bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-ancestry fine-mapping improves precision to identify causal genes in transcriptome-wide association studies
Authors: Lu Zeyun , Gopalan Shyamalika , Yuan Dong , Conti David V. , Pasaniuc Bogdan , Gusev Alexander , Mancuso Nicholas 
Published: February 2022

AbstractTranscriptome-wide association studies (TWAS) are a powerful approach to identify genes whose expression associates with complex disease risk. However, non-causal genes can exhibit association signals due to confounding by linkage disequilibrium patterns (LD) and eQTL pleiotropy at genomic risk regions which necessitates fine-mapping of TWAS signals. Here, we present MA-FOCUS, a multi-ancestry framework for the improved identification of genes underlying traits of interest. We demonstrate that by leveraging differences in ancestry-specific patterns of LD and eQTL signals, MA-FOCUS consistently outperforms single-ancestry fine-mapping approaches with equivalent total sample size across multiple metrics. We perform 15 blood trait TWAS using genome-wide summary statistics (average NEA=511k, NAA=13k) and lymphoblastoid cell line eQTL data from cohorts of primarily European and African continental ancestries. We recapitulate evidence demonstrating shared genetic architectures for eQTL and blood traits between the two ancestry groups and observe that gene-level effects correlate 20% more strongly across ancestries compared with SNP-level effects. We perform fine-mapping using MA-FOCUS and find evidence that genes at TWAS risk regions are more likely to be shared across ancestries rather than ancestry-specific. Using multiple lines of evidence to validate our findings, we find gene sets produced by MA-FOCUS are more enriched in hematopoietic categories compared to alternative approaches (P = 1.73 × 10−16). Our work demonstrates that including, and appropriately accounting for, genetic diversity can drive deeper insights into the genetic architecture of complex traits.
Conceptual and analytical approaches for modeling the developmental origins of inequality
Authors: Malani Anup , Archie Elizabeth A. , Rosenbaum Stacy 
Published: February 2022

AbstractIn many species, individuals who experience harsh conditions during development often have poor health and fitness outcomes in adulthood relative to peers who do not. There are two classes of evolutionary hypotheses for the origins of these early life contributors to inequality in adulthood: developmental constraints (DC) models, which focus on the deleterious effects of low-quality early-life environments, and predictive adaptive response (PAR) hypotheses, which emphasize the cost of mismatches between early and adult environments. Distinguishing DC and PAR models empirically is difficult for both conceptual and analytical reasons. Here, we resolve this difficulty by providing explicit mathematical definitions for DC, PARs, and related concepts, and propose a novel, quadratic regression-based statistical test derived from these definitions. Simulations show that this approach improves the ability to discriminate between DC and PAR hypotheses relative to a common alternative based on testing for interaction effects between developmental and adult environments. Simulated data indicate that the interaction effects approach often conflates PARs with DC, while the quadratic regression approach yields high sensitivity and specificity for detecting PARs. Our results highlight the value of linking verbal and visual models to a formal mathematical treatment for understanding the developmental origins of inequitable adult outcomes.
“polishCLR: a Nextflow workflow for polishing PacBio CLR genome assemblies”
Authors: Chang Jennifer , Stahlke Amanda R. , Chudalayandi Sivanandan , Rosen Benjamin D. , Childers Anna K. , Severin Andrew 
Published: February 2022

AbstractLong-read sequencing has revolutionized genome assembly, yielding highly contiguous, chromosome-level contigs. However, assemblies from some third generation long read technologies, such as Pacific Biosciences (PacBio) Continuous Long Reads (CLR), have a high error rate. Such errors can be corrected with short reads through a process called polishing. Although best practices for polishing non-model de novo genome assemblies were recently described by the Vertebrate Genome Project (VGP) Assembly community, there is a need for a publicly available, reproducible workflow that can be easily implemented and run on a conventional high performance computing environment. Here, we describe polishCLR (https://github.com/isugifNF/polishCLR), a reproducible Nextflow workflow that implements best practices for polishing assemblies made from CLR data. PolishCLR can be initiated from several input options that extend best practices to suboptimal cases. It also provides re-entry points throughout several key processes including identifying duplicate haplotypes in purge_dups, allowing a break for scaffolding if data are available, and throughout multiple rounds of polishing and evaluation with Arrow and FreeBayes. PolishCLR is containerized and publicly available for the greater assembly community as a tool to complete assemblies from existing, error-prone long-read data.
Compartmental Neuropeptide Release Measured Using a New Oxytocin Sensor
Authors: Qian Tongrui , Wang Huan , Wang Peng , Geng Lan , Mei Long , Osakada Takuya , Tang Yan , Kania Alan , Grinevich Valery , Stoop Ron , Lin Dayu , Luo Minmin , Li Yulong 
Published: February 2022

AbstractAs a peptide hormone and neuromodulator, oxytocin (OT) plays a critical role in a variety of physiological and pathophysiological processes in both the central nervous system and the periphery. However, the processes that regulate spatial OT release in the brain remain enigmatic. Here, we developed a genetically encoded GPCR activation-based (GRAB) OT sensor called GRABOT1.0. Using this sensor, we directly visualized stimulation-induced OT release from specific compartments of OT neurons in acute brain slices, and discovered that N-type calcium channels predominantly mediate axonal OT release, while L-type calcium channels mediate somatodendritic OT release. In addition, we found that components in the fusion machinery of OT release differ between axon terminals versus somata and dendrites. Finally, we demonstrated the sensor responses to the activation of OT neurons in various brain regions in vivo and revealed region specific OT release during male courtship behavior. Taken together, these results provide key insights regarding the role of compartmental OT release in the control of physiological and behavioral functions.
Microbial turnover and dispersal events occur in sync with plant phenology in the perennial evergreen tree crop, Citrus sinensis
Authors: Ginnan Nichole A. , De Anda N. Itzel , Freitas Vieira Flavia Campos , Rolshausen Philippe , Roper M. Caroline 
Published: February 2022

AbstractEmerging research indicates that plant-associated microbes can alter plant developmental timing. However, it is unclear if host phenology impacts microbial community assembly. Microbiome studies in annuals or deciduous perennial plants face challenges in separating effects of tissue age from phenological driven effects on the microbiome. In contrast, evergreen perennial trees, like Citrus sinensis, retain leaves for years allowing for uniform sampling of similarly aged leaves from the same developmental cohort. This aids in separating phenological effects on the microbiome from impacts due to annual leaf maturation/senescence. Here we used this system to test the hypothesis that host phenology acts as a driver of microbiome composition. Citrus sinensis leaves and roots were sampled during seven phenological stages. Using amplicon-based sequencing, followed by diversity, phylogenetic, differential abundance, and network analyses we examined changes in bacterial and fungal communities. Host phenological stage is the main determinant of microbiome composition, particularly within the foliar bacteriome. Microbial enrichment/depletion patterns suggest that microbial turnover and dispersal were driving these shifts. Moreover, a subset of community shifts were phylogenetically conserved across bacterial clades suggesting that inherited traits contribute to microbe-microbe and/or plant-microbe interactions during specific phenophases. Plant phenology influences microbial community composition. These findings enhance understanding of microbiome assembly and identify microbes that potentially influence plant development and reproduction.
Allele Dispersion Score: Quantifying the range of allele frequencies across populations, based on UMAP
Authors: Correard Solenne , Arbour Laura , Wasserman Wyeth W. 
Published: February 2022

