Détection et analyse de motifs structuraux et fonctionnels dans les acides ribonucléiques

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Restoration of mitochondrial integrity, telomere length, and sensitivity to oxidation by in vitro culture of Fuchs’ endothelial corneal dystrophy cells

PURPOSE. Fuchs’ endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium that leads to vision loss, is a leading cause of corneal transplantation. The cause of this disease is still unknown, but the implication of oxidative stress is strongly suggested. In this study, we analyzed the impact of FECD on mitochondrial DNA (mtDNA) integrity and telomere length, both of which are affected by the oxidative status of the cell. METHODS. We compared the levels of total mtDNA, mtDNA common deletion (4977 bp), and relative telomere length in the corneal endothelial cells of fresh Descemet’s membraneendothelium explants and cultured cells from healthy and late stage FECD subjects. Oxidantantioxidant gene expression and sensitivity to ultraviolet A (UVA)- and H2O2-induced cell death were assessed in cultured cells. RESULTS. Our results revealed increased mtDNA levels and telomere shortening in FECD explants. We also found that cell culture restores a normal phenotype in terms of mtDNA levels, telomere length, oxidant-antioxidant gene expression balance, and sensitivity to oxidative stress-induced cell death in the FECD cells compared with the healthy cells. CONCLUSIONS. Taken together, these results bring new evidence of the implication of oxidative stress in FECD. They also show that FECD does not evenly affect the integrity of corneal endothelial cells and that cell culture can rehabilitate the molecular phenotypes related to oxidative stress by selecting the more functional FECD cells

Probing the Local Magnetic Structure of the [FeIII(Tp)(CN)3]- Building Block Via Solid-State NMR Spectroscopy, Polarized Neutron Diffraction, and First-Principle Calculations

International audienceThe local magnetic structure in the [Fe (Tp)(CN) ] building block was investigated by combining paramagnetic Nuclear Magnetic Resonance (pNMR) spectroscopy and polarized neutron diffraction (PND) with first-principle calculations. The use of the pNMR and PND experimental techniques revealed the extension of spin-density from the metal to the ligands, as well as the different spin mechanisms that take place in the cyanido ligands Spin-polarization on the carbon atoms and spin-delocalization on the nitrogen atoms. The results of our combined density functional theory (DFT) and multireference calculations were found in good agreement with the PND results and the experimental NMR chemical shifts. Moreover, the ab-initio calculations allowed us to connect the experimental spin-density map characterized by PND and the suggested distribution of the spin-density on the ligands observed by NMR spectroscopy. Interestingly, significant differences were observed between the pseudo-contact contributions of the chemical shifts obtained by theoretical calculations and the values derived from NMR spectroscopy using a simple point-dipole model. These discrepancies underline the limitation of the point-dipole model and the need for more elaborate approaches to break down the experimental pNMR chemical shifts into contact and pseudo-contact contributions

Assessment of tumor redox status through (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid positron emission tomography imaging of system xc- activity

The cell's endogenous antioxidant system is vital to maintenance of redox homeostasis. Despite its central role in normal and pathophysiology, no non-invasive tools exist to measure this system in patients. The cystine/glutamate antiporter system xc- maintains the balance between intracellular reactive oxygen species and antioxidant production through the provision of cystine, a key precursor in glutathione biosynthesis. Here we show that tumor cell retention of a system xc--specific positron emission tomography radiotracer, (S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG), decreases in proportion to levels of oxidative stress following treatment with a range of redox-active compounds. The decrease in [18F]FSPG retention correlated with a depletion of intracellular cystine resulting from increased de novo glutathione biosynthesis, shown through [U-13C6, U-15N2]cystine isotopic tracing. In vivo, treatment with the chemotherapeutic doxorubicin decreased [18F]FSPG tumor uptake in a mouse model of ovarian cancer, coinciding with markers of oxidative stress but preceding tumor shrinkage and decreased glucose utilization. Having already been used in pilot clinical trials, [18F]FSPG PET could be rapidly translated to the clinic as an early redox indicator of tumor response to treatment

Sequence–structure relationships in RNA loops: establishing the basis for loop homology modeling

