bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extensive remodeling of the ubiquitination landscape during aging inC. elegans
Authors: Koyuncu Seda , Vilchez David 
Published: December 2023

AbstractIn previous work, we investigated ubiquitination changes during aging inC. elegans. We identified 2,163 peptides undergoing age-related ubiquitination changes in wild-type animals, corresponding to 1,050 proteins. While many lysine sites had increased ubiquitination with age, a larger number exhibited decreased ubiquitination. Longevity pathways, such as reduced insulin signaling and dietary restriction, prevented ubiquitination changes. Treatment with a broad-spectrum inhibitor of deubiquitinating enzymes (DUBs) or knockdown of specific DUBs ameliorated ubiquitination loss in old worms. Moreover, we identified proteins that accumulate with aging due to reduced ubiquitination and subsequent proteasomal degradation. Our conclusions were supported by multiple approaches, including ubiquitin and total proteomics, western blot, and ubiquitin-less mutations. Concerns were raised by a laboratory regarding the possibility of our protocol omitting insoluble proteins due to a centrifugation step after protein extraction and solubilization. To address these concerns, we have focused on proteins previously reported to become insoluble with aging inC. elegans. Our proteomics experiments successfully detected and quantified all these proteins in old worms. In many cases, the proteins that become insoluble with aging did not change or even increased at the total levels. However, they often exhibited ubiquitination changes, primarily a loss of ubiquitination. Independent work combining analysis of conformational changes with our datasets demonstrated that 92% of the age-dependent metastable proteins exhibit differential ubiquitination during aging. In addition, we performed experiments to confirm that the buffers used for proteomics and western blot efficiently solubilize most of the proteome. Importantly, the analysis of total homogenates combining clear lysates and the remaining debris after protein extraction also revealed decreased ubiquitination during aging, whereas DUB inhibitor treatment (4 h) in old worms restored ubiquitination levels. These data further support our previous conclusions regarding extensive ubiquitination changes during aging inC. elegans.
Systemic Inflammation and CT-Derived Coronary Plaque Characteristics Among Asymptomatic US Adults: The Miami Heart Study
Authors: Lahan Shubham , Hagan Kobina , Cainzos-Achirica Miguel , Valero-Elizondo Javier , Ali Shozab S. , Arias Lara , Saxena Anshul , Feldman Theodore , Blaha Michael J. , Shapiro Michael D. , Blankstein Ron , Sharma Garima , Al-Kindi Sadeer , Shah Svati , Cury Ricardo , Budoff Matthew J. , Fialkow Jonathan , Nasir Khurram 
Published: December 2023

AbstractObjectiveWe aimed to evaluate the association between inflammatory markers and coronary plaque features on coronary computed tomography angiography (CCTA) among asymptomatic individuals.MethodsBaseline data from Miami Heart Study — an ongoing prospective community-based study of a primary prevention cohort from the Greater Miami Area without prior known CAD — were used for this cross-sectional analysis. Independent variables included high-sensitivity C-reactive protein (hsCRP; <2 vs ≥ 2mg/L) and Interleukin-6 (IL–6; in tertiles). The outcomes of interest were CCTA-based plaque findings: any plaque, CAC>0, CAC>100, maximal stenosis >50%, and high-risk plaque. Multivariable logistic regression models were constructed to evaluate the association between inflammatory markers and coronary plaque features.ResultsWe evaluated 2,342 participants (50.4% men; mean age 53.4±6.7 years, 47% Hispanic, 43% non-Hispanic White, 8.3% diabetes, 56% hypertension, 22% on statin therapy). After adjusting for age, sex, and race/ethnicity, hsCRP ≥2 mg/L was associated with increased odds of having any plaque on CCTA [odds ratio (OR), 1.31 (95% confidence interval [CI], 1.09–1.58)] and stenosis ≥ 50% [OR, 1.69 (95% CI, 1.18–2.41)]. participants with IL–6 levels in 3rdtertile were associated with higher odds of detecting any plaque [OR, 1.59 (95% CI, (1.27–1.99)], CAC >0 [OR, 1.34 (95% CI, 1.06–1.69)], ≥50% stenosis [OR, 2.41 (95% CI, 1.56–3.81)], and any high-risk plaque [OR, 2.41 (95% CI, 1.56–3.81)] Further adjustment for LDL, diabetes, hypertension, obesity, and tobacco use yielded nonsignificant associations.ConclusionElevated levels of hsCRP and IL–6 are associated with the presence of coronary plaque and stenosis on CCTA when adjusted for demographics. However, these associations became nonsignificant after adjusting for additional cardiovascular risk factors. Our findings suggest a role of systemic inflammation as a mediator of the effect of cardiovascular risk factors on coronary plaque burden.
Reassessing the association of VDR and its polymorphisms with tuberculosis in global populations
Authors: Das Debashruti , Chaubey Gyaneshwer 
Published: December 2023

