bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions
Authors: Chen Lizhen , Zhang Zhao , Han Qinyu , Rodrigues Leticia , Zboril Emily , Adhikari Rashmi , Li Xin , Ko Su-Hyuk , Xue Pengya , Smith Emilie , Xu Kexin , Wang Qianben , Huang Tim Hui-Ming , Chong Shasha , Liu Zhijie 
Published: October 2022

SummaryTranscription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by intrinsically disordered regions (IDRs) from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports the notion that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, thereby providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.
DistinctWolbachialocalization patterns in oocytes of diverse host species reveal multiple strategies of maternal transmission
Authors: Radousky Yonah A. , Hague Michael T.J. , Fowler Sommer , Paneru Eliza , Codina Adan , Rugamas Cecilia , Hartzog Grant , Cooper Brandon S. , Sullivan William 
Published: October 2022

ABSTRACTA broad array of endosymbionts radiate through host populations via vertical transmission, yet much remains unknown concerning the cellular basis, diversity and routes underlying this transmission strategy. Here we address these issues, by examining the cellular distributions ofWolbachiastrains that diverged up to 50 million years ago in the oocytes of 18 divergentDrosophilaspecies. This analysis revealed threeWolbachiadistribution patterns: 1) a tight clustering at the posterior pole plasm (the site of germline formation); 2) a concentration at the posterior pole plasm, but with a significant bacteria population distributed throughout the oocyte; 3) and a distribution throughout the oocyte, with none or very few located at the posterior pole plasm. Examination of this latter class indicatesWolbachiaaccesses the posterior pole plasm during the interval between late oogenesis and the blastoderm formation. We also find that oneWolbachiastrain in this class concentrates in the posterior somatic follicle cells that encompass the pole plasm of the developing oocyte. In contrast, strains in whichWolbachiaconcentrate at the posterior pole plasm generally exhibit no or fewWolbachiain the follicle cells associated with the pole plasm. Taken together, these studies suggest that for someDrosophilaspecies,Wolbachiainvade the germline from neighboring somatic follicle cells. Phylogenomic analysis indicates that closely relatedWolbachiastrains tend to exhibit similar patterns of posterior localization, suggesting that specific localization strategies are a function ofWolbachia-associated factors. Previous studies revealed that endosymbionts rely ononeof two distinct routes of vertical transmission: continuous maintenance in the germline (germline-to-germline) or a more circuitous route via the soma (germline-to-soma-to-germline). Here we provide compelling evidence thatWolbachiastrains infectingDrosophilaspecies maintain the diverse arrays of cellular mechanisms necessary forbothof these distinct transmission routes. This characteristic may account for its ability to infect and spread globally through a vast range of host insect species.
Single-cell RNA-seq reveals alterations in peripheralCX3CR1and nonclassical monocytes in familial tauopathy
Authors: Sirkis Daniel W. , Solsberg Caroline Warly , Johnson Taylor P. , Bonham Luke W. , Sturm Virginia E. , Lee Suzee E. , Rankin Katherine P. , Rosen Howard J. , Boxer Adam L. , Seeley William W. , Miller Bruce L. , Geier Ethan G. , Yokoyama Jennifer S. 
Published: October 2022

AbstractBackgroundEmerging evidence from mouse models is beginning to elucidate the brain’s immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system.MethodsTo address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants inMAPT, the gene encoding tau.ResultsAnalysis of ∼181,000 individual PBMC transcriptomes fromMAPTpathogenic variant carriers (n= 8) and healthy non-carrier controls (n= 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression ofCX3CR1– the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models – in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, includingFCGR3A. Finally, we identified reductions inTMEM176AandTMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation.ConclusionsOur results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes.CX3CR1and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.
Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats
Authors: McReynolds Jayme R. , Wolf Colten P. , Starck Dylan M. , Mathy Jacob C. , Schaps Rebecca , Krause Leslie A. , Hillard Cecilia J. , Mantsch John R. 
Published: October 2022

