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Journal of Clinical Investigation
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Uncovering the etiology of pediatric chronic kidney disease
Chronic kidney disease (CKD) has a profound impact on children, including increased morbidity from hypertension and cardiovascular and neurodevelopmental complications. In many cases, the etiology of the disease is unknown. Miguel Verbitsky and colleagues performed chromosomal microarrays to detect genomic imbalances in 419 children
enrolled in the Chronic Kidney Disease in Children (CKiD) Prospective Cohort Study and compared them to 21,575 children and adults who did not have CKD. Genomic disorders were detected in 4.5% of children enrolled in the CKiD study compared to 0.45% of individuals in the control cohorts. Additionally, large, gene-disrupting copy number variations (>500kb) were detected nearly twice as often in CKD patients compared with controls. These findings indicate that a significant proportion of children with CKD have an unsuspected genomic imbalance that provides valuable diagnostic information and could potentially lead to improved personalized clinical care. In the accompanying commentary, Martin Pollak discusses the role of genomic technologies in clinical care.
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Poly(A)-specific ribonuclease deficiency in patients with dyskeratosis congenita
The inherited disorder dyskeratosis congenita is characterized by short telomeres, mucocutaneous abnormalities, and bone marrow failure. The underlying genetic mutations are known in ~40% of cases and are found within genes associated with telomere maintenance and function. In this episode, Tom Vulliamy and Hemanth Tummala discuss their work, which identifies biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in three families with severe dyskeratosis congenita. These mutations inhibit the deadenylation activity of PARN, resulting in the downregulation of 4 genes involved in telomere maintenance and shortened telomeres. The results of this study establish a causative role for PARN in a severe form of dyskeratosis congenita.
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Lipid oxidation controls dendritic cell maturation and immune specificity
Upon exposure to pathogen- or danger-associated molecular patterns (PAMPs/DAMPs), dendritic cells (DCs) undergo a maturation process that initiates specific T cell responses. This maturation process must be tightly controlled to avoid autoimmunity and non-specific responses. Tobias Rothe and colleagues demonstrate that 12/15-lipoxygenase-mediated lipid oxidation is required for the maturation and function of DCs. Loss of 12/15-lipoxygenase in murine or human DCs accelerated maturation and resulted in an altered cytokine profile that favored the differentiation of Th17 T cells and exacerbated a model autoimmune disease in mice. This effect was replicated by exposing DCs to 12/15-lipoxygenase-derived oxidized phospholipids, which control the maturation process by activating the transcription factor NRF2, thereby impeding Th17-directed differentiation.
Read the article recently published in JCI: http://buff.ly/1GTEYZI #ResearchArticle #Immunology
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Smart bomb: DNMT-TALEs direct DNA methylation at specific genetic loci
Inappropriate epigenetic modifications, such as alterations in DNA methylation, can lead to a variety of disease states, making epigenetic regulators attractive therapeutic targets; however, general inhibitors of globally expressed epigenetic regulators may have deleterious effects. Diana Bernstein and colleagues developed a method to direct DNA methylation to specific genetic loci by conjugating the catalytic domains of DNA methyltransferases (DNMTs) to engineered transcription activator-like effectors (TALEs). Using primary human fibroblasts, Bernstein and colleagues showed that they could induce methylation of the genetic locus encoding the cyclin-dependent kinase inhibitor p16, CDNK2A, resulting in decreased p16 expression and increased cellular proliferation. The accompanying image shows increased DNA replication (red) in control (left) and p16-targeted DNMT-TALE-treated cells.
Read the article recently published in JCI: http://buff.ly/1D4df5S #TechnicalAdvance #Genetics
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A new batch of articles is now available online at
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Intracellular calcium leak recasts β cell landscape
The type 2 ryanodine receptor (RyR2) is an ER-localized calcium release channel that is present in many cell types, including cardiomyocytes and pancreatic β cells. While calcium flux is pivotal for insulin secretion by pancreatic b cells, it is unclear if RyR2 plays a role in insulin release. Individuals with the rare human disease catecholaminergic polymorphic ventricular tachycardia (CPVT), which often first manifests as exercised-induced sudden death, harbor mutations that render the RyR2 channel “leaky”. Gaetano Santulli and colleagues at Columbia University Medical Center reveal that individuals with CPVT also present with glucose intolerance and impaired insulin secretion.
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Very interesting study!
