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Author Stirnemann, G.; Sterpone, F. doi  openurl
  Title Recovering Protein Thermal Stability Using All-Atom Hamiltonian Replica-Exchange Simulations in Explicit Solvent Type Journal Article
  Year 2015 Publication Abbreviated Journal Journal of Chemical Theory and Computation  
  Volume 11 Issue 12 Pages 5573-5577  
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  ISSN 1549-9618 ISBN Medium  
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  Notes Times cited: 15 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46256  
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Author Zoi, I.; Motley, M.W.; Antoniou, D.; Schramm, V.L.; Schwartz, S.D. url  openurl
  Title Enzyme homologues have distinct reaction paths through their transition states Type Journal Article
  Year 2015 Publication Abbreviated Journal J Phys Chem B  
  Volume 119 Issue 9 Pages 3662-3668  
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  Abstract Recent studies of the bacterial enzymes EcMTAN and VcMTAN showed that they have different binding affinities for the same transition state analogue. This was surprising given the similarity of their active sites. We performed transition path sampling simulations of both enzymes to reveal the atomic details of the catalytic chemical step, which may be the key for explaining the inhibitor affinity differences. Even though all experimental data would suggest the two enzymes are almost identical, subtle dynamic differences manifest in differences of reaction coordinate, transition state structure, and eventually significant differences in inhibitor binding. Unlike EcMTAN, VcMTAN has multiple distinct transition states, which is an indication that multiple sets of coordinated protein motions can reach a transition state. Reaction coordinate information is only accessible from transition path sampling approaches, since all experimental approaches report averages. Detailed knowledge could have a significant impact on pharmaceutical design.  
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  Call Number AG @ matthewjvarga @ Serial (down) 46250  
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Author Suarez, J.; Schramm, V.L. doi  openurl
  Title Isotope-specific and amino acid-specific heavy atom substitutions alter barrier crossing in human purine nucleoside phosphorylase Type Journal Article
  Year 2015 Publication Abbreviated Journal Proceedings of the National Academy of Sciences  
  Volume 112 Issue 36 Pages 11247-11251  
  Keywords Born--Oppenheimer enzymes femtosecond dynamics heavy enzymes pre--steady-state chemistry transition state coupling  
  Abstract <jats:p>Computational chemistry predicts that atomic motions on the femtosecond timescale are coupled to transition-state formation (barrier-crossing) in human purine nucleoside phosphorylase (PNP). The prediction is experimentally supported by slowed catalytic site chemistry in isotopically labeled PNP (<jats:sup>13</jats:sup>C, <jats:sup>15</jats:sup>N, and <jats:sup>2</jats:sup>H). However, other explanations are possible, including altered volume or bond polarization from carbon-deuterium bonds or propagation of the femtosecond bond motions into slower (nanoseconds to milliseconds) motions of the larger protein architecture to alter catalytic site chemistry. We address these possibilities by analysis of chemistry rates in isotope-specific labeled PNPs. Catalytic site chemistry was slowed for both [<jats:sup>2</jats:sup>H]PNP and [<jats:sup>13</jats:sup>C, <jats:sup>15</jats:sup>N]PNP in proportion to their altered protein masses. Secondary effects emanating from carbon–deuterium bond properties can therefore be eliminated. Heavy-enzyme mass effects were probed for local or global contributions to catalytic site chemistry by generating [<jats:sup>15</jats:sup>N, <jats:sup>2</jats:sup>H]His<jats:sub>8</jats:sub>-PNP. Of the eight His per subunit, three participate in contacts to the bound reactants and five are remote from the catalytic sites. [<jats:sup>15</jats:sup>N, <jats:sup>2</jats:sup>H]His<jats:sub>8</jats:sub>-PNP had reduced catalytic site chemistry larger than proportional to the enzymatic mass difference. Altered barrier crossing when only His are heavy supports local catalytic site femtosecond perturbations coupled to transition-state formation. Isotope-specific and amino acid specific labels extend the use of heavy enzyme methods to distinguish global from local isotope effects.</jats:p  
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  Notes Times cited: 18 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46225  
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Author Sokkar, P.; Boulanger, E.; Thiel, W.; Sanchez-Garcia, E. url  openurl
  Title Hybrid Quantum Mechanics/Molecular Mechanics/Coarse Grained Modeling: A Triple-Resolution Approach for Biomolecular Systems Type Journal Article
  Year 2015 Publication Abbreviated Journal J Chem Theory Comput  
  Volume 11 Issue 4 Pages 1809-1818  
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  Abstract We present a hybrid quantum mechanics/molecular mechanics/coarse-grained (QM/MM/CG) multiresolution approach for solvated biomolecular systems. The chemically important active-site region is treated at the QM level. The biomolecular environment is described by an atomistic MM force field, and the solvent is modeled with the CG Martini force field using standard or polarizable (pol-CG) water. Interactions within the QM, MM, and CG regions, and between the QM and MM regions, are treated in the usual manner, whereas the CG-MM and CG-QM interactions are evaluated using the virtual sites approach. The accuracy and efficiency of our implementation is tested for two enzymes, chorismate mutase (CM) and p-hydroxybenzoate hydroxylase (PHBH). In CM, the QM/MM/CG potential energy scans along the reaction coordinate yield reaction energies that are too large, both for the standard and polarizable Martini CG water models, which can be attributed to adverse effects of using large CG water beads. The inclusion of an atomistic MM water layer (10 Å for uncharged CG water and 5 Å for polarizable CG water) around the QM region improves the energy profiles compared to the reference QM/MM calculations. In analogous QM/MM/CG calculations on PHBH, the use of the pol-CG description for the outer water does not affect the stabilization of the highly charged FADHOOH-pOHB transition state compared to the fully atomistic QM/MM calculations. Detailed performance analysis in a glycine-water model system indicates that computation times for QM energy and gradient evaluations at the density functional level are typically reduced by 40-70% for QM/MM/CG relative to fully atomistic QM/MM calculations.  
