bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Method For Mimicking Tumour Tissue In Brain Ex-Vivo Ultrasound For Research Application And Clinical Training
Authors: Weld Alistair , Dixon Luke , Anichini Giulio , Faoro Giovanni , Menciassi Arianna , Camp Sophie , Giannarou Stamatia 
Published: October 2024

AbstractBackgroundIntraoperative ultrasound is becoming a common tool in neurosurgery. However, effective simulation methods are limited. Current, commercial, and homemade phantoms lack replication of anatomical correctness and texture complexity of brain and tumour tissue in ultrasound images.MethodsWe utilise ex-vivo brain tissue, as opposed to synthetic materials, to achieve realistic echogenic complexity and anatomical correctness. Agar, at 10-20% concentrate, is injected into brain tissue to simulate the tumour mass. A commercially available phantom was purchased for benchmarking.ResultsQualitative analysis is performed by experienced professionals, measuring the impact of the addition of agar and comparing it to the commercial phantom. Overall, the use of ex vivo tissue was deemed more accurate and representative, compared to the synthetic materials-based phantom, as it provided good visualisation of real brain anatomy and good contrast within tissue. The agar tumour correctly produced a region of higher echogenicity with slight diffusion along the margin and expected interaction with the neighbouring anatomy.ConclusionThe proposed method for creating tumour-mimicking tissue in brain tissue is inexpensive, accurate, and simple. Beneficial for both the trainee clinician and the researcher. A total of 576 annotated images are made publicly available upon request.
Risk of Incident Cytopenia in Clonal Hematopoiesis
Authors: Brogan James , Kishtagari Ashwin , Corty Robert W. , Pershad Yash , Vlasschaert Caitlyn , Sharber Brian , Heimlich J. Brett , Luo Leo , Xu Yaomin , Bick Alexander G. 
Published: October 2024

AbstractClonal hematopoiesis of indeterminate potential (CHIP) is an asymptomatic condition associated with elevated risk for myeloid neoplasms (MN). Patients with CHIP and cytopenia are at greater risk of MN. Quantifying the incidence of cytopenia and identifying risk factors among CHIP patients is critical for improving clinical management. We analyzed sequencing data from 805,249 participants in the NIH All of Us Research Program (AoU), Vanderbilt’s BioVU repository, and UK Biobank (UKB). Genetic mutations, laboratory values, and MN diagnoses were included in survival analyses to determine predictors of cytopenia in individuals with CHIP and matched controls. The cohort contained 9,374 CHIP cases and 24,749 controls. Cytopenia occurred in 13.5% of cases and 11.6% of controls (HR = 1.17, 95% confidence interval:1.10 – 1.25, P=2.5 × 10−6). Cytopenia risk factors included smoking, male sex, variant allele frequency ≥ 0.20, age ≥ 65, mean corpuscular volume ≥ 100 femtoliters, red cell distribution width ≥ 15%, mutations in high-risk CHIP genes, and ≥ 2 CHIP mutations. In BioVU, 45% of participants with ≥ 4 risk factors progressed to cytopenia within two years. Individuals with CHIP and cytopenia progressed to MN at a rate of ~2% per year, compared to <0.1% per year for those without cytopenia. Longitudinal analysis across three cohorts demonstrated an increased risk of cytopenia in CHIP patients and identified those at highest risk. These findings suggest that cytopenia is a critical step in progression from CHIP to MN, underscoring its utility as an endpoint in cancer prevention trials for CHIP patients.
Multiomics identifies unique modulators of calf muscle pathophysiology in peripheral artery disease and chronic kidney disease
Authors: Kim Kyoungrae , Thome Trace , Pass Caroline , Stone Lauren , Vugman Nicholas , Palzkill Victoria , Yang Qingping , O’Malley Kerri A. , Anderson Erik M. , Fazzone Brian , Yue Feng , Berceli Scott A. , Scali Salvatore T. , Ryan Terence E. 
Published: October 2024