AbstractBackgroundVitamin D is a hormone that regulates the calcium homeostasis of the body. Besides this classical function, it is also regarded as an important immunomodulator. Most active Vitamin D actions are mediated through the Vitamin D receptor (VDR), a transcription factor and also a member of the nuclear receptor superfamily. In this study, we explored the phylogeographic attributes of the four most well-known polymorphisms of the VDR gene namely rs7975232 (ApaI), rs731235 (TaqI), rs1544410 (BsmI), rs2228570 (FokI) and also evaluated their association with the incidence of tuberculosis in global populations. This study integrated several in-silico approaches on population databases to evaluate the pattern of distribution, linkage and selection patterns of these SNPs.ResultsThe ancestral alleles of rs7975232, rs731235, and rs1544410 are still present in over 50% frequency in modern human populations. These SNPs also have a very strong linkage disequilibrium among themselves in all population groups but no haplotype blocks are seen in South Asian populations constituting these polymorphisms. The selection results reveal a negative Tajima’s D value in West and East Eurasian populations suggesting positive selection in these regions… In correlation studies, we found no association between the incidence of tuberculosis and the allele or genotype frequency of these four SNPs.ConclusionThe four SNPs of VDR behave differently in South Asian populations as compared to West and East Eurasian populations but no significant association was found with the incidence of tuberculosis in global populations.
stGCL: A versatile cross-modality fusion method based on multi-modal graph contrastive learning for spatial transcriptomics
Authors: Yu Na , Zhang Daoliang , Zhang Wei , Liu Zhiping , Qiao Xu , Wang Chuanyuan , Zhao Miaoqing , Chao Baoting , Li Wei , De Marinis Yang , Gao Rui 
Published: December 2023

AbstractAdvances in spatial transcriptomics (ST) technologies have provided unprecedented opportunities to depict transcriptomic and histological landscapes in the spatial context. Multi-modal ST data provide abundant and comprehensive information about cellular status, function, and organization. However, in dealing with the processing and analysis of spatial transcriptomics data, existing algorithms struggle to effectively fuse the multi-modal information contained within ST data. Here, we propose a graph contrastive learning-based cross-modality fusion model named stGCL for accurate and robust integrating gene expression, spatial information as well as histological profiles simultaneously. stGCL adopts a novel histology-based Vision Transformer (H-ViT) method to effectively encode histological features and combines multi-modal graph attention auto-encoder (GATE) with contrastive learning to fuse cross-modality features. In addition, stGCL introduces a pioneering spatial coordinate correcting and registering strategy for tissue slices integration, which can reduce batch effects and identify cross-sectional domains precisely. Compared with state-of-the-art methods on spatial transcriptomics data across platforms and resolutions, stGCL achieves a superior clustering performance and is more robust in unraveling spatial patterns of biological significance. Additionally, stGCL successfully reconstructed three-dimensional (3D) brain tissue structures by integrating vertical and horizontal slices respectively. Application of stGCL in human bronchiolar adenoma (BA) data reveals intratumor spatial heterogeneity and identifies candidate gene biomarkers. In summary, stGCL enables the fusion of various spatial modality data and is a powerful tool for analytical tasks such as spatial domain identification and multi-slice integration.
Structure-Aware Dual-Target Drug Design through Collaborative Learning of Pharmacophore Combination and Molecular Simulation
Authors: Chen Sheng , Xie Junjie , Ye Renlong , Xu David Daqiang , Yang Yuedong 
Published: December 2023

