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JCI Insight

Maria Moysidou, Sevasti Karaliota, Elisavet Kodela, Maria Salagianni, Yassemi Koutmani, Antonia Katsouda, Konstantia Kodella, Panagiotis Tsakanikas, Styliani Ourailidou, Evangelos Andreakos, Nikolaos Kostomitsopoulos, Dimitris Skokos, Antonios Chatzigeorgiou, Kyoung-Jin Chung, Stefan Bornstein, Mark W Sleeman, Triantafyllos Chavakis, Katia P Karalis
Although accumulation of lymphocytes in the white adipose tissue (WAT) in obesity is linked to insulin resistance, it remains unclear whether lymphocytes also participate in the regulation of energy homeostasis in the WAT. Here, we demonstrate enhanced energy dissipation in Rag1-/- mice, increased catecholaminergic input to subcutaneous WAT, and significant beige adipogenesis. Adoptive transfer experiments demonstrated that CD8+ T cell deficiency accounts for the enhanced beige adipogenesis in Rag1-/- mice...
March 8, 2018: JCI Insight
Isaac P Thomsen, George Y Liu
The emergence of community-associated methicillin-resistant Staphylococcus aureus during the past decade along with an impending shortage of effective antistaphylococcal antibiotics have fueled impressive advances in our understanding of how S. aureus overcomes the host environment to establish infection. Backed by recent technologic advances, studies have uncovered elaborate metabolic, nutritional, and virulence strategies deployed by S. aureus to survive the restrictive and hostile environment imposed by the host, leading to a plethora of promising antimicrobial approaches that have potential to remedy the antibiotic resistance crisis...
March 8, 2018: JCI Insight
Ahmed M Mehdi, Emma E Hamilton-Williams, Alexandre Cristino, Anette Ziegler, Ezio Bonifacio, Kim-Anh Le Cao, Mark Harris, Ranjeny Thomas
Autoimmune-mediated destruction of pancreatic islet β cells results in type 1 diabetes (T1D). Serum islet autoantibodies usually develop in genetically susceptible individuals in early childhood before T1D onset, with multiple islet autoantibodies predicting diabetes development. However, most at-risk children remain islet-antibody negative, and no test currently identifies those likely to seroconvert. We sought a genomic signature predicting seroconversion risk by integrating longitudinal peripheral blood gene expression profiles collected in high-risk children included in the BABYDIET and DIPP cohorts, of whom 50 seroconverted...
March 8, 2018: JCI Insight
Jie An, Liping Wang, Michael L Patnode, Vanessa K Ridaura, Jonathan M Haldeman, Robert D Stevens, Olga Ilkayeva, James R Bain, Michael J Muehlbauer, Erin L Glynn, Steven Thomas, Deborah Muoio, Scott A Summers, James E Vath, Thomas E Hughes, Jeffrey I Gordon, Christopher B Newgard
Current obesity interventions suffer from lack of durable effects and undesirable complications. Fumagillin, an inhibitor of methionine aminopeptidase-2, causes weight loss by reducing food intake, but with effects on weight that are superior to pair-feeding. Here, we show that feeding of rats on a high-fat diet supplemented with fumagillin (HF/FG) suppresses the aggressive feeding observed in pair-fed controls (HF/PF) and alters expression of circadian genes relative to the HF/PF group. Multiple indices of reduced energy expenditure are observed in HF/FG but not HF/PF rats...
March 8, 2018: JCI Insight
Frank S Cikach, Christopher D Koch, Timothy J Mead, Josephine Galatioto, Belinda B Willard, Kelly B Emerton, Matthew J Eagleton, Eugene H Blackstone, Francesco Ramirez, Eric E Roselli, Suneel S Apte
Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls...
March 8, 2018: JCI Insight
Bruno Francois, Robin Jeannet, Thomas Daix, Andrew H Walton, Matthew S Shotwell, Jacqueline Unsinger, Guillaume Monneret, Thomas Rimmelé, Teresa Blood, Michel Morre, Anne Gregoire, Gail A Mayo, Jane Blood, Scott K Durum, Edward R Sherwood, Richard S Hotchkiss
BACKGROUND: A defining pathophysiologic feature of sepsis is profound apoptosis-induced death and depletion of CD4+ and CD8+ T cells. Interleukin-7 (IL-7) is an antiapoptotic common γ-chain cytokine that is essential for lymphocyte proliferation and survival. Clinical trials of IL-7 in over 390 oncologic and lymphopenic patients showed that IL-7 was safe, invariably increased CD4+ and CD8+ lymphocyte counts, and improved immunity. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 (CYT107) in patients with septic shock and severe lymphopenia...
