bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide CRISPR/Cas9 transcriptional activation screen identifies a histone acetyltransferase inhibitor complex as a regulator of HIV-1 integration
Authors: Zhang Qiong , Wang Shaobo , Li Wanyu , Yau Edwin , Hui Hui , Singh Parmit Kumar , Achuthan Vasudevan , Young Karris Maile Ann , Engelman Alan N , Rana Tariq M 
Published: June 2022

Abstract
The retrovirus human immunodeficiency virus-1 (HIV-1) is the causative agent of AIDS. Although treatment of HIV/AIDS with antiretroviral therapy provides suppression of viremia, latent reservoirs of integrated proviruses preclude cure by current antiviral treatments. Understanding the mechanisms of host–viral interactions may elucidate new treatment strategies. Here, we performed a CRISPR/Cas9 transcriptional activation screen using a high-complexity, genome-wide sgRNA library to identify cellular factors that inhibit HIV-1 infection of human CD4+ T cells. MT4 cells were transduced with a CRISPR/Cas9 sgRNA library and infected with nef-deficient HIV-1NL4-3 expressing ganciclovir-sensitive thymidine kinase, thus enabling selection of HIV-1-resistant cells for analysis of enriched sgRNAs. After validation of screen hits, multiple host factors essential for HIV-1 infection were identified, including SET (SET nuclear proto-oncogene) and ANP32A (acidic nuclear phosphoprotein 32A, PP32A), which together form a histone acetylase inhibitor complex. Using multiple human cell lines and peripheral blood mononuclear cells (PBMCs) from healthy donors and HIV-1-infected individuals, we demonstrate that SET depletion increased HIV-1 infectivity by augmenting DNA integration without significantly changing sites of integration. Conversely, SET overexpression decreased HIV-1 integration and infectivity. SET protein expression was significantly reduced in PBMCs from HIV-1-infected individuals and was downregulated by HIV-1 infection of healthy donor cells in vitro. Notably, HIV-1-induced downregulation of SET could be alleviated by inhibition of the protease granzyme A. Altogether, we have identified cellular inhibitors of HIV-1 infection on a genome-wide scale, which affords new insight into host–virus interactions and may provide new strategies for HIV-1 treatment.
Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression
Authors: Portuguez Avital Sarusi , Grbesa Ivana , Tal Moran , Deitch Rachel , Raz Dana , Kliker Limor , Weismann Ran , Schwartz Michal , Loza Olga , Cohen Leslie , Marchenkov-Flam Libi , Sung Myong-Hee , Kaplan Tommy , Hakim Ofir 
Published: June 2022

Abstract
The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets. We show that the chromatin interaction networks of GR-activated and repressed genes are spatially separated and vary in the features and configuration of their GBS and other non-GBS regulatory elements. The convergence of the KLF4 pathway in GR-activated domains and the STAT6 pathway in GR-repressed domains, impose opposite transcriptional effects to GR, independent of hormone application. Moreover, the ROR and Rev-erb transcription factors serve as positive and negative regulators, respectively, of GR-mediated gene activation. We found that the spatial crosstalk between GBSs and non-GBSs provides a physical platform for sequestering the Ep300 co-activator from non-GR regulatory loci in both GR-activated and -repressed gene compartments. While this allows rapid gene repression, Ep300 recruitment to GBSs is productive specifically in the activated compartments, thus providing the basis for gene induction.
DeNovoCNN: a deep learning approach to de novo variant calling in next generation sequencing data
Authors: Khazeeva Gelana , Sablauskas Karolis , van der Sanden Bart , Steyaert Wouter , Kwint Michael , Rots Dmitrijs , Hinne Max , van Gerven Marcel , Yntema Helger , Vissers Lisenka , Gilissen Christian 
Published: June 2022

Abstract
De novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes the alignment of sequence reads for a trio as 160$ \times$164 resolution images. DeNovoCNN was trained on DNMs of 5616 whole exome sequencing (WES) trios achieving total 96.74% recall and 96.55% precision on the test dataset. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing DNM calling approaches (GATK, DeNovoGear, DeepTrio, Samtools) based on the Genome in a Bottle reference dataset and independent WES and WGS trios. Validations of DNMs based on Sanger and PacBio HiFi sequencing confirm that DeNovoCNN outperforms existing methods. Most importantly, our results suggest that DeNovoCNN is likely robust against different exome sequencing and analyses approaches, thereby allowing the application on other datasets. DeNovoCNN is freely available as a Docker container and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.
Body temperature variation controls pre-mRNA processing and transcription of antiviral genes and SARS-CoV-2 replication
Authors: Los Bruna , Preußner Marco , Eschke Kathrin , Vidal Ricardo Martin , Abdelgawad Azza , Olofsson Didrik , Keiper Sandra , Paulo-Pedro Margarida , Grindel Alica , Meinke Stefan , Trimpert Jakob , Heyd Florian 
Published: June 2022

