| 1. |
- Couthouis, Julien, et al.
(författare)
-
A yeast functional screen predicts new candidate ALS disease genes
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:52, s. 20881-20890
-
Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
|
|
| 2. |
- Drignei, Dorin, et al.
(författare)
-
A Variable-Size Local Domain Approach to Computer Model Validation in Design Optimization
- 2011
-
Ingår i: SAE International Journal of Materials & Manufacturing. - : SAE International. - 1946-3979 .- 1946-3987. ; 4:1, s. 421-429
-
Tidskriftsartikel (refereegranskat)abstract
- A common approach to the validation of simulation models focuses on validation throughout the entire design space. A more recent methodology validates designs as they are generated during a simulation-based optimization process. The latter method relies on validating the simulation model in a sequence of local domains. To improve its computational efficiency, this paper proposes an iterative process, where the size and shape of local domains at the current step are determined from a parametric bootstrap methodology involving maximum likelihood estimators of unknown model parameters from the previous step. Validation is carried out in the local domain at each step. The iterative process continues until the local domain does not change from iteration to iteration during the optimization process ensuring that a converged design optimum has been obtained. The proposed methodology is illustrated using a thermal, one-dimensional, linear heat conduction problem in a solid slab with heat flux boundary conditions
|
|
| 3. |
- Gunawan, Subroto, et al.
(författare)
-
Design Optimization and Reliability Estimation with Incomplete Uncertainty
- 2006
-
Ingår i: 2006 SAE world congress. - Warrendale, Pa. : Society of Automotive Engineers, Incorporated.
-
Konferensbidrag (refereegranskat)abstract
- Existing methods for design optimization under uncertainty assume that a high level of information is available, typically in the form of data. In reality, however, insufficient data prevents correct inference of probability distributions, membership functions, or interval ranges. In this article we use an engine design example to show that optimal design decisions and reliability estimations depend strongly on uncertainty characterization. We contrast the reliability-based optimal designs to the ones obtained using worst-case optimization, and ask the question of how to obtain non-conservative designs with incomplete uncertainty information. We propose an answer to this question through the use of Bayesian statistics. We estimate the truck's engine reliability based only on available samples, and demonstrate that the accuracy of our estimates increases as more samples become available. Finally, we use this information-based reliability assessment to optimize the engine while maximizing the confidence that the design will meet or exceed a pre-specified reliability target.
|
|
| 4. |
- Hillier, Ladeana W, et al.
(författare)
-
Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
- 2004
-
Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
-
Tidskriftsartikel (refereegranskat)abstract
- We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
|
|
| 5. |
- Kokkolaras, Michael, et al.
(författare)
-
Design optimization of hierarchically decomposed multilevel systems under uncertainty
- 2004
-
Ingår i: Proceedings of the ASME Design Engineering Technical Conferences and Computers and Information in Engineering Conference - 2004. - New York : American Society of Mechanical Engineers. - 0791846946 ; , s. 613-625
-
Konferensbidrag (refereegranskat)abstract
- This paper presents a methodology for design optimization of decomposed systems in the presence of uncertainties. We extend the analytical target cascading (ATC) formulation to probabilistic design by treating stochastic quantities as random variables and parameters and posing reliability-based design constraints. We model the propagation of uncertainty throughout the multilevel hierarchy of elements that comprise the decomposed system by using the advanced mean value (AMV) method to generate the required probability distributions of nonlinear responses. We utilize appropriate metamodeling techniques for simulation-based design problems. A simple yet illustrative hierarchical bi-level engine design problem is used to demonstrate the proposed methodology.
|
|
| 6. |
- Kokkolaras, Michael, et al.
