SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants

Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants

Different genes interact with particulate matter and tobacco smoke exposure in affecting lung function decline in the general population

BACKGROUND: Oxidative stress related genes modify the effects of ambient air pollution or tobacco smoking on lung function decline. The impact of interactions might be substantial, but previous studies mostly focused on main effects of single genes. OBJECTIVES: We studied the interaction of both exposures with a broad set of oxidative-stress related candidate genes and pathways on lung function decline and contrasted interactions between exposures. METHODS: For 12679 single nucleotide polymorphisms (SNPs), change in forced expiratory volume in one second (FEV(1)), FEV(1) over forced vital capacity (FEV(1)/FVC), and mean forced expiratory flow between 25 and 75% of the FVC (FEF(25-75)) was regressed on interval exposure to particulate matter >10 microm in diameter (PM10) or packyears smoked (a), additive SNP effects (b), and interaction terms between (a) and (b) in 669 adults with GWAS data. Interaction p-values for 152 genes and 14 pathways were calculated by the adaptive rank truncation product (ARTP) method, and compared between exposures. Interaction effect sizes were contrasted for the strongest SNPs of nominally significant genes (p(interaction)>0.05). Replication was attempted for SNPs with MAF<10% in 3320 SAPALDIA participants without GWAS. RESULTS: On the SNP-level, rs2035268 in gene SNCA accelerated FEV(1)/FVC decline by 3.8% (p(interaction) = 2.5x10(-6)), and rs12190800 in PARK2 attenuated FEV1 decline by 95.1 ml p(interaction) = 9.7x10(-8)) over 11 years, while interacting with PM10. Genes and pathways nominally interacting with PM10 and packyears exposure differed substantially. Gene CRISP2 presented a significant interaction with PM10 (p(interaction) = 3.0x10(-4)) on FEV(1)/FVC decline. Pathway interactions were weak. Replications for the strongest SNPs in PARK2 and CRISP2 were not successful. CONCLUSIONS: Consistent with a stratified response to increasing oxidative stress, different genes and pathways potentially mediate PM10 and tobac smoke effects on lung function decline. Ignoring environmental exposures would miss these patterns, but achieving sufficient sample size and comparability across study samples is challengin

The relation between paracetamol use and asthma:a GA2LEN European case-control study

Studies from the UK and USA suggest that frequent use of paracetamol (acetaminophen) may increase the risk of asthma, but data across Europe are lacking. As part of a multicentric case-control study organised by the Global Allergy and Asthma European Network (GA(2)LEN), it was examined whether or not frequent paracetamol use is associated with adult asthma across Europe. The network compared 521 cases with a diagnosis of asthma and reporting of asthma symptoms within the last 12 months with 507 controls with no diagnosis of asthma and no asthmatic symptoms within the last 12 months across 12 European centres. All cases and controls were selected from the same population, defined by age (2045 yrs) and place of residence. In a random effects meta-analysis, weekly use of paracetamol, compared with less frequent use, was strongly positively associated with asthma after controlling for confounders. There was no evidence for heterogeneity across centres. No association was seen between use of other analgesics and asthma. These data add to the increasing and consistent epidemiological evidence implicating frequent paracetamol use in asthma in diverse populations

Early cancer detection among rural and urban californians

BACKGROUND: Since the stage of cancer detection generally predicts future mortality rates, a key cancer control strategy is to increase the proportion of cancers found in the early stage. This study compared stage of detection for members of rural and urban communities to determine whether disparities were present. METHODS: The California Cancer Registry (CCR), a total population based cancer registry, was used to examine the proportion of early stage presentation for patients with breast, melanoma, and colon cancer from 1988 to 2003. Cancer stage at time of detection for these cancers was compared for rural and urban areas. RESULTS: In patients with breast cancer, there were significantly more patients presenting at early stage in 2003 compared to 1988, but no difference in the percentage of patients presenting with early stage disease between rural and urban dwellers. There were no differences in incidence in early stage cancer incidence between these groups for melanoma patients, as well. In colorectal cancer in 1988, significantly more patients presented with early stage disease in the urban areas (42% vs 34%, p < 0.02). However, over time the rural patients were diagnosed with early stage disease with the same frequency in 2003 as 1988. CONCLUSION: This analysis demonstrates that people in rural and urban areas have their breast, melanoma or colorectal cancers diagnosed at similar stages. Health care administrators may take this information into account in future strategic planning

Cell death regulation during influenza A virus infection by matrix (M1) protein: a model of viral control over the cellular survival pathway

During early infection, viruses activate cellular stress-response proteins such as heat-shock proteins (Hsps) to counteract apoptosis, but later on, they modulate these proteins to stimulate apoptosis for efficient viral dissemination. Hsp70 has been attributed to modulate viral entry, transcription, nuclear translocation and virion formation. It also exerts its anti-apoptotic function by binding to apoptosis protease-activating factor 1 (Apaf-1) and disrupting apoptosome formation. Here, we show that influenza A virus can regulate the anti-apoptotic function of Hsp70 through viral protein M1 (matrix 1). M1 itself did not induce apoptosis, but enhanced the effects of apoptotic inducers. M1-small-interfering RNA inhibits virus-induced apoptosis in cells after either virus infection or overexpression of the M1 protein. M1 binds to Hsp70, which results in reduced interaction between Hsp70 and Apaf-1. In a cell-free system, the M1 protein mediates procaspase-9 activation induced by cytochrome c/deoxyadenosine triphosphate. A study involving deletion mutants confirmed the role of the C-terminus substrate-binding domain (EEVD) of Hsp70 and amino acids 128–165 of M1 for this association. The M1 mutants, which did not co-immunoprecipitate with Hsp70, failed to induce apoptosis. Overall, the study confirms the proapoptotic function of the M1 protein during influenza virus infection

The Rotterdam Study: 2010 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Variability of the chronic obstructive pulmonary disease key epidemiological data in Europe: systematic review

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is predicted to become a major cause of death worldwide. Studies on the variability in the estimates of key epidemiological parameters of COPD may contribute to better assessment of the burden of this disease and to helpful guidance for future research and public policies. In the present study, we examined differences in the main epidemiological characteristics of COPD derived from studies across countries of the European Union, focusing on prevalence, severity, frequency of exacerbations and mortality, as well as on differences between the studies' methods.</p> <p>Methods</p> <p>This systematic review was based on a search for the relevant literature in the Science Citation Index database via the Web of Science and on COPD mortality rates issued from national statistics. Analysis was finally based on 65 articles and Eurostat COPD mortality data for 21 European countries.</p> <p>Results</p> <p>Epidemiological characteristics of COPD varied widely from country to country. For example, prevalence estimates ranged between 2.1% and 26.1%, depending on the country, the age group and the methods used. Likewise, COPD mortality rates ranged from 7.2 to 36.1 per 10⁵inhabitants. The methods used to estimate these epidemiological parameters were highly variable in terms of the definition of COPD, severity scales, methods of investigation and target populations. Nevertheless, to a large extent, several recent international guidelines or research initiatives, such as GOLD, BOLD or PLATINO, have boosted a substantial standardization of methodology in data collection and have resulted in the availability of more comparable epidemiological estimates across countries. On the basis of such standardization, severity estimates as well as prevalence estimates present much less variation across countries. The contribution of these recent guidelines and initiatives is outlined, as are the problems remaining in arriving at more accurate COPD epidemiological estimates across European countries.</p> <p>Conclusions</p> <p>The accuracy of COPD epidemiological parameters is important for guiding decision making with regard to preventive measures, interventions and patient management in various health care systems. Therefore, the recent initiatives for standardizing data collection should be enhanced to result in COPD epidemiological estimates of improved quality. Moreover, establishing international guidelines for reporting research on COPD may also constitute a major contribution.</p

A review of combined advanced oxidation technologies for the removal of organic pollutants from water

Water pollution through natural and anthropogenic activities has become a global problem causing short-and long-term impact on human and ecosystems. Substantial quantity of individual or mixtures of organic pollutants enter the surface water via point and nonpoint sources and thus affect the quality of freshwater. These pollutants are known to be toxic and difficult to remove by mere biological treatment. To date, most researches on the removal of organic pollutants from wastewater were based on the exploitation of individual treatment process. This single-treatment technology has inherent challenges and shortcomings with respect to efficiency and economics. Thus, application of two advanced treatment technologies characterized with high efficiency with respect to removal of primary and disinfection by-products in wastewater is desirable. This review article focuses on the application of integrated technologies such as electrohydraulic discharge with heterogeneous photocatalysts or sonophotocatalysis to remove target pollutants. The information gathered from more than 100 published articles, mostly laboratories studies, shows that process integration effectively remove and degrade recalcitrant toxic contaminants in wastewater better than single-technology processing. This review recommends an improvement on this technology (integrated electrohydraulic discharge with heterogeneous photocatalysts) viz-a-vis cost reduction in order to make it accessible and available in the rural and semi-urban settlement. Further recommendation includes development of an economic model to establish the cost implications of the combined technology. Proper monitoring, enforcement of the existing environmental regulations, and upgrading of current wastewater treatment plants with additional treatment steps such as photocatalysis and ozonation will greatly assist in the removal of environmental toxicants