bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eg5 Inhibitor SB743921 Causes p53-Dependent Cell Cycle Arrest, Senescence and Death in Tumor Cells
Authors: Abramenko Iaroslav E. , Khamidullina Alvina I. , Kiryukhina Tamara A. , Tvorogova Anna V. , Pavlenko Nataliya G. , Bruter Alexandra V. , Tatarskiy Victor V. 
Published: January 2025

AbstractMitotic inhibitors, such as Vinca alkaloids and taxanes, are one of the most effective chemotherapeutic agents used in the clinic. Despite their advantages, there are drawbacks to their use – primarily development of resistance and a high rate of side-effects, including damage to non-proliferating tissues. A range of new inhibitors targeting mitosis, whose activity does not depend on the binding to tubulin, are currently tested in clinical trials. Among such agents, inhibitors of Eg5 kinesin are highly promising due to their high activity and specificity. Here we show that compared to other drugs that target mitosis, an Eg5 inhibitor, SB743921, preferentially eliminatesTP53-mutated cells and induces irreversible senescence, even after the drug washout, regardless of the p53 status. These effects are not defined by the immediate block of mitosis where SB743921 and a clinically used mitotic inhibitor Ixabepilone induce similar rates of mitotic arrest, apoptosis and induction of p53 and p21, but rather a long-term reaction, with absence of proteins required for replication, such as Cyclin A, E2F1, pRB. While after the washout Ixabepilone-treated cells can exit senescence and resume proliferation, cells treated with SB743921 did not exit the senescent state and did not resume proliferation as based on SA-β-galactosidase staining and EdU incorporation. The remaining senescent cells were effectively eliminated by Bcl2/Bcl-xL/Bcl- w inhibitor ABT-263, showing a potential of the combinational therapy with senolytic drugs. In total, we show the capacity of Eg5-targeting drugs for therapy of high-riskTP53-mutated tumors, which are potentially resistant to clinically approved mitotic inhibitors.
TIME-CoExpress: Temporal Trajectory Modeling of Dynamic Gene Co-expression Patterns Using Single-Cell Transcriptomics Data
Authors: Yang Shuyi , Bussing Anderson , Marra Giampiero , Brinkmeier Michelle L. , Camper Sally A. , Davis Shannon W. , Ho Yen-Yi 
Published: January 2025

AbstractThe rapid advancements of single-cell RNA sequencing (scRNAseq) technology provide high-resolution views of transcriptomic activity within a single cell. Most routine analyses of scRNAseq data focus on individual genes; however, the one-gene-at-a-time analysis is likely to miss meaningful genetic interactions. Gene co-expression analysis addresses this issue by identifying coordinated gene expression changes in response to cellular conditions, such as developmental or temporal trajectory. Identifying differential co-expression gene combinations along the cell temporal trajectory using scRNAseq data can provide deeper insight into the biological processes. Existing approaches for gene co-expression analysis assume a restrictive linear change of gene co-expression. In this paper, we propose a copula-based approach with proper data-driven smoothing functions to model non-linear gene co-expression changes along cellular temporal trajectories. Our proposed approach provides flexibility to incorporate characteristics such as over-dispersion and zero-inflation rate observed in scRNAseq data into the modeling framework. We conducted a series of simulation analyses to evaluate the performance of the proposed algorithm. We demonstrate the implementation of the proposed algorithm using a scRNAseq dataset and identify differential co-expression gene pairs along cell temporal trajectory in pituitary embryonic development comparingNxn−/−mutated versus wild-type mice.
Depicting pathogenesis of osteomyelitis by single cell RNA-sequencing and an involvement ofMorrbidin the autoinflammatory disease
Authors: Huo Qingran , Ding Jiayu , Zhou Hongxi , He Hang , Cai Lorie Chen , Liu Jingjing , Dong Ge , Cai Zhigang 
Published: January 2025

