bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of height as a disease risk factor through a phenome-wide association study of genetically-predicted height
Authors: Raghavan Sridharan , Huang Jie , Tcheandjieu Catherine , Huffman Jennifer E. , Litkowski Elizabeth , Ho Yuk-Lam A. , Hunter-Zinck Haley , Zhao Hongyu , Marouli Eirini , North Kari E. ,   the VA Million Veteran Program, Lange Ethan , Lange Leslie A. , Voight Benjamin F. , Gaziano J. Michael , Pyarajan Saiju , Hauser Elizabeth R. , Tsao Philip S. , Wilson Peter W. F. , Chang Kyong-Mi , Cho Kelly , O’Donnell Christopher J. , Sun Yan V. , Assimes Themistocles L. 
Published: August 2021

AbstractBackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and FindingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n=222,300) and non-Hispanic Black (AA, n=58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy. As a number of traits associated with genetically-predicted height frequently co-occur with diabetes mellitus and/or CHD, we evaluated effect modification by diabetes and CHD status of genetically-predicted height associations with risk factors for and complications of diabetes and CHD. We found modification of effects of MR associations by diabetes for skin and bone infections and by CHD status for atrial fibrillation/flutter.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
Transcriptional organization and regulation of thePseudomonas putidaflagellar system
Authors: Leal-Morales Antonio , Pulido-Sánchez Marta , López-Sánchez Aroa , Govantes Fernando 
Published: August 2021

SUMMARYA single region of thePseudomonas putidagenome, designated the flagellar cluster, includes 59 genes potentially involved in the biogenesis and function of the flagellar system. Here we combine bioinformatics andin vivogene expression analyses to clarify the transcriptional organization and regulation of the flagellar genes in the cluster. We have identified eleven flagellar operons and characterized twenty-two primary and internal promoter regions. Our results indicate that synthesis of the flagellar apparatus and core chemotaxis machinery is regulated by a three-tier cascade in whichfleQis a Class I gene, standing at the top of the transcriptional hierarchy. FleQ- andσ54-dependent Class II genes encode most components of the flagellar structure, part of the chemotaxis machinery and multiple regulatory elements, including the flagellarσfactor FliA. FliA activation of Class III genes enables synthesis of the filament, one stator complex and completion of the chemotaxis apparatus. Accessory regulatory proteins and an intricate operon architecture add complexity to the regulation by providing feedback and feed-forward loops to the main circuit. Because of the high conservation of the gene arrangement and promoter motifs, we believe that the regulatory circuit presented here may also apply to other environmental pseudomonads.ORIGINALITY-SIGNIFICANCE STATEMENTThis is the first integrative study of the flagellar transcriptional cascade inPseudomonas putida. Our results provide a new transcriptional organization featuring several operons with a nested architecture, detailed regulatory characterization of twenty-two flagellar promoters and a novel hierarchy for the regulatory circuit of the flagellar transcriptional cascade. The results presented represent a significant departure from previous models for other related bacteria. High conservation of flagellar gene organization and promoter sequences suggest that our observations may be relevant to other pseudomonads.
Transcriptome profiling of theCaenorhabditis elegansintestine reveals that ELT-2 negatively and positively regulates intestinal gene expression within the context of a gene regulatory network
Authors: Williams Robert T.P. , King David C. , Mastroianni Izabella R. , Hill Jessica L. , Apenes Nicolai W. , Ramirez Gabriela , Miner E. Catherine , Moore Andrew , Coleman Karissa , Osborne Nishimura Erin 
Published: August 2021

