bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterochromatin boundaries maintain centromere position, size and number
Authors: Carty Ben L , Dubocanin Danilo , Murillo-Pineda Marina , Dumont Marie , Volpe Emilia , Mikulski Pawel , Humes Julia , Whittingham Oliver , Fachinetti Daniele , Giunta Simona , Altemose Nicolas , Jansen Lars E.T. 
Published: February 2025

AbstractCentromeres are chromosomal loci that ensure proper chromosome segregation by providing a platform for kinetochore assembly and spindle force transduction during cell division. Human centromeres are defined primarily by a unique chromatin domain featuring the histone H3 variant, Centromere Protein A (CENP-A), that marks a single active centromere locus per chromosome. CENP-A chromatin typically occupies a small subregion of low DNA methylation within multi-megabase arrays of hypermethylated alpha-satellite repeats and constitutive pericentric heterochromatin. However, the mechanisms defining and maintaining precise centromere position and domain size, and the role of the underlying alpha satellite DNA sequence, are poorly characterised. Using an experimentally-induced neocentromere in RPE1 cells, we discovered that the SUV39H1 and H2 methyltransferases tri-methylate H3K9 at neocentromere boundaries to maintain CENP-A domain size independent of DNA methylation or satellite sequences. Furthermore, we found that the CENP-A domain at canonical alpha-satellite-based centromeres is characterized by local depletion of H3K9me3-mediated heterochromatin, coinciding with the DNA methylation dip region. We identified the SETDB1 methyltransferase as key to maintaining H3K9me3 within flanking active higher order alpha satellite arrays while SUV39s and SUZ12 contribute to globally heterochromatinize both alpha satellites and neighbouring repeats. Loss of this heterochromatin boundary results in the progressive expansion of the primary CENP-A domain, erosion of DNA methylation, and the nucleation of new centromeres across alpha satellite sequences. Our study identifies the functional specialization of different H3K9 methyltransferases across centromeric and pericentric domains, crucial for maintaining centromere domain size and number.
The distortion-push mechanism for the γ-subunit rotation in F1-ATPase
Authors: Motohashi Masahiro , Oide Mao , Kobayashi Chigusa , Jung Jaewoon , Muneyuki Eiro , Sugita Yuji 
Published: February 2025

AbstractF1-ATPase comprises the stator ring consisting of α₃β₃ subunits and the rotor γ subunit. The γ subunit rotation mechanism has been extensively investigated by biochemical analyses, structural studies, single-molecule measurements, and computational studies. Recent cryo-electron microscopy (cryo-EM) structures of F1-ATPase from the thermophilic bacteriumBacillusPS3 (TF1) provide us with further possibilities for a better understanding of the γ-rotation mechanisms. Using cryo-EM structures having the γ-rotation angles close to the binding dwell and catalytic dwell states, we investigate the relationships between the γ subunit rotation, conformational changes of the stator α3β3subunits, and the nucleotide-binding and release. We performed targeted molecular dynamics (MD) simulations with external forces on the α₃β₃ subunits and observed 80° substep rotations of the γ subunit. Then, we optimized the most probable transition pathway through the mean-force string method simulations with 64 images. Finally, using umbrella sampling, we calculated the potential of mean forces along the minimum free energy pathway during the 80° substep rotation. Our MD simulations suggest that 80° substep rotation is divided into the first rotation, resting, and the second rotation. Notably, the first rotation is driven by the distortion of the stator α3β3subunits, and the second rotation is induced mainly by direct β/γ subunit interactions. This model, which we call the distortion-push mechanism, is consistent with the residue-level experimental analysis on F1-ATPase and the atomic structures determined by X-ray crystallography and cryo-EM.
Genes and Pathways Comprising the Human and Mouse ORFeomes Display Distinct Codon Bias Signatures that Can Regulate Protein Levels
Authors: Davis Evan T. , Raman Rahul , Byrne Shane R. , Ghanegolmohammadi Farzan , Mathur Chetna , Begley Ulrike , Dedon Peter C. , Begley Thomas J. 
Published: February 2025

