bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Vestibular Function is Associated with Cortical Surface Shape Changes in the Frontal Cortex
Authors: Padova Dominic , Ratnanather J. Tilak , Faria Andreia V. , Agrawal Yuri 
Published: November 2024

AbstractAging-associated decline in peripheral vestibular function is linked to deficits in executive ability, self-motion perception, and motor planning and execution. While these behaviors are known to rely on the sensorimotor and frontal cortices, the precise pathways involving the frontal and sensorimotor cortices in these vestibular-associated behaviors are unknown. To fill this knowledge gap, this cross-sectional study investigates the relationship between age-related variation in vestibular function and surface shape alterations of the frontal and sensorimotor cortices, considering age, intracranial volume, and sex. Data from 117 participants aged 60+ from the Baltimore Longitudinal Study of Aging, who underwent endorgan-specific vestibular tests (cVEMP for the saccule, oVEMP for the utricle, and vHIT for the horizontal canal) and T1-weighted MRI scans on the same visit, were analyzed. We examined ten brain structures in the putative “vestibular cortex”: the middle-superior part of the prefrontal cortex (SFG_PFC), frontal pole (SFG_pole), and posterior pars of the superior frontal gyrus (SFG), the dorsal prefrontal cortex and posterior pars of middle frontal gyrus (MFG_DPFC, MFG), the pars opercularis, pars triangularis, and pars orbitalis of the inferior frontal gyrus, as well as the precentral gyrus and postcentral gyrus (PoCG) of the sensorimotor cortex. For each region of interest (ROI), shape descriptors were estimated as local compressions and expansions of the population average ROI surface using surface LDDMM. Shape descriptors were linearly regressed onto standardized vestibular variables, age, intracranial volume, and sex. Lower utricular function was linked with surface compression in the left MFG and expansion in the bilateral SFG_pole and left SFG. Reduced canal function was associated with surface compression in the right SFG_PFC and SFG_pole and left SFG. Both reduced saccular and utricular function correlated with surface compression in the posterior medial part of the left MFG. Our findings illuminate the complexity of the relationship between vestibular function and the morphology of the frontal and sensorimotor cortices in aging. Improved understanding of these relationships could help in developing interventions to enhance quality of life in aging and populations with cognitive impairment.
Predicting Treatment-seeking Status for Alcohol Use Disorder Using Polygenic Scores and Machine Learning in a Deeply-Phenotyped Sample
Authors: Jinwala Zeal , Green ReJoyce , Khan Yousef , Gelernter Joel , Kember Rachel L. , Hartwell Emily E. 
Published: November 2024

AbstractBackgroundFew individuals with alcohol use disorder (AUD) receive treatment. Previous studies have shown drinking behavior, psychological problems, and substance dependence to predict treatment seeking. However, to date, no studies have incorporated polygenic scores (PGS), a measure of genetic risk for AUD.MethodsUsing the Yale-Penn sample, we identified 9,103 individuals diagnosed with DSM-IV AUD and indicated treatment-seeking status. We implemented a random forest (RF) model to predict treatment-seeking based on 91 clinically relevant phenotypes. We calculated AUD PGS for those with genetic data (African ancestry [AFR] n=3,192, European ancestry [EUR] n=3,553) and generated RF models for each ancestry group, first without and then with PGS. Lastly, we developed models stratified by age (< and ≥40 years old).Results66.6% reported treatment seeking (Mage=40.0, 62.4% male). Across models, top predictors included years of alcohol use and related psychological problems, psychiatric diagnoses, and heart disease. In the models without PGS, we found 79.8% accuracy and 0.85 AUC for EUR and 75% and 0.78 for AFR; the addition of PGS did not substantially change these metrics. PGS was the 10thmost important predictor for EUR and 23rdfor AFR. In the age-stratified analysis, PGS ranked 8thfor <40 and 48thfor ≥40 in EUR ancestry, and it ranked 14thfor <40 and 24thfor ≥40 in the AFR sample.ConclusionAlcohol use, psychiatric issues, and comorbid medical disorders were predictors of treatment seeking. Incorporating PGS did not substantially alter performance, but was a more important predictor in younger individuals with AUD.HighlightsWhile alcohol use problems are common, few individuals seek treatmentWe used machine learning in a deeply-phenotyped sample to predict treatment-seekingWe, for the first time, incorporated polygenic risk for alcohol use as a predictorAlcohol use variables, psychiatric issues, and medical problems were key predictors
A common haplotype in the EXO5 gene can impact its protein structure and dynamics and modulate genome stability and cancer progression
Authors: Mazza Fabio , Dalfovo Davide , Bartocci Alessio , Lattanzi Gianluca , Romanel Alessandro 
Published: November 2024

