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- Glicksberg, Benjamin S., et al.
(författare)
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Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits
- 2019
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Ingår i: BMC Medical Genomics. - : BMC. - 1755-8794. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic loss-of-function variants (LoFs) associated with disease traits are increasingly recognized as critical evidence for the selection of therapeutic targets. We integrated the analysis of genetic and clinical data from 10,511 individuals in the Mount Sinai BioMe Biobank to identify genes with loss-of-function variants (LoFs) significantly associated with cardiovascular disease (CVD) traits, and used RNA-sequence data of seven metabolic and vascular tissues isolated from 600 CVD patients in the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) study for validation. We also carried out in vitro functional studies of several candidate genes, and in vivo studies of one gene.ResultsWe identified LoFs in 433 genes significantly associated with at least one of 10 major CVD traits. Next, we used RNA-sequence data from the STARNET study to validate 115 of the 433 LoF harboring-genes in that their expression levels were concordantly associated with corresponding CVD traits. Together with the documented hepatic lipid-lowering gene, APOC3, the expression levels of six additional liver LoF-genes were positively associated with levels of plasma lipids in STARNET. Candidate LoF-genes were subjected to gene silencing in HepG2 cells with marked overall effects on cellular LDLR, levels of triglycerides and on secreted APOB100 and PCSK9. In addition, we identified novel LoFs in DGAT2 associated with lower plasma cholesterol and glucose levels in BioMe that were also confirmed in STARNET, and showed a selective DGAT2-inhibitor in C57BL/6 mice not only significantly lowered fasting glucose levels but also affected body weight.ConclusionIn sum, by integrating genetic and electronic medical record data, and leveraging one of the world's largest human RNA-sequence datasets (STARNET), we identified known and novel CVD-trait related genes that may serve as targets for CVD therapeutics and as such merit further investigation.
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- Papageorgiou, Athanasios, 1984-
(författare)
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Optimization of Unmanned Aerial Vehicles : Expanding the Multidisciplinary Capabilities
- 2017
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Over the last decade, Unmanned Aerial Vehicles (UAVs) have experienced an accelerated growth, and nowadays they are being deployed in a variety of missions that have traditionally been covered by manned aircraft. This unprecedented market expansion has created new and unforeseen challenges for the manufacturing industry which is now called to further reduce the idea-to-market times while simultaneously delivering designs of even higher performance. In this environment of uncertainty and risk, it is without a doubt crucial for the involved actors to find ways to secure their strategic advantage, and hence, implementing the latest design tools has become a critical consideration in every Product Development Process (PDP).To this end, a method that has been frequently applied in the PDP and has shown many successful results in the development of complex engineering products is Multidisciplinary Design Optimization (MDO). In general, MDO can bring additional knowledge regarding the best-suited designs much earlier in the process, and in this respect, it can lead to significant cost and time savings by reducing the total number of refinement iterations. Nevertheless, the organizational and cultural integration of MDO has been often overlooked, while at the same time, several technical aspects of the method for UAV design are still at an elementary level. On the whole, research on MDO is showing a slow progress, and to this date, there are many limitations in both the disciplinary models and the available analysis capabilities.In light of the above, this thesis focuses on the particulars of the MDO methodology, and more specifically, on how it can be best adapted and evolved in order to enhance the development process of UAVs. The primary objective is to study the current trends and gaps of the MDO practices in UAV applications, and subsequently to build upon that and explore how these can be included in a roadmap that will be able to serve a guide for newcomers in the field. Compared to other studies, the problem is herein approached from both a technical as well as organizational perspective, and thus, this research not only aims to propose techniques that can lead to better designs but also solutions that will be meaningful to the PDP. Having established the above foundation, this work shows that the traditional MDO frameworks for UAV design have been neglecting several important features, and it elaborates on how those novel elements can be modeled in order to enable a better integration of MDO into the organizational functions. Overall, this thesis presents quantitative and qualitative data which illustrate the effectiveness of the new framework enhancements in the development process of UAVs, and concludes with discussions on the possible improvement directions towards achieving more and better MDO capabilities.
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