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Allosteric modulator potentiates β2AR agonist–promoted bronchoprotection in asthma models J. Clin. Invest. (IF 15.9) 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 15.9) 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
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Molecular correlates of vaccine-induced protection against typhoid fever J. Clin. Invest. (IF 15.9) Pub Date : 2023 Henderson Zhu, Irina Chelysheva, Deborah L. Cross, Luke Blackwell, Celina Jin, Malick M. Gibani, Elizabeth Jones, Jennifer Hill, Johannes Trück, Dominic F. Kelly, Christoph J. Blohmke, Andrew J. Pollard, Daniel O’Connor
BACKGROUND. Typhoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced
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A phase II study of Bruton’s tyrosine kinase inhibition for the prevention of anaphylaxis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ragha V. Suresh, Collin Dunnam, Dhananjay Vaidya, Robert A. Wood, Bruce S. Bochner, Donald W. MacGlashan Jr., Melanie C. Dispenza
BACKGROUND. IgE-mediated anaphylaxis is a potentially fatal systemic allergic reaction for which there are no currently FDA-approved preventative therapies. Bruton’s tyrosine kinase (BTK) is an essential enzyme for IgE-mediated signaling pathways and is an ideal pharmacologic target to prevent allergic reactions. In this open-label trial, we evaluated the safety and efficacy of acalabrutinib, a BTK
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Active transcription in the vascular bed characterizes rapid progression in idiopathic pulmonary fibrosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Nirmal S. Sharma, Kapil Patel, Ezgi Sari, Shruti Shankar, Maria G. Gastanadui, Diego Moncada-Giraldo, Yixel Soto-Vazquez, Delores Stacks, Louise Hecker, Kevin Dsouza, Mudassir Banday, Edward O’Neill, Paul Benson, Gregory Payne, Camilla Margaroli, Amit Gaggar
To the Editor: Idiopathic pulmonary fibrosis (IPF) is the most common manifestation of interstitial lung disease, with a median survival of 3–5 years after diagnosis. IPF is characterized by progressive fibrosis with the development of fibroblastic foci in the interstitium. Despite the short median survival, there is a striking variance in the clinical course of IPF, with some patients characterized
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Cotargeting a MYC/eIF4A-survival axis improves the efficacy of KRAS inhibitors in lung cancer J. Clin. Invest. (IF 15.9) Pub Date : 2023 Francesca Nardi, Naiara Perurena, Amy E. Schade, Ze-Hua Li, Kenneth Ngo, Elena V. Ivanova, Aisha Saldanha, Chendi Li, Prafulla C. Gokhale, Aaron N. Hata, David A. Barbie, Cloud P. Paweletz, Pasi A. Jänne, Karen Cichowski
Despite the success of KRAS G12C inhibitors in non–small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important
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Long-acting lenacapavir acts as an effective preexposure prophylaxis in a rectal SHIV challenge macaque model J. Clin. Invest. (IF 15.9) Pub Date : 2023 Elena Bekerman, Stephen R. Yant, Laurie VanderVeen, Derek Hansen, Bing Lu, William Rowe, Kelly Wang, Christian Callebaut
Long-acting antiretroviral agents for preexposure prophylaxis (PrEP) represent a promising new alternative to daily oral regimens for HIV prevention. Lenacapavir (LEN) is a first-in-class long-acting capsid inhibitor approved for the treatment of HIV-1 infection. Here, we assessed the efficacy of LEN for PrEP using a single high-dose simian-human immunodeficiency virus (SHIV) rectal challenge macaque
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Transepidermal water loss rises before food anaphylaxis and predicts food challenge outcomes J. Clin. Invest. (IF 15.9) Pub Date : 2023 Charles F. Schuler IV, Kelly M. O’Shea, Jonathan P. Troost, Bridgette Kaul, Christopher M. Launius, Jayme Cannon, David M. Manthei, George E. Freigeh, Georgiana M. Sanders, Simon P. Hogan, Nicholas W. Lukacs, James R. Baker Jr.
BACKGROUND. Food allergy (FA) is a growing health problem requiring physiologic confirmation via the oral food challenge (OFC). Many OFCs result in clinical anaphylaxis, causing discomfort and risk while limiting OFC utility. Transepidermal water loss (TEWL) measurement provides a potential solution to detect food anaphylaxis in real time prior to clinical symptoms. We evaluated whether TEWL changes
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Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration J. Clin. Invest. (IF 15.9) Pub Date : 2023 Leon Tejwani, Youngseob Jung, Hiroshi Kokubu, Sowmithra Sowmithra, Luhan Ni, Changwoo Lee, Benjamin Sanders, Paul J. Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah H. Ro, Hyoungseok Ju, Clara Liao, Sofia Massaro Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim
Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43–positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS–causing
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SCCA1/SERPINB3 suppresses antitumor immunity and blunts therapy-induced T cell responses via STAT-dependent chemokine production J. Clin. Invest. (IF 15.9) Pub Date : 2023 Liyun Chen, Victoria Shi, Songyan Wang, Lulu Sun, Rebecca Freeman, Jasmine Yang, Matthew J. Inkman, Subhajit Ghosh, Fiona Ruiz, Kay Jayachandran, Yi Huang, Jingqin Luo, Jin Zhang, Pippa Cosper, Clifford J. Luke, Catherine S. Spina, Perry W. Grigsby, Julie K. Schwarz, Stephanie Markovina
Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid
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Ruxolitinib improves hematopoietic regeneration by restoring mesenchymal stromal cell function in acute graft-versus-host disease J. Clin. Invest. (IF 15.9) Pub Date : 2023 Yan Lin, Quan Gu, Shihong Lu, Zengkai Pan, Zining Yang, Yapu Li, Shangda Yang, Yanling Lv, Zhaofeng Zheng, Guohuan Sun, Fanglin Gou, Chang Xu, Xiangnan Zhao, Fengjiao Wang, Chenchen Wang, Shiru Yuan, Xiaobao Xie, Yang Cao, Yue Liu, Weiying Gu, Tao Cheng, Hui Cheng, Xiaoxia Hu
Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC–matched
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Phospholipid scramblase-1 regulates innate type 2 inflammation in mouse lungs via CRTH2-dependent mechanisms J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ashley Hernandez-Gutierrez, Sonoor Majid, Adam Eberle, Ashley Choi, Parand Sorkhdini, Dongqin Yang, Alina Xiaoyu Yang, Carmelissa Norbrun, Chuan Hua He, Chang-min Lee, Chun Geun Lee, Jack A. Elias, Yang Zhou
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment
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Macrophage–endothelial cell crosstalk orchestrates neutrophil recruitment in inflamed mucosa J. Clin. Invest. (IF 15.9) Pub Date : 2023 Xingsheng Ren, Laura D. Manzanares, Enzo B. Piccolo, Jessica M. Urbanczyk, David P. Sullivan, Lenore K. Yalom, Triet M. Bui, Connor Lantz, Hinda Najem, Parambir S. Dulai, Amy B. Heimberger, Edward B. Thorp, Ronen Sumagin
Neutrophil (PMN) mobilization to sites of insult is critical for host defense and requires transendothelial migration (TEM). TEM involves several well-studied sequential adhesive interactions with vascular endothelial cells (ECs); however, what initiates or terminates this process is not well-understood. Here, we describe what we believe to be a new mechanism where vessel-associated macrophages through
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Pancreatic regional blood flow links the endocrine and exocrine diseases J. Clin. Invest. (IF 15.9) Pub Date : 2023 Adam A. Rizk, Michael P. Dybala, Khalil C. Rodriguez, Marjan Slak Rupnik, Manami Hara
An increasing number of studies have demonstrated that disease states of the endocrine or exocrine pancreas aggravate one another, which implies bidirectional blood flow between islets and exocrine cells. However, this is inconsistent with the current model of unidirectional blood flow, which is strictly from islets to exocrine tissues. This conventional model was first proposed in 1932, and it has
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Monocyte-derived macrophages orchestrate multiple cell-type interactions to repair necrotic liver lesions in disease models J. Clin. Invest. (IF 15.9) Pub Date : 2023 Dechun Feng, Xiaogang Xiang, Yukun Guan, Adrien Guillot, Hongkun Lu, Chingwen Chang, Yong He, Hua Wang, Hongna Pan, Cynthia Ju, Sean P. Colgan, Frank Tacke, Xin Wei Wang, George Kunos, Bin Gao
The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages
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Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth J. Clin. Invest. (IF 15.9) Pub Date : 2023 Galina Gritsina, Ka-wing Fong, Xiaodong Lu, Zhuoyuan Lin, Wanqing Xie, Shivani Agarwal, Dong Lin, Gary E. Schiltz, Himisha Beltran, Eva Corey, Colm Morrissey, Yuzhuo Wang, Jonathan C. Zhao, Maha Hussain, Jindan Yu
CXCR7 is an atypical chemokine receptor that recruits β-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle
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APOE-ε4 synergizes with sleep disruption to accelerate Aβ deposition and Aβ-associated tau seeding and spreading J. Clin. Invest. (IF 15.9) Pub Date : 2023 Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman
Alzheimer’s disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ
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Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jan Attig, Judith Pape, Laura Doglio, Anastasiya Kazachenka, Eleonora Ottina, George R. Young, Katey S.S. Enfield, Iker Valle Aramburu, Kevin W. Ng, Nikhil Faulkner, William Bolland, Venizelos Papayannopoulos, Charles Swanton, George Kassiotis
Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the underlying processes are incompletely understood. Here, we show that elevated transcription of HERVH proviruses predicted survival of lung squamous cell carcinoma (LUSC) and identified an isoform of CALB1, encoding calbindin, ectopically
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1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy J. Clin. Invest. (IF 15.9) Pub Date : 2023 Qianqian Zhuang, Fengfeng Guo, Lei Fu, Yufei Dong, Shaofang Xie, Xue Ding, Shuangyi Hu, Xuanhao D. Zhou, Yangwei Jiang, Hui Zhou, Yue Qiu, Zhaoying Lei, Mengyao Li, Huajian Cai, Mingjie Fan, Lingjie Sang, Yong Fu, Dong Zhang, Aifu Lin, Xu Li, Tilo Kunath, Ruhong Zhou, Ping Liang, Zhong Liu, Qingfeng Yan
Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition
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Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia J. Clin. Invest. (IF 15.9) Pub Date : 2023 Longlong Tu, Jonathan C. Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A. Scarcelli, Kristine M. Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu
Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we
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Anti–miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response J. Clin. Invest. (IF 15.9) Pub Date : 2023 Mihnea P. Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M. Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W. Anderson, Spencer J. Rothfuss, Robert Silasi, Ravi S. Keshari, Manuela Ferracin, Cristina Ivan, Cristian
Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array
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Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Applewhite, Kathleen Jee, Monika Deshpande, Miguel Flores-Bellver, Ming-Wen Hu, Chuanyu Guo, Shaima Salman, Yousang Hwang, Nicole M. Anders, Michelle A. Rudek, Jiang Qian, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by HIF-1 and -2 remain elevated in the eyes of people with diabetes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs, we normalized the expression of multiple vasoactive
