bluuebunny/crossref_metadata_2025_split huggingface dataset:
DARG: a Database of Alzheimer Related Genes in Model Organisms
Authors: Song Julia Y. , Zhou Eric , Hu Yanhui 
Published: February 2025

AbstractAlzheimer disease is affecting a significant portion of the aging population worldwide. Despite extensive research over the years, a comprehensive understanding of its underlying mechanisms and effective treatments remains elusive. Meanwhile, animal models, such as mouse, zebrafish, Drosophila, and C. elegans, have proven invaluable in studying human diseases. In response, we have developed DARG, a Database of Alzheimer disease-related genes in model organisms, designed to bridge the gap between human geneticists investigating the molecular mechanisms of the disease and the model organisms that can be used to explore the functions of disease-associated genes. DARG allows users to search and browse Alzheimer-related human genes from various resources and datasets, identify orthologs in model organisms, and access data on their gene expression and related phenotypes inDrosophila.
Benchmarking Long-read Sequencing Tools for Chromosome End-specific Telomere Analysis
Authors: Reed Jake , Oelkuct Mark , Coombes Kevin 
Published: February 2025

AbstractMeasuring chromosome end-specific telomeres is of great importance and could help elucidate better treatment algorithms and aid in a better understanding of cancer, aging, cardiovascular disease, and neurodegenerative diseases. In this study, we present a comparison of two cutting edge long-read sequencing telomere length analysis tools, TECAT and Telogator. We perform a comprehensive bench-marking of these two tools using Telseq as the standard. Our analysis included evaluating these tools on sensitivity, accuracy, and computational efficiency using a diverse data set of 9 samples from the 1000 Genomes Project which have matched long-read and short-read sequencing data. We found that while Teloga-tor demonstrated superior sensitivity, identifying on average 31% more telomeric reads across all samples, TECAT showed better accuracy with measurements more closely aligned with established literature values and Telseq benchmarks (R² = 0.74 vs 0.37), and TECAT displayed better computational efficiency, com-pleting tasks approximately 41% faster. Both tools successfully mapped telomere lengths to individual chromosome arms, demonstrating unprecedented resolution for telomere length analysis. Our results provide crucial insights for researchers selecting tools for telomere length analysis and highlight the current capabilities and limitations of computational approaches in telomere biology.
Neuromark dFNC Patterns: A fully automated pipeline to estimate subject-specific states from rs-fMRI data via constrained ICA of dFNC in +100k Subjects
Authors: Esfahani M. Moein , Esaulov Vladislav , Venkateswara Hemanth , Calhoun Vince 
Published: February 2025

ABSTRACTResting-state functional MRI (rs-fMRI) provides valuable insights into brain function during rest, but faces challenges in clinical applications due to individual differences in functional connectivity. While Independent Component Analysis (ICA) is commonly used, it struggles to balance individual variations with inter-subject information. To address this, constrained ICA (cICA) approaches have been developed using templates from multiple datasets to improve accuracy and comparability. In this study, we collected rs-fMRI data from 100,517 individuals across diverse datasets. Data were preprocessed through a standard fMRI pipeline. Our method first used replicable fMRI component templates as priors in constrained ICA (the NeuroMark pipeline), then estimated dynamic functional network connectivity (dFNC). Through clustering analysis, we generated replicable dFNC states, which were then used as priors in constrained ICA to automatically estimate subject-specific states from new subjects.This approach provides a robust framework for analyzing individual rs-fMRI data while maintaining consistency across large datasets, potentially advancing clinical applications of rs-fMRI.
Chronic Antigen Stimulation in Solid Tumors Induces T Cell Exhaustion and Limits Efficacy of T Cell Bispecific Therapies
Authors: Hutter-Karakoc Idil , Varypataki Eleni Maria , Neelakandhan Aparna , Lang Simone , Kramar Vesna , Varol Ahmet , Simons Sasha , Richard Marine , Pincha Mudita , Venetz Dario , Joller Nicole , Münz Christian , Umana Pablo , Klein Christian , Amann Maria 
Published: February 2025