AbstractAutoinflammatory diseases (AIDs) are defined as abnormal activation of the innate immune system leading to spontaneous and uncontrolled inflammation. The AIDs affect bone tissue and lead to chronic recurrent multifocal osteomyelitis (CRMO). However, the etiology and treatment of CRMO remain elusive. A mouse strain,Pstpip2cmo/cmo(cmo:chronic multifocal osteomyelitis), exhibits phenotypic characteristics similar to human CRMO.Morrbidis a long non-coding RNA gene and has been indicated in leukemogenesis in our previous studies. In this study, we demonstrated thatMorrbidandPstpip2are co-expressed in mature myeloid cells and hypothesized a role ofMorrbidin osteomyelitis. ThePstpip2−/−mice have the same phenotype asPstpip2cmo/cmo,mimicking CRMO, while loss ofMorrbidinPstpip2−/−mice significantly inhibited the initiation and progression of CRMO symptoms, as well as the dysregulated activation of myeloid cells and the excessive release of inflammatory cytokines. Furthermore, single-cell RNA-sequencing (scRNA-seq) analysis from thePstpip2−/−mice and the compound mutant mice supports that reduction of osteoclasts and inflammatory cells caused byMorrbidloss. The study systematically profiles the etiology of CRMO by scRNA-seq and warrants that inhibiting the lifespan of inflammatory myeloid cells by targetingMorrbidis an effective therapeutic strategy for osteomyelitis.HighlightsWe generated a frameshift mutant mouse strainPstpip2−/−, which have a classic CRMO-like phenotype as same asPstpip2cmo/cmoand could be used for testing various anti-inflammation perturbations.Loss ofMorrbidsignificantly inhibited the autoinflammatory symptoms inPstpip2−/−mice, suggesting thatMorrbidis a novel target for mitigating CRMO.scRNA-seq analysis of the affected bone marrow cells inPstpip2−/−revealed the abnormalities of osteoclasts (OC), neutrophils (NE) and granulocyte macrophage progenitors (GMP) in both their fractions and inflammatory activities.Upon loss ofMorrbid, we observed reduced composition and proliferation of OC and decreased activity ofNfkb2andRelain the compound mutants.
E2F1 Suppresses EBV Lytic Reactivation through Cellular and Viral Transcriptional Networks
Authors: Biswas Joyanta , Ali SK Asif , Malik Samaresh , Nag Subhadeep , Mukherjee Piyali , Saha Abhik 
Published: January 2025

AbstractLatent EBV infection is causally associated with various B-cell malignancies, while periodic lytic-cycle replication is essential for sustaining viral progeny. Lytic cycle induction represents a promising therapeutic strategy for EBV-associated neoplasms. Therefore, uncovering the mechanisms that regulate EBV lytic-cycle reactivation is pivotal for understanding viral pathogenesis and advancing novel therapies. Our genome-wide transcriptomic analysis reveals that E2F1 expression is transcriptionally activated during EBV latent infection in B-lymphocytes but significantly suppressed during lytic cycle reactivation. While ectopic E2F1 expression suppresses lytic replication, E2F1 depletion markedly accelerates this process. Mechanistically, we establish that E2F1 and the lytic transactivator BZLF1 form a negative transcriptional feedback loop, tightly controlling viral lytic replication. Furthermore, E2F1 positively regulates c-Myc expression and together they repress the leaky BZLF1 expression during latency. Importantly, c-Myc does not influence E2F1 expression, nor does BZLF1 modulate c-Myc transcription, underlining a distinct regulatory hierarchy. In sum, our findings reveal that EBV tightly controls the latent-to-lytic switch through precise regulation of E2F1 expression, positioning E2F1 as a pivotal regulator of both cellular and viral gene expression.SynopsisEBV coordinates the latent-to-lytic switch by sensing E2F1 abundance, which acts as a crucial transcriptional regulator of both cellular and viral gene expressions.During EBV latent infection, E2F1 promotes c-Myc transcription, and together they suppress EBV lytic cycle transactivator BZLF1 expression.E2F1 and BZLF1 form a negative feedback loop in order to control each other’s transcriptions.BZLF1-driven controlled E2F1 expression successively inhibits c-Myc level, thereby stimulating EBV lytic cycle reactivation.BZLF1 does not regulate c-Myc, nor does c-Myc reciprocally regulate E2F1, emphasizing a unidirectional regulatory hierarchy.
Unmasking Epstein-Barr Role in Gastric Carcinogenesis: A Gene Expression Approach to Virus-Positive Tumors
Authors: Santos da Silva Valeria Cristiane , Pereira Diego , Avelar Daniel de Souza , Silva Jéssica Manoelli Costa da , Mourão Ronald Matheus da Silva , Silva Rubem Ferreira da , Marcon Davi Josué , Magalhães Leandro , Vidal Amanda Ferreira , Neotti Tatiane , Anaissi Ana Karyssa Mendes , Barra Williams Fernandes , Casseb Samir Mansour , Ribeiro dos Santos Andrea Kely Campos , Demachki Samia , Ishak Geraldo , Assumpção Paulo Pimentel de , Moreira Fabiano , Burbano Rommel Mario Rodriguez 
Published: January 2025