Dual-target drug design has gained significant attention in the treatment of complex diseases, such as cancers and autoimmune disorders. A widely employed design strategy is combining pharmacophores to incorporate the knowledge of structure-activity relationships of both targets. Unfortunately, it often struggles with long and expensive trial and error, because protein pockets of two targets impose complex structural constraints on the pharmacophore combination. In this study, we propose AIxFuse, a structure-aware dual-target drug design method that learns pharmacophore fusion patterns to satisfy the dual-target structural constraints simulated by molecular docking. We utilize two self-play reinforcement learning (RL) agents to learn pharmacophore selection and fusion by comprehensive feedback including dual-target molecular docking scores. Collaboratively, the molecular docking scores are learned by active learning (AL). Through collaborative RL and AL, AIxFuse learns to generate molecules with multiple desired properties. AIxFuse is shown to outperform state-of-the-art methods in generating dual-target drugs against glycogen synthase kinase-3 beta (GSK3β) and c-Jun N-terminal kinase 3 (JNK3). When applied to another task against retinoic acid receptor-related orphan receptorγ-t (RORγt) and dihydroorotate dehydrogenase (DHODH), AIxFuse exhibits consistent performance while compared methods suffer performance drops, leading to a 5 times outperformance in success rate. Docking studies demonstrate that AIxFuse can generate molecules concurrently satisfying the binding mode required by both targets. Further free energy perturbation calculation indicates that the generated candidates have promising binding free energies against both targets.Significance StatementComplex diseases like cancers and autoimmune disorders are mostly caused by multiple genes. Designing dual-target drugs against two target proteins simultaneously can achieve synergistic effects and alleviate drug resistance. In this study, we present AIxFuse, which to our knowledge is the first structure-aware dual-target drug design method that learns pharmacophore fusion patterns to satisfy the dual-target structural constraints simulated by molecular docking. AIxFuse exhibits superior performance to previous state-of-the-art methods on comprehensive benchmarks. By generating diverse drug candidates with promising dualtarget binding free energies and other desired properties, AIxFuse holds promising prospects for accelerating the development of novel dual-target drugs for long-term therapeutic of complex diseases.
Senescence phenotype of lymph node stromal cells from patients with rheumatoid arthritis is partly restored by dasatinib treatment
Authors: de Jong T.A. , Semmelink J.F. , Bolt J.W. , Grasso C. , Hoebe R.A. , Krawczyk P.M. , van Baarsen L.G.M. 
Published: December 2023

AbstractObjectiveCellular senescence is a state of proliferation arrest of cells occurring during aging. The persistence and accumulation of senescent cells has been implicated in the pathogenesis of age-related diseases like rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which loss of immune tolerance and systemic autoimmunity precedes clinical onset of disease. Lymph node stromal cells (LNSCs) are important regulators of immune tolerance. Accordingly, accumulating senescent LNSCs may potentially lead to defective immune tolerance and the development of systemic autoimmune disease.MethodsHuman LNSCs were isolated and cultured from inguinal lymph node needle biopsies from individuals at risk of developing RA (RA-risk individuals), RA patients and seronegative healthy volunteers. Senescence hallmarks and the effect of dasatinib treatment were assessed using quantitative PCR, flow cytometry, microscopy and live-cell imaging.ResultsCell size, granularity and autofluorescence were significantly higher in RA LNSCs compared with control LNSCs. Stainings indicate more senescence associated β-galactosidase activity, more lipofuscin positive granules and increased DNA damage in RA-risk and RA LNSCs compared with control LNSCs. Moreover, we found altered gene expression levels of senescence associated genes in LNSCs from RA patients. Strikingly, the capacity to repair irradiation induced DNA damage was significantly lower in RA-risk and RA LNSCs compared with control LNSCs. Treating LNSCs with dasatinib significantly improved cell size and DNA repair capacity of cultured LNSCs.ConclusionWe observed multiple senescent hallmarks in RA LNSCs and to lesser extent already in RA-risk LNSCs, which could partly be restored by dasatinib treatment.KEY MESSAGESWhat is already known on this topic?–Synovial fibroblasts from RA patients display a senescent phenotype and accumulate in inflamed synovial tissue.What does this study add?–Lymph node stromal cells (LNSCs) from RA patients, and to a lesser extent from RA-risk, display key hallmarks of senescence.–Bothex vivoandin vitroLNSCs from RA patients have an increased cell size compared with control LNSCs.–RA and RA-risk LNSCs have an impaired ability to repair DNA damage–Treating LNSCs with dasatinib significantly improved cell size and DNA repair capacity of LNSCs.How might this study impact on clinical practice or future developments?–These hallmarks of senescence in LNSCs may indicate premature aging and loss of function of the immunomodulatory lymph node stromal compartment during RA development. Dasatinib treatment of LNSCs shows that senolytics may be an effective preclinical drug to restore cell function early in disease.
Studying social anxiety without triggering it: Establishing an age-controlled cohort of social media users for observational studies
Authors: Schmidt Ana Lucia , O’Connor Karen , Gonzalez Hernandez Graciela , Rodriguez-Esteban Raul 
Published: December 2023

