bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double negative post-transcriptional regulatory circuit underlies the virgin behavioral state
Authors: Garaulet Daniel L. , Moro Albertomaria , Lai Eric C. 
Published: May 2021

SummaryThe survival and reproductive success of animals depends on the ability to harmonize their external behaviors with their internal states. For example, females conduct numerous social programs that are distinctive to virgins, compared to post-mated and/or pregnant individuals. InDrosophila, the fact that this post-mating switch is initiated by seminal factors implies that the default state is virgin. However, we recently showed that loss of miR-iab-4/8-mediated repression of the transcription factor Homothorax (Hth) within the abdominal ventral nerve cord (VNC) causes virgin females to execute mated behaviors. To elucidate new components of this post-transcriptional regulatory circuit, we used genomic analysis ofmir-iab-4/8deletion andhth-miRNA binding site mutants (hth[BSmut]) to elucidatedoublesex(dsx) as a critical downstream factor. While Dsx has mostly been studied during sex-specific differentiation, its activities in neurons are little known. We find that accumulation of Dsx in the CNS is highly complementary to Hth, and downregulated in miRNA/hth[BSmut]mutants. Moreover, virgin behavior is highly dose-sensitive to developmentaldsxfunction. Strikingly, depletion of Dsx in SAG-1 cells, a highly restricted set of abdominal neurons, abrogates female virgin conducts in favor of mated behavioral programs. Thus, a double negative post-transcriptional pathway in the VNC (miR-iab-4/8 -| Hth -| Dsx) specifies the virgin behavioral state.
Risk of vaccine preventable diseases in UK migrants: a serosurvey and concordance analysis, 2020
Authors: Gogoi Mayuri , Martin Christopher A. , Wiselka Martin J. , Gardener Judi , Ellis Kate , Renals Valerie , Lewszuk Adam J. , Hargreaves Sally , Pareek Manish 
Published: May 2021

AbstractWe conducted a serosurvey in 2020, amongst 149 adult migrants living in the United Kingdom, to determine seroprotection rates for measles, varicella zoster, and rubella. Findings suggest a gap in seroprotection against measles (89.3%). Younger migrants and those from Europe and Central Asia may be more susceptible; self-reported vaccine/disease status is a poor predictor of seroprotection. Understanding factors associated with seroprotection among migrants is critical for informing the delivery of SARS-CoV-2 vaccine.
Multicentric Evaluation of a Novel Point of Care Electrochemical ELISA Platform for SARS-CoV-2 Specific IgG and IgM Antibody Assay
Authors: Kumar Vinay , Ghosh Kanad , Chandran Anagha , Panwar Sachin , Bhat Ananthram , Konaje Shreenivas , Das Saroj , Srikanta S , Jaganathan Latha , Prasad Sujay , Venkatesh D B , Shivaram C. , Krishnaswamy P R , Bhat Navakanta 
Published: May 2021

AbstractNew diagnostics technologies for the efficient detection and quantification of SARS-CoV-2 Antibodies is very crucial to manage the COVID-19 pandemic, especially in the context of emerging vaccination paradigms. Herein, we report on a novel point-of-care Electrochemical ELISA platform with disposable screen printed electrodes functionalized with SARS-CoV-2 Spike Glycoprotein S1, to enable fast and accurate quantitative estimation of total antibody concentration (IgG and IgM) in clinical samples. The quantification is performed with a comparison of electrochemical redox current against the current produced by the spiked monoclonal antibodies with known concentration. The assay is validated through multicentric evaluation against 3 different FDA authorized Laboratory standard techniques, using both EDTA whole blood and serum samples. We demonstrate that the proposed assay has excellent sensitivity and specificity, making it a suitable candidate for epidemiological surveys and quantification of antibodies in COVID-19 vaccination programs.
Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses
Authors: McNaughton Anna L , Paton Robert S , Edmans Matthew , Youngs Jonathan , Wellens Judith , Phalora Prabhjeet , Fyfe Alex , Belij-Rammerstorfer Sandra , Bolton Jai S , Ball Jonathan , Carnell George , Dejnirattisai Wanwisa , Dold Christina , Eyre David W , Hopkins Philip , Howarth Alison , Kooblall Kreepa , Klim Hannah , Leaver Susannah , Lee Lian , López-Camacho César , Lumley Sheila F , Macallan Derek , Mentzer Alexander J , Provine Nicholas , Ratcliff Jeremy , Slon-Compos Jose , Skelly Donal , Stolle Lucas , Supasa Piyada , Temperton Nigel , Walker Chris , Wang Beibei , Wyncoll Duncan ,   OPTIC consortium,   SNBTS consortium, Simmonds Peter , Lambe Teresa , Baillie Kenneth , Semple Malcolm G , Openshaw Peter IM ,   ISARIC4C Investigators, Obolski Uri , Turner Marc , Carroll Miles , Mongkolsapaya Juthathip , Screaton Gavin , Kennedy Stephen H , Jarvis Lisa , Barnes Eleanor , Dunachie Susanna , Lourenço José , Matthews Philippa C , Bicanic Tihana , Klenerman Paul , Gupta Sunetra , Thompson Craig P 
Published: May 2021

SummaryIt is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of ade novoSARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.
The Triangulation WIthin A STudy (TWIST) framework for causal inference within Pharmacogenetic research
Authors: Bowden Jack , Pilling Luke C. , Türkmen Deniz , Kuo Chia-Ling , Melzer David 
Published: May 2021

AbstractIn this paper we review the methodological underpinnings of the general pharmacogenetic approach for uncovering genetically-driven treatment effect heterogeneity. This typically utilises only individuals who are treated and relies on fairly strong baseline assumptions to estimate what we term the ‘genetically moderated treatment effect’ (GMTE). When these assumptions are seriously violated, we show that a robust but less efficient estimate of the GMTE that incorporates information on the population of untreated individuals can instead be used. In cases of partial violation, we clarify when Mendelian randomization and a modified confounder adjustment method can also yield consistent estimates for the GMTE. A decision framework is then described to decide when a particular estimation strategy is most appropriate and how specific estimators can be combined to further improve efficiency. Triangulation of evidence from different data sources, each with their inherent biases and limitations, is becoming a well established principle for strengthening causal analysis. We call our framework ‘Triangulation WIthin a STudy’ (TWIST)’ in order to emphasise that an analysis in this spirit is also possible within a single data set, using causal estimates that are approximately uncorrelated, but reliant on different sets of assumptions. We illustrate these approaches by re-analysing primary-care-linked UK Biobank data relating to CYP2C19 genetic variants, Clopidogrel use and stroke risk, and data relating to APOE genetic variants, statin use and Coronary Artery Disease.
Hearing aids reduce daily-life fatigue and increase social activity: a longitudinal study
Authors: Holman Jack A. , Drummond Avril , Naylor Graham 
Published: May 2021

AbstractPeople with hearing loss experience fatigue, and it is unknown whether this is alleviated by treatment with hearing aids. The objective of this study was to address this issue, and to investigate the possible concomitant effect of hearing-aid fitting on activity levels. An intervention group (n=53) who were due to be fitted with their first ever hearing aid(s) and a control group (n=53) who had hearing loss but no change in hearing aid status completed a battery of self-report outcome measures four times: once before fitting, and at two weeks, three months and six months post fitting. Self-report outcome measures at each assessment captured fatigue, listening effort, hearing handicap, auditory lifestyle, social participation restrictions and work, social and physical activity levels. Hearing-aid fitting led to a significant reduction in listening-related fatigue, but not general fatigue, in the intervention group compared to the control group. Additionally, social activity level increased and social participation restriction decreased significantly after hearing aid fitting in the intervention group compared to the control group. No significant interaction was found between working status and change in listening-related fatigue score. This study is the first to make longitudinal measurement of fatigue before and after first-ever hearing aid fitting and to identify an increase in social activity level after hearing aid fitting. These findings have important implications for future research and the clinical practice of hearing aid fitting.
Prognostic significance of protein-coding and long non-coding RNA expression profile in T-cell acute lymphoblastic leukemia
Authors: Verma Deepak , Kapoor Shruti , Sharma Disha , Singh Jay , Sharma Gunjan , Kumari Sarita , Arora Mohit , Bakhshi Sameer , Seth Rachna , Nayak Baibaswata , Sharma Atul , Pramanik Raja , Palanichamy Jayanth Kumar , Sivasubbu Sridhar , Scaria Vinod , Kumar Rajive , Chopra Anita 
Published: May 2021

