tbuckley/cabot-search huggingface dataset:
Disruption of cTnT-Mediated Sarcomere–Mitochondrial Communication Results in Dilated Cardiomyopathy
Authors: Lingqun Ye, Junwei Liu, Wei Lei, Baoqiang Ni, Xinglong Han, Yan Zhang, Yong Wang, Kaili Hao, Yuanhui Peng, Hongchun Wu, Miao Yu, Huadong Li, Zhen-Ao Zhao, Zhenya Shen, Jianyi Zhang, Shijun Hu
Journal: Circulation (2025)

BACKGROUND: Dilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere–mitochondrial communication in DCM. METHODS: Induced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify the TNNT2 (c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms. RESULTS: Through whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo. CONCLUSIONS: Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere–mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein–mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.
Author Correction: Efficient precise knockin with a double cut HDR donor after CRISPR/Cas9-mediated double-stranded DNA cleavage
Authors: Jian-Ping Zhang, Xiao-Lan Li, Guo-Hua Li, Wanqiu Chen, Cameron Arakaki, Gary D Botimer, David Baylink, Lu Zhang, Wei Wen, Ya-Wen Fu, Jing Xu, Noah Chun, Weiping Yuan, Tao Cheng, Xiao-Bing Zhang
Journal: Genome biology (2025)
ISCL/EORTC-CLTG/USCLC recommendations for the diagnosis, staging and treatment of early-stage paediatric mycosis fungoides - a modified Delphi consensus. Part 1: Diagnosis and staging
Authors: Emmilia Hodak, Iris Amitay-Laish, Martine Bagot, Maxime Battistella, Dan Ben Amitai, Antonio Cozzio, Madeleine Duvic, Katalin Ferenczi, Francine Foss, Larisa Geskin, Emmanuella Guenova, Youn H Kim, Mark Jean-Aan Koh, Montserrat Molgó, Arti Nanda, Jan Nicolay, Tim Niehues, Pablo Ortiz-Romero, Amra Osmancevic, Evangelia Papadavid, Jong Bin Park, Pietro Quaglino, José A Sanches, Julia Scarisbrick, Maria Luisa Sulis, Rudolf Stadler, Franz Trautinger, Maarten Vermeer, Iris Wohlmuth, John A Zic, Chalid Assaf
Journal: British Journal of Dermatology (2025)

Abstract Background Mycosis fungoides (MF), is considered rare in children and adolescents. Accumulating experience indicates that compared to adult MF, almost all paediatric MF patients are diagnosed at an early-stage disease, exhibits higher rates of atypical presentations, and follow a notably indolent course. Despite the need for special staging/workup and treatment-related safety considerations specific for children and adolescents, the staging of paediatric MF is currently based primarily on standard practice in adults. Objectives To develop staging recommendations on behalf of the 3 largest societies for cutaneous lymphomas, the ISCL, EORTC, and USCLC, specifically designed for MF in children and adolescents. Methods The guideline was developed through an international expert consensus process and in accordance with the EQUATOR Network’s recommendations for guideline development. A modified Delphi process was conducted, using questionnaires covering topics including the definition, characteristics, and staging of paediatric MF. Two rounds of expert feedback were conducted, with an additional one hybrid consensus meeting. Results A consensus was reached that the term paediatric MF should be reserved for MF diagnosed at ≤18 years. Panelists specified the unique clinical characteristics of paediatric MF, including a high prevalence of hypopigmented and folliculotropic variants, and reached a consensus on the indolent nature of the disease during childhood and adolescence with rare progression to advanced stage. The consensus reached recommends that while staging approach is largely similar to that in adults, imaging for early- stage paediatric MF should rely on ultrasound of the lymph nodes if indicated, rather than CT/PET-CT. Clinicians should be aware that in children palpable lymph nodes are common, owing to the increased incidence of infectious diseases. Conclusion This guideline addresses the major clinical characteristics of paediatric MF, which differ from those in adults, and provides practical staging recommendations considering the safety implications specific for this age group.
Microbiome signatures of virulence in the oral-gut-brain axis influence Parkinson’s disease and cognitive decline pathophysiology
Authors: Frederick Clasen, Suleyman Yildirim, Muzaffer Arıkan, Fernando Garcia-Guevara, Lűtfű Hanoğlu, Nesrin H. Yılmaz, Aysu Şen, Handan Kaya Celik, Alagoz Aybala Neslihan, Tuǧçe Kahraman Demir, Zeynep Temel, Adil Mardinoglu, David L. Moyes, Mathias Uhlen, Saeed Shoaie
Journal: Gut Microbes (2025)

