Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.
A more complete understanding of the physical relationships, between wall-pressure and turbulence, is required for modeling flow-induced noise and developing noise reduction strategies. In this study, the wall-pressure fluctuations, induced by low Reynolds number turbulent boundary layers, are experimentally studied using a high-resolution microphone array. Statistical characteristics obtained using traditional cross-correlation and cross-spectra analyses are complimented with wall-pressure-velocity cross-spectra and wavelet cross-correlations. Wall-pressure-velocity correlations revealed that turbulent activity in the buffer layer contributes at least 40% of the energy to the wall-pressure spectrum at all measured frequencies. As Reynolds number increases, the low-frequency energy shifts from the buffer layer to the logarithmic layer, as expected for regions of uniform streamwise momentum formed by hairpin packets. Conditional cross-spectra suggests that the majority of broadband wall-pressure energy is concentrated within the packets, with the pressure signatures of individual hairpin vortices estimated to decay on average within traveling ten displacement thicknesses, and the packet signature is retained for up to seven boundary layer thicknesses on average.
This paper discusses the development of analytical models for the prediction of aircraft cabin noise induced by the external turbulent boundary layer (TBL). While, in previous works, the contribution of an individual panel to the cabin interior noise was considered, here, the simultaneous contribution of multiple flow-excited panels is analyzed. Analytical predictions are presented for the interior sound pressure level (SPL) at different locations inside the cabin of a Blended Wing Body (BWB) aircraft, for the frequency range 0–1000 Hz. The results show that the number of vibrating panels significantly affects the interior noise levels. It is shown that the average SPL, over the cabin volume, increases with the number of vibrating panels. Additionally, the model is able to predict local SPL values, at specific locations in the cabin, which are also affected with by number of vibrating panels, and are different from the average values.
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