AbstractUnderstanding the impact of common germline variants on protein structure, function, and disease progression is crucial in cancer research. This study presents a comprehensive analysis of the EXO5 gene, which encodes a DNA exonuclease involved in DNA repair previously associated with cancer susceptibility. We employed an integrated approach combining genomic and clinical data analysis, deep learning variant effect prediction, and molecular dynamics simulations to investigate the effects of common EXO5 haplotypes on protein structure, dynamics, and cancer outcomes. We characterized the haplotype structure of EXO5 across diverse human populations, identifying five common haplotypes, and studied their impact on EXO5 protein. Our analyses revealed significant structural and dynamic differences among the EXO5 haplotypes, particularly in their catalytic region. The L151P EXO5 protein variant exhibited the most substantial conformational changes, potentially disruptive for EXO5’s function and nuclear localization. Analysis of TCGA data showed that patients carrying L151P EXO5 had significantly shorter progression-free survival in prostate and pancreatic cancers, and exhibited increased genomic instability. This study highlights the strength of our methodology in uncovering the effects of common genetic variants on protein function and their implications for disease outcomes.
Targeted CRISPR Screens Reveal Genes Essential forCryptosporidiumSurvival in the Host Intestine
Authors: Watson Lucy C , Sala Katarzyna A , Bernitz Netanya , Baumgärtel Lotta , Pallett Mitchell A , Marzook N Bishara , Straker Lorian Cobra , Peng Duo , Collinson Lucy , Sateriale Adam 
Published: November 2024

AbstractTheCryptosporidiumparasite is one of the leading causes of diarrheal morbidity and mortality in children, and adolescent infections are associated with chronic malnutrition. There are no vaccines available for protection and only one drug approved for treatment that has limited eKicacy. A major barrier to developing new therapeutics is a lack of foundational knowledge ofCryptosporidiumbiology, including which parasite genes are essential for survival and virulence. Here, we iteratively improve the tools for genetically manipulatingCryptosporidiumand develop a targeted CRISPR-based screening method to rapidly assess how the loss of individual parasite genes influence survivalin vivo. Using this method we examine the parasite’s pyrimidine salvage pathway and a set of leadingCryptosporidiumvaccine candidates. From this latter group we determined the parasite gene known as Cp23 to be essential for survival, which was confirmed through inducible knockoutin vitroandin vivo. Parasites deficient in Cp23 were able to replicate within and emerge from infected epithelial cells, yet unable to initiate gliding motility which is essential for the reinfection of neighbouring cells. The targeted screening method presented here is highly versatile and will enable researchers to more rapidly expand the knowledge base forCryptosporidiuminfection biology, paving the way for new therapeutics.
Electrical synapse molecular diversity revealed by proximity-based proteomic discovery
Authors: Michel Jennifer Carlisle , Martin E. Anne , Crow William E. , Kissinger Jane S. , Lukowicz-Bedford Rachel M. , Horrocks Max , Branon Tess C. , Ting Alice Y. , Miller Adam C. 
Published: November 2024