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Human endogenous retrovirus K contributes to a stem cell niche in glioblastoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Ashish H. Shah, Sarah R. Rivas, Tara T. Doucet-O’Hare, Vaidya Govindarajan, Catherine DeMarino, Tongguang Wang, Leonel Ampie, Yong Zhang, Yeshavanth Kumar Banasavadi-Siddegowda, Stuart Walbridge, Dragan Maric, Marta Garcia-Montojo, Robert K. Suter, Myoung-Hwa Lee, Kareem A. Zaghloul, Joseph Steiner, Abdel G. Elkahloun, Jay Chandar, Deepa Seetharam, Jelisah Desgraves, Wenxue Li, Kory Johnson, Michael
Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype
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The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression J. Clin. Invest. (IF 15.9) Pub Date : 2023 Gloria Mas, Na Man, Yuichiro Nakata, Concepcion Martinez-Caja, Daniel Karl, Felipe Beckedorff, Francesco Tamiro, Chuan Chen, Stephanie Duffort, Hidehiro Itonaga, Adnan K. Mookhtiar, Kranthi Kunkalla, Alfredo M. Valencia, Clayton K. Collings, Cigall Kadoch, Francisco Vega, Scott C. Kogan, Lluis Morey, Daniel Bilbao, Stephen D. Nimer
During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation. DPF2 is
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Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus J. Clin. Invest. (IF 15.9) Pub Date : 2023 Warren Floyd, Matthew Pierpoint, Chang Su, Rutulkumar Patel, Lixia Luo, Katherine Deland, Amy J. Wisdom, Daniel Zhu, Yan Ma, Suzanne Bartholf DeWitt, Nerissa T. Williams, Alexander L. Lazarides, Jason A. Somarelli, David L. Corcoran, William C. Eward, Diana M. Cardona, David G. Kirsch
ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus
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CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism J. Clin. Invest. (IF 15.9) Pub Date : 2023 Young Jae Bahn, Hariom Yadav, Paolo Piaggi, Brent S. Abel, Oksana Gavrilova, Danielle A. Springer, Ioannis Papazoglou, Patricia M. Zerfas, Monica C. Skarulis, Alexandra C. McPherron, Sushil G. Rane
Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that
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PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Kallesh D. Jayappa, Brian Tran, Vicki L. Gordon, Christopher Morris, Shekhar Saha, Caroline C. Farrington, Caitlin M. O’Connor, Kaitlin P. Zawacki, Krista M. Isaac, Mark Kester, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Michael J. Weber, Goutham Narla
Targeted therapies such as venetoclax (VEN) (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple antiapoptotic proteins and display resistance to proapoptotic agents. Here, we demonstrated that multidrug-resistant CLL cells in vivo exhibited apoptosis restriction at a pre-mitochondrial
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Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Benedetta Apollonio, Filomena Spada, Nedyalko Petrov, Domenico Cozzetto, Despoina Papazoglou, Peter Jarvis, Shichina Kannambath, Manuela Terranova-Barberio, Rose-Marie Amini, Gunilla Enblad, Charlotte Graham, Reuben Benjamin, Elisabeth Phillips, Richard Ellis, Rosamond Nuamah, Mansoor Saqi, Dinis P. Calado, Richard Rosenquist, Lesley A. Sutton, Jon Salisbury, Georgios Zacharioudakis, Anna Vardi, Patrick
Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled
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Prevalence and functional profile of SARS-CoV-2 T cells in asymptomatic Kenyan adults J. Clin. Invest. (IF 15.9) Pub Date : 2023 Taraz Samandari, Joshua B. Ongalo, Kimberly D. McCarthy, Richard K. Biegon, Philister A. Madiega, Anne Mithika, Joseph Orinda, Grace M. Mboya, Patrick Mwaura, Omu Anzala, Clayton Onyango, Fredrick O. Oluoch, Eric Osoro, Charles-Antoine Dutertre, Nicole Tan, Shou Kit Hang, Smrithi Hariharaputran, David C. Lye, Amy Herman-Roloff, Nina Le Bert, Antonio Bertoletti
Background. SARS-CoV-2 infection in Africa has been characterized by a less severe disease profile than what has been observed elsewhere, but the profile of SARS-CoV-2–specific adaptive immunity in these mainly asymptomatic patients has not, to our knowledge, been analyzed.
