bluuebunny/crossref_metadata_2025_split huggingface dataset:
A rare splice-site variant in cardiac troponin-T (TNNT2): The need for ancestral diversity in genomic reference datasets
Authors: Butters Alexandra , Thomson Kate , Harrington Franki , Henden Natasha , McGuire Karen , Byrne Alicia B. , Bryen Samantha , McGurk Kathryn A. , Leask Megan , Ackerman Michael J. , Atherton John , Bos Johan M. , Caleshu Colleen , Day Sharlene , Dunn Kyla , Hayes Ian , Juang Jimmy , McGaughran Julie , Nowak Natalie , Parikh Victoria N. , Ronan Anne , Semsarian Christopher , Tardiff Jil C. , Tiemensma Marianne , Merriman Tony R. , Ware James S. , Skinner Jonathan R. , MacArthur Daniel G. , Siggs Owen M. , Bagnall Richard D. , Ingles Jodie 
Published: February 2024

ABSTRACTThe underrepresentation of different ancestry groups in large genomic datasets creates difficulties in interpreting the pathogenicity of monogenic variants. Genetic testing for individuals with non-European ancestry results in higher rates of uncertain variants and a greater risk of misclassification. We report a rare variant in the cardiac troponin T gene,TNNT2; NM_001001430.3: c.571-1G>A (rs483352835) identified via research-based whole exome sequencing in two unrelated probands of Oceanian ancestry with cardiac phenotypes.The variant disrupts the canonical splice acceptor site, activating a cryptic acceptor and resulting in an in-frame deletion (p.Gln191del). The variant is rare in gnomAD v4.0.0 (13/780,762; 0.002%), with the highest frequency in South Asians (5/74,486; 0.007%) and has 16 ClinVar assertions (13 diagnostic clinical laboratories classify as variant of uncertain significance). There are at least 28 reported cases, many with Oceanian ancestry and diverse cardiac phenotypes. Indeed, among Oceanian-ancestry-matched datasets, the allele frequency ranges from 2.9-8.8% and is present in 2/4 (50%) Indigenous Australian alleles in Genome Asia 100K, with one participant being homozygous. With Oceanians deriving greater than 3% of their DNA from archaic genomes, we found c.571-1G>A in Vindija and Altai Neanderthal, but not the Altai Denisovan, suggesting an origin post Neanderthal divergence from modern humans 130-145 thousand years ago. Based on these data, we classify this variant as benign, and conclude it is not a monogenic cause of disease. Even with ongoing efforts to increase representation in genomics, we highlight the need for caution in assuming rarity of genetic variants in largely European datasets. Efforts to enhance diversity in genomic databases remain crucial.
AI-based differential diagnosis of dementia etiologies on multimodal data
Authors: Xue Chonghua , Kowshik Sahana S. , Lteif Diala , Puducheri Shreyas , Jasodanand Varuna H. , Zhou Olivia T. , Walia Anika S. , Guney Osman B. , Zhang J. Diana , Pham Serena T. , Kaliaev Artem , Andreu-Arasa V. Carlota , Dwyer Brigid C. , Farris Chad W. , Hao Honglin , Kedar Sachin , Mian Asim Z. , Murman Daniel L. , O’Shea Sarah A. , Paul Aaron B. , Rohatgi Saurabh , Saint-Hilaire Marie-Helene , Sartor Emmett A. , Setty Bindu N. , Small Juan E. , Swaminathan Arun , Taraschenko Olga , Yuan Jing , Zhou Yan , Zhu Shuhan , Karjadi Cody , Alvin Ang Ting Fang , Bargal Sarah A. , Plummer Bryan A. , Poston Kathleen L. , Ahangaran Meysam , Au Rhoda , Kolachalama Vijaya B. 
Published: February 2024

AbstractDifferential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51, 269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two cooccurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.
Retrospective Analysis of an Acute Ischemic Stroke Cohort Shows that Timing of Antidepressant Use Associated with Short-term Recovery and Functional Independence at 90-Days
Authors: Baraban Elizabeth , Lesko Alexandra , Still Kyle , Anderson Weston 
Published: February 2024

