Insights into Male Androgenetic Alopecia: Differential Gene Expression Profiling of Plucked Hair Follicles and Integration with Genetic Data

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Transcriptional regulation of Annexin A2 promotes starvation-induced autophagy.

Autophagy is an important degradation pathway, which is induced after starvation, where it buffers nutrient deprivation by recycling macromolecules in organisms from yeast to man. While the classical pathway mediating this response is via mTOR inhibition, there are likely to be additional pathways that support the process. Here, we identify Annexin A2 as an autophagy modulator that regulates autophagosome formation by enabling appropriate ATG9A trafficking from endosomes to autophagosomes via actin. This process is dependent on the Annexin A2 effectors ARP2 and Spire1. Annexin A2 expression increases after starvation in cells in an mTOR-independent fashion. This is mediated via Jun N-terminal kinase activation of c-Jun, which, in turn, enhances the trans-activation of the Annexin A2 promoter. Annexin A2 knockdown abrogates starvation-induced autophagy, while its overexpression induces autophagy. Hence, c-Jun-mediated transcriptional responses support starvation-induced autophagy by regulating Annexin A2 expression levels.Openheimer Memorial TrustThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms904

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 x10(-8)), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD

Male-pattern baldness and incident coronary heart disease and risk factors in the Heinz Nixdorf Recall Study.

Male-pattern baldness (MPB) is characterized by a progressive hair loss from the frontal and vertex scalp that affects about 80% of men at the age of 80 years. Epidemiological studies show positive associations between MPB and coronary heart disease (CHD) and CHD related risk factors such as blood pressure (BP), diabetes mellitus (DM) or elevated blood lipid levels. The results however vary with regard to the pattern of hair loss (i.e. moderate, severe, frontal or vertex). Further, no study has investigated for a shared genetic determinant between MPB and CHD as well as CHD related risk factors. Using the longitudinal data from the population-based Heinz Nixdorf Recall study we aimed to systematically investigate the association between MPB and incident CHD and CHD risk factors on (i) an epidemiological (N = 1,673 males) and (ii) a genetic (N = 1,357 males) level. The prevalence of any baldness in our study population was 88% (mean age ± SD: 64±7.5 years). Compared to men with 'no baldness', in men with any kind of baldness a slightly increased risk for CHD (Hazard ratio [95% confidence interval (95%CI)] = 1.2 [0.8; 1.9]), a slightly higher extend of coronary artery calcification (CAC) (Beta [95%CI] = 0.2 [-0.1; 0.6]), a moderately increased risk for DM (prevalence ratio [95%CI] = 1.4 [0.9; 2.0]) and higher body mass index (BMI) (Beta [95%CI] = 0.6 [0.00003; 1.2]) seem to be indicated in the adjusted model. In contrast, the MPB genetic risk score did not show any association with CHD or CHD risk factors. Taken together, the results of our study suggest a weak association between MPB and a few CHD risk factors (CAC, DM and BMI) but do not point to MPB as a strong surrogate measure for CHD and CHD risk factors in general

Sediment imbalances and flooding risk in European deltas and estuaries

Purpose We analysed the status of current water and sediment management practices in six deltas and estuaries, which were part of the European DELTANET, INTERREG-funded network. Materials and methods These systems—the Danube, Ebro and Vistula deltas and the Elbe, Minho and Severn estuaries—represent different geographic regions of Europe. This enables comparison between the sites’ approaches to common coastal issues, notably those associated with sediment budgets, contamination and flood risk. Based on documentary analysis, workshop events and expert discussion, we employ a simple classification scheme to distinguish between levels of risk from these aspects. Results We suggest that flood risk is the most significant risk, followed by upstream sediment retention and sediment aggradation. Chemical contamination, though less severe, is not unimportant. Key management issues include a lack of environmental quality standards for sediment and suspended particulate matter, as well as the limited deployment of monitoring programmes, regular sediment sampling and associated chemical analyses. Conclusions These include both general and specific recommendations. Within these, the limited scope of integrated plans that aim for sustainability of the respective systems is highlighted. It is suggested that these do not challenge traditional, classical engineering approaches sufficiently. Nor do they address the origin of many environmental problems, especially those which are closely linked to short-term political and economic priorities

Sediment imbalances and flooding risk in European deltas and estuaries

Purpose We analysed the status of current water and sediment management practices in six deltas and estuaries, which were part of the European DELTANET, INTERREG-funded network. Materials and methods These systems—the Danube, Ebro and Vistula deltas and the Elbe, Minho and Severn estuaries—represent different geographic regions of Europe. This enables comparison between the sites’ approaches to common coastal issues, notably those associated with sediment budgets, contamination and flood risk. Based on documentary analysis, workshop events and expert discussion, we employ a simple classification scheme to distinguish between levels of risk from these aspects. Results We suggest that flood risk is the most significant risk, followed by upstream sediment retention and sediment aggradation. Chemical contamination, though less severe, is not unimportant. Key management issues include a lack of environmental quality standards for sediment and suspended particulate matter, as well as the limited deployment of monitoring programmes, regular sediment sampling and associated chemical analyses. Conclusions These include both general and specific recommendations. Within these, the limited scope of integrated plans that aim for sustainability of the respective systems is highlighted. It is suggested that these do not challenge traditional, classical engineering approaches sufficiently. Nor do they address the origin of many environmental problems, especially those which are closely linked to short-term political and economic priorities

Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55-87&nbsp;years.

The heterozygous human Klotho KL-VS haplotype has been associated with improved cognitive performance but results are inconsistent. Here we assessed Klotho KL-VS haplotype and cognition using data from the third examination of the population-based Heinz Nixdorf Recall Study. We analyzed cognition tests (immediate and delayed word list, Trail-Making Test [TMT] part A and B, Maze test, interference condition of the Stroop color-word test, verbal fluency) and their associations with Klotho KL-VS haplotype. The Klotho KL-VS haplotype is classified by the V-allele at SNP rs9536314 (F352V) and the S-allele at SNP rs9527025 (C370S). Heterozygotes for the KL-VS haplotype were compared with non-carriers. Analyses were performed in 1812 subjects (55-87&nbsp;years). We found consistent but only slightly lower performance in heterozygous carriers of the KL-VS haplotype in all tasks with Z-scores ranging between Z = - 0.042 (verbal fluency) and - 0.17 (TMT part A). Differences between carriers and non-carriers were similar for men and women for all tests but TMT part B (interaction contrast = 8.4&nbsp;s (95% CI - 2.3; 19.1)). While cognition declined with age, we found an effect modification by age (55-65&nbsp;years, 66-75&nbsp;years, &gt; 75&nbsp;years). In the 66-75&nbsp;years KL-VS heterozygous age group, lower performance was seen in memory, visual attention and motor speed. Contrary to our hypothesis, heterozygous carriers of the KL-VS haplotype did not show enhanced performance in cognitive tests in our study