bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trained Immunity Causes Myeloid Cell Hypercoagulability
Authors: Rehill Aisling M. , McCluskey Seán , Ledwith Anna E. , Ryan Tristram A.J. , Leon Gemma , Charles-Messance Hugo , Gilbert Edmund H. , Day Emily A. , McMahon Corrina , O’Donnell James S. , Curtis Annie M. , O’Neill Luke A.J. , Sheedy Frederick J. , Preston Roger J.S. 
Published: July 2024

ABSTRACTVenous thromboembolism is common in individuals with chronic inflammatory diseases, but the pathogenic basis for this increased thrombotic risk remains poorly understood. Myeloid cell ‘trained immunity’ describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a novel maladaptive consequence of trained immunity. LPS stimulation of murine bone marrow-derived macrophages trained previously with either β-glucan or free haem exhibited significantly enhanced procoagulant and antifibrinolytic gene expression and activity compared to macrophages stimulated with LPS alone. The β-glucan training-mediated increase in activated myeloid cell procoagulant activity was mediated by enhanced acid sphingomyelinase-mediated tissue factor (TF) functional decryption. Furthermore, pre-treatment with methyltransferase and acetyltransferase inhibitors to erase epigenetic marks associated with innate immune memory diminished trained macrophage TF gene expression in β-glucan-trained macrophages. Functional analysis of splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Remarkably, monocyte procoagulant activity increased proportionately with time since β-glucan administration, before plateauing at 4 weeks. Furthermore, haematopoietic progenitor cells and bone marrow interstitial fluid isolated from β-glucan-trained mice possessed enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent novel therapeutic vulnerabilities in immunothrombotic disease development, opening new avenues for targeted intervention.
Inference of gene regulatory networks for overcoming low performance in real-world data
Authors: Hiki Yusuke , Tokuoka Yuta , Yamada Takahiro G. , Funahashi Akira 
Published: July 2024

AbstractThe identification of gene regulatory networks is important for understanding the mechanisms of various biological phenomena. Many methods have been proposed to infer networks from time-series gene expression data obtained by high-throughput next-generation sequencings. Such methods can effectively infer gene regulatory networks forin silicodata, but inferring the networks accurately fromin vivodata remiains a challenge because of the large noise and low time sampling rate. Here, we proposed a novel unsupervised learning method, Multi-view attention Long-short term memory for Network inference (MaLoN). It can infer gene regulatory networks with temporal changes in gene regulation using the multi-view attention Long Short-term memory model. Usingin vivobenchmark datasets inSaccharomyces cerevisiaeandEscherichia coli, we showed that MaLoN can infer gene regulatory networks more accurately than existing methods. The ablated models indicated that the multi-view attention mechanism suppressed false positives. The order of activation of gene regulations inferred by MaLoN was consistent with existing knowledge.
Analysis of the Modulation of RAF Signaling by 14-3-3 Proteins
Authors: Carlip Peter , Stites Edward C. 
Published: July 2024

AbstractThe regulation of cellular biochemical signaling reactions includes the modulation of protein activity through a variety of processes. For example, signaling by the RAF kinases, which are key transmitters of extracellular growth signals downstream from the RAS GTPases, is modulated by dimerization, protein conformational changes, post-translational modifications, and protein-protein interactions. 14-3-3 proteins are known to play an important role in RAF signal regulation, and have the ability to stabilize both inactive (monomeric) and active (dimeric) states of RAF. It is poorly understood how these antagonistic roles ultimately modulate RAF signaling. To investigate, we develop a mathematical model of RAF activation with both roles of 14-3-3, perform algebraic and numeric analyses, and compare with available experimental data. We derive the conditions necessary to explain experimental observations that 14-3-3 overexpression activates RAF, and we show that strong binding of 14-3-3 to Raf dimers alone is not generally sufficient to explain this observation. Our integrated analysis also suggests that RAF–14-3-3 binding is relatively weak for the reasonable range of parameter values, and suggests the Raf dimer–14-3-3 interactions are stabilized primarily by avidity. Lastly we find that in the limit of paired weak/avidity driven interactions between RAF and 14-3-3, the paired binding interactions may be reasonably approximated with a strong, single, equilibrium reaction. Overall, our work presents a mathematical model that can serve as a foundational piece for future, extended, studies of signaling reactions involving regulated RAF kinase activity.
SIngle cell level Genotyping Using scRna Data (SIGURD)
Authors: Graßhoff Martin , Kalmer Milena , Chatain Nicolas , Kricheldorf Kim , Maurer Angela , Weiskirchen Ralf , Koschmieder Steffen , Costa Ivan G. 
Published: July 2024