AbstractArginine, glutamic acid and selenocysteine based codon bias has been shown to regulate the translation of specific mRNAs for proteins that participate in stress responses, cell cycle and transcriptional regulation. Defining codon-bias in gene networks has the potential to identify other pathways under translational control. Here we have used computational methods to analyze the ORFeome of all unique human (19,711) and mouse (22,138) open-reading frames (ORFs) to characterize codon-usage and codon-bias in genes and biological processes. We show that ORFeome-wide clustering of gene-specific codon frequency data can be used to identify ontology-enriched biological processes and gene networks, with developmental and immunological programs well represented for both humans and mice. We developed codon over-use ontology mapping and hierarchical clustering to identify multi-codon bias signatures in human and mouse genes linked to signaling, development, mitochondria and metabolism, among others. The most distinct multi-codon bias signatures were identified in human genes linked to skin development and RNA metabolism, and in mouse genes linked to olfactory transduction and ribosome, highlighting species-specific pathways potentially regulated by translation. Extreme codon bias was identified in genes that included transcription factors and histone variants. We show that re-engineering extreme usage of C- or U-ending codons for aspartic acid, asparagine, histidine and tyrosine in the transcription factorsCEBPBandMIER1,respectively, significantly regulates protein levels. Our study highlights that multi-codon bias signatures can be linked to specific biological pathways and that extreme codon bias with regulatory potential exists in transcription factors for immune response and development.Graphical Abstract
Master control genes in the regeneration of rod photoreceptors from endogenous progenitor cells in zebrafish retina
Authors: Shihabeddin Eyad , Santhanam Abirami , Tetenborg Stephan , Aronowitz Alexandra L. , Wei Haichao , Qin Guoting , Cai Chengzhi , Wu Jiaqian , O’Brien John 
Published: February 2025

AbstractRetinitis Pigmentosa is a chronic retinal degenerative disease characterized by the gradual loss of rod, and later, cone photoreceptors until the individual is completely blind. Regeneration of photoreceptors from endogenous progenitor cells is a possible therapeutic approach, but mammals do not do this naturally. Mammalian models can be induced to generate retinal progenitors from Müller glial cells, but there has been limited success in rod photoreceptor specific regeneration. Unlike mammals, zebrafish have the natural ability to regenerate neurons after injury or disease and can provide insight into the molecular mechanisms of regeneration. In this study, we used a zebrafish model of Retinitis Pigmentosa to investigate the class of progenitors responsible for rod photoreceptor regeneration in the context of chronic disease. Using bioinformatic analyses of single-cell RNA sequencing datasets, we identified master regulator genes responsible for proliferation of retinal progenitors, differentiation of progenitors into rod photoreceptors, and maturation of the new rod photoreceptors. Using transient knockdown of gene expression in adult regenerating retina we determined thate2f1,e2f2,e2f3andaurkbare critical for proliferation of progenitors, andprdm1ais critical for differentiation of progenitors into rod photoreceptors. This study provides a list of master regulators responsible for the specific regeneration of rod photoreceptors during chronic retinal degeneration.Impact StatementIdentification of master regulating genes that drive the proliferation of progenitor cells and their differentiation specifically into rod photoreceptors provides insight that can be used to develop regenerative therapies for retinal degenerative diseases.
CUT&Tag Identifies Repetitive Genomic Loci that are Excluded from ChIP Assays
Authors: Park Brandon J , Hua Shan , Casler Karli D , Cefaloni Eric , Ayers Michael C , Lake Rahiim F , Murphy Kristin E , Vertino Paula M , O’Connell Mitchell R. , Murphy Patrick J 
Published: February 2025