The human microbiome is increasingly recognized for its crucial role in the development and progression of neurodegenerative diseases. While the gut-brain axis has been extensively studied, the contribution of the oral microbiome and gut-oral tropism in neurodegeneration has been largely overlooked. Cognitive impairment (CI) is common in neurodegenerative diseases and develops on a spectrum. In Parkinson's Disease (PD) patients, CI is one of the most common non-motor symptoms but its mechanistic development across the spectrum remains unclear, complicating early diagnosis of at-risk individuals. Here, we generated 228 shotgun metagenomics samples of the gut and oral microbiomes across PD patients with mild cognitive impairment (PD-MCI) or dementia (PDD), and a healthy cohort, to study the role of gut and oral microbiomes on CI in PD. In addition to revealing compositional and functional signatures, the role of pathobionts, and dysregulated metabolic pathways of the oral and gut microbiome in PD-MCI and PDD, we also revealed the importance of oral-gut translocation in increasing abundance of virulence factors in PD and CI. The oral-gut virulence was further integrated with saliva metaproteomics and demonstrated their potential role in dysfunction of host immunity and brain endothelial cells. Our findings highlight the significance of the oral-gut-brain axis and underscore its potential for discovering novel biomarkers for PD and CI.
Mussel‐Inspired Hemostatic Hydrogel Adhesive Formulated from a Gelatin‐Oxidized Dextrin Double Network
Authors: Baokun Liu, Jiming Zhang, Wen Liu, Dong Zhou, Ruisheng Qu, Hao Gu, Tingting Guo, Jinwei He, Yanan Pei, Qihua Wang, Tingmei Wang, Yaoming Zhang
Journal: Advanced Healthcare Materials (2025)

Abstract Hydrogels are recognized for their excellent biocompatibility and biodegradability, making them promising candidates for hemostatic materials, especially in cases of intra‐abdominal bleeding or injury to vital organs. In this study, a mussel‐inspired adhesive hemostatic hydrogel, GMOD, is developed, which features injectability, outstanding biocompatibility, and biodegradability. The hydrogel is synthesized through Schiff base crosslinking of oxidized dextran and gelatin, enhanced with dopamine to form a robust double network structure. This unique double network not only provides mechanical stability but also significantly enhances tissue adhesion as well as the adhesion of red blood cells and platelets, resulting in a 76% reduction in bleeding in a mouse liver hemorrhage model. Additionally, the incorporation of vascular endothelial growth factor (VEGF) into GMOD enables sustained release, promoting skin wound healing and reducing inflammatory responses in mice. In summary, a highly adhesive, injectable, and rapid hemostatic hydrogel is presented that demonstrates considerable potential for use in intra‐abdominal hemostasis, leveraging the advantages of a double network structure to enhance its performance.
Inflammation‐Targeted and Antioxidative Poly(Ferulic Acid) Nanoparticles Directly Treat Chronic Nonbacterial Prostatitis via Inhibiting Pyroptosis by Disrupting Nrf2/KEAP1 Multimer Formation and as a Robust Drug Carrier
Authors: Bingliang Chen, Liying Wang, Ruihui Xie, Bingheng Li, Shirong Peng, Yuan Ou, Ruilin Zhuang, Wei Zhuang, Hao Huang, Jun Wu, Hai Huang
Journal: Advanced Healthcare Materials (2025)

Abstract Chronic nonbacterial prostatitis (CNP) is challenging to treat due to limited options. This study introduces a new approach using natural ferulic acid‐based polymer nanoparticles to target CNP. Ferulic acid (FA) is polymerized into poly(ferulic acid) and forms nanoparticles (PFA NPs). Folic acid (Fa) is added for targeting, and celecoxib (Cel) is loaded, creating PFA‐Fa@Cel NPs. These nanoparticles, ≈100 nm in size, have a 39% drug encapsulation efficiency, showing good stability, biocompatibility, controlled release, and anti‐inflammatory effects, including reduced macrophage chemotaxis. PFA NPs demonstrated strong anti‐inflammatory effects and targeted oxidative stress reduction while inhibiting pyroptosis. Mechanistic studies showed that PFA‐Fa NPs disrupted the KEAP1/Nrf2 complex, leading to Nrf2 activation, enhanced antioxidant responses, and preservation of prostate epithelium integrity. In summary, PFA‐Fa NPs effectively reduce inflammation, oxidative stress, and pyroptosis, while also delivering celecoxib to inflamed tissues, improving treatment efficacy for CNP. This approach shows significant clinical promise for CNP patients.
Fe<sup>2+</sup> Triggers Endocytosis of Carrier Proteins in Mammalian Cells
Authors: Weibo Zhang, Chong Chen, Ran Wang, Yixuan Li, Yinhua Zhu, Jiazeng Sun, Yongting Luo, Junjie Luo, Liang Zhao, Yanan Sun, Huiyuan Guo, Hao Zhang, Bing Fang, Yao Hu, Rong Liu, Xiaoyu Wang, Jiayue Guo, Ping Liu, Peng An, Pengjie Wang, Juan Chen, Fazheng Ren
Journal: Advanced Healthcare Materials (2025)

