bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influences of rare protein-coding genetic variants on the human plasma proteome in 50,829 UK Biobank participants
Authors: Dhindsa Ryan S. , Burren Oliver S. , Sun Benjamin B. , Prins Bram P. , Matelska Dorota , Wheeler Eleanor , Mitchell Jonathan , Oerton Erin , Hristova Ventzislava A. , Smith Katherine R. , Carss Keren , Wasilewski Sebastian , Harper Andrew R. , Paul Dirk S. , Fabre Margarete A. , Runz Heiko , Viollet Coralie , Challis Benjamin , Platt Adam ,   AstraZeneca Genomics Initiative, Vitsios Dimitrios , Ashley Euan A. , Whelan Christopher D. , Pangalos Menelas N. , Wang Quanli , Petrovski Slavé 
Published: October 2022

AbstractCombining human genomics with proteomics is becoming a powerful tool for drug discovery. Associations between genetic variants and protein levels can uncover disease mechanisms, clinical biomarkers, and candidate drug targets. To date, most population-level proteogenomic studies have focused on common alleles through genome-wide association studies (GWAS). Here, we studied the contribution of rare protein-coding variants to 1,472 plasma proteins abundances measured via the Olink Explore 1536 assay in 50,829 UK Biobank human exomes. Through a variant-level exome-wide association study (ExWAS), we identified 3,674 rare and significant protein quantitative trait loci (pQTLs), of which 76% were undetected in a prior GWAS performed on the same cohort, and we found that rare pQTLs are less likely to be random in their variant effect annotation. In gene-based collapsing analyses, we identified an additional 166 significant gene-protein pQTL signals that were undetected through single-variant analyses. Of the total 456 protein-truncating variant (PTV)-drivencis-pQTLs in the gene-based collapsing analysis, 99.3% were associated with decreased protein levels. We demonstrate how this resource can identify allelic series and propose biomarkers for several candidate therapeutic targets, includingGRN, HSD17B13, NLRC4, and others. Finally, we introduce a new collapsing analysis framework that combines PTVs with missensecis-pQTLs that are associated with decreased protein abundance to bolster genetic discovery statistical power. Our results collectively highlight a considerable role for rare variation in plasma protein abundance and demonstrate the utility of plasma proteomics in gene discovery and unravelling mechanisms of action.
Immune response after SARS-CoV-2 infection with residual post COVID symptoms
Authors: Pongkunakorn Tanyaporn , Manosan Thamonwan , Surawit Apinya , Ophakas Suphawan , Mongkolsucharitkul Pichanun , Pumiem Sureeporn , Suta Sophida , Pinsawas Bonggochpass , Sookrung Nitat , Saelim Nawannaporn , Mahasongkram Kodchakorn , Prangtaworn Pannathee , Tungtrongchitr Anchalee , Tangjittipokin Watip , Boonnak Kobporn , Narkdontri Tassanee , Teerawattanapong Nipaporn , Jongkaewwattana Anan , Mayurasakorn Korapat 
Published: October 2022

ABSTRACTBACKGROUNDIn a number of patients, post-acute COVID syndrome develops after acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Long COVID [LC]). Here, we examined the immune responses and clinical characteristics of individuals with LC compared to age- and gender-matched healthy recovered COVID individuals (HC) during the Omicron pandemic. Immune responses following BNT162b2 (Pfizer) booster are also determined.METHODSThis retrospective cohort study included 292 patients (LC, 158; HC, 134) confirmed to have SARS-CoV-2 infection from January to August 2022. We determined anti-SARS-CoV-2 receptor-binding domain immunoglobulin G (anti-RBD IgG), surrogate virus neutralization test (sVNT), T-cell subsets, and neutralization of wild-type, BA.1 and BA.5. A subset of patients was voluntarily recruited for booster vaccination with BNT162b2 vaccine and immunogenicity was assessed 4weeks after vaccination.RESULTSCycle thresholds were higher in the HC group than in the LC group (20.7 vs. 19.7; P<0.039). Anti-RBD IgG was higher at ≤56 days after COVID-19 onset (PC) in 3-dose vaccines compared with 2-dose vaccines in the LC group (P=0.02) and after 57-84 days PC in 3-dose vaccines in the HC group (P<0.001). The sVNT in LC was significantly high against Wuhan and sVNT was 30% lower against the Omicron than the Wuhan. sVNT was relatively sustained in 3-dose vaccines than ≤ 2-dose vaccines. sVNT in the HC group reached its peak at 57-84 days PC as compared with the LC group.CONCLUSIONSThese findings imply that LC produced increased neutralizing antibody responses than those with HC. During the Omicron pandemic, immunity after LC has still waned; therefore, a booster vaccine may be needed after 2-3 months from last infection. (ClinicalTrials.govnumber,NCT05484700)
CRISPR/Cas12a-mediated ultrasensitive and on-site monkeypox viral testing
Authors: Zhao Furong , Wang Pei , Wang Haoxuan , Liu Sirui , Sohail Muhammad , Zhang Xing , Li Bingzhi , Huang He 
Published: October 2022

