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Author Al-Awqati, Q. url  openurl
  Title Kidney growth and hypertrophy: the role of mTOR and vesicle trafficking Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal J Clin Invest  
  Volume 125 Issue 6 Pages 2267-2270  
  Keywords  
  Abstract The kidney, like other organs, grows in constant proportion to the rest of the body. When one kidney is removed, the remaining one hypertrophies. In a comprehensive series of studies, Chen et al. show that growth during maturation is mediated by the mTORC1 signaling pathway, which is induced by EGF-like peptides, and requires PI3K, PDK, AKT, mTORC2, and activation of mTORC1 through the combined effects of TSC and RHEB as part of a multiprotein complex localized on lysosomes. However, compensatory growth is mediated by amino acids, which act on mTORC1 independently of the previous pathway, and requires a class III PI3K (VPS34) that is known to be involved in vesicle trafficking to the lysosomes.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45804  
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Author Akchurin, O.; Reidy, K.J. url  openurl
  Title Genetic causes of proteinuria and nephrotic syndrome: impact on podocyte pathobiology Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Pediatr Nephrol  
  Volume 30 Issue 2 Pages 221-233  
  Keywords  
  Abstract In the past 20 years, multiple genetic mutations have been identified in patients with congenital nephrotic syndrome (CNS) and both familial and sporadic focal segmental glomerulosclerosis (FSGS). Characterization of the genetic basis of CNS and FSGS has led to the recognition of the importance of podocyte injury to the development of glomerulosclerosis. Genetic mutations induce injury due to effects on the podocyte’s structure, actin cytoskeleton, calcium signaling, and lysosomal and mitochondrial function. Transgenic animal studies have contributed to our understanding of podocyte pathobiology. Podocyte endoplasmic reticulum stress response, cell polarity, and autophagy play a role in maintenance of podocyte health. Further investigations related to the effects of genetic mutations on podocytes may identify new pathways for targeting therapeutics for nephrotic syndrome.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0931-041x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45820  
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Author Amendola, L.M.; Dorschner, M.O.; Robertson, P.D.; Salama, J.S.; Hart, R.; Shirts, B.H.; Murray, M.L.; Tokita, M.J.; Gallego, C.J.; Kim, D.S.; Bennett, J.T.; Crosslin, D.R.; Ranchalis, J.; Jones, K.L.; Rosenthal, E.A.; Jarvik, E.R.; Itsara, A.; Turner, E.H.; Herman, D.S.; Schleit, J.; Burt, A.; Jamal, S.M.; Abrudan, J.L.; Johnson, A.D.; Conlin, L.K.; Dulik, M.C.; Santani, A.; Metterville, D.R.; Kelly, M.; Foreman, A.K.; Lee, K.; Taylor, K.D.; Guo, X.; Crooks, K.; Kiedrowski, L.A.; Raffel, L.J.; Gordon, O.; Machini, K.; Desnick, R.J.; Biesecker, L.G.; Lubitz, S.A.; Mulchandani, S.; Cooper, G.M.; Joffe, S.; Richards, C.S.; Yang, Y.; Rotter, J.I.; Rich, S.S.; O’Donnell, C.J.; Berg, J.S.; Spinner, N.B.; Evans, J.P.; Fullerton, S.M.; Leppig, K.A.; Bennett, R.L.; Bird, T.; Sybert, V.P.; Grady, W.M.; Tabor, H.K.; Kim, J.H.; Bamshad, M.J.; Wilfond, B.; Motulsky, A.G.; Scott, C.R.; Pritchard, C.C.; Walsh, T.D.; Burke, W.; Raskind, W.H.; Byers, P.; Hisama, F.M.; Rehm, H.; Nickerson, D.A.; Jarvik, G.P. url  openurl
  Title Actionable exomic incidental findings in 6503 participants: challenges of variant classification Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Genome Res  
  Volume 25 Issue 3 Pages 305-315  
  Keywords  
  Abstract Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.  
