bluuebunny/crossref_metadata_2025_split huggingface dataset:
CocycleHunter: cohomology-based circular gene set enrichment and genetic phase estimation in single-cell RNA-seq data
Authors: Maggs Kelly , Youssef Markus , Pulver Cyril , Isma Jovan , Nguyên Tâm J. , Karthaus Wouter , Hess Kathryn , Dotto G. Paolo 
Published: January 2025

AbstractIn this paper we introduce cocycle hunter (cHunter), a tool for identifying and exploiting diverse circular structure in single-cell RNAseq data. Our method is based on persistent cohomology in dimension one, which we use to define a system of statistically enriching gene sets for circular structure. We also develop a powerful, cohomology-based technique for estimating the phase of genes exhibiting cyclic expression patterns. We validate our method on synthetic RNA transcription models, as well as real datasets studying the cell cycle, tissue re-generation and senescence in diverse experimental conditions. Our work points towards cocycles as pervasive mathematical structures of the transcriptional program.
Integrated Techniques for Extracellular Particle Separation and Single-Particle Multiparametric Characterization to Track Cancer Biomarkers from Tissue to Biofluids
Authors: Nguyen Kim Truc , Xia Jiangping , Chang Chaoran , Hade Mangesh Dattu , Rima Xilal Y. , An Ji Yeong , Min Byung Hoon , Nagaraj Chiranth K. , Wang Lin , Huang Tony Jun , Li Feng , Kim Yong , Wong David T.W. , Reategui Eduardo 
Published: January 2025

AbstractGastric cancer (GC) remains a formidable global health challenge, with late-stage diagnosis and high recurrence rates resulting in poor patient outcomes. This study explores the potential of advanced technologies, namely Bessel Beam Excitation Separation Technology (BEST) and multiparametric biochip assay (MBA), to track single extracellular vesicle and particle (EVP) cargo from organs of pathology into biofluids such as plasma and saliva. Using GC as a study model, we conducted high throughput, multiparametric analyses of EVPs derived from plasma, saliva, and tissue samples. Our findings demonstrate the feasibility of these techniques in isolating and characterizing EVPs, revealing consistent EVP morphology and size across biofluids. Furthermore, differential expression patterns of the developed and validated salivary GC biomarkers, miR-140-5p and miR-301a-3p, were observed in GC patient biofluids, supporting the diagnostic relevance of EVP cargo. Notably, saliva emerged as the most promising biofluid for GC diagnosis, achieving superior Receiver Operating Characteristic (ROC) curve values compared to plasma and tissue. This study highlights the role of BEST and MBA in advancing single-EVP analysis and elucidating EVP trafficking, paving the way for future diagnostic applications of EVP cargo.
easyEWAS: a flexible and user-friendly R package for Epigenome-Wide Association Study
Authors: Wang Yuting , Jiang Meijie , Niu Siyuan , Gao Xu 
Published: January 2025

AbstractMotivationRapid advancements in high-throughput sequencing technologies especially the Illumina DNA methylation Beadchip greatly fueled the surge in epigenome-wide association study (EWAS), providing crucial insights into intrinsic DNA methylation modifications associated with environmental exposure, diseases, and health traits. However, current tools are complex and less user-friendly to accommodate appropriate EWAS designs and make downstream analyses and result interpretations complicated, especially for clinicians and public health professionals with limited bioinformatic skills.ResultsWe integrated the current state-of-the-art EWAS analysis methods and tools to develop a flexible and user-friendly R packageeasyEWASfor conducting DNA methylation-based research using Illumina DNA methylation Beadchips. WitheasyEWAS, we provide a battery of statistical methods to support differential methylation position analysis across various scenarios, as well as differential methylation region analysis based on the DMRcate method. To facilitate result interpretation, we provide comprehensive functional annotation and result visualization functionalities. Additionally, a bootstrap-based internal validation was incorporated intoeasyEWASto ensure the robustness of EWAS results. Evaluation in asthma patients as the example demonstrated thateasyEWAScould simplify and streamline the conduction of EWAS and corresponding downstream analyses, thus effectively advancing DNA methylation research in public health and clinical settings.Availability and implementationeasyEWASis implemented as an R package and is available athttps://github.com/ytwangZero/easyEWAS.Contactxu.gao@pku.edu.cn,ytwang@pku.edu.cn
Database Permeating through Time, Space, and Medicine: A sequence, structure, and clinical compilation and comparison of transmembrane amino acids in VGL ion channels
Authors: Yeh Frank , Patel Arya , Mun Matthew , Oh Youjin , Aldrich Richard W. 
Published: January 2025