AbstractGenomic variation plays a crucial role in biology, serving as a base for evolution - allowing for adaptation on a species or population level. At the individual level, however, specific alleles can be implicated in diseases. To interpret genetic variants identified in an individual potentially affected with a rare genetic disease, it is fundamental to know the population frequency of each allele, ideally in an ancestry matched cohort. Equity in human genomics remains a challenge for the field, and there are not yet cohorts representing most populations. Currently, when ancestry matched cohorts are not available, pooled variant libraries are used, such as gnomAD, the Human Genome Diversity Project (HGDP) or the 1,000 Genomes Project (now known as IGSR: International Genome Sample Resource). When working with a pooled collection of variant frequencies, one of the challenges is to determine efficiently if a variant is broadly spread across populations or appears selectively in one or more populations. While this can be accomplished by reviewing tables of population frequencies, it can be advantageous to have a single score that summarizes the observed dispersion. This score would not require classifying individuals into populations, which can be complicated if it is a homogenous population, or can leave individuals excluded from all the predefined population groups. Moreover, a score would not display fine-scaled population information, which could have privacy implications and consequently be inappropriate to release. Therefore, we sought to develop a scoring method based on a Uniform Manifold Approximation and Projection (UMAP) where, for each allele, the score can range from 0 (the variant is limited to a subset of close individuals within the whole cohort) to 1 (the variant is spread among the individuals represented in the cohort). We call this score the Allele Dispersion Score (ADS). The scoring system was implemented on the IGSR dataset, and compared to the current method consisting in displaying variant frequencies for several populations in a table. The ADS correlates with the population frequencies, without requiring grouping of individuals.
Suspicions of two bridgehead invasions ofXylella fastidiosasubsp.multiplexin France
Authors: Dupas Enora , Durand Karine , Rieux Adrien , Briand Martial , Pruvost Olivier , Cunty Amandine , Denancé Nicolas , Donnadieu Cécile , Legendre Bruno , Lopez-Roques Céline , Cesbron Sophie , Ravigné Virginie , Jacques Marie-Agnès 
Published: February 2022

AbstractOf American origin, a wide diversity ofXylella fastidiosastrains belonging to different subspecies have been reported in Europe since 2013 and its discovery in Italian olive groves. Strains from the subspeciesmultiplex(ST6 and ST7) were first identified in France in 2015 in urban and natural areas. To trace back the most probable scenario of introduction in France, the molecular evolution rate of this subspecies was estimated at 3.2165 × 10-7substitutions per site per year, based on heterochronous genome sequences collected worldwide. This rate allowed the dating of the divergence between French and American strains in 1987 for ST6 and in 1971 for ST7. The development of a new VNTR-13 scheme allowed tracing the spread of the bacterium in France, hypothesizing an American origin. Our results suggest that both sequence types were initially introduced and spread in Provence-Alpes-Côte d’Azur (PACA); then they were introduced in Corsica in two waves from the PACA bridgehead populations.
STAT3gain-of-function mutations connect leukemia with autoimmune disease by pathological dysregulation of NKG2DhiCD8 killer T cells
Authors: Masle-Farquhar Etienne , Jackson Katherine J.L. , Peters Timothy J. , Al-Eryani Ghamdan , Singh Mandeep , Payne Kathryn J. , Rao Geetha , Apps Gabrielle , Kingham Jennifer , Jara Christopher J. , Skvortsova Ksenia , Swarbrick Alexander , Ma Cindy S. , Suan Daniel , Uzel Gulbu , Chua Ignatius , Leiding Jennifer W. , Heiskanen Kaarina , Preece Kahn , Kainulainen Leena , O’Sullivan Michael , Cooper Megan A. , Seppänen Mikko R.J. , Mustjoki Satu , Brothers Shannon , Vogel Tiphanie P. , Brink Robert , Tangye Stuart G. , Reed Joanne H. , Goodnow Christopher C. 
Published: February 2022

