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Effects of AFQ056 on language learning in fragile X syndrome J. Clin. Invest. (IF 13.3) Pub Date : 2023 Elizabeth Berry-Kravis, Leonard Abbeduto, Randi Hagerman, Christopher S. Coffey, Merit Cudkowicz, Craig A. Erickson, Andrea McDuffie, David Hessl, Lauren Ethridge, Flora Tassone, Walter E. Kaufmann, Katherine Friedmann, Lauren Bullard, Anne Hoffmann, Jeremy Veenstra-VanderWeele, Kevin Staley, David Klements, Michael Moshinsky, Brittney Harkey, Jeff Long, Janel Fedler, Elizabeth Klingner, Dixie Ecklund
BACKGROUND. FXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old
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CTRP4/interleukin-6 receptor signaling ameliorates autoimmune encephalomyelitis by suppressing Th17 cell differentiation J. Clin. Invest. (IF 13.3) Pub Date : 2023 Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang
C1q/TNF-related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrate that Th17 cell–associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4–/– mice compared
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AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments J. Clin. Invest. (IF 13.3) Pub Date : 2023 Wenrui Zhang, Lu Cao, Jian Yang, Shuai Zhang, Jianyi Zhao, Zhonggang Shi, Keman Liao, Haiwei Wang, Binghong Chen, Zhongrun Qian, Haoping Xu, Linshi Wu, Hua Liu, Hongxiang Wang, Chunhui Ma, Yongming Qiu, Jianwei Ge, Jiayi Chen, Yingying Lin
Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase
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Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations J. Clin. Invest. (IF 13.3) Pub Date : 2023 Joseph H. Garcia, Erin A. Akins, Saket Jain, Kayla J. Wolf, Jason Zhang, Nikita Choudhary, Meeki Lad, Poojan Shukla, Jennifer Rios, Kyounghee Seo, Sabraj A. Gill, William H. Carson, Luis R. Carette, Allison C. Zheng, David R. Raleigh, Sanjay Kumar, Manish K. Aghi
While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site–directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations
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Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice J. Clin. Invest. (IF 13.3) Pub Date : 2023 Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, Michael M. Wang, Manfred
Vascular aging affects multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular readouts, remains vastly incomplete. Here, we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences
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Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells J. Clin. Invest. (IF 13.3) Pub Date : 2023 Livia de Souza Goncalves, Tifany Chu, Riya Master, Parth D. Chhetri, Qi Gao, Onur Cil
Cholera is a global health problem with no targeted therapies. The Ca2+-sensing receptor (CaSR) is a regulator of intestinal ion transport and a therapeutic target for diarrhea, and Ca2+ is considered its main agonist. We found that increasing extracellular Ca2+ had a minimal effect on forskolin-induced Cl– secretion in human intestinal epithelial T84 cells. However, extracellular Mg2+, an often-neglected
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A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III J. Clin. Invest. (IF 13.3) Pub Date : 2023 Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, Giuseppe Ronzitti
Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus–derived (rAAV-derived)
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Impaired glycine neurotransmission causes adolescent idiopathic scoliosis J. Clin. Invest. (IF 13.3) Pub Date : 2023 Xiaolu Wang, Ming Yue, Jason Pui Yin Cheung, Prudence Wing Hang Cheung, Yanhui Fan, Meicheng Wu, Xiaojun Wang, Sen Zhao, Anas M. Khanshour, Jonathan J. Rios, Zheyi Chen, Xiwei Wang, Wenwei Tu, Danny Chan, Qiuju Yuan, Dajiang Qin, Guixing Qiu, Zhihong Wu, Terry Jianguo Zhang, Shiro Ikegawa, Nan Wu, Carol A. Wise, Yong Hu, Keith Dip Kei Luk, You-Qiang Song, Bo Gao
Adolescent idiopathic scoliosis (AIS) is the most common form of spinal deformity, affecting millions of adolescents worldwide, but it lacks a defined theory of etiopathogenesis. Because of this, treatment of AIS is limited to bracing and/or invasive surgery after onset. Preonset diagnosis or preventive treatment remains unavailable. Here, we performed a genetic analysis of a large multicenter AIS
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Chronic graft-versus-host disease detected by tissue-specific cell-free DNA methylation biomarkers J. Clin. Invest. (IF 13.3) Pub Date : 2023 Batia Avni, Daniel Neiman, Elior Shaked, Ofer Gal-Rosenberg, Sigal Grisariu, Mona Kuzli, Ilai Avni, Andrea Fracchia, Polina Stepensky, Tsila Zuckerman, Ahinoam Lev-Sagie, Ilana Fox-Fisher, Sheina Piyanzin, Joshua Moss, Seth J. Salpeter, Benjamin Glaser, Ruth Shemer, Yuval Dor
BACKGROUND. Accurate detection of graft-versus-host disease (GVHD) is a major challenge in the management of patients undergoing hematopoietic stem cell transplantation (HCT). Here, we demonstrated the use of circulating cell-free DNA (cfDNA) for detection of tissue turnover and chronic GVHD (cGVHD) in specific organs.