AbstractT-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy associated with poor outcome. To unravel gene-expression profile of immunophenotypic subtypes of T-ALL, we did transcriptome analysis in 35 cases. We also analyzed the prognostic relevance of 23 targets: protein-coding genes, histone modifiers and long non-coding RNA (lncRNA) expression profile, identified on RNA sequencing, on an independent cohort of 99 T-ALL cases. We found high expression of MEF2C to be associated with prednisolone resistance (p=0.048) and CD34 expression (p=0.012). BAALC expression was associated with expression of CD34 (p=0.032) and myeloid markers (p=0.021). XIST and KDM6a expression levels were higher in females (p=0.047 and 0.011, respectively). Post-induction minimal residual disease (MRD) positivity was associated with high lncRNA PCAT18 (p=0.04), HHEX (p=0.027) and MEF2C (p=0.007). Early thymic precursor (ETP-ALL) immunophenotype was associated with high expression of MEF2C (p=0.003), BAALC (p=0.003), LYL1 (p=0.01), LYN (p=0.01), XIST (p=0.02) and low levels of ST20 (p=0.007) and EML4 (p=0.03). On survival analysis, MEF2C high expression emerged as significant predictor of 3-year event free survival (EFS) (low 71.78±6.58% vs high 36.57±10.74%, HR 3.5, p=0.0003) and overall survival (OS) (low 94.77±2.96% vs high 78.75±8.45%, HR 4.88, p=0.016) in our patients. LncRNA MALAT1 low expression also emerged as predictor inferior OS (low 76.02±10.48 vs high 94.11±3.31, HR 0.22, p=0.027).
Japan’s Covid mitigation strategy and its epidemic prediction
Authors: Tokuda Yasuharu , Kuniya Toshikazu 
Published: May 2021

AbstractThe COVID-19 epidemic curve in Japan was constructed based on daily reported data from January 14, 2020 until April 20, 2021. A SEIR compartmental model was used for the curve fitting by updating the estimation per wave. In the current vaccination pace of 1/1000, restrictions (state of emergency in Japan) would be repeated 4 times until the end of next March. In the case of 1/500, another round of restriction would be required in the summer 2021, after which the infection would be mitigated. In the case of 1/250, there would be no need for restriction after the current spring restriction. The scenario of completing the vaccination of 110 million people by the end of March 2020 corresponds to the case of 1/250 in this curve. When considering the likely spread of variant with greater infectiousness (here we assume 1.3 times greater than the original virus), 1/500 pace of vaccination would not be enough to contain it and need several series of restrictions. There are currently several variants of concern that are already spreading in urban areas in this country. In the new stage of the replacement of variants, if the vaccination pace could not be quadrupled from the current pace, Japan could not become a zero covid (zero corona) country at least one year.
Psychosis-like experiences and cognition in young adults: an observational and Mendelian randomisation study
Authors: Skirrow Caroline , Suddell Steph , Mahedy Liam , Penton-Voak Ian S. , Munafò Marcus R. , Wootton Robyn E. 
Published: May 2021

BackgroundPsychosis-like experiences (PLEs) are common and associated with mental health problems and poorer cognitive function. There is limited longitudinal research examining associations between cognition and PLEs in early adulthood.AimsWe investigated the association of PLEs with different domains of cognitive function, using cross-sectional and longitudinal observational, and Mendelian randomisation (MR) analyses.MethodParticipants from the Avon Longitudinal Study of Parents and Children (ALSPAC) completed tasks of working memory at age 18 and 24, and tasks of response inhibition and facial emotion recognition at age 24. Semi-structured interviews at age 18 and 24 established presence of PLEs (none vs. suspected/definite). Cross-sectional and prospective regression analysis tested associations between PLEs and cognition (N=3,087 imputed sample). MR examined causal pathways between schizophrenia liability and cognition.ResultsThe fully adjusted models indicated that PLEs were associated with poorer working memory performance (cross-sectional analyses: b=−0.18, 95% CI −0.27 to −0.08, p<0.001; prospective analyses: b=−0.18, 95% CI −0.31 to −0.06, p<0.01). A similar pattern of results was found for PLEs and response inhibition (cross-sectional analyses: b=7.29, 95% CI 0.96 to 13.62, p=0.02; prospective analyses: b=10.29, 95% CI 1.78 to 18.97, p=0.02). We did not find evidence to suggest an association between PLEs and facial emotion recognition. MR analyses were underpowered and did not support observational results.ConclusionsIn young adults, PLEs are associated with poorer concurrent and future working memory and response inhibition. Better powered genetically informed studies are needed to determine if these associations are causal.
Accurate prediction of protein torsion angles using evolutionary signatures and recurrent neural network
Authors: Xu Yong-Chang , ShangGuan Tian-Jun , Ding Xue-Ming , Cheung Ngaam J. 
Published: May 2021

