bluuebunny/crossref_metadata_2025_split huggingface dataset:
Learning with phenotypic similarity improves the prediction of functional effects of missense variants in voltage-gated sodium channels
Authors: Boßelmann Christian Malte , Hedrich Ulrike B.S. , Lerche Holger , Pfeifer Nico 
Published: September 2022

AbstractBackgroundMissense variants in genes encoding voltage-gated sodium channels are associated with a spectrum of severe diseases affecting neuronal and muscle cells, the so-called sodium channelopathies. Variant effects on the biophysical function of the channel correlate with clinical features and can in most cases be categorized as an overall gain- or loss-of-function. This information enables a timely diagnosis, facilitates precision therapy, and guides prognosis. Machine learning models may be able to rapidly generate supporting evidence by predicting variant functional effects.MethodsHere, we describe a novel multi-task multi-kernel learning framework capable of harmonizing functional results and structural information with clinical phenotypes. We included 62 sequence- and structure-based features such as amino acid physiochemical properties, substitution radicality, conservation, protein-protein interaction sites, expert annotation, and others. We harmonized phenotypes as human phenotype ontology (HPO) terms, and compared different measures of phenotypic similarity under simulated sparsity or noise. The final model was trained on whole-cell patch-clamp recordings of 375 unique non-synonymous missense variants each expressed in mammalian cells.ResultsOur gain- or loss-of-function classifier outperformed both conventional baseline and state-of-the-art methods on internal validation (mean accuracy 0.837 ± 0.035, mean AU-ROC 0.890 ± 0.023) and on an independent set of recently described variants (n = 30, accuracy 0.967, AU-ROC 1.000). Model performance was robust across different phenotypic similarity measures and largely insensitive to phenotypic noise or sparsity. Localized multi-kernel learning offered biological insight and interpretability by highlighting channels with implicit genotype-phenotype correlations or latent task similarity for downstream analysis.ConclusionsLearning with phenotypic similarity makes efficient use of clinical information to enable accurate and robust prediction of variant functional effects. Our framework extends the use of human phenotype ontology terms towards kernel-based methods in machine learning. Training data, pre-trained models, and a web-based graphical user interface for the model are publicly available.
Development shaped by cue reliability in the barn owl’s auditory midbrain
Authors: Shadron Keanu , Peña José L 
Published: September 2022

AbstractSensory systems display capability to preferentially choose stimuli based on their reliability at conveying accurate information. While previous reports have shown the ability of the brain to reweigh cues based on ongoing or dynamic changes in reliability, how the brain may learn and maintain neural responses to sensory statistics expected to be stable over longer time periods remain significant open questions of potential mechanisms underlying naturalistic biased perception. This study provides evidence that the barn owl’s midbrain is shaped by permanent statistics experienced during development. The barn owl’s midbrain features a topographic map of auditory space where neurons compute horizontal sound location from the interaural time difference (ITD). Previous work has shown that frequency tuning of these midbrain map neurons is correlated with the pattern of most reliable frequencies for the neurons’ preferred ITD. This pattern of ITD reliability is due to the filtering properties of the head, primarily determined by the facial ruff in the barn owl. In this study, we found that the absence of a facial ruff led to a decrease in the reliability of high frequencies originating from frontal space. To test if the owl’s frequency tuning of midbrain map neurons is driven by permanent changes in the pattern of ITD reliability, these neurons were recorded from adult owls, who had the facial ruff removed as juveniles, and from juvenile owls, before the facial ruff developed. In both groups, we found that frontally-tuned neurons displayed tunings to frequencies lower than reported in normal adult owls, consistent with the difference in ITD reliability between the normal and ruff removed conditions. Juvenile owls also exhibited more heterogeneous frequency tuning, suggesting developmental processes that refine tuning to match the pattern of ITD reliability. Additional recordings immediately upstream of the midbrain map displayed ITD tuned neural responses for all frequencies across the owl’s normal hearing range. Broader analysis of the effects of ruff-removal on the acoustical properties of spatial cues indicated a dominant role of ITD reliability in driving the adaptive changes in frequency tuning. These results support the hypothesis that frequency tuning in the midbrain map is developmentally adapted to permanent statistics of spatial cues, implementing probabilistic coding for sound localization.
A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites
Authors: Zhang Xu , Florini Francesca , Visone Joseph E. , Leonardi Irina , Gross Mackensie R. , Patal Valay , Deitsch Kirk W. 
Published: September 2022

AbstractMalaria parasites avoid immune clearance through their ability to systematically alter antigens exposed on the surface of infected red blood cells. This is accomplished by tightly regulated transcriptional control of individual members of a large, multicopy gene family called var and is the key to both the virulence and chronic nature of malaria infections. Expression of var genes is mutually exclusive and controlled epigenetically, however how large populations of parasites coordinate var gene switching to avoid premature exposure of the antigenic repertoire is unknown. Here we provide evidence for a transcriptional network anchored by a universally conserved gene called var2csa that coordinates the switching process. We describe a structured switching bias that shifts overtime and could shape the pattern of var expression over the course of a lengthy infection. Our results provide an explanation for a previously mysterious aspect of malaria infections and shed light on how parasites possessing a relatively small repertoire of variant antigen encoding genes can coordinate switching events to limit antigen exposure, thereby maintaining chronic infections.
Metatranscriptomic response of the wheat holobiont to decreasing soil water content
Authors: Pande Pranav M. , Azarbad Hamed , Tremblay Julien , St-Arnaud Marc , Yergeau Etienne 
Published: September 2022

AbstractCrops associate with microorganisms that help their resistance to biotic. However, it is not clear how the different partners of this association react during exposure to stresses. This knowledge is needed to target the right partners when trying to adapt crops to climate change. Here, we grew wheat in the field under rainout shelters that let through 100%, 75%, 50% and 25% of the precipitation. At the peak of the growing season, we sampled plant roots and rhizosphere, and extracted and sequenced their RNA. We compared the 100% and the 25% treatments using differential abundance analysis. In the roots, most of the differentially abundant (DA) transcripts belonged to the fungi, and most were more abundant in the 25% precipitation treatment. About 10% of the DA transcripts belonged to the plant and most were less abundant in the 25% precipitation treatment. In the rhizosphere, most of the DA transcripts belonged to the bacteria and were generally more abundant in the 25% precipitation treatment. Taken together, our results show that the transcriptomic response of the wheat holobiont to decreasing precipitation levels is more intense for the fungal and bacterial partners than for the plant.
Detectability of runs of homozygosity is influenced by analysis parameters and population-specific demographic history
Authors: Harder Avril M. , Kirksey Kenneth B. , Mathur Samarth , Willoughby Janna R. 
Published: September 2022

AbstractWild populations are increasingly threatened by human-mediated climate change and land use changes. As populations decline, the probability of inbreeding increases, along with the potential for negative effects on individual fitness. Detecting and characterizing runs of homozygosity (ROHs) is a popular strategy for assessing the extent of individual inbreeding present in a population and can also shed light on the genetic mechanisms contributing to inbreeding depression. Here, we analyze simulated and empirical data sets to demonstrate the downstream effects of program selection and long-term demographic history on ROH inference. We also apply a sensitivity analysis to evaluate the effects of various parameter values on ROH-calling results and demonstrate its utility for parameter value selection. We show that ROH inferences can be biased when sequencing depth and the distribution of ROH length is not interpreted in light of demographic history as well as program-specific tendencies. This is particularly important for the management of endangered species, as underestimating inbreeding signals in the genome can substantially undermining conservation initiatives. Based on our observations, we suggest using a combination of ROH detection tools and ROH length-specific inferences to generate robust population inferences regarding inbreeding history. We outline these recommendations for ROH estimation at multiple levels of sequencing effort typical of conservation genomics studies.
Role of intraflagellar transport in transcriptional control during flagellar regeneration in Chlamydomonas
Authors: Perlaza Karina , Zamora Ivan , Marshall Wallace F. 
Published: September 2022

AbstractBiosynthesis of organelle precursors is a central part of the organelle size control problem, but what systems are required to control precursor production? Genes encoding flagellar proteins are upregulated during flagellar regeneration in Chlamydomonas, and this upregulation is critical for flagella to reach their final length, but it not known how the cell triggers these genes during regeneration. Here we present two models based on transcriptional repressor that is either produced in the flagellum, or else is produced in the cell body and sequestered in the growing flagellum. We show that both models lead to stable flagellar length control, can reproduce the observed dynamics of gene expression, and are consistent with the effects of protein synthesis inhibitors on gene expression. The two models make opposite predictions regarding the effect of mutations that block intraflagellar transport (IFT). Using quantitative measurements of gene expression, we show that gene expression during flagellar regeneration is greatly reduced in mutations of FLA3, FLA8, and FLA10, which encode the three components of the heterotrimer kinesin-2 that drives IFT. This result is consistent with the predictions of the model in which a repressor is sequestered in the flagellum by IFT. In contrast to the effects of IFT mutants, we find that inhibiting axonemal assembly has much less effect on gene expression, suggesting that transport is more important than axonemal assembly. The repressor sequestration model allows precursor production to occur when flagella are growing rapidly, representing a form of derivative control.
Biogenic plate-like guanine crystals form via templated nucleation of thin crystal leaflets on amyloid scaffolds
Authors: Eyal Zohar , Deis Rachael , Varsano Neta , Dezorella Nili , Rechav Katya , Houben Lothar , Gur Dvir 
Published: September 2022

AbstractControlling the morphology of crystalline materials is challenging, as crystals have a strong tendency towards thermodynamically stable structures. Yet, organisms form crystals with distinct morphologies, such as the plate-like guanine crystals produced by many terrestrial and aquatic species for light manipulation. Regulation of crystal morphogenesis was hypothesized to entail physical growth restriction by the surrounding membrane, combined with fine-tuned interactions between organic molecules and the growing crystal. Using cryo electron tomography of developing zebrafish larvae, we found that guanine crystals form via templated nucleation of thin leaflets on preassembled scaffolds made of 20-nm-thick amyloid fibers. These leaflets then merge and coalesce into a single plate-like crystal. Our findings provide new insights into how organisms control the morphology and, thereby, the optical properties of crystals.
Whole genome sequencing and global metabolome profiling of clinical Mycobacterium tuberculosis isolates provide insights to their drug resistance status
Authors: Sahoo Ashutosh , Mohapatra Amit Kumar , Priyadarsini Haripriya , Pemmadi Raghuveer Varma , Das Anjan , Choedon Tenzin , Nikam Chaitali , Behera Rajendra Kumar , Masakapalli Shyam K. , Nanda Ranjan K. 
Published: September 2022

AbstractWhole genome sequence analysis of the Mycobacterium tuberculosis (Mtb) isolates show correlation to their drug resistance phenotype which may also reflect in their global metabolome. In this report, clinical Mtb isolates (S1, S4, S5, S6, S7, S10) harvested from the sputum of tuberculosis patients were characterized using drug sensitive test (DST), electron microscope, whole genome sequencing (WGS) and metabolomics. Majority of these Mtb isolates showed similar size (length: 1.0–3.2 μm; width: 0.32–0.52 μm) to the H37Rv Mtb strain whereas significant variations were observed in their growth kinetics, WGS and metabolome profiles. In-silico drug resistance prediction, from the WGS data (single-nulceotide polymorphisms (SNP) pattern) of these Mtb isolates showed resistance to tuberculosis drugs and matched with DST results. Differences in the genes involved in stress response, pathogenicity, drug efflux pumps were observed between isolates but genes of the central carbon metabolic pathways and amino acid metabolism were conserved. Gas chromatography and mass spectrometry (GC-MS) based metabolite profiling of these clinical isolates identified 291 metabolites involved in various metabolic pathways and a sub set of these metabolites (glutamic acid, aspartic acid and serine) contributed to the drug resistance patterns. These clinical Mtb isolates could be useful as alternate reagent for understanding host pathogen interaction and the pipeline used for WGS analysis could be used to predict drug resistance pattern of new Mtb isolates.
Sex Difference in Causes and Timing of One-Year Outcomes Among Young Acute Myocardial Infarction Patients; Results from the VIRGO Study
Authors: Sawano Mitsuaki , Lu Yuan , Caraballo Cesar , Mahajan Shiwani , Dreyer Rachel , Lichtman Judith H. , D’Onofrio Gail , Spatz Erica , Khera Rohan , Onuma Oyere , Murugiah Karthik , Spertus John A. , Krumholz Harlan M. 
Published: September 2022

AbstractBackgroundYounger women have higher recurrent hospitalization rates and worse health status than men after their index episode of acute myocardial infarction (AMI). However, whether women have a higher risk of cardiovascular events in the year after discharge is unknown.MethodsWe used data from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study, which enrolled young AMI patients aged 18 to 55 years across 103 US hospitals. Sex differences in all-cause and cause-specific hospitalizations were compared by calculating incidence rates (IR, per 1,000 person-years) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs). We then performed sequential modeling to evaluate the sex difference by calculating sub-distribution hazard ratios (SHR) accounting for deaths.ResultsAmong 2,007 women and 972 men, at least one all-cause hospitalization occurred among 905 (30.4%) participants in the year after discharge. The leading causes of hospitalization were MI-related (IR 171.8, 95% CI, 153.6-192.2 among women vs. IR 117.8, 95% CI, 97.3-142.6 among men), followed by non-cardiac (IR 145.8, 95% CI, 129.2-164.5 among women vs. IR 69.6, 95% CI, 54.5-88.9 among men) and other cardiac or stroke hospitalizations (IR 58.8, 95% CI, 48.8-70.7 among women vs. IR 53.8, 95% CI, 40.8-71.0 among men). Competing risk analysis showed that the sex difference was present for MI-related hospitalizations (SHR 1.33, 95%CI 1.04-1.70; P=0.02) and non-cardiac hospitalizations (SHR 1.51, 95%CI 1.13-2.07; P=0.01).ConclusionsYoung women with AMI have more adverse outcomes compared with men in the year after discharge. MI-related hospitalizations were the most common cause of hospitalizations, but non-cardiac hospitalizations showed the most significant sex disparity. Further studies to better understand the underlying mechanisms of non-cardiac hospitalizations are warranted.
Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index and sex: a cohort study in SCQM
Authors: Vallejo-Yagüe Enriqueta , Burkard Theresa , Finckh Axel , Burden Andrea M. 
Published: September 2022

ABSTRACTBackgroundObesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). Among obese patients, abatacept was suggested as a preferable option to tumour necrosis factor alpha (TNF) inhibitors. Sex and gender differences in RA were described.ObjectivesTo assess the comparative effectiveness of etanercept, infliximab, and abatacept, compared to adalimumab, in patients with RA stratified by body mass index (BMI) and sex.MethodsObservational cohort study in the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). RA patients were classified in BMI-based cohorts: obese, overweight, and normal weight. Each BMI cohort was studied overall and stratified by sex. The study outcome was remission within 12-months, defined as a disease activity score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction (CARRAC). Logistic regression compared the effectiveness of etanercept, infliximab, and abatacept versus adalimumab.ResultsThe study included 443 obese, 829 overweight, and 1243 normal weight RA patients. Across the BMI cohorts, there were no significant differences in the odds of remission at ≤12-months for the study drugs compared to adalimumab. However, among females, an inverse effect for infliximab was found, whereby overweight patients had higher odds of remission, while obese patients had lower odds of remission, compared to the respective adalimumab users.ConclusionsDespite the previous hypothesis, treatment with abatacept showed similar odds of remission compared to adalimumab in all BMI cohorts. Conversely, compared to adalimumab, infliximab performed better in overweight female patients but worse in female patients with obesity. However, further validation is needed.
Characterising complex health needs and the use of preventative therapies in the older population: a population-based cohort analysis of UK primary care and hospital linked data
Authors: Elhussein Leena , Jödicke Annika M. , He Ying , Delmestri Antonella , Robinson Danielle E. , Strauss Victoria Y. , Prieto-Alhambra Daniel 
Published: September 2022

ABSTRACTBackgroundSeveral definitions exist for multimorbidity, frailty or polypharmacy, but no formal definition exists for “complex health needs”. We aimed to identify and characterise older people with complex health needs based on healthcare resource use (unplanned hospitalisations or polypharmacy) or frailty.MethodsIn this cohort study, data was extracted from UK primary care records (CPRD GOLD), with linked Hospital Episode Statistics inpatient data. People aged >65 on 1st January 2010, registered in CPRD for ≥1 year were included. We identified complex health needs as the top quintile of unplanned hospitalisations, number of prescribed medicines, and electronic frailty index. We characterised all three cohorts, and quantified point-prevalence and incidence rates of preventative medicines use.ResultsOverall, 90597, 110225 and 116076 individuals were included in the hospitalisation, frailty, and polypharmacy cohorts respectively. Frailty and polypharmacy cohorts had the highest bi- directional overlap. Most comorbidities such as diabetes and chronic kidney disease were more common in the frailty and polypharmacy cohorts compared to the hospitalisation cohort. Generally, prevalence of preventative medicines use was highest in the polypharmacy cohort compared to the other two cohorts: For instance, one-year point-prevalence of statins was 64.2% in the polypharmacy cohort vs. 60.5% in the frailty cohort.ConclusionsThree distinct groups of older people with complex health needs were identified. Compared to the hospitalisation cohort, frailty and polypharmacy cohorts had more comorbidities and higher preventative therapies use. Research is needed into the benefit-risk of different definitions of complex health needs and use of preventative therapies in the older population.
Ethnic inequities in the patterns of Personalised Care Adjustments for ‘Informed Dissent’ and ‘Patient Unsuitable’: A retrospective study using Clinical Practice Research Datalink
Authors: Hayanga B. , Stafford M. , Ashworth M. , Hughes J. , Bécares L. 
Published: September 2022

ABSTRACTObjectivesTo examine patterns of PCA reporting for ‘informed dissent’ and ‘patient unsuitable’, how they vary by ethnic group, and whether ethnic inequities can be explained by socio-demographic factors or comorbidities.DesignA retrospective study using routinely collected electronic health records.SettingIndividual patient data from Clinical Practice Research Datalink collected from UK general practice.ParticipantsPatients with at least one of the 12 Quality and Outcomes Framework (QOF) conditions which had PCA coding options from a random sample of 690,00 patients aged 18+ years on the 1stof Jan 2016.Main outcomes measuresThe associations between ethnicity and two PCA reasons (‘Informed Dissent’ and ‘Patient Unsuitable’) were examined using logistic regressions after adjustment for age, sex, multiple QOF conditions and area-level deprivation.ResultsThe association between ethnicity and the two PCA reasons were in opposite directions. After accounting for age, gender, multiple QOF conditions and area-level deprivation, people of Bangladeshi [OR: 0.69, 95% CI: 0.55 to 0.87], Black African [OR: 0.70, 95% CI: 0.61 to 0.81], Black Caribbean, OR: 0.67, 95% CI: 0.58 to 0.76], Indian [OR: 0.74, 95% CI: 0.66 to 0.83], mixed [OR: 0.86, 95% CI: 0.74 to 0.99], other Asian [OR: 0.74 95% CI: 0.64 to 0.86] and other ethnicity [OR: 0.66, 95% CI: 0.55 to 0.80] were less likely to have a PCA record for ‘informed dissent’ than people of white ethnicity. Only people of Indian ethnicity were significantly less likely than people of white ethnicity to have a PCA record for ‘patient unsuitable’ in fully adjusted models [OR: 0.80, 95% CI: 0.67 to 0.94]. We found ethnic inequities in PCA reporting for ‘patient unsuitable’ among people of Black Caribbean, Black other, Pakistani, and other ethnicity, but these attenuated after adjusting for multiple QOF conditions and/or area level deprivation.ConclusionStudy findings counter the narratives that suggest that people from minoritised ethnic groups often refuse medical intervention. They illuminate the complex relationship between ‘informed dissent’ and (dis)empowerment which requires further scrutiny. They also show ethnic inequalities in PCA reporting for ‘patient unsuitable’ that are linked to clinical and social complexity and should be tackled to improve health outcomes for all.