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Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders J. Clin. Invest. (IF 13.3) Pub Date : 2023 Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, Ling Qi
Recent studies using cell type–specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum–associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification
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Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death J. Clin. Invest. (IF 13.3) Pub Date : 2023 Denisa Weis, Liangguang L. Lin, Huilun H. Wang, Zexin Jason Li, Katarina Kusikova, Peter Ciznar, Hermann M. Wolf, Alexander Leiss-Piller, Zhihong Wang, Xiaoqiong Wei, Serge Weis, Katarina Skalicka, Gabriela Hrckova, Lubos Danisovic, Andrea Soltysova, Tingxuan T. Yang, René Günther Feichtinger, Johannes A. Mayr, Ling Qi
Suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients
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Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation J. Clin. Invest. (IF 13.3) Pub Date : 2023 Magnus T. Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel C. Patin, Simon A. Smith, Emma Dean, Gemma N. Jones, Sophie E. Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen
BACKGROUND. Phase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.
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Galectin-3 aggravates microglial activation and tau transmission in tauopathy J. Clin. Invest. (IF 13.3) Pub Date : 2023 Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-Rong Huang, Hung-Chih Kuo, Fu-Tong Liu, Yijuang Chern
Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside–binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered
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Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts J. Clin. Invest. (IF 13.3) Pub Date : 2023 Nida Haider, C. Ronald Kahn
About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos
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The pan-microbiome profiling system Taxa4Meta identifies clinical dysbiotic features and classifies diarrheal disease J. Clin. Invest. (IF 13.3) Pub Date : 2023 Qinglong Wu, Shyam Badu, Sik Yu So, Todd J. Treangen, Tor C. Savidge
Targeted metagenomic sequencing is an emerging strategy to survey disease-specific microbiome biomarkers for clinical diagnosis and prognosis. However, this approach often yields inconsistent or conflicting results owing to inadequate study power and sequencing bias. We introduce Taxa4Meta, a bioinformatics pipeline explicitly designed to compensate for technical and demographic bias. We designed and
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Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring J. Clin. Invest. (IF 13.3) Pub Date : 2023 Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can
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Truncated titin protein in dilated cardiomyopathy incorporates into the sarcomere and transmits force J. Clin. Invest. (IF 13.3) Pub Date : 2023 Quentin McAfee, Matthew A. Caporizzo, Keita Uchida, Kenneth C. Bedi Jr., Kenneth B. Margulies, Zolt Arany, Benjamin L. Prosser
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance J. Travis Hinson, Stuart G. Campbell J. Travis Hinson, Stuart G. Campbell Commentary
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The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia J. Clin. Invest. (IF 13.3) Pub Date : 2023 Garth T. Whiteside, Donald J. Kyle, Ram P. Kapil, Alessandra Cipriano, Ellie He, Mingyan Zhou, Manjunath S. Shet, Michele Hummel, Terri Knappenberger, Kazuya Fukumura, Yoshiyuki Matsuo, Masahiro Uehira, Shuichi Hiroyama, Nozomi Takai, Sandra K. Willsie, Stephen C. Harris
To the Editor: Insomnia is a common disorder and public health burden. Frequently prescribed hypnotics enhance γ-aminobutyric acid or block orexin signaling. With few pharmacological modalities and limitations associated with traditional targets, there is high interest in new mechanisms involved in sleep/wake regulation. The utility of the nociceptin/orphanin FQ receptor (NOP) system as a treatment
