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JCI Insight

Julie A Lovshin, Geneviève Boulet, Yuliya Lytvyn, Leif E Lovblom, Petter Bjornstad, Mohammed A Farooqi, Vesta Lai, Leslie Cham, Josephine Tse, Andrej Orszag, Daniel Scarr, Alanna Weisman, Hillary A Keenan, Michael H Brent, Narinder Paul, Vera Bril, Bruce A Perkins, David Zi Cherney
BACKGROUND: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation...
January 11, 2018: JCI Insight
Ruojing Yang, Margaret Wu, Songnian Lin, Ravi P Nargund, Xinghai Li, Theresa Kelly, Lin Yan, Ge Dai, Ying Qian, Qing Dallas-Yang, Paul A Fischer, Yan Cui, Xiaolan Shen, Pei Huo, Danqing Dennis Feng, Mark D Erion, David E Kelley, James Mu
Hypoglycemia is commonly associated with insulin therapy, limiting both its safety and efficacy. The concept of modifying insulin to render its glucose-responsive release from an injection depot (of an insulin complexed exogenously with a recombinant lectin) was proposed approximately 4 decades ago but has been challenging to achieve. Data presented here demonstrate that mannosylated insulin analogs can undergo an additional route of clearance as result of their interaction with endogenous mannose receptor (MR), and this can occur in a glucose-dependent fashion, with increased binding to MR at low glucose...
January 11, 2018: JCI Insight
Wilson I Gonsalves, Vijay Ramakrishnan, Taro Hitosugi, Toshi Ghosh, Dragan Jevremovic, Tumpa Dutta, Dhananjay Sakrikar, Xuan-Mai Petterson, Linda Wellik, Shaji K Kumar, K Sreekumaran Nair
The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle...
January 11, 2018: JCI Insight
Susan E Birket, Joy M Davis, Courtney M Fernandez, Katherine L Tuggle, Ashley M Oden, Kengyeh K Chu, Guillermo J Tearney, Michelle V Fanucchi, Eric J Sorscher, Steven M Rowe
The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr-/- (KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities. The KO rat exhibits decreased periciliary depth, hyperacidic pH, and increased mucus solid content percentage; however, the transport rates and viscoelastic properties of the mucus are unaffected until the KO rat ages...
January 11, 2018: JCI Insight
Rithwick Rajagopal, Sheng Zhang, Xiaochao Wei, Teresa Doggett, Sangeeta Adak, Jennifer Enright, Vaishali Shah, Guoyu Ling, Shiming Chen, Jun Yoshino, Fong-Fu Hsu, Clay F Semenkovich
Membrane lipid composition is central to the highly specialized functions of neurological tissues. In the retina, abnormal lipid metabolism causes severe forms of blindness, often through poorly understood neuronal cell death. Here, we demonstrate that deleting the de novo lipogenic enzyme fatty acid synthase (FAS) from the neural retina, but not the vascular retina, results in progressive neurodegeneration and blindness with a temporal pattern resembling rodent models of retinitis pigmentosa. Blindness was not rescued by protection from light-evoked activity; by eating a diet enriched in palmitate, the product of the FAS reaction; or by treatment with the PPARα agonist fenofibrate...
January 11, 2018: JCI Insight
Aarti Asnani, Bahoui Zheng, Yan Liu, You Wang, Howard H Chen, Anita Vohra, An Chi, Ivan Cornella-Taracido, Huijun Wang, Douglas G Johns, David E Sosnovik, Randall T Peterson
Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. However, their use is limited by cardiotoxicity. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnagin-mediated cardioprotection. Structure-activity relationship studies were performed in a zebrafish model of doxorubicin cardiomyopathy...
January 11, 2018: JCI Insight
Danya Liu, I Raul Badell, Mandy L Ford
Memory T cells pose a significant problem to successful therapeutic control of unwanted immune responses during autoimmunity and transplantation, as they are differentially controlled by cosignaling receptors such as CD28 and CTLA-4. Treatment with abatacept and belatacept impede CD28 signaling by binding to CD80 and CD86, but they also have the unintended consequence of blocking the ligands for CTLA-4, a process that may inadvertently boost effector responses. Here, we show that a potentially novel anti-CD28 domain antibody (dAb) that selectively blocks CD28 but preserves CTLA-4 coinhibition confers improved allograft survival in sensitized recipients as compared with CTLA-4 Ig...
