Neutrophil Spontaneous Death Is Mediated by Down-Regulation of Autocrine Signaling through GPCR, PI3Kγ\gamma, ROS, and actin

Neutrophil spontaneous apoptosis plays a crucial role in neutrophil homeostasis and the resolution of inflammation. We previously established Akt deactivation as a key mediator of this tightly regulated cellular death program. Nevertheless, the molecular mechanisms governing the diminished Akt activation were not characterized. Here, we report that Akt deactivation during the course of neutrophil spontaneous death was a result of reduced PtdIns(3,4,5)P3 level. The phosphatidylinositol lipid kinase activity of $PI3K\gamma$, but not class IA PI3Ks, was significantly reduced during neutrophil death. The production of PtdIns(3,4,5)P3 in apoptotic neutrophils was mainly maintained by autocrinely released chemokines that elicited $PI3K\gamma$ activation via G protein–coupled receptors. Unlike in other cell types, serum-derived growth factors did not provide any survival advantage in neutrophils. $PI3K\gamma$, but not class IA PI3Ks, was negatively regulated by gradually accumulated ROS in apoptotic neutrophils, which suppressed $PI3K\gamma$ activity by inhibiting an actin-mediated positive feedback loop. Taken together, these results provide insight into the mechanism of neutrophil spontaneous death and reveal a cellular pathway that regulates PtdIns(3,4,5)P3/Akt in neutrophils

HyP-DESPOT: A Hybrid Parallel Algorithm for Online Planning under Uncertainty

Planning under uncertainty is critical for robust robot performance in uncertain, dynamic environments, but it incurs high computational cost. State-of-the-art online search algorithms, such as DESPOT, have vastly improved the computational efficiency of planning under uncertainty and made it a valuable tool for robotics in practice. This work takes one step further by leveraging both CPU and GPU parallelization in order to achieve near real-time online planning performance for complex tasks with large state, action, and observation spaces. Specifically, we propose Hybrid Parallel DESPOT (HyP-DESPOT), a massively parallel online planning algorithm that integrates CPU and GPU parallelism in a multi-level scheme. It performs parallel DESPOT tree search by simultaneously traversing multiple independent paths using multi-core CPUs and performs parallel Monte-Carlo simulations at the leaf nodes of the search tree using GPUs. Experimental results show that HyP-DESPOT speeds up online planning by up to several hundred times, compared with the original DESPOT algorithm, in several challenging robotic tasks in simulation

Analysis of an Impulsive One-Predator and Two-Prey System with Stage-Structure and Generalized Functional Response

An impulsive one-predator and two-prey system with stage-structure and generalized functional response is proposed and analyzed. By reasonable assumption and theoretical analysis, we obtain conditions for the existence and global attractivity of the predator-extinction periodic solution. Sufficient conditions for the permanence of this system are established via impulsive differential comparison theorem. Furthermore, abundant results of numerical simulations are given by choosing two different and concrete functional responses, which indicate that impulsive effects, stage-structure, and functional responses are vital to the dynamical properties of this system. Finally, the biological meanings of the main results and some control strategies are given

Cigarette Smoke (CS) and Nicotine Delay Neutrophil Spontaneous Death via Suppressing Production of Diphosphoinositol Pentakisphosphate

Diphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil death can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease

Myeloid Cell-Derived Reactive Oxygen Species Externally Regulate the Proliferation of Myeloid Progenitors in Emergency Granulopoiesis

SummaryThe cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1+ myeloid cells were uniformly distributed in the BM, and all c-kit+ progenitor cells were adjacent to Gr1+ myeloid cells. Inflammation-induced ROS production in the BM played a critical role in myeloid progenitor expansion during emergency granulopoiesis. ROS elicited oxidation and deactivation of phosphatase and tensin homolog (PTEN), resulting in upregulation of PtdIns(3,4,5)P3 signaling in BM myeloid progenitors. We further revealed that BM myeloid cell-produced ROS stimulated proliferation of myeloid progenitors via a paracrine mechanism. Taken together, our results establish that phagocytic NADPH oxidase-mediated ROS production by BM myeloid cells plays a critical role in mediating emergency granulopoiesis during acute infection