Changes in intense tropical cyclone activity for the western North Pacific during the last decades derived from a regional climate model simulation

An atmospheric regional climate model (CCLM) was employed to dynamically downscale atmospheric reanalyses (NCEP/NCAR 1, ERA 40) over the western North Pacific and South East Asia. This approach is used for the first time to reconstruct a tropical cyclone climatology, which extends beyond the satellite era and serves as an alternative data set for inhomogeneous observation-derived records (Best Track Data sets). The simulated TC climatology skillfully reproduces observations of the recent decades (1978--2010), including spatial patterns, frequency, lifetime, trends, variability on interannual and decadal time scales and their association with the large-scale circulation patterns. These skills, facilitated here with the spectral nudging method, seem to be a prerequisite to understand the factors determining spatio-temporal variability of TC activity over the western North Pacific. Long-term trends (1948--2011 and 1959--2001) in both simulations show a strong increase of intense tropical cyclone activity. This contrasts with pronounced multidecadal variations found in observations. The discrepancy may partly originate from temporal inhomogeneities in atmospheric reanalyses and Best Track Data, which affect both the model-based and observational-based trends. An adjustment, which removes the simulated upward trend, reduces the apparent discrepancy. Ultimately, our observational and modeling analysis suggests an important contribution of multi-decadal fluctuations in the TC activity during the last six decades. Nevertheless, due to the uncertainties associated with the inconsistencies and quality changes of those data sets, we call for special caution when reconstructing long-term TC statistics either from atmospheric reanalyses or Best Track Data

Association study of cholesterol-related genes in Alzheimer's disease

Alzheimer's disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some sample

LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer's Disease (LOAD)

Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ∼400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.© 2013 Lincoln et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Changes in the future summer Mediterranean climate: contribution of teleconnections and local factors

This study analyzes future climate for the Mediterranean region projected with the high-resolution coupled CM2.5 model, which incorporates a new and improved land model (LM3). The simulated climate changes suggest pronounced warming and drying over most of the region. However, the changes are distinctly smaller than those of the CMIP5 multi-model ensemble. In addition, the changes over much of southeast and central Europe indicate very modest warming compared to the CMIP5 projections and also a tendency toward wetter conditions. These differences indicate a possible role of factors such as land surface–atmospheric interactions in these regions. Our analysis also highlights the importance of correctly projecting the magnitude of changes in the summer North Atlantic Oscillation, which has the capacity to partly offset anthropogenic warming and drying over the western and central Mediterranean. Nevertheless, the projections suggest a decreasing influence of local atmospheric dynamics and teleconnections in maintaining the regional temperature and precipitation balance, in particular over arid regions like the eastern and southern Mediterranean, which show a local maximum of warming and drying. The intensification of the heat low in these regions rather suggests an increasing influence of warming land surface on the local surface atmospheric circulation and progressing desertification.</p

Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study

<p>Abstract</p> <p>Background</p> <p>A recently published genome-wide association study (GWAS) of late-onset Alzheimer's disease (LOAD) revealed genome-wide significant association of variants in or near <it>MS4A4A, CD2AP, EPHA1 </it>and <it>CD33</it>. Meta-analyses of this and a previously published GWAS revealed significant association at <it>ABCA7 </it>and <it>MS4A</it>, independent evidence for association of <it>CD2AP, CD33 </it>and <it>EPHA1 </it>and an opposing yet significant association of a variant near <it>ARID5B</it>. In this study, we genotyped five variants (in or near <it>CD2AP, EPHA1, ARID5B</it>, and <it>CD33</it>) in a large (2,634 LOAD, 4,201 controls), independent dataset comprising six case-control series from the USA and Europe. We performed meta-analyses of the association of these variants with LOAD and tested for association using logistic regression adjusted by age-at-diagnosis, gender, and <it>APOE ε4 </it>dosage.</p> <p>Results</p> <p>We found no significant evidence of series heterogeneity. Associations with LOAD were successfully replicated for <it>EPHA1 </it>(rs11767557; OR = 0.87, p = 5 × 10^-4) and <it>CD33 </it>(rs3865444; OR = 0.92, p = 0.049), with odds ratios comparable to those previously reported. Although the two <it>ARID5B </it>variants (rs2588969 and rs494288) showed significant association with LOAD in meta-analysis of our dataset (p = 0.046 and 0.008, respectively), the associations did not survive adjustment for covariates (p = 0.30 and 0.11, respectively). We had insufficient evidence in our data to support the association of the <it>CD2AP </it>variant (rs9349407, p = 0.56).</p> <p>Conclusions</p> <p>Our data overwhelmingly support the association of <it>EPHA1 </it>and <it>CD33 </it>variants with LOAD risk: addition of our data to the results previously reported (total n > 42,000) increased the strength of evidence for these variants, providing impressive p-values of 2.1 × 10^-15(<it>EPHA1</it>) and 1.8 × 10^-13(<it>CD33</it>).</p

