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71.
Schultz Jel J Glascock BJ Witt SA Nieman ML Nattamai KJ Liu LH Lorenz JN Shull GE Kimball TR Periasamy M 《American journal of physiology. Heart and circulatory physiology》2004,286(3):H1146-H1153
We recently developed a mouse model with a single functional allele of Serca2 (Serca2+/-) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/- mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that approximately 64% of coarcted Serca2+/- mice were in heart failure compared with 0% of coarcted wild-type mice (P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/- mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/- mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/- mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice (P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/- mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure. 相似文献
72.
Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors 总被引:4,自引:0,他引:4
Han Y Giroux A Grimm EL Aspiotis R Francoeur S Bayly CI Mckay DJ Roy S Xanthoudakis S Vaillancourt JP Rasper DM Tam J Tawa P Thornberry NA Paterson EP Garcia-Calvo M Becker JW Rotonda J Nicholson DW Zamboni RJ 《Bioorganic & medicinal chemistry letters》2004,14(3):805-808
The discovery of a series of potent, selective and reversible dipeptidyl caspase-3 inhibitors are reported. The iterative discovery process of using combinatorial chemistry, parallel synthesis, moleculare modelling and structural biology will be discussed. 相似文献
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Intermediate filaments, actin-containing microfilaments and microtubules are the three main cytoskeletal systems of vertebrate and many invertebrate cells. Although these systems are composed of distinctly different proteins, they are in constant and intimate communication with one another. Understanding the molecular basis of this cytoskeletal crosstalk is essential for determining the mechanisms that underlie many cell-biological phenomena. Recent studies have revealed that intermediate filaments and their associated proteins are important components in mediating this crosstalk. 相似文献
77.
Wu X Yang S Njus JM Nagarajan R Cholli AL Samuelson LA Kumar J 《Biomacromolecules》2004,5(4):1214-1218
The ability to control conformational properties of polypeptides in their films is of considerable interest for many possible applications of these materials. By rational choice of the solvent system for film fabrication, control over the conformation of the main chain, the intermolecular hydrogen bonding in the side chain is easily achieved in poly(alpha-L-glutamic acid) (PLGA) thin films. The spectral data from circular dichromism (CD), FT-IR, and solid state (13)C NMR spectroscopies suggest that the beta-sheet conformation is dominant in PLGA films cast from trifluoroacetic acid (TFA) solution, whereas the right-handed alpha-helix is dominant in those cast from pyridine or DMF solution. In comparison with films cast from TFA solutions, the films fabricated from pyridine or DMF solutions exhibit strong intermolecular hydrogen bondings between -COOH groups and have a more ordered arrangement of side chains. Moreover, the extent of alpha-helix conformation of the PLGA backbone in films cast from pyridine or DMF solution is several times higher than that observed in the PLGA powder precipitated from aqueous solution at pH 4. All spectroscopic studies indicate clearly that the solvents (used for casting these films) play a crucial role in directing the organization of PLGA in these thin films. 相似文献
78.
Evidence for sympatric speciation by host shift in the sea 总被引:1,自引:0,他引:1
The genetic divergence and evolution of new species within the geographic range of a single population (sympatric speciation) contrasts with the well-established doctrine that speciation occurs when populations become geographically isolated (allopatric speciation). Although there is considerable theoretical support for sympatric speciation, this mode of diversification remains controversial, at least in part because there are few well-supported examples. We use a combination of molecular, ecological, and biogeographical data to build a case for sympatric speciation by host shift in a new species of coral-dwelling fish (genus Gobiodon). We propose that competition for preferred coral habitats drives host shifts in Gobiodon and that the high diversity of corals provides the source of novel, unoccupied habitats. Disruptive selection in conjunction with strong host fidelity could promote rapid reproductive isolation and ultimately lead to species divergence. Our hypothesis is analogous to sympatric speciation by host shift in phytophagous insects except that we propose a primary role for intraspecific competition in the process of speciation. The fundamental similarity between these fishes and insects is a specialized and intimate relationship with their hosts that makes them ideal candidates for speciation by host shift. 相似文献
79.
The NIMA kinases are an evolutionarily conserved protein family with enigmatic roles in the regulation of mitosis. We report six new members of this family in Chlamydomonas, in addition to the previously identified NIMA-related kinase, Fa2p. Chlamydomonas NIMA-related kinases (CNKs) 1-6 were sequenced from subclones generated by RT-PCR using information from EST libraries and the recently sequenced Chlamydomonas genome. Phylogenetic and bioinformatic approaches were used to determine the relationships of the six new members with known members of the NIMA-related kinase family. Although humans express at least eleven NIMA-related kinases, the eukaryotic microbes that have been studied to date express only one or two members of the family. Thus, the discovery that Chlamydomonas expresses a total of at least seven NIMA-related kinases is intriguing. Our analyses suggest that members of this family may play roles in the assembly and function of cilia. 相似文献
80.
Rab11-family interacting protein 2 and myosin Vb are required for CXCR2 recycling and receptor-mediated chemotaxis 总被引:9,自引:0,他引:9 下载免费PDF全文
Fan GH Lapierre LA Goldenring JR Sai J Richmond A 《Molecular biology of the cell》2004,15(5):2456-2469
Agonist-stimulated internalization followed by recycling to the cell membrane play an important role in fine-tuning the activity of chemokine receptors. Because the recycling of chemokine receptors is critical for the reestablishment of the cellular responsiveness to ligand, it is crucial to understand the mechanisms underlying the receptor recycling and resensitization. In the present study, we have demonstrated that the chemokine receptor CXCR2 associated with myosin Vb and Rab11-family interacting protein 2 (FIP2) in a ligand-dependent manner. Truncation of the C-terminal domain of the receptor did not affect the association, suggesting that the interactions occur upstream of the C terminus of CXCR2. After ligand stimulation, the internalized CXCR2 colocalized with myosin Vb and Rab11-FIP2 in Rab11a-positive vesicles. The colocalization lasted for approximately 2 h, and little colocalization was observed after 4 h of ligand stimulation. CXCR2 also colocalized with myosin Vb tail or Rab11-FIP2 (129-512), the N-terminal-truncated mutants of myosin Vb and Rab11-FIP2, respectively, but in a highly condensed manner. Expression of the enhanced green fluorescent protein-tagged myosin Vb tail significantly retarded the recycling and resensitization of CXCR2. CXCR2 recycling was also reduced by the expression Rab11-FIP2 (129-512). Moreover, expression of the myosin Vb tail reduced CXCR2- and CXCR4-mediated chemotaxis. These data indicate that Rab11-FIP2 and myosin Vb regulate CXCR2 recycling and receptor-mediated chemotaxis and that passage of internalized CXCR2 through Rab11a-positive recycling system is critical for physiological response to a chemokine. 相似文献