bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability and dynamics of the human gut microbiome and its association with systemic immune traits
Authors: Byrd Allyson L. , Liu Menghan , Fujimura Kei E. , Lyalina Svetlana , Nagarkar Deepti R. , Charbit Bruno , Bergstedt Jacob , Patin Etienne , Harrison Oliver J. , Quintana-Murci Lluís , Duffy Darragh , Albert Matthew L. ,   The Milieu Intérieur Consortium
Published: January 2020

SummaryAnalysis of 1,363 deeply sequenced gut microbiome samples from 946 healthy donors of the Milieu Intérieur cohort provides new opportunities to discover how the gut microbiome is associated with host factors and lifestyle parameters. Using a genome-based taxonomy to achieve higher resolution analysis, we found an enrichment of Prevotella species in males, and that bacterial profiles are dynamic across five decades of life (20-69), with Bacteroidota species consistently increased with age while Actinobacteriota species, including Bifidobacterium, decreased. Longitudinal sampling revealed short-term stability exceeds inter-individual differences; however, the degree of stability was variable between donors and influenced by their baseline community composition. We then integrated the microbiome results with systemic immunophenotypes to show that host/microbe associations discovered in animal models, such as T regulatory cells and short chain fatty acids, could be validated in human data. These results will enable personalized medicine approaches for microbial therapeutics and biomarkers.
Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting
Authors: Lohmueller Jason , Butchy Adam A. , Tivon Yaniv , Kvorjak Michael , Miskov-Zivanov Natasa , Deiters Alexander , Finn Olivera J. 
Published: January 2020

AbstractChimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are engineered cell-surface receptors that sense a target antigen and respond by activating T cell receptor signaling or a customized gene program, respectively. To expand the targeting capabilities of these receptors, we have developed switchable adaptor receptor systems for which receptor specificity can be directed post-translationally via covalent attachment of a co-administered antibody. Instead of directly targeting an antigen, our receptors contain the SNAPtag self-labeling enzyme, which reacts with benzylguanine (BG)-conjugated antibodies to assemble covalently-associated antigen receptors. We demonstrate that activation of SNAP-CAR and SNAP-synNotch receptors and their downstream effector functions can be successfully targeted by several clinically-relevant BG-conjugated antibodies in an antigen-specific and antibody dose-dependent manner. To better define parameters affecting receptor signaling, we developed a mathematical model of switchable receptor systems. SNAP receptors provide a powerful new strategy to post-translationally reprogram the targeting specificity of engineered cells.
Mechanical Instability of Adherens Junctions Overrides Intrinsic Quiescence of Hair Follicle Stem Cells
Authors: Biswas Ritusree , Banerjee Avinanda , Lembo Sergio , Zhao Zhihai , Lakshmanan Vairavan , Nakasaki Manando , Kutyavin Vassily , Wright Graham , Palakodeti Dasaradhi , Ross Robert , Jamora Colin , Vasioukhin Valeri , Jie Yan , Raghavan Srikala 
Published: January 2020

AbstractVinculin, a mechanotransducer associated with both adherens junctions (AJ) and focal adhesions (FA) plays a central role in force transmission through these cell-cell and cell-substratum contacts. Here we describe the conditional knock out (KO) of vinculin in murine skin. Remarkably, we find that the loss of vinculin function results in the loss of bulge stem cell (BuSC) quiescence. We demonstrate that vinculin KO cells are impaired in force generation resulting in mechanically weak AJs. Mechanistically, vinculin functions by keeping α-catenin in a stretched conformation, which in turn regulates the retention of YAP1, another potent mechanotransducer and regulator of cell proliferation, to the junctions. Conditional KO of α-catenin specifically in the BuSCs further corroborates the importance of stable AJs in the maintenance of quiescence and stemness. Altogether, our data provides definitive mechanistic insights into the hitherto unexplored regulatory link between the mechanical stability of cell-junctions and the maintenance of BuSC quiescence.
Gene expression in isolated cowpea (Vigna unguiculata L. Walp) cells from meiosis to seed initiation
Authors: Gursanscky Nial , Mazurkiewicz Danielle , Juranić Martina , Johnson Susan D. , León Gloria , Escobar-Guzmán Rocio , Salinas-Gamboa Rigel , Amasende-Morales Itzel , Riboni Matteo , Hand Melanie , Spriggs Andrew , Vielle-Calzada Jean-Philippe , Koltunow Anna M.G. 
Published: January 2020