Human gammaherpesvirus 4 or Epstein-Barr virus (EBV) is an oncogenic virus linked to malignancies like gastric adenocarcinoma. Notably, EBV infection induces genetic and epigenetic modifications that play a crucial role in oncogenesis and tumor progression, underscoring the importance of analyzing viral gene expression in the context of gastric cancer (GC) to elucidate its unique characteristics. This study aimed to perform a molecular characterization of EBV gene expression using next-generation sequencing (NGS). The analysis included human gene expression patterns in EBV-positive and EBV-negative samples and the expression of viral genes in EBV-positive samples. The study received approval from the Ethics and Research Committee of João de Barros Barreto University Hospital under reference number 47580121.9.0000.5634. It utilized 76 tumor tissue samples from patients with gastric cancer who had undergone surgical resection, and both fresh and paraffin-embedded samples were gathered for total RNA sequencing (RNA-seq) and in situ hybridization (ISH). The RNA-seq was conducted in a pair-end manner on the NextSeq® platform (Illumina®, US). The NextSeq® 500 MID Output V2 kit - 150 cycles (Illumina®) were utilized following the manufacturer's instructions. ISH targeting RNA-1 of EBER1 (Y5200, DAKO, Carpinteria) was performed using the automated Dako system. Molecular characterization was conducted using the Kraken2 software. Subsequently, to elucidate the mechanisms through which EBV may influence gastric cancer, we analyzed the patterns of human gene expression in EBV-positive and EBV-negative samples. Of the 76 samples, 8 were classified as EBV-positive according to the applied methodology. Our analysis identified approximately 834 differentially expressed genes, 92 of which exhibited an AUC > 0.85. These genes are implicated in tumor progression, cellular metabolism, and both innate and adaptive immune responses. Additionally, viral genes expressed in the positive samples were evaluated, and we found manifestations of both lytic phase and latent phase genes. Finally, our study presents an efficient strategy for molecular classification of EBV-positive gastric cancer based on NGS and shows the effects of EBV on human gene expression.
Fexinidazole and Corallopyronin A targetWolbachia-infected sheath cells present in filarial nematodes
Authors: Chappell Laura , Peguero Ricardo , Conner William R , Fowler Sommer , Cooper Brandon , Pfarr Kenneth , Hoerauf Achim , Lustigman Sara , Sakanari Judy , Sullivan William 
Published: January 2025

SummaryThe discovery of the endosymbiotic bacteriaWolbachiaas an obligate symbiont of filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab and clinical studies have yielded promising results, recent animal studies reveal thatWolbachialevels may rebound following treatment with suboptimal doses of the antibiotic rifampicin. Previous work showed that a likely source of the bacterial rebound in females were dense clusters ofWolbachiain ovarian tissue. The number, size, and density of theseWolbachiaclusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of theWolbachiaclusters inBrugia pahangi(wBp) and identify drugs that also target them. We have evidence that theWolbachiaclusters originate from newly formed sheath cells adjacent to the ovarian Distal Tip Cells. The dramatically enlarged volume of an infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clusteredWolbachiapresent within the sheath cells exhibit a distinct morphology and form direct connections with the oocyte membrane and possibly the cytoplasm. This includes membrane-based channels providing a connection betweenWolbachia-infected sheath cells and oocytes. We also determined that theWolbachiawithin the sheath cells are either quiescent or replicating at a very low rate. Screens of known antibiotics and other drugs revealed that two drugs, Fexinidazole and Corallopyronin A, significantly reduced the number of clusteredWolbachialocated within the sheath cells.
TGR5-mediated Ca2+signaling in cholangiocytes
Authors: Chen Xuanmeng , Al-Shebel Amr , Pebrier Thibault , Tordjmann Thierry , Dellis Olivier 
Published: January 2025

