions: Most metabolic traits are robust to the pre- and post-storage conditions tested here and that may commonly occur in large-scale cohorts. However, concentrations of glycolysis metabolites, and amino-acids may be compromised.

55306: Nanopore sequencing enables near-complete de novo assembly of Saccharomyces cerevisiae reference strain CEN.PK113-7D
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Posted to bioRxiv 14 Aug 2017

Nanopore sequencing enables near-complete de novo assembly of Saccharomyces cerevisiae reference strain CEN.PK113-7D
5 downloads genomics

Alex N. Salazar, Arthur R Gorter de Vries, Marcel van den Broek, Melanie Wijsman, Pilar de la Torre Cortes, Anja Brickwedde, Nick Brouwers, Jean-Marc G Daran, Thomas Abeel

The haploid Saccharomyces cerevisiae strain CEN.PK113-7D is a popular model system for metabolic engineering and systems biology research. Current genome assemblies are based on short-read sequencing data scaffolded based on homology to strain S288C. However, these assemblies contain large sequence gaps, particularly in subtelomeric regions, and the assumption of perfect homology to S288C for scaffolding introduces bias. In this study, we obtained a near-complete genome assembly of CEN.PK113-7D using only Oxford Nanopore Technology's MinION sequencing platform. 15 of the 16 chromosomes, the mitochondrial genome, and the 2-micron plasmid are assembled in single contigs and all but one chromosome starts or ends in a telomere cap. This improved genome assembly contains 770 Kbp of added sequence containing 248 gene annotations in comparison to the previous assembly of CEN.PK113-7D. Many of these genes encode functions determining fitness in specific growth conditions and are therefore highly relevant for various industrial applications. Furthermore, we discovered a translocation between chromosomes III and VIII which caused misidentification of a MAL locus in the previous CEN.PK113-7D assembly. This study demonstrates the power of long-read sequencing by providing a high-quality reference assembly and annotation of CEN.PK113-7D and places a caveat on assumed genome stability of microorganisms.

55307: Comparison of Analytical Techniques for Thermal Stability Analysis of β-Cyclodextrin for an Ebola Virus Infection Treatment
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Posted to bioRxiv 22 Oct 2018

Comparison of Analytical Techniques for Thermal Stability Analysis of β-Cyclodextrin for an Ebola Virus Infection Treatment
5 downloads pharmacology and toxicology

Mayte Murillo, Braden Adams

Each New Drug Application filed with the Food and Drug Administration (FDA) must include the analytical procedures to ensure the identity, strength, quality, purity, and potency of a drug substance and drug product. The BSN389 drug product (being developed to treat Ebola virus infections) includes beta cyclodextrin. Evidence must be provided that the analytical procedures used in testing BSN389 meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose. The Bootstrap Error-adjusted Single-Sample Technique (BEST) software was used to compare the quantitative and qualitative power of IR and 1H NMR to differentiate new and partially decomposed samples of beta cyclodextrin, and the best assay will be incorporated into the thermal stability protocol for BCD.

55308: Lmx1b influences correct post-mitotic coding of mesodiencephalic dopaminergic neurons
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Posted to bioRxiv 12 Oct 2018

Lmx1b influences correct post-mitotic coding of mesodiencephalic dopaminergic neurons
5 downloads developmental biology

Iris Wever, Pablo Largo Barrientos, Elisa J. Hoekstra, Marten P Smidt

The Lim Homeobox transcription factor 1 beta (LMX1b) has been identified as one of the transcription factors important for the development of mesodiencephalic dopaminergic (mdDA) neurons. During early development, Lmx1b is essential for induction and maintenance of the Isthmic Organizer (IsO), and genetic ablation results in the disruption of inductive activity from the IsO and loss of properly differentiated mdDA neurons. To study the downstream targets of Lmx1b without affecting the IsO, we generated a conditional model in which Lmx1b was selectively deleted in Pitx3 expressing cells from embryonic day (E)13 onward. Supporting previous data, no significant changes could be observed in general dopamine (DA) marks, like Th, Pitx3 and Vmat2 at E14.5. However, in depth analysis by means of RNA-sequencing revealed that Lmx1b is important for the expression level of survival factors En1 and En2 and for the repression of mdDA subset mark Ahd2 during (late) development. Interestingly, the regulation of Ahd2 by Lmx1b was found to be Pitx3 independent, since Pitx3 levels were not altered in Lmx1b conditional knock-outs (cKO) and Ahd2 expression was also up-regulated in Lmx1b/Pitx3 double mutants compared to Pitx3 mutants. Further analysis of Lmx1b cKOs showed that post-mitotic deletion of Lmx1b additional leads to a loss of TH+ cells at 3 months age both in the VTA and SNc. Remarkably, different cell types were affected in the SNc and the VTA. While TH+AHD2+ cells were lost the SNc, TH+AHD2- neurons were affected in the VTA, reflected by a loss of Cck expression, indicating that Lmx1b is important for the survival of a sub-group of mdDA neurons.

55309: Behavioral diversity assisting obstacle navigation during group transportation in ant
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Posted to bioRxiv 28 Sep 2017

Behavioral diversity assisting obstacle navigation during group transportation in ant
5 downloads animal behavior and cognition

Shohei Utsunomiya, Atsuko Takamatsu

Cooperative transportation behavior in ants has attracted attention from a wide range of researchers, from behavioral biologists to roboticists. Ants can accomplish complex tasks as a group whereas individual ants are not intelligent (in the context of this study's tasks). In this study, group transportation and obstacle navigation in Formica japonica, an ant species exhibiting 'uncoordinated transportation' (primitive group transportation), are observed using two differently conditioned colonies. Analyses focus on the effect of group size on two key quantities: transportation speed and obstacle navigation period. Additionally, this study examines how these relationships differ between colonies. The tendencies in transportation speed differ between colonies whereas the obstacle navigation period is consistently reduced irrespective of the colony. To explain this seemingly inconsistent result in transportation speed, we focus on behavioral diversity in 'directivity', defined as the tendency of individual ants to transport a food item toward their own preferential direction. Directivity is not always toward the nest, but rather is distributed around it. The diversity of the first colony is less than that of the second colony. Based on the above results, a mechanical model is constructed. Using the translational and rotational motion equations of a rigid rod, the model mimics a food item being pulled by single or multiple ants. The directions of pulling forces exerted by individual ants are assumed to be distributed around the direction pointing toward the nest. The simulation results suggest that, as diversity in directivity increases, so does the success rate in more complicated obstacle navigation. In contrast, depending on group size, the speed of group transportation increases in the case of lower diversity while it is almost constant in the case of higher diversity. Transportation speed and obstacle navigation success rate are in a trade-off relationship.

55310: Using approximate Bayesian computation to quantify cell-cell adhesion parameters in a cell migratory process
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Posted to bioRxiv 10 Aug 2016

Using approximate Bayesian computation to quantify cell-cell adhesion parameters in a cell migratory process
5 downloads systems biology

Robert J. H. Ross, R. E. Baker, Andrew Parker, M. J. Ford, R. L. Mort, C. A. Yates

In this work we implement approximate Bayesian computational methods to improve the design of a wound-healing assay used to quantify cell-cell interactions. This is important as cell-cell interactions, such as adhesion and repulsion, have been shown to play an important role in cell migration. Initially, we demonstrate with a model of an ideal experiment that we are able to identify model parameters for agent motility and adhesion, given we choose appropriate summary statistics. Following this, we replace our model of an ideal experiment with a model representative of a practically realisable experiment. We demonstrate that, given the current (and commonly used) experimental set-up, model parameters cannot be accurately identified using approximate Bayesian computation methods. We compare new experimental designs through simulation, and show more accurate identification of model parameters is possible by expanding the size of the domain upon which the experiment is performed, as opposed to increasing the number of experimental repeats. The results presented in this work therefore describe time and cost-saving alterations for a commonly performed experiment for identifying cell motility parameters. Moreover, the results presented in this work will be of interest to those concerned with performing experiments that allow for the accurate identification of parameters governing cell migratory processes, especially cell migratory processes in which cell-cell adhesion or repulsion are known to play a significant role.

