tbuckley/cabot-search huggingface dataset:
Phosphocreatine promotes epigenetic reprogramming to facilitate glioblastoma growth through stabilizing BRD2
Authors: Lishu Chen, Qinghui Qi, Xiaoqing Jiang, Jin Wu, Yuanyuan Li, Zhaodan Liu, Yan Cai, Haowen Ran, Songyang Zhang, Cheng Zhang, Huiran Wu, Shuailiang Cao, Lanjuan Mi, Dake Xiao, Haohao Huang, Shuai Jiang, Jiaqi Wu, Bohan Li, Jiong Xie, Ji Qi, Fangye Li, Panpan Liang, Qiuying Han, Min Wu, Wenchao Zhou, Chenhui Wang, Weina Zhang, Xin Jiang, Kun Zhang, Huiyan Li, Xuemin Zhang, Ailing Li, Tao Zhou, Jianghong Man
Journal: Cancer Discovery (2024)

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase, mediated by Zinc finger E-box binding homeobox 1. PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine (cCr) leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment. Significance: Glioblastoma (GBM) exhibits an adaptable metabolism crucial for survival and therapy resistance. We demonstrate that GBM stem cells modify their epigenetics by producing phosphocreatine (PCr), which prevents bromodomain containing protein 2 (BRD2) degradation and promotes accurate chromosome segregation. Disrupting PCr biosynthesis impedes tumor growth and improves the efficacy of BRD2 inhibitors in mouse GBM models.
DNA methylation remodeling and the functional implication during male gametogenesis in rice
Authors: Xue Li, Bo Zhu, Yue Lu, Feng Zhao, Qian Liu, Jiahao Wang, Miaomiao Ye, Siyuan Chen, Junwei Nie, Lizhong Xiong, Yu Zhao, Changyin Wu, Dao-Xiu Zhou
Journal: Genome biology (2024)

Abstract Background Epigenetic marks are reprogrammed during sexual reproduction. In flowering plants, DNA methylation is only partially remodeled in the gametes and the zygote. However, the timing and functional significance of the remodeling during plant gametogenesis remain obscure. Results Here we show that DNA methylation remodeling starts after male meiosis in rice, with non-CG methylation, particularly at CHG sites, being first enhanced in the microspore and subsequently decreased in sperm. Functional analysis of rice CHG methyltransferase genes CMT3a and CMT3b indicates that CMT3a functions as the major CHG methyltransferase in rice meiocyte, while CMT3b is responsible for the increase of CHG methylation in microspore. The function of the two histone demethylases JMJ706 and JMJ707 that remove H3K9me2 may contribute to the decreased CHG methylation in sperm. During male gametogenesis CMT3a mainly silences TE and TE-related genes while CMT3b is required for repression of genes encoding factors involved in transcriptional and translational activities. In addition, CMT3b functions to repress zygotic gene expression in egg and participates in establishing the zygotic epigenome upon fertilization. Conclusion Collectively, the results indicate that DNA methylation is dynamically remodeled during male gametogenesis, distinguish the function of CMT3a and CMT3b in sex cells, and underpin the functional significance of DNA methylation remodeling during rice reproduction.
Bento: a toolkit for subcellular analysis of spatial transcriptomics data
Authors: Clarence K. Mah, Noorsher Ahmed, Nicole A. Lopez, Dylan C. Lam, Avery Pong, Alexander Monell, Colin Kern, Yuanyuan Han, Gino Prasad, Anthony J. Cesnik, Emma Lundberg, Quan Zhu, Hannah Carter, Gene W. Yeo
Journal: Genome biology (2024)

Abstract The spatial organization of molecules in a cell is essential for their functions. While current methods focus on discerning tissue architecture, cell–cell interactions, and spatial expression patterns, they are limited to the multicellular scale. We present Bento, a Python toolkit that takes advantage of single-molecule information to enable spatial analysis at the subcellular scale. Bento ingests molecular coordinates and segmentation boundaries to perform three analyses: defining subcellular domains, annotating localization patterns, and quantifying gene–gene colocalization. We demonstrate MERFISH, seqFISH + , Molecular Cartography, and Xenium datasets. Bento is part of the open-source Scverse ecosystem, enabling integration with other single-cell analysis tools.
Species-aware DNA language models capture regulatory elements and their evolution
Authors: Alexander Karollus, Johannes Hingerl, Dennis Gankin, Martin Grosshauser, Kristian Klemon, Julien Gagneur
Journal: Genome biology (2024)