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T-BET and EOMES sustain mature human NK cell identity and antitumor function J. Clin. Invest. (IF 15.9) Pub Date : 2023 Pamela Wong, Jennifer A. Foltz, Lily Chang, Carly C. Neal, Tony Yao, Celia C. Cubitt, Jennifer Tran, Samantha Kersting-Schadek, Sathvik Palakurty, Natalia Jaeger, David A. Russler-Germain, Nancy D. Marin, Margery Gang, Julia A. Wagner, Alice Y. Zhou, Miriam T. Jacobs, Mark Foster, Timothy Schappe, Lynne Marsala, Ethan McClain, Patrick Pence, Michelle Becker-Hapak, Bryan Fisk, Allegra A. Petti, Obi
Since the T-box transcription factors (TFs) T-BET and EOMES are necessary for initiation of NK cell development, their ongoing requirement for mature NK cell homeostasis, function, and molecular programming remains unclear. To address this, T-BET and EOMES were deleted in unexpanded primary human NK cells using CRISPR/Cas9. Deleting these TFs compromised in vivo antitumor response of human NK cells
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The potential role of human endogenous retrovirus K in glioblastoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Parvinder Hothi, Charles Cobbs
The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and function of HML-2 in malignant gliomas has remained unclear. In this issue of the JCI, Shah and colleagues demonstrate HML-2 overexpression in glioblastoma (GBM) and its role in maintaining the cancer stem cell phenotype. Given that stem-like
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The selenoprotein P–LRP5/6–WNT3A complex promotes tumorigenesis in sporadic colorectal cancer J. Clin. Invest. (IF 15.9) Pub Date : 2023 K. Sandeep Prabhu
Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In
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Host genetic background is a barrier to broadly effective vaccine–mediated protection against tuberculosis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Rocky Lai, Diana N. Gong, Travis Williams, Abiola F. Ogunsola, Kelly Cavallo, Cecilia S. Lindestam Arlehamn, Sarah Acolatse, Gillian L. Beamer, Martin T. Ferris, Christopher M. Sassetti, Douglas A. Lauffenburger, Samuel M. Behar
Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin–induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with
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Identification and validation of urinary CXCL9 as a biomarker for diagnosis of acute interstitial nephritis J. Clin. Invest. (IF 15.9) Pub Date : 2023 Dennis G. Moledina, Wassim Obeid, Rex N. Smith, Ivy Rosales, Meghan E. Sise, Gilbert Moeckel, Michael Kashgarian, Michael Kuperman, Kirk N. Campbell, Sean Lefferts, Kristin Meliambro, Markus Bitzer, Mark A. Perazella, Randy L. Luciano, Jordan S. Pober, Lloyd G. Cantley, Robert B. Colvin, F. Perry Wilson, Chirag R. Parikh
Background. Acute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a
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iPSC-derived reactive astrocytes from patients with multiple sclerosis protect cocultured neurons in inflammatory conditions J. Clin. Invest. (IF 15.9) Pub Date : 2023 Janis Kerkering, Bakhrom Muinjonov, Kamil S. Rosiewicz, Sebastian Diecke, Charlotte Biese, Juliane Schiweck, Claudia Chien, Dario Zocholl, Thomas Conrad, Friedemann Paul, Marlen Alisch, Volker Siffrin
Multiple sclerosis (MS) is the most common chronic central nervous system inflammatory disease. Individual courses are highly variable, with complete remission in some patients and relentless progression in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared with progressive MS (PMS). We differentiated neurons and astrocytes that
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Biomarkers in acute kidney injury: On the cusp of a new era? J. Clin. Invest. (IF 15.9) Pub Date : 2023 Mark Canney, Edward G. Clark, Swapnil Hiremath
The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease and acute kidney injury (AKI). Early diagnosis and establishment of etiology, in particular, are important for treatment of AKI. In the setting of hospital-acquired AKI, tubular injury is more common, but acute interstitial nephritis (AIN) has a more treatable etiology. However
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Discovering the fibroblastic reticular cell in the immune tumor microenvironment in lymphoma J. Clin. Invest. (IF 15.9) Pub Date : 2023 Adam Yuh Lin, Leo I. Gordon
The study of the cellular and molecular microenvironment in B cell lymphoma, especially diffuse large B cell lymphoma (DLBCL), has led to prognostic and therapeutic algorithms that may improve patient outcomes. Emerging gene signature panels provide a granular understanding of DLBCL based on the immune tumor microenvironment (iTME). In addition, some gene signatures identify lymphomas that are more
