Approximating the Termination Value of One-Counter MDPs and Stochastic Games

One-counter MDPs (OC-MDPs) and one-counter simple stochastic games (OC-SSGs) are 1-player, and 2-player turn-based zero-sum, stochastic games played on the transition graph of classic one-counter automata (equivalently, pushdown automata with a 1-letter stack alphabet). A key objective for the analysis and verification of these games is the termination objective, where the players aim to maximize (minimize, respectively) the probability of hitting counter value 0, starting at a given control state and given counter value. Recently, we studied qualitative decision problems ("is the optimal termination value = 1?") for OC-MDPs (and OC-SSGs) and showed them to be decidable in P-time (in NP and coNP, respectively). However, quantitative decision and approximation problems ("is the optimal termination value ? p", or "approximate the termination value within epsilon") are far more challenging. This is so in part because optimal strategies may not exist, and because even when they do exist they can have a highly non-trivial structure. It thus remained open even whether any of these quantitative termination problems are computable. In this paper we show that all quantitative approximation problems for the termination value for OC-MDPs and OC-SSGs are computable. Specifically, given a OC-SSG, and given epsilon > 0, we can compute a value v that approximates the value of the OC-SSG termination game within additive error epsilon, and furthermore we can compute epsilon-optimal strategies for both players in the game. A key ingredient in our proofs is a subtle martingale, derived from solving certain LPs that we can associate with a maximizing OC-MDP. An application of Azuma's inequality on these martingales yields a computable bound for the "wealth" at which a "rich person's strategy" becomes epsilon-optimal for OC-MDPs.Comment: 35 pages, 1 figure, full version of a paper presented at ICALP 2011, invited for submission to Information and Computatio

Heme oxygenase 1 is differentially involved in blood flow-dependent arterial remodeling: role of inflammation, oxidative stress, and nitric oxide

Heme oxygenase 1 is induced by hemodynamic forces in vascular smooth muscle and endothelial cells. We investigated the involvement of heme oxygenase 1 in flow (shear stress)-dependent remodeling. Two or 14 days after ligation of mesenteric resistance arteries, vessels were isolated. In rats, at 14 days, diameter increased by 23% in high-flow arteries and decreased by 22% in low-flow arteries compared with normal flow vessels. Heme oxygenase activity inhibition using Tin-protoporphyrin abolished diameter enlargement in high-flow arteries and accentuated arterial narrowing in low-flow arteries (32% diameter decrease versus 22% in control). Two days after ligation, heme oxygenase 1 expression increased in high-flow and low-flow vessels, in association with a reduced mitochondrial aconitase activity (marker of oxidative stress) in high-flow arteries only. Inhibition of macrophage infiltration (clodronate) decreased heme oxygenase 1 induction in low-flow but not in high-flow arteries. Similarly, inhibition of NADPH oxidase activity (apocynin) decreased heme oxygenase 1 induction in low-flow but not high-flow arteries. However, dihydroethidium staining was higher in high-flow and low-flow compared with normal flow arteries. In arteries cannulated in an arteriograph, heme oxygenase 1 mRNA increased in a flow-dependent manner and was abolished by N(G)-nitro-l-arginine methyl ester, catalase, or mitochondrial electron transport chain inhibition. Furthermore, heme oxygenase 1 induction using cobalt-protoporphyrin restored altered high-flow remodeling in endothelial NO synthase knockout mice. Thus, in high-flow remodeling, heme oxygenase 1 induction depends on shear stress-generated NO and mitochondria-derived hydrogen peroxide. In low-flow remodeling, heme oxygenase 1 induction requires macrophage infiltration and is mediated by NADPH oxidase-derived superoxide

Phonon-mediated thermal conductance of mesoscopic wires with rough edges

We present an analysis of acoustic phonon propagation through long, free-standing, insulating wires with rough surfaces. Due to a crossover from ballistic propagation of the lowest-frequency phonon mode at $\omega <\omega _{1}=\pi c/W$ to a diffusive (or even localized) behavior upon the increase of phonon frequency, followed by re-entrance into the quasi-ballistic regime, the heat conductance of a wire acquires an intermediate tendency to saturate within the temperature range $T\sim \hbar \omega_{1}/k_{B}$.Comment: 4 pages, 3 figures included; minor changes and corrections, figures 1 and 2 replaced by better versions; to appear in PRB Brief Report

Message in a bubble: the translational potential of extracellular vesicles

Extracellular vesicles (EVs) are small, membrane-enclosed vesicles released by cells into the extracellular milieu. They are found in all body fluids and contain a variety of functional cargo including DNA, RNA, proteins, glycoproteins and lipids, able to provoke phenotypic responses in cells, both locally and at distant sites. They are implicated in a wide array of physiological and pathological processes and hence have attracted considerable attention in recent years as potential therapeutic targets, drug delivery vehicles and biomarkers of disease. In this review we summarise the major functions of EVs in health and disease and discuss their translational potential, highlighting opportunities of – and challenges to – capitalising on our rapidly increasing understanding of EV biology for patient benefit

Service innovations: A depersonalisation research unit progress report

Depersonalisation was described clinically over 100 years ago, yet there has been little research into this interesting but distressing psychiatric disorder. The symptom of depersonalisation can occur alone or in the context of other psychiatric and neurological illnesses and is characterised by the experience of detachment from one's senses and the outside environment, and may be present for several years without remission. Two years after the establishment of the depersonalisation research unit at the Maudsley Hospital, London, we report on current neurobiological and clinical research findings, including functional magnetic resonance imaging, psychophysiology and neuroendocrinology and progress regarding the development of effective treatments

MAGDALENA PERDOMO ACEDO [Material gráfico]

ESPOSA DE JUAN PADILLA PAZCopia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications)

Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling

Differential regulation of the μ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. We used biophysical approaches to quantify spatiotemporal MOR signaling in response to different ligands. In human embryonic kidney (HEK) 293 cells over-expressing MOR, morphine caused a Gβγ-dependent increase in plasma membrane-localized protein kinase C (PKC) activity, which resulted in a restricted distribution of MOR within the plasma membrane and induced sustained cytosolic extracellular signal-regulated kinase (ERK) signaling. In contrast, the synthetic opioid peptide DAMGO ([D-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin) enabled receptor redistribution within the plasma membrane, resulting in transient increases in cytosolic and nuclear ERK activity, and, subsequently, receptor internalization. When Gβγ subunits or PKCα activity was inhibited or when the carboxyl-terminal phosphorylation sites of MOR were mutated, morphine-activated MOR was released from its restricted plasma membrane localization and stimulated a transient increase in cytosolic and nuclear ERK activity in the absence of receptor internalization. Thus, these data suggest that the ligand-induced redistribution of MOR within the plasma membrane, and not its internalization, controls its spatiotemporal signaling