tbuckley/cabot-search huggingface dataset:
MHC-related protein 1–restricted recognition of cancer via a semi-invariant TCR-α chain
Authors: Garry Dolton, Hannah Thomas, Li Rong Tan, Cristina Rius Rafael, Stephanie Doetsch, Giulia-Andreea Ionescu, Lucia F Cardo, Michael D Crowther, Enas Behiry, Théo Morin, Marine E Caillaud, Devinder Srai, Lucia Parolini, Md Samiul Hasan, Anna Fuller, Katie Topley, Aaron Wall, Jade R Hopkins, Nader Omidvar, Caroline Alvares, Joanna Zabkiewicz, John Frater, Barbara Szomolay, Andrew K Sewell
Journal: Journal of Clinical Investigation (2025)

The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosal-associated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1*01 and/or MR1*02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3-5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.
Whole-exome sequencing association study reveals genetic effects on tumor microenvironment components in nasopharyngeal carcinoma
Authors: Yanni Zeng, Chun-Ling Luo, Guo-Wang Lin, Fugui Li, Xiaomeng Bai, Josephine Mun-Yee Ko, Lei Xiong, Yang Liu, Shuai He, Jia-Xin Jiang, Wen-Xin Yan, Enya Hui Wen Ong, Zheng Li, Ya-Qing Zhou, Yun-He Zhou, An-Yi Xu, Shu-Qiang Liu, Yun-Miao Guo, Jie-Rong Chen, Xi-Xi Cheng, Yu-Lu Cao, Xia Yu, Biaohua Wu, Pan-Pan Wei, Zhao-Hui Ruan, Qiu-Yan Chen, Lin-Quan Tang, James D McKay, Wei-Hua Jia, Hai-Qiang Mai, Soon Thye Lim, Jian-Jun Liu, Dong-Xin Lin, Chiea Chuen Khor, Melvin Lee Kiang Chua, Mingfang Ji, Maria Li Lung, Yi-Xin Zeng, Jin-Xin Bei
Journal: Journal of Clinical Investigation (2025)

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.
APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer’s disease
Authors: Qiuyun Tian, Junjie Li, Bin Wu, Yayan Pang, Wenting He, Qian Xiao, Jiaojiao Wang, Lilin Yi, Na Tian, Xiuyu Shi, Lei Xia, Xin Tian, Mulan Chen, Yepeng Fan, Boqing Xu, Yuhan Tao, Weihong Song, Yehong Du, Zhifang Dong
Journal: Journal of Clinical Investigation (2025)

Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as a novel PTM, is implicated in the occurrence and development of AD. However, whether and how APP lactylation contributes to both the pathogenesis and cognitive function in AD remains unknown. Here, we observed a reduction in APP lactylation in AD patients and AD model mice and cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) as a crucial site for APP lactylation, influencing APP amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation and slowed down cognitive deficits in vivo. Mechanistically, APPK612T appeared to facilitate APP trafficking and metabolism. However, lactylated APP entering the endosome inhibited its binding to BACE1, suppressing subsequent cleavage. Instead, it promoted protein interaction between APP and CD2-associated protein (CD2AP), thereby accelerating the endosomal-lysosomal degradation pathway of APP. In the APP23/PS45 double-transgenic mouse model of AD, APP-Kla was susceptible to L-lactate regulation, which reduced Aβ pathology and repaired spatial learning and memory deficits. Thus, these findings suggest that targeting APP lactylation may be a promising therapeutic strategy for AD in humans.
Cardiac fibroblast BAG3 regulates TGFBR2 signaling and fibrosis in dilated cardiomyopathy
Authors: Bryan Z Wang, Margaretha Aj Morsink, Seong Won Kim, Lori J Luo, Xiaokan Zhang, Rajesh Kumar Soni, Roberta I Lock, Jenny Rao, Youngbin Kim, Anran Zhang, Meraj Neyazi, Joshua M Gorham, Yuri Kim, Kemar Brown, Daniel M DeLaughter, Qi Zhang, Barbara McDonough, Josephine M Watkins, Katherine M Cunningham, Gavin Y Oudit, Barry M Fine, Christine E Seidman, Jonathan G Seidman, Gordana Vunjak-Novakovic
Journal: Journal of Clinical Investigation (2025)