AbstractIon channels of the VGL superfamily are extremely diverse in their physiological roles – critical in all excitable cells. Mutations in these channels can cause clinical deficits and symptomologies. With recent advances in sequencing and structural data in the past 30 years, there is a plethora of bioinformatic information that experimentalists can utilize to draw hypotheses about structure and function. However, there is no cohesive database that has compiled this data and presents it in an easily accessible and avoids the confounds of close evolutionary lineages. Here, we seek to fill this gap in resources by compiling and comparing groups of sequences and structures across many channels of the VGL superfamily. Additionally, we corroborate the well-conserved amino acid positions with previous experimental work as well as put forth some understudied but well-conserved amino acid positions that might be fundamental to the certain generalizable mechanisms present in the VGL superfamily channels. To further lend evidence to understudied positions being critical to certain generalizable mechanisms, we also compiled clinical mutation data at these positions across many channels to show the likely functional relevance of these positions. Finally, we will make all of the alignments and resources we generated publicly available athttps://github.com/Frank-Yeh-95/VGLDatabaseCompilationfor ease of hypothesis generation.
Dynamic Face-related Eye Movement Representations in the Human Ventral Pathway
Authors: Su Zhongbin , Zhou Xiaolin , Pollmann Stefan , Wang Lihui 
Published: January 2025

AbstractMultiple brain areas along the ventral pathway have been known to represent face images. Here, in a magnetoencephalography (MEG) experiment, we show dynamic representations of face-related eye movements in the ventral pathway in the absence of image perception. Participants followed a dot presented on a uniform background, the movement of which represented gaze tracks acquired previously during their free-viewing of face and house pictures. We found a dominant role of the ventral stream in representing face-related gaze tracks, starting from the orbitofrontal cortex (OFC) and anterior temporal lobe (ATL), and extending to the medial temporal and ventral occipitotemporal cortex. Our findings show that the ventral pathway represents the gaze tracks used to explore faces, by which top-down prediction of face category in OFC and ATL may guide, via the medial temporal cortex or directly, face perception in the ventral occipitotemporal cortex.
The Mutated p.H222P A-type Lamins Drive Loxl2-Mediated Extracellular Matrix Remodeling in Both Patient-Derived Cardiomyocytes and Mouse Models of Dilated Cardiomyopathy
Authors: Kervella Marie , Peccate Cecile , Guesmia Zoheir , Grandi Fiorella , Mougenot Nathalie , Forand Anne , Charrabi Azzouz , Brochier Guy , Andriantsitohaina Ramaroson , Meli Albano C. , Muchir Antoine 
Published: January 2025

ABSTRACTLMNAcardiomyopathy, caused by mutations in theLMNAgene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derivedLMNAp.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and aLmnaH222P/H222Pmouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed thatLMNAp.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark ofLMNAcardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in bothLMNAp.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac functionin vivo. Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function inLMNAcardiomyopathy.
Ancestral and recent bursts of transposition shaped the massive genomes of plant pathogenic rust fungi
Authors: Corre Emma , Morin Emmanuelle , Duplessis Sebastien , Lorrain Cecile 
Published: January 2025

