Unmet need for the treatment of depression in Atlantic Canada

Objective: Most people with depression do not receive treatment, even though effective interventions are available. Population-based data can assist health service planners to improve access to mental health services. This study aimed to examine the determinants of untreated depression in Canada's Atlantic provinces

Cysteinyl-tRNA Deacylation Can Be Uncoupled from Protein Synthesis

Aminoacyl-tRNA synthetases (ARSs) are critical components of protein translation, providing ribosomes with aminoacyl-tRNAs. In return, ribosomes release uncharged tRNAs as ARS substrates. Here, we show that tRNA deacylation can be uncoupled from protein synthesis in an amino acid specific manner. While tRNAs coupled to radiolabeled Met, Leu Lys, or Ser are stable in cells following translation inhibition with arsenite, radiolabeled Cys is released from tRNA at a high rate. We discuss possible translation independent functions for tRNACys

The hidden horizon and black hole unitarity

We motivate through a detailed analysis of the Hawking radiation in a Schwarzschild background a scheme in accordance with quantum unitarity. In this scheme the semi-classical approximation of the unitary quantum - horizonless - black hole S-matrix leads to the conventional description of the Hawking radiation from a classical black hole endowed with an event horizon. Unitarity is borne out by the detailed exclusive S-matrix amplitudes. There, the fixing of generic out-states, in addition to the in-state, yields in asymptotic Minkowski space-time saddle-point contributions which are dominated by Planckian metric fluctuations when approaching the Schwarzschild radius. We argue that these prevent the corresponding macroscopic "exclusive backgrounds" to develop an event horizon. However, if no out-state is selected, a distinct saddle-point geometry can be defined, in which Planckian fluctuations are tamed. Such "inclusive background" presents an event horizon and constitutes a coarse-grained average over the aforementioned exclusive ones. The classical event horizon appears as a coarse-grained structure, sustaining the thermodynamic significance of the Bekenstein-Hawking entropy. This is reminiscent of the tentative fuzzball description of extremal black holes: the role of microstates is played here by a complete set of out-states. Although the computations of unitary amplitudes would require a detailed theory of quantum gravity, the proposed scheme itself, which appeals to the metric description of gravity only in the vicinity of stationary points, does not.Comment: 29 pages, 4 figures. Typos corrected. Two footnotes added (footnotes 3 and 5

Association of a Bovine Prion Gene Haplotype with Atypical BSE

Background: Atypical bovine spongiform encephalopathies (BSEs) are recently recognized prion diseases of cattle. Atypical BSEs are rare; approximately 30 cases have been identified worldwide. We tested prion gene (PRNP) haplotypes for an association with atypical BSE. Methodology/Principle Findings: Haplotype tagging polymorphisms that characterize PRNP haplotypes from the promoter region through the three prime untranslated region of exon 3 (25.2 kb) were used to determine PRNP haplotypes of six available atypical BSE cases from Canada, France and the United States. One or two copies of a distinct PRNP haplotype were identified in five of the six cases (p = 1.36×10-4, two-tailed Fisher’s exact test; CI95% 0.263–0.901, difference between proportions). The haplotype spans a portion of PRNP that includes part of intron 2, the entire coding region of exon 3 and part of the three prime untranslated region of exon 3 (13 kb). Conclusions/Significance: This result suggests that a genetic determinant in or near PRNP may influence susceptibility of cattle to atypical BSE

Dictyostelium discoideum as a Model to Study Inositol Polyphosphates and Inorganic Polyphosphate

The yeast Saccharomyces cerevisiae has given us much information on the metabolism and function of inositol polyphosphates and inorganic polyphosphate. To expand our knowledge of the metabolic as well as functional connections between inositol polyphosphates and inorganic polyphosphate, we have refined and developed techniques to extract and analyze these molecules in a second eukaryotic experimental model, the amoeba Dictyostelium discoideum. This amoeba, possessing a well-defined developmental program, is ideal to study physiological changes in the levels of inositol polyphosphates and inorganic polyphosphate, since levels of both molecules increase at late stages of development. We detail here the methods used to extract inositol polyphosphates using perchloric acid and inorganic polyphosphate using acidic phenol. We also present the postextraction procedures to visualize and quantify these molecules by polyacrylamide gel electrophoresis and by malachite green assay

Strong signature of natural selection within an FHIT intron implicated in prostate cancer risk

