Pratt and Whitney/Boeing Engine Validation of Noise Reduction Concepts: Final Report for NASA Contract NAS3-97144, Phase 1

Major airports in the world's air transportation systems face a serious problem in providing greater capacity to meet the ever increasing demands of air travel. This problem could be relieved if airports are allowed to increase their operating time, now restricted by curfews and by relaxing present limits on takeoffs and landings. The key operational issue in extending the present curfews is noise. In response to these increasing restrictive noise regulations, NASA has launched a program to validate through engine testing, noise reduction concepts and technologies that have evolved from the Advanced Subsonic Technologies (AST) Noise Reduction Program. The goal of this AST program was to develop and validate technology that reduces engine noise and improves nacelle suppression effectiveness relative to 1992 technology. Contract NAS3-97144 titled "Engine Validation of Noise Reduction Concepts" (EVNRC) was awarded to P&W on August 12, 1997 to conduct full scale noise reduction tests in two Phases on a PW4098 engine. The following Section 1.2 provides a brief description of the overall program. The remainder of this report provides a detailed documentation of Phase I of the program

APOE genotype and cognitive change in young, middle-aged, and older adults living in the community.

We examined whether the apolipoprotein E (APOE) ε4 allele was associated with cognitive benefits in young adulthood and whether it reversed to confer cognitive deficits in later life ("antagonistic pleiotropy") in the absence of dementia-related neuropathology. We also tested whether the ε2 allele was associated with disadvantages in early adulthood but offered protection against cognitive decline in early old age. Eight-year cognitive change was assessed in 2,013 cognitively normal community-dwelling adults aged 20-24, 40-44, or 60-64 years at baseline. Although cognitive decline was associated with age, multilevel models contrasting the ε2 and ε4 alleles provided no evidence that the APOE genotype was related to cognitive change in any of the age groups. The findings suggest that in the absence of clinically salient dementia pathology, APOE ε2 and ε4 alleles do not exhibit antagonistic pleiotropy in relation to cognition between the ages of 20 and 72 years

Comparative Assessment of Soil-Structure Interaction Regulations of ASCE 7-16 and ASCE 7-10

This paper evaluates the consequences of practicing soil structure interaction (SSI) regulations of ASCE 7-16 on seismic performance of building structures. The motivation for this research stems from the significant changes in the new SSI provisions of ASCE 7-16 compared to the previous 2010 edition. Generally, ASCE 7 considers SSI as a beneficial effect, and allows designer to reduce the design base shear. However, literature shows that this idea cannot properly capture the SSI effects on nonlinear systems. ASCE 7-16 is the first edition of ASCE 7 that considers the SSI effect on yielding systems. This study investigates the consequences of practicing the new provisions on a wide range of buildings with different dynamic characteristics on different soil types. Ductility demand of the structure forms the performance metric of this study, and the probability that practicing SSI provisions, in lieu of fixed-base provisions, increases the ductility demand of the structure is computed. The analyses are conducted within a probabilistic framework which considers the uncertainties in the ground motion and in the properties of the soil-structure system. It is concluded that, for structures with surface foundation on moderate to soft soils, SSI regulations of both ASCE 7-10 and ASCE 7-16 are fairly likely to result in a similar and larger structural responses than those obtained by practicing the fixed-base design regulations. However, for squat and ordinary stiff structures on soft soil or structures with embedded foundation on moderate to soft soils, the SSI provisions of ASCE 7-16 result in performance levels that are closer to those obtained by practicing the fixed-base regulations. Finally, for structures on very soft soils, the new SSI provisions of ASCE 7-16 are likely to rather conservative designs.Comment: ASCE Structures Congress, Fort Worth, TX, USA, April 19-21 (2018

Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Chromosome Xq23 Is Associated with Lower Atherogenic Lipid Concentrations and Favorable Cardiometabolic Indices

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids

Rare Coding Variants in RCN3 Are Associated with Blood Pressure

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10− 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits