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Author (up) Burnett, L.C.; LeDuc, C.A.; Sulsona, C.R.; Paull, D.; Rausch, R.; Eddiry, S.; Carli, J.F.M.; Morabito, M.V.; Skowronski, A.A.; Hubner, G.; Zimmer, M.; Wang, L.; Day, R.; Levy, B.; Fennoy, I.; Dubern, B.; Poitou, C.; Clement, K.; Butler, M.G.; Rosenbaum, M.; Salles, J.P.; Tauber, M.; Driscoll, D.J.; Egli, D.; Leibel, R.L. url  doi
openurl 
  Title Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome Type Journal Article
  Year 2017 Publication The Journal of Clinical Investigation Abbreviated Journal J Clin Invest  
  Volume 127 Issue 1 Pages 293-305  
  Keywords  
  Abstract Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.  
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  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27941249 Approved no  
  Call Number ref @ user @ Serial 95908  
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Author (up) Cole, D.C.; Giordano, C.R.; Vasilopoulos, T.; Fahy, B.G. url  doi
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  Title Resident Physicians Improve Nontechnical Skills When on Operating Room Management and Leadership Rotation Type Journal Article
  Year 2017 Publication Anesthesia and Analgesia Abbreviated Journal Anesth Analg  
  Volume 124 Issue 1 Pages 300-307  
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  Abstract BACKGROUND: Anesthesiology residency primarily emphasizes the development of medical knowledge and technical skills. Yet, nontechnical skills (NTS) are also vital to successful clinical practice. Elements of NTS are communication, teamwork, situational awareness, and decision making. METHODS: The first 10 consecutive senior residents who chose to participate in this 2-week elective rotation of operating room (OR) management and leadership training were enrolled in this study, which spanned from March 2013 to March 2015. Each resident served as the anesthesiology officer of the day (AOD) and was tasked with coordinating OR assignments, managing care for 2 to 4 ORs, and being on call for the trauma OR; all residents were supervised by an attending AOD. Leadership and NTS techniques were taught via a standardized curriculum consisting of leadership and team training articles, crisis management text, and daily debriefings. Resident self-ratings and attending AOD and charge nurse raters used the Anaesthetists' Non-Technical Skills (ANTS) scoring system, which involved task management, situational awareness, teamwork, and decision making. For each of the 10 residents in their third year of clinical anesthesiology training (CA-3) who participated in this elective rotation, there were 14 items that required feedback from resident self-assessment and OR raters, including the daily attending AOD and charge nurse. Results for each of the items on the questionnaire were compared between the beginning and the end of the rotation with the Wilcoxon signed-rank test for matched samples. Comparisons were run separately for attending AOD and charge nurse assessments and resident self-assessments. Scaled rankings were analyzed for the Kendall coefficient of concordance (omega) for rater agreement with associated chi and P value. RESULTS: Common themes identified by the residents during debriefings were recurrence of challenging situations and the skills residents needed to instruct and manage clinical teams. For attending AOD and charge nurse assessments, resident performance of NTS improved from the beginning to the end of the rotation on 12 of the 14 NTS items (P < .05), whereas resident self-assessment improved on 3 NTS items (P < .05). Interrater reliability (across the charge nurse, resident, and AOD raters) ranged from omega = .36 to .61 at the beginning of the rotation and omega = .27 to .70 at the end of the rotation. CONCLUSIONS: This rotation allowed for teaching and resident assessment to occur in a way that facilitated resident education in several of the skills required to meet specific milestones. Resident physicians are able to foster NTS and build a framework for clinical leadership when completing a 2-week senior elective as an OR manager.  
  Address From the Department of Anesthesiology, University of Florida, College of Medicine, Gainesville, Fla  
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  ISSN 0003-2999 ISBN Medium  
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  Notes PMID:27918336 Approved no  
  Call Number ref @ user @ Serial 95061  
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Author (up) Fogel, O.; Richard-Miceli, C.; Tost, J. url  doi
openurl 
  Title Epigenetic Changes in Chronic Inflammatory Diseases Type Journal Article
  Year 2017 Publication Advances in Protein Chemistry and Structural Biology Abbreviated Journal Adv Protein Chem Struct Biol  
  Volume 106 Issue Pages 139-189  
  Keywords Behcet's disease; Crohn's disease; DNA methylation; Ewas; Epigenetics; Histone modifications; Inflammatory bowel disease; Psoriasis; Spondyloarthritis; Ulcerative colitis  
  Abstract The number of people diagnosed with chronic inflammatory diseases has increased noteworthy in the last 40 years. Spondyloarthritis (SpA), inflammatory bowel diseases (IBD), and psoriasis are the most frequent chronic inflammatory diseases, resulting from a combination of genetic predisposition and environmental factors. Epigenetic modifications include DNA methylation, histone modifications, and small and long noncoding RNAs. They are influenced by environmental exposure, life-style, and aging and have recently been shown to be altered in many complex diseases including inflammatory diseases. While epigenetic modifications have been well characterized in other diseases such as cancer and autoimmune diseases, knowledge on changes in inflammatory diseases is lagging behind with some disease-specific differences. While the DNA methylation profile of different cell types in patients with IBD has been relatively well described, less is known on changes implicated in psoriasis, and no systematic genome-wide studies have so far been performed in SpA. In this chapter, we review in detail the reported changes in patterns of DNA methylation and posttranslational histone modifications in chronic inflammatory diseases highlighting potential connections between disease-associated pathophysiological changes such as the dysbiosis of the microbiome or genetic variations associated with disease susceptibility and the epigenome. We also discuss important parameters of meaningful epigenetic studies such as the use of well defined, disease-relevant cell populations, and elude on the potential future of engineering of the epigenome in inflammatory diseases.  
  Address Laboratory for Epigenetics and Environment, Centre National de Genotypage, CEA-Institut de Genomique, Evry, France. Electronic address: tost@cng.fr  
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  ISSN 1876-1623 ISBN Medium  
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  Notes PMID:28057210 Approved no  
  Call Number ref @ user @ Serial 96374  
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Author (up) Lacovich, V.; Espindola, S.L.; Alloatti, M.; Pozo Devoto, V.; Cromberg, L.E.; Carna, M.E.; Forte, G.; Gallo, J.-M.; Bruno, L.; Stokin, G.B.; Avale, M.E.; Falzone, T.L. url  doi
openurl 
  Title Tau Isoforms Imbalance Impairs the Axonal Transport of the Amyloid Precursor Protein in Human Neurons Type Journal Article
  Year 2017 Publication The Journal of Neuroscience : the Official Journal of the Society for Neuroscience Abbreviated Journal J Neurosci  
  Volume 37 Issue 1 Pages 58-69  
  Keywords App; Alzheimer's; axonal transport; splicing; tau; tauopathies  
  Abstract Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.  
  Address Instituto de Biologia y Medicina Experimental (IBYME-CONICET), Buenos Aires C1428ADN, Argentina  
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  ISSN 0270-6474 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:28053030 Approved no  
  Call Number ref @ user @ Serial 95902  
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Author (up) Li, M.; Zhao, H.; Ananiev, G.E.; Musser, M.T.; Ness, K.H.; Maglaque, D.L.; Saha, K.; Bhattacharyya, A.; Zhao, X. url  doi
openurl 
  Title Establishment of Reporter Lines for Detecting Fragile X Mental Retardation (FMR1) Gene Reactivation in Human Neural Cells Type Journal Article
  Year 2017 Publication Stem Cells (Dayton, Ohio) Abbreviated Journal Stem Cells  
  Volume 35 Issue 1 Pages 158-169  
  Keywords Drug discovery; Fmr1; Fmrp; Fragile X syndrome; High throughput; Induced pluripotent stem cells; Luciferase  
  Abstract Human patient-derived induced pluripotent stem cells (hiPSCs) provide unique opportunities for disease modeling and drug development. However, adapting hiPSCs or their differentiated progenies to high throughput assays for phenotyping or drug screening has been challenging. Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic cause of autism. FXS is caused by mutational trinucleotide expansion in the FMR1 gene leading to hypermethylation and gene silencing. One potential therapeutic strategy is to reactivate the silenced FMR1 gene, which has been attempted using both candidate chemicals and cell-based screening. However, molecules that effectively reactivate the silenced FMR1 gene are yet to be identified; therefore, a high throughput unbiased screen is needed. Here we demonstrate the creation of a robust FMR1-Nluc reporter hiPSC line by knocking in a Nano luciferase (Nluc) gene into the endogenous human FMR1 gene using the CRISPR/Cas9 genome editing method. We confirmed that luciferase activities faithfully report FMR1 gene expression levels and showed that neural progenitor cells derived from this line could be optimized for high throughput screening. The FMR1-Nluc reporter line is a good resource for drug screening as well as for testing potential genetic reactivation strategies. In addition, our data provide valuable information for the generation of knockin human iPSC reporter lines for disease modeling, drug screening, and mechanistic studies. Stem Cells 2017;35:158-169.  
  Address Department of Neuroscience, University of Wisconsin-Madison, Madison, Wisconsin, USA  
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  Series Volume Series Issue Edition  
  ISSN 1066-5099 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:27422057 Approved no  
  Call Number ref @ user @ Serial 95937  
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