Abstract Human serum albumin (HSA) plays an indispensable role as a carrier of endogenous and exogenous substances in vivo. The efficiency of endocytosis determines the transport capacity. However, the potential for enhancing the efficiency of HSA endocytosis remains largely unknown. This research represented a substantial advancement, revealing that Fe 2+ markedly increased HSA endocytosis. Moreover, Fe 2+ facilitated the endocytosis and transport of HSA in vivo. The enhancement in HSA uptake facilitated by Fe 2+ is markedly decreased following iron chelation, indicating a specific interaction between Fe 2 ⁺ and HSA that promoted endocytosis. Moreover, the study elucidated that FcRn and caveolin regulated HSA endocytosis under normal conditions. Yet, in the presence of Fe 2 ⁺, endocytosis shifted toward clathrin‐ and caveolin‐enriched membrane domains, requiring both divalent metal transporter 1 (DMT1) and FcRn for efficient process completion. Thereby a new pathway is discovered for Fe 2+ ‐dependent HSA endocytosis involving DMT1 and clathrin. This findings highlighted the crucial role of iron in enhancing HSA endocytosis and transport, establishing Fe 2+ as a vital endocytic enhancer that required binding to HSA to substantially improve its uptake. This insight into the mechanism of HSA endocytosis not only expands the understanding of protein transport but also opens new avenues for therapeutic intervention.
Therapeutic Applications of Interface-Mimicking Peptides for Targeting the SARS-CoV-2 NSP12-NSP8 RdRp Complex
Authors: Mark Anthony B Casel, Jae-Woo Ahn, Hyunjoon Kim, Isaac Choi, Seung-Gyu Jang, Rare Rollon, Ho-Young Ji, Mina Yu, Seong Cheol Min, Min-Suk Song, Young Ki Choi
Journal: Molecular Therapy (2025)
Stable Intermolecular Charge-Transfer Nanocrystals as Efficient Immunogenic Cell Death Adjuvants for Photoimmunotherapy Against Trophoblastic and Recurrent Tumors
Authors: Yijian Gao, Zhongming Huang, Wenbin Chen, Yujie Ma, Xiliang Li, Yu Wang, Yingpeng Wan, Ying Liu, Yuliang Yang, Ming-De Li, Chun-Sing Lee, Shengliang Li
Journal: Biomaterials (2025)
Mesoporous Fe<sub>3</sub>O<sub>4</sub> Nanoparticles Loaded with IR‐820 for Antibacterial Activity via Magnetic Hyperthermia Combined with Photodynamic Therapy
Authors: Yuange Li, Song Xue, Hong Sung Min, Chen Chen, Liheng Lu, Zhiheng Chen, Haojie Shan, Fuli Yin, Xiaowei Yu
Journal: Advanced Healthcare Materials (2025)

Abstract The formation of bacterial biofilms presents a major challenge in infection treatments. Antimicrobial photodynamic therapy (aPDT) typically employs photosensitizers to generate reactive oxygen species (ROS) under irradiation, causing oxidative damage to both bacteria and biofilms. While prior studies have explored the integration of PDT with various other approaches, magnetic hyperthermia therapy (MHT) has not adequately addressed. To bridge this gap, a drug delivery system is designed that incorporates mesoporous Fe 3 O 4 nanoparticles loaded with the photosensitizer IR‐820, thereby combining aPDT with MHT. This system possesses magnetic‐targeting capabilities, generates thermal energy when exposed to alternating magnetic fields, and facilitates the release of encapsulated IR‐820. Furthermore, upon exposure to near‐infrared light, IR‐820 produces ROS. The synergistic effects of elevated temperature, degradation of the biofilm matrix, and enhanced ROS production effectively disrupted bacterial biofilms. This approach demonstrated promising antibacterial efficacy in both in vitro and in vivo, including in rat models of full‐thickness infectious wound and subcutaneous abscesses. These results underscore the substantial potential of the system for future antibacterial applications.
Customizable Polymeric Nanoparticle Materials Optimized on Hypoxic Cells Facilitate mRNA Expression in the Lungs In Vivo
Authors: Palas Balakdas Tiwade, Vincent Fung, Yutian Ma, Rachel VanKeulen‐Miller, Eshan A. Narasipura, Owen S. Fenton
Journal: Advanced Healthcare Materials (2025)

