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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 Abbreviated Journal J Clin Invest  
  Volume 125 Issue 4 Pages (down) 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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  ISSN 0021-9738 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial 45848  
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Author Jones, O.C.; McDonald, I.; Rich, R.M.; Kemper, F.; Boyer, M.L.; Zijlstra, A.A.; Bendo, G.J. url  openurl
  Title A Spitzer Space Telescope survey of extreme asymptotic giant branch stars in M32 Type Journal Article
  Year 2015 Publication Mon.~Not.~R.~Astron.~Soc. Abbreviated Journal  
  Volume 446 Issue 2 Pages (down) 1584-1596  
  Keywords stars: AGB and post-AGB; stars: late-type; stars: mass-loss; galaxies: individual: M32; galaxies: stellar content; infrared: stars  
  Abstract We investigate the population of cool, evolved stars in the Local Group dwarf elliptical galaxy M32, using Infrared Array Camera observations from the Spitzer Space Telescope. We construct deep mid-infrared colour-magnitude diagrams for the resolved stellar populations within 3.5 arcmin of M32's centre, and identify those stars that exhibit infrared excess. Our data are dominated by a population of luminous, dust-producing stars on the asymptotic giant branch (AGB) and extend to approximately 3 mag below the AGB tip. We detect for the first time a sizeable population of `extreme' AGB stars, highly enshrouded by circumstellar dust and likely completely obscured at optical wavelengths. The total dust-injection rate from the extreme AGB candidates is measured to be 7.5 × 10-7 M⊙ yr-1, corresponding to a gas mass-loss rate of 1.5 × 10-4 M⊙ yr-1. These extreme stars may be indicative of an extended star formation epoch between 0.2 and 5 Gyr ago.  
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  Notes refereed; Owner: ciska; Added to JabRef: 2015.04.15 Approved no  
  Call Number ASIAA @ ciska @ Serial 41992  
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Author Allen, M.D.; Freund, S.M.V.; Zinzalla, G.; Bycroft, M. openurl 
  Title The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis Type Journal Article
  Year 2015 Publication Abbreviated Journal Structure (London, England : 1993)  
  Volume 23 Issue 7 Pages (down) 1344--1349  
  Keywords Non-Histone,genetics; Conserved Sequence; DNA-Binding Proteins,genetics; Humans; Models,Molecular; Molecular Sequence Data; Mutation; Neurilemmoma,genetics; Neurofibromatoses,genetics; Nuclear Magnetic Resonance,Biomolecular; Protein Binding; Protein Interaction Domains and Motifs; Protein Structure,Secondary; SMARCB1 Protein; Skin Neoplasms,genetics; Transcription Factors,genetics  
  Abstract SWI/SNF complexes use the energy of ATP hydrolysis to remodel chromatin. In mammals they play a central role in regulating gene expression during differentiation and proliferation. Mutations in SWI/SNF subunits are among the most frequent gene alterations in cancer. The INI1/hSNF5/SMARCB1 subunit is mutated in both malignant rhabdoid tumor, a highly aggressive childhood cancer, and schwannomatosis, a tumor-predisposing syndrome characterized by mostly benign tumors of the CNS. Here, we show that mutations in INI1 that cause schwannomatosis target a hitherto unidentified N-terminal winged helix DNA binding domain that is also present in the BAF45a/PHF10 subunit of the SWI/SNF complex. The domain is structurally related to the SKI/SNO/DAC domain, which is found in a number of metazoan chromatin-associated proteins.  
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  ISSN 1878-4186 ISBN Medium  
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  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial 47059  
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Author Émond, K.; Sainte-Marie, B.; Galbraith, P.S.; Bêty, J. url  openurl
  Title Top-down vs. bottom-up drivers of recruitment in a key marine invertebrate: Investigating early life stages of snow crab Type Journal Article
  Year 2015 Publication Abbreviated Journal ICES Journal of Marine Science  
  Volume 72 Issue 5 Pages (down) 1336-1348  
  Keywords cannibalism; climate; groundfish predation; larval production; population dynamics; recruitment; snow crab  
  Abstract Many snow crab fisheries have fluctuated widely over time in a quasi-cyclic way due to highly variable recruitment. The causes of this variability are still debated. Bottom-up processes related to climate variability may strongly affect growth and survival during early life, whereas top-down predator effects may be a major source of juvenile mortality. Moreover, intrinsic density-dependent processes, which have received much less attention, are hypothetically responsible for the cycles in recruitment. This study explored how climate, larval production, intercohort cannibalism and groundfish predation may have affected recruitment of early juvenile snow crab in the northwest Gulf of St Lawrence (eastern Canada) over a period of 23 years. Abundance of early juvenile snow crabs (2.5-22.9 mm in carapace width), representing the first 3 years of benthic life, came from an annual trawl survey and was used to determine cohort strength. Analyses revealed a cyclic pattern in abundance of 0+ crabs that may arise from cohort resonant effects. This pattern consisted of three recruitment pulses but was reduced to two pulses by age 2+, while the interannual variability of cohort strength was dampened. This reconfiguration of the earliest recruitment pattern was dictated primarily by bottom water temperature and cannibalism, which progressively overruled the pre-settlement factors of larval production and surface water temperature that best explained abundance of 0+ crabs. The results strongly suggest that bottom-up and density-dependent processes prevail over top-down control in setting the long-term trends and higher-frequency oscillations of snow crab early recruitment patterns. © 2015 International Council for the Exploration of the Sea 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.  