AbstractStress is prevalent in the lives of those with substance use disorders (SUDs) and influences SUD outcomes. Understanding the neurobiological mechanisms through which stress promotes drug use is important for the development of effective SUD interventions. We have developed a model wherein exposure to a stressor, uncontrollable electric footshock, daily at the time of cocaine self-administration (SA) escalates intake in male rats. Here we test the hypothesis that stress-induced escalation of cocaine SA requires CB1 cannabinoid receptor signaling. Male Sprague-Dawley rats self-administered cocaine (0.5 mg/kg/inf, i.v.) during 2-h sessions comprised of four 30-min SA components separated by 5-min shock sequences or 5-min shock-free periods for 14 days. Footshock produced an escalation of cocaine SA that persisted following shock removal. Systemic administration of the cannabinoid receptor type 1 (CB1R) antagonist, AM251, attenuated cocaine intake only in rats with a history of stress. This effect was localized to the mesolimbic system, as intra-nucleus accumbens (NAc) shell and intra-ventral tegmental area (VTA) micro-infusions of AM251 attenuated cocaine intake only in stress-escalated rats. Cocaine SA, regardless of stress history, increases CB1R binding site density in the VTA, but not NAc shell. Following extinction, cocaine-primed reinstatement (10 mg/kg, ip) was increased in rats with prior footshock during SA. AM251 attenuated reinstatement only in rats with a stress history. Altogether, these data demonstrate that mesolimbic CB1R signaling is required to escalate intake and heighten relapse susceptibility and suggest that repeated stress at the time of cocaine use enhances mesolimbic CB1R signaling through a currently unknown mechanism.
Allosteric mechanism of transcription inhibition by NusG-dependent pausing of RNA polymerase
Authors: Vishwakarma Rishi K. , Qayyum M. Zuhaib , Babitzke Paul , Murakami Katsuhiko S. 
Published: October 2022

AbstractNusG is a transcription elongation factor that stimulates transcription pausing in Gram+ bacteria includingBacillus subtilisby sequence-specific interaction with a conserved pause-inducing-11TTNTTT-6motif found in the non-template DNA (ntDNA) strand within the transcription bubble. To reveal the structural basis of NusG-dependent pausing, we determined a cryo-EM structure of a paused transcription complex containing RNAP, NusG, and the TTNTTT motif in the ntDNA strand. Interaction of NusG with the ntDNA strand rearranges the transcription bubble by positioning three consecutive T residues in a cleft between NusG and the β-lobe domain of RNAP. We revealed that the RNAP swivel module rotation (swiveling), which widens (swiveled state) and narrows (non-swiveled state) a cleft between NusG and the β-lobe, is an intrinsic motion of RNAP and is directly linked to nucleotide binding at the active site and to trigger loop folding, an essential conformational change of all cellular RNAPs for the RNA synthesis reaction. We also determined cryo-EM structures of RNAP escaping from a paused transcription complex. These structures revealed the NusG-dependent pausing mechanism by which NusG-ntDNA interaction inhibits the transition from swiveled to non-swiveled states, thereby preventing trigger loop folding and RNA synthesis allosterically. This motion is also reduced by formation of an RNA hairpin within the RNA exit channel. Thus, the pause half-life can be modulated by the strength of the NusG-ntDNA interaction and/or the stability of the RNA hairpin. NusG residues that interact with the TTNTTT motif are widely conserved in bacteria, suggesting that NusG-dependent pausing of transcription is widespread.Significance statementTranscription pausing by RNA polymerase (RNAP) regulates gene expression where it controls co-transcriptional RNA folding, synchronizes transcription with translation, and provides time for binding of regulatory factors. Transcription elongation factor NusG stimulates pausing in Gram+ bacteria includingBacillus subtilisandMycobacterium tuberculosisby sequence-specific interaction with a conserved pause motif found in the non-template DNA (ntDNA) strand within the transcription bubble. Our structural and biochemical results revealed that part of the conserved TTNTTT motif in ntDNA is extruded and sandwiched between NusG and RNAP. Our results further demonstrate that an essential global conformational change in RNAP is directly linked to RNA synthesis, and that the NusG-ntDNA interaction pauses RNA synthesis by interfering with this conformational change.
Distribution and survival strategies of diazotrophs in the Arctic Ocean revealed by global-scale metagenomic analysis
Authors: Shiozaki Takuhei , Nishimura Yosuke , Yoshizawa Susumu , Takami Hideto , Hamasaki Koji , Fujiwara Amane , Nishino Shigeto , Harada Naomi 
Published: October 2022

