Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 64,929 bioRxiv papers from 287,755 authors.
Most downloaded bioRxiv papers, since beginning of last month
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4 downloads evolutionary biology
Uniparental reproduction in diploids, via asexual reproduction or selfing, reduces the independence with which separate loci are transmitted across generations. This is expected to increase the extent to which a neutral marker is affected by selection elsewhere in the genome. Such effects have previously been quantified in coalescent models involving selfing. Here we examine the effects of background selection and balancing selection in diploids capable of both sexual and asexual reproduction (i.e., partial asexuality). We find that the effect of background selection on reducing coalescent time (and effective population size) can be orders of magnitude greater when rates of sex are low than when sex is common. This is because asexuality enhances the effects of background selection through both a recombination effect and a segregation effect. We show that there are several reasons that the strength of background selection differs between systems with partial asexuality and those with comparable levels of uniparental reproduction via selfing. Expectations for reductions in Ne via background selection have been verified using stochastic simulations. In contrast to background selection, balancing selection increases the coalescent time for a linked neutral site. With partial asexuality, the effect of balancing selection is somewhat dependent upon the mode of selection (e.g., heterozygote advantage vs. negative frequency dependent selection) in a manner that does not apply to selfing. This is because the frequency of heterozygotes, which are required for recombination onto alternative genetic backgrounds, is more dependent on the pattern of selection with partial asexuality than with selfing.
4 downloads bioinformatics
Motivation: Due to their special properties, the structures of transmembrane proteins are extremely hard to determine. Several methods exist to predict the propensity of successful completion of the structure determination process. However, available predictors incorporate data of any kind of proteins, hence they can hardly differentiate between crystallizable and non-crystallizable membrane proteins. Results: We implemented a web server to simplify running TMCrys prediction method that was developed specifically to separate crystallizable and non-crystallizable proteins.
4 downloads evolutionary biology
ROOT HAIR DEFECTIVE SIX-LIKE (RSL) genes control the development of structures (e.g. rhizoids, root hairs, gemmae, mucilage papillae) that develop from single cells at the surface of diverse groups of land plants. RSL proteins constitute a subclass (VIIIc) of the basic helix loop helix (bHLH) class VIII transcription factor family. We set out to determine if the function of RSL genes in the control of cell differentiation in land plants was inherited from streptophyte algal ancestor. The Charophyceae are a monophyletic class of streptophyte algae with tissue-like structures and rhizoids. We identified the single class VIII bHLH gene from the charophyceaen alga Chara braunii (CbbHLHVIII). Phylogenetic analysis suggests that this protein is sister to the RSL (bHLH subclass VIIIc) proteins and together they constitute a monophyletic group. Expression of CbbHLHVIII does not compensate for loss of the RSL function in either Marchantia polymorpha or Arabidopsis thaliana. Furthermore, CbbHLHVIII is expressed at sites of morphogenesis in C. braunii (e.g. the apices, nodes and gametangia) but not in rhizoids. This indicates that C. braunii class VIII protein is functionally different from land plant RSL proteins; they control rhizoid development in land plants but not in the charophycean algae. These data are consistent with the hypothesis that RSL proteins and their function in the differentiation of cells at the plant surface evolved in the lineage leading to land plants after the divergence of the land plants and C. braunii from their last common ancestor. This may have occurred by neofunctionalisation at or before the colonisation of the land by streptophytes.