  Address Department of Fisheries and Oceans, Maurice Lamontagne Institute, 850 Route de la Mer, Mont-Joli, QC, Canada  
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  Notes Export Date: 17 March 2016 Approved no  
  Call Number McgGll @ elizabethburgess @ Serial 42532  
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Author Skirnisdottir, I.; Seidal, T.; Åkerud, H. url  openurl
  Title Differences in Clinical and Biological Features Between Type I and Type II Tumors in FIGO Stages I-II Epithelial Ovarian Carcinoma Type Journal Article
  Year 2015 Publication Abbreviated Journal Int J Gynecol Cancer  
  Volume 25 Issue 7 Pages (down) 1239-1247  
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  Abstract OBJECTIVE: The objective of this study was to compare immunohistochemical profile for the apoptosis regulators p53, C-MYC, bax, PUMA, and PTEN and the cell cycle regulatory proteins p21 and p27, as well as clinical factors between types I and II tumors. METHODS: In total, 131 patients in FIGO (International Federation of Gynecology and Obstetrics) stages I-II were divided into 2 groups of patients after type I tumors (n = 79) and type II tumors (n = 52). Differences in the immunohistochemical profile for the cell cycle-related proteins, detected by tissue microarrays and immune-histochemistry, were compared. For statistical tests, the Pearson χ test and the logistic regression model were used. All tests were 2-sided, and the level of statistical significance was P ≤ 0.05. RESULTS: In multivariate logistic regression analysis with recurrent disease as endpoint, FIGO stage (odds ratio [OR], 4.7), type I/II tumors (OR, 3.8), body mass index (BMI) (OR, 3.5), and p53 status (OR, 4.2) all were found to be independent predictive factors. In 2 different multivariate logistic regression analyses with type I/II tumors as endpoint, both p53p21 (OR, 2.9) and p27 status (OR, 3.0) were associated with type II tumors. Differently, C-MYC status (OR, 0.4) was associated with type I tumors. Furthermore, age (OR, 1.04), BMI (OR, 0.4), and recurrent disease (OR, 4.3) all were associated to type II tumors. In survival analysis, there was a trend (P = 0.054) toward better disease-free survival for patients with type I tumors. CONCLUSIONS: Concomitant positivity for p53 and negativity for p21, positivity for p27, and negativity for C-MYC in an epithelial ovarian tumor might strengthen the diagnostic option of type II tumor ovarian carcinoma. Patients with type II tumors were older, had lower BMI, and had more often recurrent disease than patients with type I tumors.  
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  Call Number UofT @ ankit.sinha @ Serial 44930  
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Author Ignatchenko, V.; Ignatchenko, A.; Sinha, A.; Boutros, P.C.; Kislinger, T. url  openurl
  Title VennDIS: a JavaFX-based Venn and Euler diagram software to generate publication quality figures Type Journal Article
  Year 2015 Publication Abbreviated Journal Proteomics  
  Volume 15 Issue 7 Pages (down) 1239-1244  
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  Abstract Venn diagrams are graphical representations of the relationships among multiple sets of objects and are often used to illustrate similarities and differences among genomic and proteomic datasets. All currently existing tools for producing Venn diagrams evince one of two traits; they require expertise in specific statistical software packages (such as R), or lack the flexibility required to produce publication-quality figures. We describe a simple tool that addresses both shortcomings, Venn Diagram Interactive Software (VennDIS), a JavaFX-based solution for producing highly customizable, publication-quality Venn, and Euler diagrams of up to five sets. The strengths of VennDIS are its simple graphical user interface and its large array of customization options, including the ability to modify attributes such as font, style and position of the labels, background color, size of the circle/ellipse, and outline color. It is platform independent and provides real-time visualization of figure modifications. The created figures can be saved as XML files for future modification or exported as high-resolution images for direct use in publications.  
