Analysis of stress-induced hepatic gene expression in rainbow trout (Oncorhynchus mykiss) selected for high- and low-responsiveness to stress

The production and welfare of intensively reared fish would be improved by reducing stress responsiveness. One approach to achieving this goal is selective breeding utilising stress-responsive genes as direct genetic markers of the desirable trait. As a first step in this process, microarray analysis has been carried out on liver tissues of rainbow trout selectively bred for high (HR) or low (LR) responsiveness to a stressor. Microarray hybridizations provided gene expression profiles for pooled samples of fish confined for 6 h, 24 h and 168 h and for individual fish (168 h only). 161 genes were shown to be differentially regulated in HR and LR fish during confinement exposure and eight of these gene expression profiles were validated by quantitative PCR. Genes of particular interest included intelectin-2 precursor which showed greater than 100-fold higher expression in HR fish compared to LR fish irrespective of whether the fish were confined or not; interferon inducible transmembrane protein 3 which was differentially stress-induced between the two lines; and hepatic pro-opiomelanocortin B (POMC B) which was upregulated during stress in HR fish but downregulated in LR fish. All these offer potential as direct markers of low stress responsiveness in a marker-assisted selection scheme. (C) 2011 Elsevier Inc. All rights reserved.European Commission, the Natural Environment Research Council of the UK, and Enterprise Ireland. European Commission support was through contract no. Q5RS-2001-002211-STRESSGENES, contract no. 513692-AQUAFIRST, and a Marie Curie Host Fellowship to Jhansi K. Pemmasani (contract no. MTKD-CT-2004-013701-DIAGNOMICS).peer-reviewe

Analysis of stress-induced hepatic gene expression in rainbow trout (Oncorhynchus mykiss) selected for high- and low-responsiveness to stress

The production and welfare of intensively reared fish would be improved by reducing stress responsiveness. One approach to achieving this goal is selective breeding utilising stress-responsive genes as direct genetic markers of the desirable trait. As a first step in this process, microarray analysis has been carried out on liver tissues of rainbow trout selectively bred for high (HR) or low (LR) responsiveness to a stressor. Microarray hybridizations provided gene expression profiles for pooled samples of fish confined for 6 h, 24 h and 168 h and for individual fish (168 h only). 161 genes were shown to be differentially regulated in HR and LR fish during confinement exposure and eight of these gene expression profiles were validated by quantitative PCR. Genes of particular interest included intelectin-2 precursor which showed greater than 100-fold higher expression in HR fish compared to LR fish irrespective of whether the fish were confined or not; interferon inducible transmembrane protein 3 which was differentially stress-induced between the two lines; and hepatic pro-opiomelanocortin B (POMC B) which was upregulated during stress in HR fish but downregulated in LR fish. All these offer potential as direct markers of low stress responsiveness in a marker-assisted selection scheme. (C) 2011 Elsevier Inc. All rights reserved.European Commission, the Natural Environment Research Council of the UK, and Enterprise Ireland. European Commission support was through contract no. Q5RS-2001-002211-STRESSGENES, contract no. 513692-AQUAFIRST, and a Marie Curie Host Fellowship to Jhansi K. Pemmasani (contract no. MTKD-CT-2004-013701-DIAGNOMICS)

Epidemiology and Clinical Outcomes of Patients With Inflammatory Bowel Disease Presenting With Acute Coronary Syndrome.

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased acute coronary syndrome (ACS) risk. Data are limited regarding the epidemiology and outcomes of ACS in patients with IBD. METHODS: A retrospective cohort analysis of patients with IBD admitted for ACS in the U.S. Healthcare Cost and Utilization Project National Inpatient Sample for 2005 to 2015 was conducted. We analyzed trends in IBD-ACS admissions and mortality, differences in risk profiles, management strategies, and in-hospital mortality between IBD-ACS and non-IBD ACS and between ulcerative colitis (UC) and Crohn disease (CD). RESULTS: We studied 6,872,415 non-IBD ACS and 24,220 IBD-ACS hospitalizations (53% with CD). During the study period, the number of hospitalizations for IBD-ACS increased, particularly those related to CD. Compared with non-IBD ACS, patients with IBD-ACS had a lower prevalence of cardiovascular risk factors and similar rates of coronary angiography and revascularization. The in-hospital mortality rate was lower with IBD-ACS (3.9%) compared with non-IBD ACS (5.3%; odds ratio, 0.81; 95% confidence interval, 0.69-0.96; P = 0.011) and was stable between 2005 and 2015. Risk factors, ACS management strategies, and mortality were similar between CD and UC. Coagulopathy, weight loss, and gastrointestinal bleeding were more frequent in IBD-ACS and were strong independent predictors of mortality. CONCLUSIONS: Hospitalizations for ACS in patients with IBD increased in recent years but death rates were stable. The ACS-related risk profiles and mortality were modestly favorable with IBD-ACS than with non-IBD ACS and were similar between CD and UC. Complications more frequently associated with IBD were strongly associated with mortality. These findings indicate that aggressive management of IBD and ACS comorbidities is required to improve outcomes