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  Call Number AG @ matthewjvarga @ Serial (down) 46216  
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Author Shao, Y.; Gan, Z.; Epifanovsky, E.; Gilbert, A.T.B.; Wormit, M.; Kussmann, J.; Lange, A.W.; Behn, A.; Deng, J.; Feng, X.; Ghosh, D.; Goldey, M.; Horn, P.R.; Jacobson, L.D.; Kaliman, I.; Khaliullin, R.Z.; Kuś, T.; Landau, A.; Liu, J.; Proynov, E.I.; Rhee, Y.M.; Richard, R.M.; Rohrdanz, M.A.; Steele, R.P.; Sundstrom, E.J.; Woodcock, H.L.; Zimmerman, P.M.; Zuev, D.; Albrecht, B.; Alguire, E.; Austin, B.; Beran, G.J.O.; Bernard, Y.A.; Berquist, E.; Brandhorst, K.; Bravaya, K.B.; Brown, S.T.; Casanova, D.; Chang, C.-M.; Chen, Y.; Chien, S.H.; Closser, K.D.; Crittenden, D.L.; Diedenhofen, M.; DiStasio, R.A.; Do, H.; Dutoi, A.D.; Edgar, R.G.; Fatehi, S.; Fusti-Molnar, L.; Ghysels, A.; Golubeva-Zadorozhnaya, A.; Gomes, J.; Hanson-Heine, M.W.D.; Harbach, P.H.P.; Hauser, A.W.; Hohenstein, E.G.; Holden, Z.C.; Jagau, T.-C.; Ji, H.; Kaduk, B.; Khistyaev, K.; Kim, J.; Kim, J.; King, R.A.; Klunzinger, P.; Kosenkov, D.; Kowalczyk, T.; Krauter, C.M.; Lao, K.U.; Laurent, A.D.; Lawler, K.V.; Levchenko, S.V.; Lin, C.Y.; Liu, F.; Livshits, E.; Lochan, R.C.; Luenser, A.; Manohar, P.; Manzer, S.F.; Mao, S.-P.; Mardirossian, N.; Marenich, A.V.; Maurer, S.A.; Mayhall, N.J.; Neuscamman, E.; Oana, C.M.; Olivares-Amaya, R.; O’Neill, D.P.; Parkhill, J.A.; Perrine, T.M.; Peverati, R.; Prociuk, A.; Rehn, D.R.; Rosta, E.; Russ, N.J.; Sharada, S.M.; Sharma, S.; Small, D.W.; Sodt, A.; Stein, T.; Stück, D.; Su, Y.-C.; Thom, A.J.W.; Tsuchimochi, T.; Vanovschi, V.; Vogt, L.; Vydrov, O.; Wang, T.; Watson, M.A.; Wenzel, J.; White, A.; Williams, C.F.; Yang, J.; Yeganeh, S.; Yost, S.R.; You, Z.-Q.; Zhang, I.Y.; Zhang, X.; Zhao, Y.; Brooks, B.R.; Chan, G.K.L.; Chipman, D.M.; Cramer, C.J.; Goddard, W.A.; Gordon, M.S.; Hehre, W.J.; Klamt, A.; Schaefer, H.F.; Schmidt, M.W.; Sherrill, C.D.; Truhlar, D.G.; Warshel, A.; Xu, X.; Aspuru-Guzik, A.; Baer, R.; Bell, A.T.; Besley, N.A.; Chai, J.-D.; Dreuw, A.; Dunietz, B.D.; Furlani, T.R.; Gwaltney, S.R.; Hsu, C.-P.; Jung, Y.; Kong, J.; Lambrecht, D.S.; Liang, W.Z.; Ochsenfeld, C.; Rassolov, V.A.; Slipchenko, L.V.; Subotnik, J.E.; Van Voorhis, T.; Herbert, J.M.; Krylov, A.I.; Gill, P.M.W.; Head-Gordon, M. doi  openurl
  Title Advances in molecular quantum chemistry contained in the Q-Chem 4 program package Type Journal Article
  Year 2015 Publication Abbreviated Journal Molecular Physics  
  Volume 113 Issue 2 Pages 184-215  
  Keywords Q-CHEM computational modelling density functional theory electron correlation electronic structure theory quantum chemistry software  
  Abstract A summary of the technical advances that are incorporated in the fourth major release of the Q-CHEM quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order M\oller--Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr 2 dimer, exploring zeolite-catalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube.  
