bluuebunny/crossref_metadata_2025_split huggingface dataset:
BayesAge 2.0: A Maximum Likelihood Algorithm to Predict Transcriptomic Age
Authors: Mboning Lajoyce , Costa Emma K. , Chen Jingxun , Bouchard Louis-S , Pellegrini Matteo 
Published: September 2024

AbstractAging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an improved version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data. Building on the original BayesAge framework, which was developed for epigenetic age prediction, BayesAge 2.0 integrates a Poisson distribution to model count-based gene expression data and employs LOWESS smoothing to capture non-linear gene-age relationships. BayesAge 2.0 provides significant improvements over traditional linear models, such as Elastic Net regression. Specifically, it addresses issues of age bias in predictions, with minimal age-associated bias observed in residuals. Its computational efficiency further distinguishes it from traditional models, as reference construction and cross-validation are completed more quickly compared to Elastic Net regression, which requires extensive hyperparameter tuning. Overall, BayesAge 2.0 represents a notable advance in transcriptomic age prediction, offering a robust, accurate, and efficient tool for aging research and biomarker development.
HDgraphiX: A web-based tool for visualization of hydrogen deuterium exchange mass spectrometry data
Authors: Vosper Kent R. , Velyvis Algirdas , Vahidi Siavash 
Published: September 2024

AbstractSummaryHydrogen deuterium exchange mass spectrometry (HDX-MS) investigates protein structural changes by measuring deuterium incorporation into the protein amide backbone. Due to richness of information provided on protein conformational dynamics, HDX-MS data can be challenging to visualize effectively. To address this, we have developed HDgraphiX, a web-based tool that visualizes HDX data by processing outputs from two popular analysis software packages, DynamX (Waters Corp.) and HDExaminer (Sierra Analytics Inc). HDgraphiX performs statistical analyses, filters data based on statistical significance and presents the results in several forms of user-friendly publication-quality heatmaps (Chiclet plots). Unique features of this tool include the generation of Woods plots, volcano plots, and PyMOL colouring scripts, which are used to map deuterium uptake differences onto protein structures. Additionally, HDgraphiX offers numerous advanced options for customizing data processing and plotting without the need for manual data editing.Availability and ImplementationHDgraphiX is available free of charge for all users athttps://hdgraphix.net, the Python script and HTML template are deposited athttps://github.com/KentV-UofG/HDgraphiX.
Synergistic and antagonistic activities ofIRF8andFOSenhancer pairs during an immune cell fate switch
Authors: Klonizakis Antonios , Alcoverro-Bertran Marc , Massó Pere , Thomas Joanna , de Andrés-Aguayo Luisa , Wei Xiao , Varamogianni-Mamatsi Vassiliki , Nikolaou Christoforos , Graf Thomas 
Published: September 2024

AbstractCell-fate instructive genes tend to be regulated by large clusters of enhancers. Whether and how individual enhancers within such clusters cooperate in regulating gene expression is poorly understood. We have previously developed a computational method, SEGCOND, that identifies hubs consisting of enhancer clusters and their target genes, termed Putative Transcriptional Condensates (PTCs). Using SEGCOND, we identified PTCs in a CEBPA-induced B-cell to macrophage transdifferentiation system. We found them to be enriched for highly expressed, lineage-restricted genes and to associate with BRD4, a component of transcriptional condensates. Here we performed single and combinatorial deletions of enhancers within two active PTCs after transdifferentiation is induced, harboringIRF8andFOS. Two enhancers within theIRF8PTC were found to form a backup mechanism when combined, safeguardingIRF8expression and transdifferentiation kinetics. Unexpectedly, two individual enhancers within theFOSPTC antagonize each other at Day 1 of transdifferentiation, delaying the conversion of B-cells to macrophages and reducingFOSexpression, but cooperate to increaseFOSlevels in Day 7 induced cells. Our results reveal differentiation stage-specific, complex interactions, between individual enhancers within a cluster.
Molecular consequences of SCA5 mutations in the spectrin-repeat domains of β-III-spectrin
Authors: Denha Sarah A. , DeLaet Naomi R. , Abukamil Abeer W. , Alexopoulos Angelica N. , Keller Amanda R. , Atang Alexandra E. , Avery Adam W. 
Published: September 2024

