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Taking pluripotent stem cells from bench to bedside
Pluripotent stem cells (PSCs), either derived from embryos or induced from adult cells, have the ability to differentiate into any cell type, making these cells a potential boon to regenerative medicine. PSCs could be used in preclinical applications (“disease-in-a-dish” models for drug screening) and in clinical applications, in which they could be used to replaced damaged or defective tissues. In this issue, Joseph Wu and colleagues discuss the steps required to generate a therapeutic cell product and discuss the preclinical challenges in developing PSC-based therapeutics. Additionally, they discuss the advantages and disadvantages of allogeneic and autologous stem cell products, as well as clinical requirements, quality standards, time lines, and the costs of developing successful PSC-based therapies.
Read the review:http://buff.ly/1CFj5J4 #Review
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July 2015 issue published:
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Distinct immune response distinguishes severe asthma
Unlike mild-moderate asthma (MMA), severe asthma (SA) is poorly controlled by corticosteroids, suggesting that different immune mechanisms contribute to SA. Mahesh Raundhal and colleagues analyzed broncholalveolar lavage cells from MMA and SA patients and found that SA patients had a greater IFNg/Th1 immune response compared to MMA patients accompanied by low IL-17/Th2 responses. In a murine model of SA, loss of Ifng blocked airway hyperresponsiveness (AHR) without a change in airway inflammation (see the accompanying image), while loss of Il17 reduced airway inflammation, but did not impair AHR. IFNg levels were inversely correlated with secretory leukocyte protease inhibitor (SLPI), which is downregulated in both humans and mice with SA. Increasing expression of SLP1 in mice reduced AHR. These data characterize aspects of the immune response that distinguish SA from MMA.
Read the article in the JCI:http://buff.ly/1dt5RIA #ResearchArticle #Pulmonology
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Regional regulation of atherosclerosis
Atherosclerosis is characterized by the presence of flow-restricting plaques within arteries that consist of lipids, cholesterol, and cell debris. Platelet activation has been shown to be an early event in atherogenesis and is mediated by interactions with endothelial and mononuclear cells. Moreover, atherosclerotic plaques typically occur at arterial branches and other areas with disturbed blood flow, suggesting that flow-regulated factors may influence disease onset and progression. The enzyme ectonucleotide tri(di)phosphohydrolase-1 (CD39) is expressed by leukocytes and endothelial cells and inhibits both platelet activation and leukocyte recruitment. Yogendra Kanthi, Matthew Hyman, and colleagues at the University of Michigan and the University of Pennsylvania, respectively, found that Cd39 haploinsufficiency in an ApoE-deficient mouse model of atherosclerosis increases arterial plaque burden as well as circulating markers of platelet activation in response to a high-fat diet.
Read the Scientific Show Stopper in JCI: http://buff.ly/1CFd27e
Read the article:http://buff.ly/1CFd3YS #ScientificShowStopper
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Fetal lung expression of steroid receptor coactivators-1 and -2 triggers labor
Pre-term birth is a leading cause of neonatal morbidity and mortality, but the signals that initiate labor, both at term and pre-term, are not well defined. Lu Gao and colleagues show that fetal lung expression of steroid receptor coactivators-1 and -2 (SRC-1 and SRC-2) upregulates genes that trigger parturition in mice. Their finding that WT females bred to males that were doubly deficient in Src-1 and Src-2 exhibited severely delayed parturition, clearly implicates a role for the fetus in the timing of birth. This parturition delay was accompanied by decreased expression of uterine inflammatory and contractile genes and elevated circulating progesterone. The lungs and amniotic fluid of SRC-1/2-deficient fetuses had markedly reduced levels of surfactant protein-A (SP-A) and the inflammatory phospholipid platelet-activating factor (PAF); intra-amniotic injection of either of these factors rescued the delayed labor phenotype. In the accompanying commentary, Erin Reinl and Sarah England discuss how these studies identify fetal-derived factors that control the initiation of labor.
Read the article in JCI: http://buff.ly/1HA080a
Read the accompanying commentary in JCI: http://buff.ly/1HA09Bj #ResearchArticle #ReproductiveBiology
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Disruption of mechanosensing pathway inhibits apoptotic cell clearance in lupus
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by increased type I IFN and circulating apoptotic cell-derived autoantigens (AC-Ags), both of which drive autoantibody production by B cells. In this episode, John Mountz, Hui-Chen Hsu, and Hao Li describe a mechanism by which type 1 IFN prevents clearance of ACs by marginal zone macrophages (MZMs) in SLE. The authors found that in murine SLE models, type I IFN increased follicular translocation of MZ B cells in the spleen, which disrupted the interaction between these B cells and MZ macrophages (MZMs).
Watch the Author’s Take Video in JCI: http://buff.ly/1cQhwRl or Youtube: http://buff.ly/1cQhzws
Read the article in JCI: http://buff.ly/1cQhzwt #ResearchArticle #Immunology
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Dr. Robert Schrier is a nephrologist and Professor of Medicine at the University of Colorado School of Medicine, where he served as Chair of the Department of Medicine and Chief of the Kidney Division for more
than 20 years. He is an expert in patient-oriented research on acute
kidney injury, autosomal dominant polycystic kidney disease, hypertension, and diabetic nephropathy. Dr. Schrier has authored over 1,000 papers and several books and has been continuously funded by the NIH for 45 years. In an interview with JCI Editor-at-Large Ushma Neill, Schrier discusses his love of sports, his studies in Germany as a Fulbright scholar, his decision to go to medical school, and his entry into research at the Walter Reed Army Medical Center, where he became interested in kidney failure.