55311: Metaproteomics reveals biomarkers of system collapse in a dynamic aquatic ecosystem
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Posted to bioRxiv 19 Feb 2016

Metaproteomics reveals biomarkers of system collapse in a dynamic aquatic ecosystem
5 downloads ecology

Amanda C. Northrop, Rachel Brooks, Aaron M. Ellison, Nicholas J Gotelli, Bryan A. Ballif

Forecasting and preventing rapid ecosystem state changes is important but hard to achieve without functionally relevant early warning indicators. Here we use metaproteomic analysis to identify protein biomarkers indicating a state change in an aquatic ecosystem resulting from detrital enrichment. In a 14-day field experiment, we used detritus (arthropod prey) to enrich replicate aquatic ecosystems formed in the water-filled pitcher-shaped leaves of the northern pitcher plant, Sarracenia purpurea. Shotgun metaproteomics using a translated, custom metagenomic database identified proteins, molecular pathways, and microbial taxa that differentiated control oligotrophic ecosystems that captured only ambient prey from eutrophic ecosystems that were experimentally enriched. The number of microbial taxa was comparable between treatments; however, taxonomic evenness was higher in the oligotrophic controls. Aerobic and facultatively anaerobic bacteria dominated control and enriched ecosystems, respectively. The molecular pathways and taxa identified in the enriched treatments were similar to those found in a wide range of enriched or polluted aquatic ecosystems and are derived from microbial processes that occur at the base of most detrital food webs. We encourage the use of metaproteomic pipelines to identify better early-warning indicators of impending changes from oligotrophic to eutrophic states in aquatic and other detrital-based ecosystems.

55312: The impacts of historical barriers on floristic patterns of plant groups with different dispersal abilities in the Ryukyu Archipelago, Japan
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Posted to bioRxiv 01 Aug 2014

The impacts of historical barriers on floristic patterns of plant groups with different dispersal abilities in the Ryukyu Archipelago, Japan
5 downloads ecology

Koh Nakamura, Rempei Suwa, Tetsuo Denda, Masatsugu Yokota

The effects of historical barriers in biogeographical patterns are expected to persist differently depending on dispersal abilities of organisms. We tested two hypotheses that plant groups with different dispersal abilities display different floristic patterns, and that historical barriers can explain floristic differentiation patterns in plants with low dispersal ability but not in plants with higher dispersal ability, in the seed plant flora of the Ryukyu Archipelago. This area is biogeographically interesting because several similar floristic differentiation patterns have been proposed, all of which are primarily explained by two historical barriers, the Tokara Tectonic Strait (Tokara Gap) and the Kerama Gap, which arose during the formation of the islands. We calculated floristic dissimilarity distance among 26 islands based on data sets for three dispersal-ability classes. Clustering analyses based on the floristic dissimilarity distance generated similar floristic patterns regardless of dispersal-ability class. We propose that because the landscape resistance is so strong that migration of plants is severely restricted regardless of their dispersal abilities, the similar floristic differentiation patterns are generated. Multivariate regression analyses using Mantel's randomization test indicated that floristic differentiations among islands were explained by the both effects of the historical barriers and geographic distance in all dispersal-ability classes. Significance of the historical barriers is not determined by the plant dispersal abilities but presumably by the spatial distribution of the islands, stochastic dispersals, and time since the formation of the barriers.

55313: HySA: A Hybrid Structural variant Assembly approach using next generation and single-molecule sequencing technologies
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Posted to bioRxiv 16 Aug 2016

HySA: A Hybrid Structural variant Assembly approach using next generation and single-molecule sequencing technologies
5 downloads bioinformatics

Xian Fan, Mark Chaisson, Luay Nakhleh, Ken Chen

Achieving complete, accurate and cost-effective assembly of human genome is of great importance for realizing the promises of precision medicine. The abundance of repeats and genetic variations in human genome and the limitations of existing sequencing technologies call for the development of novel assembly methods that could leverage the complementary strengths of multiple technologies. We propose a Hybrid Structural variant Assembly (HySA) approach that integrates sequencing reads from next generation sequencing (NGS) and single-molecule sequencing (SMS) technologies to accurately assemble and detect structural variations (SV) in human genome. By identifying homologous SV-containing reads from different technologies through a bipartite-graph-based clustering algorithm, our approach turns a whole genome assembly problem into a set of independent SV assembly problems, each of which can be effectively solved to enhance assembly of structurally altered regions in human genome. In testing our approach using data generated from a haploid hydatidiform mole genome (CHM1) and a diploid human genome (NA12878), we found that our approach substantially improved the detection of many types of SVs, particularly novel large insertions, small INDELs (10-50bp) and short tandem repeat expansions and contractions over existing approaches with a low false discovery rate. Our work highlights the strengths and limitations of current approaches and provides an effective solution for extending the power of existing sequencing technologies for SV discovery.

