bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exposure to public housing reverses the association between neighborhood disadvantage and eosinophilic inflammation in patients with sickle cell disease
Authors: McCuskee Sarah , Chiu Yueh-Hsiu Mathilda , McCann Mariel , Wright Rosalind J , Glassberg Jeffrey A 
Published: January 2025

AbstractSickle cell disease (SCD) is a single-gene illness characterized by chronic inflammation, decreased quality of life, and early mortality; however, outcomes are highly variable between individuals, suggesting a substantial role of social and environmental factors in disease outcomes. Data suggest that individuals living with SCD have greater eosinophil counts and activation, and higher prevalence of asthma and wheezing than those without SCD, suggesting a role for eosinophilic inflammation in SCD. In other diseases, eosinophilic inflammation has been linked to social and environmental factors, particularly in minoritized populations. To date, however, few human studies have explored the pathophysiology of social and environmental exposures in SCD. This study tested whether eosinophilic inflammation was related to location-based measures of social disadvantage or public housing in 79 individuals with SCD, without diagnoses of asthma, who were prospectively followed over one year. Home addresses were geocoded and matched to principal-components derived, validated measures of local neighborhood social disadvantage and to locations of public housing facilities. Serum peripheral eosinophils, IL-13 and IL-5 were measured every 8 weeks. In fully-adjusted models, statistically significant, linear relationships were observed between the degree of social disadvantage and level of eosinophilic inflammation; however, the direction of that relationship was opposite for patients who live in public housing and those who do not. For those living in public housing, greater social disadvantage was associated with increased eosinophilic inflammation. For those in private housing, greater social disadvantage was associated with progressively less eosinophilic inflammation. These strong, and somewhat unexpected, relationships demonstrate that subtle differences in social exposures and home environment have differential effects on inflammatory profiles which may have larger implications for disease and health, especially in chronic diseases such as SCD. To understand the mechanisms of these effects may require highly granular studies that catalog the many factors underlying the social environment and inflammation.
Streamlining Large-Scale Genomic Data Management: Insights from the UK Biobank Whole-Genome Sequencing Data
Authors: Li Xihao , Wood Andrew R. , Yuan Yuxin , Zhang Manrui , Huang Yushu , Hawkes Gareth , Beaumont Robin N. , Weedon Michael N. , Li Wenyuan , Li Xiaoyu , Lin Xihong , Li Zilin 
Published: January 2025

AbstractBiobank-scale Whole-Genome Sequencing (WGS) studies are increasingly pivotal in unraveling the genetic bases of diverse health outcomes. However, managing and analyzing these datasets’ sheer volume and complexity presents significant challenges. We proposevcf2agds, an all-in-one toolkit that efficiently converts WGS data from Variant Call Format (VCF) format to the annotated Genomic Data Structure (aGDS) format, significantly reducing data size while supporting seamless genomic and functional data integration for comprehensive genetic analyses. The toolkit was applied to the UK Biobank 500k WGS data, resulting in twenty-three aGDS files, one for each chromosome, which collectively compressed 1,473.85 Tebibytes of pVCF data into 1.10 Tebibytes. Utilizing these aGDS files, we conducted a functionally informed rare variant association analysis of total cholesterol employing theSTAARpipelineand detected 480 genome-wide significant coding and noncoding associations. Overall,vcf2agdsoffers a streamlined approach facilitating the efficient management and analysis of biobank-scale WGS data across hundreds of thousands of samples.
dnaSORA - A Unified Diffusion Transformer for DNA point clouds
Authors: Koreniuk Oleksandr , Njie eMalick G. 
Published: January 2025

