tbuckley/cabot-search huggingface dataset:
Reference centiles for intrinsic capacity to monitor clinical health outcomes in real-world primary care cohorts
Authors: Philipe de Souto Barreto, Wan-Hsuan Lu, Neda Tavassoli, Fatemeh Nourhashémi, Renato Gorga Bandeira de Mello, Eduardo Ferriolli, Sophie Guyonnet, Yves Rolland, Maria Eugenia Soto Martín, Bruno Vellas
Journal: Nature Aging (2025)
MHCII <sup>hi</sup> LYVE1 <sup>lo</sup> CCR2 <sup>hi</sup> Interstitial Macrophages Promote Medial Fibrosis in Pulmonary Arterioles and Contribute to Pulmonary Hypertension
Authors: Fan Qiu, Hao-Ran Miao, Hong-Liang Hui, Lin-Jie Qiu, Yi Chen, Min Luo, Jian-Chao Zhang, Yan-Gui Lin, Dan Li, Sang-Bing Ong, Xue-Fei Hu, Bo Jiang, Yi-Qian Zhang
Journal: Circulation Research (2025)

BACKGROUND: Pulmonary hypertension (PH) is a lethal disease characterized in part by progressive pulmonary arteriole (PA) remodeling. Excessive PA fibrosis and macrophage infiltration are often present in PH, but the potential associations are obscure. We investigated the link between interstitial macrophage (iMΦ) infiltration and PA fibrosis in PH and idiopathic pulmonary arterial hypertension. METHODS: Lung tissue samples from patients with idiopathic pulmonary arterial hypertension and experimental PH animals were obtained to analyze the extent of fibrosis and iMΦ infiltration in the different layers of PAs and their correlation with disease severity. Single-cell RNA sequencing, lineage tracing, histological analyses, iMΦ and PA smooth muscle cell coculture, and transgenic animal experiments were used to investigate the cell heterogeneity and origins and molecular mechanisms by which iMΦs promote PA fibrosis. RESULTS: We found that increased collagen deposition and fibrosis in the PA media were most strongly related to the severity of PH, and medial iMΦ infiltration may be involved in these pathological processes. Single-cell transcriptomics revealed that MHCII hi LYVE1 lo CCR2 hi iMΦs were the major type of iMΦ that expanded upon Sugen-5416 and hypoxia plus normoxia stimulation and were responsible for PA medial fibrosis. Lineage tracing experiments suggested that these medial iMΦs were largely from recruited monocytes. Mechanistically, MHCII hi LYVE1 lo CCR2 hi iMΦs promoted the transition of PA smooth muscle cells to a fibroblast-like phenotype through the WNT11 (wingless member 11)/planar cell polarity (PCP) pathway. Wnt11 deletion in iMΦs from PH rats normalized the fibrotic PA smooth muscle cell phenotype and decreased PA medial fibrosis, thereby improving vascular compliance and protecting against PH. Moreover, myeloid-specific Ccr2 deficiency in PH-PAs inhibited the medial infiltration of MHCII hi LYVE1 lo CCR2 hi iMΦs, which also relieved PH. CONCLUSIONS: This study demonstrates that the recruitment of MHCII hi LYVE1 lo CCR2 hi iMΦs leads to medial fibrosis in PH-PAs associated with PH severity and that inhibition of their pathogenicity or recruitment reverses PA medial fibrosis and PH.
Dusp14-Mediated Dephosphorylation of MLKL Protects Against Cardiomyocyte Necroptosis in Hypothyroidism-Induced Heart Failure
Authors: Yitian Zheng, Yueyue Cao, Wenyao Wang, Yicheng Tong, Shuaixing Wang, Chen Li, Mingming Zhao, Yao Song, Yuan-geng-shuo Wang, Jiating Qi, Chao Wu, Jie Yang, Jilin Zheng, Jun Gao, Jingjia Wang, Qing Yang, Gang Liu, Jiajun Zhao, Yan Zhang, Han Xiao, You-Yi Zhang, Yi-Da Tang
Journal: Circulation (2025)

BACKGROUND: Hypothyroidism leads to multiple organ dysfunction, with the heart the most affected. However, the pathologic mechanism of hypothyroidism-induced heart failure remains to be completely elucidated. Thyroid hormone replacement therapy enhances myocardium systolic function but increases the occurrence of arrythmias. There is an urgent need to explore these mechanisms in detail and to discover and develop drugs that can target and manage heart failure in patients with hypothyroidism. METHODS: In this study, a mouse model of hypothyroidism-induced heart failure was established through the administration of propylthiouracil. Dusp14 knockout mice were generated, and adeno-associated virus–mediated cardiomyocyte-specific overexpression of Dusp14 (dual specificity phosphatase 14) was used in combination with related cellular experiments to investigate the protective effects of Dusp14 on hypothyroidism-induced heart failure. Further analyses confirmed the crucial involvement of necroptosis in the pathogenesis of hypothyroidism-induced heart failure, and demonstrated the protective role of Dusp14 in modulating necroptosis. In addition, a novel small molecule compound that effectively regulates Dusp14 activity in vitro was identified through molecular docking, providing a potential therapeutic avenue. RESULTS: Dusp14 regulates necroptosis and mitigates hypothyroidism-induced heart failure. Myocardial tissue sections from mice in the hypothyroidism group showed positive Evans blue dye staining, and the serum levels of the myocardial injury marker lactate dehydrogenase were significantly higher compared with the euthyroid group (n=8). In addition, phosphorylation levels of the necroptosis marker MLKL (mixed lineage kinase domain-like protein) were significantly elevated, indicating the activation of necroptosis (n=8). These findings suggest that myocardial necroptosis is activated during hypothyroidism. Myocardial-specific overexpression of Dusp14 reduced myocardial necroptosis and improved myocardial contractile function in hypothyroid mice (n=8). In contrast, Dusp14 knockout exacerbated myocardial contractile dysfunction and necroptosis in these mice (n=5–7). These results indicate that Dusp14 alleviates hypothyroidism-induced heart failure by inhibiting necroptosis. P077-0472, a small molecule compound, was identified as an activator of Dusp14, which could inhibit cardiomyocyte necroptosis from hypothyroidism (n=6). CONCLUSIONS: Dusp14 inhibits cardiomyocyte necroptosis from hypothyroidism and consequently rescues damaged cardiomyocytes. P077-0472, a novel small molecule compound that activates the dephosphorylation function of Dusp14, could inhibit cardiomyocyte necroptosis from hypothyroidism.
Multiplex imaging of amyloid-β plaques dynamics in living brains with quinoline-malononitrile-based probes
Authors: Jianfeng Dai, Weijun Wei, Chenxu Yan, Ding-Kun Ji, Caiqi Liu, Jialiang Huang, Chenyi Liang, Jianjun Liu, Zhiqian Guo, Wei-Hong Zhu
Journal: Nature Biomedical Engineering (2025)
Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution
Authors: Anne Loft, Margo P Emont, Ada Weinstock, Adeline Divoux, Adhideb Ghosh, Allon Wagner, Ann V Hertzel, Babukrishna Maniyadath, Bart Deplancke, Boxiang Liu, Camilla Scheele, Carey Lumeng, Changhai Ding, Chenkai Ma, Christian Wolfrum, Clarissa Strieder-Barboza, Congru Li, Danh D Truong, David A Bernlohr, Elisabet Stener-Victorin, Erin E Kershaw, Esti Yeger-Lotem, Farnaz Shamsi, Hannah X Hui, Henrique Camara, Jiawei Zhong, Joanna Kalucka, Joseph A Ludwig, Julie A Semon, Jutta Jalkanen, Katie L Whytock, Kyle D Dumont, Lauren M Sparks, Lindsey A Muir, Lingzhao Fang, Lucas Massier, Luis R Saraiva, Marc D Beyer, Marc G Jeschke, Marcelo A Mori, Mariana Boroni, Martin J Walsh, Mary-Elizabeth Patti, Matthew D Lynes, Matthias Blüher, Mikael Rydén, Natnael Hamda, Nicole L Solimini, Niklas Mejhert, Peng Gao, Rana K Gupta, Rinki Murphy, Saeed Pirouzpanah, Silvia Corvera, Su'an Tang, Swapan K Das, Søren F Schmidt, Tao Zhang, Theodore M Nelson, Timothy E O'Sullivan, Vissarion Efthymiou, Wenjing Wang, Yihan Tong, Yu-Hua Tseng, Susanne Mandrup, Evan D Rosen
Journal: Nature Metabolism (2025)
Focused ultrasound-microbubble treatment arrests the growth and formation of cerebral cavernous malformations
Authors: Delaney G Fisher, Tanya Cruz, Matthew R Hoch, Khadijeh A Sharifi, Ishaan M Shah, Catherine M Gorick, Victoria R Breza, Anna C Debski, Joshua D Samuels, Jason P Sheehan, David Schlesinger, David Moore, James W Mandell, John R Lukens, G Wilson Miller, Petr Tvrdik, Richard J Price
Journal: Nature Biomedical Engineering (2025)
<i>Acinetobacter Baumannii</i> Secreted Protease CpaA Inhibits Factor XII-Mediated Bradykinin Generation and Neutrophil Activation
Authors: Kris M. Blair, Dillon J. Bohinc, Kara L. Bane, Mark Warnock, Basel Abuaita, Colby Gura, Eduarda Grinsztejn, Steven H. Marshall, Brigid M. Wilson, Robert A. Bonomo, Ajay Tambralli, Jason S. Knight, Mary X. O’Riordan, Daniel A. Lawrence, Evi X. Stavrou, Maria Sandkvist
Journal: Circulation Research (2025)

BACKGROUND: FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to its active enzyme (FXIIa [activated factor XII]) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii ) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKSs (kallikrein-kinin systems) and to determine the downstream consequences on thromboinflammatory responses. METHODS: The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA. RESULTS: We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture. CONCLUSIONS: These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and KKSs and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.
FoxO1-zDHHC4-CD36 S-Acylation Axis Drives Metabolic Dysfunction in Diabetes
Authors: Kaitlyn M.J.H. Dennis, Keshav Gopal, Claudia N. Montes Aparicio, Jiashuo Aaron Zhang, Marcos Castro-Guarda, Thomas Nicol, Ríona M. Devereux, Ryan D. Carter, Saara-Anne Azizi, Tong Lan, Ujang Purnama, Carolyn A. Carr, Gul Simsek, Eleanor K. Gill, Pawel Swietach, Oana Sorop, Ilkka H.A. Heinonen, Francesco Schianchi, Joost J.F.P. Luiken, Dunja Aksentijevic, Dirk J. Dunker, Bryan C. Dickinson, Sarah De Val, John R. Ussher, William Fuller, Lisa C. Heather
Journal: Circulation Research (2025)

BACKGROUND: The fatty acid (FA) transporter CD36 (FA translocase/cluster of differentiation 36) is the gatekeeper of cardiac FA metabolism. Preferential localization of CD36 to the sarcolemma is one of the initiating cellular responses in the development of muscle insulin resistance and the type 2 diabetic heart. Posttranslational S-acylation controls protein trafficking, and in this study, we hypothesized that increased CD36 S-acylation may underpin the preferential sarcolemmal localization of CD36, driving metabolic and contractile dysfunction in diabetes. METHODS AND RESULTS: Type 2 diabetes increased cardiac CD36 S-acylation, CD36 sarcolemmal localization, FA oxidation rates, and triglyceride storage in the diabetic heart. CD36 S-acylation was increased in diabetic rats, db/db mice, diabetic pigs, and insulin-resistant human iPSC-derived cardiomyocytes, demonstrating conservation between species. The enzyme responsible for S-acylating CD36, zDHHC4, was transcriptionally upregulated in the diabetic heart, and genetic silencing of zDHHC4 using siRNA or lentiviral shRNA decreased CD36 S-acylation. We identified that zDHHC4 expression is under the regulation of the transcription factor FoxO (forkhead box O) 1, as FoxO1 binds to the promotor of zDHHC4 and induces its transcription, as assessed using chromatin immunoprecipitation-seq, chromatin immunoprecipitation-quantitative PCR, luciferase assays, and siRNA silencing. Diabetic mice with cardiomyocyte-specific FoxO1 deletion had decreased cardiac zDHHC4 expression and decreased CD36 S-acylation, which was further confirmed using diabetic mice treated with the FoxO1 inhibitor AS1842856. Pharmacological inhibition of zDHHC enzymes in diabetic hearts decreased CD36 S-acylation, sarcolemmal CD36 content, FA oxidation rates, and triglyceride storage, culminating in improved cardiac function in diabetes. Conversely, inhibiting the deacylating enzymes in control hearts increased CD36 S-acylation, sarcolemmal CD36 content, and FA metabolic rates in control hearts, recapitulating the metabolic phenotype seen in diabetic hearts. CONCLUSIONS: Activation of the FoxO1-zDHHC4-CD36 S-acylation axis in diabetes drives metabolic and contractile dysfunction in type 2 diabetic heart.