January 11, 2018: JCI Insight
Han Jun Kim, Jack W Tsao, Ansley Grimes Stanfill
Mild traumatic brain injury (mTBI) is a common occurrence, with over 3 million cases reported every year in the United States. While research into the underlying pathophysiology is ongoing, there is an urgent need for better clinical guidelines that allow more consistent diagnosis of mTBI and ensure safe return-to-play timelines for athletes, nonathletes, and military personnel. The development of a suite of biomarkers that indicate the pathogenicity of mTBI could lead to clinically useful tools for establishing both diagnosis and prognosis...
January 11, 2018: JCI Insight
Yvonne Baumer, Qimin Ng, Gregory E Sanda, Amit K Dey, Heather L Teague, Alexander V Sorokin, Pradeep K Dagur, Joanna I Silverman, Charlotte L Harrington, Justin A Rodante, Shawn M Rose, Nevin J Varghese, Agastya D Belur, Aditya Goyal, Joel M Gelfand, Danielle A Springer, Christopher Ke Bleck, Crystal L Thomas, Zu-Xi Yu, Mårten Cg Winge, Howard S Kruth, M Peter Marinkovich, Aditya A Joshi, Martin P Playford, Nehal N Mehta
Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation...
January 11, 2018: JCI Insight
Erika L Flannery, Lander Foquet, Vorada Chuenchob, Matthew Fishbaugher, Zachary Billman, Mary Jane Navarro, William Betz, Tayla M Olsen, Joshua Lee, Nelly Camargo, Thao Nguyen, Carola Schafer, Brandon K Sack, Elizabeth M Wilson, Jessica Saunders, John Bial, Brice Campo, Susan A Charman, Sean C Murphy, Margaret A Phillips, Stefan Hi Kappe, Sebastian A Mikolajczak
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria-causing parasite P...
January 11, 2018: JCI Insight
Qiyuan Tan, Ningwen Tai, Yangyang Li, James Pearson, Sean Pennetti, Zhiguang Zhou, F Susan Wong, Li Wen
B cells play an important role in type 1 diabetes (T1D) development. However, the role of B cell activation-induced cytidine deaminase (AID) in diabetes development is not clear. We hypothesized that AID is important in the immunopathogenesis of T1D. To test this hypothesis, we generated AID-deficient (AID-/-) NOD mice. We found that AID-/-NOD mice developed accelerated T1D, with worse insulitis and high levels of anti-insulin autoantibody in the circulation. Interestingly, neither maternal IgG transferred through placenta, nor IgA transferred through milk affected the accelerated diabetes development...
January 11, 2018: JCI Insight
Sonia Guedan, Avery D Posey, Carolyn Shaw, Anna Wing, Tong Da, Prachi R Patel, Shannon E McGettigan, Victoria Casado-Medrano, Omkar U Kawalekar, Mireia Uribe-Herranz, Decheng Song, J Joseph Melenhorst, Simon F Lacey, John Scholler, Brian Keith, Regina M Young, Carl H June
Successful tumor eradication by chimeric antigen receptor-expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB-based CARs...
January 11, 2018: JCI Insight
Julie Lacombe, Mark A Rishavy, Kathleen L Berkner, Mathieu Ferron
Vertebrates possess 2 proteins with vitamin K oxidoreductase (VKOR) activity: VKORC1, whose vitamin K reduction supports vitamin K-dependent (VKD) protein carboxylation, and VKORC1-like 1 (VKORC1L1), whose function is unknown. VKD proteins include liver-derived coagulation factors, and hemorrhaging and lethality were previously observed in mice lacking either VKORC1 or the γ-glutamyl carboxylase (GGCX) that modifies VKD proteins. Vkorc1-/- mice survived longer (1 week) than Ggcx-/- mice (midembryogenesis or birth), and we assessed whether VKORC1L1 could account for this difference...
January 11, 2018: JCI Insight
Lindsay Am Rein, James W Wisler, Jihee Kim, Barbara Theriot, LiYin Huang, Trevor Price, Haeyoon Yang, Minyong Chen, Wei Chen, Dorothy Sipkins, Yuri Fedoriw, Julia Kl Walker, Richard T Premont, Robert J Lefkowitz
Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis...
December 21, 2017: JCI Insight
Emma J Kenyon, Nerissa K Kirkwood, Siân R Kitcher, Molly O'Reilly, Marco Derudas, Daire M Cantillon, Richard J Goodyear, Abigail Secker, Sarah Baxendale, James C Bull, Simon J Waddell, Tanya T Whitfield, Simon E Ward, Corné J Kros, Guy P Richardson
Aminoglycoside antibiotics are used to treat life-threatening bacterial infections but can cause deafness due to hair cell death in the inner ear. Compounds have been described that protect zebrafish lateral line hair cells from aminoglycosides, but few are effective in the cochlea. As the aminoglycosides interact with several ion channels, including the mechanoelectrical transducer (MET) channels by which they can enter hair cells, we screened 160 ion-channel modulators, seeking compounds that protect cochlear outer hair cells (OHCs) from aminoglycoside-induced death in vitro...