March 8, 2018: JCI Insight
Jasmohan S Bajaj, Leroy R Thacker, Andrew Fagan, Melanie B White, Edith A Gavis, Phillip B Hylemon, Robert Brown, Chathur Acharya, Douglas M Heuman, Michael Fuchs, Swati Dalmet, Masoumeh Sikaroodi, Patrick M Gillevet
BACKGROUND: Cirrhosis is associated with gut microbial changes, but current 16S rDNA techniques sequence both dead and live bacteria. We aimed to determine the rRNA content compared with DNA from the same stool sample to evaluate cirrhosis progression and predict hospitalizations. METHODS: Cirrhotics and controls provided stool for RNA and DNA analysis. Comparisons were made between cirrhotics/controls and within cirrhosis (compensated/decompensated, infected/uninfected, renal dysfunction/not, rifaximin use/not) with respect to DNA and RNA bacterial content using linear discriminant analysis...
March 8, 2018: JCI Insight
Charitharth Vivek Lal, Nelida Olave, Colm Travers, Gabriel Rezonzew, Kalsang Dolma, Alexandra Simpson, Brian Halloran, Zubair Aghai, Pragnya Das, Nirmal Sharma, Xin Xu, Kristopher Genschmer, Derek Russell, Tomasz Szul, Nengjun Yi, J Edwin Blalock, Amit Gaggar, Vineet Bhandari, Namasivayam Ambalavanan
Premature infants are at high risk for developing bronchopulmonary dysplasia (BPD), characterized by chronic inflammation and inhibition of lung development, which we have recently identified as being modulated by microRNAs (miRNAs) and alterations in the airway microbiome. Exosomes and exosomal miRNAs may regulate cell differentiation and tissue and organ development. We discovered that tracheal aspirates from infants with severe BPD had increased numbers of, but smaller, exosomes compared with term controls...
March 8, 2018: JCI Insight
Dionysios V Chartoumpekis, Yoko Yagishita, Marco Fazzari, Dushani L Palliyaguru, Uma Nm Rao, Apostolos Zaravinos, Nicholas Kh Khoo, Francisco J Schopfer, Kurt R Weiss, George K Michalopoulos, Ian Sipula, Robert M O'Doherty, Thomas W Kensler, Nobunao Wakabayashi
Insulin resistance is associated with increased incidence and enhanced progression of cancers. However, little is known about strategies that can effectively ameliorate insulin resistance and consequently halt cancer progression. Herein, we propose that the transcription factor Nrf2 (also known as Nfe2l2) may be such a target, given its central role in disease prevention. To this end, we developed a mouse that overexpresses the Notch intracellular domain in adipocytes (AdNICD), leading to lipodystrophy-induced severe insulin resistance and subsequent development of sarcomas, as a model reflecting that Notch signaling is deregulated in cancers and shows positive associations with insulin resistance and fatty liver disease in humans...
March 8, 2018: JCI Insight
Joanna Jung, Paul Eggleton, Alison Robinson, Jessica Wang, Nick Gutowski, Janet Holley, Jia Newcombe, Elzbieta Dudek, Amber M Paul, Douglas Zochodne, Allison Kraus, Christopher Power, Luis B Agellon, Marek Michalak
In multiple sclerosis (MS), a demyelinating inflammatory disease of the CNS, and its animal model (experimental autoimmune encephalomyelitis; EAE), circulating immune cells gain access to the CNS across the blood-brain barrier to cause inflammation, myelin destruction, and neuronal damage. Here, we discovered that calnexin, an ER chaperone, is highly abundant in human brain endothelial cells of MS patients. Conversely, mice lacking calnexin exhibited resistance to EAE induction, no evidence of immune cell infiltration into the CNS, and no induction of inflammation markers within the CNS...
March 8, 2018: JCI Insight
Pedro Santos E Sousa, Séverine Ciré, Thomas Conlan, Laura Jardine, Claire Tkacz, Ivana R Ferrer, Cara Lomas, Sophie Ward, Heather West, Simone Dertschnig, Sven Blobner, Terry K Means, Stephen Henderson, Daniel H Kaplan, Matthew Collin, Vincent Plagnol, Clare L Bennett, Ronjon Chakraverty
Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location...
March 8, 2018: JCI Insight
Meagan A Jacoby, Eric J Duncavage, Gue Su Chang, Christopher A Miller, Jin Shao, Kevin Elliott, Joshua Robinson, Robert S Fulton, Catrina C Fronick, Michelle O'Laughlin, Sharon E Heath, Iskra Pusic, John S Welch, Daniel C Link, John F DiPersio, Peter Westervelt, Timothy J Ley, Timothy A Graubert, Matthew J Walter
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT...
March 8, 2018: JCI Insight
Peng Zhang, Henry Kuang, Yanlin He, Sharon O Idiga, Siming Li, Zhimin Chen, Zhao Yang, Xing Cai, Kezhong Zhang, Matthew J Potthoff, Yong Xu, Jiandie D Lin
Neuregulins (NRGs) are emerging as an important family of signaling ligands that regulate glucose and lipid homeostasis. NRG1 lowers blood glucose levels in obese mice, whereas the brown fat-enriched secreted factor NRG4 protects mice from high-fat diet-induced insulin resistance and hepatic steatosis. However, the therapeutic potential of NRGs remains elusive, given the poor plasma half-life of the native ligands. Here, we engineered a fusion protein using human NRG1 and the Fc domain of human IgG1 (NRG1-Fc) that exhibited extended half-life in circulation and improved potency in receptor signaling...