AbstractBackgroundLittle is known about how the timing of antidepressant use influences stroke outcomes. The objective of this exploratory, retrospective analysis is to examine stroke outcomes by timing of antidepressant use among patients who received stroke treatment.Methods12,590 eligible patients were treated for a primary or secondary diagnosis of ischemic stroke. Inpatient strokes and patients who were missing information on antidepressant use or stroke outcomes were excluded. The outcome variables were (1) a change in ambulation from pre-stroke to discharge; (2) a change in modified Rankin scale (mRS) from pre-stroke to discharge; and (3) a change in mRS from pre-stroke to 90-days post-discharge. The independent variable of interest was timing of antidepressant treatment. Logistic regression with generalized estimating equations was used, controlling for covariates.ResultsAt 90-days post-discharge, patients with no history of antidepressant use or with a previous history of antidepressant use were similar to patients with current antidepressant use in terms of their return to baseline functional independence. In contrast, our model predicted that a new antidepressant prescription at discharge was associated with a ∼57% decrease in the likelihood of returning to baseline functional independence at 90-days compared to patients currently using an antidepressant (AOR:0.510, CI:0.277-0.938, p=0.03). Post-hoc analyses showed females with current antidepressant use associated with a higher predicted probability of returning to baseline functional independence at 90-days compared to females with no antidepressant use. This association was not true for males. Conversely, males with a new prescription had the lowest predicted probability of returning to baseline among all groups at 90-days post-discharge.ConclusionThese results suggest that use of antidepressants was associated with stroke recovery, but the effects are moderated by sex. Further study is needed to determine if this relationship is causal and the mechanisms between timing of antidepressant treatment and outcomes.
WITHDRAWN: IL-17C plays a role in the pathophysiology of acute recurrent tonsillitis
Authors: Clapperton Megan , Kunanandam Tash , Florea Catalina D , Cunningham Margaret R , Douglas Catriona M , McConnell Gail 
Published: February 2024

Withdrawal StatementThe authors have withdrawn their manuscript owing to an error discovered in the selection and analysis of blot data. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Impaired islet function with normal exocrine enzyme secretion is consistent across the head, body, and tail pancreas regions in type 1 diabetes
Authors: Drotar Denise M. , Mojica-Avila Ana Karen , Bloss Drew T. , Cohrs Christian M. , Manson Cameron T. , Posgai Amanda L. , Williams MacKenzie D. , Brusko Maigan A. , Phelps Edward A. , Wasserfall Clive H. , Speier Stephan , Atkinson Mark A. 
Published: February 2024

SummaryHistopathological heterogeneity in human pancreas has been well documented; however, functional evidence at the tissue level is scarce. Herein we investigatedin situglucose-stimulated islet and carbachol-stimulated acinar cell secretion across the pancreas head (PH), body (PB), and tail (PT) regions in no diabetes (ND, n=15), single islet autoantibody-positive (1AAb+, n=7), and type 1 diabetes donors (T1D, <14 months duration, n=5). Insulin, glucagon, pancreatic amylase, lipase, and trypsinogen secretion along with 3D tissue morphometrical features were comparable across the regions in ND. In T1D, insulin secretion and beta-cell volume were significantly reduced within all regions, while glucagon and enzymes were unaltered. Beta-cell volume was lower despite normal insulin secretion in 1AAb+, resulting in increased volume-adjusted insulin secretion versus ND. Islet and acinar cell secretion in 1AAb+ were consistent across PH, PB and PT. This study supports low inter-regional variation in pancreas slice function and potentially, increased metabolic demand in 1AAb+.
Drug-induced cytotoxicity prediction in muscle cells, an application of the Cell Painting assay
Authors: Lambert Roman , Aparicio Pablo , Candelas Eva Serrano , Murphy Aisling , Gozalbes Rafael , Fearnhead Howard 
Published: February 2024