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  ISSN 0026-8976 ISBN Medium  
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  Notes Times cited: 1649 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46209  
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Author Boulfelfel, S.E.; Ravikovitch, P.I.; Sholl, D.S. doi  openurl
  Title Modeling Diffusion of Linear Hydrocarbons in Silica Zeolite LTA Using Transition Path Sampling Type Journal Article
  Year 2015 Publication Abbreviated Journal The Journal of Physical Chemistry C  
  Volume 119 Issue 27 Pages 15643-15653  
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  Abstract The diffusivities of linear hydrocarbons (CH4, C2H6, C2H4, C3H8, C3H6, and C4H10) in pure silica zeolite LTA (ITQ-29) are computed at 300 K and infinite dilution. To overcome the time scale problem arising from the slow diffusion process at room temperature, we used transition path sampling (TPS). The influence of framework flexibility on diffusion is investigated by combining TPS simulations with fully flexible molecular dynamics performed in the NpT ensemble. The ensemble of the collected reactive trajectories was used to characterize sets of transition states, and the corresponding configurations were analyzed to construct window size distributions during the molecular hopping events. The diffusion process is affected by framework flexibility, and the influence of framework flexibility on diffusion of propane and butane is much larger than for methane and ethane. The diffusivities of linear hydrocarbons (CH4, C2H6, C2H4, C3H8, C3H6, and C4H10) in pure silica zeolite LTA (ITQ-29) are computed at 300 K and infinite dilution. To overcome the time scale problem arising from the slow diffusion process at room temperature, we used transition path sampling (TPS). The influence of framework flexibility on diffusion is investigated by combining TPS simulations with fully flexible molecular dynamics performed in the NpT ensemble. The ensemble of the collected reactive trajectories was used to characterize sets of transition states, and the corresponding configurations were analyzed to construct window size distributions during the molecular hopping events. The diffusion process is affected by framework flexibility, and the influence of framework flexibility on diffusion of propane and butane is much larger than for methane and ethane.  
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  ISSN 1932-7447 ISBN Medium  
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  Notes Times cited: 17 Approved no  
  Call Number AG @ matthewjvarga @ Serial (down) 46121  
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Author Allegretti, A.S.; Hundemer, G.; Chorghade, R.; Cosgrove, K.; Bajwa, E.; Bhan, I. openurl 
  Title Perspectives of continuous renal replacement therapy in the intensive care unit: a paired survey study of patient, physician, and nurse views Type Journal Article
  Year 2015 Publication Abbreviated Journal BMC Nephrol  
  Volume 16 Issue Pages 105  
  Keywords KRESCENT, jclub  
  Abstract BACKGROUND: Recent studies suggest discrepancies between patients and providers around perceptions of hemodialysis prognosis. Such data are lacking for continuous renal replacement therapy (CRRT). We aim to assess patient and provider understanding of outcomes around CRRT.
METHODS: From February 1 to August 31, 2013, a triad of (1) a patient on CRRT (or health care proxy [HCP]), (2) physician and (3) primary nurse from the intensive care unit (ICU) team were surveyed. Univariate chi-square and qualitative analysis techniques were used.