AbstractT cell bispecific antibodies (TCBs) have demonstrated promising results in patients with solid tumors. However, the underlying immunological and molecular mechanisms influencing these clinical outcomes require in depth evaluation. T cell exhaustion, a state induced by prolonged antigen exposure, is known to undermine T cell-based immunotherapies, though its specific impact on TCB efficacy remains unclear. In this study, we assessed the effectiveness of TCBs on tumor-specific T cells, focusing on their functional status. Utilizing a fully immunocompetent mouse model with a solid tumor expressing an immunogenic antigen, we showed that tumor-specific T cells acquire an exhausted phenotype and fail to expand under TCB treatment. By employing both mouse and human tumor-specific T cellsin vitro, our study established that chronically stimulated tumor-specific T cells show impaired response to TCB treatment. The comparison of TCB efficacy in T cell-inflamed tumors with immunogenic antigens versus non-inflamed tumors with low antigen presence in mice revealed TCB success in solid tumors is more reliant on T cell functional fitness than on their abundance before treatment. The data also indicate that solid tumors with elevated levels of both, intratumoral regulatory T cells, and T cells expressing co-inhibitory receptors, show diminished responses to TCB therapy, aligning with similar observations described in hematological cancers. These findings highlight the critical role of T cell exhaustion due to chronic antigen exposure and illustrate that exhausted tumor-specific T cells are likely not the driver population redirected by TCBs for tumor elimination. Our research highlights the importance of maintaining T cell fitness and preventing T cell exhaustion to improve TCB therapy outcomes. This may help better identify patient populations with solid tumors that could benefit from TCB treatments most in clinical settings.
Dietary Menaquinone-9 Supplementation Does Not Influence Bone Tissue Quality or Bone Mineral Density in Mice
Authors: Liu Minying , Liu Chongshan , Cevallos Nicolas , Orbach Benjamin N , Hernandez Christopher J , Fu Xueyan , Lee Jennifer , Booth Sarah L , Shea M Kyla 
Published: February 2025

ABSTRACTVitamin K has been implicated in skeletal health because vitamin K-dependent proteins are present in bone. While there are multiple forms of vitamin K, most research has focused on phylloquinone, which is found mainly in plant-based foods, and its metabolite menaquinone-4 (MK4). However, there are additional forms of vitamin K that are bacterially produced that appear to influence bone health but have not yet been studied extensively. Herein, we evaluated the effects of menaquinone-9 (MK9), a bacterially produced form of vitamin K on bone tissue quality and density in young mice. Four-week-old male (n=32) and female (n=32) C57BL/6 mice were supplemented with 0.06 mg/kg diet or 2.1 mg/kg diet of MK9 for 12 weeks. During week 11, a sub-group of mice (n=7/sex/group) received daily deuterium-labeled MK9 to trace its metabolic fate in bone. Liver MK4 and MK9 were significantly higher in mice fed 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, regardless of sex (all p ≤ 0.017). MK4 was the only vitamin K form detected in bone, with 63-67% of skeletal MK4 in mice fed 2.1 mg MK9/kg derived from deuterium-labeled MK9. Femoral tissue strength, maximum bending moment, section modulus, and bone mineral density did not differ significantly across diet groups in either sex (all p≥0.083). Cross-sectional area (p=0.003) and moment of inertia (p=0.001) were lower in female mice receiving 2.1 mg MK9/kg compared to those receiving 0.06 mg MK9/kg, but no differences were found in male mice. Higher bone MK4 concentrations did not correlate with higher bone tissue quality or density. Despite dietary MK9 being a dietary precursor to MK4 in bone, dietary MK9 supplementation did not affect bone tissue quality or bone mineral density.Lay summaryMost research about vitamin K and bone health has focused on phylloquinone, the plant-based vitamin K form, and its metabolite menaquinone-4. Because interest in bacterially produced forms of vitamin K, which are abundant in the intestinal microbiome, is growing, we evaluated the effect of menaquinone-9 (a bacterially-produced form of vitamin K) on skeletal health. We supplemented mice with low and high doses of menaquinone-9 and also used stable-isotope labeled menaquinone-9 to trace its conversion to menaquinone-4 in bone. We found menaquinone-9 served as a precursor to menaquinone-4 in bone, but menaquinone-9 supplementation did not improve bone health.
Regulation of Ordinal DNA Translocation Cycle in Bacteriophage Φ29 through Trans-Subunit Interactions
Authors: Dargis Rokas , Pajak Joshua , Ariyawansa Pavan , Morais Marc C. , Jardine Paul J. , Arya Gaurav 
Published: February 2025