March 8, 2018: JCI Insight
Hao D Cheng, Sebastian K Grimm, Morgan Sa Gilman, Luc Christian Gwom, Devin Sok, Christopher Sundling, Gina Donofrio, Gunilla B Karlsson Hedestam, Mattia Bonsignori, Barton F Haynes, Timothy P Lahey, Isaac Maro, C Fordham von Reyn, Miroslaw K Gorny, Susan Zolla-Pazner, Bruce D Walker, Galit Alter, Dennis R Burton, Merlin L Robb, Shelly J Krebs, Michael S Seaman, Chris Bailey-Kellogg, Margaret E Ackerman
Major advances in donor identification, antigen probe design, and experimental methods to clone pathogen-specific antibodies have led to an exponential growth in the number of newly characterized broadly neutralizing antibodies (bnAbs) that recognize the HIV-1 envelope glycoprotein. Characterization of these bnAbs has defined new epitopes and novel modes of recognition that can result in potent neutralization of HIV-1. However, the translation of envelope recognition profiles in biophysical assays into an understanding of in vivo activity has lagged behind, and identification of subjects and mAbs with potent antiviral activity has remained reliant on empirical evaluation of neutralization potency and breadth...
March 8, 2018: JCI Insight
Vincent Gies, Jean-Nicolas Schickel, Sophie Jung, Aurélie Joublin, Salomé Glauzy, Anne-Marie Knapp, Anne Soley, Vincent Poindron, Aurélien Guffroy, Jin-Young Choi, Jacques-Eric Gottenberg, Jennifer H Anolik, Thierry Martin, Pauline Soulas-Sprauel, Eric Meffre, Anne-Sophie Korganow
B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10...
March 8, 2018: JCI Insight
Rebecca Liu, Jonathan Merola, Thomas D Manes, Lingfeng Qin, Gregory T Tietjen, Francesc López-Giráldez, Verena Broecker, Caodi Fang, Catherine Xie, Ping-Min Chen, Nancy C Kirkiles-Smith, Dan Jane-Wit, Jordan S Pober
Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM...
March 8, 2018: JCI Insight
Ao Li, Yuchen Xu, Song Fan, Jialin Meng, Xufeng Shen, Qian Xiao, Yuan Li, Li Zhang, Xiansheng Zhang, Guanqing Wu, Chaozhao Liang, Dianqing Wu
Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases β-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether β-catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models...
March 8, 2018: JCI Insight
Rachel Mak'Anyengo, Peter Duewell, Cornelia Reichl, Christine Hörth, Hans-Anton Lehr, Sandra Fischer, Thomas Clavel, Gerald Denk, Simon Hohenester, Sebastian Kobold, Stefan Endres, Max Schnurr, Christian Bauer
Inflammatory bowel disease (IBD) is associated with enhanced levels of the IL-1 family cytokines IL-1β and IL-18, which are activated by the Nlrp3 inflammasome. Here, we investigated the role of inflammasome-driven cytokine release on T cell polarization and DC differentiation in steady state and T cell transfer colitis. In vitro and in vivo data showed that IL-1β induces Th17 polarization and increases GM‑CSF production by T cells. Reduced IL-1β levels in Nlrp3-/- mice correlated with enhanced FLT3L levels and increased frequency of tolerogenic CD103+ DC...
March 8, 2018: JCI Insight
Valérie Besnard, Rania Dagher, Tania Madjer, Audrey Joannes, Madeleine Jaillet, Martin Kolb, Philippe Bonniaud, Lynne A Murray, Matthew A Sleeman, Bruno Crestani
Periplakin is a component of the desmosomes that acts as a cytolinker between intermediate filament scaffolding and the desmosomal plaque. Periplakin is strongly expressed by epithelial cells in the lung and is a target antigen for autoimmunity in idiopathic pulmonary fibrosis. The aim of this study was to determine the role of periplakin during lung injury and remodeling in a mouse model of lung fibrosis induced by bleomycin. We found that periplakin expression was downregulated in the whole lung and in alveolar epithelial cells following bleomycin-induced injury...
March 8, 2018: JCI Insight
Diego A Miranda, William C Krause, Amaury Cazenave-Gassiot, Miyuki Suzawa, Hazel Escusa, Juat Chin Foo, Diyala S Shihadih, Andreas Stahl, Mark Fitch, Edna Nyangau, Marc Hellerstein, Markus R Wenk, David L Silver, Holly A Ingraham
Excess lipid accumulation is an early signature of nonalcoholic fatty liver disease (NAFLD). Although liver receptor homolog 1 (LRH-1) (encoded by NR5A2) is suppressed in human NAFLD, evidence linking this phospholipid-bound nuclear receptor to hepatic lipid metabolism is lacking. Here, we report an essential role for LRH-1 in hepatic lipid storage and phospholipid composition based on an acute hepatic KO of LRH-1 in adult mice (LRH-1AAV8-Cre mice). Indeed, LRH-1-deficient hepatocytes exhibited large cytosolic lipid droplets and increased triglycerides (TGs)...
March 8, 2018: JCI Insight
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