AbstractNeuronal circuits are composed of synapses that are either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through interneuronal gap junction channels. While the molecular complexity that controls chemical synapse structure and function is well appreciated, the proteins of electrical synapses beyond the gap-junction-forming Connexins are not well defined. Yet, electrical synapses are expected to be molecularly complex beyond the gap junctions. Connexins are integral membrane proteins requiring vesicular transport and membrane insertion/retrieval to achieve function, homeostasis, and plasticity. Additionally, electron microscopy of neuronal gap junctions reveals neighboring electron dense regions termed the electrical synapse density (ESD). To reveal the molecular complexity of the electrical synapse proteome, we used proximity-dependent biotinylation (TurboID) linked to neural Connexins in zebrafish. Proteomic analysis of developing and mature nervous systems identifies hundreds of Connexin-associated proteins, with overlapping and distinct representation during development and adulthood. The identified protein classes span cell adhesion molecules, cytoplasmic scaffolds, vesicular trafficking, and proteins usually associated with the post synaptic density (PSD) of chemical synapses. Using circuits with stereotyped electrical and chemical synapses, we define molecular sub-synaptic compartments of ESD localizing proteins, we find molecular heterogeneity amongst electrical synapse populations, and we examine the synaptic intermingling of electrical and chemical synapse proteins. Taken together, these results reveal a new complexity of electrical synapse molecular diversity and highlight a novel overlap between chemical and electrical synapse proteomes. Moreover, human homologs of the electrical synapse proteins are associated with autism, epilepsy, and other neurological disorders, providing a novel framework towards understanding neuro-atypical states.
BioLLM: A Standardized Framework for Integrating and Benchmarking Single-Cell Foundation Models
Authors: Qiu Ping , Chen Qianqian , Qin Hua , Fang Shuangsang , Zhang Yanlin , Xia Tianyi , Cao Lei , Zhang Yong , Fang Xiaodong , Li Yuxiang , Hu Luni 
Published: November 2024

AbstractThe application and evaluation of single cell foundational models (scFMs) present significant challenges stemming from the heterogeneity of architectural frameworks and coding standards. To address these issues, we introduce BioLLM, a framework facilitating the integration and application of scFMs in single-cell RNA sequencing data analysis. BioLLM provides a universal interface, bridging diverse scFMs into a seamless ecosystem. By mitigating architectural disparities and coding conventions, it empowers researchers with streamlined access to scFMs. With standardized APIs and comprehensive documentation, BioLLM streamlines model switching and comparative analyses, while incorporating best practices for consistent model evaluation. Our comprehensive evaluation of scFMs revealed distinct strengths and limitations, highlighting scGPT’s robust performance across all tasks, both in zero-shot and fine-tuning scenarios. Geneformer and scFoundation also demonstrated strong capabilities in gene-level tasks, benefiting from effective pretraining strategies. In contrast, scBERT underperformed relative to other models, likely attributable to its considerably smaller parameter count and the limited size of the training dataset. Ultimately, BioLLM aims to empower the scientific community to leverage the full potential of foundational models, advancing our understanding of complex biological systems through enhanced single-cell analysis.
Light-Dependent Ethanol Assimilation By Model Red MicroagaGaldieria sulphuraria
Authors: Stadnichuk Igor , Bolychevtseva Yulia 
Published: November 2024

AbstractThe effect of ethanol on the red thermoacidophilic microalgaGaldieria sulphuraria, capable of hemo- and photoheterotrophic growth, was studied. It was found thatG. sulphurariafailed to grow and assimilate ethanol when kept in the dark, in contrast to a wide range of organic compounds known to this alga. Light conditions, on the other hand, activated ethanol uptake from the growth medium and intensify microalgal growth. The known stress effect of ethyl alcohol can be seen in the short-term increase in cellular respiration in the dark and its sustained increase throughout the growth period ofG. sulphurariain the light. Ethanol-induced increase in cellular respiration precedes light activation of photosynthesis. The growth enhancement of ethanol-supplemented culture ofG. sulphurariacompared to photoautotrophic culture is most likely due to the complete oxidation of ethanol during respiration to carbon dioxide and its use by chloroplasts as an additional intracellular substrate for photosynthesis. The absence of ethanol consumption in the dark and its metabolic uptake in the light indicate photoactivation of alcohol dehydrogenase and acetaldehyde dehydrogenase, two key sequential enzymes in the ethanol oxidation pathway.
UniversalEPI: a generalized attention-based deep ensemble model to accurately predict enhancer-promoter interactions across diverse cell types and conditions
Authors: Grover Aayush , Zhang Lin , Muser Till , Häfliger Simeon , Wang Minjia , Yates Josephine , Van Allen Eliezer M. , Theis Fabian J. , Ibarra Ignacio L. , Krymova Ekaterina , Boeva Valentina 
Published: November 2024