SummaryDetermining the genomic localization of chromatin features is an essential aspect of investigating gene expression control, and ChIP-Seq has long been the gold standard technique for interrogating chromatin landscapes. Recently, the development of alternative methods, such as CUT&Tag, have provided researchers with alternative strategies that eliminate the need for chromatin purification, and allow forin situinvestigation of histone modifications and chromatin bound factors. Mindful of technical differences, we set out to investigate whether distinct chromatin modifications were equally compatible with these different chromatin interrogation techniques. We found that ChIP-Seq and CUT&Tag performed similarly for modifications known to reside at gene regulatory regions, such as promoters and enhancers, but major differences were observed when we assessed enrichment over heterochromatin-associated loci. Unlike ChIP-Seq, CUT&Tag detects robust levels of H3K9me3 at a substantial number of repetitive elements, with especially high sensitivity over evolutionarily young retrotransposons. IAPEz-int elements for example, exhibited underrepresentation in mouse ChIP-Seq datasets but strong enrichment using CUT&Tag. Additionally, we identified several euchromatin-associated proteins that co-purify with repetitive loci and are similarly depleted when applying ChIP-based methods. This study reveals that our current knowledge of chromatin states across the heterochromatin portions of the mammalian genome is extensively incomplete, largely due to limitations of ChIP-Seq. We also demonstrate that newerin situchromatin fragmentation-based techniques, such as CUT&Tag and CUT&RUN, are more suitable for studying chromatin modifications over repetitive elements and retrotransposons.HighlightsIn situfragmentation overcomes biases produced by ChIP-Seq.Heterochromatic regions of the genome are lost to the insoluble pellet during ChIP-Seq.CUT&Tag allows for mapping chromatin features at young repetitive elements.Euchromatin-associated regulatory factors co-purify with insoluble heterochromatin.
Mycobacterium intracellulareABSURDO is a novel clinical isolate with three colony morphotypes that vary in pathogenicity and sequence at thePKSandMtrAloci
Authors: Claeys Tiffany A. , Liu Yijing , Prigodich Anneka , Peck Emily , Gokul Emily , Reed-Mera Nine , Tuah Albright , Wirekoh Abena , Quinn Kylie , Rosas Mejia Oscar , Clary Gillian , Sasindran Smitha , Dellos-Nolan Sheri , Gloag Erin , Huppler Anna R. , Hull Natalie M. , Jude Brooke A. , Robinson Richard T. 
Published: February 2025

ABSTRACTMycobacterium intracellulareis a nontuberculous mycobacteria (NTM) species which can cause serious and sometimes fatal disease in immunocompromised individuals. Other NTM species, includingM. aviumandM. abscessus, commonly exhibit two colony morphotypes (smooth and rough) which vary in appearance and liquid growth properties. Here we characterize a novel clinical isolate ofM. intracellularewhich exhibits three (not two) colony morphotypes which differ in appearance, liquid growth properties, acid-fastness andin vivosurvival following infection of mice via an inhalational exposure model. The genome of this isolate, which we have termed ABSURDO, as well as the genome of each morphotype components, aligns with that ofM. intracellulareyet contains ∼16% more protein coding sequences than theM. intracellularetype strain ATCC 13590T. Variation analysis of each morphotype genome revealed that across the three morphotypes there were only two mutations which had a high likelihood of causing a phenotype due to a genetic change: one in the gene encoding modular polyketide synthase (PKS), and another in the two component system response regulator MtrA. Neither of these genes have been previously implicated in the morphotype shifting of an NTM. In summary,M. intracellulareABSURDO is a novel pathogenic isolate with a genome that aligns with (but is nevertheless larger than) theM. intracellularetype strain and comprises three morphotype components which differ in two genes that have not been implicated in NTM appearance, acid-fastness,in vitroandin vivogrowth.
Identification of Antituberculars with Favorable Potency and Pharmacokinetics through Structure-Based and Ligand-Based Modeling
Authors: Warapande Vedang , Meng Fanwang , Bozan Alexandra , Graff David E. , Fromer Jenna C. , Mughal Khadija , Mohideen Faheem K. , Shivangi  , Paruchuri Sindhuja , Johnston Melanie L. , Sharma Pankaj , Crea Timothy R. , Rudraraju Reshma S. , George Amir , Folvar Camilla , Nelson Andrew M. , Neiditch Matthew B. , Zimmerman Matthew D. , Coley Connor W. , Freundlich Joel S. 
Published: February 2025

ABSTRACTDrug discovery is inherently challenged by a multiple criteria decision making problem. The arduous path from hit discovery through lead optimization and preclinical candidate selection necessitates the evolution of a plethora of molecular properties. In this study, we focus on the hit discovery phase while beginning to address multiple criteria critical to the development of novel therapeutics to treatMycobacterium tuberculosisinfection. We develop a hybrid structure- and ligand-based pipeline for nominating diverse inhibitors targeting the β-ketoacyl synthase KasA by employing a Bayesian optimization-guided docking method and an ensemble model for compound nominations based on machine learning models forin vitroantibacterial efficacy, as characterized by minimum inhibitory concentration (MIC), and mouse pharmacokinetic (PK) plasma exposure. The application of our pipeline to the Enamine HTS library of 2.1M molecules resulted in the selection of 93 compounds, the experimental validation of which revealed exceptional PK (41%) and MIC (19%) success rates. Twelve compounds meet hit-like criteria in terms of MIC and PK profile and represent promising seeds for future drug discovery programs.
Quorum Sensing Regulators and Non-ribosomal Peptide Synthetases Govern Antibacterial Secretions inXenorhabdus szentirmaii
Authors: Dey Ritisha , Valle Domonique Olivia , Chakraborty Abhijit , Mayer Kimberly A , Uppala Jagadeesh , Chakraborty Anish , Mirza Shama , Forst Steven , Skwor Troy , Dey Madhusudan 
Published: February 2025

