The impact of local surface changes in Borneo on atmospheric composition at wider spatial scales: coastal processes, land-use change and air quality

We present results from the OP3 campaign in Sabah during 2008 that allow us to study the impact of local emission changes over Borneo on atmospheric composition at the regional and wider scale. OP3 constituent data provide an important constraint on model performance. Treatment of boundary layer processes is highlighted as an important area of model uncertainty. Model studies of land-use change confirm earlier work, indicating that further changes to intensive oil palm agriculture in South East Asia, and the tropics in general, could have important impacts on air quality, with the biggest factor being the concomitant changes in NO(x) emissions. With the model scenarios used here, local increases in ozone of around 50 per cent could occur. We also report measurements of short-lived brominated compounds around Sabah suggesting that oceanic (and, especially, coastal) emission sources dominate locally. The concentration of bromine in short-lived halocarbons measured at the surface during OP3 amounted to about 7 ppt, setting an upper limit on the amount of these species that can reach the lower stratosphere.     

Structural insight into a novel human CCR5-V130I variant associated with resistance to HIV-1 infection

We report the identification of a novel CC chemokine receptor 5 (CCR5) variant that seems associated with resistance to HIV-1 infection. The V130I mutation of the CCR5 receptor is located in the intracellular loop ICL2 known as DRY box and described in the literature as a nonsynonymous mutation present in nonhuman primates group. Extensive molecular modeling and dynamics simulations were performed to elucidate the mechanism by which the V130I mutation may induce conformational change of the CCR5 folding protein and prevent the interaction with the β-arrestin protein. Our study provides new mechanistic insight into how a specific mutation in the regulatory domain of CCR5 might alter the structural folding of the DRY box and the possible ICL2 loop binding with the β-arrestin protein, as described in our previous computational study. The results from our large-scale simulations complement recent experimental results and clinical features and offer useful insights into the mechanism behind CCR5 protein folding and signal transduction. In order for HIV, the entry of the virus to the cells must fuse with the CCR5 receptor that sits on the surface of T-helper immune cells. The described V130I mutation in the gene encoding the CCR5 protein may results in a defective CCR5-Arrestin binding complex that blocks entry of the virus.     

Glutamate metabolism in HIV-infected macrophages: implications for the CNS

Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis. excitatory amino acid transporter; cystine-glutamate antiporter; glutathione; inflammation; oxidative stress; glutamine synthetase     

The alanine-serine-cysteine-1 (Asc-1) transporter controls glycine levels in the brain and is required for glycinergic inhibitory transmission

Asc-1 (SLC7A10) is an amino acid transporter whose deletion causes neurological abnormalities and early postnatal death in mice. Using metabolomics and behavioral and electrophysiological methods, we demonstrate that Asc-1 knockout mice display a marked decrease in glycine levels in the brain and spinal cord along with impairment of glycinergic inhibitory transmission, and a hyperekplexia-like phenotype that is rescued by replenishing brain glycine. Asc-1 works as a glycine and L-serine transporter, and its transport activity is required for the subsequent conversion of L-serine into glycine in vivo. Asc-1 is a novel regulator of glycine metabolism and a candidate for hyperekplexia disorders.     

Synergistic Interaction of Rnf8 and p53 in the Protection against Genomic Instability and Tumorigenesis

Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8^−/− mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8^−/− mice in a tissue- and cell type–specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8^−/− mice, we have generated Rnf8^−/−p53^−/− mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8^−/− mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8^−/− mice. Similarly, the senescence phenotype of Rnf8^−/− mouse embryonic fibroblasts was rescued in p53 null background. Rnf8^−/−p53^−/− cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8^−/−p53^−/− mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8^−/− or p53^−/− mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis.     

A pilot study on the relation between irisin single-nucleotide polymorphism and risk of myocardial infarction

BackgroundMyocardial infarction (MI) is the major cause of death and disability worldwide. Many recent studies revealed the relationship between circulating irisin levels, endothelial dysfunctions and subclinical atherosclerosis in adult patients.ObjectivesThe aim of this study was to investigate the distribution of Irisin gene single nucleotide polymorphism in patients with MI and its association with other clinical and laboratory variables in these patients.Patients and methodsThis study was carried out in 100 patients with MI, and 100 healthy subjects served as controls. All studied subjects underwent laboratory investigations, including measurement of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c) high-density lipoprotein cholesterol (HDL-c), creatinine kinase-MB (CK-MB), troponin I (TnI) and genotyping of rs 3480 and rs726344 of Irisin genes using the TaqMan Allelic Discrimination assay technique.ResultsThere was a significant difference of Irisin genotypes in patients when compared to controls. By estimating odd ratio (OR) an association was found between G allele of rs 3480 and A allele of rs726344with increase the risk of developing myocardial infarction by 4.03 and 3.47 fold respectively. GG of rs 3480 carriers had significantly increased Troponin I and triglyceride levels, while GA carriers of rs726344 had significantly increased CKMB, Total cholesterol, LDLc, HDLc, troponin I and triglyceride levels compared with other genotypes.ConclusionG allele of rs 3480 and A allele of rs726344can considered as genetic risk factors for MI; these findings could have an impact on preventive strategy for myocardial infarction.     

Therapeutic efficacy of human umbilical cord mesenchymal stem cells transplantation against renal ischemia/reperfusion injury in rats

Background

Acute kidney injury (AKI) is a common clinical problem raising the urgent needs to develop new strategies for treatment. The present study investigated the therapeutic potential of human umbilical cord – mesenchymal stem cells (HUC-MSCs) transplantation against renal ischemia/reperfusion injury (IRI) in rats.