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61.
Beaulieu C Isabel E Fortier A Massé F Mellon C Méthot N Ndao M Nicoll-Griffith D Lee D Park H Black WC 《Bioorganic & medicinal chemistry letters》2010,20(24):7444-7449
Identification of potent and reversible cruzipain inhibitors for the treatment of Chagas disease is described. The identified inhibitors bearing an amino nitrile warhead in P1 exhibit low nanomolar in vitro potency against cruzipain. Further SAR in P2 portion led to the identification of compounds, such as 26, that have a unique selectivity profile against other cysteine proteases and offering new opportunities for safer treatment of Chagas disease. 相似文献
62.
The identification of new diagnostic or prognostic biomarkers is one of the main aims of clinical cancer research. In recent years, there has been a growing interest in using mass spectrometry for the detection of such biomarkers. The MS signal resulting from MALDI‐TOF measurements is contaminated by different sources of technical variations that can be removed by a prior pre‐processing step. In particular, denoising makes it possible to remove the random noise contained in the signal. Wavelet methodology associated with thresholding is usually used for this purpose. In this study, we adapted two multivariate denoising methods that combine wavelets and PCA to MS data. The objective was to obtain better denoising of the data so as to extract the meaningful proteomic biological information from the raw spectra and reach meaningful clinical conclusions. The proposed methods were evaluated and compared with the classical soft thresholding denoising method using both real and simulated data sets. It was shown that taking into account common structures of the signals by adding a dimension reduction step on approximation coefficients through PCA provided more effective denoising when combined with soft thresholding on detail coefficients. 相似文献
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65.
Stewart EM Aquilina JA Easterbrook-Smith SB Murphy-Durland D Jacobsen C Moestrup S Wilson MR 《Biochemistry》2007,46(5):1412-1422
Clusterin is the first well characterized, constitutively secreted extracellular chaperone that binds to exposed regions of hydrophobicity on non-native proteins. It may help control the folding state of extracellular proteins by targeting them for receptor-mediated endocytosis and intracellular lysosomal degradation. A notable feature of secreted clusterin is its heavy glycosylation. Although carbohydrate comprises approximately 20-25% of the total mass of the mature molecule, its function is unknown. Results from the current study demonstrate that deglycosylation of human serum clusterin had little effect on its overall secondary structure content but produced a small increase in solvent-exposed hydrophobicity and enhanced the propensity of the molecule to aggregate in solution. These changes were associated with increased binding to a variety of ligands but did not substantially impact the ability of clusterin to inhibit heat-induced precipitation of citrate synthase. Evidence suggesting that the normally conjugated sugars are important in the interaction of secreted clusterin with a lectin-type receptor on liver cells is also presented. Bulk expression of fully processed, glycosylated clusterin in mammalian cells is difficult, often producing inappropriately disulfide-bonded high molecular weight aggregates; this has hampered previous studies aimed at identifying those regions of the molecule important in its chaperone action. The current results suggest that it may be possible in the future to study the structure and chaperone function of clusterin using recombinant protein (lacking sugars) conveniently bulk-expressed in bacteria. 相似文献
66.
B. Thouvenin J. L. Gonzalez J. F. Chiffoleau B. Boutier P. Le Hir 《Hydrobiologia》2007,588(1):109-124
The Seine estuary (France) is currently one of the world’s most contaminated estuaries, due in particular to its high cadmium
and lead content. Proper understanding of contaminant transfer, transformation and retention mechanisms throughout the estuary
and up to the adjacent marine zone require a range of studies involving data collections, experiments, and modeling tool.
A multivariable transport model (SiAM-3D) was used to simulate dissolved and particulate transport and it is applied to several
calculation grids; a speciation model (MOCO) was used to select key species and obtain a schematic system representation.
The coupled model for Cd and Pb was compared with field measurements. The complementary character of various tools (model
applied to annual time scale, in situ measurements and experiments) allowed to explore and quantify various hypotheses on
the high dissolved cadmium concentrations observed during low river flow. The target is to achieve a compromise between acceptable
computing times and adequate result accuracy. Although particle and contaminant behaviour is globally well-reproduced by the
coarse grid, calculation errors relating to bayward fluxes and stocks deposited inside the estuary were highlighted after
comparison with the fine grid. 相似文献
67.
Listening to classical and self-selected relaxing music after exposure to a stressor should result in significant reductions in anxiety, anger, and sympathetic nervous system arousal, and increased relaxation compared to those who sit in silence or listen to heavy metal music. Fifty-six college students, 15 males and 41 females, were exposed to different types of music genres after experiencing a stressful test. Several 4 x 2 mixed design analyses of variance were conducted to determine the effects of music and silence conditions (heavy metal, classical, or self-selected music and silence) and time (pre-post music) on emotional state and physiological arousal. Results indicate listening to self-select or classical music, after exposure to a stressor, significantly reduces negative emotional states and physiological arousal compared to listening to heavy metal music or sitting in silence. 相似文献
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69.
Daniel C. Teasley Shankar Parajuli Mai Nguyen Hayley R. Moore Elise Alspach Ying Jie Lock Yuchi Honaker Abhishek Saharia Helen Piwnica-Worms Sheila A. Stewart 《The Journal of biological chemistry》2015,290(24):15133-15145
The existence of redundant replication and repair systems that ensure genome stability underscores the importance of faithful DNA replication. Nowhere is this complexity more evident than in challenging DNA templates, including highly repetitive or transcribed sequences. Here, we demonstrate that flap endonuclease 1 (FEN1), a canonical lagging strand DNA replication protein, is required for normal, complete leading strand replication at telomeres. We find that the loss of FEN1 nuclease activity, but not DNA repair activities, results in leading strand-specific telomere fragility. Furthermore, we show that FEN1 depletion-induced telomere fragility is increased by RNA polymerase II inhibition and is rescued by ectopic RNase H1 expression. These data suggest that FEN1 limits leading strand-specific telomere fragility by processing RNA:DNA hybrid/flap intermediates that arise from co-directional collisions occurring between the replisome and RNA polymerase. Our data reveal the first molecular mechanism for leading strand-specific telomere fragility and the first known role for FEN1 in leading strand DNA replication. Because FEN1 mutations have been identified in human cancers, our findings raise the possibility that unresolved RNA:DNA hybrid structures contribute to the genomic instability associated with cancer. 相似文献
70.
Sundari Chetty Elise N. Engquist Elie Mehanna Kathy O. Lui Alexander M. Tsankov Douglas A. Melton 《The Journal of cell biology》2015,210(7):1257-1268
Driving human pluripotent stem cells (hPSCs) into specific lineages is an inefficient and challenging process. We show that a potent Src inhibitor, PP1, regulates expression of genes involved in the G1 to S phase transition of the cell cycle, activates proteins in the retinoblastoma family, and subsequently increases the differentiation propensities of hPSCs into all three germ layers. We further demonstrate that genetic suppression of Src regulates the activity of the retinoblastoma protein and enhances the differentiation potential of hPSCs across all germ layers. These positive effects extend beyond the initial germ layer specification and enable efficient differentiation at subsequent stages of differentiation. 相似文献