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Journal of Clinical Investigation
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Microglial heme oxygenase-1 mediates blood clearance after subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) causes neuronal injury and cognitive impairment, which result from cerebral inflammation induced by heme released from damaged rbcs. Using a murine model of SAH, Nils Schallner and colleagues demonstrate microglial cells express heme oxygenase-1 (HO-1) to clear blood from the subarachnoid space and attenuate neuronal injury. Loss of microglial HO-1 in mice further increased neuronal injury after SAH. Additionally, SAH patients had elevated levels of HO-1 in CSF compared to patients with unruptured cerebral aneurysms, and HO-1 activity was correlated with hematoma volume. HO-1 metabolizes free heme, generating biliverdin, iron, and carbon monoxide (CO), the last of which is a potent immune modulator. Inhalation of CO attenuated neuronal injury in both HO-1-deficient and WT mice (see accompanying image). These data demonstrate that HO-1-generated CO mediates elimination of blood after SAH and suggest that CO is a potential therapeutic modality to reduce injury after SAH.
Read the article in JCI: http://buff.ly/1HzDHZU #ResearchArticle #Neuroscience
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Cancer cells manage stress with ATF4
Cancer cells within a tumor are faced with a variety of stresses, including hypoxia and starvation. Moreover, cancer cells that metastasize from the initial tumor site must prevent activation of anoikis, a specialized cell form of cell death that initiates in response to a loss of contact with the ECM. The transcription factor ATF4 mediates activation of the integrated stress response (ISR) and promotes cancer cell survival. Additionally, ATF4 is upregulated in several tumor types and may contribute to metastatic phenotypes. Souvik Dey, Carly Sayers, and colleagues at the University of Pennsylvania determined that ATF4 protects cancer cells from anoikis and contributes to metastasis.
Read the Scientific Show Stopper in JCI: http://buff.ly/1FBtyZi #ScientificShowStopper #Oncology
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A new batch of articles is now available online at
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A signaling pathway that makes kidneys grow
Kidney mass adapts concordantly to lean body mass, and in the case of unilateral nephrectomy (UNX), the remaining kidney increases in size to meet the body’s metabolic demands. Jian-Kang Chen and colleagues demonstrate that PI3K signaling pathways regulate kidney size. Chen and colleagues engineered mice with a proximal tubule-specific knockout of the class I PI3K negative regulator phosphatase and tensin homolog (PtenptKO). UNX did not activate the class I PI3K/mTORC2/AKT pathway, but PtenptKO mice exhibited persistent activation of this pathway and kidney hypertrophy (see accompanying image) that could be reversed by administration of the mTORC1 inhibitor rapamycin or proximal tubule-specific deletion of EGFR. Exogenous delivery of amino acids, which mimics the increased metabolic requirements after UNX, resulted in activation of a class III PI3K/mTORC1/S6K signaling pathway. In the accompanying commentary, Qais Al-Awqati discusses how these findings demonstrate context-dependent roles for two different PI3K-mediated signaling pathways in kidney growth.
Read the article in JCI: http://buff.ly/1B1A0Vg
Read the commentary (subscription only): http://buff.ly/1B1A0Vj
#ResearchArticle #Nephrology
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Group B Streptococcus breaches the blood-brain-barrier
Bacterial meningitis is a life-threating infection of the central nervous system. Group B Streptococcus (GBS) is the leading cause of meningitis in newborn babies and can cause severe complications in those that survive the infection. GBS must cross the blood-brain-barrier (BBB) to cause disease but it is not clear how these organisms breach this barrier. A new study in the Journal of Clinical Investigation identifies a pathway that is induced by GBS and disrupts junctions between cells. Kelly Doran and colleagues at San Diego State University determined that GBS induces a protein, Snail1, which inhibits expression of genes involved in maintaining junctions between cells. Enhanced Snail1 disrupted junctions between cultured brain endothelial cells, increasing permeability of the cell layer. In zebrafish, Snail1 expression in response to GBS disrupted the BBB, allowing the bacteria to breach this barrier. Inhibition of Snail1 in GBS-infected fish increased survival. This works suggests that GBS directly disrupts the BBB in the development of meningitis.
Read the article in JCI: http://buff.ly/1A4Y0Mj #ResearchArticle #VascularBiology
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Read the JCI News Round Up, with coverage on:

Additional cause of dyskeratosis congenita discovered | Diabetes and Alzheimer's risk | Mechanism causing blood pressure drug ineffectiveness identified | DNA anomalies in children with chronic kidney disease | Study identifies why smoking worsens COPD in some patients | Effect of oxidative stress on the heart muscle | A vascular niche for boosted blood stem cell production | Role of calcium signaling in controlling inflammation during chronic lung infection | New understanding of eye can prevent eye problems | Preventing stillbirths

http://buff.ly/1FUfg7F
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Pain relief through a truncated μ-opioid receptor

