tbuckley/cabot-search huggingface dataset:
Modeling Cardiovascular Protection With SGLT Inhibition in Type 1 Diabetes: A Risk-Based Approach to Guide Therapy?
Authors: Luxcia Kugathasan, Pritha Dutta, Massimo Nardone, Vikas S. Sridhar, David J.T. Campbell, Anita T. Layton, Bruce A. Perkins, Sean Barbour, Tony K.T. Lam, Adeera Levin, Leif Erik Lovblom, Istvan Mucsi, Remi Rabasa-Lhoret, Valeria E. Rac, Peter Senior, Ronald J. Sigal, Aleksandra Vukobradovic, Frederik Persson, Elisabeth B. Stougaard, Alessandro Doria, David Z.I. Cherney
Journal: Diabetes Care (2025)
Disrupted Minor Intron Splicing Activates Reductive Carboxylation-mediated Lipogenesis to Drive Metabolic Dysfunction-associated Steatotic Liver Disease Progression
Authors: Yinkun Fu, Xin Peng, Hongyong Song, Xiaoyun Li, Yang Zhi, Jieting Tang, Yifan Liu, Ding Chen, Wenyan Li, Jing Zhang, Jing Ma, Ming He, Yimin Mao, Xu-Yun Zhao
Journal: Journal of Clinical Investigation (2025)

Aberrant RNA splicing is tightly linked to diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we revealed that minor intron splicing, a unique and conserved RNA processing event, is largely disrupted upon the progression of metabolic dysfunction-associated steatohepatitis (MASH) in mice and humans. We demonstrated deficiency of minor intron splicing in the liver induces MASH transition upon obesity-induced insulin resistance and LXR activation. Mechanistically, inactivation of minor intron splicing leads to minor intron retention of Insig1 and Insig2, resulting in premature termination of translation, which drives proteolytic activation of SREBP1c. This mechanism is conserved in human patients with MASH. Notably, disrupted minor intron splicing activates glutamine reductive metabolism for de novo lipogenesis through the induction of Idh1, which causes the accumulation of ammonia in the liver, thereby initiating hepatic fibrosis upon LXR activation. Ammonia clearance or IDH1 inhibition blocks hepatic fibrogenesis and mitigates MASH progression. More importantly, the overexpression of Zrsr1 restored minor intron retention and ameliorated the development of MASH, indicating that dysfunctional minor intron splicing is an emerging pathogenic mechanism that drives MASH progression. Additionally, reductive carboxylation flux triggered by minor intron retention in hepatocytes serves as a crucial checkpoint and potential target for MASH therapy.
Absence of intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia
Authors: Yongbin Chen, Scott M. Johnson, Stephanie D. Burr, Davide Povero, Aaron M. Anderson, Cailin E. McMahon, Jun Liu
Journal: Journal of Clinical Investigation (2025)

The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet, their coordinated regulation remains undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolishes diet-induced hypertriglyceridemia and significantly attenuates atherogenesis in mice. These effects are attributed to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increases circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalizes plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhances the stability of LPL protein in adipocytes, a phenomenon that can be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reduce circulating TGs.
A simple widely applicable hairy root transformation method for gene function studies in medicinal plants
Authors: Xue Cao, Zhenfen Qin, Panhui Fan, Sifan Wang, Xiangxiao Meng, Huihua Wan, Wei Yang, Shilin Chen, Hui Yao, Weiqiang Chen, Wei Sun
Journal: Acta Pharmaceutica Sinica B (2025)
Neurokinin 1 receptor inhibition alleviated mitochondrial dysfunction via restoring purine nucleotide cycle disorder driven by substance P in acute pancreatitis
Authors: Chenxia Han, Lu Li, Lin Bai, Yaling Wu, Jiawang Li, Yiqin Wang, Wanmeng Li, Xue Ren, Ping Liao, Xiaoting Chen, Yaguang Zhang, Fengzhi Wu, Feng Li, Dan Du, Qing Xia
Journal: Acta Pharmaceutica Sinica B (2025)
Dysregulation of gut microbiota stimulates NETs-driven HCC intrahepatic metastasis: therapeutic implications of healthy faecal microbiota transplantation
Authors: Zhe Deng, Si Mei, Zhaoguang Ouyang, Ruoyu Wang, Lihuai Wang, Bo Zou, Jingjing Dai, Kexin Mao, Qian Li, Qianqian Guo, Chun Yi, Fanying Meng, Mingxia Xie, Xue Zhang, Rongrong Wang, Tianhao Deng, Zhenyu Wang, Xiaozheng Li, Qing Wang, Bin Liu, Xuefei Tian
Journal: Gut Microbes (2025)

The stringent regulation of intrahepatic metastases is essential for improving survival outcomes in patients with hepatocellular carcinoma (HCC). This study investigated the impact of gut microbiota on intrahepatic metastasis of HCC and evaluated the therapeutic potential of healthy fecal microbiota transplantation (FMT). Dysregulation of the gut microbiota, characterized by a significant reduction in the abundance of beneficial bacteria, such as Anaerotruncus colihominis and Dysosmobacter welbionis, was observed in patients with intrahepatic metastatic HCC. A human flora-associated (HFA) intrahepatic metastatic HCC mouse model was successfully established through consecutive 4 weeks of human-mouse FMT. Dysregulation of gut microbiota promoted intrahepatic metastasis in the mouse model, primarily by enhancing neutrophil-mediated inflammatory responses and lead to excessive formation of neutrophil extracellular traps (NETs). Consequently, it promoted tumor vascular growth and tissue necrosis, resulting in intrahepatic metastasis of HCC. Notably, FMT from healthy donors mitigated these pathological processes. This study elucidated the role and mechanism of dysregulated gut microbiota in promoting intrahepatic metastasis of HCC. Healthy FMT emerges as a promising novel therapeutic strategy for preventing and treating intrahepatic metastasis of HCC.
A phylogenetic method identifies candidate drivers of the evolution of the SARS-CoV-2 mutation spectrum
Authors: Russ Corbett-Detig
Journal: Molecular Biology and Evolution (2025)

Abstract The molecular processes that generate new mutations evolve, but the causal mechanisms are largely unknown. In particular, the relative rates of mutation types (e.g., C&amp;gt;T), the mutation spectrum, sometimes vary among closely related species and populations. I present an algorithm for subdividing a phylogeny into distinct mutation spectra. By applying this approach to a SARS-CoV-2 phylogeny comprising approximately eight million genome sequences, I identify 10 shifts in the mutation spectrum. I find strong enrichment consistent with candidate causal amino-acid substitutions in the SARS-CoV-2 polymerase, and strikingly three appearances of the same homoplasious substitution are each associated with decreased C&amp;gt;T relative mutation rates. With rapidly growing genomic datasets, this approach and future extensions promises new insights into the mechanisms of evolution of mutational processes.
MRGPRX2 Gain-of-Function Mutation Drives Enhanced Mast Cell Reactivity in Chronic Spontaneous Urticaria
Authors: Dan Ye, Yuxin Zhang, Xi Zhao, Hongmei Zhou, Jiahua Guo, Mengyao Yang, Xinwu Niu, Xiaopeng Wang, Jingyi Yuan, Jianwen Ren, Songmei Geng, Weihui Zeng, Zhao Wang
Journal: Journal of Allergy and Clinical Immunology (2025)
Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections
Authors: Carla Martín Pérez, Sílvia Ruiz-Rius, Anna Ramírez-Morros, Marta Vidal, D Herbert Opi, Pere Santamaria, Julià Blanco, Josep Vidal-Alaball, James G Beeson, Luis M Molinos-Albert, Ruth Aguilar, Anna Ruiz-Comellas, Gemma Moncunill, Carlota Dobaño
Journal: Journal of Infection (2025)
Superoxide anion-responsive persulfide and all-trans retinoic acid co-donating peptide assemblies attenuate myocardial ischemia-reperfusion injury
Authors: Yanwen Zhang, Yuxuan Ge, Shiqi Wu, Yiyang Shao, Yujia Lu, Xueshan Zhao, Jun Gu, Yin Wang
Journal: Biomaterials (2025)
3D Bioprinted Microfluidic Based Osteosarcoma-on-a chip Model as a Physiomimetic Pre-Clinical Drug Testing Platform for Anti-Cancer Drugs
Authors: Chitra Jaiswal, Souradeep Dey, Jayant Prasad, Raghvendra Gupta, Manoj Agarwala, Biman B Mandal
Journal: Biomaterials (2025)
Autologous tumoral esterase-driven therapeutic polymers sequentially orchestrated antigen-induction, STING activation and anti-angiogenesis for systemic cancer immune therapy
Authors: Nasha Qiu, Chang Xu, Zhen Zhang, Rui Wang, Xuyong Wei, Yangla Xie, Shuai Wang, Di Lu, Kai Wang, Shengjun Xu, Chenchen Shen, Renyi Su, Beini Cen, Yanpeng Liu, Youqing Shen, Xiao Xu
Journal: Biomaterials (2025)
Regulation of Osteoimmune Microenvironment via Functional Dynamic Hydrogel for Diabetic Bone Regeneration
Authors: Peng Yang, Xu Chen, Yi Qin, Lei Yu, Gaoran Ge, Weiling Yin, Wei Zhang, Wenming Li, Wenhao Li, Wenyu Xia, Zebin Wu, Fan Ding, Jiaxiang Bai, Fanwen Meng, Dechun Geng
Journal: Biomaterials (2025)
Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12
Authors: Wataru Fujii, Osamu Yamazaki, Daigoro Hirohama, Ken Kaseda, Emiko Kuribayashi-Okuma, Motonori Tsuji, Makoto Hosoyamada, Yuta Kochi, Shigeru Shibata
Journal: Journal of Clinical Investigation (2025)

BACKGROUND. Hyperinsulinemia and insulin resistance often accompany elevated serum urate levels (hyperuricemia), a highly heritable condition that triggers gout; however, the underlying mechanisms are unclear. METHODS. We evaluated the association between the index of hyperinsulinemia and the fractional excretion of urate (FEUA) in 162 outpatients. The underlying mechanisms were investigated through single-cell data analysis and kinase screening combined with cell culture experiments. In 377,358 participants of the UK Biobank (UKBB), we analyzed serum urate, hyperinsulinemia, and salt intake. We also examined gene-environment interactions using single nucleotide variants in SLC22A12, which encodes urate transporter 1 (URAT1). RESULTS. The index of hyperinsulinemia was inversely associated with FEUA independently of other covariates. Mechanistically, URAT1 cell-surface abundance and urate transport activity were regulated by URAT1-Thr408 phosphorylation, which was stimulated by hyperinsulinemia via AKT. Kinase screening and single-cell data analysis revealed that SGK1, induced by high salt, activated the same pathway, increasing URAT1. Arg405 was essential for these kinases to phosphorylate URAT1-Thr408. In UKBB participants, hyperinsulinemia and high salt intake were independently associated with increased serum urate levels. We found that SLC22A12 eQTL rs475688 synergistically enhanced the positive association between serum urate and hyperinsulinemia. CONCLUSION. URAT1 mediates the association between hyperinsulinemia and hyperuricemia. Our data provide evidence for the role of gene-environment interactions in determining serum urate levels, paving the way for personalized management of hyperuricemia. FUNDING. ACRO Research Grants of Teikyo University; JSPS; the Japanese Society of Gout and Uric & Nucleic Acids; Fuji Yakuhin; Nanken-Kyoten; Medical Research Center Initiative for High Depth Omics.
Maintenance of graft tissue-resident Foxp3+ cells is necessary for lung transplant tolerance in mice
Authors: Wenjun Li, Yuriko Terada, Yun Zhu Bai, Yuhei Yokoyama, Hailey M. Shepherd, Junedh M. Amrute, Amit I. Bery, Zhiyi Liu, Jason M. Gauthier, Marina Terekhova, Ankit Bharat, Jon H. Ritter, Varun Puri, Ramsey R. Hachem, Hēth R. Turnquist, Peter T. Sage, Alessandro Alessandrini, Maxim N. Artyomov, Kory J. Lavine, Ruben G. Nava, Alexander S. Krupnick, Andrew E. Gelman, Daniel Kreisel
Journal: Journal of Clinical Investigation (2025)

Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung re-transplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ cells acquired transcriptional profiles resembling those of graft-resident Foxp3+ cells over time. Allografts underwent combined antibody-mediated rejection (AMR) and acute cellular rejection (ACR) when recruitment of recipient Foxp3+ cells was prevented. Finally, we showed that local administration of IL-33 could expand and activate allograft-resident Foxp3+ cells providing a platform for the design of tolerogenic therapies for lung transplant recipients. Our findings establish graft-resident Foxp3+ cells as critical orchestrators of lung transplant tolerance and highlight the need to develop lung-specific immunosuppression.
The Concept of Personal Utility in Genomic Testing: Three Ethical Tensions
Authors: Gabriel John Watts, Ainsley J. Newson
Journal: The American Journal of Bioethics (2025)

