Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1

Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.     

Stathmin Is Dispensable for Tumor Onset in Mice

The microtubule-destabilizing protein stathmin is highly expressed in several types of tumor, thus deserving the name of oncoprotein 18. High levels of stathmin expression and/or activity favor the metastatic spreading and mark the most aggressive tumors, thus representing a realistic marker of poor prognosis. Stathmin is a downstream target of many signaling pathways, including Ras-MAPK, PI3K and p53, involved in both tumor onset and progression. We thus hypothesized that stathmin could also play a role during the early stages of tumorigenesis, an issue completely unexplored. In order to establish whether stathmin expression is necessary for tumor initiation, we challenged wild type (WT), stathmin heterozygous and stathmin knock-out (KO) mice with different carcinogens. Using well-defined mouse models of carcinogenesis of skin, bladder and muscle by the means of 7,12-dimethylbenz[α]antracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and 3-methylcholanthrylene (3MC) treatments, respectively, we demonstrated that knock-out of stathmin has no impact on the onset of cancer in mice. No significant difference was noticed either when the Ras oncogene was mutated (skin carcinogenesis model) or when the p53 pathway was inactivated (bladder carcinomas and fibrosarcomas). Finally, we concomitantly impinged on p53 and Ras pathways, by generating WT and stathmin KO mouse embryo fibroblasts transformed with papilloma virus large T antigen (LgTAg) plus the K-Ras^G12V oncogene. In vivo growth of xenografts from these transformed fibroblasts did not highlight any significant difference depending on the presence or absence of stathmin. Overall, our work demonstrates that stathmin expression is dispensable for tumor onset, at least in mice, thus making stathmin a virtually exclusive marker of aggressive disease and a promising therapeutic target for advanced cancers.     

Synaptotagmin-like proteins control the formation of a single apical membrane domain in epithelial cells

The formation of epithelial tissues requires both the generation of apical-basal polarity and the coordination of this polarity between neighbouring cells to form a central lumen. During de novo lumen formation, vectorial membrane transport contributes to the formation of a singular apical membrane, resulting in the contribution of each cell to only a single lumen. Here, from a functional screen for genes required for three-dimensional epithelial architecture, we identify key roles for synaptotagmin-like proteins 2-a and 4-a (Slp2-a/4-a) in the generation of a single apical surface per cell. Slp2-a localizes to the luminal membrane in a PtdIns(4,5)P(2)-dependent manner, where it targets Rab27-loaded vesicles to initiate a single lumen. Vesicle tethering and fusion is controlled by Slp4-a, in conjunction with Rab27/Rab3/Rab8 and the SNARE syntaxin-3. Together, Slp2-a/4-a coordinate the spatiotemporal organization of vectorial apical transport to ensure that only a single apical surface, and thus the formation of a single lumen, occurs per cell.     

A pathogenic mechanism in Huntington's disease involves small CAG-repeated RNAs with neurotoxic activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.     

Effect of ubiquinol supplementation on biochemical and oxidative stress indexes after intense exercise in young athletes

Objectives: Physical exercise significantly impacts the biochemistry of the organism. Ubiquinone is a key component of the mitochondrial respiratory chain and ubiquinol, its reduced and active form, is an emerging molecule in sport nutrition. The aim of this study was to evaluate the effect of ubiquinol supplementation on biochemical and oxidative stress indexes after an intense bout of exercise.

Methods: 21 male young athletes (26?+?5 years of age) were randomized in two groups according to a double blind cross-over study, either supplemented with ubiquinol (200?mg/day) or placebo for 1 month. Blood was withdrawn before and after a single bout of intense exercise (40 min run at 85% maxHR). Physical performance, hematochemical parameters, ubiquinone/ubiquinol plasma content, intracellular reactive oxygen species (ROS) level, mitochondrial membrane depolarization, paraoxonase activity and oxidative DNA damage were analyzed.

Results: A single bout of intense exercise produced a significant increase in most hematochemical indexes, in particular CK and Mb while, on the contrary, normalized coenzyme Q₁₀ plasma content decreased significantly in all subjects. Ubiquinol supplementation prevented exercise-induced CoQ deprivation and decrease in paraoxonase activity. Moreover at a cellular level, in peripheral blood mononuclear cells, ubiquinol supplementation was associated with a significant decrease in cytosolic ROS while mitochondrial membrane potential and oxidative DNA damage remained unchanged.

Discussion: Data highlights a very rapid dynamic of CoQ depletion following intense exercise underlying an increased demand by the organism. Ubiquinol supplementation minimized exercise-induced depletion and enhanced plasma and cellular antioxidant levels but it was not able to improve physical performance indexes or markers of muscular damage.     