AbstractBackgroundTransposable elements (TEs) play a crucial role in genome evolution, influencing gene regulation, diversity, and genome architecture. Rust fungi of the order Pucciniales (Subphylum Pucciniomycotina) are the largest group of obligate biotrophic plant pathogens and harbor some of the largest and most TE-rich genomes - up to 1.2Gb - compared to other fungi. This global genomic expansion contrasts with the smaller genomes and minimal mobilome found in other Pucciniomycotina species. Despite the availability of high-quality genome assemblies, our understanding of TE dynamics in Pucciniales remains limited due to inconsistent and incomplete TE annotations.ResultsWe analyzed the mobilomes of 13 Pucciniomycotina species, producing a manually curated TE library for each genome. In Pucciniales, TEs occupy 47–92% of the genome, whereas 2- 36% of TEs are detected in other Pucciniomycotina genomes. The comparison of gene and TE repertoires indicates that TEs, particularly LTR-retrotransposons and TIR-DNA transposons, are the primary contributors to the genome expansion of the Pucciniales. We reconstructed the proliferation histories of TEs in the Pucciniales, combining sequence similarity, clustering, and molecular clock approaches. We highlight recent and ancient TE invasions with some LTR-Gypsy elements predating the divergence of Pucciniomycotina (∼176 Mya), while most TE accumulation in Pucciniales occurred within the last 50 Mya. However, the TE invasions in the Pucciniales genomes do not seem to result from specific deficiencies in known TE-control mechanisms.ConclusionOur findings uncover extensive TE proliferation in Pucciniales, predominantly driven by recent LTR-Gypsy expansions. The retention of ancestral TEs and the consistently TE-rich genomes observed in Pucciniales highlight TE proliferation as an ancestral genomic feature in rust fungi.
Myofibroblasts reduce angiogenesis and vasculogenesis in a vascularized microphysiological model of lung fibrosis
Authors: Cambria Elena , Blazeski Adriana , Ko Eunkyung Clare , Thai Tran , Dantes Shania , Barbie David A. , Shelton Sarah E. , Kamm Roger D. 
Published: January 2025

AbstractLung fibrosis, characterized by chronic and progressive scarring, has no cure. Hallmarks are the accumulation of myofibroblasts and extracellular matrix, as well as vascular remodeling. The crosstalk between myofibroblasts and vasculature is poorly understood, with conflicting reports on whether angiogenesis and vessel density are increased or decreased in lung fibrosis. We developed a microphysiological system that recapitulates the pathophysiology of lung fibrosis and disentangles myofibroblast-vascular interactions. Lung myofibroblasts maintained their phenotype in 3D without exogenous TGF-β and displayed anti-angiogenic and anti-vasculogenic activities when cultured with endothelial cells in a microfluidic device. These effects, including decreased endothelial sprouting, altered vascular morphology, and increased vascular permeability, were mediated by increased TGF-β1 and reduced VEGF secretion. Pharmacological interventions targeting these cytokines restored vascular morphology and permeability, demonstrating the potential of this model to screen anti-fibrotic drugs. This system provides insights into myofibroblast-vascular crosstalk in lung fibrosis and offers a platform for therapeutic development.
A low-complexity linker as a driver of intra- and intermolecular interactions in DNAJB chaperones
Authors: Hobbs Billy , Limmer Noor , Ossa Felipe , Knüpling Ella , Lenton Samuel , Foderà Vito , Kalverda Arnout P. , Karamanos Theodoros K. 
Published: January 2025

AbstractJ-domain proteins (JDPs) act as major regulators of the proteostasis network by driving the specificity of the Hsp70 machine. Their important functions are mediated by a low-complexity glycine-/phenylalanine-rich region (GF-linker) that links the folded J-domain with the substrate binding domain. Recently, we and others have shown that in an autoinhibited JDP state, an α-helix formed within GF blocks the Hsp70 binding site on the J-domain. However, the role of the disordered GF-linker in autoinhibition and how the latter is released, are still not understood. Here, using autoinhibited DNAJB1 and DNAJB6 constructs, we show that in combination with the J-domain, the GF-linker creates a hydrophobic, partially collapsed cluster that shows a remarkable degree of allosteric communication, disruption of which can lead to destabilisation of autoinhibition. Apart from this crucial intramolecular role, we reveal that the GF-linker can also be recognised by the substrate-binding domain of Hsc70 and dictate the lifetime of the entire JDP–Hsc70 complex. Importantly, both the intra- and intermolecular GF-linker functions are DNAJB-class member-specific.
Highly potent novel multi-armoured IL13Rα2 CAR-T subverts the immunosuppressive microenvironment of Glioblastoma
Authors: Mangolini Maurizio , Srivastava Saket , Souster Emily , Yang Yajing , Wang Huimin , Karattil Rajesh , Schultz Liam , Ma Biao , Pombal Diana , Greenig Matthew , Ramon Aubin , Sormanni Pietro , Cordoba Shaun , Onuoha Shimobi 
Published: January 2025

