The Interactome of Palmitoyl-Protein Thioesterase 1 (PPT1) Affects Neuronal Morphology and Function

Palmitoyl-protein thioesterase 1 (PPT1) is a depalmitoylation enzyme that is mutated in cases of neuronal ceroid lipofuscinosis (NCL). The hallmarks of the disease include progressive neurodegeneration and blindness, as well as seizures. In the current study, we identified 62 high-confident PPT1-binding proteins. These proteins included a self-interaction of PPT1, two V-type ATPases, calcium voltage-gated channels, cytoskeletal proteins and others. Pathway analysis suggested their involvement in seizures and neuronal morphology. We then proceeded to demonstrate that hippocampal neurons from Ppt1-/- mice exhibit structural deficits, and further investigated electrophysiology parameters in the hippocampi of mutant mice, both in brain slices and dissociated postnatal primary cultures. Our studies reveal new mechanistic features involved in the pathophysiology of this devastating neurodegenerative disease

Postglacial Colonisation Patterns and the Role of Isolation and Expansion in Driving Diversification in a Passerine Bird

Pleistocene glacial cycles play a major role in diversification and speciation, although the relative importance of isolation and expansion in driving diversification remains debated. We analysed mitochondrial DNA sequence data from 15 great reed warbler (Acrocephalus arundinaceus) populations distributed over the vast Eurasian breeding range of the species, and revealed unexpected postglacial expansion patterns from two glacial refugia. There were 58 different haplotypes forming two major clades, A and B. Clade A dominated in Western Europe with declining frequencies towards Eastern Europe and the Middle East, but showed a surprising increase in frequency in Western and Central Asia. Clade B dominated in the Middle East, with declining frequencies towards north in Central and Eastern Europe and was absent from Western Europe and Central Asia. A parsimonious explanation for these patterns is independent postglacial expansions from two isolated refugia, and mismatch distribution analyses confirmed this suggestion. Gene flow analyses showed that clade A colonised both Europe and Asia from a refugium in Europe, and that clade B expanded much later and colonised parts of Europe from a refugium in the Middle East. Great reed warblers in the eastern parts of the range have slightly paler plumage than western birds (sometimes treated as separate subspecies; A. a. zarudnyi and A. a. arundinaceus, respectively) and our results suggest that the plumage diversification took place during the easterly expansion of clade A. This supports the postglacial expansion hypothesis proposing that postglacial expansions drive diversification in comparatively short time periods. However, there is no indication of any (strong) reproductive isolation between clades and our data show that the refugia populations became separated during the last glaciation. This is in line with the Pleistocene speciation hypothesis invoking that much longer periods of time in isolation are needed for speciation to occur

Prothrombin time is predictive of low plasma prothrombin concentration and clinical outcome in patients with trauma hemorrhage: analyses of prospective observational cohort studies

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Analyses of data previously generated through ACIT and DIA-TRE-TIC studies was funded by AstraZeneca R&D Gothenburg, Sweden

Genetic Polymorphisms of CYP2E1, GSTP1, NQO1 and MPO and the Risk of Nasopharyngeal Carcinoma in a Han Chinese Population of Southern China

<p>Abstract</p> <p>Background</p> <p>Southern China is a major area for endemic nasopharyngeal carcinoma (NPC). Genetic factors as well as environmental factors play a role in development of NPC. To investigate the roles of previously described carcinogen metabolism gene variants for NPC susceptibility in a Han Chinese population, we conducted a case-control study in two independent study population groups afflicted with NPC in Guangdong and Guangxi Provinces of southern China.</p> <p>Methods</p> <p>Five single nucleotide polymorphisms (SNPs) of <it>CYP2E1</it>-rs2031920, <it>CYP2E1</it>-rs6413432, <it>GSTP1</it>-rs947894, <it>MPO</it>-rs2333227 and <it>NQO1</it>-rs1800566 were genotyped by PCR-based RFLP, sequencing and TaqMan assay in 358 NPC cases and 629 controls (phase I cohort). Logistic regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI). To confirm our results, sixteen tag SNPs for <it>GSTP1</it>, <it>MPO</it>, <it>NQO1 </it>(which 100% covered these genes), and 4 functional SNPs of <it>CYP2E1 </it>were genotyped in another cohort of 213 NPC cases and 230 controls (phase II cohort).</p> <p>Results</p> <p>No significant associations in NPC risk were observed for the five polymorphisms tested in the phase I cohort. In an additional stratified analysis for phase I, there was no significant association between cases and controls in NPC high risk population (EBV/IgA/VCA positive population). Analysis of 14 tagging SNPs within the same genes in an independent phase II cohort were in agreement with no SNPs significantly associated with NPC.</p> <p>Conclusions</p> <p>Our results suggest that polymorphism of <it>CYP2E1</it>, <it>GSTP1</it>, <it>MPO </it>and <it>NQO1 </it>genes does not contribute to overall NPC risk in a Han Chinese in southern China.</p

Increased Expression of Cannabinoid CB1 Receptors in Achilles Tendinosis

BACKGROUND: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB₁) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis. METHODOLOGY: Cannabinoid CB₁ receptor immunoreactivity (CB₁IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons. PRINCIPAL FINDINGS: CB₁IR was seen as a granular pattern in the tenocytes. CB₁IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB₁ receptor expression in tendinosis tissue compared to control tissue. CONCLUSION: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder

Biomarkers of Extracellular Matrix Metabolism (MMP-9 and TIMP-1) and Risk of Stroke, Myocardial Infarction, and Cause-Specific Mortality: Cohort Study

Objective: Turnover of the extracellular matrix in all solid organs is governed mainly by a balance between the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). An altered extracellular matrix metabolism has been implicated in a variety of diseases. We investigated relations of serum levels of MMP-9 and TIMP-1 to mortality risk from an etiological perspective. Design: The prospective Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, followed from 1991–1995 for up to 18.1 years. A random population-based sample of 1,082 71-year-old men, no loss to follow-up. Endpoints were all-cause (n = 628), cardiovascular (n = 230), non-cardiovascular (n = 398) and cancer mortality (n = 178), and fatal or non-fatal myocardial infarction (n = 138) or stroke (n = 163). Results: Serum MMP-9 and TIMP-1 levels were associated with risk of all-cause mortality (Cox proportional hazard ratio [HR] per standard deviation 1.10, 95% confidence interval [CI] 1.03–1.19; and 1.11, 1.02–1.20; respectively). TIMP-1 levels were mainly related to risks of cardiovascular mortality and stroke (HR per standard deviation 1.22, 95% CI 1.09–1.37; and 1.18, 1.04–1.35; respectively). All relations except those of TIMP-1 to stroke risk were attenuated by adjustment for cardiovascular disease risk factors. Relations in a subsample without cardiovascular disease or cancer were similar to those in the total sample. Conclusion: In this community-based cohort of elderly men, serum MMP-9 and TIMP-1 levels were related to mortality risk. An altered extracellular matrix metabolism may be involved in several detrimental pathways, and circulating MMP-9 or TIMP-1 levels may be relevant markers thereof