Abstract Background The rise of large-scale multi-species genome sequencing projects promises to shed new light on how genomes encode gene regulatory instructions. To this end, new algorithms are needed that can leverage conservation to capture regulatory elements while accounting for their evolution. Results Here, we introduce species-aware DNA language models, which we trained on more than 800 species spanning over 500 million years of evolution. Investigating their ability to predict masked nucleotides from context, we show that DNA language models distinguish transcription factor and RNA-binding protein motifs from background non-coding sequence. Owing to their flexibility, DNA language models capture conserved regulatory elements over much further evolutionary distances than sequence alignment would allow. Remarkably, DNA language models reconstruct motif instances bound in vivo better than unbound ones and account for the evolution of motif sequences and their positional constraints, showing that these models capture functional high-order sequence and evolutionary context. We further show that species-aware training yields improved sequence representations for endogenous and MPRA-based gene expression prediction, as well as motif discovery. Conclusions Collectively, these results demonstrate that species-aware DNA language models are a powerful, flexible, and scalable tool to integrate information from large compendia of highly diverged genomes.
Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response
Authors: Qingqing Qin, Ying Zhou, Jintao Guo, Qinwei Chen, Weiwei Tang, Yuchen Li, Jun You, Qiyuan Li
Journal: Genome Medicine (2024)

Abstract Background Aberrant DNA methylation is a major characteristic of cancer genomes. It remains unclear which biological processes determine epigenetic reprogramming and how these processes influence the variants in the cancer methylome, which can further impact cancer phenotypes. Methods We performed pairwise permutations of 381,900 loci in 569 paired DNA methylation profiles of cancer tissue and matched normal tissue from The Cancer Genome Atlas (TCGA) and defined conserved differentially methylated positions (DMPs) based on the resulting null distribution. Then, we derived independent methylation signatures from 2,465 cancer-only methylation profiles from the TCGA and 241 cell line-based methylation profiles from the Genomics of Drug Sensitivity in Cancer (GDSC) cohort using nonnegative matrix factorization (NMF). We correlated DNA methylation signatures with various clinical and biological features, including age, survival, cancer stage, tumor immune microenvironment factors, and immunotherapy response. We inferred the determinant genes of these methylation signatures by integrating genomic and transcriptomic data and evaluated the impact of these signatures on cancer phenotypes in independent bulk and single-cell RNA/methylome cohorts. Results We identified 7,364 differentially methylated positions (2,969 Hyper-DMPs and 4,395 Hypo-DMPs) in nine cancer types from the TCGA. We subsequently retrieved three highly conserved, independent methylation signatures (Hyper-MS1, Hypo-MS1, and Hypo-MS4) from cancer tissues and cell lines based on these Hyper and Hypo-DMPs. Our data suggested that Hypo-MS4 activity predicts poor survival and is associated with immunotherapy response and distant tumor metastasis, and Hypo-MS4 activity is related to TP53 mutation and FOXA1 binding specificity. In addition, we demonstrated a correlation between the activities of Hypo-MS4 in cancer cells and the fractions of regulatory CD4 + T cells with the expression levels of immunological genes in the tumor immune microenvironment. Conclusions Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.
Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression
Authors: Zegeng Chen, He Huang, Huangming Hong, Huageng Huang, Huawei Weng, Le Yu, Jian Xiao, Zhao Wang, Xiaojie Fang, Yuyi Yao, Jia-Xing Yue, Tongyu Lin
Journal: Genome Medicine (2024)

Abstract Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3 , TP53 , and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9 , DST , and RBMX . In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.
CAR T-cell therapy—paving the way for sensitized kidney transplant patients
Authors: Tambi Jarmi, Yan Luo, Rose Mary Attieh, Yaqing Qie, Martha E. Gadd, Tanya Hundal, Shennen Mao, Hemant S. Murthy, Burcin C. Taner, Mohamed A. Kharfan-Dabaja, Hong Qin
Journal: Kidney International (2024)
Dietary fasting and time-restricted eating in Huntington’s disease: therapeutic potential and underlying mechanisms
Authors: Russell G. Wells, Lee E. Neilson, Andrew W. McHill, Amie L. Hiller
Journal: Translational Neurodegeneration (2024)

