| 1. |
- Henderson, Neil C., et al.
(författare)
-
Targeting of alpha(v) integrin identifies a core molecular pathway that regulates fibrosis in several organs
- 2013
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 19:12, s. 1617-1624
-
Tidskriftsartikel (refereegranskat)abstract
- Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding alpha(v) integrin subunit because various alpha(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of beta(3), beta(5) or beta(6) integrins or conditional loss of beta(8) integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the alpha(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of alpha(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all alpha(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
|
|
| 2. |
- Kokkolaras, Michael, et al.
(författare)
-
Towards a comprehensive framework for simulation-based vehicle systems design validation
- 2013
-
Ingår i: International Journal of Vehicle Design. - 0143-3369 .- 1741-5314. ; 61:.1/2/3/4, s. 233-248
-
Tidskriftsartikel (refereegranskat)abstract
- We present an overview of our most recent and ongoing research efforts to develop a comprehensive framework for simulation-based design validation of vehicle systems. Specifically, we present the three major building blocks of our framework: (1) the introduction of an appropriate validation metric for dealing with the multivariate functional data that are the output of dynamic vehicle systems; (2) the robust implementation of a Bayesian interval-based hypothesis testing technique for quantifying the confidence in simulation models used for design under uncertainty; (3) the development of a sequential design optimisation and calibration-based validation methodology that addresses the inadequacy of current validation practices in simulation-based design optimisation. We present a simple yet illustrative example and discuss the techniques being developed currently that will complete the proposed framework
|
|
| 3. |
- Sarin, H., et al.
(författare)
-
Comparing time histories for validation of simulation models : Error measures and metrics
- 2010
-
Ingår i: Journal of Dynamic Systems Measurement, and Control. - : ASME International. - 0022-0434 .- 1528-9028. ; 132:6
-
Tidskriftsartikel (refereegranskat)abstract
- Computer modeling and simulation are the cornerstones of product design and development in the automotive industry. Computer-aided engineering tools have improved to the extent that virtual testing may lead to significant reduction in prototype building and testing of vehicle designs. In order to make this a reality, we need to assess our confidence in the predictive capabilities of simulation models. As a first step in this direction, this paper deals with developing measures and a metric to compare time histories obtained from simulation model outputs and experimental tests. The focus of the work is on vehicle safety applications. We restrict attention to quantifying discrepancy between time histories as the latter constitute the predominant form of responses of interest in vehicle safety considerations. First, we evaluate popular measures used to quantify discrepancy between time histories in fields such as statistics, computational mechanics, signal processing, and data mining. Three independent error measures are proposed for vehicle safety applications, associated with three physically meaningful characteristics (phase, magnitude, and slope), which utilize norms, cross-correlation measures, and algorithms such as dynamic time warping to quantify discrepancies. A combined use of these three measures can serve as a metric that encapsulates the important aspects of time history comparison. It is also shown how these measures can be used in conjunction with ratings from subject matter experts to build regression-based validation metrics.
|
|