AbstractSpinocerebellar ataxia type 5 (SCA5) mutations in the protein β-III-spectrin cluster to the N-terminal actin-binding domain (ABD) and the central spectrin-repeat domains (SRDs). We previously reported that a common molecular consequence of ABD-localized SCA5 mutations is increased actin binding. However, little is known about the molecular consequences of the SRD-localized mutations. It is known that the SRDs of β-spectrin proteins interact with α-spectrin to form an α/β-spectrin dimer. In addition, it is known that SRDs neighbouring the β-spectrin ABD enhance actin binding. Here, we tested the impact of the SRD-localized R480W and the E532_M544del mutations on the binding of β-III-spectrin to α-II-spectrin and actin. Using multiple experimental approaches, we show that both the R480W and E532_M544del mutants can bind α-II-spectrin. However, E532_M544del causes partial uncoupling of complementary SRDs in the α/β-spectrin dimer. Further, the R480W mutant forms large intracellular inclusions when co-expressed with α-II-spectrin in cells, supporting that R480W mutation grossly disrupts the α-II/β-III-spectrin physical complex. Moreover, actin-binding assays show that E532_M544del, but not R480W, increases β-III-spectrin actin binding. Altogether, these data support that SRD-localized mutations alter key interactions of β-III-spectrin with α-II-spectrin and actin.
Variant scoring performance across selection regimes depends on variant-to-gene and gene-to-disease components
Authors: Finucane Hilary K. , Parsa Sophie , Guez Jeremy , Kanai Masahiro , Satterstrom F. Kyle , Nkambule Lethukuthula L. , Daly Mark J. , Seed Cotton , Karczewski Konrad J. 
Published: September 2024

AbstractVariant scoring methods (VSMs) aid in the interpretation of coding mutations and their potential impact on health, but their evaluation in the context of human genetics applications remains inconsistent. Here, we describe GeneticsGym, a systematic approach to evaluating the real-world impact of VSMs on human genetic analysis. We show that the relative performance of VSMs varies across regimes of natural selection, and that both variant-to-gene and gene-to-disease components contribute.
Multiplexed lifetime imaging of single molecules with a gated single-photon camera
Authors: Ronceray Nathan , Bennani Salim , Mitsioni Marianna , Siegel Nicole , Marcaida Maria Josefina , Bruschini Claudio , Charbon Edoardo , Roy Rahul , Dal Peraro Matteo , Acuna Guillermo P. , Radenovic Aleksandra 
Published: September 2024

AbstractFluorescence lifetime imaging microscopy (FLIM) is a powerful tool to discriminate fluorescent molecules or probe their nanoscale environment. Traditionally, FLIM uses time-correlated single-photon counting (TCSPC), which is precise but intrinsically low-throughput due to its dependence on point detectors. Although time-gated cameras have demonstrated the potential for high-throughput FLIM in bright samples with dense labeling, their use in single-molecule microscopy has not been explored extensively. Here, we report fast and accurate single-molecule FLIM with a commercial time-gated single-photon camera. Our optimized acquisition scheme achieves single-molecule lifetime measurements with a precision only about three times less than TCSPC, while allowing for the simultaneous multiplexing of over 3000 molecules. With this approach, we demonstrate parallelized lifetime measurements of large numbers of labeled pore-forming proteins on supported lipid bilayers, and multiplexed temporal single-molecule Förster resonance energy transfer measurements at 5-25 Hz. This method holds considerable promise for advancing multi-target single-molecule localization microscopy and biopolymer sequencing.
Redefining the Limits of Functional Continuity in the Early Evolution of P-Loop NTPases
Authors: Demkiv Andrey O. , Toledo-Patiño Saacnicteh , Carmona Encarni Medina , Berg Andrej , Pinto Gaspar P. , Parracino Antonietta , Sanchez-Ruiz Jose M. , Hengge Alvan C. , Laurino Paola , Longo Liam M. , Kamerlin Shina Caroline Lynn 
Published: September 2024