ABSTRACTThe Bile Acid TGR5 receptor is well known to active the cAMP pathways leading to CFTR activation and Cl−ions secretion, needed for bile alkalinization and hydration. However, during cystic fibrosis development, only 10 to 15% of the patients present liver defect due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, TGR5 stimulation has also been reported to mobilize Ca2+ions. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca2+release from the endoplasmic reticulum and an influx of extracellular Ca2+ions. Next, this Ca2+mobilization allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca2+mobilization. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP3-Ca2+in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca2+-activated Cl−channels TMEM16A, in parallel to CFTR in non-CF cells, or to compensate in part or in totality the loss of CFTR in CF patients.HIGHLIGHTSBile acid receptor TGR5 induces Ca2+mobilization in cholangiocytesCa2+ions come from the endoplasmic reticulum and from the extracellular mediumP2Y receptors are trans-activated by TGR5 and reinforce the Ca2+mobilizationThis Ca2+pathways might compensate the CFTR defect in CF patients
CD33KO-CD33-mesothelin loop CAR design avoids fratricide and improves efficacy of iNK cells against acute myeloid leukemia
Authors: Wang Yao , Zheng Xiujuan , Wang Zhiqian , Xiao Ziyun , Lin Yunqing , Zhang Fan , Liu Yanhong , Liu Pengcheng , Weng Qitong , Zhang Leqiang , Xia Chengxiang , Huang Dehao , Liu Lijuan , Zhu Yanping , Zhang Qi , Qi Hanmeng , Chen Yi , Shen Yiyuan , Zhang Chenyuan , Xu Jiacheng , Zhao Yaoqin , Wu Jiaxin , Wang Tongjie , Zhang Mengyun , Li Minming , Qian Wenbin , Liang Aibin , Du Xin , Yang Wenyu , Chen Qi , Zhu Xiaofan , Hu Fangxiao , Wang Jinyong 
Published: January 2025

AbstractAcute myeloid leukemia (AML) patients are often older, which brings challenges of endurance and persistent efficacy of autologous CAR-T cell therapies. Allogenic CAR-NK cell therapies may offer reduced toxicities and enhanced anti-leukemic potential against AML. In this study, we designed a novel CD33-mesothelin loop CAR (Loop CAR) and evaluated its anti-tumor efficacy in human umbilical cord blood-derived NK (UCB-NK) cells and human pluripotent stem cell-derived NK (hPSC-iNK) cells. The Loop CAR exhibited superior cytotoxicity against dual-antigen-positive tumor cell lines and primary AML cells. To further avoid fratricide caused by endogenous CD33 expression in NK cells, we established a hPSC-derived cell line via knockout of CD33 gene (CD33KO) and engineered Loop CAR. Rather than enforced expression of exogenous CD16, we generated abundant mature CD33KO-Loop CAR-iNK cells highly expressing endogenous CD16 via an organoid induction approach. This innovative strategy effectively mitigated NK cell fratricide and significantly enhanced CD33 and mesothelin-mediated specific cytotoxicity. Moreover, the CD33KO-Loop CAR-iNK cells demonstrated superior tumor-killing activity in AML xenograft mice and significantly prolonged survival. hPSC-derived CD33KO-Loop CAR-iNK cells possess unique advantages and translational potential for treating AML.
MeQTL Mapping in African American Hepatocytes Reveals Shared Genetic Regulators of DNA Methylation and Gene Expression
Authors: Carver Kathryn , Clark Carolina , Zhong Yizhen , Yang Guang , Mishra Mrinal , Alarcon Cristina , Perera Minoli 
Published: January 2025