ABSTRACTBACKGROUNDChronic kidney disease (CKD) has emerged as a significant risk factor that accelerates atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the modulators underlying this exacerbated pathobiology are ill-defined. Recent work has demonstrated that uremic toxins are associated with limb amputation in PAD and have pathological effects in both the limb muscle and vasculature. Herein, we utilize multiomics to identify novel modulators of disease pathobiology in patients with PAD and CKD.METHODSA cross-sectional study enrolled four groups of participants: controls without PAD or CKD (n=28), patients with PAD only (n=46), patients with CKD only (n=31), and patients with both PAD and CKD (n=18). Both targeted (uremic toxins) and non-targeted metabolomics in plasma were performed using mass spectrometry. Calf muscle biopsies were used to measure histopathology, perform bulk and single-nucleus RNA sequencing (snRNAseq), and assess mitochondrial function. Differential gene and metabolite analyses, as well as pathway and gene set enrichment analyses were performed.RESULTSPatients with both PAD and CKD exhibited significantly lower calf muscle strength and smaller muscle fiber areas compared to controls and those with only PAD. Compared to controls, mitochondrial function was impaired in CKD patients, with or without PAD, but not in PAD patients without CKD. Plasma metabolomics revealed substantial alterations in the metabolome of patients with CKD, with significant correlations observed between uremic toxins (e.g., kynurenine, indoxyl sulfate) and both muscle strength and mitochondrial function. RNA sequencing analyses identified downregulation of mitochondrial genes and pathways associated with protein translation in patients with both PAD and CKD. Single nucleus RNA sequencing further highlighted a mitochondrial deficiency in muscle fibers along with unique remodeling of fibro-adipogenic progenitor cells in patients with both PAD and CKD, with an increase in adipogenic cell populations.CONCLUSIONSCKD significantly exacerbates ischemic muscle pathology in PAD, as evidenced by diminished muscle strength, reduced mitochondrial function, and altered transcriptome profiles. The correlation between uremic toxins and muscle dysfunction suggests that targeting these metabolites may offer therapeutic potential for improving muscle health in PAD patients with CKD.
Persistently high TB prevalence in Nairobi County neighbourhoods, 2015-2022
Authors: Ong’ang’o Jane R. , Ross Jennifer , Kiplimo Richard , Kerama Cheryl , Tram Khai Hoan , Zifodya Jerry S. , Mukiri Nellie , Nyadimo Erick , Njoroge Martha , Ronoh Aiban , Kathure Immaculate , Kirathe Dickson , Hawn Thomas R. , Nduba Videlis , Horne David J. 
Published: October 2024

AbstractNational and sub-national population-based surveys, when performed at intervals, may assess important changes in TB prevalence. In 2022 we re-surveyed nine Nairobi County neighbourhoods that were previously surveyed in 2015. We aimed to determine pulmonary TB prevalence, compare prevalence to 2015 estimates, and evaluate changes in risk groups. Participants who reported cough of any duration and/or whose chest x-ray suggested TB submitted sputum for smear microscopy, Xpert Ultra, and liquid culture. We defined prevalent TB asMycobacterium tuberculosisdetection by sputum Xpert or culture, excepting individuals who were only trace positive. Our methods differed from 2015, which used solid media, Xpert MTB/RIF, and cough duration >2 weeks. We calculated TB prevalence using random-effects logistic regression models with missing value imputations and inverse probability weighting. In 2022 among 6369 participants, 1582 submitted >1 sputum sample, among whom 42 (2·7%) had TB, a weighted TB prevalence of 806/100,000 (95% confidence interval (CI), 518-1096). An additional 31 (2·0%) participants tested Ultra trace-positive/culture-negative. For comparison to 2015, we excluded 2022 participants (n=2) whose only criterion for sputum was cough <2 weeks. There was no evidence for a decline in overall TB prevalence from 2015 to 2022. TB prevalence among men was high (1368/100,000) but unchanged compared to 2015 (p-value = 0·50). The age group with the highest estimated prevalence remained people ages 45–54 years. Among people with prevalent TB who reported cough, 76% had not sought health care. Dissimilar from other serial surveys that showed declines in TB prevalence, we found persistently high TB prevalence over a 7-year period in Nairobi County. Limitations of this study include changes in methodology between the two surveys and complex effects of the COVID-19 pandemic.
Dual Specificity Phosphatase 3 knockdown drives myeloid leukemia cells to differentiate into macrophages and polarize
Authors: Farias Jessica O. , Pacheco Diana R.D.C.G. , Magalhaes Yuli T. , Russo Lilian C. , Boell Viktor K. , Hilares Donna J.F. , Forti Fabio L. 
Published: October 2024