Loss of Bcl2-associated athanogene 3 (BAG3) is associated with dilated cardiomyopathy (DCM). BAG3 regulates sarcomere protein turnover in cardiomyocytes; however, the function of BAG3 in other cardiac cell types is understudied. In this study, we used an isogenic pair of BAG3-knockout and wild-type human induced pluripotent stem cells (hiPSCs) to interrogate the role of BAG3 in hiPSC-derived cardiac fibroblasts (CFs). Analysis of cell type-specific conditional knockout engineered heart tissues revealed an essential contribution of CF BAG3 to contractility and cardiac fibrosis, recapitulating the phenotype of DCM. In BAG3-/- CFs, we observed an increased sensitivity to TGF-β signaling and activation of a fibrogenic response when cultured at physiological stiffness (8 kPa). Mechanistically, we showed that loss of BAG3 increased transforming growth factor-β receptor 2 (TGFBR2) levels by directly binding TGFBR2 and mediating its ubiquitination and proteasomal degradation. To further validate these results, we performed single-nucleus RNA sequencing of cardiac tissue from DCM patients carrying pathogenic BAG3 variants. BAG3 pathogenic variants increased fibrotic gene expression in CFs. Together, these results extend our understanding of the roles of BAG3 in heart disease beyond the cardiomyocyte-centric view and highlight the ability of tissue-engineered hiPSC models to elucidate cell type-specific aspects of cardiac disease.
Biomimetic Nanostructural Materials Based on Placental Amniotic Membrane-derived Nanofibers for Self-healing and Anti-adhesion during Cesarean Section
Authors: Honglei Zhu, Fenghua Liu, Yuru Liao, Huayan Li, Kunjie Gao, Xiaomei Liang, Haoyuan Jiang, Feng Chen, Jianwei Wu, Qian Wang, Yifeng Wang, Xintao Shuai, Xiao Yi
Journal: Biomaterials (2025)
Phenotyping atherosclerotic plaque and perivascular adipose tissue: signalling pathways and clinical biomarkers in atherosclerosis
Authors: Kajetan Grodecki, Jolien Geers, Jacek Kwiecinski, Andrew Lin, Leandro Slipczuk, Piotr J. Slomka, Marc R. Dweck, Nitesh Nerlekar, Michelle C. Williams, Daniel Berman, Thomas Marwick, David E. Newby, Damini Dey
Journal: Nature Reviews Cardiology (2025)
Host-microbe computational proteomic landscape in oral cancer revealed key functional and metabolic pathways between Fusobacterium nucleatum and cancer progression
Authors: Camila Paz Muñoz-Grez, Mabel Angélica Vidal, Tamara Beatriz Rojas, Luciano Esteban Ferrada, Felipe Andrés Zuñiga, Agustin Andrés Vera, Sergio Andrés Sanhueza, Romina Andrea Quiroga, Camilo Daniel Cabrera, Barbara Evelyn Antilef, Ricardo Andrés Cartes, Milovan Paolo Acevedo, Marco Andrés Fraga, Pedro Felipe Alarcón-Zapata, Mauricio Alejandro Hernández, Alexis Marcelo Salas-Burgos, Francisco Tapia-Belmonte, Milly Loreto Yáñez, Erick Marcelo Riquelme, Wilfredo Alejandro González, Cesar Andrés Rivera, Angel Alejandro Oñate, Liliana Ivonne Lamperti, Estefanía Nova-Lamperti
Journal: International Journal of Oral Science (2025)