ABSTRACTMotivationBy accounting for variants within measured transcripts, it is possible to evaluate the status of somatic variants using single-cell RNA-sequencing (scRNA-seq) and to characterize their clonality. However, the sparsity (very few reads per transcript) or bias in protocols (favoring 3’ ends of the transcripts) makes the chance of capturing somatic variants very unlikely. This can be overcome by targeted sequencing or the use of mitochondrial variants as natural barcodes for clone identification. Currently, available computational tools focus on genotyping, but do not provide functionality for combined analysis of somatic and mitochondrial variants and functional analysis such as characterization of gene expression changes in detected clones.ResultsHere, we propose SIGURD, which is an R-based pipeline for the clonal analysis of single-cell RNA-seq data. This allows the quantification of clones by leveraging both somatic and mitochondrial variants. SIGURD also allows for functional analysis after clonal detection: association of clones with cell populations, detection of differentially expressed genes across clones and association of somatic and mitochondrial variants. Here, we demonstrate the power of SIGURD by analyzing single-cell data of colony-forming cells derived from patients with myeloproliferative neoplasms.AvailabilityCode and tutorial of SIGURD are available at GitHubhttps://github.com/CostaLab/sigurd.Contactivan.costa@rwth-aachen.de,skoschmieder@ukaachen.deSupplementary InformationSupplementary data are available online.
High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment
Authors: Du Wenxuan , Zhou Bryan , Forjaz André , Shin Sarah M. , Wu Fan , Crawford Ashleigh J. , Nair Praful R. , Johnston Adrian C. , West-Foyle Hoku , Tang Ashley , Kim Dongjoo , Fan Rong , Kiemen Ashley L. , Wu Pei-Hsun , Phillip Jude M. , Ho Won Jin , Sanin David E. , Wirtz Denis 
Published: July 2024

AbstractEnrichment of tumor-associated macrophages (TAMΦs) in the tumor microenvironment correlates with worse clinical outcomes in triple-negative breast cancer (TNBC) patients, prompting the development of therapies to inhibit TAMΦ infiltration. However, the lackluster efficacy of CCL2-based chemotaxis blockade in clinical trials suggests that a new understanding of monocyte/macrophage infiltration may be necessary. Here we demonstrate that random migration, and not only chemotaxis, drives macrophage tumor infiltration. We identified tumor- associated monocytes (TAMos) that display a dramatically enhanced migration capability, induced rapidly by the tumor microenvironment, that drives effective tumor infiltration, in contrast to low-motility differentiated macrophages. TAMo, not TAMΦ, promotes cancer cell proliferation through activation of the MAPK pathway. IL-6 secreted both by cancer cells and TAMo themselves enhances TAMo migration by increasing dendritic protrusion dynamics and myosin- based contractility via the JAK2/STAT3 signaling pathway. Independent from CCL2 mediated chemotaxis, IL-6 driven enhanced migration and pro-proliferative effect of TAMo were validated in a syngeneic TNBC mouse model. Depletion of IL-6 in cancer cells significantly attenuated monocyte infiltration and reversed TAMo-induced cancer cell proliferation. This work reveals the critical role random migration plays in monocyte driven TAMΦ enrichment in a tumor and pinpoints IL-6 as a potential therapeutic target in combination with CCL2 to ameliorate current strategies against TAMΦ infiltration.
Within-species variation eclipses between-species differences inPanconsolation
Authors: Brooker Jake S. , Webb Christine E. , Kordon Stephanie , de Waal Frans B. M. , Clay Zanna 
Published: July 2024