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  Series Volume Series Issue Edition  
  ISSN 1088-9051 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45831  
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Author Andrade-Oliveira, V.; Amano, M.T.; Correa-Costa, M.; Castoldi, A.; Felizardo, R.J.; de Almeida, D.C.; Bassi, E.J.; Moraes-Vieira, P.M.; Hiyane, M.I.; Rodas, A.C.; Peron, J.P.; Aguiar, C.F.; Reis, M.A.; Ribeiro, W.R.; Valduga, C.J.; Curi, R.; Vinolo, M.A.; Ferreira, C.M.; Câmara, N.O. url  openurl
  Title Gut Bacteria Products Prevent AKI Induced by Ischemia-Reperfusion Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal J Am Soc Nephrol  
  Volume 26 Issue 8 Pages 1877-1888  
  Keywords  
  Abstract Short-chain fatty acids (SCFAs) are fermentation end products produced by the intestinal microbiota and have anti-inflammatory and histone deacetylase-inhibiting properties. Recently, a dual relationship between the intestine and kidneys has been unraveled. Therefore, we evaluated the role of SCFA in an AKI model in which the inflammatory process has a detrimental role. We observed that therapy with the three main SCFAs (acetate, propionate, and butyrate) improved renal dysfunction caused by injury. This protection was associated with low levels of local and systemic inflammation, oxidative cellular stress, cell infiltration/activation, and apoptosis. However, it was also associated with an increase in autophagy. Moreover, SCFAs inhibited histone deacetylase activity and modulated the expression levels of enzymes involved in chromatin modification. In vitro analyses showed that SCFAs modulated the inflammatory process, decreasing the maturation of dendritic cells and inhibiting the capacity of these cells to induce CD4(+) and CD8(+) T cell proliferation. Furthermore, SCFAs ameliorated the effects of hypoxia in kidney epithelial cells by improving mitochondrial biogenesis. Notably, mice treated with acetate-producing bacteria also had better outcomes after AKI. Thus, we demonstrate that SCFAs improve organ function and viability after an injury through modulation of the inflammatory process, most likely via epigenetic modification.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1046-6673 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45839  
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Author Al-Nouri, Z.L.; Reese, J.A.; Terrell, D.R.; Vesely, S.K.; George, J.N. url  openurl
  Title Drug-induced thrombotic microangiopathy: a systematic review of published reports Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Blood  
  Volume 125 Issue 4 Pages 616-618  
  Keywords  
  Abstract Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA. We identified 1569 articles: 604 were retrieved for review, 344 reported evaluable data for 586 individual patients, 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA.  
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  Series Volume Series Issue Edition  
  ISSN 0006-4971 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45847  
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Author Albers, J.; Danzer, C.; Rechsteiner, M.; Lehmann, H.; Brandt, L.P.; Hejhal, T.; Catalano, A.; Busenhart, P.; Gonçalves, A.F.; Brandt, S.; Bode, P.K.; Bode-Lesniewska, B.; Wild, P.J.; Frew, I.J. url  openurl
  Title A versatile modular vector system for rapid combinatorial mammalian genetics Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal J Clin Invest  
  Volume 125 Issue 4 Pages 1603-1619  
  Keywords Animals; Apoptosis; Caspase 9; Cells, Cultured; Cloning, Molecular; Clustered Regularly Interspaced Short Palindromic Repeats; Doxycycline; Drug Resistance; Gene Deletion; Gene Knockdown Techniques; Genetic Vectors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lentivirus; Mice; Mice, SCID; PTEN Phosphohydrolase; Recombination, Genetic; research support, non-u.s. gov’t; Retinoblastoma Protein; RNA, Small Interfering; Sarcoma, Experimental; Transduction, Genetic; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays; Cas9/CRIPSR; Journal club  
  Abstract Here, we describe the multiple lentiviral expression (MuLE) system that allows multiple genetic alterations to be introduced simultaneously into mammalian cells. We created a toolbox of MuLE vectors that constitute a flexible, modular system for the rapid engineering of complex polycistronic lentiviruses, allowing combinatorial gene overexpression, gene knockdown, Cre-mediated gene deletion, or CRISPR/Cas9-mediated (where CRISPR indicates clustered regularly interspaced short palindromic repeats) gene mutation, together with expression of fluorescent or enzymatic reporters for cellular assays and animal imaging. Examples of tumor engineering were used to illustrate the speed and versatility of performing combinatorial genetics using the MuLE system. By transducing cultured primary mouse cells with single MuLE lentiviruses, we engineered tumors containing up to 5 different genetic alterations, identified genetic dependencies of molecularly defined tumors, conducted genetic interaction screens, and induced the simultaneous CRISPR/Cas9-mediated knockout of 3 tumor-suppressor genes. Intramuscular injection of MuLE viruses expressing oncogenic H-RasG12V together with combinations of knockdowns of the tumor suppressors cyclin-dependent kinase inhibitor 2A (Cdkn2a), transformation-related protein 53 (Trp53), and phosphatase and tensin homolog (Pten) allowed the generation of 3 murine sarcoma models, demonstrating that genetically defined autochthonous tumors can be rapidly generated and quantitatively monitored via direct injection of polycistronic MuLE lentiviruses into mouse tissues. Together, our results demonstrate that the MuLE system provides genetic power for the systematic investigation of the molecular mechanisms that underlie human diseases.  
