bluuebunny/crossref_metadata_2025_split huggingface dataset:
Job stress among workers who telecommute during the coronavirus disease (COVID-19) pandemic in Japan: a cross-sectional study
Authors: Ikegami Kazunori , Baba Hiroka , Ando Hajime , Hino Ayako , Tsuji Mayumi , Tateishi Seiichiro , Nagata Tomohisa , Matsuda Shinya , Fujino Yoshihisa 
Published: March 2021

AbstractObjectivesThe work system reform and the COVID-19 pandemic in Japan have prompted efforts toward telecommuting in Japan, and there has been little research regarding the stress and health effects of telecommuting. This study aimed to clarify the relationship between telecommuting and job stress among Japanese workers.Study DesignThis was a cross-sectional study.MethodsIn December 2020, during the ‘third wave’ of the COVID-19 pandemic, an Internet-based nationwide health survey of 33,087 Japanese workers (CORoNaWork study) was conducted. Data for 27,036 individuals was included as 6,051 individuals provided invalid responses. We analysed a sample of 13,468 office workers from this database. We classified participants into four groups according to telecommuting frequency and compared the subscale of the Job Content Questionnaire and subjective job stress among these groups: high-frequency, medium-frequency, and low-frequency telecommuters group and non-telecommuters group. We used a linear mixed model and ordinal logistic regression analysis.ResultsThere was a significant difference in the score of job control of the JCQ among the four groups after adjusting for multiple confounding factors. The high-frequency telecommuters group had the highest job control score. Regarding the fluctuation score of subjective job stress, the high- and medium-frequency telecommuters groups were significantly lower than those of the non-telecommuters group after adjusting for multiple confounding factors.ConclusionWe found that high-frequency telecommuting was associated with high job control. This study suggests that the widespread adoption of telecommuting as a countermeasure to the public health challenges associated with the COVID-19 pandemic may also have a positive impact on job stress.
Primary care clinical management following self-harm during the first wave of COVID-19 in the UK
Authors: Steeg Sarah , Carr Matthew J , Trefan Laszlo , Ashcroft Darren M , Kapur Nav , Nielsen Emma , McMillan Brian , Webb Roger T 
Published: March 2021

AbstractBackgroundA substantial reduction in GP-recorded self-harm occurred during the first wave of COVID-19 but effects on primary care management of self-harm are unknown.AimTo examine the impact of COVID-19 on clinical management within three months of an episode of self-harm.Design and settingProspective cohort study using data from the UK Clinical Practice Research Datalink.MethodWe compared cohorts of patients with an index self-harm episode recorded during a pre-pandemic period (10th March-10th June, 2010-2019) versus the COVID-19 first-wave period (10th March-10th June 2020). Patients were followed up for three months to capture psychotropic medication prescribing, GP/practice nurse consultation and referral to mental health services.Results48,739 episodes of self-harm were recorded during the pre-pandemic period and 4,238 during the first-wave COVID-19 period. Similar proportions were prescribed psychotropic medication within 3 months in the pre-pandemic (54.0%) and COVID-19 first-wave (54.9%) cohorts. Likelihood of having at least one GP/practice nurse consultation was broadly similar (83.2% vs. 80.3% in the COVID-19 cohort). The proportion of patients referred to mental health services in the COVID-19 cohort (3.4%) was around half of that in the pre-pandemic cohort (6.5%).ConclusionDespite the challenges experienced by primary healthcare teams during the initial COVID-19 wave, prescribing and consultation patterns following self-harm were broadly similar to pre-pandemic levels. However, the reduced likelihood of referral to mental health services warrants attention. Accessible outpatient and community services for people who have self-harmed are required as the COVID-19 crisis recedes and the population faces new challenges to mental health.
Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors
Authors: Kunze Katie L. , Johnson Patrick W. , van Helmond Noud , Senefeld Jonathon W. , Petersen Molly M. , Klassen Stephen A. , Wiggins Chad C. , Klompas Allan M. , Bruno Katelyn A. , Mills John R. , Theel Elitza S. , Buras Matthew R. , Golafshar Michael A. , Sexton Matthew A. , Soto Juan C. Diaz , Baker Sarah E. , Shepherd John R.A. , Verdun Nicole C. , Marks Peter , Paneth Nigel S. , Fairweather DeLisa , Wright R. Scott , Casadevall Arturo , Carter Rickey E. , Joyner Michael J. ,   the US EAP COVID-19 Plasma Consortium, van Buskirk Camille M. , Winters Jeffrey L. , Stubbs James R. , Senese Katherine A. , Pletsch Michaela C. , Buchholtz Zachary A. , Rea Robert F. , Herasevich Vitaly , Whelan Emily R. , Clayburn Andrew J. , Larson Kathryn F. , Ripoll Juan G. , Andersen Kylie J. , Lesser Elizabeth R. , Vogt Matthew N.P. , Dennis Joshua J. , Regimbal Riley J. , Bauer Philippe R. , Blair Janis E. 
Published: March 2021

AbstractSuccessful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma is likely to reflect the antigenic composition of local viral strains, we hypothesized that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to a national registry of hospitalized COVID-19 patients supported this hypothesis. These findings have implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.
Gene-level germline contributions to clinical risk of recurrence scores in Black and White breast cancer patients
Authors: Patel Achal , García-Closas Montserrat , Olshan Andrew F. , Perou Charles M. , Troester Melissa A. , Love Michael I. , Bhattacharya Arjun 
Published: March 2021

ABSTRACTContinuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer (BC). Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to BC disparities, evidence for biological and germline contributions is emerging. We investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N=1,043 WW, 1083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; Proliferation Score; ROR-P: ROR-S plus Proliferation Score) on imputed Genetically-Regulated tumor eXpression (GReX). Using Bayesian multivariate regression and adaptive shrinkage, we tested GReX-prioritized genes for associations with PAM50 tumor expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjustedP< 0.10, we detected 7 and 1 GReX-prioritized genes among WW and BW. Among WW, CRS were positively associated withMCM10, FAM64A, CCNB2, andMMP1GReX and negatively associated withVAV3, PCSK6, andGNG11GReX. Among BW, higherMMP1GReX predicted lower Proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among BC patients, we find differential germline associations with CRS by race, underscoring the need for larger, diverse datasets in molecular studies of BC. Our findings also suggest possible germlinetrans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings.SIGNIFICANCEWe find race-specific genetic associations with breast cancer risk-of-recurrence scores (CRS). Follow-up analyses suggest mediation of these associations by PAM50 molecular subtype and gene expression, with implications for clinical interpretation of CRS.
Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against SARS-CoV-2 Variants of Concern
Authors: Lien Chia-En , Kuo Tsun-Yung , Lin Yi-Jiun , Lian Wei-Cheng , Lin Meei-Yun , Liu Luke Tzu-Chi , Chou Yu-Chi , Chen Charles 
Published: March 2021

AbstractVaccination is currently the best weapon to control the COVID-19 pandemic. However, an alarming number of novel variants termed Variants of Concern (VoC) were found to harbor mutations that diminished the neutralizing capacity of antibodies elicited by the vaccines. We have investigated the neutralizing titers of antibodies from sera of humans and rats immunized with the MVC-COV1901 vaccine against pseudoviruses coated with the wildtype, D614G, B.1.1.7, or B.1.351 spike proteins. Rats vaccinated with two doses of adjuvanted S-2P retained neutralization activities against the B.1.351 variant, albeit with a slight reduction compared to wildtype. Phase 1 vaccinated subjects showed more reduced neutralization abilities against the B.1.351 variant. The study is among the first, to our knowledge, to demonstrate dose-dependent neutralizing responses against VoCs, particularly against B.1.351, from different doses of antigen in a clinical trial for a subunit protein COVID-19 vaccine. The appearance of vaccine escape variants is a growing concern facing many current COVID-19 vaccines and therapeutics. Strategies should be adopted against the ever-changing nature of these variants. The observations of this study grant us valuable insight into preemptive strikes against current and future variants.
From atoms to cells: bridging the gap between potency, efficacy, and safety of small molecules directed at a membrane protein
Authors: Aguayo-Ortiz Rodrigo , Creech Jeffery , Jiménez-Vázquez Eric N. , Guerrero-Serna Guadalupe , Wang Nulang , da Rocha Andre Monteiro , Herron Todd J. , Espinoza-Fonseca L. Michel 
Published: March 2021

AbstractMembrane proteins constitute a substantial fraction of the human proteome, thus representing a vast source of therapeutic drug targets. Indeed, newly devised technologies now allow targeting “undruggable” regions of membrane proteins to modulate protein function in the cell. Despite the advances in technology, the rapid translation of basic science discoveries into potential drug candidates targeting transmembrane protein domains remains challenging. We address this issue by harmonizing single molecule-based and ensemble-based atomistic simulations of ligand–membrane interactions with patient-derived induced pluripotent stem cell (iPSC)-based experiments to gain insights into drug delivery, cellular efficacy, and safety of molecules directed at membrane proteins. In this study, we interrogated the pharmacological activation of the cardiac Ca2+pump (Sarcoplasmic reticulum Ca2+-ATPase, SERCA2a) in human iPSC-derived cardiac cells as a proof-of-concept model. The combined computational-experimental approach serves as a platform to explain the differences in the cell-based activity of candidates with similar functional profiles, thus streamlining the identification of drug-like candidates that directly target SERCA2a activation in human cardiac cells. Systematic cell-based studies further showed that a direct SERCA2a activator does not induce cardiotoxic pro-arrhythmogenic events in human cardiac cells, demonstrating that pharmacological stimulation of SERCA2a activity is a safe therapeutic approach targeting the heart. Overall, this novel platform encompasses organ-specific drug potency, efficacy, and safety, and opens new avenues to accelerate the bench-to-patient research aimed at designing effective therapies directed at membrane protein domains.
High rates of plasmid cotransformation inE. colioverturn the clonality myth and reveal colony development
Authors: Tomoiaga Delia , Bubnell Jaclyn , Herndon Liam , Feinstein Paul 
Published: March 2021

AbstractThe concept of DNA transfer between bacteria was put forth by Griffith in 1928. During the dawn of molecular cloning of DNA in the 1980s, Hanahan described how the transformation of DNA plasmids into bacteria would allow for cloning of DNA fragments. Through this foundational work, it is widely taught that a typical transformation produces clonal bacterial colonies. Using low concentrations of several plasmids that encode different fluorescent proteins, under the same selective antibiotic, we show thatE. colibacteria readily accept multiple plasmids, resulting in widespread aclonality and reveal a complex pattern of colony development. Cotransformation of plasmids occurs by either CaCl2or by electroporation methods. A bacterium rod transformed with three plasmids - each expressing a high level of a unique fluorescent protein - and replated on agar, appears to reassign a random number of the three fluorescent plasmids to its daughter cell during cell division. The potential to simultaneously follow multiple lineages of clonally related bacteria in a bacteria colony would allow for mosaic analysis of gene function. We show that clonally related bacterium rods self-organize in a fractal growth pattern and can remain linked during colony development revealing a potential target against microbiota growth.
The impact of brain lesions on tDCS-induced electric field magnitude
Authors: Johnstone Ainslie , Zich Catharina , Evans Carys , Lee Jenny , Ward Nick , Bestmann Sven 
Published: March 2021

AbstractBackgroundTranscranial direct current stimulation (tDCS) has been used to enhance motor and language rehabilitation following a stroke. However, improving the effectiveness of clinical tDCS protocols depends on understanding how lesions may influence tDCS-induced current flow through the brain.ObjectiveWe systematically investigated the effect of brain lesions on the magnitude of electric fields (e-mag) induced by tDCS, and how to overcome lesion-induced inter-individual variability in e-mag.MethodsWe simulated the effect of 630 different lesions - by varying lesion location, distance from the target region of interest (ROI), size and conductivity - on tDCS-induced e-mag in the brains of two participants. Current flow modelling was conducted for two tDCS montages commonly used in clinical applications, which target either primary motor cortex (M1) or Broca’s area (BA44), respectively. We further explored how the inherent variability in e-mag that is introduced by inter-lesion differences can be overcome by individualising tDCS protocols.ResultsThe effect onabsolutee-mag was highly dependent on lesion size, conductance and the distance from the target ROI. Larger lesions, with high conductivity, closer to the ROI caused e-mag changes of more than 30%. Thesignof this change was determined by the location of the lesion. Specifically, lesions located in-line with the predominant direction of current flow increased e-mag in the ROI, whereas lesions located in the opposite direction caused a decrease. Lesions had a large impact on the optimal electrode configuration if attempting to maximise for the total e-mag in the ROI, but little impact if only the component of e-mag flowing radially inward to the cortex was maximised. Knowing the effect of a given lesion on e-mag also allows for individualising tDCS intensity to reduce variability.ConclusionsThese results demonstrate that tDCS-induced electric fields are profoundly influenced by lesion characteristics, and further exacerbate the known variability in e-mag across individuals. Additionally, the dependence of these results on the assigned conductance of the lesion underlines the need for improved estimates of lesion conductivity for current flow models. Our results highlight the need for individualised dose control of tDCS in the lesioned brain to overcome the substantial inter-individual variability in electric fields delivered to a cortical target region.Highlights-Lesions can alter tDCS-induced electric field magnitude (e-mag) in a target by 30%-Lesions can cause increases or decreases to e-mag-Direction of change depends on the position of the lesion relative to current flow-Lesion conductivity - the true value for which is unknown - also impacts change-E-mag variability can be reduced by individualising montage and stimulation intensity
Non-REM sleep in major depressive disorder
Authors: Bovy Leonore , Weber Frederik D. , Tendolkar Indira , Fernández Guillén , Czisch Michael , Steiger Axel , Zeising Marcel , Dresler Martin 
Published: March 2021

AbstractDisturbed sleep is a key symptom in major depressive disorder (MDD). REM sleep alterations are well described in the current fliterature, but little is known about non-REM sleep alterations. Additionally, sleep disturbances relate to a variety of cognitive symptoms in MDD, but which features of non-REM sleep EEG contribute to this, remains unknown. We comprehensively analyzed non-REM sleep EEG features in three independently collected datasets (N=284). These included MDD patients with a broad age range, varying duration and severity of depression, unmedicated or medicated, age- and gender-matched to healthy controls. We explored changes in sleep architecture including sleep stages and cycles, spectral power, sleep spindles, slow waves (SW), and SW-spindle coupling. Next, we analyzed the association of these sleep features with acute measures of depression severity and overnight consolidation of procedural memory. Overall, no major systematic alterations in non-REM sleep architecture were found in patients compared to controls. For the microstructure of non-REM sleep, we observed a higher spindle amplitude in unmedicated patients compared to controls, and after the start of antidepressant medication longer SWs with lower amplitude and a more dispersed SW-spindle coupling. In addition, long-term, but not short-term medication seemed to lower spindle density. Overnight procedural memory consolidation was impaired in medicated patients and associated with lower sleep spindle density. Our results suggest that alterations in non-REM sleep EEG might be more subtle than previously reported. We discuss these findings in the context of antidepressant medication intake and age.Statement of SignificanceDepression affects large and diverse populations worldwide, including their sleep. Most sleep is non-REM sleep, which is vital to cognitive function, including memory. How non-REM is affected during a depression or medical treatment remains poorly investigated. We classified non-REM sleep of depressive patients against healthy controls in unprecedented analysis detail and confidence using the largest dataset published so far while also test sleep alterations associations with impaired memory. Surprisingly, severe depression alone did not alter sleep. We observed severe non-REM sleep alterations only worsening under patient medication, which ultimately coincided with 24-hour memory impairments. Though causal influences of medication on sleep in depressive patients remains to be investigated, this cautions common clinical practice in long-term treatment with antidepressants.
Catchet-MS identifies IKZF1-targeting Thalidomide analogues as novel HIV-1 latency reversal agents
Authors: Ne Enrico , Crespo Raquel , Izquierdo-Lara Ray , Rao Shringar , Koçer Selin , Górska Alicja , van Staveren Thomas , Kan Tsung Wai , Dekkers Dick , Rokx Casper , Moulos Panagiotis , Hatzis Pantelis , Palstra Robert-Jan , Demmers Jeroen , Mahmoudi Tokameh 
Published: March 2021

AbstractA major pharmacological strategy toward HIV cure aims to reverse latency in infected cells as a first step leading to their elimination. While the unbiased identification of molecular targets physically associated with the latent HIV-1 provirus would be highly valuable to unravel the molecular determinants of HIV-1 transcriptional repression and latency reversal, due to technical limitations, this has not been possible. Here we use a dCas9 targeted chromatin and histone enrichment strategy coupled to mass spectrometry (Catchet-MS) to describe the protein composition of the latent and activated HIV-1 5’LTR. Catchet-MS identified known and novel latent 5’LTR-associated host factors. Among these, IKZF1 is a novel HIV-1 transcriptional repressor, required for Polycomb Repressive Complex 2 recruitment to the LTR. We find the clinically advanced thalidomide analogue iberdomide, and the FDA approved analogues lenalidomide and pomalidomide, to be novel LRAs that, by targeting IKZF1 for degradation, reverse HIV-1 latency in CD4+T-cells isolated from virally suppressed people living with HIV-1.One Sentence SummarydCas9 targeted chromatin and histone enrichment for mass spectrometry (Catchet-MS) led to the identification of IKZF1-targeting thalidomide analogues as novel HIV-1 latency reversal agents
Bacterial-type plant ferroxidases tune local phosphate sensing in root development
Authors: Naumann Christin , Heisters Marcus , Brandt Wolfgang , Janitza Philipp , Alfs Carolin , Tang Nancy , Nienguesso Alicia Toto , Ziegler Joerg , Imre Richard , Mechtler Karl , Dagdas Yasin , Hoehenwarter Wolfgang , Sawers Gary , Quint Marcel , Abel Steffen 
Published: March 2021

AbstractFluctuating bioavailability of inorganic phosphate (Pi), often caused by complex Pi-metal interactions, guide root tip growth and root system architecture for maximizing the foraged soil volume. Two interacting genes inArabidopsis thaliana,PDR2(P5-type ATPase) andLPR1(multicopper oxidase), are central to external Pi monitoring by root tips, which is modified by iron (Fe) co-occurrence. Upon Pi deficiency, thePDR2-LPR1module facilitates cell type-specific Fe accumulation and cell wall modifications in root meristems, inhibiting intercellular communication and thus root growth. LPR1 executes local Pi sensing, whereas PDR2 restricts LPR1 function. We show that native LPR1 displays specific ferroxidase activity and requires a conserved acidic triad motif for high-affinity Fe2+binding and root growth inhibition under limiting Pi. Our data indicate that substrate availability tunes LPR1 function and implicate PDR2 in maintaining Fe homeostasis. LPR1 represents the prototype of an ancient ferroxidase family, which evolved very early upon bacterial colonization of land. During plant terrestrialization, horizontal gene transfer transmitted LPR1-type ferroxidase from soil bacteria to the common ancestor of Zygnematophyceae algae and embryophytes, a hypothesis supported by homology modeling, phylogenomics, and activity assays of bacterial LPR1-type multicopper oxidases.