AbstractThe relatively obscure Hawaiian experiment collapses diverse phenotypes, including nearly all human genetic diseases to a singular Gaussian-like point cloud feature, structuring unstructured information. The uniformity of the feature space provides a straightforward way for AI models to learn all three billion tokens for reading the human genome as a first language. We propose a diffusion transformer, dnaSORA, for learning these features. dnaSORA has generative capacity similar to Stable Diffusion but for DNA point clouds. The model’s architecture is novel because it is unified; thus, it also functions as a discriminator that uses a frozen latent representation for classification. dnaSORA transfer learns from synthetic data emulating real genome point clouds to classify misrepresented tokens inC. elegansHawaiian data at state-of-the-art 0.3 Mb resolution. Pre-training large genome models typically requires expensive and difficult-to-obtain genomes. However, our solution provides nearly unlimited synthetic training data at negligible compute costs. Inference for new token assignments (e.g., new diseases) requires genomes from several dozen rather than thousands of individuals. These efficiencies, combined with state-of-the-art resolution, provide a pathway for rapid, massive scaling of token annotation of the entire human genome at orders of magnitude below expected costs.
Structural basis for activation and potentiation in a human α5β3 GABAAreceptor
Authors: Cowgill John , Fan Chen , Stayaert Jan , Howard Rebecca J. , Lindahl Erik 
Published: January 2025

SUMMARYGeneral anesthetics like etomidate mediate amnesic as well as sedative effects through different populations of gamma amino butyric acid receptors (GABAARs) in the central nervous system. The amnesic effects have largely been attributed to α5-subunit-containing receptors in the hippocampus, indicating a clear role in learning and memory for these receptors. The α5 subunit is thought to primarily coassemble with β3 and, in some cases, γ2 subunits, generating a variety of receptor subtypes with differential functional and pharmacological properties. However, the stoichiometry, structure, and gating mechanisms of these different subpopulations are not well understood. Here we report structures of human α5β3 GABAARs with various modulators, assembled in two stoichiometries. Our cryo-EM structures, combined with electrophysiology inXenopusoocytes, support a primary assembly of 2:3 α:β subunits, though a minority population of 1:4 α:β indicates multiple assemblies are possible. Differential glycosylation of the α5 and β3 subunits enabled reconstruction of the heteromeric complex even in the absence of added fiducials. In the resting state of the receptor, Zn2+binds to histidine residues at the M2-17′ position in the β3 subunit, blocking ion passage. In the activated state, GABA binding to the orthosteric site is associated with global rearrangements propagating to unbinding of the 17′ Zn2+atoms and opening of the 9′ hydrophobic gate. Unlike the α1β3 receptor where GABA is effectively a partial agonist, saturating GABA binding to α5β3 appears to drive activation of nearly all receptors, resulting in a single desensitized state observed under the cryo-EM conditions. In agreement with this high GABA efficacy, the GABA-bound structure is virtually unaffected by further addition of the anesthetic etomidate at the β-α transmembrane domain interface. These structures offer new detailed models for gating and modulation of a GABAAR subtype critical to learning and memory, including prospective templates for structure-based drug discovery.
The 3D genomics of lampbrush chromosomes highlights the role of active transcription in chromatin organization
Authors: Lagunov T. , Gridina M. , Nurislamov A. , Kulikova T. , Maslova A. , Konstantinov V. , Popov A. , Krasikova A. , Fishman V. 
Published: January 2025