AbstractInteractions between enhancers and gene promoters provide insights into gene regulation. Experimental techniques, including Hi-C, that map these enhancer-promoter interactions (EPIs), have high costs and labor requirements, which limits their use. Therefore, in silico methods have been developed to predict EPIs computationally, but there are challenges with the generalizability and accuracy of existing methods. Here, we introduce UniversalEPI, an attention-based deep ensemble model designed to provide uncertainty-aware predictions of EPIs up to 2 Mb apart, which can generalize across unseen cell types using only DNA sequence and chromatin accessibility (ATAC-seq) data. Benchmarking shows that UniversalEPI significantly outperforms existing approaches in accuracy and efficiency, even though it is a lightweight model that only assesses interactions between accessible chromatin regions. UniversalEPI enables statistical comparison of predicted interactions across conditions, which we demonstrated by tracking the dynamics of EPIs during human macrophage activation. We also used UniversalEPI to assess chromatin dynamics between different cancer cell states in human esophageal adenocarcinoma. Thus, UniversalEPI advances the accuracy and applicability of in silico 3D chromatin modeling to investigate chromatin dynamics in development and disease.
Characterising alphacoronavirus phenotypic traits through diversity-driven selection of spike
Authors: Gallo Giulia , Di Nardo Antonello , Dewantari Aghnia K. , Graham Stephen C. , Bailey Dalan 
Published: November 2024

AbstractThe capacity for viruses to spillover from one host to another is dependent on their ability to bind to and enter cells from a new host. Using a computational approach that maximises phylogenetic diversity, we selected an optimal subset of 40 alphacoronavirus spike proteins, including the two human viruses NL63 and 229E, and characterised their host-range using broad mammalian APN and ACE2 receptor libraries. Based on this data, we were able to determine molecular genotypes that contribute to receptor tropism and identify alphacoronaviruses with broad (generalist) or restricted (specialist) receptor usage. Strikingly, we observed that generalism and specialism can vary significantly between closely related viruses. Using structural information, we identified key residues that determine the bat tropism of 229E-like viruses, as well as residues in the ACE2 receptor that likely restrict NL63 infection of certain mammals. Furthermore, we observed that the host range of certain bat alphacoronaviruses is expanded by TMPRSS2 priming of spike. All APN- and ACE2-using alphaCoVs in our study interacted with the receptor of at least one animal species within ecological proximity to humans, suggesting new routes for spillover. However, most bat alphacoronaviruses did not use any of receptors in our screen, refining our understanding of coronavirus entry. We propose a new approach to investigating receptor usage for viral orders/families/genera, which is not constrained by focused analysis of a limited number of sequences from human-tropic viruses. Understanding phenotypic traits, such as entry, at this genus-wide level can revolutionise our ability to predict zoonotic potential.
Redox-Activated Proton Transfer through a Redundant Network in the QoSite of Cytochromebc1
Authors: Arantes Guilherme M. 
Published: November 2024

AbstractProton translocation catalyzed by cytochromebc1(respiratory complex III) during coenzyme-Q redox cycling is a critical bioenergetic process, yet its detailed molecular mechanism remains in-completely understood. Even the specific groups mediating proton transfer following coenzyme-Q oxidation have not been established. In this study, the energetics of proton transfer through multiple proton-conducting wires recently identified in the Qosite was investigated across various reactant redox states using hybrid QM/MM simulations and a specialized reaction coordinate. Key reactive groups and proton transfer mechanisms were characterized, confirming the propionate-A group of hemebLas a plausible proton acceptor. Upon quinol oxidation, a Grotthuss hopping mechanism is activated, facilitating proton transfer along three distinct pathways with comparable energetics. These pathways function redundantly, forming a robust proton-conducting network. A highly conserved tyrosine residue (Y147 inR. sphaeroidesnumbering) was found to be essential for complete proton transfer, whereas participation of H276 and D278 does not appear energetically feasible. Bioenergetic analyses exclude charged closed-shell species as likely intermediates and propose a reaction sequence for quinol oxidation proceeding as QH2→ QH•→ Q0, either via coupled proton-electron transfers or stepwise mechanisms involving open-shell intermediates. These findings elucidate mechanistic details of the Q-cycle and improve our understanding of the catalytic reactions supporting coenzyme-Q redox cycling in respiratory complexes.
GraFusionNet: Integrating Node, Edge, and Semantic Features for Enhanced Graph Representations
Authors: Tahmid Md Toki , Zaman Tanjeem Azwad , Rahman Mohammad Saifur 
Published: November 2024

ABSTRACTUnderstanding complex graph-structured data is a cornerstone of modern research in fields like cheminformatics and bioinformatics, where molecules and biological systems are naturally represented as graphs. However, traditional graph neural networks (GNNs) often fall short by focusing mainly on node features while overlooking the rich information encoded in edges. To bridge this gap, we presentGraFusionNet, a framework designed to integrate node, edge, and molecular-level semantic features for enhanced graph classification. By employing a dual-graph autoencoder, GraFusionNet transforms edges into nodes via a line graph conversion, enabling it to capture intricate relationships within the graph structure.Additionally, the incorporation of Chem-BERT embeddings introduces semantic molecular insights, creating a comprehensive feature representation that combines structural and contextual information. Our experiments on benchmark datasets, such as Tox21 and HIV, highlight GraFusionNet’s superior performance in tasks like toxicity prediction, significantly surpassing traditional models. By providing a holistic approach to graph data analysis, GraFusion-Net sets a new standard in leveraging multi-dimensional features for complex predictive tasks.CCS CONCEPTSComputing methodologies → Neural networks.ACM Reference FormatMd Toki Tahmid, Tanjeem Azwad Zaman, and Mohammad Saifur Rahman. 2018. GraFusionNet: Integrating Node, Edge, and Semantic Features for Enhanced Graph Representations. InProceedings of Make sure to enter the correct conference title from your rights confirmation email (Conference acronym ‘XX). ACM, New York, NY, USA, 9 pages.https://doi.org/XXXXXXX.XXXXXXX
Concomitant suppression of COX-1 and COX-2 is insufficient to induce enteropathy associated with chronic NSAID use
Authors: Barekat Kayla , Ricciotti Emanuela , Ghosh Soumita , Herrmann Christin , Keat Karl , Assenmacher Charles-Antoine , Tanes Ceylan , Wilson Naomi , Sengupta Arjun , Das Ujjalkumar Subhash , Joshi Robin , Ritchie Marylyn D. , Bittinger Kyle , Weljie Aalim , Cadwell Ken , Bushman Frederic D. , Wu Gary D. , FitzGerald Garret A. 
Published: November 2024

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications for the management of chronic pain; however, they are associated with numerous gastrointestinal (GI) adverse events. Although many mechanisms have been suggested, NSAID-induced enteropathy has been thought to be primarily due to inhibition of both cyclooxygenases (COX) -1 and -2, which results in suppression of prostaglandin synthesis. Yet surprisingly, we found that concomitant postnatal deletion ofCox-1and-2over 10 months failed to cause intestinal injury in mice unless they were treated with naproxen or its structural analog, phenylpropionic acid, which is not a COX inhibitor.Coxdouble knockout mice exhibit a distinct gut microbiome composition and cohousing them with controls rescues their dysbiosis and delays the onset of NSAID-induced GI bleeding. In both the UK Biobank and All of Us human cohorts, coadministration of antibiotics with NSAIDs is associated with an increased frequency of GI bleeding. These results show that prostaglandin suppression plays a trivial role in NSAID-induced enteropathy. However,Coxdeletion causes dysbiosis of the gut microbiome that amplifies the enteropathic response to NSAIDs.
Cryo-EM Structure of AAA + ATPase Thorase Reveals Novel Helical Filament Formation
Authors: Dar Mohamad Aasif , Louder Robert , Cortes Marisol , Chen Rong , Ma Qianqian , Chakrabarti Mayukh , Umanah George K.E. , Dawson Ted M. , Dawson Valina L. 
Published: November 2024

AbstractThe AAA+ (ATPasesassociated with a variety of cellularactivities) ATPase, Thorase, also known as ATAD1, plays multiple roles in synaptic plasticity, mitochondrial quality control and mTOR signaling through disassembling protein complexes like AMPAR and mTORC1 in an ATP-dependent manner. The Oligomerization of Thorase is crucial for its disassembly and remodeling functions. We show that wild-type Thorase forms long helical filamentsin vitro, dependent on ATP binding but not hydrolysis. We report the Cryogenic Electron Microscopy (cryo-EM) structure of the Thorase filament at a resolution of 4 Å, revealing the dimeric arrangement of the basic repeating unit that is formed through a distinct interface compared to the hexameric MSP1/ATAD1E193Q assembly. Structure-guided mutagenesis confirms the role of critical amino acid residues required for filament formation, oligomerization and disassembly of mTORC1 protein complex. Together, our data reveals a novel filament structure of Thorase and provides critical information that elucidates the mechanism underlying Thorase filament formation and Thorase-mediated disassembly of the mTORC1 complex.