Abstract
Antiviral innate immunity represents the first defense against invading viruses and is key to control viral infections, including SARS-CoV-2. Body temperature is an omnipresent variable but was neglected when addressing host defense mechanisms and susceptibility to SARS-CoV-2 infection. Here, we show that increasing temperature in a 1.5°C window, between 36.5 and 38°C, strongly increases the expression of genes in two branches of antiviral immunity, nitric oxide production and type I interferon response. We show that alternative splicing coupled to nonsense-mediated decay decreases STAT2 expression in colder conditions and suggest that increased STAT2 expression at elevated temperature induces the expression of diverse antiviral genes and SARS-CoV-2 restriction factors. This cascade is activated in a remarkably narrow temperature range below febrile temperature, which reflects individual, circadian and age-dependent variation. We suggest that decreased body temperature with aging contributes to reduced expression of antiviral genes in older individuals. Using cell culture and in vivo models, we show that higher body temperature correlates with reduced SARS-CoV-2 replication, which may affect the different vulnerability of children versus seniors toward severe SARS-CoV-2 infection. Altogether, our data connect body temperature and pre-mRNA processing to provide new mechanistic insight into the regulation of antiviral innate immunity.
Determining states of consciousness in the electroencephalogram based on spectral, complexity, and criticality features
Authors: Walter Nike , Hinterberger Thilo 
Published: June 2022

AbstractThis study was based on the contemporary proposal that distinct states of consciousness are quantifiable by neural complexity and critical dynamics. To test this hypothesis, it was aimed at comparing the electrophysiological correlates of three meditation conditions using nonlinear techniques from the complexity and criticality framework as well as power spectral density. Thirty participants highly proficient in meditation were measured with 64-channel electroencephalography (EEG) during one session consisting of a task-free baseline resting (eyes closed and eyes open), a reading condition, and three meditation conditions (thoughtless emptiness, presence monitoring, and focused attention). The data were analyzed applying analytical tools from criticality theory (detrended fluctuation analysis, neuronal avalanche analysis), complexity measures (multiscale entropy, Higuchi’s fractal dimension), and power spectral density. Task conditions were contrasted, and effect sizes were compared. Partial least square regression and receiver operating characteristics analysis were applied to determine the discrimination accuracy of each measure. Compared to resting with eyes closed, the meditation categories emptiness and focused attention showed higher values of entropy and fractal dimension. Long-range temporal correlations were declined in all meditation conditions. The critical exponent yielded the lowest values for focused attention and reading. The highest discrimination accuracy was found for the gamma band (0.83–0.98), the global power spectral density (0.78–0.96), and the sample entropy (0.86–0.90). Electrophysiological correlates of distinct meditation states were identified and the relationship between nonlinear complexity, critical brain dynamics, and spectral features was determined. The meditation states could be discriminated with nonlinear measures and quantified by the degree of neuronal complexity, long-range temporal correlations, and power law distributions in neuronal avalanches.
Measurement Properties of Remotely or Self-Administered Lower Extremity Mobility Performance Measures in Adults: A Systematic Review
Authors: Morgan Ashley , Bégin Diane , Heisz Jennifer , Tang Ada , Thabane Lehana , Richardson Julie 
Published: June 2022

AbstractObjectiveFor individuals who face barriers to care assessment, there is a need for remote administration or self-administration of physical performance measures that assess mobility to determine current functional status and to monitor and predict future changes in functional status. The primary purpose of this review is to evaluate the available measurement properties of scores for remotely or self-administered lower extremity mobility performance measures in adults. This review also outlines the test procedures and population suitability of these measures.MethodsData sources were Ovid MEDLINE, Ovid Embase, EBSCOhost CINAHL, Ovid AMED, and Cochrane CENTRAL—which were searched from inception to January 26, 2021—and the reference lists of relevant studies. Two individuals independently screened studies that assessed at least 1 prespecified measurement property of scores for a remote and/or self-administered lower extremity physical performance measure assessing mobility in an adult population. Two individuals independently extracted data on study characteristics, measurement properties, feasibility, and interpretability using piloted extraction forms. The COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) Risk of Bias tool was used to assess methodological quality. Data were qualitatively summarized, and results were compared against COSMIN’s criteria for good measurement properties. Level of evidence was determined using COSMIN’s modified GRADE approach.ResultsFourteen studies detailing 19 outcome measures were included. Many studies displayed “sufficient” measurement properties based on COSMIN’s criteria; however, risk of bias for most of the included studies was rated adequate or doubtful.ConclusionClinicians and researchers can consider the measurement properties of scores and feasibility of different approaches presented in this review when determining how to assess or monitor mobility in adult populations.ImpactAssessing mobility via remote or self-administered physical performance measures in adult populations appears to be feasible using a variety of methods including simple tools (chair, stopwatch), videoconferencing, and smartphone applications. This strategy may be particularly valuable for self-management of chronic conditions and decreasing barriers to accessing care.
How Do People With Knee Osteoarthritis Conceptualize Knee Confidence? A Qualitative Study
Authors: Binnie Tara , O’Sullivan Peter , Bunzli Samantha , Campbell Amity , Ng Leo , Kent Peter , Smith Anne 
Published: June 2022

