Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis
This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Qing Wu, Lulu Sun, Xiaomin Hu, Xuemei Wang, Feng Xu, Bo Chen, Xianyi Liang, Jialin Xia, Pengcheng Wang, Daisuke Aibara, Shaofei Zhang, Guangyi Zeng, Chuyu Yun, Yu Yan, Yicheng Zhu, Michael Bustin, Shuyang Zhang, Frank J. Gonzalez, Changtao Jiang Source Type: research

Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Abhishek Jauhari, Sergei V. Baranov, Yalikun Suofu, Jinho Kim, Tanisha Singh, Svitlana Yablonska, Fang Li, Xiaomin Wang, Patrick Oberly, M. Beth Minnigh, Samuel M. Poloyac, Diane L. Carlisle, Robert M. Friedlander Source Type: research

B cells, antibody-secreting cells, and virus-specific antibodies respond to herpes simplex virus 2 reactivation in skin
Tissue-based T cells are important effectors in the prevention and control of mucosal viral infections; less is known about tissue-based B cells. We demonstrate that B cells and antibody-secreting cells (ASCs) are present in inflammatory infiltrates in skin biopsy specimens from study participants during symptomatic herpes simplex virus 2 (HSV-2) reactivation and early healing. Both CD20+ B cells, most of which are antigen inexperienced based on their coexpression of IgD, and ASCs — characterized by dense IgG RNA expression in combination with CD138, IRF4, and Blimp-1 RNA — were found to colocalize with T cells...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Emily S. Ford, Anton M. Sholukh, RuthMabel Boytz, Savanna S. Carmack, Alexis Klock, Khamsone Phasouk, Danica Shao, Raabya Rossenkhan, Paul T. Edlefsen, Tao Peng, Christine Johnston, Anna Wald, Jia Zhu, Lawrence Corey Source Type: research

Bile acid–activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury
Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we i...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Adrien Guillot, Lucia Guerri, Dechun Feng, Seung-Jin Kim, Yeni Ait Ahmed, Janos Paloczi, Yong He, Kornel Schuebel, Shen Dai, Fengming Liu, Pal Pacher, Tatiana Kisseleva, Xuebin Qin, David Goldman, Frank Tacke, Bin Gao Source Type: research

Contributions of immigrants to biomedical research in the US: a personal reflection
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Sophie Paczesny Source Type: research

Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction
Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, inclu...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Se-Jin Lee Source Type: research

Pathogenic variants in TNNC2 cause congenital myopathy due to an impaired force response to calcium
Troponin C (TnC) is a critical regulator of skeletal muscle contraction; it binds Ca2+ to activate muscle contraction. Surprisingly, the gene encoding fast skeletal TnC (TNNC2) has not yet been implicated in muscle disease. Here, we report 2 families with pathogenic variants in TNNC2. Patients present with a distinct, dominantly inherited congenital muscle disease. Molecular dynamics simulations suggested that the pathomechanisms by which the variants cause muscle disease include disruption of the binding sites for Ca2+ and for troponin I. In line with these findings, physiological studies in myofibers isolated from patien...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Martijn van de Locht, Sandra Donkervoort, Josine M. de Winter, Stefan Conijn, Leon Begthel, Benno Kusters, Payam Mohassel, Ying Hu, Livija Medne, Colin Quinn, Steven A. Moore, A. Reghan Foley, Gwimoon Seo, Darren T. Hwee, Fady I. Malik, Thomas Irving, Wei Source Type: research

GMPPA defects cause a neuromuscular disorder with α-dystroglycan hyperglycosylation
GDP-mannose-pyrophosphorylase-B (GMPPB) facilitates the generation of GDP-mannose, a sugar donor required for glycosylation. GMPPB defects cause muscle disease due to hypoglycosylation of α-dystroglycan (α-DG). Alpha-DG is part of a protein complex, which links the extracellular matrix with the cytoskeleton, thus stabilizing myofibers. Mutations of the catalytically inactive homolog GMPPA cause alacrima, achalasia, and mental retardation syndrome (AAMR syndrome), which also involves muscle weakness. Here, we showed that Gmppa-KO mice recapitulated cognitive and motor deficits. As structural correlates, we found...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Patricia Franzka, Henriette Henze, M. Juliane Jung, Svenja Caren Schüler, Sonnhild Mittag, Karina Biskup, Lutz Liebmann, Takfarinas Kentache, José Morales, Braulio Martínez, Istvan Katona, Tanja Herrmann, Antje-Kathrin Huebner, J. Christopher Hennings, Source Type: research

Beryllium-specific CD4+ T cells induced by chemokine neoantigens perpetuate inflammation
Discovering dominant epitopes for T cells, particularly CD4+ T cells, in human immune-mediated diseases remains a significant challenge. Here, we used bronchoalveolar lavage (BAL) cells from HLA-DP2–expressing patients with chronic beryllium disease (CBD), a debilitating granulomatous lung disorder characterized by accumulations of beryllium-specific (Be-specific) CD4+ T cells in the lung. We discovered lung-resident CD4+ T cells that expressed a disease-specific public CDR3β T cell receptor motif and were specific to Be-modified self-peptides derived from C-C motif ligand 4 (CCL4) and CCL3. HLA-DP2–CCL/Be...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Michael T. Falta, Jeremy C. Crawford, Alex N. Tinega, Laurie G. Landry, Frances Crawford, Douglas G. Mack, Allison K. Martin, Shaikh M. Atif, Li Li, Radleigh G. Santos, Maki Nakayama, John W. Kappler, Lisa A. Maier, Paul G. Thomas, Clemencia Pinilla, Andr Source Type: research

The abscopal effect: a sense of DNA damage is in the air
Tumor metastasis is a singularly important determinant of survival in most cancers. Historically, radiation therapy (RT) directed at a primary tumor mass was associated infrequently with remission of metastasis outside the field of irradiation. This away-from-target or “abscopal effect” received fringe attention because of its rarity. With the advent of immunotherapy, there are now increasing reports of abscopal effects upon RT in combination with immune checkpoint inhibition. This sparked investigation into underlying mechanisms and clinical trials aimed at enhancement of this effect. While these studies clear...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Timothy P. Lippert, Roger A. Greenberg Source Type: research

B cells join T cell clusters in the host response to recurrent herpes simplex virus 2 infection
Recurrent genital herpes lesions are infiltrated by various leukocytes, yet the role of B cell subsets in this process is unknown. In this issue of the JCI, Ford et al. describe the presence and antibody-secreting role of local B cell populations in herpes simplex virus 2 (HSV-2) recurrent lesions. The authors analyzed a comprehensive array of sequential skin biopsy specimens from HSV-2–infected patients over time and at various stages of infection. Using immunofluorescence and in situ hybridization, the authors show the presence of rare IgD+ naive B cells and IgG-expressing antibody-secreting cells (ASCs) in recurre...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Jeff R. Gehlhausen, Akiko Iwasaki Source Type: research

An immigrant’s experience: science is a discipline without borders
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Ivor J. Benjamin Source Type: research

Detection of autoreactive CD4+ T cells by MHC class II multimers in HLA-linked human autoimmune diseases
Recognition of self-peptides in association with distinct HLA class II alleles by autoreactive CD4+ T cells is central for loss of immunological tolerance leading to autoimmune disease. However, identifying immunodominant self-peptides and characterizing autoreactive T cells is challenging. In this issue of the JCI, Falta et al. identify a disease-associated complementarity-determining region 3β motif specific for beryllium-modified C-C motif ligand 4 (CCL4) and CCL3 self-peptides in patients with chronic beryllium disease (CBD), a granulomatous lung disorder with a known HLA class II allelic association. Detection of...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Karolin Wieber, Christine L. Zimmer, Michael Hertl Source Type: research

DUOX2 variants associate with preclinical disturbances in microbiota-immune homeostasis and increased inflammatory bowel disease risk
A primordial gut-epithelial innate defense response is the release of hydrogen peroxide by dual NADPH oxidase (DUOX). In inflammatory bowel disease (IBD), a condition characterized by an imbalanced gut microbiota-immune homeostasis, DUOX2 isoenzyme is the highest induced gene. Performing multiomic analyses using 2872 human participants of a wellness program, we detected a substantial burden of rare protein-altering DUOX2 gene variants of unknown physiologic significance. We identified a significant association between these rare loss-of-function variants and increased plasma levels of interleukin-17C, which is induced also...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Helmut Grasberger, Andrew T. Magis, Elisa Sheng, Matthew P. Conomos, Min Zhang, Lea S. Garzotto, Guoqing Hou, Shrinivas Bishu, Hiroko Nagao-Kitamoto, Mohamad El-Zaatari, Sho Kitamoto, Nobuhiko Kamada, Ryan W. Stidham, Yasutada Akiba, Jonathan Kaunitz, Yae Source Type: research

Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight
The melanocortin 4 receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis, and mutations in the MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R-expressing neurons are unknown. We recently reported that the MC4R localizes to the primary cilium, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether the MC4R functions in this organelle. Here, using mouse genetic approaches, we found that cilia were required specifically o...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Yi Wang, Adelaide Bernard, Fanny Comblain, Xinyu Yue, Christophe Paillart, Sumei Zhang, Jeremy F. Reiter, Christian Vaisse Source Type: research

Decoding the matrix: multiomics reveals host-microbe biomarker for inflammatory bowel disease
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine associated with genetic susceptibility and alterations in the intestinal microbiome. Multiomics data developed and analyzed over the last several decades have yielded an unprecedented amount of genetic and microbial data. But how do we pinpoint mechanistic insight into the host-microbe relationship that will ultimately enable better care for patients with IBD? In this issue of the JCI, Grasberger et al. undertook a major decoding effort to decipher this multiomic data matrix. The authors analyzed anonymized data from more than 2800 individu...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Monica Viladomiu, Randy S. Longman Source Type: research

My journey from Japan to becoming a physician-scientist in the United States
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Yumi Imai Source Type: research

Vaccines for immunoprevention of cancer
The immunoprevention of cancer and cancer recurrence is an important area of concern for the scientific community and society as a whole. Researchers have been working for decades to develop vaccines with the potential to alleviate these health care and economic burdens. So far, vaccines have made more progress in preventing cancer than in eliminating already established cancer. In particular, vaccines targeting oncogenic viruses, such as the human papillomavirus and the hepatitis B virus, are exceptional examples of successful prevention of virus-associated cancers, such as cervical cancer and hepatocellular carcinoma. Ca...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Tomohiro Enokida, Alvaro Moreira, Nina Bhardwaj Source Type: research

Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers
Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell–mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabo...
Source: Journal of Clinical Investigation - May 3, 2021 Category: Biomedical Science Authors: Ciputra Adijaya Hartana, Yelizaveta Rassadkina, Ce Gao, Enrique Martin-Gayo, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu Source Type: research

Long-term microstructure and cerebral blood flow changes in patients recovered from COVID-19 without neurological manifestations
BACKGROUND The coronavirus disease 2019 (COVID-19) rapidly progressed to a global pandemic. Although some patients totally recover from COVID-19 pneumonia, the disease’s long-term effects on the brain still need to be explored.METHODS We recruited 51 patients with 2 subtypes of COVID-19 (19 mild and 32 severe) with no specific neurological manifestations at the acute stage and no obvious lesions on the conventional MRI 3 months after discharge. Changes in gray matter morphometry, cerebral blood flow (CBF), and white matter (WM) microstructure were investigated using MRI. The relationship between brain imaging measure...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Yuanyuan Qin, Jinfeng Wu, Tao Chen, Jia Li, Guiling Zhang, Di Wu, Yiran Zhou, Ning Zheng, Aoling Cai, Qin Ning, Anne Manyande, Fuqiang Xu, Jie Wang, Wenzhen Zhu Source Type: research

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma
CONCLUSION MuNI holds promise as a low-cost, tissue-nondestructive, H&E stain–based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.FUNDING National Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostat...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Can F. Koyuncu, Cheng Lu, Kaustav Bera, Zelin Zhang, Jun Xu, Paula Toro, German Corredor, Deborah Chute, Pingfu Fu, Wade L. Thorstad, F. Faraji, Justin A. Bishop, Mitra Mehrad, Patricia D. Castro, Andrew G. Sikora, Lester D.R. Thompson, R.D. Chernock, Kry Source Type: research

Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses
Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti–PD-1 immunotherapy. We showed that phospho-eIF4E–deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phosph...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Fan Huang, Christophe Gonçalves, Margarita Bartish, Joelle Rémy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galán, Tomasz Rzymski, Milena Ma Source Type: research

CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification
To define the contribution of CD8+ T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term CD8+ T cell depletion using a rhesusized anti-CD8β monoclonal antibody on barcoded SIVmac239 dynamics on stable ART and after ART cessation in rhesus macaques (RMs). Among the RMs with full CD8+ T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV RNA+ cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and D...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Afam A. Okoye, Derick D. Duell, Yoshinori Fukazawa, Benjamin Varco-Merth, Alejandra Marenco, Hannah Behrens, Morgan Chaunzwa, Andrea N. Selseth, Roxanne M. Gilbride, Jason Shao, Paul T. Edlefsen, Romas Geleziunas, Mykola Pinkevych, Miles P. Davenport, Kat Source Type: research

Type 1 diabetes mellitus: much progress, many opportunities
As part of the centennial celebration of insulin’s discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the β cells in the pancreatic islet and requires lifelong insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regard to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This Review highlights knowledge gaps...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Alvin C. Powers Source Type: research

B cell–activating factor modulates the factor VIII immune response in hemophilia A
Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell–activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders. Thus, we used patient samples and mouse models to investigate the potential role of BAFF in modulating FVIII inhibitors. BAFF levels were elevated in pediatric and adult HA inhibitor patients and decreased to levels similar to those o...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Bhavya S. Doshi, Jyoti Rana, Giancarlo Castaman, Mostafa A. Shaheen, Radoslaw Kaczmarek, John S.S. Butterfield, Shannon L. Meeks, Cindy Leissinger, Moanaro Biswas, Valder R. Arruda Source Type: research

Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection
CONCLUSION Our findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.Trial registration ClinicalTrials.gov NCT01281267.FUNDING Assistant Secretary of Defense and Health Affairs, through Reconstructive Transplant Research (W81XWH-17-1-0278, W81XWH-16-1-0647, W81XWH-16-1-0689, W81XWH-18-1-0784, W81XWH-1-810798); American Society of Transplantation’s Transplantation and Immunology Research Network Fellowship Research Grant; Plastic Surgery Foundation Fellowship from the ...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Thet Su Win, William J. Crisler, Beatrice Dyring-Andersen, Rachel Lopdrup, Jessica E. Teague, Qian Zhan, Victor Barrera, Shannan Ho Sui, Sotirios Tasigiorgos, Naoka Murakami, Anil Chandraker, Stefan G. Tullius, Bohdan Pomahac, Leonardo V. Riella, Rachael Source Type: research

Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis
Efferocytosis, the process through which apoptotic cells (ACs) are cleared through actin-mediated engulfment by macrophages, prevents secondary necrosis, suppresses inflammation, and promotes resolution. Impaired efferocytosis drives the formation of clinically dangerous necrotic atherosclerotic plaques, the underlying etiology of coronary artery disease (CAD). An intron of the gene encoding PHACTR1 contains rs9349379 (A>G), a common variant associated with CAD. As PHACTR1 is an actin-binding protein, we reasoned that if the rs9349379 risk allele G causes lower PHACTR1 expression in macrophages, it might link the risk a...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Canan Kasikara, Maaike Schilperoort, Brennan Gerlach, Chenyi Xue, Xiaobo Wang, Ze Zheng, George Kuriakose, Bernhard Dorweiler, Hanrui Zhang, Gabrielle Fredman, Danish Saleheen, Muredach P. Reilly, Ira Tabas Source Type: research

The BBSome: a nexus controlling energy metabolism in the brain
This study provides important insights into the mechanisms of BBS-induced obesity. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Sandra Blaess, Dagmar Wachten Source Type: research

SUMOylation promotes extracellular vesicle–mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer
Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell–secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Changhao Chen, Hanhao Zheng, Yuming Luo, Yao Kong, Mingjie An, Yuting Li, Wang He, Bowen Gao, Yue Zhao, Hao Huang, Jian Huang, Tianxin Lin Source Type: research

Gluconeogenic enzyme PCK1 deficiency promotes CHK2 O-GlcNAcylation and hepatocellular carcinoma growth upon glucose deprivation
In this study, PCK1 knockout markedly enhanced the global O-GlcNAcylation levels under low-glucose conditions. Mechanistically, metabolic reprogramming in PCK1-loss hepatoma cells led to oxaloacetate accumulation and increased de novo uridine triphosphate synthesis contributing to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis. Meanwhile, deletion of PCK1 also resulted in AMPK-GFAT1 axis inactivation, promoting UDP-GlcNAc synthesis for elevated O-GlcNAcylation. Notably, lower expression of PCK1 promoted CHK2 threonine 378 O-GlcNAcylation, counteracting its stability and dimer formation, increasing CHK2-d...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Jin Xiang, Chang Chen, Rui Liu, Dongmei Gou, Lei Chang, Haijun Deng, Qingzhu Gao, Wanjun Zhang, Lin Tuo, Xuanming Pan, Li Liang, Jie Xia, Luyi Huang, Ke Yao, Bohong Wang, Zeping Hu, Ailong Huang, Kai Wang, Ni Tang Source Type: research