4 downloads cell biology
BACKGROUND: Pancreatic islet grafts are cultured in vitro prior to transplantation and this is associated to a variable degree of beta cell loss. Optimization of culture conditions is currently hampered by the lack of a specific and sensitive in vitro indicator of beta cell death. METHODS: We developed a high-sensitivity duplex bead-based immunoassay for two protein-type biomarkers of beta cell destruction, GAD65 and UCHL1, and investigated its proficiency for in vitro toxicity profiling on rodent and human beta cells, as compared to a semi-automatic and manual image-based assessment of beta cell death, and in vivo after intraportal islet transplantation. RESULTS: Both GAD65 and UCHL1 were discharged by necrotic and apoptotic beta cells proportionate to the number of dead beta cells as counted by microscopic methods. In vitro, UCHL1 was superior to GAD65, in terms of biomarker stability providing more sensitive detection of low grade beta cell death. In vivo, however, GAD65 was consistently detected after islet transplantation while UCHL1 remained undetectable. CONCLUSION: The use of soluble biomarkers represents a fast, selective and sensitive method for beta cell toxicity profiling in vitro. UCHL1 is superior to GAD65 in vitro but not in vivo.
4 downloads ecology
Classical models of biological invasions assess species spread in homogeneous landscapes by assuming constant growth rates and random local movement. Mounting evidence suggests, however, that demographic stochasticity, environmental heterogeneity and non-random movement of individuals affect considerably the spread dynamics. Here, we show that the dynamics of biological invasions are controlled by the spatial heterogeneity of the resource distribution. We show theoretically that increasing the landscape resource autocorrelation length causes a reduction in the average speed of species spread. Demographic stochasticity plays a key role in the slowdown, which is streghtened when individuals can actively move towards resources. The reduction in the front propagation speed is verified in laboratory microcosm experiments with the flagellated protist Euglena gracilis by comparing spread in habitats characterized by different resource heterogeneity. Our theoretical and experimental findings highlight the need to account for the intrinsic stochasticity of population dynamics to describe spread in spatially extended landscapes, which are inevitably characterized by heterogeneous spatial distributions of resources controlling vital rates. Our work identifies the resource autocorrelation length as a key modulator and a simple measure of landscape susceptibility to biological invasions, with implications for predicting the characters of biological invasions within naturally heterogeneous environmental corridors.
4 downloads biochemistry
Chromokinesins NOD and KID have similar DNA binding domains and functions during cell division, while their motor domain sequences show significant variations. It has been unclear whether these motors have similar structure, chemistry, and microtubule interactions necessary to follow a similar mechanism of force mediation. We used biochemical rate measurements, cosedimentation, and structural analysis to investigate the ATPase mechanisms of the NOD and KID core domains. These experiments and analysis revealed that NOD and KID have different ATPase mechanisms, microtubule interactions, and catalytic domain structures. The ATPase cycles of NOD and KID have different rate limiting steps. The ATPase rate of NOD was robustly stimulated by microtubules albeit its microtubule affinity was weakened in all nucleotide bound states. KID bound microtubules tightly in all nucleotide states and remained associated with the microtubule for more than 100 cycles of ATP hydrolysis before dissociating. The structure of KID was most similar to conventional kinesin (KIF5). Key differences in the microtubule binding region and allosteric communication pathway between KID and NOD are consistent with our biochemical data. Our results support the model that NOD and KID utilize distinct mechanistic pathways to achieve the same function during cell division.
4 downloads cell biology
The activities of neuronal signaling receptors depend on the maturation state of the endosomal compartments in which they reside. However, it remains unclear how the distribution of these compartments within the uniquely complex morphology of neurons is regulated, and how this distribution itself affects signaling. Here we identified mechanisms by which Sorting Nexin 16 (SNX16) controls neuronal endosomal maturation and distribution. We found that higher-order assembly of SNX16 via its coiled-coil domain drives membrane tubulation in vitro and endosome association in cells. In Drosophila motor neurons, activation of Rab5 and coiled-coil-dependent self-association of SNX16 lead to its endosomal enrichment, concomitant with depletion of SNX16-positive endosomes from the synapse, and their accumulation as Rab5- and Rab7-positive tubulated compartments at the cell body. This leads to higher levels of synaptic growth-promoting BMP receptors at the cell body, and correlates with increased synaptic growth. Our results indicate that Rab regulation of SNX16 assembly controls the endosomal distribution and signaling activities of neuronal receptors.