ABSTRACTThe dual-specificity phosphatase 3 (DUSP3) has been implicated in the maintenance of genomic stability, cell cycle, proliferation, and differentiation. Recently we reported an important role of the interaction between DUSP3 and nucleophosmin (NPM) proteins on the regulation of the p53 actions to maintain genomic stability. Since both p53 and NPM often have mutations related to a diverse set of leukemia, this work aimed to evaluate the roles of DUSP3 in the differentiation of two acute myeloid leukemia cell lines not expressing the p53 protein, and the potential correlations with NPM expression. The results demonstrated higher levels of DUSP3 in THP-1 cells compared to HL-60 cells under basal conditions. After PMA-induced differentiation into macrophages, only HL-60 cells presented a dramatic decrease in DUSP3 and NPM proteins expression. The permanent DUSP3 knockdown in THP-1 and HL-60 cells contributed to their differentiation and non-classical polarization after PMA exposure, since the CD14, MHCII, and CD163 markers were decreased whereas the CD11b and CD206 markers were increased. Bioinformatics analyses identified that the negative regulation of thenpm1anddusp3genes correlates with the reduced survival of patients with acute myeloid leukemia (AML) and the strong positive correlation existing between the expression of these two genes is progressively lost according to the degree of maturation of the myeloid cells. These results suggest DUSP3 plays regulatory roles of differentiation and polarization of myeloid cells, and its association with NPM expression levels may allow a better understanding of mechanisms involved in leukemia and treatment resistance.HIGHLIGHTSDUSP3 knockdown drives myeloid leukemia cells to differentiationDUSP3 silencing drives myeloid leukemia cells to macrophage polarizationDUSP3 and NPM association are potential targets for leukemia treatment and resistance
Isobaric labeling update in MaxQuant
Authors: Ferretti Daniela , Kyriakidou Pelagia , Xiao Jinqiu , Urazbakhtin Shamil , Nart Carlo De , Cox Jürgen 
Published: October 2024

AbstractWe present an update of the MaxQuant software for isobaric labeling data and evaluate its performance on benchmark datasets. Impurity correction factors can be applied to labels mixing C- and N-type reporter ions, such as TMT Pro. Application to a single-cell multi-species mixture benchmark shows high accuracy of the impurity-corrected results. TMT data recorded with FAIMS separation can be analyzed directly in MaxQuant without splitting the raw data into separate files per FAIMS voltage. Weighted median normalization, is applied to several datasets, including large-scale human body atlas data. In the benchmark datasets the weighted median normalization either removes or strongly reduces the batch effects between different TMT plexes and results in clustering by biology. In datasets including reference channels, we find that weighted median normalization performs as well or better when the reference channels are ignored and only the sample channel intensities are used, suggesting that the measurement of reference channels is unnecessary when using weighted median normalization in MaxQuant. We demonstrate that MaxQuant including the weighted median normalization performs well on multi-notch MS3 data, as well as on phosphorylation data. MaxQuant is freely available for any purpose and can be downloaded fromhttps://www.maxquant.org/.
Ectonucleotidases and Purinergic Receptors in Mouse Prostate Gland
Authors: Yu Jovian , Sharkey Christina , Olumi Aria , Wang Zongwei 
Published: October 2024

AbstractExtracellular ATP/ADP and its metabolite adenosine are important signaling molecules that regulate cellular function by binding to P2 and P1/adenosine receptors. The kinetics of these signaling molecules are critically modulated by ectonucleotidases, enzymes that convert ATP/ADP to adenosine. Although the expression and function of these enzymes and relevant purinergic receptors in the prostate gland are not well understood, recent reports indicate impaired ATP hydrolysis activity in the aging prostate. Purinergic signaling is known for its role in inflammation, muscle contraction, pain sensation, and cell proliferation in many systems, suggesting its potential importance in normal prostate function and pathological conditions such as benign prostatic hyperplasia and prostatitis. To better understand purine-converting enzymes and purinergic receptors in the prostate, we isolated mouse prostate glands for immunofluorescent staining and microscopy imaging using specific antibodies. Our study identified a differential expression profile of purinergic enzymes and receptors in the prostate: ENTPD1 and P2×1 receptors predominantly in prostate smooth muscle cells, ENTPD2 and NT5E in prostate interstitial cells, and ALPL in prostate epithelial cells. Functionally, in addition to the P2×1-mediated prostate smooth muscle contraction induced by agonist α,β-meATP, we observed an ATPγS-induced contraction force after P2×1 desensitization. This led to the identification of multiple P2Y receptors in mouse prostate smooth muscle, including P2Y1, P2Y2, and P2Y11 receptors, which potentially mediate the ATPγS-induced contraction force. These discoveries lay the foundation for further mechanistic understanding of how purinergic signaling regulates prostate function and dysfunction in both rodents and potentially humans.
UniGEN-DDI: Computing drug-drug interactions using a unified graph embedding network
Authors: Mondal Somnath , Datta Debarghya , Pramanik Soumajit , Mehra Rukmankesh 
Published: October 2024

