104 research outputs found
Water entry of a flat elastic plate at high horizontal speed
The two-dimensional problem of an elastic-plate impact onto an undisturbed surface of water of infinite depth is analysed. The plate is forced to move with a constant horizontal velocity component which is much larger than the vertical velocity component of penetration. The small angle of attack of the plate and its vertical velocity vary in time, and are determined as part of the solution, together with the elastic deflection of the plate and the hydrodynamic loads within the potential flow theory. The boundary conditions on the free surface and on the wetted part of the plate are linearized and imposed on the initial equilibrium position of the liquid surface. The wetted part of the plate depends on the plate motion and its elastic deflection. To determine the length of the wetted part we assume that the spray jet in front of the advancing plate is negligible. A smooth separation of the free-surface flow from the trailing edge is imposed. The wake behind the moving body is included in the model. The plate deflection is governed by Eulerâs beam equation, subject to freeâfree boundary conditions. Four different regimes of plate motion are distinguished depending on the impact conditions: (a) the plate becomes fully wetted; (b) the leading edge of the plate touches the water surface and traps an air cavity; (c) the free surface at the forward contact point starts to separate from the plate; (d) the plate exits the water. We could not detect any impact conditions which lead to steady planing of the free plate after the impact. It is shown that a large part of the total energy in the fluidâplate interaction leaves the main bulk of the liquid with the spray jet. It is demonstrated that the flexibility of the plate may increase the hydrodynamic loads acting on it. The impact loads can cause large bending stresses, which may exceed the yield stress of the plate material. The elastic vibrations of the plate are shown to have a significant effect on the fluid flow in the wake
GBA and APOE Δ4 associate with sporadic dementia with Lewy bodies in European genome wide association study
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE Δ4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 à 10). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 à 10. We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders
A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease
Late-onset Alzheimerâs disease is a prevalent age-related polygenic disease that accounts for 50â70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimerâs disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimerâs disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimerâs disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimerâs disease to identify further genetic variants that contribute to Alzheimerâs pathology
The prevalence of stillbirths: a systematic review
BACKGROUND: Stillbirth rate is an important indicator of access to and quality of antenatal and delivery care. Obtaining overall estimates across various regions of the world is not straightforward due to variation in definitions, data collection methods and reporting. METHODS: We conducted a systematic review of a range of pregnancy-related conditions including stillbirths and performed meta-analysis of the subset of studies reporting stillbirth rates. We examined variation across rates and used meta-regression techniques to explain observed variation. RESULTS: We identified 389 articles on stillbirth prevalence among the 2580 included in the systematic review. We included 70 providing 80 data sets from 50 countries in the meta-analysis. Pooled prevalence rates show variation across various subgroup categories. Rates per 100 births are higher in studies conducted in less developed country settings as compared to more developed (1.17 versus 0.50), of inadequate quality as compared to adequate (1.12 versus 0.66), using sub-national sample as compared to national (1.38 versus 0.68), reporting all stillbirths as compared to late stillbirths (0.95 versus 0.63), published in non-English as compared to English (0.91 versus 0.59) and as journal articles as compared to non-journal (1.37 versus 0.67). The results of the meta-regression show the significance of two predictor variables â development status of the setting and study quality â on stillbirth prevalence. CONCLUSION: Stillbirth prevalence at the community level is typically less than 1% in more developed parts of the world and could exceed 3% in less developed regions. Regular reviews of stillbirth rates in appropriately designed and reported studies are useful in monitoring the adequacy of care. Systematic reviews of prevalence studies are helpful in explaining sources of variation across rates. Exploring these methodological issues will lead to improved standards for assessing the burden of reproductive ill-health
Polygenic overlap between C-reactive protein, plasma lipids, and Alzheimer disease
BackgroundâEpidemiological findings suggest a relationship between Alzheimer disease (AD), inflammation, and dyslipidemia, although the nature of this relationship is not well understood. We investigated whether this phenotypic association arises from a shared genetic basis. Methods and ResultsâUsing summary statistics (P values and odds ratios) from genome-wide association studies of >200 000 individuals, we investigated overlap in single-nucleotide polymorphisms associated with clinically diagnosed AD and C-reactive protein (CRP), triglycerides, and high- and low-density lipoprotein levels. We found up to 50-fold enrichment of AD single-nucleotide polymorphisms for different levels of association with C-reactive protein, low-density lipoprotein, high-density lipoprotein, and triglyceride single-nucleotide polymorphisms using a false discovery rate threshold <0.05. By conditioning on polymorphisms associated with the 4 phenotypes, we identified 55 loci associated with increased AD risk. We then conducted a meta-analysis of these 55 variants across 4 independent AD cohorts (total: n=29 054 AD cases and 114 824 healthy controls) and discovered 2 genome-wide significant variants on chromosome 4 (rs13113697; closest gene, HS3ST1; odds ratio=1.07; 95% confidence interval=1.05â1.11; P=2.86Ă10â8) and chromosome 10 (rs7920721; closest gene, ECHDC3; odds ratio=1.07; 95% confidence interval=1.04â1.11; P=3.38Ă10â8). We also found that gene expression of HS3ST1 and ECHDC3 was altered in AD brains compared with control brains. ConclusionsâWe demonstrate genetic overlap between AD, C-reactive protein, and plasma lipids. By conditioning on the genetic association with the cardiovascular phenotypes, we identify novel AD susceptibility loci, including 2 genome-wide significant variants conferring increased risk for AD.acceptedVersio
New insights into the genetic etiology of Alzheimer's disease and related dementias.
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Variant of TREM2 associated with the risk of Alzheimer's disease.
To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.BACKGROUND: Sequence variants, including the Δ4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. METHODS: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, The Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. RESULTS: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P=3.42Ă10(-10)). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1Ă10(-12) in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). CONCLUSIONS: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.).Research Council of NorwayNational Institute on Aging P50-AG025688 U01AG006781South-Eastern Norway Health AuthorityNational Institutes of Health U01HG004438National Human Genome Research Institute U01HG004610eMERGE Administrative Coordinating Center
U01HG004603National Center for Biotechnology InformationErasmus Medical CenterErasmus University, RotterdamNetherlands Organization for Health Research and DevelopmentResearch Institute for Diseases in the ElderlyMinistry of Education, Culture and ScienceMinistry for Health, Welfare and SportsMunicipality of RotterdamResearch Institute for Diseases in the Elderly 014-93-015Stichting Alzheimer Onder-zoekHersenstichting NederlandNetherlands Genomics Initiative-Netherlands Organization for Scientific Research (Center for Medical Systems Biology and the Netherlands Consortium for Healthy Aging)info:eu-repo/grantAgreement/EC/FP7/20141
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
An Efficient Multiperiod MINLP Model for Optimal Planning of Offshore Oil and Gas Field Infrastructure
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