Abstract mRNA therapy has shown great potential in treating lung diseases by enabling transient protein expression without permanently altering the genome. Despite advancements, most mRNA delivery systems, such as lipid nanoparticles and polymeric nanoparticles, predominantly express mRNA in the liver, limiting their effectiveness for extrahepatic organs like the lungs. Furthermore, hypoxia, a common feature of many pulmonary diseases, significantly reduces mRNA translation and protein synthesis, impacting therapeutic outcomes. In this study, we present a Tunable Lung Expressing Nanoparticle Platform ( TULEP ) designed to enhance mRNA delivery to the lungs and improve protein expression under hypoxic conditions. Our approach involved the combinatorial synthesis of polymers with varied hydrocarbon tail lengths and reaction equivalencies, followed by formulation into mRNA‐loaded nanoparticles. These nanoparticles were characterized for size, charge, and mRNA encapsulation efficiency, and mechanistic and efficacy studies under normoxia and hypoxia were performed in vitro. In vivo studies demonstrated that the top‐performing TULEP s improve mRNA‐encoded protein expression in the lungs in a well‐tolerated fashion as suggested by weight loss, blood paneling, and histological analyses. Taken together, these results highlight TULEP s as a viable platform for tunable expression of mRNA in the lungs and under hypoxia, highlighting their potential for long‐term disease therapy.
Dual roles of IRE1α inhibition in reversing mitochondrial ROS-induced CD8<sup>+</sup>T-cell senescence and exerting direct antitumor effects in multiple myeloma
Authors: Yike Wan, Jingjing Wang, Mengping Chen, Junying Wang, Fajun Nan, Honghui Huang, Zhiqiang Liu, Jian Hou
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells within the bone marrow (BM) microenvironment, which significantly contributes to immune suppression of CD8 + T cells. Our previous research identified that dysregulation of the IRE1α-XBP1s-SLC38A2 axis leads to decreased glutamine uptake and senescence of CD8 + T cells in MM. However, the underlying mechanisms of T-cell senescence remain unclear. Methods Single-cell RNA sequencing was used to analyze mitochondrial function in CD8 + T cells in MM. The effects of XBP1s and SLC38A2 on mitochondrial reactive oxygen species (mtROS) were evaluated by flow cytometry under loss-of-function experiments. An IRE1α inhibitor (17#) was administered to explore its effects on T-cell senescence and MM cell growth. RNA sequencing was employed to disclose pathway alterations in T cells treated with 17#. The Vk*MYC mouse model was used to assess the impact of 17# on CD8 + T cell senescence and anti-myeloma effects. Results BM-derived CD8 + T cells from patients with MM exhibited downregulated expressions of genes critical for glutamine transport (SLC38A2), mitochondrial respiratory chain, and ATP synthesis, while genes associated with ROS were upregulated. Suppression of XBP1s in CD8 + T cells resulted in decreased mtROS levels, whereas inhibition of SLC38A2 increased mtROS levels. Compound 17# significantly reduced senescence marker KLRG1 expression and increased perforin expression in nutrient-deprived BM CD8 + T cells from healthy donors and in BM CD8 + T cells from patients with MM, while promoting T-cell proliferation. Importantly, 17# did not impair the viability of peripheral blood mononuclear cells from healthy donors or alter the immune phenotypes of healthy CD8 + T cells. The NPR2-cGMP-PKG pathway was activated by IRE1α inhibition in restoring T-cell function. Furthermore, 17# exhibited direct inhibitory effects on MM cells. In Vk*MYC mouse model, 17# decreased mtROS levels in BM CD8 + T cells, reduced the proportion of senescent (KLRG1 + CD57 + CD28 − ) T cells, and resulted in a lower tumor burden. Conclusion Inhibiting IRE1α represents a promising strategy to reverse the senescence of CD8 + T cells by mitigating mtROS production. This dual mechanism not only rejuvenates T cells but also directly targets myeloma cells, offering a novel therapeutic approach for MM treatment.
Basic rules to respond to PD-1 blockade cancer immunotherapy
Authors: Antoni Ribas
Journal: Journal for ImmunoTherapy of Cancer (2025)

After 15 years of clinical testing and analyses of biopsies from patients with cancers treated with antibodies blocking the programmed death receptor 1 (PD-1) pathway, several requirements for inducing durable clinical responses have become evident. These basic rules for a response to anti-PD-1 include: (1) the cancer must be immunogenic and differentially recognizable by antitumor T cells, (2) there must be pre-existing antitumor T cells that have the ability to recognize the cancer, which had been activated and had received costimulation, but then are kept in a dysfunctional state due to the reactive cancer expression of the PD-1 ligand 1, (3) on PD-1 blockade, T cells are reinvigorated and produce increased amounts of interferon gamma, which forces the cancer cells into becoming enablers of the antitumor immune response, directly increasing the cancer cell immunogenicity and changing the tumor microenvironment from an unfriendly environment to a friendly environment for the antitumor T cells, and (4) reactivating antitumor T cells before surgery using neoadjuvant anti-PD-1 therapy improves patient outcomes, as the surgery would otherwise take away the majority of antitumor T cells. Collectively, these features are the basis of clinical responses and durable benefit of anti-PD-1 therapy in patients with cancer.