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The contribution of altered post-transcriptional gene silencing to the development of insulin resistance and type 2 diabetes mellitus so far remains elusive. Here, we demonstrate that expression of microRNA (miR)-143 and 145 is upregulated in the liver of genetic and dietary mouse models of obesity. Induced transgenic overexpression of miR-143, but not miR-145, impairs insulin-stimulated AKT activation and glucose homeostasis. Conversely, mice deficient for the miR-143–145 cluster are protected from the development of obesity-associated insulin resistance. Quantitative-mass-spectrometry-based analysis of hepatic protein expression in miR-143-overexpressing mice revealed miR-143-dependent downregulation of oxysterol-binding-protein-related protein (ORP) 8. Reduced ORP8 expression in cultured liver cells impairs the ability of insulin to induce AKT activation, revealing an ORP8-dependent mechanism of AKT regulation. Our experiments provide direct evidence that dysregulated post-transcriptional gene silencing contributes to the development of obesity-induced insulin resistance, and characterize the miR-143–ORP8 pathway as a potential target for the treatment of obesity-associated diabetes.
The powerful avalanche simulation toolbox RAMMS (Rapid Mass Movements) is based on a depth-averaged
hydrodynamic system of equations with a Voellmy-Salm friction relation. The two empirical friction parameters
μ and correspond to a dry Coulomb friction and a viscous resistance, respectively. Although μ and lack a
proper physical explanation, 60 years of acquired avalanche data in the Swiss Alps made a systematic calibration
possible. RAMMS can therefore successfully model avalanche flow depth, velocities, impact pressure and run
out distances. Pudasaini and Hutter (2003) have proposed extended, rigorously derived model equations that
account for local curvature and twist. A coordinate transformation into a reference system, applied to the actual
mountain topography of the natural avalanche path, is performed. The local curvature and the twist of the
avalanche path induce an additional term in the overburden pressure. This leads to a modification of the Coulomb
friction, the free-surface pressure gradient, the pressure induced by the channel, and the gravity components
along and normal to the curved and twisted reference surface. This eventually guides the flow dynamics and
deposits of avalanches. In the present study, we investigate the influence of curvature on avalanche flow in
real mountain terrain. Simulations of real avalanche paths are performed and compared for the different models
approaches. An algorithm to calculate curvature in real terrain is introduced in RAMMS. This leads to a curvature
dependent friction relation in an extended version of the Voellmy-Salm model equations. Our analysis provides
yet another step in interpreting the physical meaning and significance of the friction parameters used in the
RAMMS computational environment.