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In situ vaccination via tissue-targeted cDC1 expansion enhances the immunogenicity of chemoradiation and immunotherapy J. Clin. Invest. (IF 13.3) Pub Date : 2023 Brandon Lam, Yu Jui Kung, John Lin, Ssu-Hsueh Tseng, Hsin-Fang Tu, Claire Huang, Brandon Lee, Esteban Velarde, Ya Chea Tsai, Rafael Villasmil, Sung Taek Park, Deyin Xing, Chien-Fu Hung, T.-C. Wu
Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens
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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features J. Clin. Invest. (IF 13.3) Pub Date : 2023 Dong Li, Qin Wang, Allan Bayat, Mark R. Battig, Yijing Zhou, Daniëlle G.M. Bosch, Gijs van Haaften, Leslie Granger, Andrea K. Petersen, Luis A. Pérez-Jurado, Gemma Aznar-Laín, Anushree Aneja, Miroslava Hancarova, Sarka Bendova, Martin Schwarz, Radka Kremlikova Pourova, Zdenek Sedlacek, Beth A. Keena, Michael E. March, Cuiping Hou, Nora O’Connor, Elizabeth J. Bhoj, Margaret H. Harr, Gabrielle Lemire
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants
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Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation J. Clin. Invest. (IF 13.3) Pub Date : 2023 Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John A. Katzenellenbogen, Kathryn E. Carlson, Benita S. Katzenellenbogen, Mostafa Karimi, Ramya Segu Rajappachetty, Isabella S. Del Priore, Jorge S. Reis-Filho, Yang Shen, Sarat Chandarlapaty
Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through
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Cardiac noradrenergic deficiency revealed by 18F-dopamine positron emission tomography identifies preclinical central Lewy body diseases J. Clin. Invest. (IF 13.3) Pub Date : 2023 David S. Goldstein, Courtney Holmes, Patti Sullivan, Grisel Lopez, Janna Gelsomino, Sarah Moore, Risa Isonaka, Tianxia Wu, Yehonatan Sharabi
BACKGROUND. In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency
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CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses J. Clin. Invest. (IF 13.3) Pub Date : 2023 Josephine W. Thinwa, Zhongju Zou, Emily Parks, Salwa Sebti, Kelvin Hui, Yongjie Wei, Mohammad Goodarzi, Vibha Singh, Greg Urquhart, Jenna L. Jewell, Julie K. Pfeiffer, Beth Levine, Tiffany A. Reese, Michael U. Shiloh
Virophagy, the selective autophagosomal engulfment and lysosomal degradation of viral components, is crucial for neuronal cell survival and antiviral immunity. However, the mechanisms leading to viral antigen recognition and capture by autophagic machinery remain poorly understood. Here, we identified cyclin-dependent kinase–like 5 (CDKL5), known to function in neurodevelopment, as an essential regulator
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Gasdermin C sensitizes tumor cells to PARP inhibitor therapy in cancer models J. Clin. Invest. (IF 13.3) Pub Date : 2023 Shuanglian Wang, Chiung-Wen Chang, Juan Huang, Shan Zeng, Xin Zhang, Mien-Chie Hung, Junwei Hou
Several poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are approved by FDA to treat cancer with BRCA mutations. BRCA mutations are considered to fuel a PARPi killing effect by inducing apoptosis. However, resistance to PARPi is frequently observed in the clinic due to an incomplete understanding on the molecular basis of PARPi function and a lack of good markers, beyond BRCA mutations, to predict
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Targeting lysine demethylase 6B ameliorates ASXL1 truncation–mediated myeloid malignancies in preclinical models J. Clin. Invest. (IF 13.3) Pub Date : 2023 Guo Ge, Peng Zhang, Pinpin Sui, Shi Chen, Hui Yang, Ying Guo, Ivan P. Rubalcava, Asra Noor, Caroline R. Delma, Joel Agosto-Peña, Hui Geng, Edward A. Medina, Ying Liang, Stephen D. Nimer, Ruben Mesa, Omar Abdel-Wahab, Mingjiang Xu, Feng-Chun Yang
ASXL1 mutation frequently occurs in all forms of myeloid malignancies and is associated with aggressive disease and poor prognosis. ASXL1 recruits Polycomb repressive complex 2 (PRC2) to specific gene loci to repress transcription through trimethylation of histone H3 on lysine 27 (H3K27me3). ASXL1 alterations reduce H3K27me3 levels, which results in leukemogenic gene expression and the development