AbstractBackgroundPatients of certain diseases are less likely to approach the healthcare system but remain active in social media. Young Social Anxiety Disorder (SAD) patients, in particular, are a hard-to-reach population due to disease symptomatology, unmet need and age-related barriers, which makes obtaining first-hand access to patient perspectives challenging.ObjectiveTo create a curated cohort of patients from social media that report their age in the range of 13 to 25 years old and confirm having a SAD diagnosis or having received therapy for SAD, and to assess the value of the content posted by these users for observational studies of SAD.MethodsWe collected 535k posts by 118k Reddit users from the r/SocialAnxiety subreddit. We then developed precise regular expressions to extract age, diagnosis and therapy mentions. We manually annotated the full set of expressions extracted and double-annotated 5% of the age mentions and 10% of the diagnosis and therapy mentions. Using similar methodology, we identified mentions of comorbidities and substance use.ResultsOur validated cohort includes 37,073 posts by 1,102 users that meet the inclusion criteria. The age, diagnosis, and therapy mention detection had a precision of 68%, 31%, and 44%, respectively, with an inter-annotator agreement of 0.96, 0.96, and 0.78. Sixty-one percent of the users in the cohort report having one or more comorbidities on top of their SAD diagnosis (Fleiss’s Kappa=0.79) and 13% report a concerning use of drugs or alcohol (Fleiss’s Kappa=0.87). We compared the characteristics of our social media cohort to the published literature on SAD.ConclusionsPatients with SAD post actively on Reddit and their perspectives can be captured and studied directly from these data. Extracting age, therapy, substance abuse and comorbidities (and potentially other patient data) can address realworld data source biases. Thus, social media is a valuable source to create cohorts of hard-to-reach patient populations that may not enter the healthcare system.
Newly Sequenced Genomes Reveal Patterns of Gene Family Expansion in Select Dragonflies (Odonata: Anisoptera)
Authors: Tolman Ethan R. , Beatty Christopher D. , Frandsen Paul B. , Bush Jonas , Bruchim Or R. , Driever Ella Simone , Harding Kathleen M. , Jordan Dick , Kohli Manpreet K. , Park Jiwoo , Park Seojun , Reyes Kelly , Rosario Mira , Ryu Jisong L. , Wade Vincent , Suvorov Anton , Ware Jessica L. 
Published: December 2023

AbstractGene family expansions play a key role in shaping patterns of biodiversity across the tree of life. In Insecta, expanded gene families have broadly been tied to diet, pesticide resistance, immune response and survival in extreme environments. Patterns of gene family evolution are of particular interest in Odonata (dragonflies and damselflies), which are the first lineage to fly, and are one of the most exceptional predators. In Odonata, expansions of opsin genes are correlated with the diversification of the herbivorous insects that Odonata prey upon, but general trends in gene family expansion and contraction have not been studied in this order. Here, we show that two families of Anisoptera (dragonflies), Libellulidae and Petaluridae, have expanded gene families related to their unique life history and diversification patterns.Libellulidae share expanded gene families related to immune response, desiccation response, and processing free radicals, which are all related to the success of Libellulidae in low quality water bodies. The Petaluridae have expanded gene families involved in sensory perception, which can be tied to the unique semi-terrestrial lifestyle of the nymphs of this family. Furthermore, Odonata as a whole has a remarkably high (λ=.19) level of gene turnover compared to other insect orders, a phenomenon that will merit further exploration. These results are an important step towards understanding why Libellulidae is, generally, a species rich family of short lived species that are highly tolerant to poor water quality, while Petaluridae is a species poor family of habitat and behavioral specialists.
MUFFIN : A suite of tools for the analysis of functional sequencing data
Authors: de Langen Pierre , Ballester Benoit 
Published: December 2023

AbstractThe large diversity of functional genomic assays allows for the characterization of non-coding and coding events at the tissue level or at a single-cell resolution. However, this diversity also leads to protocol differences, widely varying sequencing depths, substantial disparities in sample sizes, and number of features. In this work, we have specifically designed a suite of tools for exploring the non-coding genome, particularly for identifying consensus peaks in peak-called assays, as well as linking non-coding genomic regions to genes and performing Gene Set Enrichment Analyses. We demonstrate that a generic but flexible count modelling approach can be utilised to compare different conditions across a broad range of genomic assay such as ENCODE H3K4Me3 ChIP-seq, scRNA-seq and TCGA ATAC-seq. Our Python package, MUFFIN, offers a suite of tools to address common issues associated with high-dimensional genomic data, such as normalisation, count transformation, dimensionality reduction, differential expression, and clustering. Additionally, our tool integrates with the popular Scanpy ecosystem and is available on Conda and athttps://github.com/pdelangen/Muffin.
α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
Authors: Geibl Fanni F. , Henrich Martin T. , Xie Zhong , Zampese Enrico , Tkatch Tatiana , Wokosin David L. , Nasiri Elena , Grotmann Constantin A. , Dawson Valina L. , Dawson Ted M. , Chandel Navdeep S. , Oertel Wolfgang H. , Surmeier D. James 
Published: December 2023

AbstractBackgroundPathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain.MethodsaSYN PPFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell- type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser- scanning microscopy of genetically encoded sensors for bioenergetic and redox status.ResultsIn addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure.ConclusionsTaken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.