AbstractThe decades-long gap in antibiotic discovery has led to a significant health crisis due to antimicrobial resistance (AMR). The bacterial genusXenorhabdus, which forms symbiotic relationships with the soil nematodeSteinernema, are known to secrete a variety of antimicrobial compounds with potential effectiveness against AMR. These antimicrobial compounds are primarily bio-synthesized by non-ribosomal peptide synthetases (NRPS) and polyketide synthetase (PKS) genes. In this study, we report thatX. szentirmaiiproduces high levels of antibiotic activity during the stationary phase against diverse bacteria including known antibiotic resistant pathogens. It possesses 17 operons to encode predicted NRPS and PKS enzymes, designated asste1throughste17. Theste15-ste16andste17operons are predicted to produce the known antibiotics Pax peptide and Fabclavine, respectively. Additionally, the newly identified operonsste3,ste4,ste5,ste8, ste9, andste14consist of single genes, each containing two or moreNRPSgenes. Theste13operon harbors twoNRPSgenes, while the ste7 and ste12 operons contain threeNRPSgenes each. Further, RNA-seq analysis showed thatlsrFthat encodes a quorum sensing autoinducer-2 (AI-2) aldolase was expressed at high levels during stationary phase. These findings provide evidence thatX. szentirmaiiuses quorum sensing (QS) to synchronize the expression of multiple NRPS and PKS enzymes responsible for synthesizing various antimicrobial compounds. This study underscores the potential to leverage these regulatory insights for maximizing commercial applications of novel antibiotics combating AMR, as well as broader industrial uses.
Active surveillance of cats and dogs from households with human COVID-19 cases reveals over one quarter of pets infected with SARS-CoV-2 in 2020-2021 in Texas, United States
Authors: Pauvolid-Corrêa Alex , Davila Edward , Auckland Lisa D. , Zecca Italo B. , Busselman Rachel E. , Tang Wendy , Roundy Christopher M. , Killian Mary Lea , Torchett Mia K. , Jenkins-Moore Melinda , Austerman Suelee Robbe , Lantz Kris , Mozingo Katherine , Tell Rachel , Lim Ailam , Akpalu Yao , Fischer Rebecca S. B. , Ferreira Francisco C. , Hamer Gabriel L. , Hamer Sarah A. 
Published: February 2025

AbstractHouseholds where people have COVID-19 are high risk environments for companion animals that are susceptible to SARS-CoV-2. We sampled 579 pets from 281 households with one or more laboratory-confirmed person with COVID-19 in central Texas from June 2020 to May 2021. Nineteen out of 396 (4.8%) dogs and 21 out of 157 (13.4%) cats were positive for SARS-CoV-2 by RT-qPCR. Additionally, 95/382 (25%) dogs and 52/146 (36%) cats harbored SARS-CoV-2 neutralizing antibodies. Twenty-six companion animals of ten other species were negative. Overall, 164 (29%) pets were positive for SARS-CoV-2 by molecular and/or serological tests; a total of 110 (39%) out of 281 households had at least one animal with active or past SARS-CoV-2 infection. Cats were more likely to be infected by SARS-CoV-2 and had higher endpoint antibody titers than dogs. Through viral isolation from a subset of respiratory swabs, we documented 6 different lineages in dogs and cats, including the B.1.1 lineage in a cat one month prior to the first known human case in the country. We observed animal and human-pet interaction factors associated with higher risk of infection for dogs and cats, such as days after COVID-19 diagnosis and sharing food. Frequency of clinical signs of disease reported by owners of pets with active infections did not differ from uninfected ones, suggesting that not all reported signs are attributed to SARS-CoV-2 infection. Characterizing animal infections using active SARS-CoV-2 surveillance in pets at risk of infection may aid in One Health pandemic prevention, response, and management.
Genetic basis of partner choice
Authors: Zheng Qinwen , van Alten Sjoerd , Lyngstad Torkild Hovde , Ciscato Edoardo , Sun Zhongxuan , Miao Jiacheng , Wu Yuchang , Dorn Stephen , Zheng Boyan , Havdahl Alexandra , Corfield Elizabeth C. , Nivard Michel , Galama Titus J. , Turley Patrick , Chiappori Pierre-André , Fletcher Jason M. , Lu Qiongshi 
Published: February 2025