AbstractELT-2 is the major transcription factor required forCaenorhabditis elegansintestinal development. ELT-2 expression initiates in embryos to promote development and then persists after hatching through the larval and adult stages. Though the sites of ELT-2 binding are characterized and the transcriptional changes that result from ELT-2 depletion are known, an intestine-specific transcriptome profile spanning developmental time has been missing. We generated this dataset by performing Fluorescence Activated Cell Sorting (FACS) on intestine cells at distinct developmental stages. We analyzed this dataset in conjunction with previously conducted ELT-2 studies to evaluate the role of ELT-2 in directing the intestinal gene regulatory network through development. We found that only 33% of intestine-enriched genes in the embryo were direct targets of ELT-2 but that number increased to 75% by the L3 stage. This suggests additional transcription factors promote intestinal transcription especially in the embryo. Furthermore, only half of ELT-2’s direct target genes were dependent on ELT-2 for their proper expression levels, and an equal proportion of those responded toelt-2depletion with over-expression as with under-expression. That is, ELT-2 can either activate or repress direct target genes. Additionally, we observed that ELT-2 repressed its own promoter, implicating new models for its autoregulation. Together, our results illustrate that ELT-2 impacts roughly 20 – 50% of intestine-specific genes, that ELT-2 both positively and negatively controls its direct targets, and that the current model of the intestinal regulatory network is incomplete as the factors responsible for directing the expression of many intestinal genes remain unknown.
Biosynthetic gene cluster profiling predicts the positive association between antagonism and phylogeny in Bacillus
Authors: Xia Liming , Miao Youzhi , Cao A’li , Liu Yan , Liu Zihao , Sun Xinli , Xue Yansheng , Xu Zhihui , Xun Weibing , Shen Qirong , Zhang Nan , Zhang Ruifu 
Published: August 2021

AbstractUnderstanding the driving forces and intrinsic mechanisms of microbial competition is a fundamental question in microbial ecology. Despite the well-established negative correlation between exploitation competition and phylogenetic distance, the process of interference competition that is exemplified by antagonism remains controversial. Here, we studied the genus Bacillus, a commonly recognized producer of multifarious antibiotics, to explore the role of phylogenetic patterns of biosynthetic gene clusters (BGCs) in mediating the relationship between antagonism and phylogeny. Comparative genomic analysis revealed a positive association between BGC distance and phylogenetic distance. Antagonistic tests demonstrated that the inhibition phenotype positively correlated with both phylogenetic and predicted BGC distance, especially for antagonistic strains possessing abundant BGCs. Mutant-based verification showed that the antagonism was dependent on the BGCs that specifically harbored by the antagonistic strain. These findings highlight that BGC-phylogeny coherence regulates the positive correlation between congeneric antagonism and phylogenetic distance, which deepens our understanding of the driving force and intrinsic mechanism of microbial interactions.
Mitochondrial mRNA is a stable and convenient reference for the normalization of RNA-seq data
Authors: Liu Yusheng , Zhang Yiwei , Lu Falong , Wang Jiaqiang 
Published: August 2021

AbstractThe normalization of high-throughput RNA sequencing (RNA-seq) data is needed to accurately analyze gene expression levels. Traditional normalization methods can either correct the differences in sequencing depth, or correct both the sequencing depth and other unwanted variations introduced during sequencing library preparation through exogenous spike-ins1-4. However, the exogenous spike-ins are prone to variation5,6. Therefore, a better normalization approach with a more appropriate reference is an ongoing demand. In this study, we demonstrated that mitochondrial mRNA (mRNA encoded by mitochondria genome) can serve as a steady endogenous reference for RNA-seq data analysis, and performs better than exogenous spike-ins. We also found that using mitochondrial mRNA as a reference can reduce batch effects for RNA-seq data. These results provide a simple and practical normalization strategy for RNA-seq data, which will serve as a valuable tool widely applicable to transcriptomic studies.
Nanopore-Based Enrichment of Antimicrobial Resistance Genes – A Case-Based Study
Authors: Viehweger Adrian , Marquet Mike , Hölzer Martin , Dietze Nadine , Pletz Mathias W. , Brandt Christian 
Published: August 2021

AbstractRapid screening of hospital admissions to detect asymptomatic carriers of resistant bacteria can prevent pathogen outbreaks. However, the resulting isolates rarely have their genome sequenced due to cost constraints and long turn-around times to get and process the data, limiting their usefulness to the practitioner. Here we use real-time, on-device target enrichment (“adaptive”) sequencing as a highly multiplexed assay covering 1,147 antimicrobial resistance genes. We compare its utility against standard and metagenomic sequencing, focusing on an isolate ofRaoultella ornithinolyticaharbouring three carbapenemases (NDM,KPC,VIM). Based on this experimental data, we then model the influence of several variables on the enrichment results and predict a large effect of nucleotide identity (higher is better) and read length (shorter is better). Lastly, we show how all relevant resistance genes are detected using adaptive sequencing on a miniature (“Flongle”) flow cell, motivating its use in a clinical setting to monitor similar cases and their surroundings.
ATM phosphorylates PP2A subunit A resulting in nuclear export and spatiotemporal regulation of the DNA damage response
Authors: Sule Amrita , Golding Sarah E. , Farhan Syed F. , Watson James , Ahmed Mostafa H. , Kellogg Glen E. , Bernas Tytus , Koebley Sean , Reed Jason C. , Povirk Lawrence F. , Valerie Kristoffer 
Published: August 2021