AbstractThe unexpected transmission of monkeypox virus (MPXV) from Central and West Africa to previously non-endemic locations is triggering a global panic. The ultrasensitive, rapid, and specific detection of MPXV is crucial for controlling its spreading, while such technology has rarely been reported. Herein, we proposed an MPXV assay combining recombinase-aided amplification (RAA) and CRISPR/Cas12a for the first time. This assay targeted MPXVF3Lgene and yielded a low detection limit (LOD) of 101copies/μL. Deriving from the high specificity nature of RAA and CRISPR/Cas12a, through rational optimizations of probes and conditions, this assay showed high selectivity that could distinguish MPXV from other orthopox viruses and current high-profile viruses. To facilitate on-site screening of potential MPXV carriers, a kit integrating lateral flow strips was developed, enabling naked-eye MPXV detection with a LOD of 104copies/μL. Our RAA-Cas12a-MPXV assay was able to detect MPXV without the need for sophisticated operation and expensive equipment. We envision that this RAA-Cas12a-MPXV assay can be deployed in emerging viral outbreaks for on-site surveillance of MPXV.For TOC only
A Concerted Mechanism Involving ACAT and SREBPs By which Oxysterols Deplete Accessible Cholesterol To Restrict Microbial Infection
Authors: Heisler David B. , Johnson Kristen A. , Ohlson Maikke B. , Ma Duo , Zhang Lishu , Tran Michelle , Corley Chase D. , Abrams Michael E. , McDonald Jeffrey G. , Schoggins John W. , Alto Neal M. , Radhakrishnan Arun 
Published: October 2022

AbstractMost of the cholesterol in the plasma membranes (PMs) of animal cells is sequestered through interactions with phospholipids and transmembrane domains of proteins. However, as cholesterol concentration rises above the PM’s sequestration capacity, a new pool of cholesterol, called accessible cholesterol, emerges. The transport of accessible cholesterol between the PM and the endoplasmic reticulum (ER) is critical to maintain cholesterol homeostasis. This pathway has also been implicated in the suppression of both bacterial and viral pathogens by immunomodulatory oxysterols. Here, we describe a mechanism of depletion of accessible cholesterol from PMs by the oxysterol 25-hydroxycholesterol (25HC). We show that 25HC-mediated activation of acyl coenzyme A: cholesterol acyltransferase (ACAT) in the ER creates an imbalance in the equilibrium distribution of accessible cholesterol between the ER and PM. This imbalance triggers the rapid internalization of accessible cholesterol from the PM, which is sustained for long periods of time through 25HC-mediated suppression of SREBPs. In support of a physiological role for this mechanism, 25HC failed to suppress Zika virus and human coronavirus infection in ACAT-deficient cells, andListeria monocytogenesinfection in ACAT-deficient cells and mice. We propose that selective depletion of accessible PM cholesterol triggered by ACAT activation and sustained through SREBP suppression underpins the immunological activities of 25HC and a functionally related class of oxysterols.
Publicly Available Privacy-preserving Benchmarks for Polygenic Prediction
Authors: Witteveen Menno J. , Pedersen Emil M. , Meijsen Joeri , Andersen Michael Riis , Privé Florian , Speed Doug , Vilhjálmsson Bjarni J. 
Published: October 2022