Artificial intelligence for automating the measurement of histologic image biomarkers
Artificial intelligence has been applied to histopathology for decades, but the recent increase in interest is attributable to well-publicized successes in the application of deep-learning techniques, such as convolutional neural networks, for image analysis. Recently, generative adversarial networks (GANs) have provided a method for performing image-to-image translation tasks on histopathology images, including image segmentation. In this issue of the JCI, Koyuncu et al. applied GANs to whole-slide images of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) to automate the calculation of a multinucleation index (...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Toby C. Cornish Source Type: research

Age-specific effects of vaccine egg adaptation and immune priming on A(H3N2) antibody responses following influenza vaccination
A(H3N2) influenza vaccine effectiveness (VE) was low during the 2016–19 seasons and varied by age. We analyzed neutralizing antibody responses to egg- and cell-propagated A(H3N2) vaccine and circulating viruses following vaccination in 375 individuals (aged 7 months to 82 years) across all vaccine-eligible age groups in 3 influenza seasons. Antibody responses to cell- versus egg-propagated vaccine viruses were significantly reduced due to the egg-adapted changes T160K, D225G, and L194P in the vaccine hemagglutinins. Vaccine egg adaptation had a differential impact on antibody responses across the different age groups...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Feng Liu, F. Liaini Gross, Stacie N. Jefferson, Crystal Holiday, Yaohui Bai, Li Wang, Bin Zhou, Min Z. Levine Source Type: research

Identification of SARS-CoV-2–specific immune alterations in acutely ill patients
Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g.,...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Rose-Marie Rébillard, Marc Charabati, Camille Grasmuck, Abdelali Filali-Mouhim, Olivier Tastet, Nathalie Brassard, Audrey Daigneault, Lyne Bourbonnière, Sai Priya Anand, Renaud Balthazard, Guillaume Beaudoin-Bussières, Romain Gasser, Mehdi Benlarbi, An Source Type: research

Lymphohematopoietic graft-versus-host responses promote mixed chimerism in patients receiving intestinal transplantation
In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without c...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Jianing Fu, Julien Zuber, Brittany Shonts, Aleksandar Obradovic, Zicheng Wang, Kristjana Frangaj, Wenzhao Meng, Aaron M. Rosenfeld, Elizabeth E. Waffarn, Peter Liou, Sai-ping Lau, Thomas M. Savage, Suxiao Yang, Kortney Rogers, Nichole M. Danzl, Shilpa Rav Source Type: research

A sobering addition to the literature on COVID-19 and the brain
Several coronavirus disease 2019 (COVID-19) studies have focused on neuropathology. In this issue of the JCI, Qin, Wu, and Chen et al. focused specifically on people whose acute infection lacked obvious neurological involvement. Severely infected patients showed abnormal gray matter volumes, white matter diffusion, and cerebral blood flow compared with healthy controls and those with mild infection. The data remain associative rather than mechanistic, but correlations with systemic immune markers suggest effects of inflammation, hypercoagulation, or other aspects of disease severity. Mechanistic research is warranted. Give...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Amit Mahajan, Graeme F. Mason Source Type: research

TYRO3 induces anti–PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis
Immune checkpoint blockade therapy has demonstrated promising clinical outcomes for multiple cancer types. However, the emergence of resistance as well as inadequate biomarkers for patient stratification have largely limited the clinical benefits. Here, we showed that tumors with high TYRO3 expression exhibited anti–programmed cell death protein 1/programmed death ligand 1 (anti–PD-1/PD-L1) resistance in a syngeneic mouse model and in patients who received anti–PD-1/PD-L1 therapy. Mechanistically, TYRO3 inhibited tumor cell ferroptosis triggered by anti–PD-1/PD-L1 and facilitated the development of ...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Zhou Jiang, Seung-Oe Lim, Meisi Yan, Jennifer L. Hsu, Jun Yao, Yongkun Wei, Shih-Shin Chang, Hirohito Yamaguchi, Heng-Huan Lee, Baozhen Ke, Jung-Mao Hsu, Li-Chuan Chan, Gabriel N. Hortobagyi, Liuqing Yang, Chunru Lin, Dihua Yu, Mien-Chie Hung Source Type: research

Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance
Adoptive transfer of Tregs has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrate an innovative approach to engineering an orthogonal IL-2/IL-2 receptor (IL-2R) pair, the parts of which selectively interact with each other, transmitting native IL-2 signals, but do not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Toshihito Hirai, Teresa L. Ramos, Po-Yu Lin, Federico Simonetta, Leon L. Su, Lora K. Picton, Jeanette Baker, Jian-Xin Lin, Peng Li, Kinya Seo, Juliane K. Lohmeyer, Sara B. Wagers, Melissa Mavers, Warren J. Leonard, Bruce R. Blazar, K. Christopher Garcia, Source Type: research

Epilepsy channelopathies go neddy: stabilizing NaV1.1 channels by neddylation
Loss-of-function mutations of SCN1A encoding the pore-forming α subunit of the NaV1.1 neuronal sodium channel cause a severe developmental epileptic encephalopathy, Dravet syndrome (DS). In this issue of the JCI, Chen, Luo, Gao, et al. describe a phenocopy for DS in mice deficient for posttranslational conjugation with neural precursor cell expressed, developmentally downregulated 8 (NEDD8) (neddylation), selectively engineered in inhibitory interneurons. Pursuing the possibility that this phenotype is also caused by loss of NaV1.1, Chen, Luo, Gao, and colleagues show that interneuron excitability and GABA release ar...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Stephen C. Cannon Source Type: research

Genetic therapies for the first molecular disease
Sickle cell disease (SCD) is a monogenic disorder characterized by recurrent episodes of severe bone pain, multi-organ failure, and early mortality. Although medical progress over the past several decades has improved clinical outcomes and offered cures for many affected individuals living in high-income countries, most SCD patients still experience substantial morbidity and premature death. Emerging technologies to manipulate somatic cell genomes and insights into the mechanisms of developmental globin gene regulation are generating potentially transformative approaches to cure SCD by autologous hematopoietic stem cell (H...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Phillip A. Doerfler, Akshay Sharma, Jerlym S. Porter, Yan Zheng, John F. Tisdale, Mitchell J. Weiss Source Type: research

Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell–derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Liheng Wang, Yang Liu, George Stratigopoulos, Sunil Panigrahi, Lina Sui, Yiying Zhang, Charles A. Leduc, Hannah J. Glover, Maria Caterina De Rosa, Lisa C. Burnett, Damian J. Williams, Linshan Shang, Robin Goland, Stephen H. Tsang, Sharon Wardlaw, Dieter E Source Type: research

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long–chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced satu...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Quentin Raas, Malu-Clair van de Beek, Sonja Forss-Petter, Inge M.E. Dijkstra, Abigail Deschiffart, Briana C. Freshner, Tamara J. Stevenson, Yorrick R.J. Jaspers, Liselotte Nagtzaam, Ronald J.A. Wanders, Michel van Weeghel, Joo-Yeon Engelen-Lee, Marc Engel Source Type: research

Neddylation stabilizes Nav1.1 to maintain interneuron excitability and prevent seizures in murine epilepsy models
The excitability of interneurons requires Nav1.1, the α subunit of the voltage-gated sodium channel. Nav1.1 deficiency and mutations reduce interneuron excitability, a major pathological mechanism for epilepsy syndromes. However, the regulatory mechanisms of Nav1.1 expression remain unclear. Here, we provide evidence that neddylation is critical to Nav1.1 stability. Mutant mice lacking Nae1, an obligatory component of the E1 ligase for neddylation, in parvalbumin-positive interneurons (PVINs) exhibited spontaneous epileptic seizures and premature death. Electrophysiological studies indicate that Nae1 deletion reduced...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Wenbing Chen, Bin Luo, Nannan Gao, Haiwen Li, Hongsheng Wang, Lei Li, Wanpeng Cui, Lei Zhang, Dong Sun, Fang Liu, Zhaoqi Dong, Xiao Ren, Hongsheng Zhang, Huabo Su, Wen-Cheng Xiong, Lin Mei Source Type: research