AbstractCertain viruses such as tailed bacteriophages and herpes simplex virus package double-stranded DNA into empty procapsids via powerful, ring-shaped molecular motors. High resolution structures and force measurements on the DNA packaging motor of bacteriophage Φ29 revealed that its five ATPase subunits coordinate ATP hydrolysis with each other to maintain the proper cyclic sequence of DNA translocation steps about the ring. Here, we explore how the Φ29 motor regulates translocation by timing key events, namely ATP binding/hydrolysis and DNA gripping, through trans-subunit interactions. We used subunit dimers bound to DNA as our model system, a minimal system that still captures the conformation and trans-subunit interactions of the full pentametric motor complex. Molecular dynamics simulations of all-ATP and mixed ATP-ADP dimers revealed that the nucleotide occupancy of one subunit strongly affects the ability to hydrolyze ATP in the adjacent subunit by altering the free energy landscape of its catalytic glutamate approaching the gamma phosphate of ATP. Specifically, one ATP-bound subunit donates residues in trans that sterically block the neighboring subunit’s catalytic glutamate. This steric hindrance is resolved when the first subunit hydrolyzes ATP and is ADP-bound. This obstructive mechanism is supported by functional mutagenesis and appears to be conserved across several Φ29 relatives. Mutual information analysis of our simulations revealed intersubunit signaling pathways, via the trans-acting obstructive residues, that allow for sensing and communication between the binding pockets of adjacent subunits. This work shows that the sequential order of DNA translocation events amongst subunits is preserved through novel trans-subunit interactions and pathways.
A Clinical Trial to Determine the Impact of Tumor Size, Histological Subtype, and Vitamin D Status on the Therapeutic Response of Basal Cell Carcinoma to Photodynamic Therapy
Authors: Maytin Edward V. , Zeitouni Nathalie C. , Updyke Abigail , Negrey Jeffrey , Shen Alan S. , Heusinkveld Lauren E. , Mack Judith A. , Hu Bo , Anand Sanjay , Maytin Terence A. , Giostra Laura , Warren Christine B. , Hasan Tayyaba 
Published: February 2025

ABSTRACTPhotodynamic therapy (PDT) with topical aminolevulinic acid (ALA) can be effective for select basal cell carcinoma (BCC) lesions. However, the histological depth and subtype of tumors that respond to PDT remain uncertain. Here, we report a clinical trial of high-dose oral Vitamin D (VD), used as a PDT neoadjuvant for BCC. In this multi-institutional, intra-patient, randomized trial, 35 patients (9 with Gorlin Syndrome) received three PDT sessions (20% ALA; 417 nm blue light) preceded by oral VD, placebo, or no pretreatment. Tumors (122 BC) were monitored using 3D photography and computer-assisted volumetric analysis. Values for absolute volume (3DAbsVol) and average height (3DAvHt) were calculated and used to quantify tumor response kinetics. From histological sections, 3DAvHt was found to correlate with actual tumor depth, although 3DAvHt is only ∼10-20% of the latter. Importantly, 3DAvHt measurements revealed a distinct depth threshold that predicts PDT responsiveness. Of 122 tumors analyzed, 70% cleared after PDT; remaining tumors were micronodular or other aggressive histologic subtypes. To evaluate VD’s effects upon treatment response kinetics after PDT, only 40% of original lesions were available for analysis. By stratifying remaining tumors by 3DAvHt, we found 65% of thin tumors to be VD-responsive, whereas only 28% of thick tumors responded to VD. Overall, PDT was effective for the majority of BCC lesions in our study. Tumors most likely to respond can be predicted histologically and by noninvasive 3D morphometry. For PDT-appropriate BCC lesions, neoadjuvant oral Vitamin D represents a safe and beneficial way to accelerate tumor resolution.CLINICAL TRANSLATION STATEMENTFor photodynamic therapy (PDT) of basal cell carcinoma (BCC), a clinical challenge is deciding which tumors to treat since the penetration depth of visible light into the skin is limited. In this clinical trial, noninvasive 3D photography and computer analysis were used to determine the height and volume of BCC tumors and to correlate these calculated parameters with tumor clearance after PDT, with or without the use of oral vitamin D3 (VD) as a neoadjuvant. Two very practical findings emerged. First, tumor height (3DAvHt) was found to correlate with BCC tumor depth and to predict therapeutic response; tumors below a height threshold of 0.13 mm (∼1.5 - 2 mm histological depth) were highly likely to respond. Second, adding VD as a neoadjuvant prior to PDT of appropriate BCC tumors (superficial and thin nodular subtypes) is a safe and effective way to boost PDT efficacy.
Segmentation-Free Pretherapeutic Assessment of BRAF-Status in Pediatric Low-Grade Gliomas
Authors: Kudus Kareem , Wagner Matthias , Sheng Min , Bennett Julie , Liu Anthony , Tabori Uri , Hawkins Cynthia , Ertl-Wagner Birgit Betina , Khalvati Farzad 
Published: February 2025