AbstractFinding drug-drug interaction is crucial for patient safety and treatment efficacy. Two drugs may show a synergistic effect but may sometimes cause a severe health issue, including lethality. Wet lab studies are often performed to understand such interactions but are limited by cost and time. However, the biochemical data generated can be explored to compute unknown interactions. Here, we developed a computational model named UniGEN-DDI (UnifiedGraphEmbeddingNetwork forDrug-Drug Interaction) for the estimation of interactions between drugs. It is a simple unified network model containing the biochemical information of drug association developed using the compiled data from DrugBank 5.1.0. The feature learning of the drugs was carried out using a combination of GraphSAGE and Node2Vec algorithms, which were found efficient in extracting diverse features. The simple architecture of our model led to a significant reduction in computational time compared to the baselines, while maintaining a high prediction accuracy. The model performed well on the data, which was equally distributed between interacting and non-interacting drugs. As a more challenging evaluation, we performed non-overlapping splitting of the data based on the drug action on different parts of the body, and our model performed well in both interaction estimation and time efficiency. Our model successfully identified the 12 unknown drug interactions in DrugBank 5.1.0, which were updated in DrugBank 6.0.HighlightsUniGEN-DDI: A simple unified network model was developed for drug-drug interactions.Node embeddings were generated using GraphSAGE and Node2Vec algorithms.A significantly higher computational efficiency was achieved compared to baselines.Model validated in non-overlapping splitting of data targetting multiple body parts.UniGEN-DDI estimated unknown interactions verified in the updated DrugBank 6.0.Graphical abstract
Distinct expression profile reveals glia involvement in the trigeminal system attributing to post-traumatic headache
Authors: Nagarajan Gurueswar , Zhang Yumin 
Published: October 2024

AbstractPost-traumatic headache (PTH) is a common comorbid symptom affecting at least one-third of patients with mild traumatic brain injury (mTBI). While neuroinflammation is known to contribute to the development of PTH, the cellular mechanisms in the trigeminal system crucial for understanding the pathogenesis of PTH remain unclear. Male mice underwent a non-invasive repetitive mTBI protocol (4 impacts, 24-hour intervals) targeting either the bregma or pre-bregma region of the head. Periorbital allodynia and spontaneous pain behavior were assessed using von Frey tests and grimace scores, respectively. Quantitative PCR was used to evaluate the extent of mTBI-induced pathology in several brain regions. RNA sequencing was performed to obtain transcriptomic profile of the trigeminal ganglion (TG), trigeminal nucleus caudalis (Sp5C) and periaqueductal gray (PAG) at 7 days post-TBI. Subsequently, quantitative PCR, in situ hybridization and immunohistochemistry were used to examine mRNA and protein expression of glia specific markers and pain associated molecules. The repetitive impacts at the bregma, but not pre-bregma site led to periorbital hypersensitivity, which was correlated with enhanced inflammatory gene expression in multiple brain regions. RNA sequencing identified distinct transcriptomic profiles in the peripheral TG, central Sp5C and PAG following mTBI. Using gene set enrichment analysis, positive enrichment of non-neuronal cells in the TG and neuroinflammation in the Sp5C were identified to be essential in the pathogenesis of PTH. In situ assays also revealed that gliosis of satellite glial cells in the TG and astrocytes in the Sp5C were prominent days after injury. Furthermore, immunohistochemical study revealed a close interaction between activated microglia and reactive astrocytes correlating with increased calretinin interneurons in the Sp5C. Transcriptomics analysis indicated that non-neuronal cells in peripheral TG and successive in situ assays revealed that glia in the central Sp5C are crucial in modulating headache-like symptoms. Thus, selective targeting of glia cells can be a therapeutic strategy for PTH attributed to repetitive mTBI.
Neuronally differentiated endothelial cell subtype regulates organ blood flow and immune balance
Authors: Gyarmati Georgina , Rust Ruslan , Calderon Alejandra Becerra , Izuhara Audrey , Trogen Greta , Deepak Sachin , Chen Yibu , Ruffins Seth Walter , Junge Jason A. , Zlokovic Berislav V. , Fraser Scott , Peti-Peterdi János 
Published: October 2024