Remodeling glycerophospholipids affects obesity-related insulin signaling in skeletal muscle
It has long been known that fatty acids can either adversely or positively affect insulin signaling in skeletal muscle, depending on chain length or saturation, and can therefore be primary drivers of systemic insulin sensitivity. However, the detailed mechanisms linking fatty acids to insulin signaling in skeletal muscle have been elusive. In this issue of the JCI, Ferrara et al. suggest a model whereby membrane lipid remodeling mediates skeletal muscle insulin sensitivity. The authors demonstrate that membrane glycerophospholipid fatty acid remodeling by lysophosphatidylcholine acyltransferase 3 (LPCAT3) in skeletal musc...
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Michael J. Wolfgang Source Type: research

Lysophospholipid acylation modulates plasma membrane lipid organization and insulin sensitivity in skeletal muscle
In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action. (Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 15, 2021 Category: Biomedical Science Authors: Patrick J. Ferrara, Xin Rong, J. Alan Maschek, Anthony R.P. Verkerke, Piyarat Siripoksup, Haowei Song, Thomas D. Green, Karthickeyan C. Krishnan, Jordan M. Johnson, John Turk, Joseph A. Houmard, Aldons J. Lusis, Micah J. Drummond, Joseph M. McClung, James Source Type: research

ATP11B mediates platinum resistance in ovarian cancer
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Myrthala Moreno-Smith, J.B. Halder, Paul S. Meltzer, Tamas A. Gonda, Lingegowda S. Mangala, Rajesha Rupaimoole, Chunhua Lu, Archana S. Nagaraja, Kshipra M. Gharpure, Yu Kang, Cristian Rodriguez-Aguayo, Pablo E. Vivas-Mejia, Behrouz Zand, Rosemarie Schmand Source Type: research

Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticu...
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Maarten A.J. De Smet, Alessio Lissoni, Timur Nezlobinsky, Nan Wang, Eef Dries, Marta Pérez-Hernández, Xianming Lin, Matthew Amoni, Tim Vervliet, Katja Witschas, Eli Rothenberg, Geert Bultynck, Rainer Schulz, Alexander V. Panfilov, Mario Delmar, Karin R. Source Type: research

APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Feng-Wei Wang, Chen-Hui Cao, Kai Han, Yong-Xiang Zhao, Mu-Yan Cai, Zhi-Cheng Xiang, Jia-Xing Zhang, Jie-Wei Chen, Li-Ping Zhong, Yong Huang, Su-Fang Zhou, Xiao-Han Jin, Xin-Yuan Guan, Rui-Hua Xu, Dan Xie Source Type: research

ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects
(Source: Journal of Clinical Investigation)
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Haiyan Qiu, Sebum Lee, Yulei Shang, Wen-Yuan Wang, Kin Fai Au, Sherry Kamiya, Sami J. Barmada, Steven Finkbeiner, Hansen Lui, Caitlin E. Carlton, Amy A. Tang, Michael C. Oldham, Hejia Wang, James Shorter, Anthony J. Filiano, Erik D. Roberson, Warren G. To Source Type: research

Sensitive tracking of circulating viral RNA through all stages of SARS-CoV-2 infection
CONCLUSION Results of this study indicate that sensitive detection of SARS-CoV-2 RNA in blood by CRISPR-augmented RT-PCR permits accurate COVID-19 diagnosis, and can detect COVID-19 cases with transient or negative nasal swab RT-qPCR results, suggesting that this approach could improve COVID-19 diagnosis and the evaluation of SARS-CoV-2 infection clearance, and predict the severity of infection.TRIAL REGISTRATION ClinicalTrials.gov. NCT04358211.FUNDING Department of Defense, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and the National Center for Research ...
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Zhen Huang, Bo Ning, He S. Yang, Brady M. Youngquist, Alex Niu, Christopher J. Lyon, Brandon J. Beddingfield, Alyssa C. Fears, Chandler H. Monk, Amelie E. Murrell, Samantha J. Bilton, Joshua P. Linhuber, Elizabeth B. Norton, Monika L. Dietrich, Jim Yee, W Source Type: research

Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance
Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusi...
Source: Journal of Clinical Investigation - April 2, 2021 Category: Biomedical Science Authors: Cynthia Ju, Meng Wang, Eunyoung Tak, Boyun Kim, Christoph Emontzpohl, Yang Yang, Xiaoyi Yuan, Huban Kutay, Yafen Liang, David R. Hall, Wasim A. Dar, J. Steve Bynon, Peter Carmeliet, Kalpana Ghoshal, Holger K. Eltzschig Source Type: research