TGF-β-responsive CAR-T cells promote anti-tumor immune function.

A chimeric antigen receptor (CAR) that responds to transforming growth factor beta (TGF-β) enables the engineering of T cells that convert this immunosuppressive cytokine into a potent T-cell stimulant. However, clinical translation of TGF-β CAR-T cells for cancer therapy requires the ability to productively combine TGF-β responsiveness with tumor-targeting specificity. Furthermore, the potential concern that contaminating, TGF-β?producing regulatory T (Treg) cells may preferentially expand during TGF-β CAR-T cell manufacturing and suppress effector T (Teff) cells demands careful evaluation. Here, we demonstrate that TGF-β CAR-T cells significantly improve the anti-tumor efficacy of neighboring cytotoxic T cells. Furthermore, the introduction of TGF-β CARs into mixed T-cell populations does not result in the preferential expansion of Treg cells, nor do TGF-β CAR-Treg cells cause CAR-mediated suppression of Teff cells. These results support the utility of incorporating TGF-β CARs in the development of adoptive T-cell therapy for cancer

Multiscale modeling of thermal ablation in fiber reinforced composites

The development of improved numerical methods and physical models of thermal ablation is necessary for reducing uncertainties in the prediction of Thermal Protection System (TPS) performance and hence the reduction of TPS weight and the maximization of aerospace vehicle payloads. Models simulating ablation must address significantly disparate temporal and spatial scales, including molecular scale chemical physics of resin pyrolysis and macroscale resin and fiber ablation. Numerical methods must also be able to account for solid erosion effects and the resulting geometry evolution. This research has developed the first discrete nonholonomic Hamiltonian approach for the multiscale modeling of thermal ablation. The model incorporates three scales of interest, including a reacting molecular dynamics model at the nanoscale and hybrid particle element models at the meso and macro scales. Unlike all previous works in literature, the disparate temporal and spatial scales of the ablation problem are addressed, in part, by incorporating a fully coupled chemical-thermomechanical ablation model at the mesoscale. The research builds on previous work on the hybrid particle element method by the addition of variable mass particles at the meso and macro scales, as well as a description of the resin and fiber composite architecture in the macroscale model. Solid erosion effects and the resulting surface recession are accounted for explicitly in the particle-element kinematics. The presented methodology improves on existing macroscale models in three main respects: first, the solid dynamics is modeled explicitly with full chemical-thermomechanical coupling at the mesoscale and thermomechanical coupling at the macroscale, second mass and energy is rigorously conserved in the formulation of the state space equations, and third a general method of accounting for solid erosion effects and geometry evolution is included. The formulation is validated by comparison with published ablation experiments on fiber reinforced phenolic and cyanate ester composites.Mechanical Engineerin

Difficulty and reasons for sustainable roadway design – the case from Taiwan

To accomplish sustainable design, it is essential to understand its barriers or limitations. This study investigated difficulties and their reasons for sustainable design using roadways as an example. A checklist of 60 sustainability items for roadway design was used to interview roadway designers to identify levels of difficulty, reasons for difficulty and proportions of difficulty reasons when designing these sustainability items. The results were analyzed and compared among sustainable items and design work. The difficulties of incorporating sustainability into designs are classified into three levels as compared with conventional design: equal, medium and high. The average difficulty for sustainable roadway design is between low and medium level; 28 of the 60 items were found to be at the same level of difficulty as conventional design. The technical items are regarded more difficult to adopt than material items. Nine reasons were identified for sustainable roadway design difficulty in which four are in the pre-design stage and five are in the design stage. The proportions of difficulty reasons in the pre-design and design stages are 63% and 37%, respectively. This implies that more difficulties will be encountered in the pre-design stage, and the designers can try to overcome or reduce difficulty in design stage. The top three reasons are natural preconditions; criteria and specifications; and owner, policy and law, which cause 33%, 20% and 14% of the difficulty, respectively. This study pointed out the difficulties and reasons for sustainable roadway design. Having a comprehensive understanding of the difficulties allows a designer to more accurately determine potential limitation, and to make better choices as to which sustainable items a particular construction project should pursue

Tenodesis Grasp Emulator: Kinematic Assessment of Wrist-Driven Orthotic Control

Wrist-driven orthotics have been designed to assist people with C6-7 spinal cord injury, however, the kinematic constraint imposed by such a control strategy can impede mobility and lead to abnormal body motion. This study characterizes body compensation using the novel Tenodesis Grasp Emulator, an adaptor orthotic that allows for the investigation of tenodesis grasping in subjects with unimpaired hand function. Subjects perform a series of grasp-and-release tasks in order to compare normal (test control) and constrained wrist-driven modes, showing significant compensation as a result of the constraint. A motor-augmented mode is also compared against traditional wrist-driven operation, to explore the potential role of hybrid human-robot control. We find that both the passive wrist-driven and motor-augmented modes fulfill different roles throughout various tasks tested. Thus, we conclude that a flexible control scheme that can alter intervention based on the task at hand holds the potential to reduce compensation in future work.Comment: 7 pages, 11 figures, submitted to International Conference on Robotics and Automation (ICRA) 2022. Video Supplement: https://youtu.be/NIgKg5R3Ro