AbstractIn silicotoxicity prediction offers the chance of reducing or replacing most animal testing through the integration of large experimental assay datasets with the appropriate computational approaches. The use of Cell Painting to detect various phenotypic changes induced by chemicals is emerging as a powerful technique in toxicity prediction. However, most Cell Painting approaches use cancer cells that are less relevant for many toxicological endpoints, which may limit the usefulness of this data. In this study, a myoblast cell line is used to characterize cellular responses to a panel of 30 known myotoxicants. In place of traditional structural descriptors, here each perturbation is described by a fingerprint of calculated properties, deducted from the intensity, shape, or texture of individual cells. We show that these kinds of descriptors convey information to allow the prediction of the cellular viability and fate of cells in myoblasts and differentiated myotubes of the C2C12 cell line, and the clustering of drugs by their cytotoxicity responses.Author SummaryStudying the toxicity of chemical compounds and drugs is crucial to avoid potentially lethal adverse effects of commercialized products, but also to detect the unsuspected toxicity of existing drugs. While these assays traditionally rely on animal models raising important ethical concerns, a need forin vitroandin silicomodels is present and increasing in recent years. We here propose a predictive model capable of predicting the values of a cell viability assay using cell morphology profiles captured with a microscopy experiment. This model predicts the healthiness of muscle cells treated with 30 compounds suspected to induce muscular damage or even myopathies in humans. We also use these profiles to find an interesting morphological similarity between two different classes of drugs: statins (used for cholesterol treatments) and tyrosine kinase inhibitors (anti-cancer drugs). This analysis opens a new perspective for understanding the mechanisms responsible for drug-induced muscular toxicity, an area of toxicology that is currently under-researched.
Network pharmacology of xylazine to understand Its health consequences and develop mechanistic based remediations
Authors: Kumar Arun HS 
Published: February 2024

AbstractBackgroundThe recent raise in xylazine use disorders (XUD) in humans is a significant cause for concern as comprehensive understanding of its molecular pathology is limited and hence the ability to reverse the potential adverse effects are lacking. To address this gap, this study evaluates the dose-dependent impact of xylazine and its interactions with various potential targets, to identify an optimal reversal strategy.MethodsA trichotomized (Low, medium, and high) dose, volume of distribution and predicted plasma concentration of xylazine were defined. A detailed analysis of xylazine’s network protein targets and their tissue-specific expression was performed using classical pharmacoinformatic tools. Molecular docking was used to assess the drug-target affinities and identify potential reversal agents.ResultsThe study categorized xylazine plasma concentrations ranging from 5-8μM, 14-20μM, and 28-40μM, as low, medium, and high respectively. Xylazine displayed preferential affinity for hydrolases, kinases, transporters, and ion channels. Xylazine’s network analysis revealed the following proteins, ABCC9, RET, RAPGEF4, ACHE, TGFBR1, PGR, KCNH2, KCNN2, and TRPM8 as its high affinity targets. The tissue-specific expression of these high-affinity targets suggested potential adverse effects on various organs, particularly skeletal and smooth muscles, and the adrenal gland. The study further explored the potential reversal of xylazine pharmacology using alpha2AR-antagonists and CNS stimulants. Prazosin emerged as the most promising candidate, exhibiting a 200 to 2000-fold superior affinity against all high-affinity targets of xylazine.ConclusionThis study contributes to our understanding of xylazine’s molecular mechanisms and suggests that prazosin can serve as an effective therapeutic option for mitigating xylazine-induced adverse effects in XUD patients, which warrants clinical investigation.
Congenital T cell activation impairs transitional to follicular B cell maturation in humans
Authors: Allard-Chamard Hugues , Hillier Kirsty , Ramseier Michelle L. , Bertocchi Alice , Kaneko Naoki , Premo Katherine , Lam Tiffany , Yuen Grace , Karpel Marshall , Mahajan Vinay S. , Tsekeri Christina , Vencic Jean , Crotty Rory , Sharda Anish , Barmettler Sara , Westermann-Clark Emma , Walter Jolan E. , Ghebremichael Musie , Shalek Alex K. , Farmer Jocelyn R. , Pillai Shiv 
Published: February 2024