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Net39 protects muscle nuclei from mechanical stress during the pathogenesis of Emery-Dreifuss muscular dystrophy J. Clin. Invest. (IF 15.9) Pub Date : 2023 Yichi Zhang, Andres Ramirez-Martinez, Kenian Chen, John R. McAnally, Chunyu Cai, Mateusz Z. Durbacz, Francesco Chemello, Zhaoning Wang, Lin Xu, Rhonda Bassel-Duby, Ning Liu, Eric N. Olson
Mutations in genes encoding nuclear envelope proteins lead to diseases known as nuclear envelopathies, characterized by skeletal muscle and heart abnormalities, such as Emery-Dreifuss muscular dystrophy (EDMD). The tissue-specific role of the nuclear envelope in the etiology of these diseases has not been extensively explored. We previously showed that global deletion of the muscle-specific nuclear
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Disrupting pathologic phase transitions in neurodegeneration J. Clin. Invest. (IF 15.9) Pub Date : 2023 Bryan T. Hurtle, Longxin Xie, Christopher J. Donnelly
Solid-like protein deposits found in aged and diseased human brains have revealed a relationship between insoluble protein accumulations and the resulting deficits in neurologic function. Clinically diverse neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis, exhibit unique and disease-specific biochemical
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SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions J. Clin. Invest. (IF 15.9) Pub Date : 2023 Jennifer M. Pilat, Rachel E. Brown, Zhengyi Chen, Nathaniel J. Berle, Adrian P. Othon, M. Kay Washington, Shruti A. Anant, Suguru Kurokawa, Victoria H. Ng, Joshua J. Thompson, Justin Jacobse, Jeremy A. Goettel, Ethan Lee, Yash A. Choksi, Ken S. Lau, Sarah P. Short, Christopher S. Williams
Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP’s contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into
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Gluconeogenic enzyme PCK1 supports S-adenosylmethionine biosynthesis and promotes H3K9me3 modification to suppress hepatocellular carcinoma progression J. Clin. Invest. (IF 15.9) Pub Date : 2023 Dongmei Gou, Rui Liu, Xiaoqun Shan, Haijun Deng, Chang Chen, Jin Xiang, Yi Liu, Qingzhu Gao, Zhi Li, Ailong Huang, Kai Wang, Ni Tang
Deciphering the crosstalk between metabolic reprogramming and epigenetic regulation is a promising strategy for cancer therapy. In this study, we discovered that the gluconeogenic enzyme PCK1 fueled the generation of S-adenosylmethionine (SAM) through the serine synthesis pathway. The methyltransferase SUV39H1 catalyzed SAM, which served as a methyl donor to support H3K9me3 modification, leading to
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Enhancing immunotherapy response in melanoma: myeloid-derived suppressor cells as a therapeutic target J. Clin. Invest. (IF 15.9) Pub Date : 2023 Feyza Gul Ozbay Kurt, Samantha Lasser, Ihor Arkhypov, Jochen Utikal, Viktor Umansky
Despite the remarkable success of immune checkpoint inhibitors (ICIs) in melanoma treatment, resistance to them remains a substantial clinical challenge. Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that can suppress antitumor immune responses mediated by T and natural killer cells and promote tumor growth. They are major contributors to ICI resistance
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Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations J. Clin. Invest. (IF 15.9) Pub Date : 2023 Zibo Zhao, Kaixiang Cao, Jun Watanabe, Cassandra N. Philips, Jacob M. Zeidner, Yukitomo Ishi, Qixuan Wang, Sarah R. Gold, Katherine Junkins, Elizabeth T. Bartom, Feng Yue, Navdeep S. Chandel, Rintaro Hashizume, Issam Ben-Sahra, Ali Shilatifard
Epigenetic status–altering mutations in chromatin-modifying enzymes are a feature of human diseases, including many cancers. However, the functional outcomes and cellular dependencies arising from these mutations remain unresolved. In this study, we investigated cellular dependencies, or vulnerabilities, that arise when enhancer function is compromised by loss of the frequently mutated COMPASS family
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Poly(ADP-ribose) polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production J. Clin. Invest. (IF 15.9) Pub Date : 2023 Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A. Rosa, Mark Boothby, Sung Hoon Cho, Javier Rangel-Moreno, Stanley K. Mbandi, Valérie Schreiber, Ananya Gupta, Joaquin Zuniga, Makedonka Mitreva, Deepak Kaushal, Thomas J. Scriba, Shabaana A. Khader
The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here
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KIR-HLA interactions extend human CD8+ T cell lifespan in vivo J. Clin. Invest. (IF 15.9) Pub Date : 2023 Yan Zhang, Ada W.C. Yan, Lies Boelen, Linda Hadcocks, Arafa Salam, Daniel Padrosa Gispert, Loiza Spanos, Laura Mora Bitria, Neda Nemat-Gorgani, James A. Traherne, Chrissy Roberts, Danai Koftori, Graham P. Taylor, Daniel Forton, Paul J. Norman, Steven G.E. Marsh, Robert Busch, Derek C. Macallan, Becca Asquith
