13 research outputs found
Roughness of Crack Interfaces in Two-Dimensional Beam Lattices
The roughness of crack interfaces is reported in quasistatic fracture, using
an elastic network of beams with random breaking thresholds. For strong
disorders we obtain 0.86(3) for the roughness exponent, a result which is very
different from the minimum energy surface exponent, i.e., the value 2/3. A
cross-over to lower values is observed as the disorder is reduced, the exponent
in these cases being strongly dependent on the disorder.Comment: 9 pages, RevTeX, 3 figure
Structural insight into repair of alkylated DNA by a new superfamily of DNA glycosylases comprising HEAT-like repeats
3-methyladenine DNA glycosylases initiate repair of cytotoxic and promutagenic alkylated bases in DNA. We demonstrate by comparative modelling that Bacillus cereus AlkD belongs to a new, fifth, structural superfamily of DNA glycosylases with an alpha–alpha superhelix fold comprising six HEAT-like repeats. The structure reveals a wide, positively charged groove, including a putative base recognition pocket. This groove appears to be suitable for the accommodation of double-stranded DNA with a flipped-out alkylated base. Site-specific mutagenesis within the recognition pocket identified several residues essential for enzyme activity. The results suggest that the aromatic side chain of a tryptophan residue recognizes electron-deficient alkylated bases through stacking interactions, while an interacting aspartate–arginine pair is essential for removal of the damaged base. A structural model of AlkD bound to DNA with a flipped-out purine moiety gives insight into the catalytic machinery for this new class of DNA glycosylases
Secretogranin II; a Protein Increased in the Myocardium and Circulation in Heart Failure with Cardioprotective Properties
Background: Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology. Methodology/Principal Findings: SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-beta and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age-and gender-matched control subjects: median 0.16 (Q1-3 0.14-0.18) vs. 0.12 (0.10-0.14) nmol/L, p<0.001. Conclusions: We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker
Prevalence, Employment Rate, and Cost of Schizophrenia in a High-Income Welfare Society: A Population-Based Study Using Comprehensive Health and Welfare Registers
Structural model with proposed active site and lesion recognition pocket of AlkD
<p><b>Copyright information:</b></p><p>Taken from "Structural insight into repair of alkylated DNA by a new superfamily of DNA glycosylases comprising HEAT-like repeats"</p><p></p><p>Nucleic Acids Research 2007;35(7):2451-2459.</p><p>Published online 29 Mar 2007</p><p>PMCID:PMC1874660.</p><p>© 2007 The Author(s)</p> The model contains residues 11 through to 226 and is lacking α-helix α1 and the 11 C-terminal residues (predicted to be disordered). () Cartoon rendering of the protein which comprises 13 α-helices contributing to the six repeats in . () APBS () calculated electrostatic potential mapped onto the protein surface (red = negative, white = neutral and blue = positive) showing the 20–25 Å wide, positively charged, putative DNA binding groove. () Amino acid residue conservation in 43 AlkD homologs mapped onto the space filling representation of the model generated with ConSurf (). The scale extends from magenta (highly conserved), through white to cyan (highly variable). There is a nest of conserved residues in the putative DNA binding groove, and several conserved basic amino acid residues (Arg and Lys) are sited along the upper and lower edge of the groove. () Stereo view of a close-up of the highly conserved nest shows the eight conserved residues that were mutated by site-directed mutagenesis. The catalytic activity and MMS sensitivity of the resulting mutants were determined (). The eight conserved residues have identical geometry in the experimental structure 2B6C. The orientation of the protein in space is identical in all panels. The model is also available as Supplementary Video 1 online