55314: Mendelian randomization does not support serum calcium in prostate cancer risk
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Posted to bioRxiv 09 Apr 2018

Mendelian randomization does not support serum calcium in prostate cancer risk
5 downloads epidemiology

James Yarmolinsky, Katie Berryman, Ryan Langdon, Carolina Bonilla, the PRACTICAL consortium, George Davey Smith, Richard M Martin, Sarah J Lewis

Background: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. Objective: We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer. Design: A genetic instrument was constructed using 5 single nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (N ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls). Results: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI: 0.63-1.08; P=0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI: 0.57-1.70; P=0.93). Conclusions: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.

55315: The evolution of cooperation under local regulation and non-additive gene action: building on Hamilton's ideas
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Posted to bioRxiv 06 Aug 2014

The evolution of cooperation under local regulation and non-additive gene action: building on Hamilton's ideas
5 downloads evolutionary biology

Roberto H. Schonmann, Robert Boyd, Renato Vicente

We study evolution of cooperation in a population structured in a large number of groups of variable size, connected by random migration at rate $m$. Social interactions, including cooperation and competition occur only inside the groups. Assuming that groups are large, we define a parameter $\lambda$ that measures the strength of the local regulation, i.e., the rigidity of group sizes. Individuals are of two possible genotypes, one typically assumed to produce a non-cooperative phenotype and the other a phenotype that is cooperative with all members of its own group. Gene action may be additive, producing fitness functions that are linear in the number of cooperators in a group, or not. Assuming weak selection, we obtain the following two contrasting conclusions. (1) ``Hamilton regime'': If $\lambda << m$, then cooperative behavior can spread under a certain condition, which in the additive, i.e., linear, case is precisely Hamilton's rule. The general version of this condition is also relatively easy to apply and is based on Wright's classical beta distribution for the frequency of alleles in infinite island models. We call it the ``beta version of Hamilton's rule''. (2) ``Taylor regime'': If $m << \lambda$, then cooperation that is costly to the actor is eliminated by selection.

55316: Read-Based Phasing of Related Individuals
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Posted to bioRxiv 18 Jan 2016

Read-Based Phasing of Related Individuals
5 downloads bioinformatics

Shilpa Garg, Marcel Martin, Tobias Marschall

Motivation: Read-based phasing deduces the haplotypes of an individual from sequencing reads that cover multiple variants, while genetic phasing takes only genotypes as input and applies the rules of Mendelian inheritance to infer haplotypes within a pedigree of individuals. Combining both into an approach that uses these two independent sources of information -- reads and pedigree -- has the potential to deliver results better than each individually. Results: We provide a theoretical framework combining read-based phasing with genetic haplotyping, and describe a fixed-parameter algorithm and its implementation for finding an optimal solution. We show that leveraging reads of related individuals jointly in this way yields more phased variants and at a higher accuracy than when phased separately, both in simulated and real data. Coverages as low as 2x for each member of a trio yield haplotypes that are as accurate as when analyzed separately at 15x coverage per individual.

55317: Dynamic changes in clonal architecture during disease progression in follicular lymphoma
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Posted to bioRxiv 11 Sep 2017

Dynamic changes in clonal architecture during disease progression in follicular lymphoma
5 downloads cancer biology

Christoffer Flensburg, Tobias Sargeant, Astrid Bosma, Roelof J. C. Kluin, Robby E. Kibbelaar, Mels Hoogendoorn, Warren S. Alexander, Andrew W. Roberts, René Bernards, Daphne de Jong, Ian Majewski

Follicular lymphoma (FL) is typically a slow growing cancer that can be effectively treated. Some patients undergo transformation to diffuse large B cell lymphoma (DLBCL), which is frequently resistant to chemotherapy and is generally fatal. Targeted sequencing of DNA and RNA was applied to identify mutations and transcriptional changes that accompanied transformation in a cohort of 16 patients, including 14 with paired samples. In most cases we found mutations that were specific to the FL clone dominant at diagnosis, supporting the view that DLBCL does not develop directly from FL, but from an ancestral progenitor. We identified frequent mutations in TP53, cell cycle regulators (cyclins and cyclin-dependent kinases) and the PI3K pathway, as well as recurrent somatic copy number variants (SCNVs) on chromosome 3, 7 and 17p associated with transformation. An integrated analysis of RNA and DNA identified allele specific expression changes in oncogenes, including MYC, that could be attributed to structural rearrangements. By focusing on serial samples taken from two patients, we identified evidence of convergent tumour evolution, where clonal expansion was repeatedly associated with mutations targeting the same genes or pathways. Analysis of serial samples is a powerful way to identify core dependencies that support lymphoma growth.