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TREM2 keeps myelinated axons under wraps
The polyanion-binding cell surface receptor TREM2 is expressed on myeloid cell populations, including microglia of the CNS. Individuals with inactivating mutations in TREM2 or TYROBP, which encodes the TREM2 adapter DAP12, develop Nasu-Hakola disease, a rare, lethal dementia that manifests in early adulthood and is characterized by demyelinating lesions. The link between loss of TREM2 function and dysfunctional myelination is not clear. Pietro Poliani, Yaming Wang, and colleagues at the University of Brescia School of Medicine used murine models to investigate a possible role for microglial TREM2 in myelin repair following injury.
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A network of diuretic resistance
The maintenance of body fluid homeostasis and blood pressure is regulated by the selective excretion and absorption of salt by the kidney. Current treatments for hypertension rely on drugs, such as thiazide diuretics to restore fluid balance; however, diuretic resistance often develops over time. The thiazide-sensitive sodium chloride co-transporter NCC mediates salt reabsorption and is activated by the kinase SPAK. Despite the prominence of NCC in maintaining electrolyte balance, loss of NCC function in patients results in only mild salt wasting, suggesting compensatory mechanisms. Using a systems biology approach to evaluate compensatory responses in SPAK-deficient mice, Richard Grimm and colleagues at University of Maryland School of Medicine, uncovered adaptive renal mechanisms that allow salt reabsorption even in the absence of the critical salt transporter, NCC.
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Read the JCI News Round Up

Coverage on Gene therapy slows vision loss in mouse models of retinal degeneration | Insulin-resistance mutation discovery | Severity of RSV worsened by gene variation and environment | Stem cell associated with leukemia | Pancreatic cell defect could lead to diabetes treatment | Metabolic compensation underlies drug resistance in glioblastoma | Bone growth as possible therapy for osteoporosis and obesity | Study may identify new cause of brain bleeds in fetuses and newborns | Huntington's disease human clinical trial | Reprogramming hepatocyte memory of liver disease | Biomarkers could enable TB test diagnosis and monitoring | Identification of drug combinations that reverse HIV-1 latency | Novel drug combination may lead to effective colon and bladder cancer treatment

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A therapeutic window of opportunity in Angelman syndrome
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a lack of maternal UBE3A expression. Children with AS exhibit motor impairments, epilepsy, intellectual disability, anxiety, and autistic traits. Activation of the paternal allele could potentially ameliorate the disorder, but previous studies have indicated that activation in adulthood is insufficient to rescue most neurocognitive phenotypes in a murine AS model. Sara Silva-Santos and colleagues reinstated Ube3a expression at different time points in AS mice to determine the window for therapeutic intervention for AS-relevant phenotypes. They found that early embryonic expression of Ube3a expression completely rescued the neurological and behavioral phenotype of AS mice. Post-natal reactivation rescued motor deficits, but did not rescue autism- or anxiety-related phenotypes. In contrast, electrophysiological alterations could be rescued at any age. These results indicate that early UBE3A expression is necessary to rescue AS behavioral phenotypes.
Read the article recently published in JCI: http://buff.ly/1D4f9n3 #ResearchArticle #Genetics
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Smothering Von Hippel-Lindau syndrome-associated phenotypes
The inherited disease Von Hippel-Lindau (VHL) syndrome results from loss-of-function mutations in VHL, which encodes a negative regulator of the hypoxia inducible transcription factors HIF1α and HIF2α. Individuals with VHL syndrome commonly present with hypervascular tumors, renal cell cancers, and elevated levels of circulating rbc. Targeted therapies for VHL syndrome are currently limited, and surgical removal of tumors is often the only course of action. Ana Metelo and colleagues at Harvard Medical School developed a zebrafish model of VHL and demonstrated that treatment of these animals with a HIF2α inhibitor ameliorates VHL-associated phenotypes.
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Tracking Huntington’s disease progression in human cerebrospinal fluid
Huntington’s disease (HD) is caused by a mutation in the huntingtin protein (mHTT). Genetic testing can identify individuals with HD prior to the development of symptoms; however, the clinical course of the disease is unpredictable. Edward Wild, Roberto Boggio, and colleagues used an immunoassay method to quantify levels of mHTT in cerebrospinal fluid (CSF) from two independent patient cohorts. They were able to detect mHTT in mutation carriers but not in control volunteers. CSF mHTT concentrations were higher in patients manifesting disease symptoms compared to premanifest mutation carriers and CSF mHTT concentrations were higher at later disease stages. Moreover, mHTT levels could independently predict patient performance on cognitive assessments. These results demonstrate that mHTT levels in CSF can serve as a biomarker to track HD progression and may be useful in the assessment of new HD therapeutics.
Read the article recently published in JCI: http://buff.ly/1NlHKMN #ClinicalMedicine #ClinicalTrials #Neuroscience
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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.