Abstract Huntington's disease (HD) is a devastating neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein, resulting from a CAG repeat expansion in the huntingtin gene HTT . HD is characterized by a variety of debilitating symptoms including involuntary movements, cognitive impairment, and psychiatric disturbances. Despite considerable efforts, effective disease-modifying treatments for HD remain elusive, necessitating exploration of novel therapeutic approaches, including lifestyle modifications that could delay symptom onset and disease progression. Recent studies suggest that time-restricted eating (TRE), a form of intermittent fasting involving daily caloric intake within a limited time window, may hold promise in the treatment of neurodegenerative diseases, including HD. TRE has been shown to improve mitochondrial function, upregulate autophagy, reduce oxidative stress, regulate the sleep–wake cycle, and enhance cognitive function. In this review, we explore the potential therapeutic role of TRE in HD, focusing on its underlying physiological mechanisms. We discuss how TRE might enhance the clearance of mHTT, recover striatal brain-derived neurotrophic factor levels, improve mitochondrial function and stress-response pathways, and synchronize circadian rhythm activity. Understanding these mechanisms is critical for the development of targeted lifestyle interventions to mitigate HD pathology and improve patient outcomes. While the potential benefits of TRE in HD animal models are encouraging, future comprehensive clinical trials will be necessary to evaluate its safety, feasibility, and efficacy in persons with HD.
Pathogen-specific alterations in intestinal microbiota precede urinary tract infections in preterm infants: a longitudinal case-control study
Authors: Luyang Hong, Yihuang Huang, Junyan Han, Shujuan Li, Lan Zhang, Qi Zhou, Xincheng Cao, Weiyin Yu, Xinhui Guo, Yi Yang, Yufeng Zhou, Weili Yan, Shangyu Hong, Siyuan Jiang, Yun Cao
Journal: Gut Microbes (2024)

Urinary tract infections (UTIs) are among the most common late-onset infections in preterm infants, characterized by nonspecific symptoms and a pathogenic spectrum that diverges from that of term infants and older children, which present unique diagnostic and therapeutic challenges. Existing data on the role of gut microbiota in UTI pathogenesis in this demographic are limited. This study aims to investigate alterations in gut microbiota and fecal calprotectin levels and their association with the development of UTIs in hospitalized preterm infants. A longitudinal case-control study was conducted involving preterm infants admitted between January 2018 and October 2020. Fecal samples were collected weekly and analyzed for microbial profiles and calprotectin levels. Propensity score matching, accounting for key perinatal factors including age and antibiotic use, was utilized to match samples from UTI-diagnosed infants to those from non-UTI counterparts. Among the 151 preterm infants studied, 53 were diagnosed with a UTI, predominantly caused by Enterobacteriaceae (79.3%) and Enterococcaceae (19.0%). Infants with UTIs showed a significantly higher abundance of these families compared to non-UTI infants, for both Gram-negative and positive pathogens, respectively. Notably, there was a significant pre-UTI increase in the abundance of pathogen-specific taxa in infants later diagnosed with UTIs, offering high predictive value for early detection. Shotgun metagenomic sequencing further confirmed the dominance of specific pathogenic species pre-UTI and revealed altered virulence factor profiles associated with Klebsiella aerogenes and Escherichia coli infections. Additionally, a decline in fecal calprotectin levels was observed preceding UTI onset, particularly in cases involving Enterobacteriaceae. The observed pathogen-specific alterations in the gut microbiota preceding UTI onset offer novel insight into the UTI pathogenesis and promising early biomarkers for UTIs in preterm infants, potentially enhancing the timely management of this common infection. However, further validation in larger cohorts is essential to confirm these findings.
Interatrial shunt therapy in advanced heart failure: Outcomes from the open‐label cohort of the RELIEVE‐HF trial
Authors: Josep Rodés‐Cabau, JoAnn Lindenfeld, William T. Abraham, Michael R. Zile, Saibal Kar, Antoni Bayés‐Genís, Neal Eigler, Richard Holcomb, Julio Núñez, Elizabeth Lee, Michal Laufer Perl, Gil Moravsky, Michael Pfeiffer, John Boehmer, John Gorcsan, Jeroen J. Bax, Stefan Anker, Gregg W. Stone
Journal: European Journal of Heart Failure (2024)
Correction: CircPTK2 (hsa_circ_0005273) as a novel therapeutic target for metastatic colorectal cancer
Authors: Hongbao Yang, Xiaobo Li, Qingtao Meng, Hao Sun, Shenshen Wu, Weiwei Hu, Guilai Liu, Xianjing Li, Yong Yang, Rui Chen
Journal: Molecular Cancer (2024)
Enhancing HepG2 cell apoptosis with a combined nanoparticle delivery of miR-128-3p agomir and Oroxin B: A novel drug delivery approach based on PI3K-AKT and VEGF pathway crosstalk
Authors: Hechen Wang, Xudan Shen, Xinlan Zhu, Su Zeng, Sheng Cai
Journal: Asian Journal of Pharmaceutical Sciences (2024)

