ATF4-SLC7A11-GSH axis mediates the acquisition of immunosuppressive properties by activated CD4+ T cells in low arginine condition.

The tumor microenvironment (TME) is restricted in metabolic nutrients including the semi-essential amino acid arginine. While complete arginine deprivation causes T cell dysfunction, it remains unclear how arginine levels fluctuate in the TME to shape T cell fates. Here, we find that the 20-µM low arginine condition, representing the levels found in the plasma of patients with cancers, confers Treg-like immunosuppressive capacities upon activated T cells. In vivo mouse tumor models and human single-cell RNA-sequencing datasets reveal positive correlations between low arginine condition and intratumoral Treg accumulation. Mechanistically, low arginine-activated T cells engage in metabolic and transcriptional reprogramming, using the ATF4-SLC7A11-GSH axis, to preserve their suppressive function. These findings improve our understanding of the role of arginine in human T cell biology with potential applications for immunotherapy strategies.

On Hierarchical Multi-UAV Dubins Traveling Salesman Problem Paths in a Complex Obstacle Environment.

This article aims to solve a hierarchical multi-UAV Dubins traveling salesman problem (HMDTSP). Optimal hierarchical coverage and multi-UAV collaboration are achieved by the proposed approaches in a 3-D complex obstacle environment. A multi-UAV multilayer projection clustering (MMPC) algorithm is presented to reduce the cumulative distance from multilayer targets to corresponding cluster centers. A straight-line flight judgment (SFJ) was developed to reduce the calculation of obstacle avoidance. An improved adaptive window probabilistic roadmap (AWPRM) algorithm is addressed to plan obstacle-avoidance paths. The AWPRM improves the feasibility of finding the optimal sequence based on the proposed SFJ compared with a traditional probabilistic roadmap. To solve the solution to TSP with obstacles constraints, the proposed sequencing-bundling-bridging (SBB) framework combines the bundling ant colony system (BACS) and homotopic AWPRM. An obstacle-avoidance optimal curved path is constructed with a turning radius constraint based on the Dubins method and followed up by solving the TSP sequence. The results of simulation experiments indicated that the proposed strategies can provide a set of feasible solutions for HMDTSPs in a complex obstacle environment.

Trajectory Consensus for Coordination of Multiple Curvature-Bounded Vehicles.

This article addresses the trajectory consensus problem of coordinating the trajectories of vehicles at multiple future time points. The objective is the consensus of the geometry of the vehicles' planned trajectories. The geometric feature of trajectories is parameterized by a set of trajectory states defined as required lengths along the trajectory to reduce the distance to its ending point to specific values. To solve this special consensus problem involving coupled state variables, the conventional consensus model is extended by attaching it to a mapping from the state variables to the trajectory's geometry. This mapping is established using a homotopic structure that creates a compact and efficient form for the mapping. The geometry of the homotopic structure is based on the shapes of its envelopes, and the elements in the structure are derived from their deformation. Through a homotopic search in the structure, an asymptotic consensus of trajectory states is achieved. Simulation results show the proposed coupled state consensus method can achieve better performance on the consensus of multiple vehicles than the conventional isolated state consensus method.

Single-Beat Measurement of Left Ventricular Contractility in Normothermic Ex Situ Perfused Porcine Hearts.

OBJECTIVE: For heart transplantation, donor heart status needs to be evaluated during normothermic ex situ perfusion (ESHP). Left ventricular end-systolic elastance (E es) measures the left ventricular contractile function, but its estimation requires the occlusion of the left atrium line in the ESHP, which may cause unnecessary damage to the donor heart. We present a novel method to quantify E es based on hemodynamic parameters obtained from only one steady-state PV loop in ESHP. METHODS: E es was obtained by the end-systolic point (P es, V es) and the volume axis intercept point of E es (V 0). V 0 was estimated through the support vector machine regression (SVR) method using parameters derived from the measured steady-state PV loop. To achieve high V 0 estimation accuracy, a filter-based support vector machine recursive feature elimination method (SVM-RFE) algorithm selected the parameters for V 0 estimation. Hemodynamic parameter samples (n = 101) obtained from ESHP experiments with pig's hearts were used to train the E es calculation model. Early post-transplantation outcomes in six heart transplantation experiments were then estimated from the trained E es calculation model. RESULTS: E es calculated by the proposed method agreed well with conventional multi-beat estimates obtained by the occlusion process (r = 0.88, p < 0.001, n = 101) and was capable of predicting the early post-transplant cardiac index (r = 0.84, p < 0.05, n = 6). CONCLUSION: This method effectively assesses left ventricular contractility during ESHP and predicts early post-transplant outcomes in the porcine model. SIGNIFICANCE: Our approach is the first to quantify E es by estimating V 0 from steady-state beats in ESHP for accurately predicting early post-transplantation outcomes.

Primed Left Ventricle Heart Perfusion Creates Physiological Aortic Pressure in Porcine Hearts.

This article presents a primed left ventricle heart perfusion method to generate physiologic aortic pressure (AoP) and perform functional assessment. Isolated hearts of male Yorkshire pigs were used to study the hemodynamic behaviors of AoPs generated in the primed left ventricle heart perfusion (n = 6) and conventional (zero-loaded left ventricle) Langendorff perfusion (n = 6). The measurement results show that left ventricular pressure generated in the primed left ventricle heart perfusion is a determinant of physiologic AoP (i.e. systolic and diastolic pressures within physiologic range). The aortic pulse pressure (systolic pressure = 124.5 ± 1.7 mm Hg, diastolic pressure = 87.8 ± 0.9 mm Hg, aortic pulse pressure = 36.7 ± 2.6 mm Hg) from the primed left ventricle heart perfusion represents close match with the in vivo physiologic data. The volume in the left ventricle remains constant throughout the primed left ventricle heart perfusion, which allows us to perform isovolumetric left ventricular pressure measurement in ex vivo heart perfusion (EVHP). Left ventricular contractility measurements (maximum and minimum rates of left ventricular pressure change) were derived for cardiac assessment. In summary, the proposed primed left ventricle heart perfusion method is able to create physiologic AoP and enables left ventricular functional assessment in EVHP in porcine hearts.