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PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation J. Clin. Invest. (IF 13.3) Pub Date : 2023 Jian Wang, Yuke Chen, Shiwei Li, Wanchang Liu, Xiao Albert Zhou, Yefei Luo, Zhanzhan Xu, Yundong Xiong, Kaiqi Cheng, Mingjian Ruan, Wei Yu, Xiaoman Li, Weibin Wang, Jiadong Wang
Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising
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A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib–restricted CD8+ regulatory T cells J. Clin. Invest. (IF 13.3) Pub Date : 2023 Hye-Jung Kim, Hidetoshi Nakagawa, John Y. Choi, Xuchun Che, Andrew Divris, Qingshi Liu, Andrew E. Wight, Hengcheng Zhang, Anis Saad, Zhabiz Solhjou, Christa Deban, Jamil R. Azzi, Harvey Cantor
Although most CD8+ T cells are equipped to kill infected or transformed cells, a subset may regulate immune responses and preserve self-tolerance. Here, we describe a CD8 lineage that is instructed to differentiate into CD8 T regulatory cells (Tregs) by a surprisingly restricted set of T cell receptors (TCRs) that recognize MHC-E (mouse Qa-1) and several dominant self-peptides. Recognition and elimination
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Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies J. Clin. Invest. (IF 13.3) Pub Date : 2023 Stephanie M. Salabarria, Manuela Corti, Kirsten E. Coleman, Megan B. Wichman, Julie A. Berthy, Precilla D’Souza, Cynthia J. Tifft, Roland W. Herzog, Melissa E. Elder, Lawrence R. Shoemaker, Carmen Leon-Astudillo, Fatemeh Tavakkoli, David H. Kirn, Jonathan D. Schwartz, Barry J. Byrne
BACKGROUND. Systemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome–like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.
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Breast cancer immunopeptidomes contain numerous shared tumor antigens J. Clin. Invest. (IF 13.3) Pub Date : 2023 Eralda Kina, Jean-Philippe Laverdure, Chantal Durette, Joël Lanoix, Mathieu Courcelles, Qingchuan Zhao, Anca Apavaloaei, Jean-David Larouche, Marie-Pierre Hardy, Krystel Vincent, Patrick Gendron, Leslie Hesnard, Catherine Thériault, Maria Virginia Ruiz Cuevas, Grégory Ehx, Pierre Thibault, Claude Perreault
Hormone receptor–positive breast cancer (HR+) is immunologically cold and has not benefited from advances in immunotherapy. In contrast, subsets of triple-negative breast cancer (TNBC) display high leukocytic infiltration and respond to checkpoint blockade. CD8+ T cells, the main effectors of anticancer responses, recognize MHC I–associated peptides (MAPs). Our work aimed to characterize the repertoire
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Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists J. Clin. Invest. (IF 13.3) Pub Date : 2023 Amin Abedini, Andrea Sánchez-Navaro, Junnan Wu, Konstantin A. Klötzer, Ziyuan Ma, Bibek Poudel, Tomohito Doke, Michael S. Balzer, Julia Frederick, Hana Cernecka, Hongbo Liu, Xiujie Liang, Steven Vitale, Peter Kolkhof, Katalin Susztak
Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to
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A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice J. Clin. Invest. (IF 13.3) Pub Date : 2023 Adhithi Rajagopalan, Yubin Feng, Meher B. Gayatri, Erik A. Ranheim, Taylor Klungness, Daniel R. Matson, Moon Hee Lee, Mabel Minji Jung, Yun Zhou, Xin Gao, Kalyan V.G. Nadiminti, David T. Yang, Vu L. Tran, Eric Padron, Shigeki Miyamoto, Emery H. Bresnick, Jing Zhang
We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in NrasG12D/+ p53–/– (NP–/–) mice, NrasG12D/+ p53R172H/+ (NPmut) mice rapidly developed
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Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases J. Clin. Invest. (IF 13.3) Pub Date : 2023 Xuefei Tian, Christopher E. Pedigo, Ke Li, Xiaotao Ma, Patricia Bunda, John Pell, Angela Lek, Jianlei Gu, Yan Zhang, Paulina X. Medina Rangel, Wei Li, Eike Schwartze, Soichiro Nagata, Gabriel Lerner, Sudhir Perincheri, Anupama Priyadarshini, Hongyu Zhao, Monkol Lek, Madhav C. Menon, Rongguo Fu, Shuta Ishibe
The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular
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Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation J. Clin. Invest. (IF 13.3) Pub Date : 2023 Boa Kim, Wencao Zhao, Soon Y. Tang, Michael G. Levin, Ayon Ibrahim, Yifan Yang, Emilia Roberts, Ling Lai, Jian Li, Richard K. Assoian, Garret A. FitzGerald, Zoltan Arany
Metabolic syndrome, today affecting more than 20% of the US population, is a group of 5 conditions that often coexist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here, we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial
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A brain-tumor neural circuit controls breast cancer progression in mice J. Clin. Invest. (IF 13.3) Pub Date : 2023 Si-Yi Xiong, Hui-Zhong Wen, Li-Meng Dai, Yun-Xiao Lou, Zhao-Qun Wang, Yi-Lun Yi, Xiao-Jing Yan, Ya-Ran Wu, Wei Sun, Peng-Hui Chen, Si-Zhe Yang, Xiao-Wei Qi, Yi Zhang, Guang-Yan Wu
Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing
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Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction J. Clin. Invest. (IF 13.3) Pub Date : 2023 Sasha Smolgovsky, Abraham L. Bayer, Kuljeet Kaur, Erin Sanders, Mark Aronovitz, Mallory E. Filipp, Edward B. Thorp, Gabriele G. Schiattarella, Joseph A. Hill, Robert M. Blanton, Juan R. Cubillos-Ruiz, Pilar Alcaide
Heart failure with preserved ejection fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune pathophysiology. Using a 2-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occurred concomitantly with cardiac pathology and that diastolic dysfunction, cardiomyocyte
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Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases J. Clin. Invest. (IF 13.3) Pub Date : 2023 Jawad Fares, Edgar Petrosyan, Deepak Kanojia, Crismita Dmello, Alex Cordero, Joseph T. Duffy, Ragini Yeeravalli, Mayurbhai H. Sahani, Peng Zhang, Aida Rashidi, Victor A. Arrieta, Ilya Ulasov, Atique U. Ahmed, Jason Miska, Irina V. Balyasnikova, C. David James, Adam M. Sonabend, Amy B. Heimberger, Maciej S. Lesniak
A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as
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Hepatitis B virus infection disrupts homologous recombination in hepatocellular carcinoma by stabilizing resection inhibitor ADRM1 J. Clin. Invest. (IF 13.3) Pub Date : 2023 Ming Zeng, Zizhi Tang, Laifeng Ren, Haibin Wang, Xiaojun Wang, Wenyuan Zhu, Xiaobing Mao, Zeyang Li, Xianming Mo, Jun Chen, Junhong Han, Daochun Kong, Jianguo Ji, Antony M. Carr, Cong Liu
Many cancers harbor homologous recombination defects (HRDs). A HRD is a therapeutic target that is being successfully utilized in treatment of breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations do not prevail in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus–bearing (HBV-bearing)
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Bone-derived PDGF-BB drives brain vascular calcification in male mice J. Clin. Invest. (IF 13.3) Pub Date : 2023 Jiekang Wang, Ching-Lien Fang, Kathleen Noller, Zhiliang Wei, Guanqiao Liu, Ke Shen, Kangping Song, Xu Cao, Mei Wan
Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed
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OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity J. Clin. Invest. (IF 13.3) Pub Date : 2023 Adriana Lofrano-Porto, Sidney Alcântara Pereira, Andrew Dauber, Jordana C.B. Bloom, Audrey N. Fontes, Naomi Asimow, Olívia Laquis de Moraes, Petra Ariadne T. Araujo, Ana Paula Abreu, Michael H. Guo, Silviene F. De Oliveira, Han Liu, Charles Lee, Wendy Kuohung, Michella S. Coelho, Rona S. Carroll, Rulang Jiang, Ursula B. Kaiser
Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression
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Microenvironmental network of clonal CXCL13+CD4+ T cells and Tregs in pemphigus chronic blisters J. Clin. Invest. (IF 13.3) Pub Date : 2023 Dawoon Han, A Yeong Lee, Taehee Kim, Ji Young Choi, Mi Yeon Cho, Ahreum Song, Changhyeon Kim, Joon Ho Shim, Hyun Je Kim, Honesty Kim, Hillary Blaize D’Angio, Ryan Preska, Aaron T. Mayer, Miri Kim, Eun-Ji Choi, Tae-Gyun Kim, Eui-Cheol Shin, Kyemyung Park, Do-Young Kim, Soo-Chan Kim, Jong Hoon Kim
BACKGROUND. Pemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.