AbstractLampbrush chromosomes are giant meiotic bivalents in growing oocyte nuclei that have served as a classic model system for studying chromatin organization and RNA synthesis for over a century. Despite their importance, the molecular mechanisms underlying lampbrush chromosomes formation and their distinctive chromomere-loop architecture have remained poorly understood. Here, we provide the first comprehensive genomic, cytological, and biophysical analysis of lampbrush chromosome organization by integrating single-cell Hi-C, RNA-seq, NOMe-seq, FISH mapping, and chromatin simulations. Single-nucleus Hi-C analysis revealed CTCF-independent contact domains with stable boundaries defined by transcription units in a convergent orientation. Сontact domains identified through Hi-C analysis correspond to insulated chromomeres in lampbrush chromosomes. Small transcriptionally inactive contact domains surrounded by transcription units in the diverged orientation form ‘chromatin knots’, which are often detached from the chromosome axis. Transcription loops frequently manifest as a ‘cross’ pattern with reduced contacts within chromatin domains. Integrative analysis of the whole-genome data uncovers the mechanisms underlying lampbrush chromosome structure, revealing how hypertranscription modulates chromatin stiffness and repositions SMC complexes to establish the distinctive chromomere-loop organisation. Biophysical modeling through polymer simulation reproduces key features of lampbrush chromosomes, including transcription loop formation, chromomere compaction, and insulation patterns. These findings offer a unifying framework for understanding the remarkable chromatin architecture of lampbrush chromosomes and their transcription-dependent organization.Highlights-First integration of single-cell Hi-C, RNA-seq, NOMe-seq and microscopy methods uncovers molecular mechanisms underlying lampbrush chromosome architecture.-Hi-C reveals contact patterns corresponding to lampbrush chromomeres and transcription loops, validated through BAC-based FISH mapping.-Lampbrush chromosomes are segmented into contact domains formed via a CTCF-independent mechanism, with boundaries coinciding with convergently oriented gene pairs.-Hypertranscription shapes lampbrush chromosome through multiple mechanisms, increasing stiffness and decreasing compaction of transcribed units, generating outward pressure, pushing transcription loops away from the chromosome axis, and repositioning SMC complexes to form transcription-dependent domains with stable boundaries.-Polymer simulations including these mechanisms replicate key features of LBC organization, supporting the proposed model of lampbrush chromosomes formation.Graphical Abstract
Hypoxia modulates human pulmonary arterial adventitial fibroblast phenotype through HIF-1α activation
Authors: Philip Jennifer L , Caneba Christine A , Caggiano Laura R , Prakash Nandhini , Cheng Tik-Chee , Barlow Katherine A. , Mustafa Tasneem , Tabima Diana M , Hacker Timothy A , Masters Kristyn S , Chesler Naomi C 
Published: January 2025

AbstractHypoxic pulmonary hypertension (HPH) develops in association with diseases characterized by low oxygen levels leading to pulmonary artery (PA) narrowing and death. Hypoxia has been linked to increased PA collagen and changes in PA adventitial fibroblast (PAAF) metabolism. However, the mechanisms by which hypoxia regulates PAAF function are unknown. Hypoxia-inducible factor-1α (HIF-1α) is a subunit of a transcription factor that is degraded in normoxia but stabilized in hypoxia and is involved in extracellular matrix remodeling by fibroblasts. We examined the role of hypoxia and HIF-1α in regulating PAAF function. Human PAAF (HPAAF) were cultured in normoxic and hypoxic conditions. Cells were further treated with HIF1-α inhibitor or no drug. Protein expression, mRNA expression, enzyme activity, and metabolite concentration were examined. Male C57BL6/J mice were exposed to 0 or 10 days of hypoxia after which right ventricular hemodynamics and tissue metabolism were assessed. Hypoxia led to an increase in collagen content and decrease in matrix metalloproteinase-2 (MMP2) activity. HIF-1α inhibition limited collagen accumulation and restored MMP2 activity. HPAAF demonstrated elevated lactic acid concentration and decreased ATP in hypoxia. HIF-1α inhibition blunted these effects. Mice exposed to hypoxia developed significant elevation in right ventricle systolic pressures and had decreased ATP levels in pulmonary tissue. This study investigated the mechanisms by which hypoxia drives HPAAF-mediated collagen accumulation and metabolic changes. We identify the key role of HIF-1α in regulating changes. These findings provide important insights into understanding HPAAF-mediated PA remodeling and help identify possible novel therapeutic targets.
Light-activated tetanus neurotoxin for conditional proteolysis and inducible synaptic inhibitionin vivo
Authors: Roh Heegwang , Kim Dongwook , Kim Byeongchan , Jeon Younghyeon , Kim Yeonghye , Jacko Martin , Xu Fei , Lin Chang , Um Ji Won , Ting Alice Y. 
Published: January 2025

