bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signal transfer of visual stimuli to V4 occurs in gamma-rhythmic, pulsed information packages
Authors: Lisitsyn Dmitriy , Grothe Iris , Kreiter Andreas K. , Ernst Udo A. 
Published: February 2020

SummarySelective visual attention allows the brain to focus on behaviorally relevant information while ignoring irrelevant signals. As a possible mechanism, routing by synchronization was proposed: neural populations sending attended signals align their gamma-rhythmic activities with receiving populations, such that spikes from the senders arrive at excitability peaks of the receivers, enhancing signal transfer. Conversely, the non-attended signals arrive unaligned to the receiver’s oscillation, reducing signal transfer. Therefore, visual signals should be transferred through periodically pulsed information packages, resulting in a modulation of the stimulus content within the receiver’s activity by its gamma phase and amplitude. To test this prediction, we quantified gamma phase-specific stimulus content within neural activity from area V4 of macaques performing a visual attention task. For the attended stimulus we find enhanced stimulus content reaching its maximum near excitability peaks, with effect magnitude increasing with oscillation amplitude, establishing a functional link between selective processing and gamma activity.
A single-cell RNAseq atlas of the pathogenic stage ofSchistosoma mansoniidentifies a key regulator of blood feeding
Authors: Wendt George , Zhao Lu , Chen Rui , Liu Chenxi , O’Donoghue Anthony J. , Caffrey Conor R. , Collins James J. 
Published: February 2020

AbstractSchistosomiasis is an ancient and chronic neglected tropical disease that infects over 240 million people and kills over 200,000 of the world’s poorest people every year1, 2. There are no vaccines and because there is only one drug available, the need for new therapeutics is great. The causative agents of this disease are flatworm parasites that dwell inside the host’s circulation, often for decades, where they feed on blood and lay eggs which are primarily responsible for disease pathology. As metazoans comprised of multiple tissue types, understanding the schistosome’s tissues on a molecular level and their functions during what can be decades of successful parasitism could suggest novel therapeutic strategies. Here, we employ single-cell RNAseq to characterize 43,642 cells from the pathogenic (adult) stage of the schistosome lifecycle. From these data, we characterize 68 molecularly distinct cell populations that comprise nearly all tissues described morphologically, including the nervous and reproductive systems. We further uncover a lineage of somatic stem cells responsible for producing and maintaining the parasite’s gut – the primary tissue responsible for digestion of host blood. Finally, we show that a homologue ofhepatocyte nuclear factor 4(hnf4) is expressed in this gut lineage and required for gut maintenance, blood feeding and inducing egg-associated pathologyin vivo. Together, the data highlight the utility of this single-cell RNAseq atlas to understand schistosome biology and identify potential therapeutic interventions.
EslB is required for cell wall biosynthesis and modification inListeria monocytogenes
Authors: Rismondo Jeanine , Schulz Lisa M. , Yacoub Maria , Wadhawan Ashima , Hoppert Michael , Dionne Marc S. , Gründling Angelika 
Published: February 2020

ABSTRACTLysozyme is an important component of the innate immune system. It functions by hydrolysing the peptidoglycan (PG) layer of bacteria. The human pathogenListeria monocytogenesis intrinsically lysozyme resistant. The peptidoglycanN-deacetylase PgdA andO-acetyltransferase OatA are two known factors contributing to its lysozyme resistance. Furthermore, it was shown that the absence of components of an ABC transporter, here referred to as EslABC, leads to reduced lysozyme resistance. How its activity is linked to lysozyme resistance is still unknown. To investigate this further, a strain with a deletion ineslB, coding for a membrane component of the ABC transporter, was constructed inL. monocytogenesstrain 10403S. TheeslBmutant showed a 40-fold reduction in the minimal inhibitory concentration to lysozyme. Analysis of the PG structure revealed that theeslBmutant produced PG with reduced levels ofO-acetylation. Using growth and autolysis assays, we show that the absence of EslB manifests in a growth defect in media containing high concentrations of sugars and increased endogenous cell lysis. A thinner PG layer produced by theeslBmutant under these growth conditions might explain these phenotypes. Furthermore, theeslBmutant had a noticeable cell division defect and formed elongated cells. Microscopy analysis revealed that an early cell division protein still localized in theeslBmutant indicating that a downstream process is perturbed. Based on our results, we hypothesize that EslB affects the biosynthesis and modification of the cell wall inL. monocytogenesand is thus important for the maintenance of cell wall integrity.IMPORTANCEThe ABC transporter EslABC is associated with the intrinsic lysozyme resistance ofListeria monocytogenes. However, the exact role of the transporter in this process and in the physiology ofL. monocytogenesis unknown. Using different assays to characterize aneslBdeletion strain, we found that the absence of EslB not only affects lysozyme resistance, but also endogenous cell lysis, cell wall biosynthesis, cell division and the ability of the bacterium to grow in media containing high concentrations of sugars. Our results indicate that EslB is by a yet unknown mechanism an important determinant for cell wall integrity inL. monocytogenes.
Dynamical gene regulatory networks are tuned by transcriptional autoregulation with microRNA feedback
Authors: Minchington Thomas G , Griffiths-Jones Sam , Papalopulu Nancy 
Published: February 2020