AbstractMethylation quantitative trait loci (meQTL) mapping can provide insight into the genetic architecture underlying the epigenome by identifying single-nucleotide polymorphisms (SNPs) associated with differential methylation at methylation sites (CpGs) across the genome. Given that the epigenetic architecture underlying differences in gene expression can vary across racial populations, performing epigenomic studies in African Americans is crucial for understanding the interplay between genetic variation, DNA methylation, and gene expression in this understudied group. By performing cis-meQTL mapping in African American hepatocytes, we identified 410,186 cis-meQTLs associated with methylation at 24,425 CpGs in the liver. Through colocalization analysis, we found that 18,206 of these meQTLs are also colocalized with known liver eQTLs. Additionally, we found that using African American eQTL data results in an increased ability to detect additional colocalized variants that exhibit strong differences in allele frequency between people of European and African ancestry. Furthermore, the presence of smaller linkage disequilibrium blocks in African Americans allows us to identify narrower genomic regions of potentially causal variants compared to when data from Europeans is used. Importantly, these colocalized SNPs are significantly enriched for genetic associations with lipid and inflammatory traits in the GWAS catalog, suggesting that DNA methylation may contribute to the etiologies of these diseases. Furthermore, while it is generally presumed that the genetic regulation of DNA methylation is shared between blood and liver, we found that only 5.4% of African American liver meQTLs colocalize with blood meQTLs. Overall, our results reveal that studying African American populations results in the identification of additional genetic and epigenetic factors that may regulate gene expression in the liver, thereby expanding our understanding of gene regulation in African Americans.
Single-cell and spatial transcriptomics reveal the pathogenesis of chronic granulomatous disease in a natural model
Authors: Yu Hanzhi , Zhang Guorong , Ma Yunxi , Ding Jiayu , Liu Jingjing , Zhou Zhiliang , Jiao Shaozhuo , Dong Ge , Cai Zhigang 
Published: January 2025

AbstractGenetic defects in NOX2 can cause chronic granulomatous disease (CGD), characterized by increased susceptibility to infections and pronounced inflammatory responses that lead to granuloma formation. We developed a CGD model usingNcf2-/-mice through controlled environmental exposure. Unlike in specific pathogen-free environment, these mice spontaneously developed pulmonary granulomas under clean-grade conditions. Employing single-cell RNA sequencing, we observed an expansion of neutrophils and monocyte-derived macrophages (MDMs) within the lung tissue, identifying pro-inflammatory NOS2high-neutrophils and a distinct MDMs subset marked by NOS2 and ARG1. Spatial transcriptomics demonstrated that NOS2high-neutrophils were located at the core area, while the MDMs subset was positioned at the periphery, facilitating extracellular matrix remodeling. Pharmacological targeting of MIF, deletion of the pro-survival geneMorrbid, and elimination ofIl1r1all suppressed granuloma formation by mitigating inflammation. This study underscores how environmental control can establish a natural CGD model, elucidates the mechanisms of granuloma formation, and develops potent therapeutic interventions.HighlightsThrough installing a mutation in a NOX2 subunit geneNcf2and changing the husbandry environment, we generated a natural CGD mouse model with progressive pulmonary granuloma formation.NOS2highneutrophils located in the core region of CGD lung granulomas, exhibit a pro-inflammatory transcriptional profile.Monocyte-derived macrophages marked byNos2andArg1are located at the periphery of granulomas and exhibit a profibrotic transcriptional profile.The transcriptomic studies assist the development of three effective perturbations for treating the rare disease CGD via targetingIl1r1, Morrbid,andMifrespectively.
Benchmarking Data Leakage on Link Prediction in Biomedical Knowledge Graph Embeddings
Authors: Brière Galadriel , Stosskopf Thomas , Loire Benjamin , Baudot Anaïs 
Published: January 2025

AbstractIn recent years, Knowledge Graphs (KGs) have gained significant attention for their ability to organize complex biomedical knowledge into entities and relationships. Knowledge Graph Embedding (KGE) models facilitate efficient exploration of KGs by learning compact data representations. These models are increasingly applied to biomedical KGs for link prediction, for instance to uncover new therapeutic uses for existing drugs.While numerous KGE models have been developed and benchmarked for link prediction, existing evaluations often over-look the critical issue of data leakage. Data leakage leads the model to learn patterns it would not encounter when deployed in real-world settings, artificially inflating performance metrics and compromising the overall validity of benchmark results. In machine learning, data leakage can arise when (1) there is inadequate separation between training and test sets, (2) the model leverages illegitimate features, or (3) the test set does not accurately reflect real-world inference scenarios.In this study, we implement a systematic procedure to control train-test separation for KGE-based link prediction and demonstrate its impact on models’ performance. In addition, through permutation experiments, we investigate the potential use of node degree as an illegitimate predictive feature, finding no evidence of such leveraging. Finally, by evaluating KGE models on a curated dataset of rare disease drug indications, we demonstrate that performance metrics achieved on real-world drug repurposing tasks are substantially worse than those obtained on drug-disease indications sampled from the KG.