The effect of missense mutations was assessed using in EPZ5676 silico predictions and protein modeling. Risk effects of common genetic variants were estimated by logistic regression analysis and gene-based haplotype association analysis.\n\nResults: We observed seven missense mutations in eight patients (1.3%). Convincing pathogenic evidence was obtained for two missense mutations, p. Cys139Arg and p. Pro451Leu, affecting PGRN protein folding and leading to loss of PGRN by degradation of the misfolded protein. In addition, we showed that PGRN haplotypes were associated with increased risk for AD.\n\nConclusions: Our data support a role for PGRN in patients with clinically diagnosed Alzheimer disease (AD).

Further, we hypothesize that at least some PGRN missense

mutations might lead to loss of functional protein. Whether the underlying pathology in our cases proves to be AD, frontotemporal lobar degeneration, or a combination of the two must await further investigations.”
“Potentially mutagenic impurities in new pharmaceuticals are controlled to levels with negligible risk, the TTC (threshold of toxicological concern, 1.5 mu g/day for a lifetime). The TTC was based on the more potent rodent carcinogens, excluding NCT-501 the highly potent “cohort of concern” (COC; for mutagenic carcinogens these are N-nitroso, Aflatoxin-like, and azoxy structures). We compared molecules with DEREK “structural check details alerts” for mutagenicity used in drug syntheses with the mutagenic carcinogens in the Gold Carcinogenicity Potency Database. Data from 108 diverse synthetic routes from 13 companies confirm that many “alerting” or mutagenic chemicals are in structural classes with lower carcinogenic potency than those used to derive the TTC. Acceptable daily intakes can be established that are higher than the default TTC for many structural classes (e.g., mono-functional alkyl halides and certain aromatic amines). Examples of ADIs for lifetime and shorter-term exposure are given for chemicals of various potencies. The percentage

of chemicals with DEREK 123 alerts that proved mutagenic in the Ames test ranged from 36% to 83%, depending on structural class, demonstrating that such SAR analysis to “flag” potential mutagens is conservative. We also note that aromatic azoxy compounds need not be classed as COC, which was based on alkyl azoxy chemicals. (C) 2013 Elsevier Inc. All rights reserved.”
“Sea ice can contain high concentrations of dissolved organic carbon (DOC), much of which is carbohydrate-rich extracellular polymeric substances (EPS) produced by microalgae and bacteria inhabiting the ice. Here we report the concentrations of dissolved carbohydrates (dCHO) and dissolved EPS (dEPS) in relation to algal standing stock [estimated by chlorophyll (Chl) a concentrations] in sea ice from six locations in the Southern and Arctic Oceans.