BACKGROUND. There is increasing evidence, in transgenic mice and in vitro, that inhibitory killer cell immunoglobulin-like receptors (iKIRs) can modulate T cell responses. Furthermore, we have previously shown that iKIRs are an important determinant of T cell–mediated control of chronic viral infection and that these results are consistent with an increase in the CD8+ T cell lifespan due to iKIR-ligand
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Mechanisms for regulation of RAS palmitoylation and plasma membrane trafficking in hematopoietic malignancies J. Clin. Invest. (IF 15.9) Pub Date : 2023 Fang Yu, Zhijian Qian
Palmitoylation is a critical posttranslational modification that enables the cellular membrane localization and subsequent activation of RAS proteins, including HRAS, KRAS, and NRAS. However, the molecular mechanism that regulates RAS palmitoylation in malignant diseases remains unclear. In this issue of the JCI, Ren, Xing, and authors shed light on this topic and revealed how upregulation of RAB27B
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C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps J. Clin. Invest. (IF 15.9) Pub Date : 2023 Bruna M. Silva, Giovanni F. Gomes, Flavio P. Veras, Seppe Cambier, Gabriel V.L. Silva, Andreza U. Quadros, Diego B. Caetité, Daniele C. Nascimento, Camilla M. Silva, Juliana C. Silva, Samara Damasceno, Ayda H. Schneider, Fabio Beretta, Sabrina S. Batah, Icaro M.S. Castro, Isadora M. Paiva, Tamara Rodrigues, Ana Salina, Ronaldo Martins, Guilherme C.M. Cebinelli, Naira L. Bibo, Daniel M. Jorge, Helder
Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved
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A randomized controlled experimental medicine study of ghrelin in value-based decision making J. Clin. Invest. (IF 15.9) Pub Date : 2023 Michal Pietrzak, Adam Yngve, J. Paul Hamilton, Robin Kämpe, Rebecca Boehme, Anna Asratian, Emelie Gauffin, Andreas Löfberg, Sarah Gustavson, Emil Persson, Andrea J. Capusan, Lorenzo Leggio, Irene Perini, Gustav Tinghög, Markus Heilig
BACKGROUND. The stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards.
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Complement C3aR depletion reverses HIF-1α–induced metabolic impairment and enhances microglial response to Aβ pathology J. Clin. Invest. (IF 15.9) Pub Date : 2023 Manasee Gedam, Michele M. Comerota, Nicholas E. Propson, Tao Chen, Feng Jin, Meng C. Wang, Hui Zheng
Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the APPNL-G-F–knockin (APP-KI) background revealed a significant shift of microglia
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Tau pathology in neurodegenerative disease: disease mechanisms and therapeutic avenues J. Clin. Invest. (IF 15.9) Pub Date : 2023 Niyatee Samudra, Courtney Lane-Donovan, Lawren VandeVrede, Adam L. Boxer
Tauopathies are disorders associated with tau protein dysfunction and insoluble tau accumulation in the brain at autopsy. Multiple lines of evidence from human disease, as well as nonclinical translational models, suggest that tau has a central pathologic role in these disorders, historically thought to be primarily related to tau gain of toxic function. However, a number of tau-targeting therapies
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DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice J. Clin. Invest. (IF 15.9) Pub Date : 2023 Allison B. Herman, Dimitrios Tsitsipatis, Carlos Anerillas, Krystyna Mazan-Mamczarz, Angelica E. Carr, Jordan M. Gregg, Mingyi Wang, Jing Zhang, Marc Michel, Charnae’ A. Henry-Smith, Sophia C. Harris, Rachel Munk, Jennifer L. Martindale, Yulan Piao, Jinshui Fan, Julie A. Mattison, Supriyo De, Kotb Abdelmohsen, Robert W. Maul, Toshiko Tanaka, Ann Zenobia Moore, Megan E. DeMouth, Simone Sidoli, Luigi
Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated
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Loss of STAT2 may be dangerous in a world filled with viruses J. Clin. Invest. (IF 15.9) Pub Date : 2023 Michael B. Jordan
Type I IFNs, a family of cytokines that signal through a single receptor and signaling mechanism, were originally named for their ability to interfere with viral replication. While type II IFN (IFN-γ) largely protects against intracellular bacteria and protozoa, type I IFNs largely protect from viral infections. Inborn errors of immunity in humans have demonstrated this point and its clinical relevance
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Human inherited complete STAT2 deficiency underlies inflammatory viral diseases J. Clin. Invest. (IF 15.9) Pub Date : 2023 Giorgia Bucciol, Leen Moens, Masato Ogishi, Darawan Rinchai, Daniela Matuozzo, Mana Momenilandi, Nacim Kerrouche, Catherine M. Cale, Elsa R. Treffeisen, Mohammad Al Salamah, Bandar K. Al-Saud, Alain Lachaux, Remi Duclaux-Loras, Marie Meignien, Aziz Bousfiha, Ibtihal Benhsaien, Anna Shcherbina, Anna Roppelt, COVID Human Genetic Effort, Florian Gothe, Nadhira Houhou-Fidouh, Scott J. Hackett, Lisa M.
STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients’ cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood
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Removing uncertainty from variants of unknown significance J. Clin. Invest. (IF 15.9) Pub Date : 2023 Elizabeth M. McNally
Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E Chengcheng Li, … , Conrad C. Weihl, Gabe Haller Chengcheng Li, … , Conrad C. Weihl, Gabe Haller Research Article Genetics Muscle biology
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Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia J. Clin. Invest. (IF 15.9) Pub Date : 2023 Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang
Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we
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Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E J. Clin. Invest. (IF 15.9) Pub Date : 2023 Chengcheng Li, Jackson Wilborn, Sara Pittman, Jil Daw, Jorge Alonso-Pérez, Jordi Díaz-Manera, Conrad C. Weihl, Gabe Haller
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein
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An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity J. Clin. Invest. (IF 15.9) Pub Date : 2023 Kathryn L. Roche, Stacy Remiszewski, Matthew J. Todd, John L. Kulp III, Liudi Tang, Alison V. Welsh, Ashley P. Barry, Chandrav De, William W. Reiley, Angela Wahl, J. Victor Garcia, Micah A. Luftig, Thomas Shenk, James R. Tonra, Eain A. Murphy, Lillian W. Chiang
Most drugs used to treat viral disease target a virus-coded product. They inhibit a single virus or virus family, and the pathogen can readily evolve resistance. Host-targeted antivirals can overcome these limitations. The broad-spectrum activity achieved by host targeting can be especially useful in combating emerging viruses and for treatment of diseases caused by multiple viral pathogens, such as
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Ventilator-associated pneumonia in ICU patients with severe pneumonia and respiratory failure J. Clin. Invest. (IF 15.9) Pub Date : 2023 Sarah Jackson
Machine learning links unresolving secondary pneumonia to mortality in patients with severe pneumonia, including COVID-19 Catherine A. Gao, … , Benjamin D. Singer, The NU SCRIPT Study Investigators Catherine A. Gao, … , Benjamin D. Singer, The NU SCRIPT Study Investigators Clinical Medicine Infectious disease Pulmonology
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Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor J. Clin. Invest. (IF 15.9) Pub Date : 2023 Chunhui Jiang, Ashwani Kumar, Ze Yu, Tracey Shipman, Yong Wang, Renee M. McKay, Chao Xing, Lu Q. Le
Neurofibromatosis type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes more than 50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment
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Machine learning links unresolving secondary pneumonia to mortality in patients with severe pneumonia, including COVID-19 J. Clin. Invest. (IF 15.9) Pub Date : 2023 Catherine A. Gao, Nikolay S. Markov, Thomas Stoeger, Anna Pawlowski, Mengjia Kang, Prasanth Nannapaneni, Rogan A. Grant, Chiagozie Pickens, James M. Walter, Jacqueline M. Kruser, Luke Rasmussen, Daniel Schneider, Justin Starren, Helen K. Donnelly, Alvaro Donayre, Yuan Luo, G.R. Scott Budinger, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer, The NU SCRIPT Study Investigators
BACKGROUND. Despite guidelines promoting the prevention and aggressive treatment of ventilator-associated pneumonia (VAP), the importance of VAP as a driver of outcomes in mechanically ventilated patients, including patients with severe COVID-19, remains unclear. We aimed to determine the contribution of unsuccessful treatment of VAP to mortality for patients with severe pneumonia.