AbstractRecently, several new approaches for creating polygenic scores (PGS) have been developed and this trend shows no sign of abating. However, it has thus far been challenging to determine which approaches are superior, as different studies report seemingly conflicting benchmark results. This heterogeneity in benchmark results is in part due to different outcomes being used, but also due to differences in the genetic variants being used, data preprocessing, and other quality control steps. As a solution, a publicly available benchmark for polygenic prediction is presented here, which allows researchers to bothtrainandtestpolygenic prediction methods using only summary-level information, thus preserving privacy. Using simulations and real data, we show that model performance can be estimated with accuracy, using only linkage disequilibrium (LD) information and genome-wide association summary statistics for target outcomes. Finally, we make this PGS benchmark - consisting of 8 outcomes, including somatic and psychiatric disorders - publicly available for researchers to download on our PGS benchmark platform (http://www.pgsbenchmark.org). We believe this benchmark can help establish a clear and unbiased standard for future polygenic score methods to compare against.
Efficient and rapid fluorescent protein knock-in with universal donors in mammalian stem cells
Authors: Shi Yu , Kopparapu Nitya , Ohler Lauren , Dickinson Daniel J. 
Published: October 2022

AbstractFluorescent protein (FP) tagging is a foundational approach in cell biology because it allows observation of protein distribution, dynamics, and interaction with other proteins in living cells. However, the typical approach using overexpression of tagged proteins can perturb cell behavior and introduce localization artifacts. To preserve native expression, fluorescent proteins can be inserted directly into endogenous genes. This approach has been standard in yeast for decades, and more recently in invertebrate model organisms with the advent of CRISPR/Cas9. However, endogenous fluorescent protein tagging has not been widely used in mammalian cells due to inefficient homology-directed repair (HDR). Here, we describe a streamlined method for efficient and fast integration of FP tags into native loci via non-homologous end joining (NHEJ) in mouse embryonic stem cells. Our protocol minimizes cloning with universal donors, allows for N or C-terminal tagging of endogenous proteins, and requires less than 2 weeks from transfection to imaging, thereby improving the applicability of FP knock-in in mammalian cells.
Gαs slow conformational transition upon GTP binding and a novel Gαs regulator
Authors: Ahn Donghoon , Provasi Davide , Duc Nguyen Minh , Xu Jun , Salas-Estrada Leslie , Spasic Aleksandar , Yun Min Woo , Kang Juyeong , Gim Dongmin , Lee Jaecheol , Du Yang , Filizola Marta , Chung Ka Young 
Published: October 2022

SUMMARYG proteins are major signaling partners for G protein-coupled receptors (GPCRs). Although stepwise structural changes during GPCR–G protein complex formation and guanosine diphosphate (GDP) release have been reported, no information is available with regard to guanosine triphosphate (GTP) binding. Here, we used a novel Bayesian integrative modeling framework that combines data from hydrogen-deuterium exchange mass spectrometry, tryptophan-induced fluorescence quenching, and metadynamics simulations to derive a kinetic model and atomic-level characterization of stepwise conformational changes incurred by the β2-adrenergic receptor (β2AR)-Gs complex after GDP release and GTP binding. Our data suggest rapid GTP binding and GTP-induced dissociation of Gαs from β2AR and Gβγ, as opposed to a slow closing of the Gαs α-helical domain (AHD). Yeast-two-hybrid screening using Gαs AHD as bait identified melanoma-associated antigen D2 (MAGE D2) as a novel AHD-binding protein, which was also shown to accelerate the GTP-induced closing of the Gαs AHD.
Novel genetic traits inXanthomonasunveiled by the complete genome sequencing of three clade-1 xanthomonads
Authors: Peduzzi Chloé , Sagia Angeliki , Burokienė Daiva , Nagy Ildikó Katalin , Saux Marion Fischer-Le , Portier Perrine , Dereeper Alexis , Cunnac Sébastien , Roman-Reyna Veronica , Jacobs Jonathan M. , Bragard Claude , Koebnik Ralf 
Published: October 2022

