Semantics and Proof Theory of the Epsilon Calculus

The epsilon operator is a term-forming operator which replaces quantifiers in ordinary predicate logic. The application of this undervalued formalism has been hampered by the absence of well-behaved proof systems on the one hand, and accessible presentations of its theory on the other. One significant early result for the original axiomatic proof system for the epsilon-calculus is the first epsilon theorem, for which a proof is sketched. The system itself is discussed, also relative to possible semantic interpretations. The problems facing the development of proof-theoretically well-behaved systems are outlined.Comment: arXiv admin note: substantial text overlap with arXiv:1411.362

Epigenetic re-wiring of breast cancer by pharmacological targeting of C-terminal binding protein

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention

Gorab is a Golgi protein required for structure and duplication of Drosophila centrioles.

We demonstrate that a Drosophila Golgi protein, Gorab, is present not only in the trans-Golgi but also in the centriole cartwheel where, complexed to Sas6, it is required for centriole duplication. In addition to centriole defects, flies lacking Gorab are uncoordinated due to defects in sensory cilia, which lose their nine-fold symmetry. We demonstrate the separation of centriole and Golgi functions of Drosophila Gorab in two ways: first, we have created Gorab variants that are unable to localize to trans-Golgi but can still rescue the centriole and cilia defects of gorab null flies; second, we show that expression of C-terminally tagged Gorab disrupts Golgi functions in cytokinesis of male meiosis, a dominant phenotype overcome by mutations preventing Golgi targeting. Our findings suggest that during animal evolution, a Golgi protein has arisen with a second, apparently independent, role in centriole duplication.D.M.G. is grateful for a Wellcome Investigator Award, which supported this work. The study was initiated with support from Cancer Research UK

Invasive fungal infection among hematopoietic stem cell transplantation patients with mechanical ventilation in the intensive care unit

<p>Abstract</p> <p>Background</p> <p>Invasive fungal infection (IFI) is associated with high morbidity and high mortality in hematopoietic stem cell transplantation (HSCT) patientsThe purpose of this study was to assess the characteristics and outcomes of HSCT patients with IFIs who are undergoing MV at a single institution in Taiwan.</p> <p>Methods</p> <p>We performed an observational retrospective analysis of IFIs in HSCT patients undergoing mechanical ventilation (MV) in an intensive care unit (ICU) from the year 2000 to 2009. The characteristics of these HSCT patients and risk factors related to IFIs were evaluated. The status of discharge, length of ICU stay, date of death and cause of death were also recorded.</p> <p>Results</p> <p>There were 326 HSCT patients at the Linkou Chang-Gung Memorial Hospital (Taipei, Taiwan) during the study period. Sixty of these patients (18%) were transferred to the ICU and placed on mechanical ventilators. A total of 20 of these 60 patients (33%) had IFIs. Multivariate analysis indicated that independent risk factors for IFI were admission to an ICU more than 40 days after HSCT, graft versus host disease (GVHD), and high dose corticosteroid (<it>p </it>< 0.01 for all). The overall ICU mortality rate was 88% (53 of 60 patients), and was not significantly different for patients with IFIs (85%) and those without IFIs (90%, <it>p </it>= 0.676).</p> <p>Conclusion</p> <p>There was a high incidence of IFIs in HSCT patients requiring MV in the ICU in our study cohort. The independent risk factors for IFI are ICU admission more than 40 days after HSCT, GVHD, and use of high-dose corticosteroid.</p

MF59®-Adjuvanted H5N1 Vaccine Induces Immunologic Memory and Heterotypic Antibody Responses in Non-Elderly and Elderly Adults

Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed.Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations.Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs.(ClinicalTrials.gov) NCT00311480

Results of noninvasive ventilation in very old patients

International audienceABSTRACT: BACKGROUND: Noninvasive ventilation (NIV) is frequently used for the management of acute respiratory failure (ARF) in very old patients (>80 years), often in the context of a do-not-intubate order (DNI). We aimed to determine its efficacy and long-term outcome. METHODS: Prospective cohort of all patients admitted to the medical ICU of a tertiary hospital during a 2-year period and managed using NIV. Characteristics of patients, context of NIV, and treatment intensity were compared for very old and younger patients. Six-month survival and functional status were assessed in very old patients. RESULTS: During the study period, 1,019 patients needed ventilatory support and 376 (37%) received NIV. Among them, 163 (16%) very old patients received ventilatory support with 60% of them managed using NIV compared with 32% of younger patients (p < 0.0001). Very old patients received NIV more frequently with DNI than in younger patients (40% vs. 8%). Such cases were associated with high mortality for both very old and younger patients. Hospital mortality was higher in very old than in younger patients but did not differ when NIV was used for cardiogenic pulmonary edema or acute-on-chronic respiratory failure (20% vs. 15%) and in postextubation (15% vs. 17%) out of a context of DNI. Six-month mortality was 51% in very old patients, 67% for DNI patients, and 77% in case of NIV failure and endotracheal intubation. Of the 30 hospital survivors, 22 lived at home and 13 remained independent for activities of daily living. CONCLUSIONS: Very old patients managed using NIV have an overall satisfactory 6-month survival and functional status, except for endotracheal intubation after NIV failure

The Functional −765G→C Polymorphism of the COX-2 Gene May Reduce the Risk of Developing Crohn's Disease

Contains fulltext : 87827.pdf (publisher's version ) (Open Access)BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the conversion of arachidonic acid into prostaglandins. COX-2 is mainly induced at sites of inflammation in response to proinflammatory cytokines such as interleukin-1alpha/beta, interferon-gamma and tumor necrosis factor-alpha produced by inflammatory cells. AIM: The aim of this study was to investigate the possible modulating effect of the functional COX-2 polymorphisms -1195 A-->G and -765G-->C on the risk for development of inflammatory bowel disease (IBD) in a Dutch population. METHODS: Genomic DNA of 525 patients with Crohn's disease (CD), 211 patients with ulcerative colitis (UC) and 973 healthy controls was genotyped for the -1195 A-->G (rs689466) and -765G-->C (rs20417) polymorphisms. Distribution of genotypes in patients and controls were compared and genotype-phenotype interactions were investigated. RESULTS: The genotype distribution of the -1195A-->G polymorphism was not different between the patients with CD or UC and the control group. The -765GG genotype was more prevalent in CD patients compared to controls with an OR of 1.33 (95%CI 1.04-1.69, pC polymorphism was associated with a reduced risk for developing Crohn's disease in a Dutch population

Resequencing PNMT in European hypertensive and normotensive individuals: no common susceptibilily variants for hypertension and purifying selection on intron 1

<p>Abstract</p> <p>Background</p> <p>Human linkage and animal QTL studies have indicated the contribution of genes on Chr17 into blood pressure regulation. One candidate gene is <it>PNMT</it>, coding for phenylethanolamine-N-methyltransferase, catalyzing the synthesis of epinephrine from norepinephrine.</p> <p>Methods</p> <p>Fine-scale variation of <it>PNMT </it>was screened by resequencing hypertensive (n = 50) and normotensive (n = 50) individuals from two European populations (Estonians and Czechs). The resulting polymorphism data were analyzed by statistical genetics methods using Genepop 3.4, PHASE 2.1 and DnaSP 4.0 software programs. <it>In silico </it>prediction of transcription factor binding sites for intron 1 was performed with MatInspector 2.2 software.</p> <p>Results</p> <p><it>PNMT </it>was characterized by minimum variation and excess of rare SNPs in both normo- and hypertensive individuals. None of the SNPs showed significant differences in allelic frequencies among population samples, as well as between screened hypertensives and normotensives. In the joint case-control analysis of the Estonian and the Czech samples, hypertension patients had a significant excess of heterozygotes for two promoter region polymorphisms (SNP-184; SNP-390). The identified variation pattern of <it>PNMT </it>reflects the effect of purifying selection consistent with an important role of PNMT-synthesized epinephrine in the regulation of cardiovascular and metabolic functions, and as a CNS neurotransmitter. A striking feature is the lack of intronic variation. <it>In silico </it>analysis of <it>PNMT </it>intron 1 confirmed the presence of a human-specific putative Glucocorticoid Responsive Element (GRE), inserted by <it>Alu</it>-mediated transfer. Further analysis of intron 1 supported the possible existence of a full Glucocorticoid Responsive Unit (GRU) predicted to consist of multiple gene regulatory elements known to cooperate with GRE in driving transcription. The role of these elements in regulating <it>PNMT </it>expression patterns and thus determining the dynamics of the synthesis of epinephrine is still to be studied.</p> <p>Conclusion</p> <p>We suggest that the differences in PNMT expression between normotensives and hypertensives are not determined by the polymorphisms in this gene, but rather by the interplay of gene expression regulators, which may vary among individuals. Understanding the determinants of PNMT expression may assist in developing PNMT inhibitors as potential novel therapeutics.</p

The Hemorrhagic Coli Pilus (HCP) of Escherichia coli O157:H7 Is an Inducer of Proinflammatory Cytokine Secretion in Intestinal Epithelial Cells

Enterohemorrhagic Escherichia coli (EHEC) O157:H7, the causative agent of hemorrhagic colitis and the hemolytic uremic syndrome (HUS), produces long bundles of type IV pili (TFP) called hemorrhagic coli pili (HCP). HCP are capable of mediating several phenomena associated with pathogenicity: i) adherence to human and bovine epithelial cells; ii) invasion of epithelial cells; iii) hemagglutination of rabbit erythrocytes; iv) biofilm formation; v) twitching motility; and vi) specific binding to laminin and fibronectin. HCP are composed of a 19 kDa pilin subunit (HcpA) encoded by the hcpA chromosomal gene (called prepilin peptidase-dependent gene [ppdD] in E. coli K-12).In this study we investigated the potential role of HCP of E. coli O157:H7 strain EDL933 in activating the release of pro- and anti-inflammatory cytokines from a variety of host epithelial cells. We found that purified HCP and a recombinant HcpA protein induced significant release of IL-8 and TNF-alpha, from cultured polarized intestinal cells (T84 and HT-29 cells) and non-intestinal HeLa cells. Levels of proinflammatory IL-8 and TNF-alpha, but not IL-2, IL6, or IL-10 cytokines, were increased in the presence of HCP and recombinant HcpA after 6 h of incubation with >or=50 ng/ml of protein, suggesting that stimulation of IL-8 and TNF-alpha are dose and time-dependent. In addition, we also demonstrated that flagella are potent inducers of cytokine production. Furthermore, MAPK activation kinetics studies showed that EHEC induces p38 phosphorylation under HCP-producing conditions, and ERK1/2 and JNK activation was detectable after 3 h of EHEC infection. HT-29 cells were stimulated with epidermal growth factor stimulation of HT-29 cells for 30 min leading to activation of three MAPKs.The HcpA pilin monomer of the HCP produced by EHEC O157:H7 is a potent inducer of IL-8 and TNF-alpha release, an event which could play a significant role in the pathogenesis of hemorrhagic colitis caused by this pathogen