Conformational Altered p53 as an Early Marker of Oxidative Stress in Alzheimer's Disease

In order to study oxidative stress in peripheral cells of Alzheimer's disease (AD) patients, immortalized lymphocytes derived from two peculiar cohorts of patients, referring to early onset AD (EOSAD) and subjects harboured AD related mutation (ADmut), were used. Oxidative stress was evaluated measuring i) the typical oxidative markers, such as HNE Michel adducts, 3 Nitro-Tyrosine residues and protein carbonyl on protein extracts, ii) and the antioxidant capacity, following the enzymatic kinetic of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRD). We found that the signs of oxidative stress, measured as oxidative marker levels, were evident only in ADmut but not in EOSAD patients. However, oxidative imbalance in EOSAD as well as ADmut lymphocytes was underlined by a reduced SOD activity and GRD activity in both pathological groups in comparison with cells derived from healthy subjects. Furthermore, a redox modulated p53 protein was found conformational altered in both EOSAD and ADmut B lymphocytes in comparison with control cells. This conformational altered p53 isoform, named “unfolded p53”, was recognized by the use of two specific conformational anti-p53 antibodies. Immunoprecipitation experiments, performed with the monoclonal antibodies PAb1620 (that recognizes p53wt) and PAb240 (that is direct towards unfolded p53), and followed by the immunoblotting with anti-4-hydroxynonenal (HNE) and anti- 3-nitrotyrosine (3NT) antibodies, showed a preferential increase of nitrated tyrosine residues in unfolded p53 isoform comparing to p53 wt protein, in both ADmut and EOSAD. In addition, a correlation between unfolded p53 and SOD activity was further found. Thus this study suggests that ROS/RNS contributed to change of p53 tertiary structure and that unfolded p53 can be considered as an early marker of oxidative imbalance in these patients

The influence of spectral nudging on typhoon formation in regional climate models

Regional climate models can successfully simulate tropical cyclones and typhoons. This has been shown and was evaluated for hindcast studies of the past few decades. But often global and regional weather phenomena are not simulated at the observed location, or occur too often or seldom even though the regional model is driven by global reanalysis data which constitute a near-realistic state of the global atmosphere. Therefore, several techniques have been developed in order to make the regional model follow the global state more closely. One is spectral nudging, which is applied for horizontal wind components with increasing strength for higher model levels in this study. The aim of this study is to show the influence that this method has on the formation of tropical cyclones (TC) in regional climate models. Two ensemble simulations (each with five simulations) were computed for Southeast Asia and the Northwestern Pacific for the typhoon season 2004, one with spectral nudging and one without. First of all, spectral nudging reduced the overall TC number by about a factor of 2. But the number of tracks which are similar to observed best track data (BTD) was greatly increased. Also, spatial track density patterns were found to be more similar when using spectral nudging. The tracks merge after a short time for the spectral nudging simulations and then follow the BTD closely; for the no nudge cases the similarity is greatly reduced. A comparison of seasonal precipitation, geopotential height, and temperature fields at several height levels with observations and reanalysis data showed overall a smaller ensemble spread, higher pattern correlations and reduced root mean square errors and biases for the spectral nudged simulations. Vertical temperature profiles for selected TCs indicate that spectral nudging is not inhibiting TC development at higher levels. Both the Madden-Julian Oscillation and monsoonal precipitation are reproduced realistically by the regional model, with results slightly closer to reanalysis data for the spectral nudged simulations. On the basis of this regional climate model hindcast study of a single typhoon season, spectral nudging seems to be favourable since it has mostly positive effects on typhoon formation, location and general circulation patterns in the generation areas of TCs