METTL3 Is Essential for Exercise Benefits in Diabetic Cardiomyopathy
Authors: Chunyan Wang, Siman Shen, Jiayi Kang, Aya Sugai-Munson, Xiao Xiao, Yajing Zhang, Junyuan Zhu, Zipeng Liu, Tina B. McKay, Oluwaseun Akeju, Eric R. Jonas, Amrut V. Ambarar, Michael R. Bristow, Weifeng Yao, Haobo Li
Journal: Circulation (2025)

BACKGROUND: Exercise improves functional outcomes in patients with diabetic cardiomyopathy (DiaCM). The molecular mechanism underlying cardiac benefits of exercise in DiaCM remains incompletely understood. N6-methyladenosine (m6A) is the most common form of messenger RNA modification in eukaryotes and has been implicated in cardiac development and disease. However, the role of m6A in DiaCM and in the mitigating effects of exercise on this disease are unclear. METHODS: Cardiomyocyte-specific N6-adenosine-methyltransferase-like 3 (METTL3, an m6A methyltransferase) knockout mice and their wild-type littermates were subjected to either chow diet or high-fat diet feeding and injection of streptozotocin to induce DiaCM, followed by an 8-week exercise training and assessment of cardiac function. Some of the mice were injected with adeno-associated viral vector encoding METTL3 to overexpress METTL3 in cardiomyocytes. Cardiac METTL3 expressions were assessed in patients with nonischemic primary dilated cardiomyopathies without or with diabetes. Potential METTL3 downstream effector YBX1 (Y-box binding protein 1) was identified through RNA sequencing. The functional role of YBX1 was examined through adeno-associated viral vector overexpression or knockdown in cardiomyocytes in DiaCM mice. RESULTS: We showed that cardiac METTL3 protein expression and m6A level were downregulated in patient with dilated cardiomyopathy and further downregulated in patients with dilated cardiomyopathy and diabetes. Consistently, cardiac METTL3 and m6A were downregulated in mouse with DiaCM, whereas they were upregulated by exercise. Cardiomyocyte-specific METTL3 knockout eliminated the cardiac benefits of exercise on DiaCM. Conversely, cardiomyocyte-specific METTL3 overexpression improved systolic and diastolic function in 2 DiaCM mouse models. We demonstrated that exercise enhanced cardiac METTL3 expression in DiaCM through signal transducer and activator of transcription 3. Moreover, METTL3 attenuated DiaCM through m6A-depdendent YBX1 upregulation and the subsequent activation of Nrf2. Cardiomyocyte-specific YBX1 overexpression promoted Nrf2 activation and attenuated oxidative stress, resulting in an improvement in cardiac function in DiaCM. In contrast, cardiomyocyte-specific YBX1 gene knockdown abolished the effect of METTL3 on cardiac improvement in mice with DiaCM. Further, pharmacological activation of METTL3 using a small molecule attenuated cardiac dysfunction in DiaCM. CONCLUSIONS: These studies reveal an essential role of METTL3 in the cardiac benefits of exercise and identify METTL3 and YBX1 as promising therapeutic targets for treating DiaCM.
Metabolic reprogramming of interleukin-17-producing γδ T cells promotes ACC1-mediated de novo lipogenesis under psoriatic conditions
Authors: Yu-San Kao, Mario Lauterbach, Aleksandra Lopez Krol, Ute Distler, Gloria Janet Godoy, Matthias Klein, Rafael Jose Argüello, Fatima Boukhallouk, Sara Vallejo Fuente, Kathrin Luise Braband, Assel Nurbekova, Monica Romero, Panagiota Mamareli, Luana Silva, Luis Eduardo Alves Damasceno, Francesca Rampoldi, Luciana Berod, Lydia Lynch, Karsten Hiller, Tim Sparwasser
Journal: Nature Metabolism (2025)
Revisiting the Open Vein Hypothesis to Reduce the Postthrombotic Syndrome: Implications for Multidisciplinary Care and Research: A Scientific Statement From the American Heart Association
Authors: Wenzhu Li, Suresh Vedantham, Farouc A. Jaffer, Stavros K. Kakkos, Jean-Philippe Galanaud, Paul P. Dobesh, Eri Fukaya, Mary O. Whipple, Olamide Alabi, Rachel P. Rosovsky, Peter K. Henke
Journal: Circulation (2025)

The “open vein hypothesis” postulates that early thrombus clearance and restoration of venous blood flow may prevent postthrombotic syndrome after proximal deep vein thrombosis. Since its proposal several decades ago, new insights from basic and clinical studies have motivated a re-evaluation and refinement of this hypothesis. According to data from these studies, susceptibility to postthrombotic syndrome occurs as a result of differences in genetic composition, thrombophilic conditions, predilection to inflammation and fibrosis, endogenous fibrinolytic capability, timing of s ymptom presentation and treatment initiation, and efficacy of antithrombotic therapy. Although initial restoration of an open vein appears to be beneficial for selected patient groups, freedom from postthrombotic syndrome is more likely in the setting of long-term venous patency, reduced recurrent thrombotic episodes, and reduced perithrombotic (eg, vein wall and valve) inflammation. These underlying biological mechanisms need further elucidation, with a long-term goal of personalizing treatment by mapping the individuals’ clinical presentation with their underlying risk factors and assessing time-dependent biological processes that occur as a clinical venous thrombosis resolves. This scientific statement (1) highlights historical fundamentals of the open vein hypothesis and then showcases new research insights into the pathophysiological factors driving postthrombotic syndrome; (2) discusses advantages and disadvantages of imaging modalities for deep vein thrombosis used in clinical practice, including the potential to depict thrombus chronicity and status of vein wall injury; (3) proposes measures to develop integrated multidisciplinary care for deep vein thrombosis focused on the reduction of postthrombotic syndrome; and (4) identifies priority areas and questions for further research.
Combination of a therapeutic cancer vaccine targeting the endogenous retroviral envelope protein ERVMER34-1 with immune-oncology agents facilitates expansion of neoepitope-specific T cells and promotes tumor control
Authors: Maria Del Mar Maldonado, Maria Gracia-Hernandez, Loc Huu Le, Masafumi Iida, James L Gulley, Renee N Donahue, Claudia Palena, Jeffrey Schlom, Duane H Hamilton
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Endogenous retroviruses (ERVs) are remnants of retrovirus germline infections that occurred over the course of evolution and constitute between 5% and 8% of the human genome. While ERVs tend to be epigenetically silenced in normal adult human tissues, they are often overexpressed in carcinomas and may represent novel immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine. Methods The expression of ERVMER34-1 in multiple healthy adult and cancer tissues was assessed, as was its immunogenicity, to ascertain whether specific T cells could lyse human carcinoma cell lines expressing ERVMER34-1. Furthermore, the ability of a rationally designed ERVMER34-1-targeted therapeutic vaccine to induce tumor clearance in two murine carcinoma models expressing ERVMER34-1 was examined either as a monotherapy or in combination with anti-programmed cell death protein-1/programmed death-ligand 1 monoclonal antibody (mAb) or the interleukin-15 superagonist N-803. Results The ERVMER34-1 protein was shown to be overexpressed in 232/376 of human carcinomas analyzed while being absent in most healthy adult tissues. High levels of ERVMER34-1 RNA expression associate with decreased survival in uveal melanoma, adenoid cystic, and head and neck carcinomas. ERVMER34-1-specific T cells were detected in peripheral blood mononuclear cells (PBMCs) of patients with cancer but not healthy donors following an overnight stimulation. However, reactive T cells are readily expanded from both healthy donor and patient with cancer PBMCs following a 7- day in vitro stimulation. Furthermore, ERVMER34-1-specific T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A novel, rationally designed, therapeutic cancer vaccine targeting ERVMER34-1 mediated tumor control in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. When combined with checkpoint blockade, the vaccine promoted expansion of neoepitope-reactive T cells whose function was further enhanced when combined with N-803. This expansion of neoepitope-reactive T cells was associated with tumor control. Conclusions This study reveals the potential of a vaccine that targets the retroviral envelope protein ERVMER34-1 and supports its continued development toward clinical testing as a new class of therapeutic cancer vaccine.
Regional distribution of HLA frequencies in the USA: implications for TCR-based therapies
Authors: Christian Roy, Tomasz Sewastianik, Ileana Saenz, Gregory J Opiteck, Sean Stagg, Martin Maiers, Dirk Nagorsen
Journal: Journal for ImmunoTherapy of Cancer (2025)

Understanding regional distribution of HLA frequencies is crucial for optimizing enrollment in HLA-restricted clinical trials and to promote trial diversity per the Food and Drug Administration’s 2020 mandate. Using US HLA frequency data and census demographics we developed a method to create high-resolution HLA class 1 genotypic frequency maps. Analyzing HLA-A*11:01 and HLA-B*58:01 as alleles of interest, we found significant US regional variations. HLA-A*11:01, which presents KRAS neoantigen mutations targeted by TCR T-cell therapies, showed 10–15% genotypic frequency (national average 11.2%), with western US states 1.5 times higher than average and local variations within California (10–19%). These insights can be used to guide clinical trial site selection, for example, in National Cancer Institute (NCI) cancer center catchment areas. For HLA-B*58:01, which reacts pharmacogenetically with allopurinol and results in severe cutaneous adverse reactions, Mississippi had a high frequency among US states, which could be used to guide potential public safety campaigns. This method can identify regions with high HLA type representation, aiding efficient patient identification and enrollment for HLA-specific clinical trials and health-awareness efforts.