4 downloads genetics
Bean rust is a devastating disease of common bean in the Americas and Africa. The historically important Ur-3 gene confers resistance to many races of the highly variable bean rust pathogen that overcome all known rust resistance genes. Existing molecular markers tagging Ur-3 for use in marker assisted selection produce false results. We described here the fine mapping of Ur-3 for the development of highly accurate markers linked to this gene. An F2 population from Pinto 114 × Aurora was evaluated for its reaction to four different races of the bean rust pathogen. A bulked segregant analysis using the SNP chip BARCBEAN6K_3 positioned the approximate location of the Ur-3 locus to the lower arm of chromosome Pv11. Specific SSR and SNP markers and haplotype analysis of 18 sequenced bean lines led to position the Ur-3 locus to a 46.5 Kb genomic region. We discovered a KASP marker, SS68 that was tightly linked to the Ur-3 locus. Validation of SS68 on a panel of 130 diverse common bean lines and varieties containing all known rust resistance genes revealed that it was highly accurate producing no false results. The SS68 marker will be of great value to pyramid Ur-3 with other rust resistance genes. It will also reduce significantly time and labor associated with the current phenotypic detection of Ur-3. This is the first utilization of fine mapping to discover markers linked to a rust resistance in common bean.
4 downloads cancer biology
Sticker sarcoma - a highly aneuploid, contagious neoplasm circulating in a domestic dog population - is broadly referred as a canine transmissible venereal tumour (CTVT). The karyotype of transmissible Sticker sarcoma appears as a collage of numerical and structural aberrations; the CTVT genome represents the generalized but stable neoplastic aneuploidy of monoclonal origins. Presented is an analysis of genetic events and variants underlying the aneuploid genomic structure of Sticker sarcoma described previously by Murchison et al. (2014) and Decker et al. (2015). Here we explored the above CTVT genomic compendia and mined the existing data - specifically looking for cases of convergence of multiple non-synonymous variants onto a single gene - the mutational patterns indicative for Knudsonian 'two-hit' kinetics. A Table I is given, providing theoretical estimates of retaining the intact wild-type copy, expected as a function of a cumulative mutational convergence observed in unphased sequence consensus. We demonstrate that the two canine RecQ-like helicases: Bloom syndrome helicase and RECQL4, encoded by the aneuploid transmissible tumour, have accumulated a multitude of different mutations. Among the sets of most intensely mutated transmissible sarcoma genes, we also identified a canine FANCD2 - yet another previously unnoticed multiple-hit candidate factor. We discuss a possible role of mutated RecQ-like helicases and other cooperating factors, perceivably involved in the maintenance of the neoplastic aneuploidy. We suggest the proposed cooperative actions of CTVT RecQ-like DNA helicases could be relevant interpreting whether variants contributing to RecQ-dependent karyotypic traits, respond to selective pressures that preserve the aneuploid genomic structure of transmissible Sticker sarcoma.
4 downloads evolutionary biology
Although there are many correlational studies, unbiased estimates of inbreeding depression only come from experimental studies that create inbred and outbred individuals. Few such studies determine the extent to which inbreeding depression in males is due to natural or sexual selection. Importantly, traits that are closely related to fitness are predicted to be most strongly affected by inbreeding depression, so measuring fitness or key fitness components, rather than phenotypic traits, is necessary to estimate inbreeding depression accurately. Here, we experimentally created inbred and outbred male mosquitofish (Gambusia holbrooki) by mating full-sibs (f=0.25). We show this led to a 23% reduction in genome-wide heterozygosity. Males were then raised on different diets early in life. We then allowed adult males to compete freely for females to test if inbreeding, early diet, and their interaction affect a male's share of paternity. Early diet had no effect on paternity, but outbred males sired almost twice as many offspring as inbred males. We also found that males with a relatively long gonopodium (intromittent organ) had greater reproductive success. We demonstrate that inbreeding has important consequences because it negatively affects a key component of male fitness. Given there was no difference in adult mortality this finding can only be due to inbreeding negatively affecting sexually selected traits.