RESULTS: Ninety-six total participants (32 survey triads) were completed. Ninety one percent of patients/HCPs correctly identified that CRRT replaced the function of the kidneys. Six percent of patients/HCPs, 44 % of physicians, and 44 % of nurses identified rates of survival to hospital discharge that were consistent with published literature. Both physicians and nurses were more likely than patients/HCPs to assess survival consistently with published data (p = 0.001). Patients/HCPs were more likely to overestimate survival rates than physicians and nurses (p < 0.001). Thirty eight percent of patients/HCPs, 38 % of physicians, and 28 % of nurses identified rates of lifelong dialysis-dependence among surviving patients that were consistent with published literature.
CONCLUSIONS: There is mismatch between patients, HCPs, and providers around prognosis of CRRT. Patients/HCPs are more likely to overestimate chances of survival than physicians or nurses. Further intervention is needed to improve this knowledge gap.
 
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  Call Number UofT @ mathieu.lemaire @ Serial (down) 46000  
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Author Astanina, K.; Koch, M.; Jüngst, C.; Zumbusch, A.; Kiemer, A.K. url  openurl
  Title Lipid droplets as a novel cargo of tunnelling nanotubes in endothelial cells Type Journal Article
  Year 2015 Publication Abbreviated Journal Sci Rep  
  Volume 5 Issue Pages 11453  
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  Abstract Intercellular communication is a fundamental process in the development and functioning of multicellular organisms. Recently, an essentially new type of intercellular communication, based on thin membrane channels between cells, has been reported. These structures, termed intercellular or tunnelling nanotubes (TNTs), permit the direct exchange of various components or signals (e.g., ions, proteins, or organelles) between non-adjacent cells at distances over 100 μm. Our studies revealed the presence of tunnelling nanotubes in microvascular endothelial cells (HMEC-1). The TNTs were studied with live cell imaging, environmental scanning electron microscopy (ESEM), and coherent anti-Stokes Raman scattering spectroscopy (CARS). Tunneling nanotubes showed marked persistence: the TNTs could connect cells over long distances (up to 150 μm) for several hours. Several cellular organelles were present in TNTs, such as lysosomes and mitochondria. Moreover, we could identify lipid droplets as a novel type of cargo in the TNTs. Under angiogenic conditions (VEGF treatment) the number of lipid droplets increased significantly. Arachidonic acid application not only increased the number of lipid droplets but also tripled the extent of TNT formation. Taken together, our results provide the first demonstration of lipid droplets as a cargo of TNTs and thereby open a new field in intercellular communication research.  
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  ISSN 2045-2322 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial (down) 45959  
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Author Andeen, N.K.; Nguyen, T.Q.; Steegh, F.; Hudkins, K.L.; Najafian, B.; Alpers, C.E. url  openurl
  Title The phenotypes of podocytes and parietal epithelial cells may overlap in diabetic nephropathy Type Journal Article
  Year 2015 Publication Abbreviated Journal Kidney Int  
  Volume 88 Issue 5 Pages 1099-1107  
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  Abstract Reversal of diabetic nephropathy (DN) has been achieved in humans and mice, but only rarely and under special circumstances. As progression of DN is related to podocyte loss, reversal of DN requires restoration of podocytes. Here, we identified and quantified potential glomerular progenitor cells that could be a source for restored podocytes. DN was identified in 31 human renal biopsy cases and separated into morphologically early or advanced lesions. Markers of podocytes (WT-1, p57), parietal epithelial cells (PECs) (claudin-1), and cell proliferation (Ki-67) were identified by immunohistochemistry. Podocyte density was progressively reduced with DN. Cells marking as podocytes (p57) were present infrequently on Bowman’s capsule in controls, but significantly increased in histologically early DN. Ki-67-expressing cells were identified on the glomerular tuft and Bowman’s capsule in DN, but rarely in controls. Cells marking as PECs were present on the glomerular tuft, particularly in morphologically advanced DN. These findings show evidence of phenotypic plasticity in podocyte and PEC populations and are consistent with studies in the BTBR ob/ob murine model in which reversibility of DN occurs with podocytes potentially regenerating from PEC precursors. Thus, our findings support, but do not prove, that podocytes may regenerate from PEC progenitors in human DN. If so, progression of DN may represent a modifiable net balance between podocyte loss and regeneration.  
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  ISSN 0085-2538 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial (down) 45953  
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Author Aiff, H.; Attman, P.O.; Aurell, M.; Bendz, H.; Ramsauer, B.; Schön, S.; Svedlund, J. url  openurl
  Title Effects of 10 to 30 years of lithium treatment on kidney function Type Journal Article
  Year 2015 Publication Abbreviated Journal J Psychopharmacol  
  Volume 29 Issue 5 Pages 608-614  
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  Abstract Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10-29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function.  
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  ISSN 0269-8811 ISBN Medium  
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  Call Number UofT @ mathieu.lemaire @ Serial (down) 45943  
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