AbstractConcepts from dynamical systems theory, including multi-stability, oscillations, robustness and stochasticity, are increasingly implicated in the control of gene expression during cell fate decisions, inflammation and stem cell heterogeneity. However, the prevalence of the underlying structures within gene networks which drive these dynamical behaviours, such as direct autoregulation or feedback by microRNAs, is unknown.We integrate transcription factor binding site (TFBS) and microRNA target data to generate a gene interaction network across 28 human tissues. This network was interrogated to identify network motifs capable of driving dynamical gene expression, in particular oscillations. Autoregulatory motifs were identified in 56% of transcription factors (TFs) investigated, 89% of which were also found in dual feedback motifs with a microRNA. Both the autoregulatory and dual feedback motifs were enriched in the network. TFs that autoregulate were found to be highly conserved between tissues. Dual feedback motifs with microRNAs were also conserved, but less so. Such dual feedback motifs were conserved between tissues, although TFs regulate different combinations of microRNAs in a tissue-dependent manner.TFs which autoregulate are prevalent among human TFs and have more interactions with microRNAs than non-autoregulatory genes. The enrichment of such motifs within the human transcriptional network indicates that more genes may have interesting expression dynamics than previously thought. These data provide a resource for the identification of TFs which regulate the dynamical properties of human gene expression. These findings support the development of dynamical conceptual frameworks for the study of fundamental biological processes.
Mining Whole Genome Sequence data to efficiently attribute individuals to source populations
Authors: Pérez-Reche Francisco J. , Rotariu Ovidiu , Lopes Bruno S. , Forbes Ken J. , Strachan Norval J.C. 
Published: February 2020

ABSTRACTWhole genome sequence (WGS) data could transform our ability to attribute individuals to source populations. However, methods that effectively mine these data are yet to be developed. We present a minimal multilocus distance (MMD) method which rapidly deals with these large data sets as well as methods for optimally selecting loci. This was applied on WGS data to determine the source of human campylobacteriosis, the geographical origin of diverse biological species including humans and proteomic data to classify breast cancer tumours. The MMD method provides a highly accurate attribution which is computationally efficient for extended genotypes. These methods are generic, easy to implement for WGS and proteomic data and have wide application.
The parasiteSchistocephalus solidussecretes proteins with putative host manipulation functions
Authors: Berger Chloé Suzanne , Laroche Jérôme , Maaroufi Halim , Martin Hélène , Moon Kyung-Mee , Landry Christian R. , Foster Leonard J. , Aubin-Horth Nadia 
Published: February 2020

ABSTRACTBackgroundManipulative parasites are thought to liberate molecules in their external environment acting as manipulation factors with biological functions implicated in their host’s physiological and behavioural alterations. These manipulation factors are part of a complex mixture called the secretome. While the secretomes of various parasites have been described, there is very little data for a putative manipulative parasite. It is necessary to study the molecular interaction between a manipulative parasite and its host to better understand how such alterations evolve.MethodsHere, we used proteomics to characterize the secretome of a model cestode with a complex life cycle based on trophic transmission. We studiedSchistocephalus solidusduring the life stage in which behavioural changes take place in its obligatory intermediate fish host, the threespine stickleback (Gasterosteus aculeatus). We produced a novel genome sequence and assembly ofS. solidusto improve protein coding gene prediction and annotation for this parasite. We then described the whole worm’s proteome and its secretome during fish host infection using LC-MS/MS.ResultsA total of 2 290 proteins were detected in the proteome ofS. solidus, and 30 additional proteins were detected specifically in the secretome. We found that the secretome contains proteases, proteins with neural and immune functions, as well as proteins involved in cell communication. We detected Receptor-type tyrosine-protein phosphatases, which were reported in other parasitic systems to be manipulation factors. We also detected 12S. solidus-specific proteins in the secretome that may play important roles in host-parasite interactions.ConclusionsOur results suggest thatS. solidusliberates molecules with putative host manipulation functions in the host and that many of them are species specific.
Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes
Authors: Lotta Luca A. , Pietzner Maik , Stewart Isobel D. , Wittemans Laura B.L. , Li Chen , Bonelli Roberto , Raffler Johannes , Biggs Emma K. , Oliver-Williams Clare , Auyeung Victoria P.W. , Luan Jian’an , Wheeler Eleanor , Paige Ellie , Surendran Praveen , Michelotti Gregory A. , Scott Robert A. , Burgess Stephen , Zuber Verena , Sanderson Eleanor , Koulman Albert , Imamura Fumiaki , Forouhi Nita G. , Khaw Kay-Tee ,   MacTel Consortium, Griffin Julian L. , Wood Angela M. , Kastenmüller Gabi , Danesh John , Butterworth Adam S. , Gribble Fiona M. , Reimann Frank , Bahlo Melanie , Fauman Eric , Wareham Nicholas J. , Langenberg Claudia 
Published: February 2020