ABSTRACTGlioblastoma (GBM) remains one of the most challenging and lethal brain cancers, with limited treatment options. While CAR-T cells have shown promise in some patients, sustaining T-cell activity and overcoming the immunosuppressive tumour microenvironment (TME) remain significant hurdles. Here, we present an armoured CAR-T cell design to address these challenges and enhance persistence in GBM tumours. We developed a highly specific humanised single-domain antibody (VHH) targeting IL13Rα2 and included it alongside four additional modular elements in a single retroviral vector for CAR-T generation. Our results demonstrate that this single-cassette CAR-T cell design possesses high resilience against TGF-β-mediated immunosuppression, enhanced tumour-killing capacity through IL-12 secretion while maintaining a favourable safety profile, extended persistence in the host, and an additional layer of safety control through the incorporation of a suicide switch. Importantly, despite its complexity, the construct can still be manufactured efficiently. These advancements represent a significant step forward in addressing key challenges associated with CAR-T cell therapy in solid tumours.
Localized delivery of corticosteroids via insitumodification of gut commensals using a synthetic stem peptide prodrug
Authors: Baryakova Tsvetelina H. , Yu Marina H. , Segatori Laura , McHugh Kevin J. 
Published: January 2025

SUMMARYOral colonic drug delivery systems (CDDSs) are oftentimes associated with a short duration of action and poor tissue specificity. To address these challenges, we engineered an oral prodrug that leverages the engraftment and semi-permanence of gut commensals to create a long-acting colonic drug depot. We show that two synthetic stem peptide probes can be stereoselectively incorporated onto the surface of gut bacteria in C57BL/6 mice following oral administration. We then show that a prodrug consisting of budesonide, a corticosteroid with otherwise limiting side effects used to treat ulcerative colitis (UC), conjugated to one of these probes via a hydrolyzable ester is significantly less bioactive and is cleaved over a period of days to weeks in simulated physiological fluids. This prodrug can be integrated into the bacterial peptidoglycanin vitroand be cleaved into free budesonide over time, thereby improving drug localization and potentially rendering it safer for longer-term use.GRAPHICAL ABSTRACTSIGNIFICANCECorticosteroids are highly effective anti-inflammatory drugs used in the treatment of a variety of conditions. Unfortunately, long-term corticosteroid ingestion can lead to a host of dangerous and undesirable side effects including osteoporosis, glaucoma, and a higher risk of infection, among others. Topical corticosteroids delivered via inhalation (chiefly, budesonide and fluticasone) are the primary long-term treatment modality for chronic asthma symptoms. In contrast to oral corticosteroids, they are considered safer for long-term use when given in moderation because they are directly applied to the airways and exhibit low systemic bioavailability. We sought to apply this successful paradigm to another autoimmune-related disease, ulcerative colitis (UC). We developed a drug delivery system that combines the weakly targeting method of ingestion with a highly specific parameter, microbe prevalence along the gastrointestinal tract, to help improve the specificity and colonic retention of the corticosteroid budesonide, which is currently limited to being used as a short-term treatment for moderate-to-severe UC. Our approach utilizes a largely inert prodrug that can be incorporated into the peptidoglycan of commensal bacteria found at high densities in the colon. After tethering to the bacterial surface via a synthetic stem peptide, the prodrug passively hydrolyzes (cleaves) to release the active, unadulterated form of the drug into the local area, whereas prodrug that traffics elsewhere has a higher chance of being cleared from the body before cleavage. In this manner, we can achieve targeted immunosuppression and sustained release, rendering corticosteroids, and potentially other small molecules, safer for longer term use in treating patients with UC.
Exploring the Role of Kv1.3 and MAPK14 in Mediating Microglial Oxidative Stress and Neuroinflammation Following Organic Dust Exposure
Authors: Massey Nyzil , Bhat Sanjana Mahadev , Shrestha Denusha , Malovic Emir , Karriker Locke A. , Choudhary Shivani , Robertson Alan P. , Nguyen Hai Minh , Wulff Heike , Kanthasamy Anumantha G. , Charavaryamath Chandrashekhar 
Published: January 2025