Watch the interview: http://buff.ly/1JkPUQl
Read the article in JCI:http://buff.ly/1JkPWYz
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http://buff.ly/1CFdHWb Author's Take Video:
Read the related article in the JCI:http://buff.ly/1CFdK4h
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Restoring synaptic function in X-linked retinoschisis
X-linked retinoschisis (XLRS) is an inherited retinal synaptic disorder caused by mutation of the extracellular matrix (ECM) gene retinoschisin (RS1), which is required to preserve the structure and function of the retina. Jingxing Ou, Camasamudram Vijayasarathy, and colleagues demonstrated that photoreceptor-depolarizing bipolar cell (DBC) synaptic function can be rescued with adenovirus-associated virus-mediated delivery of Rs1 (AAV8-RS1) in a murine model of XLRS (see the accompanying image). RS1 restoration induced proper localization of the metabotropic glutamate receptor 6 (mGluR6)/transient receptor potential cation channel M1 (TRPM1) signaling components, allowing for normal synaptic function. In the accompanying commentary, Bernd Wissinger discusses how therapeutic strategies to restore synaptic organization and function could potentially be used to treat a number of neurological disorders that involve synaptic pathology.
Read the article in JCI: http://buff.ly/1cQk2Hr
Read the accompanying commentary in JCI: http://buff.ly/1cQk0iF #ResearchArticle #Opthamology
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Localizing estrogen’s effects on energy homeostasis
Estrogen is a critical regulator of energy homeostasis. Brain-specific deletion of estrogen receptor-α (ERα) leads to increased body weight and adiposity in both male and female mice. In this issue, Pingwen Xu and colleagues show that neurons expressing simple minded 1 (SIM1) in the medial amygdala mediate estrogen’s effects on bodyweight. Loss of ERα in SIM1 neurons resulted in hypoactivity and obesity in male and female mice, and increased susceptibility to diet-induced obesity in males, but not in females. Conversely, overexpression of ERα in medial amygdala neurons partially prevented diet-induced obesity in male mice. Using specially engineered receptor constructs known as designer receptors exclusively activated by designer drugs (DREADDs), Xu and colleagues selectively activated SIM1 neurons in the medial amygdala (see accompanying image), which increased physical activity. In the accompanying commentary, Chia Li and Michael Krashes discuss how these results indicate that ERα stimulates SIM1 neurons in the medial amygdala to increase physical activity and prevent diet-induced obesity.
Read the article in JCI: http://buff.ly/1GyXJ51
Read the accompanying commentary in JCI: http://buff.ly/1GyXGGi #ResearchArticle #Neuroscience
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Directing the maturation of pancreatic β cells epigenetically
Pancreatic β cells respond to postprandial glucose increases by secreting insulin and to fasting conditions by inhibiting insulin secretion. These cells only acquire the ability to respond to glucose post-natally, indicating that epigenetic mechanisms direct β cell maturation after birth. Sangeeta Dhawan and colleagues demonstrate that the DNA methyltransferase DNMT3A mediates the coupling of insulin secretion to glucose levels. Mice with β cell-specific deletion of Dnmt3a did not develop the ability to secrete insulin in response to increased glucose. Mechanistically, DNMT3A-mediated de novo methylation repressses the expression of hexokinase-1, lactate dehydrogenase A, and aldolase B. Importantly, this mechanism is conserved in humans. In the accompanying commentary, Frans Schuit discusses how these studies identify an epigenetic mechanism that directs post-natal β cell maturation.
Read the article in JCI: http://buff.ly/1GyWsuK
Read the accompanying commentary in JCI: http://buff.ly/1GyWsuL #ResearchArticle #Endocrinology
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Fetal lung expression of steroid receptor coactivators-1 and -2 triggers labor
Pre-term birth is a leading cause of neonatal morbidity and mortality, but the signals that initiate labor, both at term and pre-term, are not well defined. Lu Gao and colleagues show that fetal lung expression of steroid receptor coactivators-1 and -2 (SRC-1 and SRC-2) upregulates genes that trigger parturition in mice. Their finding that WT females bred to males that were doubly deficient in Src-1 and Src-2 exhibited severely delayed parturition, clearly implicates a role for the fetus in the timing of birth. This parturition delay was accompanied by decreased expression of uterine inflammatory and contractile genes and elevated circulating progesterone. The lungs and amniotic fluid of SRC-1/2-deficient fetuses had markedly reduced levels of surfactant protein-A (SP-A) and the inflammatory phospholipid platelet-activating factor (PAF); intra-amniotic injection of either of these factors rescued the delayed labor phenotype. In the accompanying commentary, Erin Reinl and Sarah England discuss how these studies identify fetal-derived factors that control the initiation of labor.
Read the article in JCI: http://buff.ly/1L5yVo2
Read the accompanying commentary in JCI:
#ResearchArticle #ReproductiveBiology
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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.