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31.
Iris Postmus Stella Trompet Anton J. M. de Craen Brendan M. Buckley Ian Ford David J. Stott Naveed Sattar P. Eline Slagboom Rudi G. J. Westendorp J. Wouter Jukema 《Journal of lipid research》2013,54(2):561-566
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10−12), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events. 相似文献
32.
Ratnakar Deole Jean Challacombe Douglas W. Raiford Wouter D. Hoff 《The Journal of biological chemistry》2013,288(1):581-588
Halophilic archaea accumulate molar concentrations of KCl in their cytoplasm as an osmoprotectant and have evolved highly acidic proteomes that function only at high salinity. We examined osmoprotection in the photosynthetic Proteobacteria Halorhodospira halophila and Halorhodospira halochloris. Genome sequencing and isoelectric focusing gel electrophoresis showed that the proteome of H. halophila is acidic. In line with this finding, H. halophila accumulated molar concentrations of KCl when grown in high salt medium as detected by x-ray microanalysis and plasma emission spectrometry. This result extends the taxonomic range of organisms using KCl as a main osmoprotectant to the Proteobacteria. The closely related organism H. halochloris does not exhibit an acidic proteome, matching its inability to accumulate K+. This observation indicates recent evolutionary changes in the osmoprotection strategy of these organisms. Upon growth of H. halophila in low salt medium, its cytoplasmic K+ content matches that of Escherichia coli, revealing an acidic proteome that can function in the absence of high cytoplasmic salt concentrations. These findings necessitate a reassessment of two central aspects of theories for understanding extreme halophiles. First, we conclude that proteome acidity is not driven by stabilizing interactions between K+ ions and acidic side chains but by the need for maintaining sufficient solvation and hydration of the protein surface at high salinity through strongly hydrated carboxylates. Second, we propose that obligate protein halophilicity is a non-adaptive property resulting from genetic drift in which constructive neutral evolution progressively incorporates weakly stabilizing K+-binding sites on an increasingly acidic protein surface. 相似文献
33.
Olga Kononova Joost Snijder Melanie Brasch Jeroen Cornelissen Ruxandra?I. Dima Kenneth?A. Marx Gijs?J.L. Wuite Wouter?H. Roos Valeri Barsegov 《Biophysical journal》2013,105(8):1893-1903
Physical properties of capsids of plant and animal viruses are important factors in capsid self-assembly, survival of viruses in the extracellular environment, and their cell infectivity. Combined AFM experiments and computational modeling on subsecond timescales of the indentation nanomechanics of Cowpea Chlorotic Mottle Virus capsid show that the capsid’s physical properties are dynamic and local characteristics of the structure, which change with the depth of indentation and depend on the magnitude and geometry of mechanical input. Under large deformations, the Cowpea Chlorotic Mottle Virus capsid transitions to the collapsed state without substantial local structural alterations. The enthalpy change in this deformation state ΔHind = 11.5–12.8 MJ/mol is mostly due to large-amplitude out-of-plane excitations, which contribute to the capsid bending; the entropy change TΔSind = 5.1–5.8 MJ/mol is due to coherent in-plane rearrangements of protein chains, which mediate the capsid stiffening. Direct coupling of these modes defines the extent of (ir)reversibility of capsid indentation dynamics correlated with its (in)elastic mechanical response to the compressive force. This emerging picture illuminates how unique physico-chemical properties of protein nanoshells help define their structure and morphology, and determine their viruses’ biological function. 相似文献
34.
Arco J. van Strien Tim Termaat Vincent Kalkman Marijn Prins Geert De Knijf Anne-Laure Gourmand Xavier Houard Brian Nelson Calijn Plate Stephen Prentice Eugenie Regan David Smallshire Cédric Vanappelghem Wouter Vanreusel 《Biodiversity and Conservation》2013,22(3):673-686
There is limited information available on changes in biodiversity at the European scale, because there is a lack of data from standardised monitoring for most species groups. However, a great number of observations made without a standardised field protocol is available in many countries for many species. Such opportunistic data offer an alternative source of information, but unfortunately such data suffer from non-standardised observation effort and geographical bias. Here we describe a new approach to compiling supranational trends using opportunistic data which adjusts for these two major imperfections. The non-standardised observation effort is dealt with by occupancy modelling, and the unequal geographical distribution of sites by a weighting procedure. The damselfly Calopteryx splendens was chosen as our test species. The data were collected from five countries (Ireland, Great Britain, the Netherlands, Belgium and France), covering the period 1990–2008. We used occupancy models to estimate the annual number of occupied 1 × 1 km sites per country. Occupancy models use presence-absence data, account for imperfect detection of species, and thereby correct for between-year variability in observation effort. The occupancy models were run per country in a Bayesian mode of inference using JAGS. The occupancy estimates per country were then aggregated to assess the supranational trend in the number of occupied 1 × 1 km2. To adjust for the unequal geographical distribution of surveyed sites, we weighted the countries according to the number of sites surveyed and the range of the species per country. The distribution of C. splendens has increased significantly in the combined five countries. Our trial demonstrated that a supranational trend in distribution can be derived from opportunistic data, while adjusting for observation effort and geographical bias. This opens new perspectives for international monitoring of biodiversity. 相似文献
35.
36.
Oana I. Stanisor Sophie A. van Diest Zhumei Yu Olaf Welting Noor Bekkali Jing Shi Wouter J. de Jonge Guy E. Boeckxstaens Rene M. van den Wijngaard 《PloS one》2013,8(6)
Background
The histamine-1 receptor (H1R) antagonist ketotifen increased the threshold of discomfort in hypersensitive IBS patients. The use of peripherally restricted and more selective H1R antagonists may further improve treatment possibilities. We examined the use of fexofenadine and ebastine to reverse post-stress visceral hypersensitivity in maternally separated rats.Methods
The visceromotor response to colonic distension was assessed in adult maternally separated and nonhandled rats pre- and 24 hours post water avoidance. Subsequently rats were treated with vehicle alone or different dosages of fexofenadine (1.8 and 18 mg/kg) or ebastine (0.1 and 1.0 mg/kg) and re-evaluated. Colonic tissue was collected to assess relative RMCP-2 and occludin expression levels by Western blot and histamine-1 receptor by RT-qPCR. β-hexosaminidase release by RBL-2H3 cells was used to establish possible mast cell stabilizing properties of the antagonists.Key results
Water avoidance only induced enhanced response to distension in maternally separated rats. This response was reversed by 1.8 and 18 mg/kg fexofenadine. Reversal was also obtained by 1.0 but not 0.1 mg/kg ebastine. RMCP-2 expression levels were comparable in these two ebastine treatment groups but occludin was significantly higher in 1.0 mg/kg treated rats. There were no differences in histamine-1 receptor expression between nonhandled and maternally separated rats. Fexofenadine but not ebastine showed mast cell stabilizing quality.Conclusions
Our results indicate that the peripherally restricted 2nd generation H1-receptor antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rat. These data justify future IBS patient trials with these well tolerated compounds. 相似文献37.
Mihály K. de Bie Maurits S. Buiten André Gaasbeek Mark J. Boogers Cornelis J. Roos Joanne D. Schuijf M. Jacqueline Krol Ton J. Rabelink Jeroen J. Bax Martin J. Schalij J. Wouter Jukema 《PloS one》2013,8(7)
Purpose
Significant obstructive coronary artery disease (CAD) is common in asymptomatic dialysis patients. Identifying these high risk patients is warranted and may improve the prognosis of this vulnerable patient group. Routine catheterization of incident dialysis patients has been proposed, but is considered too invasive. CT-angiography may therefore be more appropriate. However, extensive coronary calcification, often present in this patient group, might hamper adequate lumen evaluation. The objective of this study was to assess the feasibility of CT-angiography in this patient group.Methods
For this analysis all patients currently participating in the ICD2 trial (ISRCTN20479861), with no history of PCI or CABG were included. The major epicardial vessels were evaluated on a segment basis (segment 1–3, 5–8, 11 and 13) by a team consisting of an interventional and an imaging specialist. Segments were scored as not significant, significant and not interpretable.Results
A total of 70 dialysis patients, with a mean age of 66±8 yrs and predominantly male (70%) were included. The median calcium score was 623 [79, 1619].Over 90% of the analyzed segments were considered interpretable. The incidence of significant CAD on CT was 43% and was associated with cardiovascular events during follow-up. The incidence of cardiovascular events after 2-years follow-up: 36% vs. 0% in patients with no significant CAD (p<0.01).Conclusion
Despite the high calcium scores CT-angiography is feasible for the evaluation of the extent of CAD in dialysis patients. Moreover the presence of significant CAD on CT was associated with events during follow-up. 相似文献38.
Liselotte W. Wijsman Anton J. M. de Craen Stella Trompet Jacobijn Gussekloo David J. Stott Nicolas Rodondi Paul Welsh J. Wouter Jukema Rudi G. J. Westendorp Simon P. Mooijaart 《PloS one》2013,8(3)
Background
Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).Methods
Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.Results
Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.Conclusion
We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence. 相似文献39.
Sarah Berry Wouter Coppieters Stephen Davis Alayna Burrett Natalie Thomas David Palmer Van Kelly Vladimir Obolonkin Kathryn Sanders Richard Spelman Michel Georges Klaus Lehnert Russell Snell 《PloS one》2013,8(3)
The aim of this study was to determine a genetic basis for IgA concentration in milk of Bos taurus. We used a Holstein-Friesian x Jersey F2 crossbred pedigree to undertake a genome-wide search for QTL influencing IgA concentration and yield in colostrum and milk. We identified a single genome-wide significant QTL on chromosome 16, maximising at 4.8 Mbp. The polymeric immunoglobulin receptor gene (PIGR) was within the confidence interval of the QTL. In addition, mRNA expression analysis revealed a liver PIGR expression QTL mapping to the same locus as the IgA quantitative trait locus. Sequencing and subsequent genotyping of the PIGR gene revealed three divergent haplotypes that explained the variance of both the IgA QTL and the PIGR expression QTL. Genetic selection based on these markers will facilitate the production of bovine herds producing milk with higher concentrations of IgA. 相似文献
40.
Sara Vandenwijngaert Peter Pokreisz Hadewich Hermans Hilde Gillijns Marijke Pellens Noortje A. M. Bax Giulia Coppiello Wouter Oosterlinck Agnes Balogh Zoltan Papp Carlijn V. C. Bouten Jozef Bartunek Jan D'hooge Aernout Luttun Erik Verbeken Marie Christine Herregods Paul Herijgers Kenneth D. Bloch Stefan Janssens 《PloS one》2013,8(3)