AbstractVascular endothelial cells (ECs) perform key pleiotropic functions to maintain body homeostasis via the regulation of organ blood flow, vascular permeability, tissue growth and inflammation, and angiogenesis. Recent transcriptomic studies uncovered many EC subtypes across organs; however their specific functions are incompletely understood. Here we identified and characterized a novel, minority subtype of scattered ECs with a well-defined arteriovenous zonal localization exclusively in small resistance (strain) arterioles, and with the highest density in the brain>retina>kidney. Due to their expression of both endothelial and neuron-like functional and gene transcriptomic signatures, they were termed neuro-endothelial cells (NECs). High resolution single-cell transcriptome analysis of mouse brain and kidney ECs identified neuronal nitric oxide synthase (Nos1) and cytokine-like 1 (Cytl1) as top NEC biomarkers. Intravital multiphoton imaging of optogenetic mouse models with NEC gain/loss-of-function revealed NEC and Nos1-dependent vasodilation/vasoconstriction of intact brain and kidney arterioles and elevation/reduction in blood flow. Silencing NEC Nos1 and Cytl1 gene expression in vivo caused marked segmental arteriolar vasoconstrictions, reductions in vascular density and organ blood flow, increased vascular permeability and immune cell homing. Cytl1 administration triggered vasodilation and increased blood flow acutely, and increased capillary density and clonal EC remodeling chronically. NECs play major vasodilatory, angiogenic and anti-inflammatory functions that may be therapeutically targeted for vascular and inflammatory diseases.
Methylomes reveal recent evolutionary changes in populations of two plant species
Authors: Korfmann Kevin , Zauchner Andreas , Huo Bing , Grünke Corinna , Wang Yitong , Tellier Aurélien , Arunkumar Ramesh 
Published: October 2024

AbstractPlant DNA methylation changes occur hundreds to thousands of times faster than DNA mutations and can be transmitted transgenerationally, making them useful for studying population-scale patterns in clonal or selfing species. However, a state-of-the-art approach to use them for inferring population genetic processes and demographic histories is lacking. To address this, we compare evolutionary signatures extracted from CG methylomes and genomes inArabidopsis thalianaandBrachypodium distachyon. While methylation variants (SMPs) are less effective than single nucleotide polymorphisms (SNPs) for identifying population differentiation inA. thaliana, they can classify phenotypically divergentB. distachyonsubgroups that are otherwise genetically indistinguishable. The site frequency spectra generated using methylation sites from varied genomic locations and evolutionary conservation exhibit an excess of rare alleles. Nucleotide diversity estimates were three orders of magnitude higher for methylation variants than for SNPs in both species, driven by the higher epimutation rate. Correlations between SNPs and SMPs in nucleotide diversity and allele frequencies at gene exons are weak or absent inA. thaliana, possibly because the two sources of variation reflect evolutionary forces acting at different timescales. Linkage disequilibrium quickly decays within 100 bp for methylation variants in both plant species. Finally, we developed a deep learning-based demographic inference approach. We identified recent population expansions inA. thalianaandB. distachyonusing methylation variants that were not identified when using SNPs. Our study demonstrates the unique evolutionary insights methylomes provide that SNPs alone cannot reveal.
Better confidence intervals in simulation-based inference of historical demography from population genetic data
Authors: Rousset François , Leblois Raphaël , Estoup Arnaud , Marin Jean-Michel 
Published: October 2024

AbstractWe describe and evaluate a method of statistical inference of model parameters, which revisits the idea of inferring a likelihood surface using simulation when the likelihood function cannot be evaluated. The method aims in particular to provide confidence intervals with controlled coverage, and its performance is assessed accordingly. It is based on a combining the random forest machine learning method, and multivariate Gaussian mixture (MGM) models, in an effective inference workflow, here used to fit models with up to 15 variable parameters. Masked autoregressive flows, a deep learning technique, is also tested as an alternative to MGM models. The method is compared to that of approximate Bayesian computation (ABC) with random forests, with which it shares some technical features, on scenarios of inference of historical demography from population genetic data. These comparisons highlight the importance of an iterative workflow for exploring the parameter space efficiently. For equivalent simulation effort of the data-generating process, the new summary-likelihood method provides better control of coverage than ABC with random forests, and than generally reported for ABC methods.