4 downloads epidemiology
Background: Mycoplasma genitalium is a common cause of non-gonococcal non-chlamydial urethritis and cervicitis. Testing of asymptomatic populations has been proposed, but prevalence rates in asymptomatic populations are not well established. We aimed to estimate the prevalence of M. genitalium in adults in the general population, in clinic-based samples, pregnant women, men who have sex with men (MSM) and female sex workers (FSW). Methods: We searched Embase, Medline, IndMED, AIM and LILACS from 1 January 1991 to 12 July 2016 without language restrictions. We included studies with 500 participants or more. We screened and selected studies and extracted data in duplicate. We examined eligible studies in forest plots and conducted random effects meta-analysis to estimate prevalence, if appropriate. Between study heterogeneity was examined using the I2 statistic and meta-regression. Results: Of 3,316 screened records, 63 were included. In randomly selected samples from the general population, the summary prevalence estimate was 1.3% (95% confidence intervals, CI 1.0 to 1.8%, I2 41.5%, 3 studies) in countries with higher levels of development and 3.9% (95% CI 2.2 to 6.7, I2 89.2%, 3 studies) in countries with lower levels. Prevalence estimates were similar in women and men (p=0.47). In clinic-based samples prevalence estimates were higher, except in asymptomatic patients (0.8%, 95% CI 0.4 to 1.4, I2 0.0%, 3 studies). Summary prevalence estimates were: pregnant women 0.9% (95% CI 0.6 to 1.4%, I2 0%, 4 studies); MSM in the community 3.2% (95% CI 2.1 to 5.1, I2 78.3%, 5 studies); FSW in the community 15.9% (95% CI 13.5 to 18.9, I2 =79.9%, 4 studies). Discussion: This systematic review can inform testing guidelines for M. genitalium infection. The low estimated prevalence of M. genitalium in the general population, pregnant women and asymptomatic attenders at clinics does not support expansion of testing asymptomatic people in these groups.
4 downloads biochemistry
The Nrd1-Nab3-Sen1 (NNS) complex carries out the transcription termination of non-coding RNAs (ncRNAs) in yeast, although the detailed interactions among its subunits remain obscure. Here we have identified three sequence motifs in Sen1 that mediate direct interactions with the RNA polymerase II CTD interaction domain (CID) of Nrd1, determined the crystal structures of these Nrd1 interaction motifs (NIMs) bound to the CID, and characterized the interactions in vitro and in yeast.
4 downloads neuroscience
A universal unanswered question in neuroscience and machine learning is whether computers can decode the patterns of the human brain. Multi-Voxels Pattern Analysis (MVPA) is a critical tool for addressing this question. However, there are two challenges in the previous MVPA methods, which include decreasing sparsity and noises in the extracted features and increasing the performance of prediction. In overcoming mentioned challenges, this paper proposes Anatomical Pattern Analysis (APA) for decoding visual stimuli in the human brain. This framework develops a novel anatomical feature extraction method and a new imbalance AdaBoost algorithm for binary classification. Further, it utilizes an Error-Correcting Output Codes (ECOC) method for multi-class prediction. APA can automatically detect active regions for each category of the visual stimuli. Moreover, it enables us to combine homogeneous datasets for applying advanced classification. Experimental studies on 4 visual categories (words, consonants, objects and scrambled photos) demonstrate that the proposed approach achieves superior performance to state-of-the-art methods.
4 downloads microbiology
Two species with similar resource requirements respond in a characteristic way to variations in their habitat -- their abundances rise and fall in concert. We use this idea to learn how bacterial populations in the microbiota respond to habitat conditions that vary from person-to-person across the human population. Our mathematical framework shows that habitat fluctuations are sufficient for explaining intra-bodysite correlations in relative species abundances from the Human Microbiome Project. We explicitly show that the relative abundances of phylogenetically related species are positively correlated and can be predicted from taxonomic relationships. We identify a small set of functional pathways related to metabolism and maintenance of the cell wall that form the basis of a common resource sharing niche space of the human microbiota.