AbstractThe light chain of tetanus neurotoxin (TeNT) is a 52 kD metalloprotease that potently inhibits synaptic transmission by cleaving the endogenous vesicle fusion protein VAMP2. To mitigate the toxicity of TeNT and harness it as a conditional tool for neuroscience, we engineered Light-Activated TeNT (LATeNT) via insertion of the light-sensitive LOV domain into an allosteric site. LATeNT was optimized by directed evolution and shown to have undetectable activity in the dark mammalian brain. Following 30 seconds of weak blue light exposure, however, LATeNT potently inhibited synaptic transmission in multiple brain regions. The effect could be reversed over 24 hours. We used LATeNT to discover an interneuron population in hippocampus that controls anxiety-like behaviors in mouse, and to control the secretion of endogenous insulin from pancreatic beta cells. Synthetic circuits incorporating LATeNT converted drug, Ca2+, or receptor activation into transgene expression or reporter protein secretion. Due to its large dynamic range, rapid kinetics, and highly specific mechanism of action, LATeNT should be a robust tool for conditional proteolysis and spatiotemporal control of synaptic transmissionin vivo.
Clonal relationships between Tph and Tfh cells in patients with SLE and in murine lupus
Authors: Sasaki Takanori , Sowerby John , Xiao Yinan , Wang Runci , Marks Kathryne E. , Horisberger Alice , Gao Yidan , Lee Pui Y. , Qu Yujie , Sze Marc A. , Alves Stephen E. , Levesque Marc C. , Fujio Keishi , Costenbader Karen H. , Rao Deepak A. 
Published: January 2025

AbstractPathologic T cell-B cell interactions drive disease in systemic lupus erythematosus (SLE). The T cells that activate B cell responses include T peripheral helper (Tph) and T follicular helper (Tfh) cells, yet the developmental and clonal relationships between these B cell-helper T cell populations are unclear. Here we use T cell receptor (TCR) profiling to demonstrate clonal overlap between Tph and Tfh cells in the circulation of patients with SLE. Expanded Tph and Tfh cell clones persist over the course of 1 year in patients with a new diagnosis of SLE, and clones are observed to shift both from Tfh to Tph cells and from Tph to Tfh cells over time. High resolution analysis of cells sorted as Tph cells (CXCR5-PD-1hi) and Tfh cells (CXCR5+PD-1hi) from SLE patients revealed considerable heterogeneity among cells sorted as Tph cells and highlighted a specific cluster of cells that expressed transcriptomic features of activated B cell-helper T cells. This cell population, marked by expression ofTOXandCXCL13,was found in both sorted Tph and Tfh cells, and was clonally linked in these two populations. Analysis of B cell-helper T cells in murine pristane-induced lupus demonstrated similar populations of Tph and Tfh cells in both lung and spleen with strong clonal overlap. T cell-specific loss of Bcl6 prevented accumulation of Tfh cells and reduced accumulation of Tph cells in pristane-treated mice, indicating a role for Bcl6 in the survival and expansion of both populations. Together, these observations demonstrate a shared developmental path among pathologically expanded Tph and Tfh cells in lupus. The persistence of expanded Tph and Tfh cells clones over time may impose barriers to induction of stable tolerance by immunosuppressive medications or by B cell depletion.
Cognitive Performance in Relation to Systemic and Brain Iron at Perimenopause
Authors: Barnett Amy L. , Wenger Michael J. , Miles Pamela , Wu Dee , Isingizwe Zitha Redempta , Benbrook Doris M. , Yuan Han 
Published: January 2025

AbstractBackgroundThe literature on the relationships among blood iron levels, cognitive performance, and brain iron levels specific to women at the menopausal transition is ambiguous at best. The need to better to understand these potential relationships in women for whom monthly blood loss (and thus iron loss) is ceasing is highlighted by the fact that iron accumulates in brain tissue over time and that accumulation is thought to be a factor in the development of neurodegenerative disease.MethodsNon-anemic women who were either low in iron or had normal iron levels for their age and race/ethnicity provided blood samples, underwent MRI scans to estimate brain iron levels, and performed a set of cognitive tasks with concurrent EEG. Results: Cognitive performance as well as brain dynamics were positively related to iron levels, including measures associated with oxygen transport. There were no relationships between any of the blood measures of iron and brain iron.ConclusionsHigher iron status was associated with better cognitive performance in a sample of women who were neither iron deficient nor anemic, without there being any indication that higher levels of systemic iron were related to higher levels of brain. Consequently, addressing low iron levels at the menopausal transition may be a candidate approach for alleviating the “brain fog” commonly experienced at menopause.
Multi-resolution vision transformer model for skin cancer subtype classification using histopathology slides
Authors: Chaurasia Abadh K , Toohey Patrick W , Harris Helen C , Hewitt Alex W 
Published: January 2025