AbstractBackgroundBRAF status is crucial for treating pediatric low-grade gliomas (pLGG) and can be assessed non-invasively from segmented tumor regions on MRI using machine learning (ML). However, there are inherent limitations to manual and automated tumor segmentations.PurposeTo assess the performance of automated segmentation algorithms and to develop and assess a segmentation-free ML classification pipeline that identifies BRAF status from whole-brain FLAIR MRI sequences.Materials and MethodsIn this REB-approved retrospective study, molecularly-characterized tumors and whole-brain FLAIR MR images were collected from 455 patients with pLGG treated between 1999 and 2023 at a single tertiary care children’s hospital. We trained and evaluated three medical segmentation models, TransBTS, MedNeXt, and MedicalNet. Next, we developed a model to identify BRAF status from whole-brain FLAIR MRI, without any reliance on manual or automated segmentations. We then implemented a novel pretraining regimen that embedded segmentation knowledge into the whole-brain FLAIR MRI classification model. Finally, we trained and evaluated a baseline model that used manual segmentations as inputs. All ML models were trained and evaluated under a nested-cross validation scheme, and mean performance across all test folds was compared using the corresponding t-test.ResultsThe MedNeXt segmentation model (mean Dice score: 0.555) outperformed both the convolutional neural network (CNN) based MedicalNet (0.516) and the CNN-transformer hybrid TransBTS (0.449) (p <0.05 for all comparisons). The MedNeXt style classification model achieved a one-vs-rest area under the ROC curve of 0.741 using the whole brain FLAIR sequence as an input, without any segmentation knowledge. This was improved to 0.772 through pretraining on the segmentation task, which was not significantly different from the baseline manual segmentation-based model (0.756, p-value: 0.141).ConclusionBRAF status can be assessed non-invasively using ML models based on whole-brain FLAIR sequences. Dependence on inconsistent manual or automated segmentations can be reduced by integrating tumor region information into the model through pretraining.
Gender Differences in Work Expectations and Psychological Distress: Insights from the United States and South Korea
Authors: Dang Linh , Antonucci Toni , Mendes de Leon Carlos , Mezuk Briana 
Published: February 2025

ABSTRACTObjectivesOver the past 50 years, women’s roles have changed significantly, from primarily domestic roles to active labor force participation. Women from the “Baby Boom” cohort (born 1948-1965) have experienced unprecedented access to educational and employment opportunities, which has implications for work and mental health later in life. This study examined gender differences in the association between work expectations and psychological distress among Baby Boomers in the United States and South Korea.MethodsData came from the 2006-2018 waves of the Health and Retirement Study (n=14,005) and Korean Longitudinal Study of Aging (n=2,362). Perceived expectations of working in the next five years were reported on a probability scale (0-100%). Psychological distress was assessed by the Center for Epidemiologic Studies Depression Scale. Multivariate mixed-effects logistic regression models were used to examine the longitudinal association between work expectations and psychological distress for men and women.ResultsIn both countries, women had higher CES-D scores and lower expectations of working in the next 5 years than men. Higher work expectations were robustly associated with lower odds of psychological distress among both men and women in Korea; however, this inverse association was more modest in the US. Moreover, the association between work expectations and distress was stronger among Korean men (ORmen=0.82 [0.78, 0.87]) compared to women (ORwomen=0.88 [0.83, 0.93]), but there were no gender differences among US respondents (ORmen=0.99 [0.96, 1.01]; ORwomen=0.96 [0.95, 0.98]).DiscussionFindings highlight the complex interplay between biology sex and social contexts in shaping expectations regarding work in later life.
Genetic control of the leaf ionome in pearl millet and correlation with root and agromorphological traits
Authors: Nakombo-Gbassault Princia , Arenas Sebastian , Affortit Pablo , Faye Awa , Flis Paulina , Sine Bassirou , Moukouanga Daniel , Gantet Pascal , Kosh Komba Ephrem , Kane Ndjido , Bennett Malcolm , Wells Darren , Cubry Philippe , Bailey Elizabeth , Grondin Alexandre , Vigouroux Yves , Laplaze Laurent 
Published: February 2025