ABSTRACTEvolutionary early-branching xanthomonads, also referred to as clade-1 xanthomonads, include major plant pathogens, most of which colonize monocotyledonous plants. Seven species have been validly described, among them the two sugarcane pathogensXanthomonas albilineansandXanthomonas sacchari, andXanthomonas translucens, which infects small grain cereals, diverse grasses, but also asparagus and pistachio trees. Single-gene sequencing and genomic approaches indicated that this clade likely contains more, yet undescribed species. In this study, we sequenced representative strains of three novel species using long-read sequencing technology.Xanthomonassp. pv.phormiicolastrain CFBP 8444 causes bacterial streak on New Zealand flax, another monocotyledonous plant.Xanthomonassp. strain CFBP 8443 has been isolated from common bean andXanthomonassp. strain CFBP 8445 originated from banana. Complete assemblies of the chromosomes confirmed their unique taxonomic position within clade 1 ofXanthomonas. Genome mining revealed novel genetic traits, hitherto undescribed in other members of theXanthomonasgenus. In strain CFBP 8444, we identified genes related to the synthesis of coronatine-like compounds, a phytotoxin produced by several pseudomonads, which raises interesting questions about the evolution and pathogenicity of this pathogen. In addition, strain CFBP 8444 was found to encode a second, atypical flagellar gene cluster in addition to the canonical flagellar gene cluster. Overall, this research represents an important step toward better understanding the evolutionary history and biology of early-branching xanthomonads.
Variation in the rate lateral gene transfers accumulate in a grass lineage
Authors: Raimondeau Pauline , Bianconi Matheus E. , Pereira Lara , Parisod Christian , Christin Pascal-Antoine , Dunning Luke T. 
Published: October 2022

AbstractLateral gene transfer (LGT) has been reported in multiple eukaryotes. This process seems particularly widespread in the grass family, although we know very little about the underlying dynamics and how it impacts gene content variation within a species.Alloteropsis semialatais a tropical grass, and multiple LGT were detected in a reference genome assembled from an Australian individual. As part of this study we assemble three additionalde novogenomes forA. semialataand one for its sister speciesAlloteropsis angusta. In total we detect 168 LGT across the five reference genomes. Using whole-genome resequencing data for a further 40 individuals we establish the distribution of these transfers and map their origin along the species phylogeny. This shows that many LGTs were acquired relatively recently, with numerous secondary losses. Exponential decay models indicate that the rate of LGT acquisitions varied significantly among lineages [6-28 per Ma], with a high rate of subsequent LGT losses [11-24% per Ma] that largely exceeds that of native loci [0.02-0.8% per Ma]. This high turnover creates large intraspecific structural variants, with a preponderance of LGT occurring as accessory genes in theAlloteropsispangenome. The acquired genes represent unparalleled genetic novelties, having independently evolved for tens of millions of years before they were transferred. Ultimately, the rapid LGT turnover generates standing variation that can fuel local adaptation.
Modeling of possible quadruplexes and i-motifs formed during DNA contacts: strategy, classification, most probable shapes, origami based on quadruplexes
Authors: Tsvetkov Vladimir B. 
Published: October 2022

ABSTRACTA strategy for creating 3D models of non-canonical forms of DNA and RNA is proposed in this research. Through this strategy, models of all possible forms of non-canonical structures created by contacts of single-stranded DNA with sequence (G3T)nG3and/or duplexes with (G3T)nG3and (C3A)nC3fragments were built and tested by MD. In particular, models of stacks formed from right and left twisted quadruplexes; the structure resembling the Holliday structure, with the hole, on the border of which the quadruplex (G4) and the i-motif (IM) were located opposite each other; layers formed from G4s grids were constructed. The most probable of these non-canonical forms arising from contacts of duplexes with (G3T)nG3for n=1,3,5 were determined by estimating the contributions to the free energy.
Bidirectional regulation of postmitotic H3K27me3 distributions underlie cerebellar granule neuron maturation dynamics
Authors: Ramesh Vijyendra , Liu Fang , Minto Melyssa S. , Chan Urann , West Anne E. 
Published: October 2022