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  Call Number UofT @ ankit.sinha @ Serial 45271  
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Author Robinson, M.S. openurl 
  Title Forty Years of Clathrin-coated Vesicles Type Journal Article
  Year 2015 Publication Abbreviated Journal Traffic  
  Volume 16 Issue 12 Pages (down) 1210-1238  
  Keywords JHU, CME, review  
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  Notes disease information Approved no  
  Call Number AG @ matthewjvarga @ Serial 46711  
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Author Dzierlenga, M.W.; Antoniou, D.; Schwartz, S.D. doi  openurl
  Title Another Look at the Mechanisms of Hydride Transfer Enzymes with Quantum and Classical Transition Path Sampling Type Journal Article
  Year 2015 Publication Abbreviated Journal The Journal of Physical Chemistry Letters  
  Volume 6 Issue 7 Pages (down) 1177-1181  
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  Abstract The mechanisms involved in enzymatic hydride transfer have been studied for years, but questions remain due, in part, to the difficulty of probing the effects of protein motion and hydrogen tunneling. In this study, we use transition path sampling (TPS) with normal mode centroid molecular dynamics (CMD) to calculate the barrier to hydride transfer in yeast alcohol dehydrogenase (YADH) and human heart lactate dehydrogenase (LDH). Calculation of the work applied to the hydride allowed for observation of the change in barrier height upon inclusion of quantum dynamics. Similar calculations were performed using deuterium as the transferring particle in order to approximate kinetic isotope effects (KIEs). The change in barrier height in YADH is indicative of a zero-point energy (ZPE) contribution and is evidence that catalysis occurs via a protein compression that mediates a near-barrierless hydride transfer. Calculation of the KIE using the difference in barrier height between the hydride and deuteride agreed well with experimental results.  
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  ISSN 1948-7185 ISBN Medium  
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  Notes NULL Times cited: 21 Approved no  
  Call Number AG @ matthewjvarga @ Serial 46386  
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Author Świderek, K.; Tuñón, I.; Martí, S.; Moliner, V. url  openurl
  Title Protein Conformational Landscapes and Catalysis. Influence of Active Site Conformations in the Reaction Catalyzed by L-Lactate Dehydrogenase Type Journal Article
  Year 2015 Publication Abbreviated Journal ACS Catal  
  Volume 5 Issue 4 Pages (down) 1172-1185  
  Keywords KIEs LDH QM/MM free energy surfaces reaction mechanism single-molecule experiments  
  Abstract In the last decade L-Lactate Dehydrogenase (LDH) has become an extremely useful marker in both clinical diagnosis and in monitoring the course of many human diseases. It has been assumed from the 80s that the full catalytic process of LDH starts with the binding of the cofactor and the substrate followed by the enclosure of the active site by a mobile loop of the protein before the reaction to take place. In this paper we show that the chemical step of the LDH catalyzed reaction can proceed within the open loop conformation, and the different reactivity of the different protein conformations would be in agreement with the broad range of rate constants measured in single molecule spectrometry studies. Starting from a recently solved X-ray diffraction structure that presented an open loop conformation in two of the four chains of the tetramer, QM/MM free energy surfaces have been obtained at different levels of theory. Depending on the level of theory used to describe the electronic structure, the free energy barrier for the transformation of pyruvate into lactate with the open conformation of the protein varies between 12.9 and 16.3 kcal/mol, after quantizing the vibrations and adding the contributions of recrossing and tunneling effects. These values are very close to the experimentally deduced one (14.2 kcal·mol^-1^) and ~2 kcal·mol^-1^ smaller than the ones obtained with the closed loop conformer. Calculation of primary KIEs and IR spectra in both protein conformations are also consistent with our hypothesis and in agreement with experimental data. Our calculations suggest that the closure of the active site is mainly required for the inverse process; the oxidation of lactate to pyruvate. According to this hypothesis H4 type LDH enzyme molecules, where it has been propose that lactate is transformed into pyruvate, should have a better ability to close the mobile loop than the M4 type LDH molecules.  
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  ISSN 2155-5435 ISBN Medium  
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  Call Number AG @ matthewjvarga @ Serial 46623  
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Author Surinova, S.; Choi, M.; Tao, S.; Schüffler, P.J.; Chang, C.Y.; Clough, T.; Vysloužil, K.; Khoylou, M.; Srovnal, J.; Liu, Y.; Matondo, M.; Hüttenhain, R.; Weisser, H.; Buhmann, J.M.; Hajdúch, M.; Brenner, H.; Vitek, O.; Aebersold, R. url  openurl
  Title Prediction of colorectal cancer diagnosis based on circulating plasma proteins Type Journal Article
  Year 2015 Publication Abbreviated Journal EMBO Mol Med  
  Volume 7 Issue 9 Pages (down) 1166-1178  
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  Abstract Non-invasive detection of colorectal cancer with blood-based markers is a critical clinical need. Here we describe a phased mass spectrometry-based approach for the discovery, screening, and validation of circulating protein biomarkers with diagnostic value. Initially, we profiled human primary tumor tissue epithelia and characterized about 300 secreted and cell surface candidate glycoproteins. These candidates were then screened in patient systemic circulation to identify detectable candidates in blood plasma. An 88-plex targeting method was established to systematically monitor these proteins in two large and independent cohorts of plasma samples, which generated quantitative clinical datasets at an unprecedented scale. The data were deployed to develop and evaluate a five-protein biomarker signature for colorectal cancer detection.  
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  Notes Approved no  
  Call Number UofT @ ankit.sinha @ Serial 45345  
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