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Engineered hydrogel reveals contribution of matrix mechanics to esophageal adenocarcinoma and identifies matrix-activated therapeutic targets J. Clin. Invest. (IF 13.3) Pub Date : 2023 Ricardo Cruz-Acuña, Secunda W. Kariuki, Kensuke Sugiura, Spyros Karaiskos, Eleanor M. Plaster, Claudia Loebel, Gizem Efe, Tatiana Karakasheva, Joel T. Gabre, Jianhua Hu, Jason A. Burdick, Anil K. Rustgi
Increased extracellular matrix (ECM) stiffness has been implicated in esophageal adenocarcinoma (EAC) progression, metastasis, and resistance to therapy. However, the underlying protumorigenic pathways are yet to be defined. Additional work is needed to develop physiologically relevant in vitro 3D culture models that better recapitulate the human tumor microenvironment and can be used to dissect the
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Hypertriglyceridemia in Apoa5–/– mice results from reduced amounts of lipoprotein lipase in the capillary lumen J. Clin. Invest. (IF 13.3) Pub Date : 2023 Ye Yang, Anne P. Beigneux, Wenxin Song, Le Phuong Nguyen, Hyesoo Jung, Yiping Tu, Thomas A. Weston, Caitlyn M. Tran, Katherine Xie, Rachel G. Yu, Anh P. Tran, Kazuya Miyashita, Katsuyuki Nakajima, Masami Murakami, Yan Q. Chen, Eugene Y. Zhen, Joonyoung R. Kim, Paul H. Kim, Gabriel Birrane, Peter Tontonoz, Michael Ploug, Robert J. Konrad, Loren G. Fong, Stephen G. Young
Why apolipoprotein AV (APOA5) deficiency causes hypertriglyceridemia has remained unclear, but we have suspected that the underlying cause is reduced amounts of lipoprotein lipase (LPL) in capillaries. By routine immunohistochemistry, we observed reduced LPL staining of heart and brown adipose tissue (BAT) capillaries in Apoa5–/– mice. Also, after an intravenous injection of LPL-, CD31-, and GPIHBP1-specific
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Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1 J. Clin. Invest. (IF 13.3) Pub Date : 2023 Callum Beach, David MacLean, Dominika Majorova, Stavros Melemenidis, Dhanya K. Nambiar, Ryan K. Kim, Gabriel N. Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily V.S. Hillson, Ashley K. McCulloch, Ross K. McMahon, Kathryn Pennel, Joanne Edwards, Sean M. O’Cathail, Campbell S. Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang
An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved
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Endothelial ADAM10 utilization defines a molecular pathway of vascular injury in mice with bacterial sepsis J. Clin. Invest. (IF 13.3) Pub Date : 2023 Danielle N. Alfano, Mark J. Miller, Juliane Bubeck Wardenburg
The endothelium plays a critical role in the host response to infection and has been a focus of investigation in sepsis. While it is appreciated that intravascular thrombus formation, severe inflammation, and loss of endothelial integrity impair tissue oxygenation during sepsis, the precise molecular mechanisms that lead to endothelial injury remain poorly understood. We demonstrate here that endothelial
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Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing J. Clin. Invest. (IF 13.3) Pub Date : 2023 Rizwan Ahmad, Balawant Kumar, Ishwor Thapa, Raju Lama Tamang, Santosh K. Yadav, Mary K. Washington, Geoffrey A. Talmon, Alan S. Yu, Dhundy K. Bastola, Punita Dhawan, Amar B. Singh
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its
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USP47 inhibits m6A-dependent c-Myc translation to maintain regulatory T cell metabolic and functional homeostasis J. Clin. Invest. (IF 13.3) Pub Date : 2023 Aiting Wang, Haiyan Huang, Jian-Hong Shi, Xiaoyan Yu, Rui Ding, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Xia Li, Ren Zhao, Qiang Zou
The functional integrity of Tregs is interwoven with cellular metabolism; however, the mechanisms governing Treg metabolic programs remain elusive. Here, we identified that the deubiquitinase USP47 inhibited c-Myc translation mediated by the RNA N6-methyladenosine (m6A) reader YTHDF1 to maintain Treg metabolic and functional homeostasis. USP47 positively correlated with the tumor-infiltrating Treg
