Investigation of free surface flow generated by a planing flat plate using smoothed particle hydrodynamics method and FLOW3D simulations

In this article, smoothed particle hydrodynamics method is applied in order to study the free surface flow generated by two-dimensional planing flat plate. For this purpose, a two-dimensional smoothed particle hydrodynamics code is developed and validated by the well-known dam breaking problem. Four trim angles and three different velocities are considered to perform a parametric study to examine their physical effects. The obtained results from smoothed particle hydrodynamics are compared against the corresponding Reynolds-averaged Navier Stokes solutions. It is observed that at lower velocities, there exists a good agreement between the smoothed particle hydrodynamics and Reynolds-averaged Navier Stokes solutions, while at higher velocities, some inconsistency is observed. A brief discussion is presented to clarify the physical reasons behind the increase of the velocity and the height of the spray with the trim angle. Some formulas have also been derived to examine the variation of the ratio between the final wetted length of the flat plate and the initial wetted length at different velocities and trim angles.</p

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8 T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.No embarg

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin

Abstract Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases