Semaphorin 4A (Sema4A) exerts a stabilizing effect on human Treg cells in PBMC and CD4+ T cell cultures by engaging Plexin B1. Sema4A deficient mice display enhanced allergic airway inflammation accompanied by fewer Treg cells, while Sema4D deficient mice displayed reduced inflammation and increased Treg cell numbers even though both Sema4 subfamily members engage Plexin B1. The main objectives of this study were: 1. To compare the in vitro effects of Sema4A and Sema4D proteins on human Treg cells; and 2. To identify function-determining residues in Sema4A critical for binding to Plexin B1 based on Sema4D homology modeling. We report here that Sema4A and Sema4D display opposite effects on human Treg cells in in vitro PBMC cultures; Sema4D inhibited the CD4+CD25+Foxp3+ cell numbers and CD25/Foxp3 expression. Sema4A and Sema4D competitively bind to Plexin B1 in vitro and hence may be doing so in vivo as well. Bayesian Partitioning with Pattern Selection (BPPS) partitioned 4505 Sema domains from diverse organisms into subgroups based on distinguishing sequence patterns that are likely responsible for functional differences. BPPS groups Sema3 and Sema4 into one family and further separates Sema4A and Sema4D into distinct subfamilies. Residues distinctive of the Sema3,4 family and of Sema4A (and by homology of Sema4D) tend to cluster around the Plexin B1 binding site. This suggests that the residues both common to and distinctive of Sema4A and Sema4D may mediate binding to Plexin B1, with subfamily residues mediating functional specificity. We mutated the Sema4A-specific residues M198 and F223 to alanine; notably, F223 in Sema4A corresponds to alanine in Sema4D. Mutant proteins were assayed for Plexin B1-binding and Treg stimulation activities. The F223A mutant was unable to stimulate Treg stability in in vitro PBMC cultures despite binding Plexin B1 with an affinity similar to the WT protein. This research is a first step in generating potent mutant Sema4A molecules with stimulatory function for Treg cells with a view to designing immunotherapeutics for asthma.
Deformable mirrors (DMs) are an enabling and mission-critical technology in any coronagraphic instrument designed to directly image exoplanets. A new ferrofluid deformable mirror technology for high-contrast imaging is currently under development at Princeton, featuring a flexible optical surface manipulated by the local electromagnetic and global hydraulic actuation of a reservoir of ferrofluid. The ferrofluid DM is designed to prioritize high optical surface quality, high-precision/low-stroke actuation, and excellent low-spatial-frequency performance-capabilities that meet the unique demands of high-contrast coronagraphy in a space-based platform. To this end, the ferrofluid medium continuously supports the DM facesheet, a configuration that eliminates actuator print-through (or, quilting) by decoupling the nominal surface figure from the geometry of the actuator array. The global pressure control allows independent focus actuation. In this paper we describe an analytical model for the quasi-static deformation response of the DM facesheet to both magnetic and pressure actuation. These modeling efforts serve to identify the key design parameters and quantify their contributions to the DM response, model the relationship between actuation commands and DM surface-profile response, and predict performance metrics such as achievable spatial resolution and stroke precision for specific actuator configurations. Our theoretical approach addresses the complexity of the boundary conditions associated with mechanical mounting of the facesheet, and makes use of asymptotic approximations by leveraging the three distinct length scales in the problem-namely, the low-stroke (∼nm) actuation, facesheet thickness (∼mm), and mirror diameter (∼cm). In addition to describing the theoretical treatment, we report the progress of computational multiphysics simulations which will be useful in improving the model fidelity and in drawing conclusions to improve the design.
The low-latency adaptive optical mirror system (LLAMAS) is designed to push the limits on achievable latencies and frame rates. It has 21 subapertures across its pupil. A reformulated version of the linear quadratic Gaussian (LQG) method predictive Fourier control is implemented in LLAMAS; for all modes, it takes just 30 µs to compute. In the testbed, a turbulator mixes hot and ambient air to produce wind-blown turbulence. Wind prediction clearly improves correction when compared to an integral controller. Closed-loop telemetry shows that wind-predictive LQG removes the characteristic “butterfly” and reduces temporal error power by up to a factor of three for mid-spatial frequency modes. Strehl changes seen in focal plane images are consistent with telemetry and the system error budget.
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