AbstractMolecular knowledge of pathways regulating seed formation in legumes, remains scarce. Thirteen isolated cell-type transcriptomes were developed, spanning temporal events of male and female gametogenesis and seed initiation, to examine pathways involved in cowpea seed formation.In situhybridization confirmed localization ofin silicoidentified cell-specific genes, verifying transcriptome utility. Cowpea andArabidopsisreproductive cells showed some conservation in regulators enabling cell-type expression as some cowpea cell-specific genes promoters and theirArabidopsishomologs directed expression to identical reproductive cell-types in transgenic plants.In silicoanalyses revealed gene expression similarities and differences with genes in pathways regulating reproductive events in other plants. Meiosis-related genes were expressed at mitotic stages of gametogenesis and during sporophytic development in cowpea. Plant hormone pathways showing preferential expression at particular reproductive stages were identified. Expression of epigenetic pathways, resembling those found inArabidopsis,including microRNA mediated gene silencing, RNA directed DNA methylation and histone modification were associated with particular stages of male and female gametophyte development, suggesting roles in gametogenic cell specification and elaboration. Analyses of cell-cycle related gene expression in mature cowpea female gametophytes, indicated that the egg and central cell were arrested at the G1/S and G2/M cell cycle phases, respectively, prior to fertilization. Pre-fertilization female gametophyte arrest was characterized by barely detectable auxin biosynthesis gene expression levels, and elevated expression of genes involved in RNA-mediated gene silencing and histone modification. These transcriptomes provide a useful resource for additional interrogation to support functional analyses for development of higher yielding cowpea and syntenic legume crops.One sentence summaryAnalyses of laser capture derived cell-type transcriptomes spanning meiosis to seed initiation revealed gene expression profiles during cell specification and reproductive development in cowpea.
Developing an endogenous quorum-sensing based CRISPRi circuit for autonomous and tunable dynamic regulation of multiple targets in industrialStreptomyces
Authors: Tian Jinzhong , Yang Gaohua , Gu Yang , Sun Xinqiang , Lu Yinhua , Jiang Weihong 
Published: January 2020

ABSTRACTDynamic regulation has emerged as an effective strategy to improve product titers by balancing metabolic networks, which can be implemented by coupling gene expression to pathway-independent regulatory elements, such as quorum-sensing (QS) systems. However, these QS-based circuits are often created on heterologous systems and must be carefully tuned through tedious testing and optimization process to make them work well, which hampers their application in industrial microbes including streptomycetes. In this study, we design a pathway-independent QS circuit by directly integrating an endogenous QS system with CRISPRi (named EQCi) in the industrial rapamycin-producing strainStreptomyces rapamycinicus. EQCi has the advantages of both the QS system and CRISPRi, which enables tunable, fully autonomous and dynamic regulation of multiple targets simultaneously. To demonstrate its effectiveness, we downregulate three key nodes in essential pathways separately to divert metabolic flux toward rapamycin biosynthesis. In each case, significant increases in rapamycin titers are achieved. We further apply EQCi to simultaneously control these three key nodes with proper repression strength by changing sgRNA targeting positions. The final rapamycin titer reaches to 1836±191 mg/L, which is the highest reported titer. Notably, compared to traditional static engineering strategy, which result in growth arrest and suboptimal rapamycin titers, EQCi regulation substantially promote rapamycin titers without affecting cell growth, which indicates that it can achieve the trade-off between essential pathways and product synthesis. Collectively, this study provides a simple and effective strategy for optimizing product titers and may have the potential to apply to other industrial microorganisms.
Control of Slc7a5 sensitivity by the voltage-sensing domain of Kv1 channels
Authors: Sharmin Nazlee , Lamothe Shawn M. , Baronas Victoria A. , Silver Grace , Hao Yubin , Kurata Harley T. 
Published: January 2020