AbstractAt the heart of many nucleoside triphosphatases is a conserved sequence motif that binds phosphate. A current model of early enzyme evolution proposes that this 6-8 residue motif could have sparked the emergence of the very first nucleoside triphosphatases – a striking example of evolutionary continuity from simple beginnings, if true. To test whether this provocative evolutionary model holds for the ancient and ubiquitous P-Loop NTPases, the properties of seven disembodied Walker A-derived peptides were extensively characterized by Hamiltonian replica exchange molecular dynamics simulations. Although dynamic flickers of nest-like conformations were observed, significant structural similarity between the situated peptide and its disembodied counterpart was not detected – even in the presence of orthophosphate or a nucleotide. Simulations suggest that phosphate binding is non-specific, with a slight preference for GTP over orthophosphate. Control peptides with the same amino acid composition but different sequences and situated conformations behaved similarly to the Walker A peptides with respect to conformational dynamics and phosphate binding, revealing no indication that the Walker A sequence is privileged as a disembodied peptide. We conclude that the evolutionary history of the P-Loop NTPase family is unlikely to have started with a disembodied Walker A peptide in an aqueous environment. The limits of evolutionary continuity for this protein family, and the environmental context within which it emerged, must be reconsidered. Finally, we argue that motifs such as the Walker A motif may represent incomplete or fragmentary molecular fossils – the true nature of which have been eroded by time.Significance StatementThe first proteins were undoubtedly small, but when did those seeds emerge, and what did they look like? It is widely believed that the Walker A P-loop motif is a seed for the emergence of phosphate binding proteins, snugly binding phosphate in a structurally conserved nest. We probe this hypothesis through detailed computational characterization of disembodied Walker A and control peptides, showing that any nest formation is transient, and phosphate binding is weak and non-specific. Thus, we do not find structural continuity represented in the conserved Walker A motif, and current models of early P-loop evolution require revision. Further, care is required when interpreting highly conserved sequence fragments more broadly, as these may merely represent eroded molecular fossils.
Genomic Determinants of Biological Age Estimated By Deep Learning Applied to Retinal Images
Authors: Huang Yu , Syed Mohammad Ghouse , Chen Ruiye , Li Cong , Shang Xianwen , Wang Wei , Zhang Xueli , Zhang Xiayin , Tang Shulin , Liu Jing , Liu Shunming , Srinivasan Sundar , Hu Yijun , Mookiah Muthu Rama Krishnan , Wang Huan , Trucco Emanuele , Yu Honghua , Palmer Colin , Zhu Zhuoting , Doney Alexander S F , He Mingguang 
Published: September 2024

AbstractWith the development of deep learning (DL) techniques, there has been a successful application of this approach to determine biological age from latent information contained in retinal images. Retinal age gap (RAG) defined as the difference between chronological age and predicted retinal age has been established previously to predict the age-related disease. In this study, we performed discovery genome-wide association analysis (GWAS) on the RAG using the 31271 UK Biobank participants and replicated our findings in 8034 GoDARTs participants. The genetic correlation between RAGs predicted from the two cohorts was 0.67 (P=0.021). After meta-analysis, we found 13 RAG loci which might be related to retinal vessel density and other aging processes. The SNP-wide heritability (h2) of RAG was 0.15. Meanwhile, by performing Mendelian Randomization analysis, we found that glycated hemoglobin, inflammation hemocytes and anemia might be associated with accelerated retinal aging. Our study explored the biological implications and molecular level mechanism of RAG, which might enable causal inference of the aging process as well as provide potential pharmaceutical intervention targets for further treatment.
Digital Engagement of Neurocutaneous Syndrome Communities on Facebook: A Descriptive Study
Authors: Momen Donia , Patel Kushagra , Muzyka Logan , DeCuypere Michael , Lam Sandi K. , Raskin Jeffrey S. 
Published: September 2024

AbstractIntroductionSocial media has become a platform for healthcare providers and parents to communicate about common and rare pediatric disorders. Neurocutaneous syndromes including Tuberous Sclerosis Complex, Neurofibromatosis, and Sturge-Weber syndrome require lifelong monitoring and complex treatments. Clinician directed information is supplemented by online support groups, non-profit fundraising organizations, and educational programs through various Facebook features.ObjectiveThe objective of this study is to explore the socialization patterns of individuals affected by neurocutaneous syndromes as they interact and engage within various Facebook forums.MethodsPublic accounts on Facebook were analyzed throughout August 2022. The search terms used were “Sturge-Weber Syndrome”, “Sturge Weber”, “SWS”, “Tuberous Sclerosis”, “Tuberous Sclerosis Complex (TSC)”, and “Neurofibromatosis”, “Neurofibromatosis 1 (NF1)”, and “Neurofibromatosis 2 (NF2)”. Facebook accounts were analyzed on the basis of page ownership and video content.ResultsSearching Sturge-Weber syndrome (SWS) yielded 99 Facebook pages and 37 Facebook videos. Tuberous sclerosis resulted in 100 Facebook pages and 139 Facebook videos. Neurofibromatosis yielded 102 Facebook pages and 129 Facebook Videos. Patient released stories comprised 51% of the Facebook videos (157/305), educational videos comprised 37% (112/305), and 12% (36/305) related to the syndromes’ awareness day. Facebook Pages were managed by nonprofit organizations 37% (111/301), community support groups 36% (108/301), and patients creating a “private blog” 23% (70/301), and physicians 4% (12/301). Figure 1 shows a breakdown of the Facebook page ownership and video content of neurocutaneous syndromes.ConclusionThis study describes the online discussion of neurocutaneous syndromes through social media. The benefits of anonymized discussion for patients and families are many. Physicians manage only 4% of the Facebook pages and this may represent an opportunity to further disseminate medical advice in the future.
Rare Variant Association Analysis Uncovers Involvement ofVNN2in Stroke Outcome
Authors: Alcaide-Consuegra Estefanía , Mola-Caminal Marina , Escaramís Georgia , Lazcano Uxue , Pérez Isabel Fernández , Jimenez-Balado Joan , Giralt-Steinhauer Eva , Cuadrado-Godia Elisa , Ois Angel , Rodríguez-Campello Ana , Vallverdú Marta , Medina-Dols Aina , Jiménez Carmen , Tur Silvia , Díaz Rosa M , Bruque Carlos David , Andreu-Somavilla Nuria , González-Navarrete Irene , Vives-Bauzà Cristòfol , Fernández-Cadenas Israel , Jiménez-Conde Jordi , Balcells Susanna , Rabionet Raquel 
Published: September 2024