Center-surround vs. distance-independent lateral connectivity in the olfactory bulb

Lateral neuronal interactions are known to play important roles in sensory information processing. A center-on surround-off local circuit arrangement has been shown to play a role in mediating contrast enhancement in the visual, auditory, and somatosensory systems. The lateral connectivity and the influence of those connections have been less clear for the olfactory system. A critical question is whether the synaptic connections between the primary projection neurons, mitral and tufted (M/T) cells, and their main inhibitory interneurons, the granule cells (GCs), can support a center-surround motif. Here, we study this question by injecting a “center” in the glomerular layer of the olfactory bulb (OB) with a marker of synaptic connectivity, the pseudorabies virus (PRV), then examines the distribution of labeling in the “surround” of GCs. We use a novel method to score the degree to which the data fits a center-surround model vs. distance-independent connectivity. Data from 22 injections show that M/T cells generally form lateral connections with GCs in patterns that lie between the two extremes

Surface-guided computing to analyze subcellular morphology and membrane-associated signals in 3D

Signal transduction and cell function are governed by the spatiotemporal organization of membrane-associated molecules. Despite significant advances in visualizing molecular distributions by 3D light microscopy, cell biologists still have limited quantitative understanding of the processes implicated in the regulation of molecular signals at the whole cell scale. In particular, complex and transient cell surface morphologies challenge the complete sampling of cell geometry, membrane-associated molecular concentration and activity and the computing of meaningful parameters such as the cofluctuation between morphology and signals. Here, we introduce u-Unwrap3D, a framework to remap arbitrarily complex 3D cell surfaces and membrane-associated signals into equivalent lower dimensional representations. The mappings are bidirectional, allowing the application of image processing operations in the data representation best suited for the task and to subsequently present the results in any of the other representations, including the original 3D cell surface. Leveraging this surface-guided computing paradigm, we track segmented surface motifs in 2D to quantify the recruitment of Septin polymers by blebbing events; we quantify actin enrichment in peripheral ruffles; and we measure the speed of ruffle movement along topographically complex cell surfaces. Thus, u-Unwrap3D provides access to spatiotemporal analyses of cell biological parameters on unconstrained 3D surface geometries and signals.Comment: 49 pages, 10 figure

Lateral Connectivity in the Olfactory Bulb is Sparse and Segregated

Lateral connections in the olfactory bulb were previously thought to be organized for center–surround inhibition. However, recent anatomical and physiological studies showed sparse and distributed interactions of inhibitory granule cells (GCs) which tended to be organized in columnar clusters. Little is known about how these distributed clusters are interconnected. In this study, we use transsynaptic tracing viruses bearing green or red fluorescent proteins to further elucidate mitral- and tufted-to-GC connectivity. Separate sites in the glomerular layer were injected with each virus. Columns with labeling from both viruses after transsynaptic spread show sparse red or green GCs which tended to be segregated. However, there was a higher incidence of co-labeled cells than chance would predict. Similar segregation of labeling is observed from dual injections into olfactory cortex. Collectively, these results suggest that neighboring mitral and tufted cells receive inhibitory inputs from segregated subsets of GCs, enabling inhibition of a center by specific and discontinuous lateral elements

Hedgehog Spin-texture and Berry's Phase tuning in a Magnetic Topological Insulator

Understanding and control of spin degrees of freedom on the surfaces of topological materials are key to future applications as well as for realizing novel physics such as the axion electrodynamics associated with time-reversal (TR) symmetry breaking on the surface. We experimentally demonstrate magnetically induced spin reorientation phenomena simultaneous with a Dirac-metal to gapped-insulator transition on the surfaces of manganese-doped Bi2Se3 thin films. The resulting electronic groundstate exhibits unique hedgehog-like spin textures at low energies, which directly demonstrate the mechanics of TR symmetry breaking on the surface. We further show that an insulating gap induced by quantum tunnelling between surfaces exhibits spin texture modulation at low energies but respects TR invariance. These spin phenomena and the control of their Fermi surface geometrical phase first demonstrated in our experiments pave the way for the future realization of many predicted exotic magnetic phenomena of topological origin.Comment: 38 pages, 18 Figures, Includes new text, additional datasets and interpretation beyond arXiv:1206.2090, for the final published version see Nature Physics (2012