December 21, 2017: JCI Insight
Oscar Okwudiri Onyema, Yizhan Guo, Qing Wang, Mark H Stoler, Christine Lau, Kang Li, Christopher Daniel Nazaroff, Xingan Wang, Wenjun Li, Daniel Kreisel, Andrew E Gelman, James J Lee, Elizabeth A Jacobsen, Alexander Sasha Krupnick
Lungs allografts have worse long-term survival compared with other organ transplants. This is most likely due to their unique immunoregulation that may not respond to traditional immunosuppression. For example, local NO generation by inducible NOS (iNOS) is critical for lung allograft acceptance but associates with rejection of other solid organs. The source of NO in accepting lung allografts remains unknown. Here, we report that, unlike the case for other pulmonary processes in which myeloid cells control NO generation, recipient-derived eosinophils play a critical and nonredundant role in iNOS-mediated lung allograft acceptance...
December 21, 2017: JCI Insight
Ke Li, Kun-Yi Wu, Weiju Wu, Na Wang, Ting Zhang, Naheed Choudhry, Yun Song, Conrad A Farrar, Liang Ma, Lin-Lin Wei, Zhao-Yang Duan, Xia Dong, En-Qi Liu, Zong-Fang Li, Steven H Sacks, Wuding Zhou
C5a receptor 1 (C5aR1) is a G protein-coupled receptor for C5a and also an N-linked glycosylated protein. In addition to myeloid cells, C5aR1 is expressed on epithelial cells. In this study, we examined the role of C5aR1 in bacterial adhesion/colonization of renal tubular epithelium and addressed the underlying mechanisms of this role. We show that acute kidney infection was significantly reduced in mice with genetic deletion or through pharmacologic inhibition of C5aR1 following bladder inoculation with uropathogenic E...
December 21, 2017: JCI Insight
Bracha Erlanger Avigdor, Ashley Cimino-Mathews, Angelo M DeMarzo, Jessica L Hicks, James Shin, Saraswati Sukumar, John Fetting, Pedram Argani, Ben H Park, Sarah J Wheelan
Heterogeneity within and among tumors in a metastatic cancer patient is a well-established phenomenon that may confound treatment and accurate prognosis. Here, we used whole-exome sequencing to survey metastatic breast cancer tumors from 5 patients in a rapid autopsy program to construct the origin and genetic development of metastases. Metastases were obtained from 5 breast cancer patients using a rapid autopsy protocol and subjected to whole-exome sequencing. Metastases were evaluated for sharing of somatic mutations, correlation of copy number variation and loss of heterozygosity, and genetic similarity scores...
December 21, 2017: JCI Insight
Tara N Rindler, Courtney A Stockman, Alyssa L Filuta, Kari M Brown, John M Snowball, Wenjia Zhou, Ruud Veldhuizen, Erika M Zink, Sydney E Dautel, Geremy Clair, Charles Ansong, Yan Xu, James P Bridges, Jeffrey A Whitsett
Adaptation to air breathing after birth is dependent upon the synthesis and secretion of pulmonary surfactant by alveolar type 2 (AT2) cells. Surfactant, a complex mixture of phospholipids and proteins, is secreted into the alveolus, where it reduces collapsing forces at the air-liquid interface to maintain lung volumes during the ventilatory cycle. ABCA3, an ATP-dependent Walker domain containing transport protein, is required for surfactant synthesis and lung function at birth. Mutations in ABCA3 cause severe surfactant deficiency and respiratory failure in newborn infants...
December 21, 2017: JCI Insight
Kelly E Seaton, Nathan A Vandergrift, Aaron W Deal, Wes Rountree, John Bainbridge, Eduard Grebe, David A Anderson, Sheetal Sawant, Xiaoying Shen, Nicole L Yates, Thomas N Denny, Hua-Xin Liao, Barton F Haynes, Merlin L Robb, Neil Parkin, Breno R Santos, Nigel Garrett, Matthew A Price, Denise Naniche, Ann C Duerr, Sheila Keating, Dylan Hampton, Shelley Facente, Kara Marson, Alex Welte, Christopher D Pilcher, Myron S Cohen, Georgia D Tomaras
Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i...
December 21, 2017: JCI Insight
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