AbstractThe functional maturation of neurons is a prolonged process that extends well beyond mitotic exit and is mediated by the chromatin-dependent orchestration of gene transcription programs. We find that the postnatal maturation of cerebellar granule neurons (CGNs) requires dynamic changes in the genomic distribution of histone H3 lysine 27 trimethylation (H3K27me3), demonstrating a function for this chromatin modification beyond its role in cell fate specification. The developmental loss of H3K27me3 at promoters of genes that turn on as CGNs mature is facilitated by the lysine demethylase, and ASD-risk gene, Kdm6b. Interestingly, inhibition of the H3K27 methyltransferase EZH2 in newborn CGNs not only blocks the repression of progenitor genes but also impairs the induction of mature CGN genes, showing the importance of bidirectional H3K27me3 regulation across the genome. These data demonstrate that H3K27me3 turnover in developing postmitotic neurons regulates the temporal coordination of gene expression programs that underlie functional neuronal maturation.
Co-option of ancestral signal elements in the evolution of a cooperative parental behavior
Authors: Moss Jeanette B. , Tumulty James P. , Fischer Eva K. 
Published: October 2022

AbstractThe emergence of complex social interactions is predicted to be an important selective force in the diversification of communication systems. Parental care presents a key social context in which to study the evolution of novel signals, as care often requires communication and behavioral coordination between parents and is an evolutionary stepping-stone towards increasingly complex social systems. Anuran amphibians (frogs and toads) are a classic model of acoustic communication and the vocal repertoires of many species have been characterized in the contexts of advertisement, courtship, and aggression; yet quantitative descriptions of calls elicited in the context of parental care are lacking. The biparental poison frog,Ranitomeya imitator, exhibits a remarkable parenting behavior in which females, cued by the calls of their male partners, feed tadpoles unfertilized eggs. Here, we characterized and compared calls across three social contexts, for the first time including a parental care context. We found that egg feeding calls share some properties with both advertisement and courtship calls but also had unique properties. Multivariate analysis revealed high classification success for advertisement and courtship calls but misclassified nearly half of egg feeding calls as either advertisement or courtship calls, suggesting additional signal modalities play a role in parental communication. Egg feeding and courtship calls both contained less identity information than advertisement calls, as expected for signals used in close-range communication where uncertainty about identity is low. Taken together, egg feeding calls likely borrowed and recombined elements of both ancestral call types to solicit a novel, context-dependent parenting response.Significance StatementParental care has evolved independently in every major animal lineage and represents a major step in the evolution of complex sociality. Communication systems may need to increase in complexity. To explore these ideas, we characterized calls associated with trophic egg feeding, a unique cooperative parental behavior in the biparental mimic poison frog and compared them to calls associated with mate attraction (advertisement and courtship calls). Our analysis revealed some distinct, but many shared properties of signals elicited during egg feeding, suggesting that signals deployed in a novel social context evolve via modification and recombination of existing signals. These findings deepen our understanding of the relationship between complexity of social and communication systems.
Signal integration by a bHLH circuit enables fate choice in neural stem cells
Authors: Nandagopal Nagarajan , Terrio Alexsandra , Vicente Fernando Z. , Jambhekar Ashwini , Lahav Galit 
Published: October 2022

AbstractStem cells integrate information from multiple signals in their environment to make fate decisions. It is unclear how signal integration is linked to the coordinated activation of a target fate program and simultaneous inactivation of competing fates. Here, we investigated this question in mouse neural stem cells, which differentiate synergistically into astrocytes in response to combined treatment with Bone Morphogenetic Protein (BMP) and Leukemia Inhibitory Factor (LIF) at the expense of alternative neuronal or oligodendrocyte fates. Analysis of the expression dynamics of Glial Fibrillary Acidic Protein (GFAP), an early astrocyte marker, showed that its synergistic activation in BMP and LIF reflects early activation by LIF which is sustained by a delayed contribution to its expression from BMP. In parallel, multiplexed RNA-FISH analysis of 14 basic helix-loop-helix (bHLH) transcription factors, known to regulate alternative fates, showed that LIF and BMP individually control different subsets of bHLHs, but together suppress all bHLHs known to promote alternative fates. Ectopic expression experiments showed that these bHLHs also inhibit GFAP induction, suggesting that suppression of alternative fates by BMP + LIF simultaneously relieves GFAP inhibition. In particular, BMP primarily affected inhibitory bHLHs indirectly, through induction of Id factors, explaining why it has a delayed contribution to GFAP transcription compared to LIF. These results show that a circuit of bHLH factors enables both synergistic astrocytic differentiation and suppression of alternative fates in NSCs. Signal integration by bHLH circuits for fate choice could be broadly relevant, given the widespread utilization of these and other bHLH factors across diverse developmental contexts.