Abstract Oral squamous cell carcinoma (OSCC) is the most common manifestation of oral cancer. It has been proposed that periodontal pathogens contribute to OSCC progression, mainly by their virulence factors. However, the main periodontal pathogen and its mechanism to modulate OSCC cells remains not fully understood. In this study we investigate the main host-pathogen pathways in OSCC by computational proteomics and the mechanism behind cancer progression by the oral microbiome. The main host-pathogen pathways were analyzed in the secretome of biopsies from patients with OSCC and healthy controls by mass spectrometry. Then, functional assays were performed to evaluate the host-pathogen pathways highlighted in oral cancer. Host proteins associated with LPS response, cell migration/adhesion, and metabolism of amino acids were significantly upregulated in the human cancer proteome, whereas the complement cascade was downregulated in malignant samples. Then, the microbiome analysis revealed large number and variety of peptides from Fusobacterium nucleatum ( F. nucleatum ) in OSCC samples, from which several enzymes from the L-glutamate degradation pathway were found, indicating that L-glutamate from cancer cells is used as an energy source, and catabolized into butyrate by the bacteria. In fact, we observed that F. nucleatum modulates the cystine/glutamate antiporter in an OSCC cell line by increasing SLC7A11 expression, promoting L-glutamate efflux and favoring bacterial infection. Finally, our results showed that F. nucleatum and its metabolic derivates promote tumor spheroids growth, spheroids-derived cell detachment, epithelial-mesenchymal transition and Galectin-9 upregulation. Altogether, F. nucleatum promotes pro-tumoral mechanism in oral cancer.
Expert consensus on apical microsurgery
Authors: Hanguo Wang, Xin Xu, Zhuan Bian, Jingping Liang, Zhi Chen, Benxiang Hou, Lihong Qiu, Wenxia Chen, Xi Wei, Kaijin Hu, Qintao Wang, Zuhua Wang, Jiyao Li, Dingming Huang, Xiaoyan Wang, Zhengwei Huang, Liuyan Meng, Chen Zhang, Fangfang Xie, Di Yang, Jinhua Yu, Jin Zhao, Yihuai Pan, Shuang Pan, Deqin Yang, Weidong Niu, Qi Zhang, Shuli Deng, Jingzhi Ma, Xiuping Meng, Jian Yang, Jiayuan Wu, Yi Du, Junqi Ling, Lin Yue, Xuedong Zhou, Qing Yu
Journal: International Journal of Oral Science (2025)

Abstract Apical microsurgery is accurate and minimally invasive, produces few complications, and has a success rate of more than 90%. However, due to the lack of awareness and understanding of apical microsurgery by dental general practitioners and even endodontists, many clinical problems remain to be overcome. The consensus has gathered well-known domestic experts to hold a series of special discussions and reached the consensus. This document specifies the indications, contraindications, preoperative preparations, operational procedures, complication prevention measures, and efficacy evaluation of apical microsurgery and is applicable to dentists who perform apical microsurgery after systematic training.
MDMA and MDMA-Assisted Therapy
Authors: Aaron S. Wolfgang, Gregory A. Fonzo, Joshua C. Gray, John H. Krystal, Adrienne Grzenda, Alik S. Widge, Nina V. Kraguljac, William M. McDonald, Carolyn I. Rodriguez, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2025)

MDMA (i.e., 3,4-methylenedixoymethamphetamine), commonly known as "Ecstasy" or "Molly," has been used since the 1970s both in recreational and therapeutic settings. The Food and Drug Administration (FDA) designated MDMA-Assisted Therapy (MDMA-AT) as a Breakthrough Therapy for posttraumatic stress disorder (PTSD) in 2017, and the FDA is requiring an additional phase 3 trial after rejecting the initial New Drug Application in 2024. Unlike other psychedelics, MDMA uniquely induces prosocial subjective effects of heightened trust and self-compassion while maintaining ego functioning as well as cognitive and perceptual lucidity. While recreational use in nonmedical settings may still cause harm, especially due to adulterants or when used without proper precautions, conclusions that can be drawn from studies of recreational use are limited by many confounds. This especially limits the extent to which evidence related to recreational use can be extrapolated to therapeutic use. A considerable body of preliminary evidence suggests that MDMA-AT delivered in a controlled clinical setting is a safe and efficacious treatment for PTSD. After a course of MDMA-AT involving three MDMA administrations supported by psychotherapy, 67%-71% of individuals with PTSD no longer meet diagnostic criteria after MDMA-AT versus 32%-48% with placebo-assisted therapy, and effects endure at long-term follow-up. This review primarily aims to distinguish evidence of recreational use in nonclinical settings versus MDMA-AT using pharmaceutical-grade MDMA in controlled clinical settings. This review further describes the putative neurobiological mechanisms of MDMA underlying its therapeutic effects, the clinical evidence of MDMA-AT, considerations at the level of public health and policy, and future research directions.
Psilocybin: From Psychiatric Pariah to Perceived Panacea
Authors: Gregory A. Fonzo, Aaron S. Wolfgang, Bryan R. Barksdale, John H. Krystal, Linda L. Carpenter, Nina V. Kraguljac, Adrienne Grzenda, William M. McDonald, Alik S. Widge, Carolyn I. Rodriguez, Charles B. Nemeroff
Journal: American Journal of Psychiatry (2025)