Health Technology Assessment (HTA) has traditionally focused on efficacy, safety, and cost-effectiveness. There has long been concern, however, that this is determined by the goals of healthcare providers/payers, not patients. As a result, HTA arguably fails to reflect the overall value of health technologies—including their "non-clinical" or "personal" utility to patients and their families. The use of genomic testing in clinical care is one domain where this problem is evident, as the personal utility of results is often especially significant. As such, there are growing calls for HTA frameworks to adopt personal utility as a distinct element of value when assessing clinical genomic tests. We agree that personal utility is important to HTA in clinical genomics. However, against a trend toward comprehensive conceptions of personal utility within HTA, we advocate for a restrictive approach to assessing the value of personal utility in the case of clinical genomic testing.
Author Correction: Glycolytic neutrophils accrued in the spleen compromise anti-tumour T cell immunity in breast cancer
Authors: Yu Wang, Muhan Xu, Jian Sun, Xiaoxiao Li, Huazheng Shi, Xuefeng Wang, Benming Liu, Tao Zhang, Xu Jiang, Liangyu Lin, Qing Li, Yin Huang, Yong Liang, Mingyuan Hu, Fanjun Zheng, Fengyu Zhang, Jian Sun, Yufang Shi, Ying Wang
Journal: Nature Metabolism (2025)
IDO Believe in Immunotherapy
Authors: Peter D. Zang, Tanya B. Dorff
Journal: Clinical Cancer Research (2025)

Abstract IDO1 is central to immune downregulation. A recent phase I/II study tested the IDO1 inhibitor linrodostat with nivolumab +/- ipilimumab in patients with advanced solid tumors. While efficacy was not augmented, correlative analyses identified TDO2 as a resistance mechanism; dual targeting may be necessary to realize improved response to PD-1 inhibition.
Deficiency of GADD45α-R-Loop Pathway and Kidney Injury in Diabetic Nephropathy
Authors: Xue Qi Li, Jia Xiu Zhang, Liang Li, Qin Yi Wu, Xiong Zhong Ruan, Pei Pei Chen, Kun Ling Ma
Journal: Journal of the American Society of Nephrology (2025)

Background: Diabetic nephropathy is a primary cause of kidney failure. Persistent hyperglycemia causes metabolic perturbations epigenetically dysregulating gene expression in renal cells, thereby leading to diabetic nephropathy pathogenesis. On analyzing the GEO database by using machine learning algorithms, our preliminary results demonstrated that growth arrest and DNA damage-inducible 45α (GADD45α) might serve as key regulators in diabetic nephropathy. Furthermore, emerging evidence has shown that R-loops, the three-stranded DNA–RNA structures, are crucial to gene expression during diabetic nephropathy. Therefore, this study aimed to investigate the role of GADD45α in diabetic nephropathy by modulating epigenetic alterations through interaction with R-loops. Methods: A diabetic mouse model was established by injecting streptozotocin intraperitoneally into mice. Kidney histology and biochemical markers were analyzed in wild-type, GADD45α knockout, and renal tubule-specific GADD45α-overexpressing mice. The GADD45α lentivirus was used to induce the overexpression of GADD45α in HK-2 cells, while high-glucose treatment was applied to verify the mechanisms in vitro. Results: GADD45α expression was reduced in kidneys of diabetic nephropathy, correlating with kidney dysfunction. GADD45α knockout worsened kidney injuries, while overexpression mitigated them. Mechanistically, GADD45α interacted with R-loops on the STEAP4 promoter, recruiting TET1 to activate STEAP4 transcription. Deficiency in the GADD45α-R-loop pathway exacerbated mitochondrial injury, disrupted lipid metabolism, and increased oxidative stress in diabetic nephropathy. Conclusions: Deficiency of GADD45α exacerbates diabetic nephropathy by interacting with R-loops and inhibiting STEAP4 promoter demethylation. Targeting the GADD45α-R-loop pathway offers therapeutic potential against diabetic nephropathy.
Differential aortic aneurysm formation provoked by chemogenetic oxidative stress
Authors: Apabrita Ayan Das, Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, Taylor A. Covington, Thomas Michel
Journal: Journal of Clinical Investigation (2025)

