Spatial Modeling of Vesicle Transport and the Cytoskeleton: The Challenge of Hitting the Right Road

The membrane trafficking machinery provides a transport and sorting system for many cellular proteins. We propose a mechanistic agent-based computer simulation to integrate and test the hypothesis of vesicle transport embedded into a detailed model cell. The method tracks both the number and location of the vesicles. Thus both the stochastic properties due to the low numbers and the spatial aspects are preserved. The underlying molecular interactions that control the vesicle actions are included in a multi-scale manner based on the model of Heinrich and Rapoport (2005). By adding motor proteins we can improve the recycling process of SNAREs and model cell polarization. Our model also predicts that coat molecules should have a high turnover at the compartment membranes, while the turnover of motor proteins has to be slow. The modular structure of the underlying model keeps it tractable despite the overall complexity of the vesicle system. We apply our model to receptor-mediated endocytosis and show how a polarized cytoskeleton structure leads to polarized distributions in the plasma membrane both of SNAREs and the Ste2p receptor in yeast. In addition, we can couple signal transduction and membrane trafficking steps in one simulation, which enables analyzing the effect of receptor-mediated endocytosis on signaling

Cobalamin in inflammation III — glutathionylcobalamin and methylcobalamin/adenosylcobalamin coenzymes: the sword in the stone? How cobalamin may directly regulate the nitric oxide synthases

Several mysteries surround the structure and function of the nitric oxide synthases (NOS). The NOS oxygenase domain structure is unusually open with a large area of solvent that could accommodate an unidentified ligand. The exact mechanism of the two-step five-electron monoxygenation of arginine to NG-hydroxy-L-arginine, thence to citrulline and nitric oxide (NO), is not clear, particularly as arginine/NG-hydroxy-L-arginine is bound at a great distance to the supposed catalytic heme Fe [III], as the anti-stereoisomer. The Return of the Scarlet Pimpernel Paper proposed that cobalamin is a primary indirect regulator of the NOS. An additional direct regulatory effect of the ‘base-off’ dimethylbenzimidazole of glutathionylcobalamin (GSCbl), which may act as a sixth ligand to the heme iron, promote Co-oriented, BH4/BH3 radical catalysed oxidation of L-arginine to NO, and possibly regulate the rate of inducible NOS/NO production by the NOS dimers, is further advanced. The absence of homology between the NOS and methionine synthase/methylmalonyl CoA mutase may enable GSCbl to regulate both sets of enzymes simultaneously by completely separate mechanisms. Thus, cobalamin may exert central control over both pro-and anti-inflammatory systems

Affective interpersonal touch in close relationships: a cross-cultural perspective

Interpersonal touch behavior differs across cultures, yet no study to date has systematically tested for cultural variation in affective touch, nor examined the factors that might account for this variability. Here, over 14,000 individuals from 45 countries were asked whether they embraced, stroked, kissed, or hugged their partner, friends, and youngest child during the week preceding the study. We then examined a range of hypothesized individual-level factors (sex, age, parasitic history, conservatism, religiosity, and preferred interpersonal distance) and cultural-level factors (regional temperature, parasite stress, regional conservatism, collectivism, and religiosity) in predicting these affective-touching behaviors. Our results indicate that affective touch was most prevalent in relationships with partners and children, and its diversity was relatively higher in warmer, less conservative, and religious countries, and among younger, female, and liberal people. This research allows for a broad and integrated view of the bases of cross-cultural variability in affective touch

Potential of pyrazolooxadiazinone derivatives as serine protease inhibitors

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