Zinc inhibits TRPV1 to alleviate chemotherapy-induced neuropathic pain

Zinc is a transition metal that has a long history of use as an anti-inflammatory agent. It also soothes pain sensations in a number of animal models. However, the effects and mechanisms of zinc on chemotherapy-induced peripheral neuropathy remain unknown. Here we show that locally injected zinc markedly reduces neuropathic pain in male and female mice induced by paclitaxel, a chemotherapy drug, in a TRPV1-dependent manner. Extracellularly applied zinc also inhibits the function of TRPV1 expressed in HEK293 cells and mouse DRG neurons, which requires the presence of zinc-permeable TRPA1 to mediate entry of zinc into the cytoplasm. Moreover, TRPA1 is required for zinc-induced inhibition of TRPV1-mediated acute nociception. Unexpectedly, zinc transporters, but not TRPA1, are required for zinc-induced inhibition of TRPV1-dependent chronic neuropathic pain produced by paclitaxel. Together, our study demonstrates a novel mechanism underlying the analgesic effect of zinc on paclitaxel-induced neuropathic pain that relies on the function of TRPV1

X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis

BACKGROUND: Mutation in the Wiskott-Aldrich syndrome Protein (WASP) causes Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN). The majority of missense mutations causing WAS and XLT are found in the WH1 (WASP Homology) domain of WASP, known to mediate interaction with WIP (WASP Interacting Protein) and CIB1 (Calcium and Integrin Binding). RESULTS: We analyzed two WASP missense mutants (L46P and A47D) causing XLT for their effects on T cell chemotaxis. Both mutants, WASP(R)(L46P) and WASP(R)(A47D) (S1-WASP shRNA resistant) expressed well in Jurkat(WASP-KD) T cells (WASP knockdown), however expression of these two mutants did not rescue the chemotaxis defect of Jurkat(WASP-KD) T cells towards SDF-1α. In addition Jurkat(WASP-KD) T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1α. WASP exists in a closed conformation in the presence of WIP, however both the mutants (WASP(R)(L46P) and WASP(R)(A47D)) were found to be in an open conformation as determined in the bi-molecular complementation assay. WASP protein undergoes proteolysis upon phosphorylation and this turnover of WASP is critical for T cell migration. Both the WASP mutants were found to be stable and have reduced tyrosine phosphorylation after stimulation with SDF-1α. CONCLUSION: Thus our data suggest that missense mutations WASP(R)(L46P) or WASP(R)(A47D) affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12929-014-0091-1) contains supplementary material, which is available to authorized users

A Decomposition-Based Heuristic Method for Inventory Routing Problem

International audienceThe inventory routing problem (IRP) arises in a broad spectrum of real-life applications related to joint decisions of inventory and routing. In the basic IRP, a supplier has to make decisions about the delivery timing, delivered quantity of a single product and routing with a single vehicle to a set of retailers without backlog. It poses computational challenge due to its natural complexity. To tackle this problem, we propose a two-phase decomposition-based heuristic method. In Phase 1, a logic-based Benders like decomposition method is employed to first determine the retailers' replenishments, followed by the routing decisions individually for each period. Valid cuts, inequalities for diversification constraints and for greedy search are employed. Then, the solutions obtained in Phase 1 are improved with a restricted mixed integer linear programming (MILP) model in Phase 2. Computational experiments are conducted on 220 benchmark problem instances with up to 200 retailers and 6 periods. The results show the high performance of the proposed method and it is comparable to the state-of-the-art heuristics in terms of both efficiency and effectiveness

A Relax-and-fix Heuristic for Multiple Team Formation Problem

International audienceThe multi-functional team formation problem (TFP) aims to construct an appropriate team balancing the coverage gains of the skills set and the cost such as communication and individual cost. Existing works focus on optimizing these objectives separately although they impact the team gain together. In this paper, we study a new problem that considers multiple projects and aims to minimize the total cost of communication and individual team member. The problem is named after the Team Formation Problem for multiple projects (TFP-MP). The problem is firstly formulated as a constrained quadratic set covering problem, which is further equivalently transformed to a mixed integer programming (MIP) model. To solve the problem, we propose a relax-and-fix heuristic by exploring the model structure and we evaluate the computational performances by solving different problem instances based randomly generated data. The computational experiment results show that the proposed relax-and-fix heuristic algorithm can solve large instances

Approximate and exact algorithms for an energy minimization traveling salesman problem

International audienceEnergy saving is a great challenge for clean transportation. In this paper, we study the Energy Minimization Traveling Salesman Problem (EMTSP), which is a generation of the classical Traveling Salesman Problem (TSP), and an important theoretical basis and a special case of the Energy Minimization Vehicle Routing Problem (EMVRP). The objective of the studied problem is to minimize the sum of the product of load (including curb weight of the vehicle) and traveled distances. An approximation algorithm based on the Christofides's Heuristic is proposed and its worst-case ratio bound is proven. A branch and bound (B&B) algorithm integrated with a fast 1-tree based lower bound is developed to obtain optimal solutions. The results of computational experiments show the efficiency and the effectiveness of the B&B algorithm, as well as the heuristic methods

Membrane effect of geosynthetic reinforcement subjected to localized sinkholes

Membrane effect often occurs in geosynthetic-reinforced structures, where subsoil may have voids or sinkholes. An analytical model is proposed to estimate membrane effect of geosynthetic reinforcement subjected to localized sinkholes. The upper interface friction in subsided area and vertical deformation of supporting soil in anchorage area are considered simultaneously. The maximum geosynthetic strain and the maximum surface settlement, served as key design points, can be determined. Based on the proposed method verified using a full-scale experiment, a parametric study is conducted. The results show that ignoring upper interface friction results in significant undervaluation of maximum geosynthetic strain, and ignoring vertical deformation of supporting soil leads to obvious undervaluation of maximum surface settlement. A practical design framework is also proposed and it is an applicable tool for preliminary design of geosynthetic-reinforced structures especially for cases with soft ground.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author