bluuebunny/crossref_metadata_2025_split huggingface dataset:
Beta turn propensity and a model polymer scaling exponent identify disordered proteins that phase separate
Authors: Paiz Elisia A. , Allen Jeffre H. , Correia John J. , Fitzkee Nicholas C. , Hough Loren E. , Whitten Steven T. 
Published: July 2020

AbstractThe complex cellular milieu can spontaneously de-mix in a process controlled in part by proteins that are intrinsically disordered (ID). A protein’s propensity to de-mix is thought to be driven by the preference for protein-protein rather than protein-solvent interactions. The hydrodynamic size of monomeric proteins, as quantified by the polymer scaling exponent (v), is driven by a similar balance. We hypothesize that meanv, as predicted by the protein sequence, will be smaller for proteins with a strong propensity to de-mix. To test this hypothesis, we analyzed protein databases containing subsets that are either folded, disordered, or disordered and known to spontaneously phase separate. We find that the phase separating disordered proteins, on average, have lower calculated values ofvcompared to their non-phase separating counterparts. Moreover, these proteins have a higher sequence-predicted propensity for β-turns. Using a simple, surface areabased model, we propose a physical mechanism for this difference: transient β-turn structures reduce the desolvation penalty of forming a protein-rich phase and increase exposure of atoms involved in π/sp2electronic interactions. By this mechanism, β-turns act as energetically favored nucleation points, which may explain the increased propensity for turns in ID regions (IDRs) that are utilized biologically for phase separation. Phase separating IDRs, non-phase separating IDRs, and folded regions could be distinguished by combiningvand β-turn propensity, and we propose a new algorithm, ParSe (partitionsequence), for predicting phase separating protein regions. ParSe is able to accurately identify folded, disordered, and phase-separating protein regions from the primary sequence.
MAPK signaling links the injury response to Wnt-regulated patterning inHydraregeneration
Authors: Tursch Anja , Bartsch Natascha , Holstein Thomas W. 
Published: July 2020

AbstractHydrahas a long history as an informative model to study pattern formation and regeneration. Wnt signaling is a critical component ofHydrapatterning that must be activated during regeneration, but it is largely unknown how the injury stimulus ultimately leads to this activation. In a proteomic screen we previously identified mitogen protein kinases (MAPKs) among the earliest injury response factors inHydraregeneration, making them attractive candidates to transmit injury-response signals to the initial steps of patterning, which inHydraincludes Wnt signaling. Our data demonstrate that three MAPKs, p38, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERK), are essential to initiate regeneration inHydra. This activation occurs in response to an injury signal, which consists of calcium and reactive oxygen species (ROS) signaling. Phosphorylated MAPKs exhibit cross-talk with a mutual antagonism between the ERK1/2 pathway and the stress induced MAPKs. The activation of these MAPK pathways, as well as the induction of apoptosis, occurs in all injuries regardless of the position of the wound. MAPK phosphorylation is required for the transcriptional activation of position independentWnt3andWnt9/10cligands. In summary, our data show that the activation of MAPKs is an essential component of the wound response which transmits the injury signal to induce the transcriptional activation ofWntligands, which are essential for patterning the regenerating tissue. Given the high level of evolutionary conservation of MAPKs and Wnts in the injury response, this likely represents a deeply conserved pathway in animals.
Dual mechanism estrogen receptor inhibitors
Authors: Min Jian , Nwachukwu Jerome C. , Srinivasan Sathish , Rangarajan Erumbi S. , Nettles Charles C. , Guillen Valeria Sanabria , Ziegler Yvonne , Yan Shunchao , Carlson Kathryn E. , Hou Yingwei , Kim Sung Hoon , Novick Scott , Pascal Bruce D. , Houtman Rene , Griffin Patrick R. , Izard Tina , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Nettles Kendall W. 
Published: July 2020

AbstractEfforts to improve estrogen receptor-a (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, non-canonical structural perturbations of the receptor ligand-binding domain (LBD) to drive antagonism of proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Solution structural and coregulator peptide binding analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access non-consensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.Significance StatementTo address the unmet clinical need for effectively suppressing estrogen receptor (ER) activity with both de novo resistance and in advanced ER-positive breast cancers that are resistant to standard-of-care antiestrogens, we have developed dual-mechanism ER inhibitors (DMERIs) that employ two distinct ER targeting moieties. These DMERI elicited non-canonical structural perturbations of the receptor ligand-binding domain and stabilized multiple antagonist sub-states within the dimer to generate highly efficacious antagonism of proliferation in ER-positive breast cancer cells and in allele-specific resistance models. This work reveals new conformational modes by which the activity of ER can be effectively suppressed to block breast cancer proliferation.
Proteomic profiling of mitochondrial-derived vesicles in brain reveals enrichment of respiratory complex sub-assemblies and small TIM chaperones
Authors: Roberts Rosalind F. , Bayne Andrew N. , Goiran Thomas , Lévesque Dominique , Boisvert François-Michel , Trempe Jean-François , Fon Edward A. 
Published: July 2020

ABSTRACTThe generation of mitochondrial-derived vesicles (MDVs) is implicated in a plethora of vital cell functions, from mitochondrial quality control to peroxisomal biogenesis. The discovery of distinct subtypes of MDVs has revealed the selective inclusion of mitochondrial cargo in response to varying stimuli. However, the true scope and variety of MDVs is currently unclear, and unbiased approaches have yet to be used to understand their biology. Furthermore, as mitochondrial dysfunction has been implicated in many neurodegenerative diseases, it is essential to understand MDV pathways in the nervous system. To address this, we sought to identify the cargo in brain MDVs. We used an in vitro budding assay and proteomic approach to identify proteins selectively enriched in MDVs. 72 proteins were identified as MDV enriched, of which 31% were OXPHOS proteins. Interestingly, the OXPHOS proteins localized to specific modules of the respiratory complexes, hinting at the inclusion of sub-assemblies in MDVs. Small TIM chaperones were also highly enriched in MDVs, linking mitochondrial chaperone-mediated protein transport to MDV formation. As the two Parkinson’s disease genes PINK1 and Parkin have been previously implicated in MDV biogenesis in response to oxidative stress, we compared the MDV proteomes from the brains of wild-type mice with those of PINK1-/-and Parkin-/-mice. No significant difference was found, suggesting that PINK1- and Parkin-dependent MDVs make up a small proportion of all MDVs in the brain. Our findings demonstrate a previously uncovered landscape of MDV complexity and provide a foundation from which to discover further novel MDV functions.
Renin-angiotensin-aldosterone system inhibitors and COVID-19 infection or hospitalization: a cohort study
Authors: Dublin Sascha , Walker Rod , Floyd James S. , Shortreed Susan M. , Fuller Sharon , Albertson-Junkans Ladia , Harrington Laura B. , Greenwood-Hickman Mikael Anne , Green Beverly B. , Psaty Bruce M. 
Published: July 2020

AbstractThere are plausible mechanisms by which angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may increase the risk of COVID-19 infection or affect disease severity. To examine the association between these medications and COVID-19 infection or hospitalization, we conducted a retrospective cohort study within a US integrated healthcare system. Among people aged ≥18 years enrolled in the health plan for at least 4 months as of 2/29/2020, current ACEI and ARB use was identified from pharmacy data, and the estimated daily dose was calculated and standardized across medications. COVID-19 infections were identified through 6/14/2020 from laboratory and hospitalization data. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals. Among 322,044 individuals, 720 developed COVID-19 infection. Among people using ACEI/ARBs, 183/56,105 developed COVID-19 (3.3 per 1000 individuals) compared with 537/265,939 without ACEI/ARB use (2.0 per 1000), yielding an adjusted OR of 0.94 (95% CI 0.75-1.16). For use of < 1 defined daily dose vs. nonuse, the adjusted OR for infection was 0.89 (95% CI 0.62-1.26); for 1 to < 2 defined daily doses, 0.97 (95% CI 0.71-1.31); and for ≥2 defined daily doses, 0.94 (95% CI 0.72-1.23). The OR was similar for ACEIs and ARBs and in subgroups by age and sex. 29% of people with COVID-19 infection were hospitalized; the adjusted OR for hospitalization in relation to ACEI/ARB use was 0.92 (95% CI 0.54-1.57), and there was no association with dose. These findings support current recommendations that individuals on these medications continue their use.
Multi-Omics integration analysis of respiratory specimen characterizes baseline molecular determinants associated with COVID-19 diagnosis
Authors: Maras Jaswinder Singh , Sharma Shvetank , Bhat Adil , aggrawal Reshu , Gupta Ekta , Sarin Shiv K 
Published: July 2020

AbstractRapid diagnosis and precise prognostication of SARS-CoV-2 infection remains a major challenge. A multi-omic approach was adopted, and in the discovery phase, global proteome/metaproteome/metabolome were analysed in the respiratory specimens of SARS-CoV-2 positive [n=20], negative [n=20], and H1N1 positive [n=5] cases. We identified MX1 (MX Dynamin Like GTPase 1) and WARS (Tryptophan--tRNA ligase) as clues to viral diagnosis and validated in 200 SARS-CoV-2 suspects. MX1 >30pg/ml and WARS >25ng/ml segregated virus positives patients [(AUC=94%CI(0.91-0.97)]. Distinct increase in SARS-CoV-2 induced immune activation, metabolic reprograming and a decrease in oxygen transport, wound healing, fluid regulation, vitamin and steroid metabolism was seen (p<0.05). Multi-omics profiling correlated with viraemia and segregated asymptomatic COVID-19 patients. Additionally, the multiomics approach identified increased respiratory pathogens [Burkholderiales, Klebsiella pneumonia] and decreased lactobacillus salivarius (FDR<0.05, p<0.05) in COVID-19 specimens.ConclusionNovel proteins [MX1 and WARS] can rapidly and reliably diagnose SARS-CoV-2 infection and identify asymptomatic and mild disease.
Characterisation of alcohol polygenic risk scores in the context of mental health outcomes: Within-individual and intergenerational analyses in the Avon Longitudinal Study of Parents and Children
Authors: Easey Kayleigh E , Wootton Robyn E , Sallis Hannah M , Haan Elis , Schellhas Laura , Munafò Marcus R , Timpson Nicholas , Zuccolo Luisa 
Published: July 2020

AbstractBackgroundHeavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages.DesignWe characterised a PRS reliably associated with patterns of adult alcohol consumption by 1) validating whether it predicts own alcohol use at different life-stages (pregnancy, adolescence) of interest for mental health impact. Additionally, we explored associations of alcohol PRS on mental health phenotypes 2) within-individuals (using own alcohol PRS on own phenotypes) and 3) intergenerationally (using maternal alcohol PRS on offspring phenotypes). We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=960 to 7841). Additional substance abuse behaviours and mental health/behavioural outcomes were investigated (alcohol phenotypesn=22; health phenotypesn=91).Findings:Maternal alcohol PRS was associated with consumption during pregnancy (strongest signal: alcohol frequency at 18 weeks’ gestation:β=0.041, 95% CI=1.02 to 1.8),p=1.01×10−5, adjusted R2=1.16%), offspring alcohol PRS did not predict offspring alcohol consumption. We found evidence for an association of maternal alcohol PRS with own perinatal depression (OR=1.10, 95% CI=0.02 to 0.06,p=0.02) and decreased offspring intellectual ability (β=−0.209, 95% CI −0.38 to 0.04,p=0.016).Conclusions: These alcohol PRS are a valid proxy for maternal alcohol use in pregnancy. Offspring alcohol PRS was not associated with drinking in adolescence.Consistently with results from different study designs, we found evidence that maternal alcohol PRS are associated with both prenatal depression and decreased offspring intellectual ability.
Can antiepileptic drug efficacy be studied from electronic health records? A review of current approaches
Authors: Decker Barbara M , Hill Chloé E , Baldassano Steven N , Khankhanian Pouya 
Published: July 2020

SUMMARYAs automated data extraction and natural language processing (NLP) are rapidly evolving, applicability to harness large data to improve healthcare delivery is garnering great interest. Assessing antiepileptic drug (AED) efficacy remains a barrier to improving epilepsy care. In this review, we examined automatic electronic health record (EHR) extraction methodologies pertinent to epilepsy examining AED efficacy. We also reviewed more generalizable NLP pipelines to extract other critical patient variables.Our review found varying reports of performance measures. Whereas automated data extraction pipelines are a crucial advancement, this review calls attention to standardizing NLP methodology and accuracy reporting for greater generalizability. Moreover, the use of crowdsourcing competitions to spur innovative NLP pipelines would further advance this field.HIGHLIGHTSAutomated data extraction is rapidly evolving and can be harnessed to efficiently mine the electronic health record.Natural language processing (NLP) of unstructured text improves data extraction accuracy when added to ICD coding and structured fields.We review these techniques specific to epilepsy and highlight strengths as well as areas of further improvement.
Application of Safety Attitudes Questionnaire (SAQ) in Adult Intensive Care Units: a cross-sectional study
Authors: Alqahtani Abdullah S. , Evley Rachel 
Published: July 2020

AbstractPurposeTo achieve a positive safety culture, staff perception of safety must be frequently measured. There are several active and reactive methods to use to measure safety cultures such as near-miss occurrence, accidental data collection, measuring behavior, self-report method, and safety questionnaires. The safety attitudes questionnaire (SAQ) tool was used to measure safety culture. This tool is widely used in literature and among researchers and has been used and validated in middle eastern cultures. In addition, it has a validated Arabic version.MethodsA cross-sectional study was conducted using anonymous and random sampling. I surveyed all ICU staff working in all the adult ICUs in two of the major hospitals in the eastern province of Saudi Arabia. The short version of the Safety Attitudes Questionnaire was used to assess participants’ attitudes towards safety culture. The study involved all healthcare providers working in Adult ICU.ResultsThe study occurred over a three-week period in March 2019. A total of 82 completed questionnaires were returned which represented a response rate of 82%. On average, the domain that scored the highest number of positive responses was Job satisfaction with 68.5%, followed by teamwork climate 67.8%, then working conditions 60.1%, 57.1% safety climate, then preparation of management with 53.4%, and finally 46% in Stress recognition. A statistically significant difference was found between the mean SAQ score and the educational level of the participants. Participants with bachelor’s degrees scored a mean of 50.17 compared to participants hold diploma degrees who scored a mean of 68.81 (P=0.02). Moreover, a significant difference was found between the mean SAQ score and participants’ specialties. Attending/Staff Physician mean score was 36.40, Nurse Manager/Charge Nurse scored 39.78, and Respiratory therapist mean score was 47.88, compared to mean score of 62.27 for Registered Nurse, and Respiratory supervisor 67.0 (P=0.04). In addition, 79.2% of the respondents did not report any incidents in the last 12 months.ConclusionsThe result of the study shows an unsatisfying level of safety culture among healthcare staff in ICUs. The importance of this study is to establish a baseline for safety climate in these hospitals and specifically ICUs. In addition, by exposing the system weaknesses it helps the administration to strengthen and improve patient care. By decreasing workload and job stress, studies show they have a positive association with increasing job performance.
Examining the association between family status and depression in the UK Biobank
Authors: Giannelis Alexandros , Palmos Alish , Hagenaars Saskia P. , Breen Gerome , Lewis Cathryn M. , Mutz Julian 
Published: July 2020

AbstractBackgroundWe examined associations between family status (living with a spouse or partner, number of children) and lifetime depression.MethodsWe used data from the UK Biobank, a large prospective study of middle-aged and older adults. Lifetime depression was assessed as part of a follow-up mental health questionnaire. Logistic regression was used to estimate associations between family status and depression. We included extensive adjustment for social, demographic and other potential confounders, including depression polygenic risk scores.Results52,078 participants (mean age=63.6, SD=7.6; 52% female) were included in our analyses. Living with a spouse or partner was associated with substantially lower odds of lifetime depression (OR=0.67, 95%CI 0.62-0.74). Compared to individuals without children, we found higher odds of lifetime depression for parents of one child (OR=1.17, 95%CI 1.07-1.27), and parents of three (OR=1.11, 95%CI 1.03-1.20) or four or more children (OR=1.27, 95%CI 1.14-1.42). Amongst those not cohabiting, having any number of children was associated with higher odds of lifetime depression. Our results were consistent across age groups, the sexes, neighbourhood deprivation and genetic risk for depression. Exploratory Mendelian randomisation analyses suggested a causal effect of number of children on lifetime depression.LimitationsOur data did not allow distinguishing between non-marital and marital cohabitation. Results may not generalise to all ages or populations.ConclusionsLiving with a spouse or partner was strongly associated with reduced odds of depression. Having one or three or more children was associated with increased odds of depression, especially in individuals not living with a spouse or partner.
Why we like Google Scholar: postgraduate students' perceptions of factors influencing their intention to use
Authors: Alotaibi Faiz , Johnson Frances 
Published: July 2020

PurposeThis study examines the use of the search engine, Google Scholar, from the perspective of a specific study group, that of international postgraduate students. Based on the theory of task perceived performance and effort expectancy influencing intention to use, further factors of system, individual, social and organisational, in the postgraduate student context are explored.Design/methodology/approachThe questionnaire for the measurement of 11 factors was developed from related studies of e-library use, and data were collected from 200 international postgraduate students studying in the UK. Analysis using confirmatory factor analysis established the contextual influencing factors, and structural equation modeling examined the predicted model.FindingsThe findings confirmed the influence of the task-based factors of performance and expectancy and revealed that these were based on the perception of the visibility, accessibility and relevance of the system, and on perceived self-efficacy. The perception postgraduates held of themselves as competent users of Google Scholar was further borne out in the participants' own words when asked for the reason for their preference.Originality/valueThe approach taken enables research into use of search tools to go beyond ease of use as a main driver and to explore the relationship held among the internal and external influences of use. Recommendations for further user research are suggested as well as possible impact on the university library provision and support of services for students.