Hepatocellular carcinoma (HCC) shows the highest morbidity among liver cancers and accounts for a major factor inducing cancer-associated mortality globally. It is characterized by genetic mutations in hepatocytes, leading to uncontrolled cell growth and proliferation. Treatment options for HCC include surgery, chemotherapy, and immunotherapy. But chemotherapeutics, which focus on single-targeted drug therapy, are still associated with certain limitations and may affect the treatment outcomes. Compared with chemotherapy drugs, natural products also show the anticancer effect of HCC and hypotoxicity, but overall low activity of natural products limits their further application. MiRNAs can modulate post-transcriptional functions of target genes. An increasing body of evidence has demonstrated that miRNAs are the key regulators in HCC by targeting different molecules in different signaling pathways. However, miRNAs are fragile and liable to catabolism by RNases in serum and other body fluids and small molecules separated from natural products may have limited bio-availability. According to this background, a chitosan based, targeted sustained-release nanoparticle delivery miR-128-3p agomir (NA-miR-128-3p) was developed in this work. This nanoparticle was prepared by pentasodium tripolyphosphate (TPP), chitosan hydrochloride, and miR-128-3p agomir with target aptamer which was loaded into the chitosan nanoparticle by self-assembly. It can intervene in HCC progress by affecting AKT1 expression. Based on this, a novel, efficient, long-acting, multi-mechanism, low-dosage combination drug delivery strategy was proposed in this work and showed a prominent anti-tumor effect. NA-miR-128-3p combined with natural product Oroxin B significantly affected HCC progression by the interference with VEGF and PI3K-AKT pathways, better than using NA-miR-128-3p and Oroxin B alone. Taken together, this nanoparticle and combinative administration compensate for the shortcomings of the fragile RNA drugs and the low activity of natural products, with high prospects in HCC treatment.
Relationships between lung function, allergy, and wheezing in urban children
Authors: Aya Konno-Yamamoto, Vinay Goswamy, Agustin Calatroni, Peter J. Gergen, Molly Johnson, Ronald L. Sorkness, Leonard B. Bacharier, George T. O’Connor, Meyer Kattan, Robert A. Wood, Lisa Gagalis, Cynthia M. Visness, James E. Gern
Journal: Journal of Allergy and Clinical Immunology (2024)
A 10‐year follow‐up of high‐dose ambroxol treatment combined with enzyme replacement therapy for neuropathic Gaucher disease
Authors: Soojin Hwang, Hyunwoo Bae, Ji‐Hee Yoon, Dohyung Kim, Hyo‐Sang Do, Sun Hee Heo, Soyoung Kim, Han‐Wook Yoo, Majdolen Istaiti, Ari Zimran, Beom Hee Lee
Journal: American Journal of Hematology (2024)

High-dose ambroxol therapy combined with ERT in patients with neuropathic Gaucher disease.
Association Between Chest Compression Pause Duration and Survival After Pediatric In-Hospital Cardiac Arrest
Authors: Kasper G. Lauridsen, Ryan W. Morgan, Robert A. Berg, Dana E. Niles, Monica E. Kleinman, Xuemei Zhang, Heather Griffis, Jimena Del Castillo, Sophie Skellett, Javier J. Lasa, Tia T. Raymond, Robert M. Sutton, Vinay M. Nadkarni
Journal: Circulation (2024)

The association between chest compression (CC) pause duration and pediatric in-hospital cardiac arrest survival outcomes is unknown. The American Heart Association has recommended minimizing pauses in CC in children to <10 seconds, without supportive evidence. We hypothesized that longer maximum CC pause durations are associated with worse survival and neurological outcomes.
Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation
Authors: Konstantinos Zifkos, Magdalena L. Bochenek, Rajinikanth Gogiraju, Stéphane Robert, Denise Pedrosa, Klytaimnistra Kiouptsi, Kateryna Moiko, Mathias Wagner, Felix Mahfoud, Philippe Poncelet, Thomas Münzel, Wolfram Ruf, Christoph Reinhardt, Laurence Panicot-Dubois, Christophe Dubois, Katrin Schäfer
Journal: Circulation Research (2024)

Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutrophil adhesion to End.PTP1B-KO endothelial cells in vitro. Circulating levels of annexin V+ procoagulant endothelial CD62E+ (E-selectin) and neutrophil (Ly6G+) extracellular vesicles were also elevated in End.PTP1B-KO mice after inferior vena cava ligation. Higher plasma MPO (myeloperoxidase) and Cit-H3 (citrullinated histone-3) levels and neutrophil elastase activity indicated neutrophil activation and extracellular trap formation. Infusion of End.PTP1B-KO extracellular vesicles into C57BL/6J wild-type mice most prominently enhanced the recruitment of endogenous neutrophils, and this response was blunted in VWF-deficient mice or by VWF-blocking antibodies. Reduced PTP1B binding and tyrosine dephosphorylation of SNAP23 (synaptosome-associated protein 23) resulting in increased VWF exocytosis and neutrophil adhesion were identified as mechanisms, all of which could be restored by NF-κB kinase inhibition using BAY11-7082. Our findings show that endothelial PTP1B deletion promotes venous thromboinflammation by enhancing SNAP23 phosphorylation, endothelial VWF exocytosis, and neutrophil recruitment.