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Biofilm derived oxylipin 10-HOME mediated immune response in women with breast implants. J. Clin. Invest. (IF 13.3) Pub Date : 2023-11-30 Imran Khan,Robert E Minto,Christine Kelley-Patteson,Kanhaiya Singh,Lava Timsina,Lily J Suh,Ethan Rinne,Bruce W Van Natta,Colby R Neumann,Ganesh Mohan,Mary Lester,R Jason VonDerHaar,Rana German,Natascia Marino,Aladdin H Hassanein,Gayle M Gordillo,Mark H Kaplan,Chandan K Sen,Marshall E Kadin,Mithun Sinha
The study investigates a mechanistic link if bacterial biofilm mediated host-pathogen interaction leads to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. The study included 178 subjects divided
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TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-Cadherin internalization. J. Clin. Invest. (IF 13.3) Pub Date : 2023-11-28 Jingshu Tang,Yuying Kang,Yujun Zhou,Nianying Shang,Xinnan Li,Hongyue Wang,Jiaqi Lan,Shuai Wang,Lei Wu,Ying Peng
Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting matrix metalloproteinase (MMP) activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular
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Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains. J. Clin. Invest. (IF 13.3) Pub Date : 2023-11-28 Hye Sun Kuehn,Inga S Sakovich,Julie E Niemela,Agustin A Gil Silva,Jennifer L Stoddard,Ekaterina A Polyakova,Ana Esteve-Sole,Svetlana N Aleshkevich,Tatjana A Uglova,Mikhail V Belevtsev,Vladislav R Vertelko,Tatsiana V Shman,Aleksandra N Kupchinskaya,Jolan E Walter,Thomas A Fleisher,Luigi D Notarangelo,Xiao P Peng,Ottavia Maria Delmonte,Svetlana O Sharapova,Sergio D Rosenzweig
AIOLOS, also known as IKZF3, is a transcription factor highly expressed in the lymphoid lineage and critical for lymphocyte differentiation and development. Here we report nine individuals from three unrelated families carrying AIOLOS variants Q402* or E82K leading to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric
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TV005 dengue vaccine protects against dengue serotype 2 and 3 controlled human infection. J. Clin. Invest. (IF 13.3) Pub Date : 2023-11-16 Kristen K Pierce,Anna P Durbin,Mary-Claire Walsh,Marya Carmolli,Beulah P Sabundayo,Dorothy M Dickson,Sean A Diehl,Stephen S Whitehead,Beth D Kirkpatrick
BACKGROUND Disease due to dengue viruses is a growing global health threat, causing 100-400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all four serotypes in phase 3 efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help down select vaccine candidates and supply critical
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Effectiveness of the BNT162b2 mRNA COVID-19 vaccine in children under 5 years. J. Clin. Invest. (IF 13.3) Pub Date : 2023-11-01 Christoph Strumann,Otavio Ranzani,Jeanne Moor,Reinhard Berner,Nicole Töpfner,Cho-Ming Chao,Matthias B Moor
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BCMA- and CST6-specific CAR T cells lyse multiple myeloma cells and suppress murine osteolytic lesions. J. Clin. Invest. (IF 13.3) Pub Date : 2023-10-26 Fumou Sun,Yan Cheng,Jin-Ran Chen,Visanu Wanchai,David E Mery,Hongwei Xu,Dongzheng Gai,Samer Al Hadidi,Carolina Schinke,Sharmilan Thanendrarajan,Maurizio Zangari,Frits van Rhee,Guido Tricot,John D Shaughnessy,Fenghuang Zhan
We have previously demonstrated that cystatin E/M (CST6), elevated in a subset of multiple myeloma (MM) patients lacking osteolytic lesions (OL), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. We have developed B cell
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Activation of mTOR signaling in adult lung microvascular progenitor cells accelerates lung aging. J. Clin. Invest. (IF 13.3) Pub Date : 2023-10-24 Emma C Mason,Swapna Menon,Benjamin R Schneider,Christa F Gaskill,Maggie M Dawson,Camille M Moore,Laura Craig Armstrong,Okyong J Cho,Bradley W Richmond,Jonathan A Kropski,James D West,Patrick Geraghty,Brigitte N Gomperts,Kevin C Ess,Fabienne Gally,Susan M Majka