AbstractCirculating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p<4.9×10-10) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such asASNS(rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10-30)]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.
High MHC gene copy number maintains diversity despite homozygosity in a Critically Endangered single-island endemic bird, but no evidence of MHC-based mate choice
Authors: Stervander Martin , Dierickx Elisa G. , Thorley Jack , Brooke M. de L. , Westerdahl Helena 
Published: February 2020

AbstractSmall population sizes can, over time, put species at risk due to the loss of genetic variation and the deleterious effects of inbreeding. Losing diversity in the major histocompatibility complex (MHC) could be particularly harmful, given its key role in the immune system. Here, we assess MHC class I (MHC-I) diversity and its effects on mate choice and survival in the Critically Endangered Raso larkAlauda razae, a species restricted to the 7 km2islet of Raso (Cape Verde) since ~1460, whose population size has dropped as low as 20 pairs. Exhaustively genotyping 122 individuals, we find no effect of MHC-I genotype/diversity on mate choice or survival. However, we demonstrate that MHC-I diversity has been maintained through extreme bottlenecks by retention of a high number of gene copies (at least 14), aided by co-segregation of multiple haplotypes comprising 2–8 linked MHC-I loci. Within-locus homozygosity is high, contributing to comparably low population-wide diversity. Conversely, each individual had comparably many alleles, 6–16 (average 11), and the large and divergent haplotypes occur at high frequency in the population, resulting in high within-individual MHC-I diversity. This functional immune gene diversity will be of critical importance for this highly threatened species’ adaptive potential.
PxdA interacts with the DipA phosphatase to regulate endosomal hitchhiking of peroxisomes
Authors: Salogiannis John , Christensen Jenna R. , Aguilar-Maldonado Adriana , Shukla Nandini , Reck-Peterson Samara L. 
Published: February 2020

AbstractIn canonical microtubule-based transport, adaptor proteins link cargos to the molecular motors dynein and kinesin. Recently, an alternative mode of transport known as ‘hitchhiking’ was discovered, in which a cargo achieves motility by hitching a ride on an already-motile cargo, rather than attaching to a motor protein. Hitchhiking has been best-studied in two filamentous fungi,Aspergillus nidulansandUstilago maydis. InU. maydis, ribonucleoprotein complexes, peroxisomes, lipid droplets, and endoplasmic reticulum all hitchhike on early endosomes. InA. nidulans, peroxisomes hitchhike using a putative molecular linker, PxdA, that associates with early endosomes. However, whether other organelles use PxdA to hitchhike on early endosomes is unclear, as are the molecular mechanisms that regulate hitchhiking inA. nidulans. Here we find that the proper distribution of lipid droplets, mitochondria and autophagosomes do not require PxdA, suggesting that PxdA is a molecular linker specific to peroxisomes. We also identify two newpxdAalleles, including a point mutation (R2044P) that disrupts PxdA’s ability to associate with early endosomes and reduces peroxisome movement. Finally, we identify a novel regulator of peroxisome hitchhiking, the phosphatase DipA. DipA co-localizes with early endosomes and its early endosome-association relies on PxdA.
Genome-Wide Identification and Characterization of MLO Gene Family in Octoploid Strawberry (Fragaria ×ananassa)
Authors: Tapia Ronald R. , Barbey Christopher R. , Chandra Saket , Folta Kevin M. , Whitaker Vance M. , Lee Seonghee 
Published: February 2020

AbstractPowdery mildew (PM) caused by Podosphaera aphanis is a major fungal disease in cultivated strawberry. Mildew Resistance Locus O (MLO) is a gene family described for having conserved seven-transmembrane domains. Induced loss-of-function in specific MLO genes can confer durable and broad resistance against PM pathogens. However, the underlying biological role of MLO genes in strawberry is still unknown. In the present study, the genomic structure of MLO genes were characterized in both diploid (Fragaria vesca) and octoploid strawberry (Fragaria ×ananassa), and the potential sources of MLO-mediated susceptibility were identified. Twenty MLO-like sequences were identified in F. vesca, with sixty-eight in F. ×ananassa. Phylogenetic analysis divides strawberry MLO genes into eight different clades, in which three FveMLO and ten FaMLO genes were grouped together with the functionally known MLO susceptibility. Out of ten FaMLO genes, FaMLO17-2 and FaMLO17-3 showed the highest similarity to the known susceptibility MLO proteins. Gene expression analysis of FaMLO genes was conducted using a multi-parental segregating population. Three expression quantitative trait loci (eQTL) were substantially associated with MLO transcript levels in mature fruits, suggesting discrete genetic control of susceptibility. These results are a critical first step in understanding allele function of MLO genes, and are necessary for further genetic studies of PM resistance in cultivated strawberry.
Microtubule Assembly and Pole Coalescence: Early Steps inC. elegansOocyte Meiosis I Spindle Assembly
Authors: Chuang Chien-Hui , Schlientz Aleesa J. , Yang Jie , Bowerman Bruce 
Published: February 2020

