Accelerating SAT solving with best-first-search

Solvers for Boolean satisfiability (SAT), like other algorithms for NP-complete problems, tend to have a heavy-tailed runtime distribution. Successful SAT solvers make use of frequent restarts to mitigate this problem by abandoning unfruitful parts of the search space after some time. Although frequent restarting works fairly well, it is a quite simplistic technique that does not do anything explicitly to make the next try better than the previous one. In this paper, we suggest a more sophisticated method: using a best-first-search approach to quickly move between different parts of the search space. This way, the search can always focus on the most promising region. We investigate empirically how the performance of frequent restarts, best-first-search, and a combination of the two compare to each other. Our findings indicate that the combined method works best, improving 36-43\% on the performance of frequent restarts on the used set of benchmark problems

Isolation, chemical and functional characterization of several new K+-channel blocking peptides from the venom of the scorpion Centruroides tecomanus

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The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation

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Capture at the ER-Mitochondrial Contacts Licenses IP

Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when ‘parked’, mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication

Probing pattern and dynamics of disulfide bridges using synthesis and NMR of an ion channel blocker peptide toxin with multiple diselenide bonds

Anuroctoxin (AnTx), a 35-amino-acid scorpion toxin contg. four disulfide bridges, is a high affinity blocker of the voltage-gated potassium channel Kv1.3, but also blocks Kv1.2. To improve the potential therapeutic use of the toxin, we have designed a double substituted analog, [N17A/F32T]-AnTx, which showed comparable Kv1.3 affinity to the wild-type peptide, but 2500-fold increase in the selectivity for Kv1.3 over Kv1.2. In the present study we have achieved the chem. synthesis of a Sec-analog in which all cysteine (Cys) residues have been replaced by selenocysteine (Sec) forming four diselenide bonds. To the best of our knowledge this is the first time to replace, by chem. synthesis, all disulfide bonds with isosteric diselenides in a peptide/protein. Gratifyingly, the key pharmacol. properties of the Sec-[N17A/F32T]-AnTx are retained since the peptide is functionally active. We also propose here a combined exptl. and theor. approach including NOE- and 77Se-based NMR supplemented by MD simulations for conformational and dynamic characterization of the Sec-[N17A/F32T]-AnTx. The use of such combined approach allowed us to attain unequivocal assignment of all four diselenide bonds and supplemental MD simulations allowed to characterize the conformational dynamics around each disulfide/diselenide bridge. [on SciFinder(R)