SUMMARYThe association between cancer and autoimmune disease is unexplained, exemplified by T-cell large granular lymphocytic leukemia (T-LGL) where gain-of-function somatic mutations inSTAT3correlate with co-existing autoimmunity. To resolve whether these mutations are the cause or consequence of CD8 clonal expansions and autoimmunity, here we analyse patients with germlineSTAT3GOF syndrome and mice with the T-LGL mutationSTAT3K658Nor the most common germline mutation,STAT3T716M. STAT3 GOF mutations drove accumulation of effector CD8 T cell clones highly expressing the NKG2D receptor for MHC-I-related molecules expressed on stressed cells, and the genes for inflammatory/cytotoxic granzymes, perforin, interferon-γ andCcl5/Rantes. CD8 cells were essential to lethal disease inStat3K658Nmice and their accumulation required NKG2D and the receptor for IL-15 and IL-2, IL2RB. These results demonstrate thatSTAT3GOF mutations cause effector CD8 T cell oligoclonal accumulation and that these rogue T cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.IN BRIEFLeukemia and autoimmune-associatedSTAT3gain-of-function mutations dysregulate CD8 T cells to cause autoimmune pathology and oligoclonal expansion of cytotoxic killer CD8 T cells, that depend upon NKG2D and IL2RB receptors for signals displayed on stressed, damaged, infected, or mutated tissues.
Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling
Authors: Overhoff M. , Tellkamp F. , Hess S. , Tutas J. , Tolve M. , Faerfers M. , Ickert L. , Mohammadi M. , De Bruyckere E. , Kallergi E. , Dell Vedove A. , Nikoletopoulou V. , Wirth B. , Isensee J. , Hucho T. , Puchkov D. , Isbrandt D. , Krüger M. , Kloppenburg P. , Kononenko N.L. 
Published: February 2022

AbstractAutophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.
Comparative genomics of Staphylococcus capitis reveals determinants of speciation
Authors: Chong Charlotte E. , Bengtsson Rebecca J. , Horsburgh Malcolm J. 
Published: February 2022

AbstractStaphylococcus capitis is primarily described as a human skin commensal but is now emergent as an opportunistic pathogen isolated from bloodstream and prosthetic joint infections, and neonatal intensive care unit (NICU) associated sepsis. We used comparative genomic analyses of S. capitis to provide new insights of commensal scalp isolates from varying skin states, and to expand our current knowledge of the species populations (scalp isolates, n = 59, contextual isolates, n = 127). A highly recombinogenic population structure was revealed, with genomes including the presence of a range of previously described staphylococcal virulence factors, cell wall-associated proteins, and two-component systems. Genomic differences between the two described S. capitis subspecies were explored and reveal determinants associated exclusively with each. The subspecies ureolyticus was distinguished from subspecies capitis by differences in antimicrobial resistance genes and gene clusters linked to survival on the skin. This study will aid further research into classification of S. capitis and virulence linked phylogroups that is important to monitor the spread and evolution of S. capitis.
Niche-specific genome degradation and convergent evolution shaping Staphylococcus aureus adaptation during severe infections
Authors: Giulieri Stefano G. , Guérillot Romain , Duchene Sebastian , Hachani Abderrahman , Daniel Diane , Seemann Torsten , Davis Joshua S. , Tong Steve Y.C. , Young Bernadette , Wilson Daniel J. , Stinear Timothy P. , Howden Benjamin P. 
Published: February 2022

ABSTRACTDuring severe infections, Staphylococcus aureus moves from its colonising sites to blood and tissues, and is exposed to new selective pressures, thus potentially driving adaptive evolution. Previous studies have shown the key role of the agr locus in S. aureus pathoadaptation, however a more comprehensive characterisation of genetic signatures of bacterial adaptation may enable prediction of clinical outcomes and reveal new targets for treatment and prevention of these infections. Here, we measured adaptation using within-host evolution analysis of 2,590 S. aureus genomes from 396 independent episodes of infection. By capturing a comprehensive repertoire of single-nucleotide and structural genome variations, we found evidence of a distinctive evolutionary pattern within the infecting populations compared to colonising bacteria. These invasive strains had up to 20-fold enrichments for genome degradation signatures and displayed significantly convergent mutations in a distinctive set of genes, linked to antibiotic response and pathogenesis. In addition to agr-mediated adaptation we identified non-canonical, genome-wide significant loci including sucA-sucB and stp1. The prevalence of adaptive changes increased with infection extent, emphasising the clinical significance of these signatures. These findings provide a high-resolution picture of the molecular changes when S. aureus transitions from colonisation to severe infection and may inform correlation of infection outcomes with adaptation signatures.
T Cell Traction Forces show temporal patterns which Depend on Stimulation and Cell Subtype
Authors: Mustapha Farah , Biarnes-Pelicot Martine , Torro Remy , El Husseiny Jana , Sengupta Kheya , Puech Pierre-Henri 
Published: February 2022