AbstractPrevious genetic studies of human assortative mating have primarily focused on searching for its genomic footprint but have revealed limited insights into its biological and social mechanisms. Combining insights from the economics of the marriage market with advanced tools in statistical genetics, we perform the first genome-wide association study (GWAS) on a latent index for partner choice. Using 206,617 individuals from four global cohorts, we uncover phenotypic characteristics and social processes underlying assortative mating. We identify a broadly robust genetic component of the partner choice index between sexes and several countries and identify its genetic correlates. We also provide solutions to reduce assortative mating-driven biases in genetic studies of complex traits by conditioning GWAS summary statistics on the genetic associations with the latent partner choice index.
Genome-wide association study of neuropathic pain phenotypes implicates loci involved in neural cell adhesion, channels, collagen matrix formation and immune regulation
Authors: Packer Richard , Coley Kayesha , Williams Alexander T , Shrine Nick , Izquierdo Abril G , Chen Jing , Batini Chiara , Marttila Mikko , Rao Balasubramanya S , Bratty Raymond , Dudbridge Frank , Hennah William , Tobin Martin D. 
Published: February 2025

AbstractBackgroundNeuropathic pain is a common and debilitating symptom with limited treatment options. Genetic studies, which can provide vital evidence for drug development, have identified only five genome-wide significant signals for neuropathic pain traits. To address this, we performed the largest genome-wide association study (GWAS) to date of all-cause neuropathic pain and neuropathic pain subtypes.MethodsWe defined all-cause neuropathic pain and 33 neuropathic pain subtypes using DeepPheWAS software in the UK Biobank, taking advantage of the longitudinal drug prescription data alongside clinical and self-reported records. We performed a GWAS of all-cause neuropathic pain (33,278 cases, 140,134 controls) as our primary analysis and GWASs of neuropathic pain subtypes as secondary analyses. We used eight variant-to-gene criteria to identify putative causal genes.ResultsWe identified seven independent novel genome-wide associations for neuropathic pain phenotypes which mapped to 22 novel putative causal genes.NCAM1was the only gene identified from the primary analysis of all-cause neuropathic pain and met the most variant-to-gene criteria (four) of any identified gene. Of the 21 other genes,ASCC1, CHST3, C4A/C4BandKCNN2had the most compelling evidence for mechanistic involvement in neuropathic pain.DiscussionWe have performed the largest GWAS to date of all-cause neuropathic pain and more than doubled the number of genome-wide significant associations for neuropathic pain traits, identifying putative causal genes. There is strong evidence for the involvement ofNCAM1in neuropathic pain which merits for further study for drug development.
Rapid water flow navigates long-distance migration of thermophilic bacteria
Authors: Uemura Naoki A. , Chiba Naoya , Morikawa Ryota , Tamakoshi Masatada , Nakane Daisuke 
Published: February 2025

AbstractBacteria thrive in nearly all environments on Earth, demonstrating remarkable adaptability to physical stimuli, as well as chemicals and light. However, the mechanisms by which bacteria locate and settle in ecological niches optimal for their growth remains poorly understood. Here, we show thatThermus thermophilus, a highly thermophilic non-flagellated species of bacteria, exhibits positive rheotaxis, navigating upstream in unidirectional rapid water flow. Mimicking their natural habitat at 70°C with a water current under optical microscopy, cells traveled distances up to 1 mm in 30 min, with infrequent directional changes. This long-distance surface migration is driven by type IV pili, facilitating vertical attachment at the cell pole, and shear-induced tilting of the cell body, resulting in alignment of the leading pole toward the direction of water flow. Direct visualization of T4P filaments and their dynamics revealed that rheotaxis is triggered by weakened attachment at the cell pole, regulated by ATPase activity, which was further validated by a mathematical modeling. Flow experiments on 16 bacterial strains and species in theDeinococcus-Thermusphylum revealed that positive rheotaxis is highly conserved among rod-shapedThermaceae, whereas no rheotactic behavior was observed in spherical-shapedDeinococcus. Our findings suggest that thermophilic bacteria reach their ecological niches by responding to the physical stimulus of rapid water flow, a ubiquitous feature in hot spring environments. This study highlights unforeseen survival strategies, showcasing an evolutionary adaptation to a surface-associated lifestyle where swimming bacteria would otherwise be swept away.