55318: Exploring the mutational robustness of nucleic acids by searching genotype neighbourhoods in sequence space
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Posted to bioRxiv 03 Dec 2016

Exploring the mutational robustness of nucleic acids by searching genotype neighbourhoods in sequence space
5 downloads evolutionary biology

Qingtong Zhou, Xianbao Sun, Xiaole Xia, Zhou Fan, Zhaofeng Luo, Suwen Zhao, Haojun Liang, Eugene Shakhnovich

To assess the mutational robustness of nucleic acids, many genome- and protein-level studies have been performed; in these investigations, nucleic acids are treated as genetic information carriers and transferrers. However, the molecular mechanism through which mutations alter the structural, dynamic and functional properties of nucleic acids is poorly understood. Here, we performed SELEX in silico study to investigate the fitness distribution of the nucleic acid genotype neighborhood in a sequence space for L-Arm binding aptamer. Although most mutants of the L-Arm-binding aptamer failed to retain their ligand-binding ability, two novel functional genotype neighborhoods were isolated by SELEX in silico and experimentally verified to have similar binding affinity (Kd = 69.3 μM and 110.7 μM) as the wild-type aptamer (Kd = 114.4 μM). Based on data from the current study and previous research, mutational robustness is strongly influenced by the local base environment and ligand-binding mode, whereas bases distant from the binding pocket provide potential evolutionary pathways to approach global fitness maximum. Our work provides an example of successful application of SELEX in silico to optimize an aptamer and demonstrates the strong sensitivity of mutational robustness to the site of genetic variation.

55319: Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A
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Posted to bioRxiv 24 Jan 2017

Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A
5 downloads biochemistry

Sandra Markovic-Mueller, Edward Stuttfeld, Mayanka Asthana, Tobias Weinert, Spencer Edward Bliven, Kenneth N. Goldie, Kaisa Kisko, Guido Capitani, Kurt Ballmer-Hofer

Vascular Endothelial Growth Factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (RTKs), VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single particle electron microscopy, small angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here we describe the structure of the full-length VEGFR-1 extracellular domain (ECD) in complex with VEGF-A at 4 Å resolution. We combined X-ray crystallography, single 9 particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in Ig-domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity.

55320: Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways
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Posted to bioRxiv 16 Aug 2016

Systems Biomedicine of Rabies Delineates the Affected Signaling Pathways
5 downloads systems biology

Sadegh Azimzadeh Jamalkandi, Hamid Gholami Pourbadie, Mehdi Mirzaie, Sayed Hamid Reza Mozhgani, Farsheed Noorbakhsh, Behrouz Vaziri, Alireza Gholami, Naser Ansari-Pour, Mohieddin Jafari

The prototypical neurotropic virus, rabies, is a member of the Rhabdoviridae family that causes lethal encephalomyelitis. Although there have been a plethora of studies investigating the etiological mechanism of the rabies virus and many precautionary methods have been implemented to avert the disease outbreak over the last century, the disease has surprisingly no definite remedy at its late stages. The psychological symptoms and the underlying etiology, as well as the rare survival rate from rabies encephalitis, has still remained a mystery. We, therefore, undertook a systems biomedicine approach to identify the network of gene products implicated in rabies. This was done by meta-analyzing whole-transcriptome microarray datasets of the CNS infected by strain CVS-11, and integrating them with interactome data using computational and statistical methods. We first determined the differentially expressed genes (DEGs) in each study and horizontally integrated the results at the mRNA and microRNA levels separately. A total of 61 seed genes involved in signal propagation system were obtained by means of unifying mRNA and microRNA detected integrated DEGs. We then reconstructed a refined protein-protein interaction network (PPIN) of infected cells to elucidate biological signaling transduction pathways affected by rabies virus. To validate our findings, we confirmed differential expression of randomly selected genes in the network using Real-time PCR. In conclusion, the identification of seed genes and their network neighborhood within the refined PPIN can be useful for demonstrating signaling pathways including interferon circumvent, toward proliferation and survival, and neuropathological clue, explaining the intricate underlying molecular neuropathology of rabies infection and thus rendered a molecular framework for predicting potential drug targets.

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