Allosteric conversation in the androgen receptor ligand-binding domain surfaces

Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design.

Long-lived States in an intrinsically disordered protein domain

Long-lived states (LLS) are relaxation-favoured eigenstates of J-coupled magnetic nuclei. LLS were measured, along with classical 1H and 15 N relaxation rate constants, in aminoacids of the N-terminal Unique domain of the c-Src kinase (USrc), which is disordered in vitro under physiological conditions. The relaxation rates of LLS are a probe for motions and interactions in biomolecules. LLS of the aliphatic protons of glycines, with lifetimes ca. four times longer than their spin-lattice relaxation times, are reported for the first time in an intrinsically disordered protein domain (IDP). LLS relaxation experiments were integrated with 2D spectroscopy methods, further adapting them for studies on proteins.

A maximal domain of preferences for tops-only rules in the division problem

The division problem consists of allocating an amount M of a perfectly divisible good among a group of n agents. Sprumont (1991) showed that if agents have single-peaked preferences over their shares, the uniform rule is the unique strategy-proof, efficient, and anonymous rule. Ching and Serizawa (1998) extended this result by showing that the set of single-plateaued preferences is the largest domain, for all possible values of M, admitting a rule (the extended uniform rule) satisfying strategy-proofness, efficiency and symmetry. We identify, for each M and n, a maximal domain of preferences under which the extended uniform rule also satisfies the properties of strategy-proofness, efficiency, continuity, and "tops-onlyness". These domains (called weakly single-plateaued) are strictly larger than the set of single-plateaued preferences. However, their intersection, when M varies from zero to infinity, coincides with the set of single-plateaued preferences.

Lectura de máquinas recreativas con terminal portátil

Servimatic S.L. utiliza un terminal electrónico, prácticamente obsoleto hoy en día, el cual lleva incorporado un lector de infrarrojos y una impresora integrada parcialmente. El problema se plantea cuando la empresa encargada de los componentes de infrarrojos y de las impresoras prevé, en un futuro próximo, el cierre del ciclo de vida de estos productos, dejando de dar soporte de mantenimiento y reparación de los mismos. Nuestra intención es realizar un sistema que nos permita automatizar el proceso de recaudación de máquinas recreativas, capaz de adaptarse a la gran variedad de fabricantes que conviven en el mercado y de sustituir el actual sistema.

Scheduling of straddle carriers in a container terminal

Report for the scientific sojourn at the University of California at Berkeley between September 2007 to February 2008. The globalization combined with the success of containerization has brought about tremendous increases in the transportation of containers across the world. This leads to an increasing size of container ships which causes higher demands on seaport container terminals and their equipment. In this situation, the success of container terminals resides in a fast transhipment process with reduced costs. For these reasons it is necessary to optimize the terminal’s processes. There are three main logistic processes in a seaport container terminal: loading and unloading of containerships, storage, and reception/deliver of containers from/to the hinterland. Moreover there is an additional process that ensures the interconnection between previous logistic activities: the internal transport subsystem. The aim of this paper is to optimize the internal transport cycle in a marine container terminal managed by straddle carriers, one of the most used container transfer technologies. Three sub-systems are analyzed in detail: the landside transportation, the storage of containers in the yard, and the quayside transportation. The conflicts and decisions that arise from these three subsystems are analytically investigated, and optimization algorithms are proposed. Moreover, simulation has been applied to TCB (Barcelona Container Terminal) to test these algorithms and compare different straddle carrier’s operation strategies, such as single cycle versus double cycle, and different sizes of the handling equipment fleet. The simulation model is explained in detail and the main decision-making algorithms from the model are presented and formulated.