Reactivation and dysregulation of the mTOR signaling pathway is a hallmark of aging and chronic lung disease, however the impact on microvascular progenitor cells (MVPC), capillary angiostasis and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue resident MVPC
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High-dimensional immunophenotyping reveals immune cell aberrations in patients with undiagnosed inflammatory and autoimmune diseases. J. Clin. Invest. (IF 13.3) Pub Date : 2023-10-24 Alisa A Mueller,Takanori Sasaki,Joshua W Keegan,Jennifer P Nguyen,Alec Griffith,Alice M Horisberger,Thomas Licata,Elizabeth Fieg,Ye Cao,Mehreen Elahee,Kathryne E Marks,Daimon P Simmons,Lauren C Briere,Laurel A Cobban,J Carl Pallais,Frances A High,Melissa A Walker,Jenny J Linnoila,Jeffrey A Sparks,V Michael Holers,Karen H Costenbader,Undiagnosed Diseases Network Udn,David A Sweetser,Joel B Krier,Joseph
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A splice-switching oligonucleotide treatment ameliorates glycogen storage disease type 1a in mice with G6PC c.648G>T. J. Clin. Invest. (IF 13.3) Pub Date : 2023-12-01 Kentaro Ito,Go Tajima,Chikako Kamisato,Miyuki Tsumura,Mitsuhiro Iwamoto,Yukiko Sekiguchi,Yukinobu Numata,Kyoko Watanabe,Yoshiyuki Yabe,Satomi Kanki,Yusuke Fujieda,Koichi Goto,Yoshitaka Sogawa,Masataka Oitate,Hiroyuki Nagase,Shinnosuke Tsuji,Tomohiro Nishizawa,Masayo Kakuta,Takeshi Masuda,Yoshiyuki Onishi,Makoto Koizumi,Hidefumi Nakamura,Satoshi Okada,Masafumi Matsuo,Kiyosumi Takaishi
Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-α (G6Pase-α, encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities
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Recruitment of naive CD4+ T cells by the recombinant zoster vaccine correlates with persistent immunity. J. Clin. Invest. (IF 13.3) Pub Date : 2023-12-01 Kerry J Laing,Emily S Ford,Michael J Johnson,Myron J Levin,David M Koelle,Adriana Weinberg
Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying
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AlphaFold developers Demis Hassabis and John Jumper share the 2023 Albert Lasker Basic Medical Research Award. J. Clin. Invest. (IF 13.3) Pub Date : 2023-09-21 Tobin R Sosnick
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Optical coherence tomography: when a picture is worth a million words. J. Clin. Invest. (IF 13.3) Pub Date : 2023-09-21 Simone Tzaridis,Martin Friedlander
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Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models J. Clin. Invest. (IF 13.3) Pub Date : 2023 Seungkirl Ahn, Harm Maarsingh, Julia K.L. Walker, Samuel Liu, Akhil Hegde, Hyeje C. Sumajit, Alem W. Kahsai, Robert J. Lefkowitz
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote — with limited efficacy — bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands that bind the same site as endogenous epinephrine. We recently isolated a β2AR-selective positive allosteric modulator (PAM), compound-6 (Cmpd-6)
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Specific Cryptosporidium antigens associate with reinfection immunity and protection from cryptosporidiosis J. Clin. Invest. (IF 13.3) Pub Date : 2023 Carol A. Gilchrist, Joseph J. Campo, Jozelyn V. Pablo, Jennie Z. Ma, Andy Teng, Amit Oberai, Adam D. Shandling, Masud Alam, Mamun Kabir, A.S.G. Faruque, Rashidul Haque, William A. Petri Jr.
There is no vaccine to protect from cryptosporidiosis, a leading cause of diarrhea in infants in low- and middle-income countries. Here, we comprehensively identified parasite antigens associated with protection from reinfection. A Cryptosporidium protein microarray was constructed by in vitro transcription and translation of 1,761 C. parvum, C. hominis, or C. meleagridis antigens, including proteins