The specific function of RNA molecules frequently resides in their seemingly unstructured loop regions. We performed a systematic analysis of RNA loops extracted from experimentally determined three-dimensional structures of RNA molecules. A comprehensive loop-structure data set was created and organized into distinct clusters based on structural and sequence similarity. We detected clear evidence of the hallmark of homology present in the sequence–structure relationships in loops. Loops differing by <25% in sequence identity fold into very similar structures. Thus, our results support the application of homology modeling for RNA loop model building. We established a threshold that may guide the sequence divergence-based selection of template structures for RNA loop homology modeling. Of all possible sequences that are, under the assumption of isosteric relationships, theoretically compatible with actual sequences observed in RNA structures, only a small fraction is contained in the Rfam database of RNA sequences and classes implying that the actual RNA loop space may consist of a limited number of unique loop structures and conserved sequences. The loop-structure data sets are made available via an online database, RLooM. RLooM also offers functionalities for the modeling of RNA loop structures in support of RNA engineering and design efforts

Improving Tree-Thinking One Learnable Skill at a Time

Introducerande artikel inom Läslyftsmodulen Från Vardagsspråk till ÄmnesspråkIntroduction to language sensitive teaching a s part of a Skolverket professional development module in the program Reading Boost

Replicable parallel branch and bound search

Combinatorial branch and bound searches are a common technique for solving global optimisation and decision problems. Their performance often depends on good search order heuristics, refined over decades of algorithms research. Parallel search necessarily deviates from the sequential search order, sometimes dramatically and unpredictably, e.g. by distributing work at random. This can disrupt effective search order heuristics and lead to unexpected and highly variable parallel performance. The variability makes it hard to reason about the parallel performance of combinatorial searches. This paper presents a generic parallel branch and bound skeleton, implemented in Haskell, with replicable parallel performance. The skeleton aims to preserve the search order heuristic by distributing work in an ordered fashion, closely following the sequential search order. We demonstrate the generality of the approach by applying the skeleton to 40 instances of three combinatorial problems: Maximum Clique, 0/1 Knapsack and Travelling Salesperson. The overheads of our Haskell skeleton are reasonable: giving slowdown factors of between 1.9 and 6.2 compared with a class-leading, dedicated, and highly optimised C++ Maximum Clique solver. We demonstrate scaling up to 200 cores of a Beowulf cluster, achieving speedups of 100x for several Maximum Clique instances. We demonstrate low variance of parallel performance across all instances of the three combinatorial problems and at all scales up to 200 cores, with median Relative Standard Deviation (RSD) below 2%. Parallel solvers that do not follow the sequential search order exhibit far higher variance, with median RSD exceeding 85% for Knapsack

Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism

We have recently reported that the bioactive lipid sphingosine-1-phosphate (S1P), usually signaling proliferation and anti-apoptosis induces neuronal death when generated by sphingosine-kinase2 and when accumulation due to S1P-lyase deficiency occurs. In the present study, we identify the signaling cascade involved in the neurotoxic effect of sphingoid-base phosphates. We demonstrate that the calcium-dependent cysteine protease calpain mediates neurotoxicity by induction of the endoplasmic reticulum stress-specific caspase cascade and activation of cyclin-dependent kinase5 (CDK5). The latter is involved in an abortive reactivation of the cell cycle and also enhances tau phosphorylation. Neuroanatomical studies in the cerebellum document for the first time that indeed neurons with abundant S1P-lyase expression are those, which degenerate first in S1P-lyase-deficient mice. We therefore propose that an impaired metabolism of glycosphingolipids, which are prevalent in the central nervous system, might be linked via S1P, their common catabolic intermediate, to neuronal death

United We Stand, Divided We Fall: Historical Trajectory of Strategic Renewal Activities at Scandinavian Airlines System, 1946-2012

Although the second half of the twentieth century saw the rise and fall of ‘multi-flag companies’ in the civil aviation industry, our understanding of how some managed to buck the trend and achieve longevity remains limited. This paper advances business history and strategic management research by examining the strategic renewal activities of Scandinavian Airlines (formerly Scandinavian Airlines System) during the period 1946-2012. The study sheds light on the key roles of private and state owners, rivals as well as banks, in critical financial phases are discussed in terms of longevity in the company. The longevity of the business stems from the leaders’ ability to develop as anticipated and respond to change in their competitive arena in close interaction with the owners. Thus, incumbent firms that strategically renew themselves prior to or during market reform, such as deregulation, enhance their chances of developing the size of their networks and revenue streams. Our main contribution to business history and strategic management literatures is the development of context-specific stages, which shed light on the evolution of strategic renewal activities and shifts from older processes and routines towards customer service and efficiency