ABSTRACTMany voltage-dependent ion channels are regulated by accessory proteins, although the underlying mechanisms and consequences are often poorly understood. We recently reported a novel function of the amino acid transporter Slc7a5 as a powerful regulator of Kv1.2 voltage-dependent activation. In this study, we report that Kv1.1 channels are also regulated by Slc7a5, albeit with different functional outcomes. In heterologous expression systems, Kv1.1 exhibits prominent current enhancement (‘disinhibition’) with holding potentials more negative than −120 mV. Disinhibition of Kv1.1 is strongly attenuated by shRNA knockdown of endogenous Slc7a5. We investigated a variety of chimeric combinations of Kv1.1 and Kv1.2, demonstrating that exchange of the voltage-sensing domain controls the sensitivity and response to Slc7a5. Overall, our study highlights additional Slc7a5-sensitive Kv1 subunits, and demonstrates that features of Slc7a5 sensitivity can be swapped by exchanging voltage-sensing domains.IMPACT STATEMENTThe voltage-sensing mechanism of a subfamily of potassium channels can be powerfully modulated in unconventional ways, by poorly understood regulatory partners.
Novel ratio-metric features enable the identification of new driver genes across cancer types
Authors: Sudhakar Malvika , Rengaswamy Raghunathan , Raman Karthik 
Published: January 2020

ABSTRACTAn emergent area of cancer genomics has been the identification of driver genes. Driver genes confer a selective growth advantage to the cell and push it towards tumorigenesis. Functionally, driver genes can be divided into two categories, tumour suppressor genes (TSGs) and oncogenes (OGs), which have distinct mutation type profiles. While several driver genes have been discovered, many remain undiscovered, especially those that are mutated at a low frequency across samples. The current methods are not sufficient to predict all driver genes because the underlying characteristics of these genes are not yet well understood. Thus, to predict novel genes, we need to define new features and models that are not biased and identify genes that might otherwise be overshadowed by mutation profiles of recurrent driver genes. In this study, we define new features and build a model to identify novel driver genes. We overcome overfitting and show that certain mutation types such as nonsense mutations are more important for classification. Some known cancer driver genes, which are predicted by the model as TSGs with high probability are ARID1A, TP53, and RB1. In addition to these known genes, potential driver genes predicted are CD36, ZNF750 and ARHGAP35 as TSGs and TAB3 as an oncogene. Overall, our approach surmounts the issue of low recall and bias towards genes with high mutation rates and predicts potential novel driver genes for further experimental screening.
Morphological profiling of human T and NK lymphocytes identifies actin-mediated control of the immunological synapse
Authors: German Yolla , Vulliard Loan , Rubio Aude , Boztug Kaan , Ferrand Audrey , Menche Jörg , Dupré Loïc 
Published: January 2020

AbstractThe detection and neutralization of infected cells and tumors by cytotoxic lymphocytes is a vital immune defense mechanism. The immunological synapse orchestrates the target recognition process and the subsequent cytotoxic activity. Here, we present an integrated experimental and computational strategy to systematically characterize the morphological properties of the immunological synapse of human cytotoxic lymphocytes. Our approach combines high-content imaging with an unbiased, data-driven identification of high-resolution morphological profiles. Such profiling discriminates with high accuracy immunological synapse perturbations induced by an array of actin drugs in both model cell lines and primary lymphocytes. It reveals inter-individual heterogeneity in lymphocyte morphological traits. Furthermore, it uncovers immunological synapse alterations in functionally defective CD8+T cells from immunodeficient patients carryingARPC1Bmutations. Our study thus provides a foundation for the application of morphological profiling as a powerful and scalable approach to monitor lymphocyte activation status in experimental and disease settings.
Mixed Logistic Regression in Genome-Wide Association Studies
Authors: Milet Jacqueline , Perdry Hervé 
Published: January 2020