The authors critically examine the evidence base for psilocybin administered with psychological support/therapy (PST) in the treatment of psychiatric disorders and offer practical recommendations to guide future research endeavors.
Compass Psychological Support Model for COMP360 Psilocybin Treatment of Serious Mental Health Conditions
Authors: Namik Kirlić, Molly Lennard-Jones, Merve Atli, Ekaterina Malievskaia, Nadav L. Modlin, Stephanie Knatz Peck, Alice Gaillard, Guy M. Goodwin, Don Koelpin
Journal: American Journal of Psychiatry (2025)

The psychedelic experience can be challenging. There is a need for a structured framework for providing psychological support to individuals with mental health conditions receiving investigational psilocybin treatment. The primary benefit of such a framework is to support a safe and meaningful psilocybin experience. It also enables future research on the facets of psychological support and/or psychotherapy that most optimally complement psilocybin treatment. The authors describe the Compass Psychological Support Model (CPSM), currently used to support participants with treatment-resistant depression in Compass-sponsored clinical trials of investigational COMP360 psilocybin treatment. The authors also outline the therapist training, mentoring, and fidelity assessment programs they have developed to ensure the quality and consistency of the CPSM delivery.
BRISC-Mediated PPM1B-K63 Deubiquitination and Subsequent TGF-β Pathway Activation Promote High-Fat/High-Sucrose Diet–Induced Arterial Stiffness
Authors: Yanan Liu, Mengke Li, Zhipeng Chen, Min Zuo, Kaiwen Bao, Ziyan Zhao, Meng Yan, Yongping Bai, Ding Ai, Hu Wang, Hongfeng Jiang
Journal: Circulation Research (2025)

BACKGROUND: Metabolic syndrome heightens cardiovascular disease risk primarily through increased arterial stiffness. We previously demonstrated the involvement of YAP (Yes-associated protein) in high-fat/high-sucrose diet (HFHSD)–induced arterial stiffness via modulation of PPM1B (protein phosphatase Mg 2+ /Mn 2+ –dependent 1B)-lysine63 (K63) deubiquitination. In this study, we aimed to elucidate the role and mechanisms underlying PPM1B deubiquitination in HFHSD-induced arterial stiffness. METHODS: Enzymes governing PPM1B deubiquitination were identified through siRNA screening and mass spectrometry. Glutathione S-transferase pull-down, coimmunoprecipitation, protein purification, and immunofluorescence were used to explore the mechanism underlying PPM1B deubiquitination. Doppler ultrasound was used to evaluate HFHSD-induced arterial stiffness in mice, and telemetry was used to record pulsatile (systolic and diastolic) blood pressure. RESULTS: Smooth muscle cell–specific PPM1B overexpression attenuated HFHSD-induced arterial stiffness in mice in a PPM1B-K326-K63–linked polyubiquitination-dependent manner. Mechanistically, ABRO1 (Abraxas brother 1; a core BRCC36 [BRCA1/BRCA2–containing complex subunit 36] isopeptidase complex component) directly bound YAP and underwent liquid-liquid phase separation with YAP and PPM1B in a YAP-dependent manner, which in turn promoted PPM1B deubiquitination. Furthermore, smooth muscle cell–specific Abro1 -knockout mice and Brcc3 -knockout mice showed attenuated HFHSD-induced arterial stiffness and activation of transforming growth factor-β–Smad signaling. CONCLUSIONS: We elucidated the PPM1B deubiquitination mechanisms and highlighted a potential therapeutic target for metabolic syndrome–related arterial stiffness.
Transmission as a Key Driver of Resistance to the New Tuberculosis Drugs
Authors: Galo A. Goig, Chloé Loiseau, Nino Maghradze, Kakha Mchedlishvili, Teona Avaliani, Daniela Brites, Sonia Borrell, Rusudan Aspindzelashvili, Zaza Avaliani, Maia Kipiani, Nestani Tukvadze, Levan Jugheli, Sebastien Gagneux
Journal: New England Journal of Medicine (2025)
Systemically administered platelet-inspired nanoparticles to reduce inflammation surrounding intracortical microelectrodes
Authors: Longshun Li, Dhariyat M Menendez-Lustri, Aniya Hartzler, Anna Pogharian, Brett Zaorski, Alex Chen, Jaquelynn Palen, Baylee Traylor, Emma Quill, Christa L Pawlowski, Michael A Bruckman, Anirban Sen Gupta, Jeffrey R Capadona, Andrew J Shoffstall
Journal: Biomaterials (2025)
Spatiotemporal dynamics of early oogenesis in pigs
Authors: Wei Ge, Yi-Lin Niu, Yu-Kang Li, Li Li, Han Wang, Wen-Wen Li, Tian Qiao, Yan-Ni Feng, Yu-Qing Feng, Jing Liu, Jun-Jie Wang, Xiao-Feng Sun, Shun-Feng Cheng, Lan Li, Wei Shen
Journal: Genome biology (2025)