AbstractCTLA4-deficient patients exhibit profound humoral immune dysfunction, yet the basis for the B cell defect is not known. We observed a marked reduction in transitional to follicular B cell development in CTLA4-deficient patients, correlating with decreased CTLA4 function in regulatory T cells and increased mTORC1 signaling in transitional B cells. Treatment of transitional B cells with CD40L was sufficient to induce mTORC1 signaling and inhibit follicular B cell maturationin vitro. Frequent cell-cell contacts between CD40L+T cells and naïve IgD+CD27−B cells were observed in patient lymph nodes. Follicular B cell maturation in CTLA-deficient patients was partially rescued following CTLA4 replacement therapyin vivo. We conclude that functional regulatory T cells and the containment of excessive T cell activation are required for follicular B cells to mature and attain metabolic quiescence and thus acquire a state of immunological self-tolerance.One Sentence SummaryCongenital T cell activation in CTLA4-deficient patients impairs transitional to follicular B cell maturation and can be rescued by CTLA4 replacement therapyin vivo.
Neodymium-Doped Nanocrystals for Diffraction-limitedin vitroTemperature Sensing
Authors: Bravo M. , Yang S. , Wen D. , Krzyzowska S. , Taemaitree F. , Zaman S. , Fortuni B. , Rocha S. , Mulvaney P. , Uji-i H. , Brooke S. , Hutchison J. 
Published: February 2024

AbstractLocalized hyperthermia is a promising approach to cancer therapy. However, its clinical potential is limited by heterogeneous heat distribution within tumors, and advanced methods to measure temperature at the sub-micron level are therefore required. To address this challenge, luminescent nanothermometers, such as lanthanide-doped nanocrystals (Ln-NC) operating in the near-infrared (NIR), have been investigated for accurate spatiotemporal thermal monitoring. In this study, the synthesis of neodymium-doped, sodium yttrium fluoride nanocrystals (Nd-NCs) was optimized to achieve high photoluminescence (PL) intensity by adjusting the dopant concentration and by shelling with inert layers. Standard curves for luminescence-based temperature readout were developed using ratiometric analysis of the temperature-dependent PL spectra in the 850-920 nm biological window, showing excellent linearity and high thermal sensitivity. A silica shell was added to the particles and shown to confer excellent aqueous stability and biocompatibility in A549 lung cancer cells. Finally, luminescent thermal readout was demonstratedin vitroin A549 cells by spectrally resolving the diffraction-limited luminescence spots at a single-particle scale over a clinically relevant temperature range from 20-50 °C. The application of the developed nanothermometer as preclinical tools for NP-HT characterization could provide crucial information on the therapeutic temperature achieved in and around the tumor area. This could be key to optimizing NP properties and therapeutic parameters, for the development of viable hyperthermal cancer treatments.Abstract Figure
Multimodal illumination platform for 3D single-molecule super-resolution imaging throughout mammalian cells
Authors: Nelson Tyler , Vargas-Hernández Sofía , Freire Margareth , Cheng Siyang , Gustavsson Anna-Karin 
Published: February 2024