AbstractAtaxia telangiectasia mutated (ATM) is a serine-threonine protein kinase and important regulator of the DNA damage response (DDR). One critical ATM target is the structural subunit A (PR65) of protein phosphatase 2A (PP2A), known to regulate diverse cellular processes such as mitosis and cell growth as well as dephosphorylating many proteins during the recovery from the DDR. We generated mouse embryonic fibroblasts expressing PR65-WT, -S401A (cannot be phosphorylated), and -S401D (phosphomimetic) transgenes. Significantly, S401 mutants exhibited extensive chromosomal aberrations, impaired DNA double-strand break (DSB) repair and underwent increased mitotic catastrophe after radiation. Our study demonstrates that the phosphorylation of a single, critical PR65 amino acid (S401) by ATM fundamentally controls the DDR, and balances DSB repair quality, cell survival and growth by spatiotemporal PR65 nuclear-cytoplasmic shuttling mediated by the nuclear export receptor CRM1.
Cholinergic interneurons mediate cocaine extinction through similar plasticity across medium spiny neuron subtypes
Authors: Fleming Weston , Lee Junuk , Briones Brandy A. , Bolkan Scott , Witten Ilana B. 
Published: August 2021

AbstractCholinergic interneurons (ChINs) in the nucleus accumbens (NAc) have been implicated in the acquisition and extinction of drug associations, as well as related plasticity in medium spiny neurons (MSNs). However, since most previous work has relied on artificial manipulations, if and how endogenous patterns of cholinergic signaling relate to drug associations is unknown. Moreover, despite great interest in the opposing effects of dopamine on MSN subtypes, whether ChIN-mediated effects are similar or different across MSN subtypes is also unknown. Here, we find that endogenous acetylcholine event frequency during extinction negatively correlates with the strength and persistence of cocaine-context associations across individuals, consistent with effects of artificial manipulation of ChIN activity during extinction. Moreover, ChIN activation during extinction produces a reduction in excitatory synaptic strength on both MSN subtypes, similar to the effect of multiple extinction sessions in the absence of ChIN manipulations. Together, our findings indicate that natural variation in NAc acetylcholine may contribute to individual differences in drug-context extinction by modulating glutamatergic presynaptic strength similarly at both D1R and D2R MSN subtypes.Graphical abstract
Deep brain stimulation in the subthalamic nucleus for Parkinson’s disease can restore dynamics of striatal networks
Authors: Adam Elie M , Brown Emery N , Kopell Nancy , McCarthy Michelle M 
Published: August 2021

AbstractDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson’s disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma and theta oscillations. These rhythms are at the heart of selection, initiation and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of the behavioral deficits observed in PD patients. Interrupting abnormal rhythms and restoring the interaction of rhythms as observed in the healthy striatum may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD, and how DBS can restore normal beta, gamma and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, that were recently shown to preferentially target fast spiking interneurons (FSI) in the striatum. We find that DBS in STN is able to normalize striatal medium spiny neuron (MSN) activity by recruiting FSI dynamics, and restoring the inhibitory potency of FSIs observed in normal condition. We also find that DBS allows the re-expression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study shows how BG connectivity can amplify beta oscillations, and delineates the role of DBS in disrupting beta oscillations and providing corrective input to STN efferents to restore healthy striatal dynamics. It also suggests how gamma oscillations can be leveraged to enhance or supplement DBS treatment and improve its effectiveness.
The control of transcriptional memory by stable mitotic bookmarking
Authors: Bellec Maëlle , Dufourt Jérémy , Hunt George , Lenden-Hasse Hélène , Trullo Antonio , El Aabidine Amal Zine , Lamarque Marie , Gaskill Marissa M , Faure-Gautron Heloïse , Mannervik Mattias , Harrison Melissa M , Andrau Jean-Christophe , Favard Cyril , Radulescu Ovidiu , Lagha Mounia 
Published: August 2021

AbstractTo maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is thought to be mediated, in part, by mitotic bookmarking by transcription factors (TF). However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses ofDrosophilaearly embryos, we provide evidence that the pioneer-like transcription factor GAF acts as stable mitotic bookmarker during zygotic genome activation. We report that GAF remains associated to a large fraction of its interphase targets including atcis-regulatory sequences of key developmental genes, with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and are bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we provide evidence that GAF binding establishes competence for rapid activation upon mitotic exit.
Topological sensitivity analysis revisited for time-harmonic wave scattering problems. Part I: the free space case
Authors: Le Louër Frédérique , Rapún María-Luisa 
Published: August 2021