4 downloads epidemiology
Joseph A Lewnard, Benjamin A Lopman, Umesh D Parashar, Aisleen Bennett, Naor Bar-Zeev, Nigel A Cunliffe, Prasanna Samuel, M Lourdes Guerrero, Guillermo Ruiz-Palacios, Gagandeep Kang, Virginia E Pitzer
Variation in susceptibility is a known contributor to bias in studies estimating immune protection acquired from vaccination or natural infection. However, difficulty measuring this heterogeneity hinders assessment of its influence on estimates. Cohort studies, randomized trials, and post-licensure studies have reported reduced natural and vaccine-derived protection against rotavirus gastroenteritis in low- and middle-income countries (LMICs). We sought to understand differences in susceptibility among children enrolled in two birth-cohort studies of rotavirus in LMICs, and to explore the implications for estimation of immune protection. We re-analyzed data from studies conducted in Mexico City, Mexico and Vellore, India. Cumulatively, 573 unvaccinated children experienced 1418 rotavirus infections and 371 episodes of rotavirus gastroenteritis (RVGE) over 17,636 child-months. We developed a model characterizing susceptibility to rotavirus infection and RVGE among children, accounting for aspects of the natural history of rotavirus and differences in transmission rates between settings, and tested whether model-generated susceptibility measurements were associated with demographic and anthropometric factors. We identified greater variation in susceptibility to rotavirus infection and RVGE in Vellore than in Mexico City. In both cohorts, susceptibility to rotavirus infection and RVGE were associated with male sex, lower birth weight, lower maternal education, and having fewer siblings; within Vellore, susceptibility was also associated with lower socioeconomic status. Children who were more susceptible to rotavirus also experienced higher rates of diarrhea due to other causes. Simulations suggest that discrepant estimates of naturally-acquired immunity against RVGE can be attributed, in part, to between-setting differences in transmission intensity and susceptibility of children. We found that more children in Vellore than in Mexico City belong to a high-risk group for rotavirus infection and RVGE, and demonstrate that bias owing to differences in rotavirus transmission intensity and population susceptibility may hinder comparison of estimated immune protection against RVGE.
4 downloads cell biology
Duchenne muscular dystrophy is (DMD) a lethal muscle degenerative disease caused by nonsense or out of frame deletion mutations in the DMD gene, which encodes Dystrophin. While multiple therapeutic strategies to ameliorate the disease symptoms are under development, there is currently no cure. Here we report an unexpected finding that intramuscular injections of the anti-inflammatory interleukin 4 or 13 (IL4/13) not only reduce inflammation but also restore Dystrophin protein production in the mdx mouse model. IL4/13 restores Dystrophin production by inducing changes in the Dmd pre-mRNA splicing pattern that exclude the mutated exon and restore the reading frame. We further show that systemic delivery of IL4-Fc can restore Dystrophin in multiple muscle groups and increase muscle endurance and strength in mdx mice. Importantly, IL4/13 treatment of mdx myoblasts is sufficient to induce exon skipping and restore Dmd reading frame in vitro. Moreover, IL4-treated DMD patient myoblasts produce Dystrophin-positive myofibers after transplantation. In light of the established clinical safety of IL4 treatment, we recommend IL4 as an agent of immediate consideration for treating Duchenne muscular dystrophy.