AbstractEmpathy and its subcomponents are well documented throughout the animal kingdom, indicating the deep evolutionary origins of this socioemotional capacity. A key behavioural marker of empathy is consolation, or unsolicited bystander affiliation directed towards distressed others. Consolation has been observed in our closest living relatives, bonobos (Pan paniscus) and chimpanzees (P. troglodytes). However, systematic comparisons are absent, despite potential for interspecific differences. Bonobos are often considered less aggressive, more emotionally sensitive, and more socially tolerant than chimpanzees—key characteristics purported to drive consolation. Furthermore, social and individual factors also appear to drive intraspecific variation in empathy. To address within- and between-species variability inPanconsolation, we systematically tested the consolatory tendencies of large sanctuary-living groups of both species. Bonobos and chimpanzees exhibited similar consolation tendencies; however, within-species analyses revealed further similarities and variation. Bonobo consolation was most often directed towards and received by younger individuals, while chimpanzee consolation was most often directed towards close social partners. In addition, males and females of both species showed decreased consolation with age, with some evidence for chimpanzee males consoling more than young females. Our findings support the notion that within-species variation inPansocio-emotional abilities is greater than between-species differences, highlighting the presence of striking behavioural diversity across our two closest cousins.
NR2F2 is required in the embryonic testis for Fetal Leydig Cell development
Authors: Perea-Gomez Aitana , Bellido-Carreras Natividad , Dhellemmes Magali , Tang Furong , Le Gallo Coralie , Chaboissier Marie-Christine 
Published: July 2024

AbstractMale genital development in XY mammalian fetuses is triggered by the action of hormones, including testosterone, secreted by the developing testes. Defects in this process are a cause for Differences in Sex Development (DSD), one of the most common congenital abnormalities in humans. Fetal Leydig Cells (FLC) play a central role for the synthesis of masculinizing hormones in the developing testes. Yet, the genetic cascade controlling their differentiation is poorly understood. Here we investigate the role of the orphan nuclear receptor NR2F2 (COUP-TFII) in FLC development. We report that NR2F2 is expressed in interstitial progenitor cells of the mouse embryonic testes and is downregulated upon their differentiation into FLC. By using two mouse models for conditional mutation ofNr2f2in the developing testes, we demonstrate that NR2F2 is required for testis morphogenesis and FLC development. NR2F2 acts in interstitial progenitors to regulate the initiation and progression of FLC differentiation. These results establish NR2F2 as an essential regulator of FLC development and steroid hormone synthesis in the mouse fetal testis and provide an entry point to understand the etiology of 46, XY DSD associated with pathogenic NR2F2 variants.
Establishing a Male-Positive Genetic Sexing Strain in the Asian Malaria VectorAnopheles stephensi
Authors: Weng Shih-Che , Chen Fangying , Li Ming , Lee Sammy , Gerry Connor , Turksoy Dylan Can , Akbari Omar S. 
Published: July 2024

AbstractGenetic biocontrol interventions targeting mosquito-borne diseases require the release of male mosquitoes exclusively, as only females consume blood and transmit human pathogens. This reduces the risk of spreading pathogens while enabling effective population control. Robust sex sorting methods to enable early larval sorting in mosquitoes need to be developed to allow for scalable sex sorting for genetic biocontrol interventions. This study applies the SEPARATOR (Sexing Element Produced by Alternative RNA-splicing of A Transgenic Observable Reporter) system, previously developed forAedes aegypti, to the Asian malaria vectorAnopheles stephensi. We hypothesized that the intron from thedoublesexgene inAnopheles gambiaewould function inAn. stephensidue to evolutionary conservation. Our results confirm that the splicing module fromAn. gambiaeoperates effectively inAn. stephensi, demonstrating evolutionary conservation in sex-specific splicing events between these species. This system enables reliable positive male selection from first instar larval to pupal stages. RT-PCR analysis demonstrates that male-specific EGFP expression is dependent ondoublesexsex-specific splicing events. The SEPARATOR system’s independence from sex-chromosome linkage confers resistance to meiotic recombination and chromosomal rearrangements. This approach may facilitate the mass release of males, and the cross-species portability of SEPARATOR establishes it as a valuable tool for genetic biocontrol interventions across various pest species.
MLSPred-Bench: ML-Ready Benchmark Leveraging Seizure Detection EEG data for Predictive Models
Authors: Mohammad Umair , Saeed Fahad 
Published: July 2024