AbstractT cells use forces to read out and act on the mechanical parameters of their microenvironment, where antigen-presenting cells (APCs) are the most prominent biomechanical partners. Here we explore the early interaction of T cells with an APC-mimicking ultra-soft polymer gel exhibiting physiologically relevant stiffness in the range of 350-450 Pa. We quantify the dependence of cell spreading and stiffness on gel elasticity, and measure early time traction forces. We find that coating the surface with an antibody against the CD3 region of the TCR-complex elicits small but measurable gel deformation in the early recognition phase, which we report as maximal stress and integrated energy. We show that the time evolution of the energy follows one of three distinct patterns: active fluctuations, intermittent, or sigmoidal signals. When using a classical T cell line, we observed that addition of either anti-CD28 or anti-LFA1 has little impact on the total integrated energy or the maximum stress. However, the relative distribution of the energy patterns does depend on the additional ligands. When using primary human T cells, we determined that the subtype and initial state of the cells are strongly affecting the force patterns, in a way that appears coherent with their physiological role.Graphical abstract
Translational reprogramming in response to accumulating stressors ensures critical threshold levels of Hsp90 for mammalian life
Authors: Bhattacharya Kaushik , Maiti Samarpan , Zahoran Szabolcs , Weidenauer Lorenz , Hany Dina , Wider Diana , Bernasconi Lilia , Quadroni Manfredo , Collart Martine , Picard Didier 
Published: February 2022

AbstractThe cytosolic molecular chaperone Hsp90 is essential for eukaryotic life1, 2. It is involved in multiple branches of proteostasis2, 3, and as a molecular capacitor in morphological evolution4. Although reduced Hsp90 levels cause phenotypic variations5, 6 and correlate with aging7, whether eukaryotic cells and organisms can tune the basal Hsp90 protein levels to alleviate physiologically accumulated stress is unknown. To begin to explore this question, we investigated whether and how mice adapt to the deletion of three out of four alleles encoding cytosolic Hsp90, one Hsp90β allele being the only remaining one. While the vast majority of such mouse embryos die during gestation, survivors apparently manage to increase their Hsp90β protein to at least wild-type levels. Further mechanistic studies revealed an internal ribosome entry site in the 5’UTR of the Hsp90β mRNA allowing translational reprogramming to compensate for the genetic loss of Hsp90 alleles and in response to stress. We found that the minimum amount of total Hsp90 that is required to support viability of mammalian cells and organisms is 50-70% of what is normally there. Those that fail to maintain a threshold level are subject to accelerated senescence, proteostatic collapse, and ultimately death. Therefore, considering that Hsp90 levels can be reduced ≥100-fold in the unicellular budding yeast, critical threshold levels of Hsp90 have been markedly increased during eukaryotic evolution. The incompressible part of the steady-state levels of Hsp90 may have increased to accommodate the ever-growing complexity of the proteome8 on the path towards mammals.
Cell cycle and developmental control of cortical excitability in Xenopus laevis
Authors: Swider Zachary T , Michaud Ani , Leda Marcin , Landino Jennifer , Goryachev Andrew B. , Bement William M. 
Published: February 2022

AbstractInterest in cortical excitability – the ability of the cell cortex to generate traveling waves of protein activity – has grown considerably over the past twenty years. Attributing biological functions to cortical excitability requires an understanding of the natural behavior of excitable waves and the ability to accurately quantify wave properties. Here we have investigated and quantified the onset of cortical excitability in X. laevis eggs and embryos, and the changes in cortical excitability throughout early development. We found that cortical excitability begins to manifest shortly after egg activation. Further, we identified a close relationship between wave properties – such as wave frequency and amplitude – and cell cycle progression as well as cell size. Finally, we identified quantitative differences between cortical excitability in the cleavage furrow relative to non-furrow cortical excitability and showed that these wave regimes are mutually exclusive.