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Unwind to the beat: chromatin and cardiac conduction
Douglas J. Chapski, Thomas M. Vondriska
Douglas J. Chapski, Thomas M. Vondriska
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e165663. https://doi.org/10.1172/JCI165663.
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Unwind to the beat: chromatin and cardiac conduction

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Abstract

How chromatin accessibility and structure endow highly specialized cells with their unique phenotypes is an area of intense investigation. In the mammalian heart, an exclusive subset of cardiac cells comprise the conduction system. Many molecular components of this system are well studied and genetic variation in some of the components induces abnormal cardiac conduction. However, genetic risk for cardiac arrhythmias in human populations also occurs in noncoding regions. A study by Bhattacharyya, Kollipara, et al. in this issue of the JCI examines how chromatin accessibility and structure may explain the mechanisms by which noncoding variants increase susceptibility to cardiac arrhythmias. We discuss the implications of these findings for cell type–specific gene regulation and highlight potential therapeutic strategies to engineer locus-specific epigenomic remodeling in vivo.

Authors

Douglas J. Chapski, Thomas M. Vondriska

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Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1
Tingting Li, Man-Kyo Chung
Tingting Li, Man-Kyo Chung
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e167338. https://doi.org/10.1172/JCI167338.
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Striving toward hyperthermia-free analgesia: lessons from loss-of-function mutations of human TRPV1

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Abstract

Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.

Authors

Tingting Li, Man-Kyo Chung

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Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy
Aneesh Kallapur, Tamer Sallam
Aneesh Kallapur, Tamer Sallam
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e167047. https://doi.org/10.1172/JCI167047.
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Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy

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Abstract

Long noncoding RNAs (lncRNAs) have emerged as key mediators of regulated gene expression in diverse biologic contexts, including cardiovascular disease. In this issue of the JCI, Tang, Luo, and colleagues explored the contributions of lncRNAs in diabetic vasculopathy. The authors identified the lncRNA LEENE as a key mediator of angiogenesis and ischemic response. In a model of diabetic peripheral arterial disease, loss of LEENE led to impaired vascular perfusion, while its overexpression rescued the ischemic defect. The authors used unbiased chromatin affinity assays to decipher LEENE’s interactome and mode of action. These findings offer insights as to why patients with diabetes are uniquely susceptible to developing peripheral vascular disease and fill important gaps in our understanding of mechanisms that connect metabolic dysregulation with impaired angiogenesis.

Authors

Aneesh Kallapur, Tamer Sallam

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Avoid being trapped by your liver: ischemia-reperfusion injury in liver transplant triggers S1P-mediated NETosis
Davide Scozzi, Andrew E. Gelman
Davide Scozzi, Andrew E. Gelman
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e167012. https://doi.org/10.1172/JCI167012.
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Avoid being trapped by your liver: ischemia-reperfusion injury in liver transplant triggers S1P-mediated NETosis

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Abstract

Liver transplantation can be a life-saving treatment for end-stage hepatic disease. Unfortunately, some recipients develop ischemia-reperfusion injury (IRI) that leads to poor short- and long-term outcomes. Recent work has shown neutrophils contribute to IRI by undergoing NETosis, a form of death characterized by DNA ejection resulting in inflammatory extracellular traps. In this issue of the JCI, Hirao and Kojima et al. report that sphingosine-1-phosphate (S1P) expression induced by liver transplant–mediated IRI triggers NETosis. They also provide evidence that neutrophil expression of the carcinoembryonic antigen–related cell adhesion molecule-1 (CC1) long isoform inhibited NETosis by controlling S1P receptor–mediated autophagic flux. These findings suggest stimulating regulatory mechanisms that suppress NETosis could be used to prevent IRI.

Authors

Davide Scozzi, Andrew E. Gelman

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Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines
Mihai G. Netea, Leo A.B. Joosten
Mihai G. Netea, Leo A.B. Joosten
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e166467. https://doi.org/10.1172/JCI166467.
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Beyond adaptive immunity: induction of trained immunity by COVID-19 adenoviral vaccines

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Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus, has resulted in much human suffering and societal disruption. The ChAdOx1 nCoV-19 vaccine against COVID-19 has had a crucial role in the fight against the pandemic. While ChAdOx1 nCoV-19 has been shown to induce adaptive B and T cell responses, which protect against COVID-19, in this issue of the JCI, Murphy et al. show that this vaccine also induces trained innate immunity. This finding contributes to a better understanding of the complex immunological effects of adenoviral-based vaccines, provides the possibility of clinically relevant heterologous effects of these vaccines, and suggests that other adenoviral-based vaccines may induce trained immunity.

Authors

Mihai G. Netea, Leo A.B. Joosten

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The kynurenine pathway implicated in patient delirium: possible indications for indoleamine 2,3 dioxygenase inhibitors
Amy B. Heimberger, Rimas V. Lukas
Amy B. Heimberger, Rimas V. Lukas
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e164577. https://doi.org/10.1172/JCI164577.
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The kynurenine pathway implicated in patient delirium: possible indications for indoleamine 2,3 dioxygenase inhibitors

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Abstract

Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. Notably, Kyn metabolites bind the N-methyl-d-aspartate receptor (NMDAR), essential for memory encoding, and in turn, cognition. Aberrant NMDAR activity through agonist binding influences excitability and cell death. In this issue of the JCI, Watne and authors demonstrate that KP pathway end products were elevated in the serum and the cerebrospinal fluid (CSF) of subjects with delirium. This observation provides insight regarding the basis of a variety of commonly observed clinical conditions including sundowning, abnormal sleep-wake cycles in hospitalized patients, neurodegenerative cognitive impairment, radiation-induced cognitive impairment, neurocognitive symptomatology related to COVID-19, and clinical outcomes observed in patients with CNS tumors, such as gliomas.

Authors

Amy B. Heimberger, Rimas V. Lukas

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Take your mother’s ferry: preimplantation embryo development requires maternal karyopherins for nuclear transport
Momal Sharif, … , Laura Detti, Ignatia B. Van den Veyver
Momal Sharif, … , Laura Detti, Ignatia B. Van den Veyver
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e166279. https://doi.org/10.1172/JCI166279.
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Take your mother’s ferry: preimplantation embryo development requires maternal karyopherins for nuclear transport

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Abstract

The genetic basis of preimplantation embryo arrest is slowly being unraveled. Recent discoveries point to maternally expressed proteins required for cellular functions before the embryonic genome is activated. In this issue of the JCI, Wang, Miyamoto, et al. suggest a critical role for karyopherin-mediated protein cargo transport between oocyte cytoplasm and nucleus. Defective maternal oocyte–expressed human karyopherin subunit α7 (KPNA7) and mouse KPNA2 fail to bind a critical substrate, ribosomal L1 domain-containing protein 1 (RSL1D1), affecting its transport to the nucleus. As shown in embryos of Kpna2-null females, the consequences are disrupted zygotic genome activation and arrest of development. These findings have important implications for diagnosis and treatment of female infertility.

Authors

Momal Sharif, Laura Detti, Ignatia B. Van den Veyver

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A phosphorylation switch controls androgen biosynthesis in prostate cancer
Yun Qiu
Yun Qiu
Published January 17, 2023
Citation Information: J Clin Invest. 2023;133(2):e166499. https://doi.org/10.1172/JCI166499.
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A phosphorylation switch controls androgen biosynthesis in prostate cancer

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Abstract

Androgen biosynthesis enzyme 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) encoded by HSD3B1 has emerged as a potential driver for therapeutic resistance in prostate cancer. Patients with homozygous HSD3B1(1245C) inheritance are intrinsically more resistant to currently available androgen/androgen receptor–targeting (AR-targeting) drugs. In this issue of the JCI, Li et al. present data on the regulation of 3βHSD1 phosphorylation and activity by tyrosine kinase BMX. Inhibition of BMX activity by genetic or pharmacologic approaches blocked androgen biosynthesis in prostate cancer cells and inhibited tumor growth in preclinical xenograft models. The findings provide insights into mechanisms underlying castration resistance in prostate cancer and reveal a potential strategy to circumvent therapeutic resistance in patients with homozygous HSD3B1(1245C) inheritance.

Authors

Yun Qiu

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Liver-resident CD8+ T cells in viral hepatitis: not always good guys
Hendrik Luxenburger, Christoph Neumann-Haefelin
Hendrik Luxenburger, Christoph Neumann-Haefelin
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e165033. https://doi.org/10.1172/JCI165033.
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Liver-resident CD8+ T cells in viral hepatitis: not always good guys

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Abstract

More than twenty years ago, non–HBV-specific CD8+ T cells were found to contribute to liver immunopathology in chronic HBV infection, while HBV-specific CD8+ T cells were noted to contribute to viral control. The role of HBV-specific CD8+ T cells in viral control and the mechanisms of their failure in persistent infection have been intensively studied during the last two decades, but the exact nature of nonspecific bystander CD8+ T cells that contribute to immunopathology has remained elusive. In this issue of the JCI, Nkongolo et al. report on their application of two methodological advances, liver sampling by fine-needle aspiration (FNA) and single-cell RNA sequencing (scRNA-Seq), to define a liver-resident CD8+ T cell population that was not virus specific but associated with liver damage, thus representing hepatotoxic bystander CD8+ T cells.

Authors

Hendrik Luxenburger, Christoph Neumann-Haefelin

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Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children
Magali Noval Rivas, Moshe Arditi
Magali Noval Rivas, Moshe Arditi
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e166016. https://doi.org/10.1172/JCI166016.
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Notch1 signaling impairs regulatory T cells during multisystem inflammatory syndrome in children

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Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a rare pediatric inflammatory disorder characterized by immune cell hyperactivation, cytokine storm, and the production of autoantibodies. The mechanisms underlying such immune dysregulation still need to be unraveled. In this issue of the JCI, Benamar et al. demonstrated the critical role of the Notch receptor 1/CD22 (Notch1/CD22) axis in Tregs, which, when activated, impairs Treg functions and promotes inflammation. They showed that the Notch1/CD22 axis contributed to dysregulated immune responses in MIS-C. These findings may have implications for MIS-C and many other inflammatory diseases.

Authors

Magali Noval Rivas, Moshe Arditi

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