PurposeIn this paper, the authors revisit the computation of closed-form expressions of the topological indicator function for a one step imaging algorithm of two- and three-dimensional sound-soft (Dirichlet condition), sound-hard (Neumann condition) and isotropic inclusions (transmission conditions) in the free space.Design/methodology/approachFrom the addition theorem for translated harmonics, explicit expressions of the scattered waves by infinitesimal circular (and spherical) holes subject to an incident plane wave or a compactly supported distribution of point sources are available. Then the authors derive the first-order term in the asymptotic expansion of the Dirichlet and Neumann traces and their surface derivatives on the boundary of the singular medium perturbation.FindingsAs the shape gradient of shape functionals are expressed in terms of boundary integrals involving the boundary traces of the state and the associated adjoint field, then the topological gradient formulae follow readily.Originality/valueThe authors exhibit singular perturbation asymptotics that can be reused in the derivation of the topological gradient function that generates initial guesses in the iterated numerical solution of any shape optimization problem or imaging problems relying on time-harmonic acoustic wave propagation.
Board gender diversity and firms' social engagement in the Gulf Cooperation Council (GCC) countries
Authors: Jizi Mohammad , Nehme Rabih , Melhem Cynthia 
Published: August 2021

PurposeThe Gulf Cooperation Council (GCC) countries form a unique socioeconomic environment that makes the conclusions of the prior literature not likely to be applicable. GCC countries have huge oil reserves, yet they are aiming at reducing oil dependency through enhancing transparency, increasing foreign direct investments and reforming their governance structure. Their firms are mainly family owned and have low female representation in leadership positions. The study seeks to fill a literature gap by providing a business case supporting the call for gender diverse boards for better governance.Design/methodology/approachThe study examines a sample of GCC-listed firms for the years 2009–2018. Three measures are used to proxy for firm social engagement, namely, CSR strategy score, environmental, social and governance (ESG) disclosure score and social pillar score. To ensure whether the presence of women on board or the number of women on board is influential on social engagements, the authors use the existence of women on board and the percentage of women on board variables. Data are collected using Thomson Reuters, and generalized least squares (GLS) panel data regression is used to estimate relationships.FindingsThe authors find that female representation on GCC corporate boards is increasing, yet in a slow path. The reported results support the role of women on boards in prompting firms' social agenda and enhancing the level of sustainability reporting. The results also show that female board representation supports the implementation of climate change policy, business ethics policy and health and safety policy.Originality/valueThe paper evidence the add value of women participation on GCC corporate boards in enhancing boards' functionality and governance. The empirical findings encourage firms and policymakers in the GCC countries to increase the share of females on corporate boards to improve firms' citizenship and facilitate attracting foreign investors.
Witnessing Wonderland: Research with Black girls imagining freer futures
Authors: Young Alexis Morgan 
Published: August 2021

PurposeThis paper aims to contribute to a growing body of work (re)imagining the future for Black girls by calling Western notions of time into question. At its core, this paper argues that all Black girls are imaginative beings and that it is essential that Black girlhood imagination as a mode of future-making praxis be considered an integral component in the pursuit of Black liberation. To do such the author engages Black feminist futurity Campt (2017) and Black Quantum Futurity Phillips (2015) to illuminate ways a reconceptualization of time provides us with an analytical tool to amplify Black girls’ liberatory fantasies.Design/methodology/approachA literature review was conducted to synthesize Black girls’ freedom dreams (Kelley, 2002) across time in an effort to demonstrate that Black girls, despite their conditions, are experts in self-defining their dreams of the future. It also highlights methods that researchers use to elucidate the freedom dreams of Black girls years past.FindingsThis paper underscores the urgency in applying future-oriented research practices in the attempt to create a new world for Black girls. It also demonstrates that Black girls have always been and always be, imaginative beings that engaged in future-making dreaming.Research limitations/implicationsThe author offers a conceptual framework for researchers committed to witnessing Black girl imaginations and in an effort to work in concert with Black girls to get them freer, faster.Originality/valueThis paper makes the argument that studying the imaginations and freedom dreams of Black girls requires the employment of future-oriented theories that have a racial, gender and age-based analysis.