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Journal of Clinical Investigation
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The shelterin complex in telomere protection and hematopoiesis

The shelterin complex protects mammalian telomeres from DNA repair mechanisms and regulates telomerase activity. Telomere erosion is known to contribute to a range of human diseases, including bone marrow failure, premature aging, and cancer. Ivan Maillard and colleagues review the function of each of the components of the shelterin complex, as well as the effect of knocking out individual components in mice. Additionally, the discuss the role of the shelterin complex in human bone marrow failure syndromes, including dyskeratosis congenital (DC), a rare genetic disorder caused by mutations in genes that are important for the processing, integrity, or function of the telomerase holoenzyme. These findings point to a broader role for the shelterin complex in hematopoiesis.

#ReviewArticle: http://buff.ly/23dP9Ae #Telomeres #UniversityofMichigan
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The JCI congratulates Associate Editor Dr. Michael Kastan of Duke University on his election to the National Academy of Sciences.
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From JCI insight: Murine models of arrhythmogenic cardiomyopathy benefit from GSK3β inhibition

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease that results from mutations in genes that encode components of the cardiac desmosome, which forms the junction between cardiac muscle and the epithelium. Patients with ACM have an increased risk of sudden death due to the breakdown of the muscle wall of the heart with age. A previous chemical screen in a zebrafish ACM model identified a glycogen synthase kinase 3β (GSK3β) inhibitor (SB2) that reversed disease. In this issue of JCI insight, investigators led by Jeffrey Saffitz of Harvard Medical School and Daniel Judge of John’s Hopkins School of Medicine examined the effects of the GSK3β inhibitor SB2 in two murine models of ACM. SB2 improved cardiac function, reduced fibrosis and inflammation, and improved survival in both ACM models. In cardiac cells from healthy mice, GSK3β was in the cytosol. However, GSK3β localized to intercellular junctions in mice with ACM. The same GSK3β distribution patterns were also present in cardiac cells from healthy individual and patients with ACM. The results of this study provide further evidence that GSK3β inhibition has potential as a therapeutic strategy for treating ACM.

#ResearchArticle: http://buff.ly/1SydhZx #Cardiology
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Breaking down skin barrier function in mice with pruritic dermatitis

The skin serves as a powerful barrier against microbial, physical, and chemical insults and is maintained through constant proliferation and differentiation of epidermal cells. However, the mechanisms that regulate skin homeostasis are not fully understood. In this episode, Hisahiro Yoshida describes the development and characterization of a strain of mice that exhibit progressive pruritic dermatitis due to the presence of a mutation that results in hyperactivation of JAK1 tyrosine kinase. Treatment of these mice with JAK1 inhibitors delayed disease onset, indicating that JAK1-mediated signaling plays an important role in maintenance of skin barrier function.

Watch the Author’s take #video: http://buff.ly/1Sy6Y8d #ResearchArticle: http://buff.ly/1Sy6Wx3 #Dermatology #Dermatitis
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From JCI insight: Critical immunotherapy target marks dysfunctional regulatory T cells in brain cancer
Immunotherapy represents an exciting advance in cancer treatment that harnesses the immune system to seek and destroy cancer cells. The programmed death 1 (PD-1) pathway dampens immune responses to tumor cells, and several clinical trials have shown favorable outcomes by targeting PD-1 or its ligand PD-1L. In this issue of JCI Insight, David Hafler and colleagues at Yale University and Massachusetts Institute of Technology examined PD-1-expressing regulatory T cells in glioblastoma multiforme, an extremely aggressive form of brain cancer. Regulatory T cells normally constrain immune responses and keep other types of T cells from mounting hyper-aggressive responses. Although anti-PD1 therapy is generally thought to promote conventional T cell activity, the Hafler team now reports that PD-1 expression on regulatory T cells from the tumors of glioblastoma multiforme patients correlates with regulatory T cell dysfunction. They also found that glioblastoma multiforme patients treated with a PD-1 blocking antibody had a higher proportion of dysfunctional regulatory T cells. These observations suggest the possibility that PD-1 targeting therapies could work, in part, by driving further regulatory T cell dysfunction. Future studies will be needed to more fully understand the contribution of this pathway to anti-tumor effects.

#ResearchArticle:http://buff.ly/211BbSr #Oncology #YaleUniversity #MIT
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A new batch of articles is now available online at
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A conversation with Bert Vogelstein and Ken Kinzler

Bert Vogelstein, M.D., and Kenneth Kinzler, Ph.D., are co-directors of the Ludwig Center for Cancer Genetics and Therapeutics at the Sidney Kimmel Comprehensive Cancer Center of the Johns Hopkins University School of Medicine. Vogelstein and Kinzler demonstrated that colorectal cancer results from the sequential accumulation of mutations in oncogenes and tumor suppressor genes, establishing a paradigm for modern cancer genomics. Additionally, they discovered the tumor suppressors APC and TP53, they were the first to perform exomic sequencing in tumors, and they developed digital PCR. In an interview with JCI’s Editor-at-large Ushma Neill, Vogelstein and Kinzler reflect on their career trajectories and past discoveries, and discuss their goals as scientists.