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  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45848  
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Author Afshinnekoo, E.; Meydan, C.; Chowdhury, S.; Jaroudi, D.; Boyer, C.; Bernstein, N.; Maritz, J.M.; Reeves, D.; Gandara, J.; Chhangawala, S.; Ahsanuddin, S.; Simmons, A.; Nessel, T.; Sundaresh, B.; Pereira, E.; Jorgensen, E.; Kolokotronis, S.O.; Kirchberger, N.; Garcia, I.; Gandara, D.; Dhanraj, S.; Nawrin, T.; Saletore, Y.; Alexander, N.; Vijay, P.; Hénaff, E.M.; Zumbo, P.; Walsh, M.; O’Mullan, G.D.; Tighe, S.; Dudley, J.T.; Dunaif, A.; Ennis, S.; O’Halloran, E.; Magalhaes, T.R.; Boone, B.; Jones, A.L.; Muth, T.R.; Paolantonio, K.S.; Alter, E.; Schadt, E.E.; Garbarino, J.; Prill, R.J.; Carlton, J.M.; Levy, S.; Mason, C.E. url  openurl
  Title Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Cell Syst  
  Volume 1 Issue Pages 72-87  
  Keywords Aop  
  Abstract The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.g., Acinetobacter). Predicted ancestry of human DNA left on subway surfaces can recapitulate U.S. Census demographic data, and bacterial signatures can reveal a station’s history, such as marine-associated bacteria in a hurricane-flooded station. Some evidence of pathogens was found (Bacillus anthracis), but a lack of reported cases in NYC suggests that the pathogens represent a normal, urban microbiome. This baseline metagenomic map of NYC could help long-term disease surveillance, bioterrorism threat mitigation, and health management in the built environment of cities.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 2405-4712 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45849  
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Author Alkuraya, F.S. url  openurl
  Title Natural human knockouts and the era of genotype to phenotype Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Genome Med  
  Volume 7 Issue 1 Pages 48  
  Keywords  
  Abstract Complete loss of gene function in humans by naturally occurring biallelic loss-of-function mutations (human knockout) is not a new concept. However, the recent identification of human knockouts along the entire spectrum of health and disease by next-generation sequencing promises to unlock their full potential to accelerate the medical and functional annotation of the human genome.  