AbstractBACKGROUNDA stroke’s functional outcome presents vast variability among patients, which is influenced by age, sex, characteristics of the lesion, and genetic factors. However, there is very little knowledge about stroke recovery genetics. Recently, some GWAS (Genome-Wide Association Studies) have highlighted the involvement of common or low-frequency variants near or withinPATJ,PPP1R21, PTCH1, NTN4andTEK genes, whereas the role of rare variants is still unclear. This study aims to identify the genetic contributions to differences in stroke outcome analyzing the effect of rare variants.METHODSWe performed a pilot study analyzing 90 exomes of extreme good or bad recovery (modified Rankin Scale (mRS) at 3 months 0-1 vs 4-5) to select target genes involved in stroke recovery. To expand this study, 702 additional samples were sequenced by Targeted Next-Generation Sequencing capturing loci selected from the pilot study, GWAS studies and literature input. Here, we performed continuous (mRS 0-6) and dichotomous (mRS 0-1 vs 3-6) analyses, yielding one candidate gene. Protein structure and stability analysis were performed on selected variants.RESULTSOur work identified rare coding variants inVNN2associated with patients with a better stroke recovery (ΔDIC > 10, equivalent to p-value < 0.001). Six rare variants were predicted to significantly affect protein stability (ΔΔG > 1.6 kcal/mol), meanwhile, another variant, located in the active site, could affect the electrostatic surface.CONCLUSIONSVNN2could play a role in post-stroke inflammation altering the cell adhesion and migration of neutrophils during recovery.
Pangenome-Informed Language Models for Privacy-Preserving Synthetic Genome Sequence Generation
Authors: Huang Pengzhi , Charton François , Schmelzle Jan-Niklas M. , Darnell Shelby S. , Prins Pjotr , Garrison Erik , Suh G. Edward 
Published: September 2024

AbstractThe public availability of genome datasets, such as The Human Genome Project (HGP), The 1000 Genomes Project, The Cancer Genome Atlas, and the International HapMap Project, has significantly advanced scientific research and medical understanding. Here our goal is to share such genomic information for downstream analysis while protecting the privacy of individuals through Differential Privacy (DP). We introduce synthetic DNA data generation based on pangenomes in combination with Pretrained-Language Models (PTLMs).We introduce two novel tokenization schemes based on pangenome graphs to enhance the modeling of DNA. We evaluated these tokenization methods, and compared them with classical single nucleotide andk-mer tokenizations. We findk-mer tokenization schemes, indicating that our tokenization schemes boost the model’s performance consistency with long effective context length (covering longer sequences with the same number of tokens). Additionally, we propose a method to utilize the pangenome graph and make it comply with DP privacy standards. We assess the performance of DP training on the quality of generated sequences with discussion of the trade-offs between privacy and model accuracy. The source code for our work will be published under a free and open source license soon.
Rendering Proteins Fluorescent Inconspicuously: Genetically Encoded 4-Cyanotryptophan Conserves Their Structure and Enables the Detection of Ligand Binding Sites
Authors: Qianzhu Haocheng , Abdelkader Elwy H. , Welegedara Adarshi P. , Habel Edan , Paul Nathan , Frkic Rebecca L. , Jackson Colin J. , Huber Thomas , Otting Gottfried 
Published: September 2024