AbstractMotivationMixed linear models (MLM) have been widely used to account for population structure in case-control genome-wide association studies, the status being analyzed as a quantitative phenotype. Chenet al.proved that this method is inappropriate and proposed a score test for the mixed logistic regression (MLR). However this test does not allow an estimation of the variants’ effects.ResultsWe propose two computationally efficient methods to estimate the variants’ effects. Their properties are evaluated on two simulations sets, and compared with other methods (MLM, logistic regression). MLR performs the best in all circumstances. The variants’ effects are well evaluated by our methods, with a moderate bias when the effect sizes are large. Additionally, we propose a stratified QQ-plot, enhancing the diagnosis ofp-values inflation or deflation, when population strata are not clearly identified in the sample.AvailabilityAll methods are implemented in the R packagemilorGWASavailable athttps://github.com/genostats/milorGWAS.Contactherve.perdry@u-psud.frSupplementary informationSupplementary data are available atBioinformaticsonline.
Wege: A New Metric for Ranking Locations for Biodiversity Conservation
Authors: Farooq Harith , Anderson Josue , Belluardo Francesco , Nanvonamuquitxo Cristovao , Bennett Dominic , Moat Justin , Soares Amadeu , Faurby Soren , Antonelli Alexandre 
Published: January 2020

ABSTRACTAimIn order to implement effective conservation policies, it is crucial to know how biodiversity is distributed and one of the most widely used systems is the Key Biodiversity Areas (hereafter KBA) criteria, developed by the International Union for Conservation of Nature (IUCN). Here we develop a tool to rank Key Biodiversity Areas in a continuous scale to allow the ranking between KBAs and test this tool on a simulated dataset of 10 000 scenarios of species compositions of reptiles and mammals in eight locations in Mozambique.LocationMozambique, AfricaMethodsWe compare the KBA criteria with four priorisation metrics (weighted endemism, extinction risk, evolutionary distinctiveness and EDGE score) to rank the biodiversity importance of eight sites with a randomly generated species composition of reptiles and mammals in Mozambique.ResultsWe find that none of these metrics is able to provide a suitable ranking of the sites surveyed that would ultimately allow prioritization. We therefore develop and validate the “WEGE index” (Weighted Endemism including Global Endangerment index), which is an adaptation of the EDGE score (Evolutionarily Distinct and Globally Endangered) and allows the ranking of sites according to the KBA criteria but on a continuous scale.Main conclusionsFor our study system, the WEGE index scores areas that trigger KBA status higher and is able to rank their importance in terms of biodiversity by using the range and threat status of species present at the site. Prioritization may be crucial for policy making and real-life conservation, allowing the choice between otherwise equally qualified sites according to the KBA categories. WEGE is intended to support a transparent decision-making process in conservation.
Non-essential function of KRAB zinc finger gene clusters in retrotransposon suppression
Authors: Wolf Gernot , de Iaco Alberto , Sun Ming-An , Bruno Melania , Tinkham Matthew , Hoang Don , Mitra Apratim , Ralls Sherry , Trono Didier , Macfarlan Todd S. 
Published: January 2020

AbstractThe Krüppel-associated box zinc finger protein (KRAB-ZFP) family amplified and diversified in mammals by segmental duplications, but the function of the majority of this gene family remains largely unexplored due to the inaccessibility of the gene clusters to conventional gene targeting. We determined the genomic binding sites of 61 murine KRAB-ZFPs and genetically deleted in mouse embryonic stem (ES) cells five large KRAB-ZFP gene clusters encoding nearly one tenth of the more than 700 mouse KRAB-ZFPs. We demonstrate that clustered KRAB-ZFPs directly bind and silence retrotransposons and block retrotransposon-borne enhancers from gene activation in ES cells. Homozygous knockout mice generated from ES cells deleted in one of two KRAB-ZFP clusters were born at sub-mendelian frequencies in some matings, but heterozygous intercrosses could also yield knockout progeny with no overt phenotype. We further developed a retrotransposon capture-sequencing approach to assess mobility of the MMETn family of endogenous retrovirus like elements, which are transcriptionally activated in KRAB-ZFP cluster KOs, in a pedigree of KRAB-ZFP cluster KO and WT mice. We identified numerous somatic and several germ-line MMETn insertions, and found a modest increase in activity in mutant animals, but these events were detected in both wild-type and KO mice in stochastic and highly variable patterns. Our data suggests that the majority of young KRAB-ZFPs play a non-essential role in transposon silencing, likely due to the large redundancy with other KRAB-ZFPs and other transposon restriction pathways in mice.One Sentence SummaryMegabase-scale deletions of KRAB-ZFP gene clusters in mice leads to retrotransposon activation.
Changing the fallow paradigm: A win–win strategy for the post‐2020 Common Agricultural Policy to halt farmland bird declines
Authors: Tarjuelo Rocío , Margalida Antoni , Mougeot François 
Published: January 2020