AbstractPearl millet (Pennisetum glaucum) thrives in arid and nutrient-poor environments, establishing its role as a crucial cereal crop for food security in sub-Saharan Africa. Despite its remarkable adaptability, its yields remain below genetic potential, primarily due to limited water and nutrient availability. In this study, we conducted ionomic profiling and genome-wide association studies (GWAS) in field conditions across two growing seasons to unravel the genetic basis of nutrient acquisition in pearl millet. Soil ion content analyses revealed significant differences in nutrient distribution between field sites, while certain ions, such as phosphorus (P) and zinc (Zn), consistently displayed stratified accumulation patterns across years, suggesting stable depth-dependent trends. Evaluation of a genetically diverse panel of inbred lines revealed substantial variation in leaf ion concentrations, with high heritability estimates. Correlations between leaf ion content and root anatomical or agromorphological traits highlighted the intricate interplay between genetic and environmental factors shaping leaf ion accumulation. These analyses also uncovered potential trade-offs in nutrient acquisition strategies. GWAS identified genomic regions associated with leaf ion concentrations, and the integration of genetic and gene expression data facilitated the identification of candidate genes implicated in ion transport and homeostasis. Our findings provide valuable insights into the genetic regulation of nutrient acquisition in pearl millet, offering potential targets for breeding nutrient-efficient and climate-resilient varieties. This study underscores the importance of integrating genetic, physiological, and root architectural traits to enhance agricultural productivity and sustainability in resource-constrained environments.
Activation of alternative oxidase ensures carbon supply for ethylene and carotenoid biosynthesis during tomato fruit ripening
Authors: Iglesias-Sanchez Ariadna , Del-Saz Nestor Fernandez , Ezquerro Miguel , Feixes-Prats Elisenda , Ribas-Carbo Miquel , Fernie Alisdair R. , Rodriguez-Concepción Manuel , Florez-Sarasa Igor 
Published: February 2025

ABSTRACTTomato (Solanum lycopersicum) is a climacteric fruit displaying a peak of respiration at the onset of ripening accompanied by increased synthesis of ethylene and carotenoid pigments. Chromoplast and mitochondrial respiration participate at different stages of fruit ripening, but theirin vivoregulation and function remains unclear. We determined thein vivoactivities of the mitochondrial alternative oxidase (AOX) and cytochrome oxidase pathways and quantified the levels of respiratory- and ripening-related gene transcripts, primary metabolites and carotenoids in ripening tomato fruits with or without a functional chromorespiration. Furthermore, we carried out physiological, molecular and metabolic analyses of CRISPR-Cas9 mutants defective in AOX1a, the main AOX isoform up-regulated during tomato fruit ripening. We confirmed that PTOX-dependent chromorespiration is only relevant at late stages of ripening and found thatin vivoAOX activity significantly increased at the breaker stage, becoming the main contributor to climacteric respiration when ripening is unleashed. This activation did not correlate with gene expression but was likely due to increased levels of AOX activators such as pyruvate (a metabolic precursor of carotenoids), 2-oxoglutarate and succinate. A strong alteration of ripening-related metabolites was observed inaox1amutant fruits, highlighting a key role of the AOX pathway at the onset of ripening. Our data suggest that increased supply of TCA cycle intermediates at climacteric stage allosterically enhance AOX activity, thus allowing the reoxidation of NAD(P)H to ensure carbon supply for triggering ethylene and carotenoid biosynthesis.
B cell stimulation changes the structure and higher-order organization of the inactive X chromosome
Authors: Sierra Isabel , Toothacre Natalie E. , van der Weide Robin H. , Lovell Claudia D. , Nguyen Son C. , Jordan Barnett R. , Cook Ashley L. , Ryu Han-Seul , Pyfrom Sarah , Wang Harrison , Beiting Daniel , Philips-Cremins Jennifer E. , Joyce Eric F. , Anguera Montserrat C. 
Published: February 2025

SUMMARYX Chromosome Inactivation (XCI) equalizes X-linked gene expression between sexes. B cells exhibit dynamic XCI, with Xist RNA/heterochromatic marks absent on the inactive X (Xi) in naive B cells but returning following mitogenic stimulation. The impact of dynamic XCI on Xi structure and maintenance was previously unknown. Here, we find dosage compensation of the Xi with state-specific XCI escape genes in naive andin vitroactivated B cells. Allele-specific OligoPaints indicate similar Xi and Xa territories in B cells that are less compact than in fibroblasts. Allele-specific Hi-C reveals a lack of TAD-like structures on the Xi of naive B cells, and stimulation-induced alterations in TAD-like boundary strength independent of gene expression. Notably,Xistdeletion in B cells changes TAD boundaries and large-scale Xi compaction. Altogether, our results uncover B cell-specific Xi plasticity which could underlie sex-biased biological mechanisms.