(författare)
-
Design optimization of hierarchically decomposed multilevel systems under uncertainty
- 2006
-
Ingår i: Journal of mechanical design (1990). - : ASME International. - 1050-0472 .- 1528-9001. ; 128:2, s. 503-508
-
Tidskriftsartikel (refereegranskat)abstract
- This paper presents a methodology for design optimization of hierarchically decomposed systems under uncertainty. We propose an extended, probabilistic version of the deterministic analytical target cascading (ATC) formulation by treating uncertain quantities as random variables and posing probabilistic design constraints. A bottom-to-top coordination strategy is used for the ATC process. Given that first-order approximations may introduce unacceptably large errors, we use a technique based on the advanced mean value method to estimate uncertainty, propagation through the multilevel hierarchy of elements that comprise the decomposed system. A simple yet illustrative hierarchical bilevel engine design problem is used to demonstrate the proposed methodology. The results confirm the applicability of the proposed probabilistic ATC formulation and the accuracy of the uncertainty propagation technique
|
|
| 7. |
- Kokkolaras, Michael, et al.
(författare)
-
Design Under Uncertainty and Assessment of Performance Reliability of a Dual-Use Medium Truck with Hydraulic-Hybrid Powertrain and Fuel Cell Auxiliary Power Unit
- 2005
-
Ingår i: 2005 SAE world congress. - Warrendale, Pa : Society of Automotive Engineers, Incorporated.
-
Konferensbidrag (refereegranskat)abstract
- Medium trucks constitute a large market segment of the commercial transportation sector, and are also used widely for military tactical operations. Recent technological advances in hybrid powertrains and fuel cell auxiliary power units have enabled design alternatives that can improve fuel economy and reduce emissions dramatically. However, deterministic design optimization of these configurations may yield designs that are optimal with respect to performance but raise concerns regarding the reliability of achieving that performance over lifetime. In this article we identify and quantify uncertainties due to modeling approximations or incomplete information. We then model their propagation using Monte Carlo simulation and perform sensitivity analysis to isolate statistically significant uncertainties. Finally, we formulate and solve a series of reliability-based optimization problems and quantify tradeoffs between optimality and reliability. The most relevant design parameters of the diesel engine, fuel cell, driveline and vehicle are considered. The results demonstrate the necessity for addressing uncertainty to make valid assessments and design decisions
|
|
| 8. |
- Kokkolaras, Michael, et al.
(författare)
-
Impact of uncertainty quantification on design decisions for a hydraulic-hybrid powertrain engine
- 2006
-
Ingår i: 47th AIAA/ASME/ASCE/AHS/ASC Structures, Structural Dynamics, and Materials Conference. - Reston, Va. : American Institute of Aeronautics and Astronautics, AIAA. - 1563477963 ; , s. 4954-4963
-
Konferensbidrag (refereegranskat)abstract
- The method for solving an optimal design problem under uncertainty depends on how the latter is quantified. When sufficient information is available the popular probabilistic approach can (and should) be adopted. In reality however, we often do not have sufficient data to infer appropriate probability distributions for the uncertain quantities modeled as random variables. The amount of available information about the uncertain quantities may be limited to ranges of values (intervals). In this case, the interval analysis approach can be employed to reformulate and solve the optimal design problem. In this study, we use both approaches to solve an engine design optimization problem that considers fuel economy and acceleration performance of a medium-sized truck with a hydraulic-hybrid powertrain. We then contrast the obtained results and comment on the characteristics and features of the two approaches. We also demonstrate an extension of the interval analysis approach to multilevel systems using a simple yet illustrative engine-related example
|
|
| 9. |
- Li, Jing, et al.
(författare)
-
Validating Designs Through Sequential Simulation-Based Optimization
- 2010
-
Ingår i: Proceedings of the ASME International Design Engineering Technical Conferences and Computers and Information in Engineering Conference - 2010. - New York : American Society of Mechanical Engineers. ; , s. 1023-1031
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Computational simulation models support a rapid design process. Given model approximation and operating conditions uncertainty, designers must have confidence that the designs obtained using simulations will perform as expected. This paper presents a methodology for validating designs as they are generated during a simulation-based optimization process. Current practice focuses on validation of simulation models throughout the entire design space. In contrast, the proposed methodology requires validation only at design points generated during optimization. The goal of such validation is confidence in the resulting design rather than in the underlying simulation model. The proposed methodology is illustrated on a simple cantilever beam design subject to vibration
|
|