ABSTRACTNitrogen fixation is the major source of reactive nitrogen in the ocean and has been considered to occur specifically in low-latitude oligotrophic oceans. Recent studies have shown that nitrogen fixation also occurs in the polar regions and thus is a global process, although the physiological and ecological characteristics of polar diazotrophs are not yet known. Here, we successfully reconstructed genomes, including that of cyanobacterium UCYN-A (Candidatus‘Atelocyanobacterium thalassa’), from metagenome data corresponding to 111 samples isolated from the Arctic Ocean. These diazotrophs were highly abundant in the Arctic Ocean (max., 1.28% of the total microbial community), suggesting that they have important roles in the Arctic ecosystem and biogeochemical cycles. Diazotrophs in the Arctic Ocean were either Arctic-specific or universal species. Arctic-specific diazotrophs, including Arctic UCYN-A, had unique gene sets (e.g., aromatics degradation) and/or a very small cell size (<0.2 µm), suggesting adaptations to Arctic-specific conditions. Universal diazotrophs were generally heterotrophs and commonly had the gene that encodes the cold-inducible RNA chaperone, which presumably makes their survival possible even in deep, cold waters and polar regions. Thus both types of diazotroph have physiological traits adaptable to their environments, which allow nitrogen fixation on a global scale.
Vascular endothelial growth factor A contributes to the increasing of mammalian respiratory epithelial permeability induced byPasteurella multocidainfection
Authors: Lin Lin , Yang Jie , Zhang Dajun , Lv Qingjie , Wang Fei , Liu Peng , Wang Mixue , Shi Congcong , Huang Xi , Liang Wan , Tan Chen , Wang Xiangru , Chen Huanchun , Wilson Brenda A , Wu Bin , Peng Zhong 
Published: October 2022

AbstractInfections withPasteurella multocidacan cause significant zoonotic respiratory problems in both humans and animals.In vivotests in mouse infection models were used to investigate the mechanisms of respiratory epithelial barrier dysfunction during respiratory bacterial infection with these pathogens. Results revealed thatP. multocidainfection significantly increased epithelial permeability and increased expression of vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) in murine tracheae and lungs. In murine lung epithelial cell (MLE-12) models,P. multocidainfection decreased the expression of tight junctions (ZO-1) and adherens junctions (β-catenin, E-cadherin), but induced the activation of the hypoxia-inducible factor-1α (HIF-1α) and VEGFA signaling. When expression of HIF-1α is suppressed, the induction of VEGFA and ZO-1expression byP. multocidainfection is decreased. We also found that intervention of HIF-1α and VEGFA signaling affected infection outcomes caused by respiratory bacteria in mouse models. Most importantly, we demonstrated thatP. multocidainfection increased permeability of human respiratory epithelial cells and this process was associated with the activation of the HIF-1α and VEGFA signaling and likely contributes to the pathogenesis ofP. multocidain humans.ImportanceMammalian respiratory epithelium forms the first line of defense against infections withPasteurella multocida, an important zoonotic respiratory pathogen. In this study, we foundP. multocidainfection increased respiratory epithelial permeability and promoted the induction of the hypoxia-HIF-1α-VEGFA axis in both mouse and murine cell models. Similar findings were also demonstrated in human respiratory epithelial cells. The results from this study gain important knowledge about the pathogenesis ofP. multocidacausing infections in both animals and humans.
Behavioral interventions to improve sleep outcomes in people with multiple sclerosis: A systematic review
Authors: Turkowitch David , Donkers Sarah J. , Costa Silvana L. , Vaduvathiriyan Prasanna , Williams Joy , Siengsukon Catherine 
Published: October 2022