Abstract

Objective
Reduced knee confidence is common in people with knee osteoarthritis (OA) and is likely to influence how people with knee OA engage with movement and activities. However, there is conflicting evidence surrounding the association between confidence and function. This may be because knee confidence has been assessed via a single questionnaire item that was not developed for people with knee OA and thus may not provide an accurate or comprehensive assessment of confidence in this population. A better understanding of knee confidence could inform a more thorough assessment of the construct both in clinical and research contexts. Therefore, the aim of this study was to explore the meaning of knee confidence from the perspective of people with knee OA.

Methods
Fifty-one people with a clinical diagnosis of knee OA took part in a one-to-one semistructured interview. Interviews explored how each participant conceptualized knee confidence. Reflexive thematic analysis was selected as a flexible approach for identifying patterns of meaning across cases through a combination of data-driven and theory-informed coding of the transcribed data.

Results
People with knee OA conceptualized confidence with reference to 1 or more of 4 themes: (1) symptoms, (2) functional ability, (3) the internal structure of the knee, and (4) knowledge about knee OA and its management. Each conceptualization of confidence was associated with present and future concerns.

Conclusion
Because people with knee OA conceptualize knee confidence in different ways, a single-item measure is unlikely to capture all of the aspects of this construct in this population. This may explain the conflicting evidence around the association between reduced knee confidence and function in people with knee OA.

Impact
This study showed that a multi-item measure is needed to measure knee confidence in people with knee OA. Clinicians and researchers need to understand what knee confidence means to people with knee OA, because it is likely to influence how these individuals engage with movement and activities. Understanding this relationship can enable more targeted education and functional rehabilitation for people with knee OA.
Validation of the parent global assessment as a health-related quality of life measure in juvenile idiopathic arthritis: results from ReACCh-Out
Authors: Oen Kiem , Toupin-April Karine , Feldman Brian M , Berard Roberta A , Duffy Ciẚran M , Tucker Lori B , Tian Jiahao , Rumsey Dax G , Guzman Jaime ,   ReACCh-Out investigators, Bolaria Roxana , Cabral David , Gross Katherine , Houghton Kristin , Morishita Kimberly , Petty Ross , Turvey Stuart E , Ellsworth Janet , Benseler Susanne , Johnson Nicole , Miettunen Paivi , Schmeling Heinrike , Larche Maggie , Cameron Bonnie , Laxer Ronald M , Spiegel Lynn , Schneider Rayfel , Silverman Earl , Yeung Rae S M , Levy Deborah M , Tse Shirley , Gibbon Michele , Roth Johannes , Duffy Karen Watanabe , Chetaille Anne-Laure , Dorval Jean , Boire Gilles , Bruns Alessandra , Campillo Sarah , Chedeville Gaelle , LeBlanc Claire , Scuccimarri Rosie , Haddad Elie , Cyr Claire St , Feldman Debbie , Lang Bianca , Ramsey Suzanne E , Stringer Elizabeth , Huber Adam M , Dancey Paul 
Published: June 2022

AbstractObjectivesTo (i) validate the JIA parent global assessment (parent global) as a health-related quality of life (HRQoL) instrument; (ii) evaluate measurement properties of accepted HRQoL measures relative to those of the parent global; and (iii) assess causal pathways determining parent global scores.MethodsData from the Research in Arthritis in Canadian Children emphasizing outcomes (ReACCh-Out) cohort were used. Measurement properties were assessed in 344 patients at enrolment and 6 months later. Causal pathways were tested by structural equation modelling to understand root causes and mediators leading to parent global scores.ResultsConstruct validity was supported by Spearman correlations of 0.53–0.70 for the parent global with the Juvenile Arthritis Quality of Life Questionnaire, Quality of My Life health scale (HRQoML), Pediatric Quality of Life Inventory (PedsQL)-Parent, and Child Health Questionnaire (CHQ)-Physical. Exceptions were PedsQL-Child (0.44) and CHQ-Psychosocial (0.31). Correlations were lower (0.14–0.49) with disease activity measures (physician global assessment of disease activity, active joint count, ESR). Responsiveness of the parent global to improvement according to parent ratings (0.51) was acceptable and within the range (0.32–0.71) of that of other measures. Reliability estimates and measurement errors for all measures were unsatisfactory, likely due to the prolonged time between assessments. Causal pathways for the parent global matched those previously reported for HRQoML.ConclusionsOur results offer support for the parent global as a valid measure of HRQoL for JIA. If confirmed, existing studies using the parent global may be re-interpreted, enhancing our knowledge of HRQoL in children with JIA.
The democratic paradox: are national elections always good for satisfaction with democracy in Europe?
Authors: Krishnarajan Suthan 
Published: June 2022

