bluuebunny/crossref_metadata_2025_split huggingface dataset:
X-chromosome upregulation is dynamically linked to the X-inactivation state
Authors: Lentini Antonio , Coucoravas Christos , Andrews Nathanael , Enge Martin , Deng Qiaolin , Reinius Björn 
Published: July 2020

AbstractMammalian X-chromosome dosage balance is regulated by X-chromosome inactivation (XCI) and X-chromosome upregulation (XCU), but the dynamics of XCU as well as the interplay between the two mechanisms remain poorly understood. Here, we mapped XCU throughout early mouse embryonic development at cellular and allelic resolution, revealing sex- and lineage-specific dynamics along key events in X-chromosome regulation. Our data show that XCU is linearly proportional to the degree of XCI, indicating that dosage compensation ensues based on mRNA levels rather than number of active X chromosomes. In line with this, we reveal that the two active X chromosomes in female naïve embryonic stem cells are not hyperactive as previously thought. In all lineages, XCU was underlain by increased transcriptional burst frequencies, providing a mechanistic basis in vivo. Together, our results demonstrate unappreciated flexibility of XCU in balancing X-chromosome expression, and we propose a general model for allelic dosage balance, applicable for wider mechanisms of transcriptional regulation.
SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells
Authors: Kim Ji Young , Bai Yuntao , Jayne Laura A. , Abdulkader Ferdos , Gandhi Megha , Parikh Samir V. , Song Min-Ae , Bajwa Amandeep , Pabla Navjot Singh 
Published: July 2020

AbstractAcute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, as well as cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxic, cytotoxic, and inflammatory insults to renal tubular epithelial cells (RTECs) resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene upregulation is a common transcriptional stress response in RTECs to ischemia, cisplatin, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuro-endocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia, cisplatin, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, addback experiments showed that aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf upregulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney epithelial cells.
ArabidopsisUGT76B1 glycosylatesN-hydroxy-pipecolic acid and inactivates systemic acquired resistance in tomato
Authors: Holmes Eric C. , Chen Yun-Chu , Mudgett Mary Beth , Sattely Elizabeth S. 
Published: July 2020

AbstractSystemic acquired resistance (SAR) is a mechanism that plants utilize to connect a local pathogen infection to global defense responses.N-hydroxy-pipecolic acid (NHP) and a glycosylated derivative are produced during SAR, yet their individual roles in the response have not yet been elucidated. Here we report thatArabidopsis thalianaUGT76B1 can generate glycosylated NHP (NHP-Glc)in vitroand when transiently expressed alongside Arabidopsis NHP biosynthetic genes in two Solanaceous plants. During infection, Arabidopsisugt76b1mutants do not accumulate NHP-Glc and accumulate less glycosylated salicylic acid (SA-Glc) than wild type plants. The metabolic changes inugt76b1mutant plants are accompanied by enhanced defense to the bacterial pathogenPseudomonas syringae, suggesting that glycosylation of SAR molecules NHP and SA by UGT76B1 plays an important role in defense modulation. Transient expression of ArabidopsisUGT76B1with the Arabidopsis NHP biosynthesis genesALD1andFMO1in tomato increases NHP-Glc production and reduces NHP accumulation in local tissue, and abolishes the systemic resistance seen when expressing NHP-biosynthetic genes alone. These findings reveal that the glycosylation of NHP by UGT76B1 alters defense priming in systemic tissue and provide further evidence for the role of the NHP aglycone as the active metabolite in SAR signaling.
Neutrophil extracellular traps impair regeneration
Authors: Wier Eric , Asada Mayumi , Wang Gaofeng , Alphonse Martin P. , Li Ang , Hintelmann Chase , Youn Christine , Pielstick Brittany , Ortines Roger , Miller Lloyd S. , Archer Nathan K. , Garza Luis A. 
Published: July 2020

AbstractFibrosis is a major health burden across diseases and organs. To remedy this, we study wound induced hair follicle regeneration (WIHN) as a model of non-fibrotic healing that recapitulates embryogenesis for de novo hair follicle morphogenesis after wounding. We have previously demonstrated that TLR3 promotes WIHN through binding dsRNA, but the source of which is still unclear. Here, we demonstrate that multiple distinct contexts of high WIHN all show a strong neutrophil signature, and given the likelihood of nuclear dsRNA release during the production of neutrophil extracellular trap (NETs), we hypothesized that mature neutrophils and NETs might promote WIHN. Consistent with this, in addition to the presence of mature neutrophils shortly after wounding, neutrophils remain within the wound after the barrier is reestablished, where they produce extracellular traps (NETs) that likely release spliceosomal U1 dsRNA. Contrary to our hypothesis, genetic models of neutrophil depletion show enhanced WIHN. Pad4 null mice that are defective in NET production also augment WIHN. Finally, using single-cell RNA sequencing, we identified a dramatic increase in mature neutrophils in the wound beds of low regenerating Tlr3-/- mice. Taken together, these results demonstrate that although mature neutrophils are stimulated by a common pro-regenerative cue, their presence and NETs hinder WIHN.
Quantitative profiling of native RNA modifications and their dynamics using nanopore sequencing
Authors: Begik Oguzhan , Lucas Morghan C , Pryszcz Leszek P , Ramirez Jose Miguel , Medina Rebeca , Milenkovic Ivan , Cruciani Sonia , Liu Huanle , Vieira Helaine Graziele Santos , Sas-Chen Aldema , Mattick John S , Schwartz Schraga , Novoa Eva Maria 
Published: July 2020

ABSTRACTA broad diversity of modifications decorate RNA molecules. Originally conceived as static components, evidence is accumulating that some RNA modifications may be dynamic, contributing to cellular responses to external signals and environmental circumstances. A major difficulty in studying these modifications, however, is the need of tailored protocols to map each modification type individually. Here, we present a new approach that uses direct RNA nanopore sequencing to identify and quantify RNA modifications present in native RNA molecules. First, we show that each RNA modification type results in a distinct and characteristic base-calling ‘error’ signature, which we validate using a battery of genetic strains lacking either pseudouridine (Y) or 2’-O-methylation (Nm) modifications. We then demonstrate the value of these signatures forde novoprediction of Y modifications transcriptome-wide, confirming known Y-modified sites as well as uncovering novel Y sites in mRNAs, ncRNAs and rRNAs, including a previously unreported Pus4-dependent Y modification in yeast mitochondrial rRNA, which we validate using orthogonal methods. To explore the dynamics of pseudouridylation across environmental stresses, we treat the cells with oxidative, cold and heat stresses, finding that yeast ribosomal rRNA modifications do not change upon environmental exposures, contrary to the general belief. By contrast, our method reveals many novel heat-sensitive Y-modified sites in snRNAs, snoRNAs and mRNAs, in addition to recovering previously reported sites. Finally, we develop a novel software,nanoRMS, which we show can estimate per-site modification stoichiometries from individual RNA molecules by identifying the reads with altered current intensity and trace profiles, and quantify the RNA modification stoichiometry changes between two conditions. Our work demonstrates that Y RNA modifications can be predictedde novoand in a quantitative manner using native RNA nanopore sequencing.
Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection
Authors: Rathnasinghe Raveen , Strohmeier Shirin , Amanat Fatima , Gillespie Virginia L. , Krammer Florian , García-Sastre Adolfo , Coughlan Lynda , Schotsaert Michael , Uccellini Melissa 
Published: July 2020

AbstractSevere acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2)(1-3). Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in both the lung and brain leading to lethality. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the lung, and no clinical signs of infection with a challenge dose of 104 plaque forming units. The K18-hACE2 model provides a stringent model for testing the ability of vaccines and antivirals to protect against disease, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.
Stress-induced epigenetic regulation of transcription in neocortical excitatory neurons drives depression-like behavior
Authors: Kwon Deborah Y. , Hu Peng , Zhao Ying-Tao , Beagan Jonathan A. , Nofziger Jonathan H. , Cui Yue , Xu Bing , Zaitseva Daria , Phillips-Cremins Jennifer E. , Blendy Julie A. , Wu Hao , Zhou Zhaolan 
Published: July 2020

ABSTRACTProlonged stress exposure is a major risk factor for the development of depression and comorbid anxiety. Efforts to understand how recurrent stress induces behavioral maladaptation have largely concentrated on the neuronal synapse with limited understanding of the underlying epigenetic mechanisms. Here, we performed complementary bulk nuclei- and single-nucleus transcriptome profiling and mapped fine-scale chromatin architecture in mice subjected to chronic unpredictable stress (CUS) to identify the cell type-specific epigenetic alterations that drive complex behavior. We find that neocortical excitatory neurons are particularly vulnerable to chronic stress and acquire signatures of transcription and chromatin configuration that denote reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in excitatory neurons of the prefrontal cortex (PFC) enhances stress sensitivity in mice, inducing depressive- and anxiety-related behaviors and deregulating the expression of stress-associated genes following an abbreviated stress exposure. Notably, we find that loss of YY1 in PFC excitatory neurons provokes more maladaptive behaviors in stressed females than males. These findings demonstrate how chronic stress provokes maladaptive behavior by epigenetically shaping excitatory neurons in the PFC, identifying a novel molecular target for therapeutic treatment of stress-related mood and anxiety disorders.
Role of SARS-CoV-2 in altering the RNA binding protein and miRNA directed post-transcriptional regulatory networks in humans
Authors: Srivastava Rajneesh , Daulatabad Swapna Vidhur , Srivastava Mansi , Janga Sarath Chandra 
Published: July 2020

AbstractThe outbreak of a novel coronavirus SARS-CoV-2 responsible for COVID-19 pandemic has caused worldwide public health emergency. Due to the constantly evolving nature of the coronaviruses, SARS-CoV-2 mediated alteration on post-transcriptional gene regulation across human tissues remains elusive. In this study, we analyze publicly available genomic datasets to systematically dissect the crosstalk and dysregulation of human post-transcriptional regulatory networks governed by RNA binding proteins (RBPs) and micro-RNAs (miRs), due to SARS-CoV-2 infection. We uncovered that 13 out of 29 SARS-CoV-2 encoded proteins directly interact with 51 human RBPs of which majority of them were abundantly expressed in gonadal tissues and immune cells. We further performed a functional analysis of differentially expressed genes in mock-treated versus SARS-CoV-2 infected lung cells that revealed enrichment for immune response, cytokine-mediated signaling, and metabolism associated genes. This study also characterized the alternative splicing events in SARS-CoV-2 infected cells compared to control demonstrating that skipped exons and mutually exclusive exons were the most abundant events that potentially contributed to differential outcomes in response to viral infection. Motif enrichment analysis on the RNA genomic sequence of SARS-CoV-2 clearly revealed the enrichment for RBPs such as SRSFs, PCBPs, ELAVs, and HNRNPs suggesting the sponging of RBPs by SARS-CoV-2 genome. A similar analysis to study the interactions of miRs with SARS-CoV-2 revealed functionally important miRs that were highly expressed in immune cells, suggesting that these interactions may contribute to the progression of the viral infection and modulate host immune response across other human tissues. Given the need to understand the interactions of SARS-CoV-2 with key post-transcriptional regulators in the human genome, this study provides a systematic computational analysis to dissect the role of dysregulated post-transcriptional regulatory networks controlled by RBPs and miRs, across tissues types during SARS-CoV-2 infection.
AdmixPipe: Population analyses in Admixture for non-model organisms
Authors: Mussmann Steven M. , Douglas Marlis R. , Chafin Tyler K. , Douglas Michael E. 
Published: July 2020

AbstractBackgroundResearch on the molecular ecology of non-model organisms, while previously constrained, has now been greatly facilitated by the advent of reduced-representation sequencing protocols. However, tools that allow these large datasets to be efficiently parsed are often lacking, or if indeed available, then limited by the necessity of a comparable reference genome as an adjunct. This, of course, can be difficult when working with non-model organisms. Fortunately, pipelines are currently available that avoid this prerequisite, thus allowing data to bea prioriparsed. An oft-used molecular ecology program (i.e., Structure), for example, is facilitated by such pipelines, yet they are surprisingly absent for a second program that is similarly popular and computationally more efficient (i.e., Admixture). The two programs differ in that Admixtureemploys a maximum-likelihood framework whereas Structureuses a Bayesian approach, yet both produce similar results. Given these issues, there is an overriding (and recognized) need among researchers in molecular ecology for bioinformatic software that will not only condense output from replicated Admixtureruns, but also infer from these data the optimal number of population clusters (K).ResultsHere we provide such a program (i.e., AdmixPipe) that (a) filters SNPs to allow the delineation of population structure in Admixture, then (b) parses the output for summarization and graphical representation via Clumpak. Our benchmarks effectively demonstrate how efficient the pipeline is for processing large, non-model datasets generated via double digest restriction-site associated DNA sequencing (ddRAD). Outputs not only parallel those from Structure, but also visualize the variation among individual Admixtureruns, so as to facilitate selection of the most appropriateK-value.ConclusionsAdmixPipesuccessfully integrates Admixtureanalysis with popular variant call format (VCF) filtering software to yield file types readily analyzed by Clumpak. Large population genomic datasets derived from non-model organisms are efficiently analyzed via the parallel-processing capabilities of Admixture. AdmixPipeis distributed under the GNU Public License and freely available for Mac OSX and Linux platforms at:https://github.com/stevemussmann/admixturePipeline.
The effect of sequence learning on sensorimotor adaptation
Authors: Liu Yang , Block Hannah J. 
Published: July 2020

AbstractMotor skill learning involves both sensorimotor adaptation (calibrating the response to task dynamics and kinematics), and sequence learning (executing the task elements in the correct order at the necessary speed). These processes typically occur together in natural behavior and share much in common, such as working memory demands, development, and possibly neural substrates. However, sensorimotor and sequence learning are usually studied in isolation in research settings, for example as force field adaptation or serial reaction time tasks (SRTT), respectively. It is therefore unclear whether having predictive sequence information during sensorimotor adaptation would facilitate performance, perhaps by improving sensorimotor planning, or if it would impair performance, perhaps by occupying neural resources needed for sensorimotor learning. Here we evaluated adaptation to a distance-dependent force field in two different SRTT contexts: In Experiment 1, 28 subjects reached between 4 targets in a sequenced or random order. In Experiment 2, 40 subjects reached to one target, but 3 force field directions were applied in a sequenced or random order. We did not observe any consistent influence of target position sequence on force field adaptation in Experiment 1. However, sequencing of force field directions facilitated sensorimotor adaptation and retention in Experiment 2. This is inconsistent with the idea that sensorimotor and sequence learning share neural resources in any mutually exclusive fashion. These findings indicate that under certain conditions, perhaps especially when the sequence is related to the sensorimotor perturbation itself as in Experiment 2, sequence learning may interact with sensorimotor learning in a facilitatory manner.
Dynamics of Prion Proliferation Under Combined Treatment of Pharmacological Chaperones and Interferons via a Mathematical Model
Authors: Garzón Doménica N. , Castillo Yair , Navas-Zuloaga M. Gabriela , Culik Nora , Darwin Leah , Hardin Abigail , Yang Anji , Castillo-Garsow Carlos , Ríos-Soto Karen , Arriola Leon , Ghosh Aditi 
Published: July 2020

AbstractPrion diseases are lethal neurodegenerative disorders such as mad cow disease in bovines, chronic wasting disease in cervids, and Creutzfeldt-Jakob disease in humans. They are caused when the prion protein PrPCmisfolds into PrPSc, which is capable of inducing further misfolding in healthy PrPCproteins. Recentin vivoexperiments show that pharmacological chaperones can temporarily prevent this conversion by binding to PrPCmolecules, and thus constitute a possible treatment. A second strategic approach uses interferons to decrease the concentration of PrPSc. In order to study the quantitative effects of these treatments on prion proliferation, we develop a model using a non-linear system of ordinary differential equations. By evaluating their efficacy and potency, we find that interferons act at lower doses and achieve greater prion decay rates. However, there are benefits in combining them with pharmacological chaperones in a two-fold therapy. This research is crucial to guide future prion experiments and inform potential treatment protocols.
Early Identification of Patients with Acute Gastrointestinal Bleeding using Electronic Health Record Phenotyping
Authors: Shung Dennis , Tsay Cynthia , Laine Loren , Thomas Prem , Partridge Caitlin , Simonov Michael , Hsiao Allen , Taylor Andrew 
Published: July 2020

Background and AimGuidelines recommend risk stratification scores in patients presenting with gastrointestinal bleeding (GIB), but such scores are uncommonly employed in practice. Automation and deployment of risk stratification scores in real time within electronic health records (EHRs) would overcome a major impediment. This requires an automated mechanism to accurately identify (“phenotype”) patients with GIB at the time of presentation. The goal is to identify patients with acute GIB by developing and evaluating EHR-based phenotyping algorithms for emergency department (ED) patients.MethodsWe specified criteria using structured data elements to create rules for identifying patients, and also developed a natural-language-processing (NLP)-based algorithm for automated phenotyping of patients, tested them with tenfold cross-validation (n=7144) and external validation (n=2988), and compared them with the standard method for encoding patient conditions in the EHR, Systematized Nomenclature of Medicine (SNOMED). The gold standard for GIB diagnosis was independent dual manual review of medical records. The primary outcome was positive predictive value (PPV).ResultsA decision rule using GIB-specific terms from ED triage and from ED review-of-systems assessment performed better than SNOMED on internal validation (PPV=91% [90%-93%] vs. 74% [71%-76%], P<0.001) and external validation (PPV=85% [84%-87%] vs. 69% [67%-71%], P<0.001). The NLP algorithm (external validation PPV=80% [79-82%]) was not superior to the structured-datafields decision rule.ConclusionsAn automated decision rule employing GIB-specific triage and review-of-systems terms can be used to trigger EHR-based deployment of risk stratification models to guide clinical decision-making in real time for patients with acute GIB presenting to the ED.