4 downloads cancer biology
The nature of host organs and genes that underlie tumor-induced physiological disruption on host remains ill-defined. Here, we establish a novel zebrafish intestinal tumor model that is optimized for addressing this issue, and find that hepatic cyp7a1, the rate-limiting factor for synthesizing bile acids (BAs), is such a host gene. Inducing krasG12D by Gal4 specifically expressed in the posterior intestine resulted in formation of an intestinal tumor classified as dysplasia. The local intestinal tumor caused systemic detrimental effects on host including liver inflammation, hepatomegaly, growth defects, and organismal death. Whole-organismal level gene expression analysis and metabolite measurements revealed that the intestinal tumor reduced total BAs levels via down-regulation of hepatic cyp7a1. Genetically rescuing cyp7a1 expression in the liver restored the BAs synthesis and ameliorated tumor-induced liver inflammation, but not other tumor-dependent phenotypes. Thus, we found a previously unknown role of cyp7a1 as the host gene that links the intestinal tumor, hepatic cholesterol-BAs metabolism, and liver inflammation in tumor-bearing fish. Our model provides an important basis to discover host genes responsible for tumor-induced phenotypes and to uncover mechanisms underlying how tumors adversely affect host organisms.
4 downloads evolutionary biology
When females mate promiscuously, sperm compete within females to fertilise the ova. In theory, a male can increase his success at siring offspring by inducing the female to lay more eggs, as well as by producing more competitive sperm. Here we report that the evolutionary consequences of fecundity stimulation extend beyond rival males, by experimentally uncovering effects on offspring. With experiments on the burying beetle Nicrophorus vespilloides, we show that smaller subordinate males are better able to stimulate female fecundity than larger, dominant males. Furthermore dominant males also benefit from the greater fecundity induced by smaller males, and so gain from the female's earlier promiscuity - just as predicted by theory. By inducing females to produce more offspring on a limited resource, smaller males cause each larva to be smaller, even those they do not sire themselves. Fecundity stimulation thus promotes the non-genetic inheritance of offspring body size, and provides a mechanism for telegony.
4 downloads genomics
In this work we have investigated the genetic changes underlying the high glutathione (GSH) production showed by the evolved Saccharomyces cerevisiae strain UMCC 2581, selected in a molybdate-enriched environment after sexual recombination of the parental wine strain UMCC 855. To reach our goal, we first generated strains with the desired phenotype, and then we mapped changes underlying adaptation to molybdate by using a whole-genome sequencing. Moreover, we carried out the RNA-seq that allowed an accurate measurement of gene expression and an effective comparison between the transcriptional profiles of parental and evolved strains, in order to investigate the relationship between genotype and high GSH production phenotype. Among all genes evaluated only two genes, MED2 and RIM15 both related to oxidative stress response, presented new mutations in the UMCC 2581 strain sequence and were potentially related to the evolved phenotype. Regarding the expression of high GSH production phenotype, it included over-expression of amino acids permeases and precursor biosynthetic enzymes rather than the two GSH metabolic enzymes, whereas GSH production and metabolism, transporter activity, vacuolar detoxification and oxidative stress response enzymes were probably added resulting in the molybdate resistance phenotype. This work provides an example of a combination of an evolution-based strategy to successful obtain yeast strain with desired phenotype and inverse engineering approach to genetic characterize the evolved strain. The obtained genetic information could be useful for further optimization of the evolved strains and for providing an even more rapid approach to identify new strains, with a high GSH production, through a marked-assisted selection strategy.
4 downloads developmental biology
Erythropoiesis is the process by which new red blood cells (RBCs) are formed and defects in this process can lead to anemia or thalassemia. The GATA1 transcription factor is an established mediator of RBC development. However, the upstream mechanisms that regulate the expression of GATA1 are not completely characterized. Cholesterol is one potential upstream mediator of GATA1 expression because previously published studies suggest that defects in cholesterol synthesis disrupt RBC differentiation. Here we characterize RBC development in a zebrafish harboring a single missense mutation in the hmgcs1 gene (Vu57 allele). hmgcs1 encodes the first enzyme in the cholesterol synthesis pathway and mutation of hmgcs1 inhibits cholesterol synthesis. We analyzed the number of RBCs in hmgcs1 mutants and their wildtype siblings. Mutation of hmgcs1 resulted in a decrease in the number of mature RBCs, which coincides with reduced gata1a expression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but that gata1a expression is isoprenoid dependent. Collectively, our results reveal two novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.
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