Critical behaviour of the stochastic Wilson-Cowan model

Spontaneous brain activity is characterized by bursts and avalanche-like dynamics, with scale-free features typical of critical behaviour. The stochastic version of the celebrated Wilson-Cowan model has been widely studied as a system of spiking neurons reproducing non-trivial features of the neural activity, from avalanche dynamics to oscillatory behaviours. However, to what extent such phenomena are related to the presence of a genuine critical point remains elusive. Here we address this central issue, providing analytical results in the linear approximation and extensive numerical analysis. In particular, we present results supporting the existence of a bona fide critical point, where a second-order-like phase transition occurs, characterized by scale-free avalanche dynamics, scaling with the system size and a diverging relaxation time-scale. Moreover, our study shows that the observed critical behaviour falls within the universality class of the mean-field branching process, where the exponents of the avalanche size and duration distributions are, respectively, 3/2 and 2. We also provide an accurate analysis of the system behaviour as a function of the total number of neurons, focusing on the time correlation functions of the firing rate in a wide range of the parameter space.     

Life cycle assessment of Australian automotive door skins

Background, aim, and scope  Policy initiatives, such as the EU End of Life Vehicle (ELV) Directive for only 5% landfilling by 2015, are increasing the pressure for higher material recyclability rates. This is stimulating research into material alternatives and end-of-life strategies for automotive components. This study presents a Life Cycle Assessment (LCA) on an Australian automotive component, namely an exterior door skin. The functional unit for this study is one door skin set (4 exterior skins). The material alternatives are steel, which is currently used by Australian manufacturers, aluminium and glass-fiber reinforced polypropylene composite. Only the inputs and outputs relative to the door skin production, use and end-of-life phases were considered within the system boundary. Landfill, energy recovery and mechanical recycling were the end-of-life phases considered. The aim of the study is to highlight the most environmentally attractive material and end-of-life option. Methods  The LCA was performed according to the ISO 14040 standard series. All information considered in this study (use of fossil and non fossil based energy resources, water, chemicals etc.) were taken up in in-depth data. The data for the production, use and end-of-life phases of the door skin set was based upon softwares such as SimaPro and GEMIS which helped in the development of the inventory for the different end-of-life scenarios. In other cases, the inventory was developed using derivations obtained from published journals. Some data was obtained from GM-Holden and the Co-operative research Centre for Advanced Automotive Technology (AutoCRC), in Australia. In cases where data from the Australian economy was unavailable, such as the data relating to energy recovery methods, a generic data set based on European recycling companies was employed. The characterization factors used for normalization of data were taken from (Saling et. al. Int J Life Cycle Assess 7(4):203–218 2002) which detailed the method of carrying out an LCA. Results  The production phase results in maximum raw material consumption for all materials, and it is higher for metals than for the composite. Energy consumption is greatest in the use phase, with maximum consumption for steel. Aluminium consumes most energy in the production phase. Global Warming Potential (GWP) also follows a trend similar to that of energy consumption. Photo Oxidants Creation Potential (POCP) is the highest for the landfill scenario for the composite, followed by steel and aluminium. Acidification Potential (AP) is the highest for all the end-of-life scenarios of the composite. Ozone Depletion Potential (ODP) is the highest for the metals. The net water emissions are also higher for composite in comparison to metals despite high pollution in the production phases of metallic door skins. Solid wastes are higher for the metallic door skins. Discussion  The composite door skin has the lowest energy consumption in the production phase, due to the low energy requirements during the manufacturing of E-glass and its fusion with polypropylene to form sheet molding compounds. In general, the air emissions during the use phase are strongly dependent on the mass of the skins, with higher emissions for the metals than for the composite. Material recovery through recycling is the highest in metals due to efficient separation techniques, while mechanical recycling is the most efficient for the composite. The heavy steel skins produce the maximum solid wastes primarily due to higher fuel consumption. Water pollution reduction benefit is highest in case of metals, again due to the high efficiency of magnetic separation technique in the case of steel and eddy current separation technique in the case of aluminium. Material recovery in these metals reduces the amount of water needed to produce a new door skin set (water employed mainly in the ingot casting stage). Moreover, the use of heavy metals, inorganic salts and other chemicals is minimized by efficient material recovery. Conclusions  The use of the studied type of steel for the door skins is a poor environmental option in every impact category. Aluminium and composite materials should be considered to develop a more sustainable and energy efficient automobile. In particular, this LCA study shows that glass-fiber composite skins with mechanical recycling or energy recovery method could be environmentally desirable, compared to aluminium and steel skins. However, the current limit on the efficiency of recycling is the prime barrier to increasing the sustainability of composite skins. Recommendations and perspectives  The study is successful in developing a detailed LCA for the three different types of door skin materials and their respective recycling or end-of-life scenarios. The results obtained could be used for future work on an eco-efficiency portfolio for the entire car. However, there is a need for a detailed assessment of toxicity and risk potentials arising from each of the four different types of door skin sets. This will require greater communication between academia and the automotive industry to improve the quality of the LCA data. Sensitivity analysis needs to be performed such as the assessment of the impact of varying substitution factors on the life cycle of a door skin. Incorporation of door skin sets made of new biomaterials need to be accounted for as another functional unit in future LCA studies. Discussion contributions to this article from the readership would the highly welcome. The authors     

EAACI position paper on occupational rhinitis

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.