Aortic aneurysms are potentially fatal focal enlargements of the aortic lumen; the disease burden disease is increasing as the human population ages. Pathological oxidative stress is implicated in development of aortic aneurysms. We pursued a chemogenetic approach to create an animal model of aortic aneurysm formation using a transgenic mouse line DAAO-TGTie2 that expresses yeast D-amino acid oxidase (DAAO) under control of the endothelial Tie2 promoter. In DAAO-TGTie2 mice, DAAO generates the reactive oxygen species hydrogen peroxide (H2O2) in endothelial cells only when provided with D-amino acids. When DAAO-TGTie2 mice are chronically fed D-alanine, the animals become hypertensive and develop abdominal but not thoracic aortic aneurysms. Generation of H2O2 in the endothelium leads to oxidative stress throughout the vascular wall. Proteomic analyses indicate that the oxidant-modulated protein kinase JNK1 is dephosphorylated by the phophoprotein phosphatase DUSP3 in abdominal but not thoracic aorta, causing activation of KLF4-dependent transcriptional pathways that trigger phenotypic switching and aneurysm formation. Pharmacological DUSP3 inhibition completely blocks aneurysm formation caused by chemogenetic oxidative stress. These studies establish that regional differences in oxidant-modulated signaling pathways lead to differential disease progression in discrete vascular beds, and identify DUSP3 as a potential pharmacological target for the treatment of aortic aneurysms.
Short-Term Limited Duration Insurance Plan Policies and Cancer Stage at Diagnosis
Authors: Nuo Nova Yang, Jingxuan Zhao, Justin M. Barnes, Anne C. Kirchhoff, Fumiko Chino, K. Robin Yabroff, Xuesong Han
Journal: JAMA Network Open (2025)

Importance Many short-term limited duration (STLD) insurance plans do not cover essential health benefits, such as cancer screenings, potentially delaying diagnoses. In October 2018, federal regulations loosened restrictions on STLD plans by extending the allowable duration from 3 months to 36 months. States expanded, restricted, or eliminated the sale or terms of STLD plans, both prior to 2018 and afterwards. The association of state-level policies and late-stage cancer diagnosis is largely undocumented. Objective To examine associations of state-level policies regarding STLD plans and late-stage cancer diagnosis before and after the 2018 federal rule. Design, Setting, and Participants This cross-sectional study included adults aged 18 to 64 years newly diagnosed with cancer (January 2016 to February 2020) in 47 states and the District of Columbia from the National Cancer Database. Patients were grouped by state-level STLD plan policies: (1) states continuously prohibited STLD plans before and after 2018; (2) states stopped offering STLD plans after 2018; (3) states allowed the sale of STLD plans with additional restrictions to the 2018 federal rules; (4) states with no additional STLD regulation. Difference-in-differences analyses were conducted to evaluate changes in late-stage diagnoses (stages III/IV) pre-2018 (January 2016 to June 2018) and post-2018 (January 2019 to February 2020) for groups 2, 3, and 4 vs group 1 for all cancers combined and for 5 common cancers, adjusting for sociodemographic factors (age group, sex, metropolitan status, zip code-level poverty), diagnosis year, and state random effect. All analyses were performed from May 2023 to January 2025. Exposures State-level STLD plan policies. Main Outcomes and Measures Change in percentages of late-stage cancer diagnosis. Results Among 1 289 366 adults newly diagnosed with cancer (mean [SD] age, 53 [9.2] years; 536 514 [41.6%] female; 73 061 [5.7%] Hispanic, 110 564 [8.6%] non-Hispanic Asian and Pacific Islander and other, 172 246 [13.4%] non-Hispanic Black, 921 722 [71.5%] non-Hispanic White), 604 882 (46.9%) were from group 4 states (no additional STLD regulations). Group 4 had a net increase of 0.76 (95% CI, 0.22-1.29) percentage points ( P = .01) and group 3 (some STLD regulations) had a net increase of 0.84 (95% CI, 0.26-1.42) percentage points ( P = .005) in late-stage diagnoses compared with group 1 (continuously prohibited STLD plans). Similar patterns were observed for female breast and colorectal cancers. Conclusions and Relevance In this cross-sectional study of state-level policies regarding STLD plans and late-stage cancer diagnosis, loosened federal restrictions on STLD plans in 2018 were associated with a net increase in late-stage cancer diagnoses in states without or with inadequate regulatory protections, underscoring the critical role of state policies in regulating STLD plans.