Abstract

Farmland bird populations have declined sharply due to agricultural intensification. In Europe, these negative population trends have been linked to the loss of semi‐natural vegetation types, particularly fallow land. The work of Sanz‐Pérez et al. (2019) has far‐reaching implications for the conservation of farmland biodiversity. We argue that it supports a new paradigm for the understanding and management of fallows that should be integrated into the forthcoming post‐2020 Common Agricultural Policy (CAP).

Following the abolition of mandatory set‐aside by the European Union in 2008, fallows declined steadily in Europe until 2015, when the CAP implemented greening measures. These restored the requirement to leave 5% of arable land as ecological focus areas (EFAs) to enhance biodiversity. While fallows are one of the most beneficial forms of EFA for farmland birds, farmers prefer the less conservation effective planting of nitrogen‐fixing and catch crops (currently more than 70% of EFAs). CAP incentives have been insufficient to make unproductive EFAs such as fallows more attractive to farmers.

Sanz‐Pérez et al. (2019) evaluated the impact of different fallow land management practices on the abundance of specialist farmland birds. They concluded that extensive practices – such as tilling or shredding once or twice per year before the breeding season – were more beneficial to these declining species than leaving fallows unmanaged and recommended their incorporation into agri‐environment schemes. But such schemes have had low uptake, and thus a limited potential to drive the widespread recovery of farmland birds at either national or European levels. The post‐2020 CAP, currently under development, should integrate simple fallow management practices within new conditionalities or eco‐schemes to address this problem.

Synthesis and applications. The loss of fallow land underlies the decline of farmland birds. The post‐2020 CAP must overcome past mismatches between incentives to farmers and biodiversity benefits and increase farmers’ uptake of the most beneficial options for biodiversity, including fallows. Promoting light management of fallow land within the new CAP eco‐schemes is a win–win strategy because it would simultaneously allow farmers to continue extensive weed control and enhance habitat quality for farmland birds.
Long inter‐fire intervals do not guarantee a large seed bank in a serotinous shrub (Banksia spinulosa Sm.)
Authors: Whelan Robert J. , Ayre David J. 
Published: January 2020

Abstract

It is often assumed that long‐lived woody perennials with canopy‐stored seed banks steadily accumulate seeds over time since fire. Trends in flowering and fruiting have usually been inferred from synchronic studies of sites of different post‐fire ages or counting stored seeds in apparent age classes, and mostly in obligate‐seeder species. Long‐term longitudinal studies on a broader range of species are needed to fully understand the dynamics of flower and fruit production and accumulation of viable seeds. Key questions are as follows: What is the annual trend in flowering and cone production? Is this matched by accumulation of cones and seeds? How is seed germinability related to cone age at the time of a fire?

We counted inflorescences and tagged cones produced annually by the resprouting shrub Banksia spinulosa in 315 plants over 13 years at one site and in 46 plants over 20 years at another. At the end of the study, we harvested all accumulated cones, burned them and assessed seed viability using germination trials.

We detected enormous inter‐plant variation in reproductive effort and output. 50% of inflorescences was produced by only 10%–15% of plants. There was a potential for accumulation of massive seed banks. However, (a) only 8%–10% of inflorescences became cones; (b) only 44%–50% of these were retained until harvest; (c) many retained cones suffered seed predation; and (d) viability of retained seeds declined with cone age. The result of these processes meant that the accumulated seed bank was only two to four seeds per plant, 82%–94% of the viable seeds had been produced in 6 years prior to harvest and only 12%–26% of plants contributed to this viable seed bank.

Synthesis: Cone and seed losses and declining seed viability in B. spinulosa mean that almost all viable seeds come from the past few years of flowering even though apparently intact cones may be retained for decades. If this is typical for resprouting serotinous shrubs, it is important to understand trends in flowering and fruit set over time because the magnitude of recruitment will depend on fecundity in the few years prior to a fire.