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  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 1756-994x ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45850  
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Author Ariceta, G.; Lara, E.; Camacho, J.A.; Oppenheimer, F.; Vara, J.; Santos, F.; Muñoz, M.A.; Cantarell, C.; Gil Calvo, M.; Romero, R.; Valenciano, B.; García-Nieto, V.; Sanahuja, M.J.; Crespo, J.; Justa, M.L.; Urisarri, A.; Bedoya, R.; Bueno, A.; Daza, A.; Bravo, J.; Llamas, F.; Jiménez Del Cerro, L.A. url  openurl
  Title Cysteamine (Cystagon®) adherence in patients with cystinosis in Spain: successful in children and a challenge in adolescents and adults Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Nephrol Dial Transplant  
  Volume 30 Issue 3 Pages 475-480  
  Keywords  
  Abstract BACKGROUND: Cysteamine has improved survival and prognosis in cystinosis. Increasing numbers of patients reach adulthood and face new challenges such as compliance that wanes over time. The aim of this study was to evaluate adherence to cysteamine treatment in a group of cystinotic patients in Spain in an attempt to identify potential therapy pitfalls and improve the overall care of affected individuals. Despite the impact of cysteamine on prognosis, there is a paucity of data regarding adherence. METHOD: Thirty-four cystinotic patients (21 male) 38% ≥18 years were enrolled in a voluntary, anonymous survey. Replies were obtained from patients (15/34), mothers (11/34), fathers (4/34) and both parents (4/34). RESULTS: Patient age (median and interquartile range) at diagnosis was 1 year (0.57-1), and patient age at Cystagon® initiation was also 1 year (0.8-1.8). Sixteen (47%) were kidney transplant (KTx) recipients; six were retransplanted. Age at first KTx 10 years (8.7-13.7). Patient understanding of multiorgan involvement in cystinosis: 4.1 organs reported; eye 97% and kidney 91%. Cysteamine was given by mother (100%) and father (83%) in <11 year olds, or self-administered (94%) in ≥11 year olds. Four daily doses in 89% versus 56% in <11 year olds or ≥11 year olds, with fixed schedule in 94% versus 50% in <11 or ≥11 year olds and progressive loss of reminders over time. Furthermore, 44% complained of unpleasant smell. Motivation for treatment compliance was 100% versus 40% in <11 versus ≥11 year olds, respectively. Disease impact in patients <18 years is as follows: school (29%), social (14%), ‘feeling different’ (10%); in patients ≥18 years: ‘feeling different’ (62%), professional (39%) and job absenteeism (31%). Referring physician: paediatric nephrologist (94%) and nephrologist (63%) in <11 versus ≥11 year olds. Ophthalmological follow-up: 83% versus 38% in <11 versus ≥11 year olds. Patient opinion of physician expertise: paediatric nephrologist (94%) and nephrologist (44%). New treatment options (65%) and better information (42%) were demanded to improve adherence. CONCLUSION: Treatment with Cystagon is effective in young patients. However, adherence diminishes over time in adolescents and adults despite disease impact. Strategies such as better information on the disease, patient self-care promotion and facilitated transition to adult healthcare services are required to improve compliance and the clinical management of cystinosis.  
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  ISSN 0931-0509 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45856  
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Author Aichler, M.; Walch, A. url  openurl
  Title MALDI Imaging mass spectrometry: current frontiers and perspectives in pathology research and practice Type Journal Article
  Year 2015 Publication (up) Abbreviated Journal Lab Invest  
  Volume 95 Issue 4 Pages 422-431  
  Keywords  
  Abstract MALDI Imaging mass spectrometry has entered the field of tissue-based research by providing unique advantages for analyzing tissue specimen in an unprecedented detail. A broad spectrum of analytes ranging from proteins, peptides, protein modification over small molecules, drugs and their metabolites as well as pharmaceutical components, endogenous cell metabolites, lipids, and other analytes are made accessible by this in situ technique in tissue. Some of them were even not accessible in tissues within the histological context before. Thereby, the great advantage of MALDI Imaging is the correlation of molecular information with traditional histology by keeping the spatial localization information of the analytes after mass spectrometric measurement. This method is label-free and allows multiplex analysis of hundreds to thousands of molecules in the very same tissue section simultaneously. Imaging mass spectrometry brings a new quality of molecular data and links the expert discipline of pathology and deep molecular mass spectrometric analysis to tissue-based research. This review will focus on state-of-the-art of MALDI Imaging mass spectrometry, its recent applications by analyzing tissue specimen and the contributions in understanding the biology of disease as well as its perspectives for pathology research and practice.  
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  Series Volume Series Issue Edition  
  ISSN 0023-6837 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45924  
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