ABSTRACTThe amino acid sequence of a protein contains all the necessary information to specify its shape, which dictates its biological activities. However, it is challenging and expensive to experimentally determine the three-dimensional structure of proteins. The backbone torsion angles, as an important structural constraint, play a critical role in protein structure prediction, and accurately predicting the angles can considerably advance the tertiary structure prediction by accelerating efficient sampling of the large conformational space for low energy structures. On account of the rapid growth of protein databases and striking breakthroughs in deep learning algorithms, computational advances allow us to extract knowledge from large-scale data to address key biological questions. Here we propose evolutionary signatures that are computed from protein sequence profiles, and a deep neural network, termed ESIDEN, that adopts a straightforward architecture of recurrent neural networks with a small number of learnable parameters. The proposed ESIDEN is validated on three benchmark datasets, including D2020, TEST2016/2018, and CASPs datasets. On the D2020, using the combination of the four novel features and basic features, the ESIDEN achieves the mean absolute error (MAE) of 15.7 and 19.8 forϕandψ, respectively. Comparing to the best-so-far methods, we show that the ESIDEN significantly improves the angleψby the MAE decrements of more than 3.5 degrees on both TEST2016 and TEST2018 and achieves better MAE of the angleϕby decrements of at least 0.3 degrees although it adopts simple architecture and fewer learnable parameters. On fifty-nine template-free modeling targets, the ESIDEN achieves high accuracy by reducing the MAEs by 0.6 and more than 2.3 degrees on average for the torsion anglesϕandψin the CASPs, respectively. Using the predicted torsion angles, we infer the tertiary structures of four representative template-free modeling targets that achieve high precision with regard to the root-mean-square deviation and TM-score by comparing them to the native structures. The results demonstrate that the ESIDEN can make accurate predictions of the torsion angles by leveraging the evolutionary signatures. The proposed evolutionary signatures would be also used as alternative features in predicting residue-residue distance, protein structure, and protein-ligand binding sites. Moreover, the high-precision torsion angles predicted by the ESIDEN can be used to accurately infer protein tertiary structures, and the ESIDEN would potentially pave the way to improve protein structure prediction.
Discoidin Domain Receptor 2 regulates AT1R expression in Angiotensin II-stimulated cardiac fibroblasts via fibronectin-dependent Integrin-β1 signaling
Authors: Titus Allen Sam , Venugopal Harikrishnan , Ushakumary Mereena George , Wang Mingyi , Cowling Randy T. , Lakatta Edward G. , Kailasam Shivakumar 
Published: May 2021

AbstractRecent reports on the cardioprotective effects of fibronectin inhibition following myocardial injury suggest a largely unexplored role for the extracellular matrix (ECM) glycoprotein in cardiac fibroblast function. We probed the molecular regulation and functional implications of fibronectin gene expression in cardiac fibroblasts exposed to Angiotensin II, a major pro-fibrotic factor in the myocardium. Using gene knockdown and over-expression approaches, western blotting and promoter pull-down assay, we show that collagen type I-activated Discoidin Domain Receptor 2 (DDR2) mediates Angiotensin II-stimulated transcriptional up-regulation of fibronectin by Yes-activated Protein in cardiac fibroblasts. Further, siRNA-mediated fibronectin knockdown attenuated Angiotensin II-stimulated expression of collagen type I and anti-apoptotic cIAP2, and enhanced susceptibility to apoptosis. Importantly, an obligate role for fibronectin was observed in Angiotensin II-stimulated expression of AT1R, the Angiotensin II receptor, which would link ECM signaling and Angiotensin II signaling in cardiac fibroblasts. Moreover, conditioned medium from DDR2- or fibronectin-silenced cardiac fibroblasts reduced AT1R expression in H9c2 cardiomyoblasts. The regulatory role of fibronectin in Angiotensin II-stimulated cIAP2, collagen type I and AT1R expression was mediated by Integrin-β1-integrin-linked kinase signaling. In vivo, we observed modestly reduced basal levels of AT1R in DDR2-null mouse myocardium, associated with the previously reported reduction in myocardial Integrin-β1 levels. The role of fibronectin, downstream of DDR2, could be a critical determinant of cardiac fibroblast-mediated wound healing following myocardial injury. In summary, our findings suggest a complex mechanism of regulation of cardiac fibroblast function involving two major extracellular matrix proteins, collagen type I and fibronectin, and their receptors, DDR2 and Integrin-β1.
Endothelial restoration of CAD GWAS gene PLPP3 by nanomedicine suppresses YAP/TAZ activity and reduces atherosclerosisin vivo
Authors: Zhu Jiayu , Yeh Chih-Fan , Huang Ru-Ting , Lee Tzu-Han , Shentu Tzu-Pin , Wu David , Yang Kai-Chien , Fang Yun 
Published: May 2021

AbstractGenome-wide association studies (GWAS) have suggested new molecular mechanisms in vascular cells driving atherosclerotic diseases such as coronary artery disease (CAD) and ischemic stroke (IS). Nevertheless, a major challenge to develop new therapeutic approaches is to spatiotemporally manipulate these GWAS-identified genes in specific vascular tissuesin vivo. YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) have merged as critical transcriptional regulators in cells responding to biomechanical stimuli, such as in athero-susceptible endothelial cells activated by disturbed flow (DF). The molecular mechanisms by which DF activates while unidirectional flow (UF) inactivates YAP/TAZ remain incompletely understood. Recent studies demonstrated that DF and genetic predisposition (risk allele) of CAD/IS locus 1p32.2 converge to reduce phospholipid phosphatase 3 (PLPP3) expression in vascular endothelium. Restoration of endothelialPLPP3 in vivo, although remains challenging and unexplored, is hypothesized to reduce atherosclerosis. We devised a nanomedicine system integrating nanoparticles andCdh5promoter-driven plasmids to successfully restorePLPP3expression in activated endothelium, resulting in suppressed YAP/TAZ activity and reduced DF-induced atherosclerosis in mice. Mechanistically, our studies discovered a molecular paradigm by which CAD/IS GWAS genePLPP3inactivates YAP/TAZ by reducing lysophosphatidic acid (LPA)-induced myosin II and ROCK in endothelium under UF. These results highlight a new mechanistic link between GWAS and YAP/TAZ mechano-regulation and moreover, establish a proof of concept of vascular wall-based therapies employing targeted nanomedicine to manipulate CAD/IS GWAS genesin vivo.
3D Echo Planar Time-resolved Imaging (3D-EPTI) for ultrafast multi-parametric quantitative MRI
Authors: Wang Fuyixue , Dong Zijing , Reese Timothy G. , Rosen Bruce , Wald Lawrence L. , Setsompop Kawin 
Published: May 2021

AbstractMulti-parametric quantitative MRI has shown great potential to improve the sensitivity and specificity of clinical diagnosis and to enhance our understanding of complex brain processes, but suffers from long scan time especially at high spatial resolution. To address this long-standing challenge, we introduce a novel approach, termed 3D Echo Planar Time-resolved Imaging (3D-EPTI), which significantly increases the acceleration capacity of MRI sampling, and provides high acquisition efficiency for multi-parametric MRI. This is achieved by exploiting the spatiotemporal correlation of MRI data at multiple timescales through new encoding strategies within and between efficient continuous readouts. Specifically, an optimized spatiotemporal CAIPI encoding within the readouts combined with a radial-block sampling strategy across the readouts enables an acceleration rate of 800 folds in thek-tspace. A subspace reconstruction was employed to resolve thousands of artifact-free high-quality multi-contrast images spaced at a time interval of ~1 ms. We have demonstrated the ability of 3D-EPTI to provide robust and repeatable whole-brain simultaneous T1, T2, T2*, PD and B1+mapping at high isotropic resolution within minutes (e.g., 1-mm isotropic resolution in 3 minutes), and to enable submillimeter multi-parametric imaging to study detailed brain structures.HighlightsUltra-fast acquisition for 3D multi-parametric quantitative MRI.Simultaneous T1T2T2* PD and B1+mapping.3-minute scan at 1-mm isotropic resolution with whole-brain coverage.Multi-parametric mapping at 700-μm isotropic resolution in 10 minutes.Repeatable quantification and cortical-depth analysis.