Oprm1, which encodes the μ opioid receptor (MOR), undergoes multiple alternative pre-mRNA splicing events that result in different MOR isoforms. The majority of these isoforms have seven full-length transmembrane domains (7TM); however, others have only six transmembrane domains (6TM). Zhigang Lu and colleagues demonstrate that a new opiate analgesic, 3-iodobenzoyl-6β-naltrexamide (IBNtxA), exerts its effects exclusively through a 6TM MOR. While IBNtxA was a highly effective analgesic in wildtype mice, its analgesic effects were lost in mice lacking a set of 6TM MOR splice variants. Re-expression of the 6TM variant mMOR-1G restored IBNtxA analgesia. Importantly, IBNtxA did not cause common opiate analgesic side effects such as respiratory depression or physical dependence. In the accompanying commentary, Michael Iadarola discusses how these findings indicate that 6TM variants may be attractive therapeutic targets for opiate-like analgesics.
Read the article in JCI: http://buff.ly/1ApdoTD
Read the commentary: http://buff.ly/1EnWTCh #BriefReport #Neuroscience
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IL-33 supports dysregulated myelopoiesis in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of malignant clonal hematopoietic diseases that are characterized by cytokine dysregulation. Using murine models of MPN-like disease, Lukas Mager and colleagues demonstrated that the inflammatory cytokine IL-33 supports dysregulated myelpoiesis to drive MPN pathogenesis. Genetic ablation of IL-33 signaling pathway components restored normal hematopoiesis and prevented the development of MPNs. Moreover, the authors detected increased numbers of IL-33-producing cells in the bone marrow of MPN patients, while exogenous IL-33 increased cytokine production and colony formation by primary MPN stem and progenitor cells from patients. These data identify a crucial role for IL-33 signaling in MPN pathogenesis.
Read the article in JCI: http://buff.ly/1FsY2fO #ResearchArticle #Hematology
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Improving broadly neutralizing antibodies for HIV-1
Recent HIV-1 vaccine efforts have been focused on the development of broadly neutralizing mAbs that target the viral envelope glycoproteins (Env1/2). Jordan Willis and colleagues describe an in silico approach to identify mutations in these antibodies that improve epitope binding and virus neutralization. They focused on the heavy chain complementarity-determining region 3 (HCDR3) of PG9, a mAb that is currently in clinical trials. Using ROSETTA modeling software, Willis and colleagues designed PG9 antibodies with variations in the HCDR3 loop and engineered a variant, PG9_N100FY. This variant exhibited increased neutralization potency and breadth, as measured by in vitro neutralization assays with a diverse panel of PG9-susceptible and -resistant HIV-1 strains. A crystal structure of the antibody (see accompanying image) and differential scanning calorimetry revealed that the HCDR3 region of PG9_N100FY was more thermodynamically stable than the HCDR3 region of wild-type PG9. In the accompanying commentary, George Lewis discusses how this approach could potentially aid in vaccine development.
Read the article in JCI: http://buff.ly/1ICNeQ6
Read the commentary (subscription only): http://buff.ly/1ICNeQ7
#ResearchArticle #AIDS/HIV
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Insight into Kallmann syndrome
The inherited disease Kallmann syndrome (KS) is characterized by gonadotropin-releasing hormone (GnRH) deficiency, hypogonadism, reproductive defects, and compromised olfaction. The relatively small number of patients with this disease has restricted the identification of KS-causing genes, resulting in a limited understanding of the pathobiology of KS. Using a multifaceted approach, Anna Cariboni and colleagues at University College London demonstrated that the class 3 semaphorin SEMA3E promotes survival of hypothalamic GnRH neurons.
Read the ScientificShowStopper in JCI: http://buff.ly/1e5FcTd
Read the article: http://buff.ly/1e5Fc5F
Read the commentary (subscription only): http://buff.ly/1e5FcTg #ScientificShowStopper #Endocrinology
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An Interview with Daniel Abravanel
In the June 2015 issue of the JCI, Abravanel et al. explore the role of Notch signaling in breast cancer recurrence and dormancy. The authors found that inhibitors targeting the oncogenic HER2/neu receptor led to upregulated Notch signaling in breast cancer cells, including resistant cells that enter a dormant state. In a series of studies in mice, the authors demonstrated that the activation of Notch signaling is directly associated with an increased recurrence rate of breast cancer. In this interview, we had the chance to talk with first author Daniel Abravanel about this research and his pathway to becoming an independent physician-scientist.
Read the First Author Perspective in JCI: http://buff.ly/1KSbb3f
Read the article in JCI: http://buff.ly/1KSbdIs #FirstAuthorPerspective #Oncology
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Nephrotic syndrome-associated mutations
Nephrotic syndrome (NS) results from disruption of the kidney filtration barrier and is associated with proteinuria, hypoalbuminemia, and edema. Many children with NS respond to steroid therapy; however, steroid-resistant NS (SRNS) progresses to end-stage disease that requires renal replacement therapy. In many cases, the underlying cause of SNRS is unknown; however, recent studies have identified monogenic mutations that underlie disease. Several proteins encoded by NS-associated genes localize to podocytes, which are essential for maintenance of the glomerular filtration barrier. Heon Yung Gee, Fujian Zhang, and colleagues at Harvard Medical School and Children’s National Medical Center evaluated families with NS and identified recessive mutations in the kidney ankyrin repeat-containing protein-encoding genes KANK1, KANK2, and KANK4.
Read the Scientific Show Stopper in JCI: http://buff.ly/1GU0v0N
Read the article: http://buff.ly/1GU0v0O #ScientificShowStopper #Nephrology
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Ginger Tissier's profile photo
Mosima Ewusi's profile photo
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Tamara Hall's profile photo
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mcg w .c's profile photo
CarDia X'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 2013 Impact Factor of 13.765. 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.