The Role of TLR4 in the Paclitaxel Effects on Neuronal Growth In Vitro

Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. © 2013 Ustinova et al

Use of clustering in human solutions of the traveling salesperson problem

The traveling salesperson problem (TSP) is an NP-Hard problem that computers find difficult to solve. Humans are surprisingly good at solving the TSP, with solutions within 10% of optimal for problems with up to 100 points, constructed in time linear with the number of points. We propose that humans solve the TSP by initially clustering the points and then connecting them first within and then between clusters. In this study, 67 participants first clustered 40 stimuli and then solved them as TSPs. Strikingly, participants' TSP solutions perfectly followed their clusters for 52% of the stimuli. Further, participants' TSP solutions' were more congruent with their clusters for stimuli with statistically higher levels of clustered structure. This provides strong evidence for the clustering proposal. Random TSP solutions, however, showed no such congruence to cluster structure. These findings suggest that clustering might be a fundamental ability for reasoning about graph-theoretic algorithmic problems

The role of clustering in the efficient solution of small Traveling Salesperson Problems

Human solutions to the Traveling Salesperson Problem (TSP) are surprisingly close to optimal and unexpectedly efficient. We posit that humans solve instances of the TSP by first clustering the points into smaller regions and then solving each cluster as a simpler TSP. Prior research has shown that participants cluster visual stimuli reliably. That is, their clustering and re-clustering of the same stimulus are similar, especially when the stimulus is relatively more clustered. In this study, participants solved the same TSP instances twice. On the second presentation, half of the instances were flipped about the horizontal and vertical axes. Participants solved the TSP reliably, with their two tours of the same instance sharing 77 percent of the same edges on average. In addition, within-participant reliability was higher for more clustered versus more dispersed instances. Our findings are consistent with the proposal that people use clustering strategies to solve the TSP