AbstractBackgroundAgricultural contaminants, including inhaled organic dust (OD) and gases, are known to cause inflammation in the lungs and the brain. We investigated the role of the potassium channel Kv1.3 in organic dust (OD)-induced neuroinflammation models. Kv1.3 channels play a multifaceted role in microglial immune modulation, cancer, neurodegenerative diseases, and constitute a potential therapeutic target.MethodsWe usedin vivo(C57BL/6 mice),in vitro(microglial cell line, primary microglia), andex vivo(brain slice culture) models of OD-induced neuroinflammation. A sterile OD extract (ODE) was prepared, and mice were exposed to either normal saline or ODE intra-nasally for 5 weeks (5 days/week) to simulate an occupational exposure scenario. Primary microglia were isolated from neonatal mice for total RNA sequencing (RNA-seq). The ODE-induced expression of Kv1.3 was quantified usingin vitroandex vivomodels with and without PAP-1 treatments. Exposure-induced changes in cytokines and reactive species markers were measured. Using western blot, we quantified phosphorylated p38 MAPK14 (p-p38 MAPK) and NOX2. We measured the currents through Kv1.3 channels using a microglial patch-clamp assay.ResultsExposure to ODE increased the expression of Kv1.3 and p-p38 MAPK in mouse microglia without affecting the Kv1.3 currents at the cell surface. Exposure increased the levels of inflammatory cytokines and NOX2. Kv1.3 inhibition with PAP-1 decreased inflammatory markers (TNF-α and IL-6), levels of Kv1.3, p-p38 MAPK, NOX2, and nitrites.ConclusionOur study revealed that pharmacological inhibition of Kv1.3 potassium channels reduces ODE-induced neuroinflammation by decreasing inflammatory and oxidative stress markers.
Broad PFAS binding with fatty acid binding protein 4 is enabled by variable binding modes
Authors: Birchfield Aaron S. , Musayev Faik N. , Castillo Abdul J. , Zorn George , Fuglestad Brian 
Published: January 2025

AbstractPer- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants that bioaccumulate in wildlife and humans, yet the molecular basis of their protein interactions remains poorly understood. Here, we show that human adipocyte fatty acid-binding protein (FABP4) can bind a diverse array of PFAS, including next-generation replacements for legacy chemicals and longer-chain perfluorocarboxylic acids. Shorter-chain PFAS, although weaker binders, still displayed measurable affinities—surpassing those of their nonfluorinated analogs. We determined crystal structures of FABP4 bound to perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), and perfluorohexadecanoic acid (PFHxDA), revealing three distinct binding modes. Notably, PFOA binds in two separate sites, and two distinct conformations define single-ligand binding of PFDA and PFHxDA. These arrangements enhance hydrophobic interactions within the binding cavity and likely explain the low micromolar dissociation constants observed in fluorescence competition assays. Our findings underscore the critical roles of chain length, headgroup functionality, and protein conformation in PFAS–FABP4 interactions. Given the emerging implications of the role of FABP4 in endocrine function, even subtle PFAS-induced perturbations could affect metabolic regulation and disease risk. Overall, this work highlights the value of direct structural and biochemical insights into PFAS–FABP4 interactions and paves the way for future research on PFAS transport and toxicological outcomes.