AbstractSingle-molecule super-resolution imaging is instrumental for investigating cellular architecture and organization at the nanoscale. Achieving precise 3D nanometric localization when imaging structures throughout mammalian cells, which can be multiple microns thick, requires careful selection of the illumination scheme in order to optimize the fluorescence signal to background ratio (SBR). Thus, an optical platform that combines different wide-field illumination schemes for target-specific SBR optimization would facilitate more precise, 3D nanoscale studies of a wide range of cellular structures. Here we demonstrate a versatile multimodal illumination platform that integrates the sectioning and background reduction capabilities of light sheet illumination with homogeneous, flat-field epi-and TIRF illumination. Using primarily commercially available parts, we combine the fast and convenient switching between illumination modalities with point spread function engineering to enable 3D singlemolecule super-resolution imaging throughout mammalian cells. For targets directly at the coverslip, the homogenous intensity profile and excellent sectioning of our flat-field TIRF illumination scheme improves single-molecule data quality by providing low fluorescence background and uniform fluorophore blinking kinetics, fluorescence signal, and localization precision across the entire field of view. The increased contrast achieved with LS illumination, when compared with epi-illumination, makes this illumination modality an excellent alternative when imaging targets that extend throughout the cell. We validate our microscopy platform for improved 3D super-resolution imaging by two-color imaging of paxillin – a protein located in the focal adhesion complex – and actin in human osteosarcoma cells.
Loss of endogenous estrogen alters mitochondrial metabolism and muscle clock-related protein Rbm20 in femalemdxmice
Authors: Timpani Cara A. , Debrincat Didier , Kourakis Stephanie , Boyer Rebecca , Formosa Luke E. , Steele Joel R. , Zhang Haijian , Schittenhelm Ralf B. , Russell Aaron P. , Rybalka Emma , Lindsay Angus 
Published: February 2024

AbstractFemale carriers of aDuchenne muscular dystrophy(DMD) gene mutation manifest exercise intolerance and metabolic anomalies that may be exacerbated following menopause due to the loss of estrogen, a known regulator of skeletal muscle function and metabolism. Here, we studied the impact of estrogen depletion (via ovariectomy) on exercise tolerance and muscle mitochondrial metabolism in femalemdxmice and the potential of estrogen replacement therapy (using estradiol) to protect against functional and metabolic perturbations. We also investigated the effect of estrogen depletion, and replacement, on the skeletal muscle proteome through an untargeted proteomic approach with TMT-labelling. Our study confirms that loss of estrogen in femalemdxmice reduces exercise capacity, tricarboxylic acid cycle intermediates and citrate synthase activity but that these deficits can be offset through estrogen replacement therapy. Furthermore, ovariectomy downregulated protein expression of RNA binding motif factor 20 (Rbm20), a critical regulator of sarcomeric and muscle homeostasis gene splicing, which impacted pathways involving ribosomal and mitochondrial translation. Estrogen replacement modulated Rbm20 protein expression and promoted metabolic processes and the upregulation of proteins involved in mitochondrial dynamics and metabolism. Our data suggests that estrogen mitigates dystrophinopathic features in femalemdxmice and that estrogen replacement may be a potential therapy for post-menopausal DMD carriers.
Integrating Dynamic Network Analysis with AI for Enhanced Epitope Prediction in PD-L1:Affibody Interactions
Authors: Gomes Diego E.B. , Yang Byeongseon , Vanella Rosario , Nash Michael A. , Bernardi Rafael C. 
Published: February 2024

AbstractUnderstanding binding epitopes involved in protein-protein interactions and accurately determining their structure is a long standing goal with broad applicability in industry and biomedicine. Although various experimental methods for binding epitope determination exist, these approaches are typically low throughput and cost intensive. Computational methods have potential to accelerate epitope predictions, however, recently developed artificial intelligence (AI)-based methods frequently fail to predict epitopes of synthetic binding domains with few natural homologs. Here we have developed an integrated method employing generalized-correlation-based dynamic network analysis on multiple molecular dynamics (MD) trajectories, initiated from AlphaFold2 Multimer structures, to unravel the structure and binding epitope of the therapeutic PD-L1:Affibody complex. Both AlphaFold2 and conventional molecular dynamics trajectory analysis alone each proved ineffectual in differentiating between two putative binding models referred to as parallel and perpendicular. However, our integrated approach based on dynamic network analysis showed that the perpendicular mode was significantly more stable. These predictions were validated using a suite of experimental epitope mapping protocols including cross linking mass spectrometry and next-generation sequencing-based deep mutational scanning. Our research highlights the potential of deploying dynamic network analysis to refine AI-based structure predictions for precise predictions of protein-protein interaction interfaces.