ABSTRACTHow oocytes assemble bipolar meiotic spindles in the absence of centrosomes as microtubule organizing centers remains poorly understood. We have used live cell imaging inC. elegansto investigate requirements for the nuclear lamina and for conserved regulators of microtubule dynamics during oocyte meiosis I spindle assembly, assessing these requirements with respect to recently identified spindle assembly steps. We show that the nuclear lamina is required for microtubule bundles to form a cage-like structure that appears shortly after oocyte nuclear envelope breakdown and surrounds the oocyte chromosomes, although bipolar spindles still assembled in its absence. Although two conserved regulators of microtubule nucleation, RAN-1 and γ-tubulin, are not required for bipolar spindle assembly, both contribute to normal levels of spindle-associated microtubules and spindle assembly dynamics. Finally, the XMAP215 ortholog ZYG-9 and the nearly identical minus-end directed kinesins KLP-15/16 are required for proper assembly of the early cage-like structure of microtubule bundles, and for early spindle pole foci to coalesce into a bipolar structure. Our results provide a framework for assigning molecular mechanisms to recently described steps inC. elegansoocyte meiosis I spindle assembly.
Profiling of Human Gut Virome with Oxford Nanopore Technology
Authors: Cao Jiabao , Zhang Yuqing , Dai Min , Xu Jiayue , Chen Liang , Zhang Faming , Zhao Na , Wang Jun 
Published: February 2020

AbstractHuman gut virome play critical roles in maintaining gut microbial composition and functionality, as well as host physiology and immunology. Yet, there are insufficient amount of studies on this topic mainly due to methodological limitations, including enrichment of viruses (phages and host viruses) as well as short read-length from current sequencing technology. Here we developed a full working protocol for analyzing human gut virome using physical enrichment, reverse transcription and random amplification, and eventually the state-of-art single-molecule real-time sequencing (SMRT) platform of Oxford Nanopore Technology (ONT). We demonstrate that sequencing viral DNA directly, or viral DNA/cDNA after amplification using ONT achieves much longer reads and provides more information regarding virome diversity, many of the virome sequences do not have match in current databases. Moreover, direct DNA sequencing of virome provides first insights into the epigenetic modifications on phages, where signals of methylations can be directly detected. Our study demonstrates that progressing sequencing technology and bioinformatic improvements will bring more knowledge into virome composition, diversity and potentially their important functions.HighlightsVirus-like particles were enriched from human stool samples;Viral nucleotides were sequenced with Oxford Nanopore Technology with and without amplification;Gut virome in humans showed highly individualized composition;Novel sequences and contigs were found to be the majority in the resulted sequences;Epigenetic modifications were detected directly on virus genomes.
Mesoscopic Liquid Clusters Represent a Distinct Condensate of Mutant p53
Authors: Yang David S. , Saeedi Arash , Davtyan Aram , Fathi Mohsen , Safari Mohammad S. , Klindziuk Alena , Barton Michelle C. , Varadarajan Navin , Kolomeisky Anatoly B. , Vekilov Peter G. 
Published: February 2020

AbstractThe oncogenic properties of mutant p53 have been ascribed to destabilization of the p53 conformation, followed by aggregation into insoluble fibrils. Here we combine immunofluorescent 3D confocal microscopy of breast cancer cells expressing the p53 mutant Arg248Gln (R248Q) with light scattering from solutions of the purified protein and molecular simulations to probe the mechanisms that govern phase behaviors of the mutant across multiple length scales, from cellular to molecular. We establish that p53 R248Q forms mesoscopic protein-rich clusters, an anomalous liquid phase with several unique properties. We demonstrate that the clusters host and facilitate the nucleation of amyloid fibrils. The distinct characteristics of the clusters of R248Q and wild-type p53 and theoretical models indicate that p53 condensation into clusters is driven by the structural destabilization of the core domain and not by interactions of its extensive disordered region. Two-step nucleation of mutant p53 amyloids suggests means to control fibrillization and the associated pathologies through modifying the cluster behaviors. In a broader context, our findings exemplify interactions between distinct protein phases that activate complex physicochemical mechanisms operating in biological systems.