WIP1 phosphatase as a potential therapeutic target in neuroblastoma.

The wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that negatively regulates multiple proteins involved in DNA damage response including p53, CHK2, Histone H2AX, and ATM, and it has been shown to be overexpressed or amplified in human cancers including breast and ovarian cancers. We examined WIP1 mRNA levels across multiple tumor types and found the highest levels in breast cancer, leukemia, medulloblastoma and neuroblastoma. Neuroblastoma is an exclusively TP53 wild type tumor at diagnosis and inhibition of p53 is required for tumorigenesis. Neuroblastomas in particular have previously been shown to have 17q amplification, harboring the WIP1 (PPM1D) gene and associated with poor clinical outcome. We therefore sought to determine whether inhibiting WIP1 with a selective antagonist, GSK2830371, can attenuate neuroblastoma cell growth through reactivation of p53 mediated tumor suppression. Neuroblastoma cell lines with wild-type TP53 alleles were highly sensitive to GSK2830371 treatment, while cell lines with mutant TP53 were resistant to GSK2830371. The majority of tested neuroblastoma cell lines with copy number gains of the PPM1D locus were also TP53 wild-type and sensitive to GSK2830371A; in contrast cell lines with no copy gain of PPM1D were mixed in their sensitivity to WIP1 inhibition, with the primary determinant being TP53 mutational status. Since WIP1 is involved in the cellular response to DNA damage and drugs used in neuroblastoma treatment induce apoptosis through DNA damage, we sought to determine whether GSK2830371 could act synergistically with standard of care chemotherapeutics. Treatment of wild-type TP53 neuroblastoma cell lines with both GSK2830371 and either doxorubicin or carboplatin resulted in enhanced cell death, mediated through caspase 3/7 induction, as compared to either agent alone. Our data suggests that WIP1 inhibition represents a novel therapeutic approach to neuroblastoma that could be integrated with current chemotherapeutic approaches

T.: Justifications for logic programs under answer set semantics

Abstract. The paper introduces the notion of off-line justification for Answer Set Programming (ASP). Justifications provide a graph-based explanation of the truth value of an atom w.r.t. a given answer set. The notion of justification accounts for the specifics of answer set semantics. The paper extends also this notion to provide justification of atoms during the computation of an answer set (on-line justification), and presents an integration of on-line justifications within the computation model of SMODELS. Justifications offer a basic data structure to support methodologies and tools for debugging answer set programs. A preliminary implementation has been developed in ASP − PROLOG.

Constraint-based model checking of data-independent systems

Abstract Data-independent systems are an important class of infinitestate systems which can be subject to model checking by first building finite-state property-preserving abstractions. Exploiting data independence in practice involves user guidance, either in terms of the abstraction itself or in terms of symmetry properties of the system. In this paper we present a constraint-based verification technique that automatically handles data-independent systems. Our technique introduces a unified, automata-based model for infinite-state systems and LTL formulas. The technique can be seen as a generalization of explicit state model checker for reachability and LTL properties. We have implemented our technique using logic programming with tabulation and constraints. We also describe an extension to the automata model that permits verification of a richer class of systems. We show its power by analyzing configuration (security) vulnerabilities in a computer system.

WIP1 expression correlates with neuroblastoma disease stage.

<p><b>A</b>, Analysis of a large patient cohort (88 patients) with annotated clinical data and long term follow up (Versteeg-88-Mas5.0) demonstrates higher <i>PPM1D</i> levels in stage 4 metastatic subgroup (# = p < 0.01, # # = p < 0.005, by Student T-test). <b>B</b>, Long-term survival was also significantly (Kaplan-Meier analysis p = 0.005) different for high (n = 50) versus low (n = 38) expression of <i>PPM1D</i>.</p