Previously, a candidate gene linkage approach on brother pairs affected with prostate cancer identified a locus of prostate cancer susceptibility at D3S1234 within the fragile histidine triad gene (FHIT), a tumor suppressor that induces apoptosis. Subsequent association tests on 16 SNPs spanning approximately 381 kb surrounding D3S1234 in Americans of European descent revealed significant evidence of association for a single SNP within intron 5 of FHIT. In the current study, resequencing and genotyping within a 28.5 kb region surrounding this SNP further delineated the association with prostate cancer risk to a 15 kb region. Multiple SNPs in sequences under evolutionary constraint within intron 5 of FHIT defined several related haplotypes with an increased risk of prostate cancer in European-Americans. Strong associations were detected for a risk haplotype defined by SNPs 138543, 142413, and 152494 in all cases (Pearson's χ2 = 12.34, df 1, P = 0.00045) and for the homozygous risk haplotype defined by SNPs 144716, 142413, and 148444 in cases that shared 2 alleles identical by descent with their affected brothers (Pearson's χ2 = 11.50, df 1, P = 0.00070). In addition to highly conserved sequences encompassing SNPs 148444 and 152413, population studies revealed strong signatures of natural selection for a 1 kb window covering the SNP 144716 in two human populations, the European American (π = 0.0072, Tajima's D= 3.31, 14 SNPs) and the Japanese (π = 0.0049, Fay & Wu's H = 8.05, 14 SNPs), as well as in chimpanzees (Fay & Wu's H = 8.62, 12 SNPs). These results strongly support the involvement of the FHIT intronic region in an increased risk of prostate cancer. © 2008 Ding et al

Association analysis of PRNP gene region with chronic wasting disease in Rocky Mountain elk

<p>Abstract</p> <p>Background</p> <p>Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) of cervids including white-tailed (<it>Odocoileus virginianus</it>) and mule deer (<it>Odocoileus hemionus</it>), Rocky Mountain elk (<it>Cervus elaphus nelsoni</it>), and moose (<it>Alces alces</it>). A leucine variant at position 132 (132L) in prion protein of Rocky Mountain elk confers a long incubation time with CWD, but not complete resistance. However, variants in regulatory regions outside the open reading frame of <it>PRNP </it>have been associated with varying degrees of susceptibility to prion disease in other species, and some variants have been observed in similar regions of Rocky Mountain elk <it>PRNP</it>. Thus, additional genetic variants might provide increased protection, either alone or in combination with 132L.</p> <p>Findings</p> <p>This study provided genomic sequence of all exons for <it>PRNP </it>of Rocky Mountain elk. Many functional sites in and around the <it>PRNP </it>gene region were sequenced, and this report approximately doubled (to 75) the number of known variants in this region. A haplotype-tagging approach was used to reduce the number of genetic variants required to survey this variation in the <it>PRNP </it>gene region of 559 Rocky Mountain elk. Eight haplotypes were observed with frequencies over 1.0%, and one haplotype was present at 71.2% frequency, reflecting limited genetic diversity in the <it>PRNP </it>gene region.</p> <p>Conclusions</p> <p>The presence of 132L cut odds of CWD by more than half (Odds Ratio = 0.43; P = 0.0031), which was similar to a previous report. However after accounting for 132L, no association with CWD was found for any additional variants in the <it>PRNP </it>region (P > 0.05).</p

Potentiation of thrombus instability: a contributory mechanism to the effectiveness of antithrombotic medications

© The Author(s) 2018The stability of an arterial thrombus, determined by its structure and ability to resist endogenous fibrinolysis, is a major determinant of the extent of infarction that results from coronary or cerebrovascular thrombosis. There is ample evidence from both laboratory and clinical studies to suggest that in addition to inhibiting platelet aggregation, antithrombotic medications have shear-dependent effects, potentiating thrombus fragility and/or enhancing endogenous fibrinolysis. Such shear-dependent effects, potentiating the fragility of the growing thrombus and/or enhancing endogenous thrombolytic activity, likely contribute to the clinical effectiveness of such medications. It is not clear how much these effects relate to the measured inhibition of platelet aggregation in response to specific agonists. These effects are observable only with techniques that subject the growing thrombus to arterial flow and shear conditions. The effects of antithrombotic medications on thrombus stability and ways of assessing this are reviewed herein, and it is proposed that thrombus stability could become a new target for pharmacological intervention.Peer reviewedFinal Published versio