AbstractCyano-tryptophans (CN-Trp) are privileged multimodal reporters on protein structure. They are similar in size to the canonical amino acid tryptophan and some of them exhibit bright fluorescence which responds sensitively to changes in the environment. We selected aminoacyl-tRNA synthetases specific for 4-, 5-, 6-, and 7-CN-Trp for high-yield in vivo production of proteins with a single, site-specifically introduced nitrile label. The absorption maximum of 4-CN-Trp is distinct from Trp, allowing the selective excitation of its intense fluorescence. 4-CN-Trp features bright fluorescence in the visible range. Crystal structures of maltose binding protein demonstrate near-complete structural conservation when a native buried Trp residue is replaced by 4-CN-Trp. Besides presenting an inconspicuous tag for live cell microscopy, the high fluorescence of 4-CN-Trp enables measurements of subnanomolar ligand binding affinities in isotropic solution, as demonstrated by the complex between rapamycin and the peptidyl–prolyl isomerase FKBP12 furnished with a 4-CN-Trp residue in the substrate binding pocket. Furthermore, 4-CN-Trp residues positioned at different locations of a protein containing multiple tryptophan residues permits using fluorescence quenching experiments to detect the proximity of individual Trp residues to the binding site of aromatic ligands.
One Health in Eastern Africa: No barriers for ESBL producingE. colitransmission or independent antimicrobial resistance gene flow across ecological compartments
Authors: Musicha Patrick , Beale Mathew A , Cocker Derek , Oruru Fiona A , Zuza Allan , Salifu Chifundo , Katende George , Nanono Sylvia , Isaasi Fred , Chidziwisano Kondwani , Mugisha Lawrence , Kajumbula Henry , Musoke David , Morse Tracy , Jacob Shevin , Feasey Nicholas A , Thomson Nicholas R 
Published: September 2024

AbstractThe One Health paradigm considers the interdependence of human, animal and environmental health. In high-income countries, limited evidence has been found from recent studies to support the importance of a One Health approach to addressing spread of antimicrobial resistance (AMR). Given AMR is a global threat, and we are all interconnected it would be important to know if closer interaction of humans with animals and the environment in low-income present a contrasting picture. We used whole genome sequencing to investigate the genomic diversity and to infer transmission of extended spectrum beta-lactamase producingEscherichia coli(ESBL-Ec) between different ecological niches (humans, animals and the environment). We found high diversity of ESBL-Ec with 172 genomic clusters and 167 sequence types identified from 2,344 genomes. Common ESBL genes,blaCTX-M-15(67.6%) andblaCTX-M-27(14.2%) were carried on a complex network of different plasmids, presenting multiple pathways for dissemination and revealing the high force of selection. Using fine-scale genomic clustering across multiple thresholds ranging from 0 to 20 single nucleotide polymorphisms, we found that genomes isolated from humans, animals and the environment formed overlapping clusters, indicating recent ESBL-Ec transmission and co-circulation both within and between ecological compartments. These findings demonstrate that the One Health approach is highly relevant to tackling AMR in low-income settings, and therefore critical to consider if we are to address the rise of AMR globally.
MicroED Structures of Fluticasone Furoate and Fluticasone Propionate Provide New Insights to Their Function
Authors: Lin Jieye , Unge Johan , Gonen Tamir 
Published: September 2024

AbstractThe detailed understanding of fluticasone, a widely prescribed medicine for allergic rhinitis, asthma, and chronic obstructive pulmonary disease (COPD), has not been complete due to challenges in structural elucidation. The three-dimensional (3D) structure of fluticasone furoate1remained undetermined for decades, while the existing structures of fluticasone propionate2required refinement against improved data. In this study, we applied microcrystal electron diffraction (MicroED) to determine the 3D structures of1and2in their drug formulation state. Density functional theory (DFT) calculations were utilized to model solvent effects to determine the preferred geometries in solution. A comparative analysis of structures of1and2across three states (drug formulation state, in solution, and biologically active state) revealed major conformational changes during the entire transition. Potential energy plots were calculated for the most dynamic bonds, uncovering their rotational barriers. This study underscores the combined use of MicroED and DFT calculations to provide a comprehensive understanding of conformational and energy changes during drug functioning in humans. The quantitative comparison highlights the subtle structural differences that can lead to significant functional changes in pharmaceutical properties.