AbstractObjectiveTo determine effective behavioral interventions to improve sleep in people with MS.MethodsSystematic review following PRISMA guidelines.Data SourcesLiterature searches were performed in December 2021 in Ovid MEDLINE, CINAHL, and Web of Science along with hand searching for grey literature and cited references. Out of the 837 search results, 830 unique references were reviewed after duplicates were removed.Study SelectionFour reviewers independently reviewed titles and abstracts (two reviewers for each article), and a fifth reviewer resolved discrepancies. The full-text articles (n = 81) were reviewed independently by four reviewers (two for each article) for eligibility, and consensus for inclusion was achieved by a fifth reviewer as needed. Thirty-seven articles were determined eligible for inclusion.Data ExtractionFour reviewers extracted relevant data from each study (two reviewers for each article) using a standard data-extraction table. Consensus was achieved for completeness and accuracy of the data extraction table by a fifth reviewer. Four reviewers (two reviewers for each article) conducted a quality appraisal of each article to assess the risk for bias and quality of the articles and consensus was achieved by a fifth reviewer as needed.Data SynthesisDescriptions were used to describe types of interventions, sleep outcomes, results, and key components across interventions.ConclusionsThe variability in the intervention types, intervention dose, outcomes used, training/expertise of interventionist, specific sample included, and quality of the study made it difficult to compare and synthesize results. Overall, the CBT-I, CBT/psychotherapy, and education/self-management support interventions reported positive improvements in sleep outcomes. The quality appraisal scores ranged from low to high quality indicating potential for bias. Further research is necessary to demonstrate efficacy of most of the interventions.
Engagement with the HCV care cascade among high-risk groups: a population-based study
Authors: Erman Aysegul , Everett Karl , Wong William W. L. , Forouzannia Farinaz , Greenaway Christina , Janjua Naveed , Kwong Jeffrey C. , Sander Beate 
Published: October 2022

AbstractBackgroundHepatitis C virus (HCV) elimination requires a thorough understanding of the care cascade. A direct-acting-antiviral (DAA)-era description of the care cascade has not been undertaken in Ontario, Canada. Our primary objective was to describe the current population-level care cascade in the general Ontario population and among key risk-groups — baby-boomers, immigrants, and individuals experiencing residential instability. The secondary objective was to identify predictors of engagement.MethodsWe conducted a population-based cohort study of Ontario residents undergoing HCV testing between January 1, 1999, and December 31, 2018, and mapped the care cascade [antibody diagnosed, RNA tested, RNA positive, genotyped, treated, achieved sustained virologic response (SVR), reinfected/relapsed] as of December 31, 2018. The cascade was stratified by risk groups. Cause-specific hazard modeling was used to identify demographic, and socioeconomic predictors of engagement with key steps of the cascade.ResultsAmong 108,428 Ontario resident living with an HCV antibody diagnosis, 88% received confirmatory RNA testing; of these, 62% tested positive and 94% of positive tests were genotyped. Of those with confirmed viremia, 53% initiated treatment and 76% of treated individuals achieved SVR, while ∼1% experienced reinfection or relapse. Males, older birth cohorts, long-term residents, those with a history of substance use disorder and social marginalisation (e.g., material deprivation, residential instability), and those initially diagnosed in the pre-DAA era exhibited lower rates of engagement with almost every step of HCV care.ConclusionsDespite DAA-era improvements, treatment initiation remains a major gap. HCV screening and linkage-to-treatment, particularly for those with a history of substance use disorder and social marginalisation, will be needed to equitably close gaps in HCV care in Ontario.
Prevalence of comorbidities and their impact on survival among older adults with the five most common cancers in Taiwan: A population study
Authors: Chien Li-Hsin , Tseng Tzu-Jui , Chen Tzu-Yu , Chen Chung-Hsing , Chen Chia-Yu , Jiang Hsin-Fang , Tsai Fang-Yu , Ku Hsiu-Ying , Jiang Shih Sheng , Hsiung Chao A. , Liu Tsang-Wu , Chang I-Shou 
Published: October 2022

AbstractBecause of the cancer incidence increase and population aging in Taiwan, we aimed to assess the cancer prevalence, to summarize the comorbidities of older patients with the five most common cancers (i.e., breast, colorectal, liver, lung, and oral), and to develop a Taiwan comorbidity index (TCI) for studying their actual prognosis. The linkage of the Taiwan Cancer Registry, Cause of Death Database, and National Health Insurance Research Database was used. We followed the standard statistical learning steps to obtain a survival model with good discriminatory accuracy in predicting death due to noncancer causes, from which we obtained the TCI and defined comorbidity levels. We reported the actual prognosis by age, stage, and comorbidity level. In Taiwan, cancer prevalence nearly doubled in 2004–2014, and comorbidities were common among older patients. Stage was the major predictor of patients’ actual prognoses. For localized and regional breast, colorectal, and oral cancers, comorbidities correlated with noncancer-related deaths. Compared with the US, the chances of dying from comorbidities in Taiwan were lower and the chances of dying from cancer were higher for breast, colorectal, and male lung cancers. These actual prognoses could help clinicians and patients in treatment decision-making and help policymakers in resource planning.