In humans and other mammals, the process of oogenesis initiates asynchronously in specific ovarian regions, leading to the localization of dormant and growing follicles in the cortex and medulla, respectively; however, the current understanding of this process remains insufficient. Here, we integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to comprehend spatial–temporal gene expression profiles and explore the spatial organization of ovarian microenvironments during early oogenesis in pigs. Projection of the germ cell clusters at different stages of oogenesis into the spatial atlas unveils a "cortical to medullary (C-M)" distribution of germ cells in the developing porcine ovaries. Cross-species analysis between pigs and humans unveils a conserved C-M distribution pattern of germ cells during oogenesis, highlighting the utility of pigs as valuable models for studying human oogenesis in a spatial context. RNA velocity analysis with ST identifies the molecular characteristics and spatial dynamics of granulosa cell lineages originating from the cortical and medullary regions in pig ovaries. Spatial co-occurrence analysis and intercellular communication analysis unveils a distinct cell–cell communication pattern between germ cells and somatic cells in the cortex and medulla regions. Notably, in vitro culture of ovarian tissues verifies that intercellular NOTCH signaling and extracellular matrix (ECM) proteins played crucial roles in initiating meiotic and oogenic programs, highlighting an underappreciated role of ovarian microenvironments in orchestrating germ cell fates. Overall, our work provides insight into the spatial characteristics of early oogenesis and the regulatory role of ovarian microenvironments in germ cell fate within a spatial context.
Parkin inhibits iron overload-induced cardiomyocyte ferroptosis by ubiquitinating ACSL4 and modulating PUFA-phospholipids metabolism
Authors: Dandan Xiao, Wenguang Chang, Xiang Ao, Lin Ye, Weiwei Wu, Lin Song, Xiaosu Yuan, Luxin Feng, Peiyan Wang, Yu Wang, Yi Jia, Xiaopeng Tang, Jianxun Wang
Journal: Acta Pharmaceutica Sinica B (2025)

Iron overload is strongly associated with heart disease. Ferroptosis is a new form of regulated cell death indicated in cardiac ischemia-reperfusion (I/R) injury. However, the specific molecular mechanism of myocardial injury caused by iron overload in the heart is still unclear, and the involvement of ferroptosis in iron overload-induced myocardial injury is not fully understood. In this study, we observed that ferroptosis participated in developing of iron overload and I/R-induced cardiomyopathy. Mechanistically, we discovered that Parkin inhibited iron overload-induced ferroptosis in cardiomyocytes by promoting the ubiquitination of long-chain acyl-CoA synthetase 4 (ACSL4), a crucial protein involved in ferroptosis-related lipid metabolism pathways. Additionally, we identified p53 as a transcription factor that transcriptionally suppressed Parkin expression in iron-overloaded cardiomyocytes, thereby regulating iron overload-induced ferroptosis. In animal studies, cardiac-specific Parkin knockout mice (Myh6-CreER T2 /Parkin fl/fl ) fed a high-iron diet presented more severe myocardial damage, and the high iron levels exacerbated myocardial I/R injury. However, the ferroptosis inhibitor Fer-1 significantly suppressed iron overload-induced ferroptosis and myocardial I/R injury. Moreover, Parkin effectively protected against impaired mitochondrial function and prevented iron overload-induced mitochondrial lipid peroxidation. These findings unveil a novel regulatory pathway involving p53-Parkin-ACSL4 in heart disease by inhibiting of ferroptosis.