ABSTRACTIntroductionDigital pathology has significantly advanced cancer diagnosis by enabling high-resolution visualisation and assessment of tissue specimens. However, the manual analysis of these images remains labour-intensive and susceptible to human error, resulting in inconsistencies in diagnosis and treatment decisions. Herein, we developed and externally validated a multi-resolution model for classifying subtypes of skin cancer from whole slide images ( WSIs).MethodsWe constructed a dataset comprising approximately 1.13 million histological patches (dividing the WSIs into non-overlapping tiles) from the Non-Melanoma Skin Cancer Segmentation (NMSCS) and Heidelberg datasets. All the patches were normalised using the Macenko method before training a self-supervised vision transformer-based model to classify the most common subtypes of skin cancer: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), intraepidermal carcinoma (IEC), Melanoma, Naevi, and Non-cancerous. Our multi-resolution model was designed to classify melanoma and non-melanoma skin cancer subtypes, incorporating multi-resolution data at 10x, 20x, 40x, and 400x magnifications. The model was externally validated on 5,147 slides from 4,066 patients for non-melanoma cancer subtypes. The model’s performance was evaluated using classification metrics, and the quadratic weighted Cohen’s Kappa (k) score was used to measure the agreement between the model’s predictions and the actual labels with a 95% confidence interval (CI).ResultsOur multi-resolution model demonstrated strong classification performance across six classes, achieving an overallkscore of 0.859 (95% CI: 0.851, 0.866) and 0.898 (95% CI: 0.892, 0.904) on the validation and testing sets, respectively, reflecting robust performance across diverse skin cancer subtypes. The multi-resolution model for non-melanoma skin cancer exhibited superior performance, achieving an overallkscore of 0.919 (95% CI: 0.914, 0.924) on the validation set. On the testing set, thekscore ranged from 0.996 to 0.889 with magnifications of 10x, 20x, 40x, and 400x. The attention maps highlighted clinically relevant features for cancerous tissue at different magnifications. Additionally, the model obtained akscore of 0.791 (95% CI: 0.774, 0.808) on the external data at the slide level, indicating substantial agreement between the model’s prediction and the actual label of WSIs.ConclusionOur multi-resolution model has the potential to assist anatomical pathologists in automatically detecting, highlighting, and classifying subtypes of melanoma and non-melanoma skin cancer subtypes directly from WSIs. This capability could ultimately improve patient outcomes and more effective clinical decision-making in digital pathology. For non-melanoma cancer, our model could be deployed in regions with limited access to experienced dermatopathologists and a high incidence of the disease, particularly in low-resource settings.
Asymmetric limits on timely interventions from noisy epidemic data
Authors: Parag Kris V. , Lambert Ben , Donnelly Christl A. , Beregi Sandor 
Published: January 2025

AbstractDeciding on when to initiate or relax an intervention in response to an emerging infectious disease is both difficult and important. Uncertainties from noise in epidemiological surveillance data must be hedged against the potentially unknown and variable costs of false alarms and delayed actions. Here we clarify and quantify how case under-reporting and latencies in case ascertainment, which are predominant surveillance noise sources, can restrict the timeliness of decision-making. Decisions are modelled as binary choices between responding or not that are informed by reported case curves or transmissibility estimates from those curves. Optimal responses are triggered by thresholds on case numbers or estimate confidence levels, with thresholds set by the costs of the various choices. We show that, for growing epidemics, both noise sources induce additive delays on hitting any case-based thresholds and multiplicative reductions in our confidence in estimated reproduction numbers or growth rates. However, for declining epidemics, these noise sources have counteracting effects on case data and limited cumulative impact on transmissibility estimates. We find this asymmetry persists even if more sophisticated feedback control algorithms that consider the longer-term effects of interventions are employed. Standard surveillance data therefore provide substantially weaker support for deciding when to initiate a control action or intervention than for determining when to relax it. This information bottleneck during epidemic growth may justify proactive intervention choices.