http://buff.ly/23dLhzd #‎DigitalPCR #JohnsHopkinsUniversity
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May 2016 issue published:
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Gut microbiota regulate bone loss in a model of osteoporosis

In post-menopausal osteoporosis, estrogen deficiency drives inflammation that is linked to bone loss. Mice lacking intestinal bacteria are resistant to this bone loss, which may indicate an effect of estrogen deficiency on the immune response to gut microbiota. Jau-Yi Li and colleagues investigated the mechanisms linking gut microbiota to sex steroid-induced bone loss. In a mouse model of post-menopausal osteoporosis, mice kept in germ-free conditions were protected against bone loss, but lost this protection after conventional bacterial exposure. Sex steroid-deficiency increased intestinal permeability and inflammation in the bone marrow and intestine of conventionally housed mice, but this effect was absent in the germ-free mice. Supplementing mice with probiotics prevented estrogen deficiency-induced increases in bone loss, gut permeability, and inflammation. In the accompanying commentary (http://buff.ly/1WvsAXs), Jameel Iqbal and colleagues discuss the therapeutic potential of probiotics in treating osteoporosis.

#ResearchArticle: http://buff.ly/1WvsD5G #Endocrinology #EmoryUniversity
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From JCI insight: Resolvin D1 ameliorates inflammatory arthritis in mouse model

Rheumatoid arthritis (RA) is a debilitating autoimmune disorder that is characterized by the accumulation of inflammatory cells within the fluid of the joints. Current therapeutic strategies mostly serve to ease pain and rarely are able to reverse damage or resolve inflammation. A study in this issue of <i>JCI</i> Insight indicates that the lipid mediator resolvin D1 has anti-arthritic properties and should be further explored for treating RA. A team led by Charles Serhan of Harvard Medical School and Mauro Perritti of Queen Mary University of London determined that resolvin D1 is elevated in joint fluid from both arthritic mice and patients. Administration of resolvin D1 in mice with inflammatory arthritis dramatically reduced disease and promoted remission. The authors determined that resolvin D1 promotes expression of genes associated with cartilage repair and reduces factors associated with joint damage. The results of this study indicate that resolving D1 be further explored as a therapeutic strategy for treating RA.

#ResearchArticle: http://buff.ly/1UffNIt #Immunology #Inflammation #QMUL
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Serotonin transporter variants mediate gut dysfunction in a murine model

Gastrointestinal dysfunction is a common autism spectrum disorder (ASD) comorbidity. Many individuals with ASD possess rare, hyperactive variants of serotonin’s transporter (SERT) that produce behavioral effects similar to ASD when expressed in mice. Kara Gross Margolis and colleagues tested the hypothesis that hyperactive SERT also drives gastrointestinal dysfunction in a murine ASD model. Mice expressing a hyperactive SERT variant had underdeveloped enteric nervous systems (see the accompanying image) and slower gastrointestinal transit than controls. Mice lacking SERT expression and mice exposed prenatally to a SERT inhibitor displayed the opposite phenotype. The reciprocal effects of SERT hyperactivity and SERT hypofunction on gut development and function suggest that impaired serotonin signaling in ASD may underlie associated gastrointestinal abnormalities.

#ResearchArticle: http://buff.ly/1Sn9GgJ #Gastroenterology
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HIV controller T cell receptors confer improved HIV targeting
Destruction of CD4+ T cells determines HIV disease progression to AIDS. A small population of HIV-infected patients maintains a low viral load without antiretroviral therapies, possibly due to particularly efficient T cell responses. Daniela Benati, Moran Galperin, and colleagues characterized T cell receptor (TCR) repertoires in patients with controlled HIV to identify molecular determinants that improve CD4+ T cell-mediated responses. TCRs associated with controlled HIV had high affinity for the most prevalent epitope in HIV capsid. These TCRs could be transferred to healthy donor CD4+ T cells to recapitulate TCR function seen in HIV controllers. Additionally, transfer of TCRs to CD8+ T cells redirected these cells to target HIV-1 capsid. Thus, transfer of TCRs from HIV controllers shows potential as an immunological approach to HIV treatment.

#ResearchArticle: http://buff.ly/1r2sqv5 #HIV #AIDS #PasteurInstitute
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In their circles
2 people
Have them in circles
98 people
Teed Co's profile photo
Karl Meisterheim's profile photo
Lucy Shieh's profile photo
DEMOSTHENES BOUROS's profile photo
Joslin Diabetes Center's profile photo
tony hong's profile photo
World Health Day, 7 April's profile photo
PETER AMIET's profile photo
Ginger Tissier's profile photo
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Premiere venue for discoveries in basic and clinical biomedical science.
Introduction
The Journal of Clinical Investigation (JCI) is a top-tier venue for discoveries in basic and clinical biomedical research that will advance the practice of medicine. Founded in 1924, the journal is published by the American Society for Clinical Investigation (ASCI) and has a 2014 Impact Factor of 13.261. Since 2012, the JCI has been headed by Dr. Howard A. Rockman, Editor, with an Editorial Board of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. The JCI provides free access to all of its research articles.