AbstractPredicting epileptic seizures is a significantly challenging task as compared to detection. While electroen-cephalography (EEG) data annotated for detection is available from multiple repositories, they cannot readily be used for predictive modeling. In this paper, we designed and developed a strategy that can be used for converting any EEG big data annotated for detection into ML-ready data suitable for prediction. The generalizability of our strategy is demonstrated by executing it on Temple University Seizure (TUSZ) corpus which is annotated for seizure detection. This execution results in 12 ML-ready datasets, collectively calledMLSPred-Benchbenchmark, which constitutes data for training, validating and testing seizure prediction models. Our strategy uses different variations of seizure prediction horizon (SPH) and the seizure occurrence period (SOP) to make more than 150GB of ML-ready data. To illustrate that the generated data can be used for predictive modeling, we executed an ML model on all the benchmarks which resulted in variable performances when compared with the original model and its performance. We expect that our strategy can be used as a general method to transform seizure detection EEG big data into ML-ready datasets useful for seizure prediction. Our code and related materials will be made available athttps://github.com/pcdslab/MLSPred-Bench.
Oral citrate supplementation mitigates age-associated pathological intervertebral disc calcification in LG/J mice
Authors: Ottone Olivia K. , Mundo Jorge J. , Kwakye Boahen N. , Slaweski Amber , Collins John A. , Wu Qinglin , Connelly Margery A. , Niaziorimi Fatemeh , van de Wetering Koen , Risbud Makarand V. 
Published: July 2024

AbstractDespite the high prevalence of age-dependent intervertebral disc calcification, there is a glaring lack of treatment options for this debilitating pathology. Here, we investigate the efficacy of long-term oral K3Citrate supplementation in ameliorating disc calcification in LG/J mice, a model of spontaneous age-associated disc calcification. K3Citrate successfully reduced the incidence of disc calcification in LG/J mice without deleterious effects on vertebral bone structure, plasma chemistry, and locomotion. Notably, a positive effect on grip strength was evident in treated mice. Spectroscopic investigation of the persisting calcified nodules indicated K3Citrate did not alter the mineral composition and revealed that reactivation of an endochondral differentiation program in endplates may drive LG/J disc calcification. Importantly, K3Citrate reduced calcification incidence without altering the pathological endplate chondrocyte hypertrophy, suggesting mitigation of disc calcification primarily occurred through Ca2+chelation, a conclusion supported by chondrogenic differentiation and Seahorse metabolic assays. Overall, this study underscores the therapeutic potential of K3Citrate as a systemic intervention strategy for disc calcification.TeaserOral citrate mitigates intervertebral disc mineralization in a mouse model of age-dependent spontaneous disc calcification.
Compliance to Iron Folic Acid Supplementation and its associated factors among post-partum mothers of Bharatpur Metropolitan
Authors: Pokhrel Amshu , Bhatta Bimala , Adhikari Anup 
Published: July 2024

AbstractBackgroundAnemia is a major global health issue, especially affecting young children, pregnant and postpartum women, and adolescent girls, with 1.92 billion affected in 2021, notably in sub-Saharan Africa and South Asia. Iron deficiency is a key cause, requiring interventions like iron and folic acid supplementation. Despite efforts in Nepal, anemia prevalence fluctuates, with compliance a concern. This study assesses iron and folic acid supplementation compliance among postpartum mothers in Bharatpur Metropolitan City.MethodA community-based cross-sectional study was conducted among 303 postpartum mothers with babies aged 45days to 1 year in Bharatpur Metropolitan City. Data were collected through face-to-face interviews using a pre-tested questionnaire.ResultsThe compliance rate for iron and folic acid supplementation among postpartum mothers was 48.2%. Among different sociodemographic variables, religion of participants was found to be significantly associated with compliance to iron folic acid supplementation (OR 5.367, 95% CI 1.173-16.636). Moreover, participants having more than four antenatal visits (OR 3.465, 95% CI 1.366-8.792), participants having good knowledge about anemia (OR 5.554, 95% CI 2.485-12.415), and participants having good knowledge about iron and folic acid supplementation (OR 2.442, 95% CI 1.064-5.60) were also significantly associated with higher compliance.ConclusionTo improve IFAS adherence, healthcare providers should focus on health education on the postpartum importance of iron and folic acid supplementation, along with diligent follow-up using culturally tailored strategies. Enhanced compliance will lead to better health outcomes for mothers and their babies.
Protocol for: A Simple, Accessible, Literature-based Drug Repurposing Pipeline
Authors: Lange Maximin , Martyn Meredith , Gogarty Eoin , Braude Philip , Fayez Feras , Carter Ben 
Published: July 2024

AbstractWe will develop a novel approach to drug repurposing, utilising Natural Language Processing (NLP) and Literature Based Discovery (LBD) techniques. This will present a simplified, accessible drug repurposing pipeline using Word2Vec embeddings trained on PubMed abstracts to identify potential new medications to be repurposed. We present this approach in the context of antipsychotics, but it could be repeated for any available medication.The research is structured in three stages:Identification of candidate medications using Word2Vec algorithm trained on scientific literature.Empirical testing of identified candidates using a large hospital dataset to explore protective effects against disease onset.Validation of findings using a second, independent dataset to assess generalizability.This method addresses limitations in current machine learning-based drug repurposing approaches, including lack of external validation and limited accessibility. By leveraging Word2Vec’s ability to capture semantic relationships between words, the study aims to uncover hidden connections in medical literature that may lead to novel therapeutic discoveries.The protocol emphasizes transparency and reproducibility, utilizing publicly available electronic health record (EHR) databases for validation. This approach allows for tangible results even for researchers with limited machine learning expertise, bridging the gap between biomedical and information systems communities.
Genetic Transformer: An Innovative Large Language Model Driven Approach for Rapid and Accurate Identification of Causative Variants in Rare Genetic Diseases
Authors: Liang Lungang , Chen Yulan , Wang Taifu , Jiang Dan , Jin Jishuo , Pang Yanmeng , Na Qin , Liu Qiang , Jiang Xiaosen , Dai Wentao , Tang Meifang , Du Yutao , Peng Dirong , Jin Xin , Zhao Lijian 
Published: July 2024

AbstractBackgroundIdentifying causative variants is crucial for the diagnosis of rare genetic diseases. Over the past two decades, the application of genome sequencing technologies in the field has significantly improved diagnostic outcomes. However, the complexity of data analysis and interpretation continues to limit the efficiency and accuracy of these applications. Various genotype and phenotype-driven filtering and prioritization strategies are used to generate a candidate list of variants for expert curation, with the final report variants determined through knowledge-intensive and labor-intensive expert review. Despite these efforts, the current methods fall short of meeting the growing demand for accurate and efficient diagnosis of rare disease. Recent developments in large language models (LLMs) suggest that LLMs possess the potential to augment or even supplant human labor in this context.MethodsIn this study, we have developed Genetic Transformer (GeneT), an innovative large language model (LLM) driven approach to accelerate identification of candidate causative variants for rare genetic disease. A comprehensive evaluation was conducted between the fine-tuned large language models and four phenotype-driven methods, including Xrare, Exomiser, PhenIX and PHIVE, alongside six pre-trained LLMs (Qwen1.5-0.5B, Qwen1.5-1.8B, Qwen1.5-4B, Mistral-7B, Meta-Llama-3-8B, Meta-Llama-3-70B). This evaluation focused on performance and hallucinations.ResultsGenetic Transformer (GeneT) as an innovative LLM-driven approach demonstrated outstanding performance on identification of candidate causative variants, identified the average number of candidate causative variants reduced from an average of 418 to 8, achieving recall rate of 99% in synthetic datasets. Application in real-world clinical setting demonstrated the potential for a 20-fold increase in processing speed, reducing the time required to analyze each sample from approximately 60 minutes to around 3 minutes. Concurrently, the recall rate has improved from 94.36% to 97.85%. An online analysis platform iGeneT was developed to integrate GeneT into the workflow of rare genetic disease analysis.ConclusionOur study represents the inaugural application of fine-tuned LLMs for identifying candidate causative variants, introducing GeneT as an innovative LLM-driven approach, demonstrating its superiority in both simulated data and real-world clinical setting. The study is unique in that it represents a paradigm shift in addressing the complexity of variant filtering and prioritization of whole exome or genome sequencing data, effectively resolving the challenge akin to finding a needle in a haystack.