Abstract
This article challenges the widespread notion that national elections are unequivocally good for people’s satisfaction with democracy. Instead, it argues that elections have enduring and disparate effects on democratic satisfaction, depending on the economic situation in which they take place; that is the election economy. When held during economic upturns, national elections increase subsequent satisfaction with democracy during most of the following electoral term—regardless of election results and economic growth after the election. When held during economic downturns, elections reduce democratic satisfaction until the next election—again, regardless of such post-election developments. An analysis of 29 European democracies in the period 1973–2019 supports these propositions and suggests that the disparate effects of national elections endure during most of the electoral term. These findings are robust to an array of model specifications, including when accounting for several pre-election and post-election developments.
Social participation restriction among persons with leprosy discharged from a multidrug therapy clinic in northern Nigeria
Authors: Dahiru Tahir , Iliyasu Zubairu , Aliyu Muktar H 
Published: June 2022

AbstractBackgroundThe burden of leprosy-related disability, stigma and social participation after completing treatment is not well documented in Nigeria. We assessed the extent of disability, level of stigma and predictors of activity limitation and social participation restriction after completing multidrug therapy (MDT) for leprosy in Kano, Nigeria.MethodsA consecutively recruited cross-section of 354 persons discharged from MDT and 360 community members were interviewed. The Eyes, Hands and Feet sum score, Screening of Activity Limitation and Safety Awareness scale, Participation scale and Jacoby Stigma scale were used for affected persons. The Exploratory Model Interview Catalogue scale was used to assess community-perceived stigma. Levels of disability, activity limitation, participation restriction and stigma were scored. Adjusted ORs for predictors were generated from logistic regression models.ResultsMost (91.5%, n=324) respondents had a disability; (8.2%, n=29) and (83.3%, n=295) were WHO grades 1 and 2, respectively. Similarly, 321 participants (90.7%) had activity limitation and 316 respondents (89.3%) experienced participation restriction. Further, 88.7% of participants (n=314) anticipated stigma. Activity limitation was higher among unemployed participants, men, persons with disability and those who anticipated stigma. Participation restriction was higher among low income earners (≤1000 Nigerian Naira per month (equivalent to US$2.50 per month)) and persons with disability, limited activity and anticipated stigma.ConclusionLeprosy-related disability, stigma, activity limitation and social participation restriction are high after treatment. We recommend community-based rehabilitation to sustain self-care, reduce stigma and ensure social inclusion.
SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF‐2α signaling pathway in arrhythmogenic cardiomyopathy
Authors: Yang Zhe , Li Tengling , Xian Jianzhong , Chen Jia , Huang Yin , Zhang Qin , Lin Xiufang , Lu Hongyun , Lin Yubi 
Published: June 2022

AbstractExcessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Whether sodium‐glucose cotransporter‐2 inhibitor (SGLT2i), as a new hypoglycemic drug, benefits ACM remains unclear. Cardiomyocyte‐specific Dsg2 exon‐11 knockout and wild‐type (WT) littermate mice were used as the animal model of ACM and controls, respectively. Mice were administered by gavage with either SGLT2i dapagliflozin (DAPA, 1 mg/kg/day) or vehicle alone for 8 weeks. HL‐1 cells were treated with DAPA to identify the molecular mechanism in vitro. All mice presented normal glucose homeostasis. DAPA not only significantly ameliorated cardiac dysfunction, adverse remodeling, and ventricular dilation in ACM but also attenuated ACM‐associated cardiac fibrofatty replacement, as demonstrated by the echocardiography and histopathological examination. The protein expressions of HIF‐2α and HIF‐1α were decreased and increased respectively in cardiac tissue of ACM, which were compromised after DAPA treatment. Additionally, NF‐κB P65 and IκB phosphorylation, as well as fibrosis indicators (including TGF‐β, α‐SMA, Collagen I, and Collagen III) were increased in ACM. However, these trends were markedly suppressed by DAPA treatment. Consistent with these results in vitro, DAPA alleviated the IκB phosphorylation and NF‐κB p65 transcriptional activity in DSG2‐knockdown HL‐1 cells. Interestingly, the elective HIF‐2α inhibitor PT2399 almost completely blunted the DAPA‐mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM‐associated cardiac dysfunction and adverse remodeling in a glucose‐independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF‐2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM.