bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene
Authors: Kim Kookjoo , Li Huan , Yuan Qi , Melville Zephan , Zalk Ran , des Georges Amédée , Frank Joachim , Hendrickson Wayne A. , Marks Andrew R. , Clarke Oliver B. 
Published: October 2024

AbstractMalignant hyperthermia (MH) is a life-threatening pharmacogenetic condition triggered by volatile anesthetics, which activate pathogenic RyR1 mutants. The small molecule therapeutic dantrolene has long been used to treat MH. However, the binding site and mechanism of dantrolene remain unclear. Here, we present cryo-EM structures of RyR1 bound to dantrolene and the MH trigger agent 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change in this domain which is allosterically coupled to pore closure. Functional analyses revealed that ATP or ADP was required for dantrolene inhibition, and a single point mutation that disrupts the peripheral ATP binding site abolished ATP/ADP-dependent dantrolene inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules, suggesting a possible role in ATP/ADP ratio sensing.
ProteoSeeker: A Feature-Rich Metagenomic Analysis Tool for Accessible and Comprehensive Metagenomic Exploration
Authors: Filis Georgios , Bezantakou Dimitra , Rigkos Konstantinos , Noti Despina , Saridis Pavlos , Zarafeta Dimitra , Skretas Georgios 
Published: October 2024

AbstractMetagenomics have served as a key driver of biotechnology advancements through, among others, the identification of novel proteins. The lack of standardized guidelines and benchmarks in the field, however, complicates the selection of appropriate bioinformatics tool ensembles and hinders faster progress. This study introducesProteoSeeker, an automated pipeline designed for accessible and comprehensive metagenomic exploration of whole-genome sequencing data.ProteoSeekeridentifies proteins within user-defined protein families and uncovers the taxonomy of the host organisms. It is implemented as a command-line tool to facilitate metagenomic dataset analysis for non-expert users, thus enabling facilitated and streamlined protein discovery.
Fast-lived Vertebrate Hosts Exhibit Higher Potential for Mosquito-borne Parasite Transmission
Authors: Dahlin Kyle J.-M. , O’Regan Suzanne M. , Schmidt John Paul , Han Barbara A. , Drake John M. 
Published: October 2024

AbstractThe emergence of mosquito-borne zoonoses has continually increased over the past decade, posing a significant global public health challenge. Ecological theory can point to the characteristics of populations that make them more likely to form reservoirs of disease. The pace of life hypothesis posits that species with more rapid reproduction and shorter lifespans are more likely to be disease reservoirs than their slower-living cousins. Mathematical modeling suggests theoretical conditions under which this hypothesis is correct for directly- and environmentally-transmitted pathogens but its applicability to mosquito-borne disease systems has yet to be examined. We parameterized a mechanistic model with host trait data to investigate the link between the position of a species on the fast-slow life history continuum and the potential for it to spread mosquitoborne diseases. We evaluated the resulting relationships for four medically important mosquito species across their thermal niches and for four pathogens characterized by infection duration and the level of susceptibility of the focal host to infection. Finally, because the fast-slow life history continuum differs across taxonomic ranks, we considered the theory in the context of two orders of vertebrate hosts, Rodentia and Primates. After parameterizing our model, we found that, near universally across all the axes of variation considered, fast-lived hosts have higher transmission potential than slow-lived hosts. There was one exception: slower-lived hosts have higher transmission potential for parasites that cause long-enduring infections to which these hosts are highly susceptible. Generally, however, these connections hinge on the often unknown links between immunological traits, population density, and pace of life. Our analyses highlight immunological traits as a key knowledge gap with strong influence over the potential for transmission. Further investigation of the pace of life hypothesis will require a better understanding of how, for mosquito-borne parasitic infections, susceptibility and infection duration vary across the members of a taxonomic order.
CADET: Enhanced transcriptome-wide association analyses in admixed samples using eQTL summary data
Authors: Head S. Taylor , Dai Qile , Schildkraut Joellen , Cutler David J. , Yang Jingjing , Epstein Michael P. 
Published: October 2024

ABSTRACTA transcriptome-wide association study (TWAS) is a popular statistical method for identifying genes whose genetically-regulated expression (GReX) component is associated with a trait of interest. Most TWAS approaches fundamentally assume that the training dataset (used to fit the gene expression prediction model) and testing GWAS dataset are from the same ancestrally homogenous population. If this assumption is violated, studies have shown a marked negative impact on expression prediction accuracy as well as reduced power of the downstream genetrait association test. These issues pose a particular problem for admixed individuals, whose genomes represent a mosaic of multiple continental ancestral segments. To resolve these issues, we present CADET, which enables powerful TWAS of admixed cohorts leveraging the local-ancestry (LA) information of the cohort along with summary-level eQTL data from reference panels of different ancestral groups. CADET combines multiple polygenic risk score models based on the summary-level eQTL reference data to predict LA-aware GReX components in admixed test samples. Using simulated data, we compare the imputation accuracy, power, and type I error rate of our proposed LA-aware approach to LA-unaware methods for performing TWASs. We show that CADET performs optimally in nearly all settings regardless of whether the genetic architecture of gene expression is dependent or independent of ancestry. We further illustrate CADET by performing a TWAS of 29 common blood biochemistry phenotypes within an admixed cohort from the UK Biobank and identify 18 hits unique to our LA-aware strategy with the majority of hits supported by existing GWAS findings.
Polyphosphate Discriminates Protein Conformational Ensembles More Efficiently than DNA Promoting Diverse Assembly and Maturation Behaviors
Authors: Goyal Saloni , Rajendran Divya , Mani Anup Kumar , Naganathan Athi N. 
Published: October 2024

ABSTRACTDisordered proteins and domains often assemble into condensates with polyanionic nucleic acids, primarily via charge complementarity, regulating numerous cellular functions. However, the assembly mechanisms associated with the other abundant and ubiquitous, anionic, stress-response regulating polymer, polyphosphate (polyP), is less understood. Here, we employ the intrinsically disordered DNA binding domain (DBD) of cytidine repressor (CytR) fromE.colito study the nature of assembly processes with polyP and DNA. CytR forms metastable liquid-like condensates with polyP and DNA, while undergoing liquid-to-solid transition in the former and solubilizing in the latter. On mutationally engineering the ensemble to exhibit more or less structure and dimensions than the WT, the assembly process with polyP is directed to either condensates with partial time-dependent solubilization or spontaneous aggregation, respectively. On the other hand, the CytR variants formonlyliquid-like but metastable droplets with DNA which solubilize within a few hours. Polyphosphate induces large secondary-structure changes, with two of the mutants adopting polyproline II-like structures within droplets, while DNA has only minimal structural effects. Our findings reveal how polyphosphate can more efficiently discern conformational heterogeneity in the starting protein ensemble, its structure, and compactness, with broad implications in assembly mechanisms involving polyP and stress response in bacterial systems.
Aerobic capacity and exercise mediate protection against hepatic steatosis via enhanced bile acid metabolism
Authors: Kugler Benjamin A. , Maurer Adrianna , Fu Xiaorong , Franczak Edziu , Ernst Nick , Schwartze Kevin , Allen Julie , Li Tiangang , Crawford Peter A. , Koch Lauren G. , Britton Steven L. , Burgess Shawn C. , Thyfault John P. 
Published: October 2024

AbstractHigh cardiorespiratory fitness and exercise show evidence of altering bile acid (BA) metabolism and are known to protect or treat diet-induced hepatic steatosis, respectively. Here, we tested the hypothesis that high intrinsic aerobic capacity and exercise both increase hepatic BA synthesis measured by the incorporation of2H2O. We also leveraged mice with inducible liver-specific deletion ofCyp7a1(LCyp7a1KO), which encodes the rate-limiting enzyme for BA synthesis, to test if exercise-induced BA synthesis is critical for exercise to reduce hepatic steatosis. The synthesis of hepatic BA, cholesterol, andde novolipogenesis was measured in rats bred for either high (HCR) vs. low (LCR) aerobic capacity consuming acute and chronic high-fat diets. HCR rats had increased synthesis of cholesterol and certain BA species in the liver compared to LCR rats. We also found that chronic exercise with voluntary wheel running (VWR) (4 weeks) increased newly synthesized BAs of specific species in male C57BL/6J mice compared to sedentary mice. Loss ofCyp7a1resulted in fewer new BAs and increased liver triglycerides compared to controls after a 10-week high-fat diet. Additionally, exercise via VWR for 4 weeks effectively reduced hepatic triglycerides in the high-fat diet-fed control male and female mice as expected; however, exercise in LCyp7a1KO mice did not lower liver triglycerides in either sex. These results show that aerobic capacity and exercise increase hepatic BA metabolism, which may be critical for combatting hepatic steatosis.HighlightsRats with intrinsic high aerobic capacity have more significant reductions inde novolipogenesis and increased cholesterol and bile acid synthesis on a high-fat diet compared to rats with low aerobic capacity.Chronic exercise increases hepatic bile acid synthesis in mice.Loss ofCyp7a1blunts the capacity for exercise to increase bile acid synthesis and treat hepatic steatosis in male and female mice fed a high-fat diet.
Bur1-driven G1-to-S phase transition induces hydroxyurea sensitivity in yeast checkpoint mutants
Authors: da Silva Stefany Cristine Rodrigues , Bastos de Oliveira Francisco Meirelles 
Published: October 2024

AbstractInSaccharomyces cerevisiae, the cyclin-dependent kinase Bur1 is known for its role in promoting transcription elongation and histone modifications, thereby regulating gene expression. In this study, we investigated the genetic interactions between a hypomorphicBUR1allele (bur1-107) and null mutants of the checkpoint kinases Mec1 and Rad53. Our findings show that thebur1-107allele suppresses hydroxyurea (HU) sensitivity inmec1andrad53mutants, indicating that Bur1 activity may be detrimental in the absence of functional checkpoint signaling. Additionally, thebur1-107mutation delays the G1-to-S phase transition, indicating a key role for Bur1 in cell cycle progression. Notably,bur1-107reduces γ-H2A accumulation, facilitates S-phase resumption, and supresses the sub-G1 population in HU-treatedmec1mutants. These findings suggest that Bur1-driven G1-to-S phase progression exacerbates DNA damage and cell death in checkpoint-deficient cells exposed to HU. This study highlights a novel role for Bur1 in modulating the cellular response to replication stress in checkpoint-compromised cells.
Antagonistic activity of AEA on TAT treated Human Astrocytes identify Inflammaging pathways
Authors: Duraikkannu Durairaj , Khatak Kamini , Nagarajan Hemavathy , Sudharshan Sridharan , Chatterjee Nivedita 
Published: October 2024

AbstractPhysiologically, the endocannabinoids are known to reduce inflammation by decreasing production of inflammatory factors in immune and glial cells. Astrocytes secrete soluble inflammatory mediators and prolonged activation of astrocytes is associated with accelerated aging in Central Nervous System. Many reports show miRNAs as critical gene regulators in inflammation and astrogliosis in astrocytes. The aim of this study is to investigate the microRNA changes affected by Anandamide on HIV1 TAT (Trans-activator of transcription protein) stimulated normal human astrocytes. We performed global microRNA profile in TAT activated astrocytes and analysed changes on exposure to AEA. To delineate the mechanism of action we assessed with bioinformatic tools miRWalk, KEGG and Cytoscape the global microarray for significantly impacted miRNAs, and their gene targets. TAT activation in astrocytes upregulated 122 miRNAs significantly (p < 0.05). Addition of AEA in activated astrocytes downregulate the expression of 57 miRNAs significantly. Out of 122 upregulated miRNAs on TAT treatment, 37 miRNAs which were common in TAT and TAT+AEA cells showed reversal suggesting clues to critical miRNAs for the AEA-induced mitigation of neuroinflammation. Reversal in expression of selected group of miRNAs identify antagonistic pathways which are promoting anti-inflammatory environment. Pathway analysis of key 37 miRNAs show gene targets that regulate inflammation and senescence.
Outcomes of children with serious traumatic brain injury treated in pediatric vs. adult departments
Authors: Bruns Nora , Hojeij Rayan , Brensing Pia , Nonnemacher Michael , Dammann Philipp , Dudda Marcel , Felderhoff-Müser Ursula , Stang Andreas , Dohna-Schwake Christian 
Published: October 2024

AbstractThe impact of treatment in a non-pediatric department on mortality and outcomes of children with traumatic brain injury (TBI) is unknown. This study aimed to quantify the impact of the treating department (pediatric (PD) or adult (AD)) on in-hospital case fatality and functional short-term outcomes in children with serious TBI who survived the initial 12 hours after hospital admission.A Nationwide retrospective cohort study was conducted from a dataset that comprises all discharges from German hospitals from 2016 to 2021. Disease and procedural codes were used to retrieve clinical and outcome information. Hierarchical multilevel logistic regression modeling was performed to quantify the effect of the treating department on the outcomes of interest. Eligibility criteria were age < 18 years and hospital admission with serious TBI.The main outcome was in-hospital death and secondary outcomes were pediatric complex chronic conditions category (PCCC) ≥ 2 in survivors, composite outcome (death or PCCC ≥ 2), and adjusted mean PCCC in survivors.Of 13,492,528 pediatric cases, 12,275 were included. The adjusted odds ratio (OR) for death was 3.00 (95 % confidence interval 1.93–4.68) for children treated in ADs compared to PDs. The OR for PCCC ≥ 2 was 0.93 (0.78–1.12) and 1.04 (0.87–1.25) for the composite outcome.Adjusted average PCCC were 0.40 (0.37–0.44) in ADs and 0.44 (0.42–0.46) in PDs.This comprehensive nationwide study found increased odds for in-hospital death but similar functional outcomes at discharge among surviving children with serious TBI who were treated outside of PDs.
A systematised review of seasonal influenza case-fatality risk
Authors: Filipe Johnny A N , Wong Carlos K H , van Leeuwen Edwin , Goodfellow Lucy , Procter Simon R , Jit Mark 
Published: October 2024

AbstractCase-fatality risk (CFR) is an important indicator of disease severity for influenza infection. However, estimates based on laboratory-confirmed cases (cCFR) are more-highly sensitive to features of the local health-care system and surveillance. Estimates based on diagnosed-symptomatic cases (sCFR) are more consistent across health systems but less commonly reported. We present a systematised review of sCFR for seasonal influenza. We identified 10 studies reporting sCFR, or primary data for its direct estimation, resulting in 40 location and season-specific point estimates (range 0.3-908 per 100,000 cases). The wide variation across studies and lack of studies in many world regions point to the need for standardised protocols and more data collection.
Frequency-specific hemispheric bias in phase entrainment of neural oscillations in unilateral spatial neglect
Authors: Okazaki Yuka O. , Hattori Noriaki , Kawano Teiji , Hatakenaka Megumi , Miyai Ichiro , Kitajo Keiichi 
Published: October 2024

AbstractLeft unilateral spatial neglect (USN), typically caused by a right hemisphere lesion, impairs left-side stimulus perception. Attention influences perception via cortical oscillations, shown as phase shifts and power changes in electroencephalography (EEG). Given this relationship, USN may stem from hemispheric imbalance in synchronizing cortical oscillations internally and externally. We studied this using steady-state visual evoked potentials (SSVEPs) from flickering stimuli of various frequencies. Our study included USN and non-USN patients with a right hemisphere lesion, but no hemianopsia, as well as healthy controls. Importantly, we confirmed that the affected hemisphere’s visual cortex in both patient groups responded to all flickering frequencies, ensuring a valid comparison. Comparing SSVEP power between the intact and affected hemispheres revealed no differences in non-USN patients. In USN patients, both hemispheres responded equally to most frequencies; however, SSVEP power was enhanced in the intact visual cortex with 9-Hz stimulation, resulting in a significant hemispheric bias. This bias was not caused by deficiencies in generating oscillations (we observed no significant differences in spontaneous pre-stimulus alpha oscillations) but rather by abnormal alpha-band synchronization with external inputs. Further analyses revealed increased phase-amplitude coupling between alpha phase and gamma amplitude in the intact hemisphere and elevated transfer entropy from the right visual cortex to the left frontal cortex in USN patients. These results reveal that USN involves complex alterations in neural synchronization stemming from imbalanced entrainment of oscillators to alpha-frequency stimuli, beyond merely local damage. This alpha-specific effect provides insights into frequency-specific synchronization in spatial attention, potentially guiding targeted therapies.Significance StatementThis study provides crucial insight into the neural mechanisms underlying unilateral spatial neglect (USN), a sequela of stroke. By examining the frequency-specific hemispheric bias in neural synchronization, we identified a significant imbalance in brain activity, particularly in the alpha frequency range. This imbalance was not merely a result of local deficits but involved complex compensatory mechanisms at both the local and global network levels. Our findings highlight how disrupted neural oscillations and impairments in the capacity to modulate these oscillations for synchronization contribute to cognitive deficits in patients with USN. This research addresses gaps in our understanding of attention function and disorders, which will aid the development of more targeted therapeutic interventions and rehabilitation strategies.
The effectiveness of medical face masks and respirators in reducing SARS-CoV-2 transmission in community settings: a scoping review
Authors: Vardavas Constantine I. , Marou Valia , Aslanoglou Katerina , Manta Anastasia , Lagou Ioanna , Plyta Zinovia , Leonardi-Bee Jo , Lamb Favelle , Cenciarelli Orlando , Baka Agoritsa 
Published: October 2024

ABSTRACTBackgroundDuring the COVID-19 pandemic, various public health and social measures (PHSM) were implemented with the primary objective of curtailing the transmission of SARS-CoV-2. This review aims to synthesise existing evidence on the effectiveness of medical facemasks and/or respirators (FFP2/KN95/N95) in reducing SARS-CoV-2 transmission/infection in community settings.MethodsA scoping literature review adhering to PRISMA was performed. All relevant study designs within community settings, excluding modelling studies, published between January 2000 and January 2023 and indexed in Medline and Embase were included with no geographical limitation. Studies not specifying facemask/respirator type or not presenting isolated outcomes for specific facemask/respirator types were excluded.ResultsOf the 10,185 studies identified, two randomised controlled trials (RCT) and two case-control studies met all inclusion criteria. The largest RCT identified an adjusted prevalence ratio of 0.89 (95%CI: 0.78-1.00) for medical vs. cloth masks. In a smaller RCT, the between-group difference favoured the mask vs no mask group (-0.3 percentage points; 95%CI: -1.2 to 0.4). Within one case-control study, N95/KN95 respirators (aOR 0.17; 95%CI: 0.05-0.64) or medical masks (aOR 0.34; 95%CI: 0.13-0.90) were associated with statistically significant lower adjusted odds of a positive test result compared to no facemask use. A second case-control study associated medical mask use with reduced COVID-19 risk in unadjusted models (OR 0.25; 95% CI: 0.12-0.53) but this effect was not independently associated with infection in multivariable models (aOR 0.61; 95%CI: 0.25-1.49).ConclusionsLimited published evidence exists on the effectiveness of medical facemask use in community settings. Medical masks and respirators (compared to cloth masks) may reduce SARS-CoV-2 transmission, but interpretation requires caution. Mask use in community settings was rarely implemented in isolation to other PHSMs so deciphering whether the effect is solely because of mask-wearing or a combined effect is extremely challenging necessitating additional studies.
Performance of deep-learning based approaches to improve polygenic scores
Authors: Kelemen Martin , Xu Yu , Jiang Tao , Hua Zhao Jing , Anderson Carl , Wallace Chris , Butterworth Adam , Inouye Michael 
Published: October 2024

AbstractBackground/ObjectivesPolygenic scores (PGS), which estimate an individual’s genetic propensity for a disease or trait, have the potential to become part of genomic healthcare. In maximising the predictive performance of PGS, neural-network (NN) based deep learning has emerged as a method of intense interest to model complex, nonlinear phenomena, which may be adapted to exploit gene-gene (GxG) and gene-environment (GxE) interactions.MethodsTo infer the amount of nonlinearity present in a phenotype, we present a framework for using NNs, which controls for the potential confounding effect of correlation between genetic variants, i.e. linkage disequilibrium (LD). We fit NN models to both simulated traits and 28 real disease and anthropometric traits in the UK Biobank.ResultsSimulations confirmed that our framework adequately controls LD and can infer nonlinear effects, when such effects genuinely exist. Using this approach on real data, we found evidence for small amounts of nonlinearity due to GxG and GxE which mildly improved prediction performance (r2) by ∼7% and ∼4%, respectively. Despite evidence for nonlinear effects, NN models were outperformed by linear regression models for both genetic-only and genetic+environmental input scenarios with ∼7% and ∼5% differences in r2, respectively. Importantly, we found substantial evidence for confounding by joint tagging effects, whereby inferred GxG was actually LD with due to unaccounted for additive genetic variants.ConclusionOur results indicate that the usefulness of NNs for generating polygenic scores for common traits and diseases may currently be limited and may be confounded by joint tagging effects due to LD.