First stereocontrolled acetylation of a hydroxypropargylpiperidone by lipase CALB

Hydroxypropargylpiperidones rac-1-3 were efficiently obtained by a one-pot three-component coupling reaction; enantioenriched propargylpiperidones were then obtained by a kinetic resolution process using the lipase from Candida antarctica. Lipase CALB has been shown to efficiently catalyse the stereocontrolled acetylation of hydroxypropargylpiperidones rac-3 by promoting stereodiscrimination at the carbinolic centre. The enzymatic catalytic processes allow the separation of the (S,R)- and (S,S)-3 diastereoisomers into the corresponding acetates produced as a (R,S)- and (R,R)-6 diastereoisomeric pair. The CALB was able to discriminate the stereogenic centre of the secondary (R)-enantiomer of rac-3 according to the Kaslauzkas rule. The remote stereogenic centre was not discriminated by the lipase. The functionalised enantioenriched diastereoisomers obtained are important building blocks in organic synthesis. (C) 2010 Elsevier Ltd. All rights reserved.

Metabolic oxidative stress elicited by the copper(II) complex [Cu(isaepy)(2)] triggers apoptosis in SH-SY5Y cells through the induction of the AMP-activated protein kinase/p38(MAPK)/p53 signalling axis: evidence for a combined use with 3-bromopyruvate in neuroblastoma treatment

We have demonstrated previously that the complex bis[(2-oxindol-3-ylimino)-2-(2-aminoethyl)pyridine-N,N`]copper(II), named [Cu(isaepy)(2)], induces AMPK (AMP-activated protein kinase)-dependent/p53-mediated apoptosis in tumour cells by targeting mitochondria. In the present study, we found that p38(MAPK) (p38 mitogen-activated protein kinase) is the molecular link in the phosphorylation cascade connecting AMPK to p53. Transfection of SH-SY5Y cells with a dominant-negative mutant of AMPK resulted in a decrease in apoptosis and a significant reduction in phospho-active p38(MAPK) and p53. Similarly, reverse genetics of p38(MAPK) yielded a reduction in p53 and a decrease in the extent of apoptosis, confirming an exclusive hierarchy of activation that proceeds via AMPK/p38(MAPK)/p53. Fuel supplies counteracted [Cu(isaepy)(2)]-induced apoptosis and AMPK/p38(MAPK)/p53 activation, with glucose being the most effective, suggesting a role for energetic imbalance in [Cu(isaepy)(2)] toxicity. Co-administration of 3BrPA (3-bromopyruvate), a well-known inhibitor of glycolysis, and succinate dehydrogenase, enhanced apoptosis and AMPK/p38(MAPK)/p53 signalling pathway activation. Under these conditions, no toxic effect was observed in SOD (superoxide dismutase)-overexpressing SH-SY5Y cells or in PCNs (primary cortical neurons), which are, conversely, sensitized to the combined treatment with [Cu(isaepy)(2)] and 3BrPA only if grown in low-glucose medium or incubated with the glucose-6-phosphate dehydrogenase inhibitor dehydroepiandrosterone. Overall, the results suggest that NADPH deriving from the pentose phosphate pathway contributes to PCN resistance to [Cu(isaepy)(2)] toxicity and propose its employment in combination with 3BrPA as possible tool for cancer treatment.

Bcl-2 expression and apoptosis induction in human HL60 leukaemic cells treated with a novel organotellurium(IV) compound RT-04

Organotellurium(]V) compounds have been reported to have multiple biological activities including cysteine protease-inhibitory activity, mainly cathepsin B. As cathepsin B is a highly predictive indicator for prognosis and diagnosis of cancer, a possible antitumor potential for these new compounds is expected. In this work, it was investigated the effectiveness of organotellurium(IV) RT-04 to produce lethal effects in the human promyelocytic leukaemia cell line HL60. Using the MTT tetrazolium reduction test, and trypan blue exclusion assay, the IC50 for the compound after 24 h incubation was 6.8 and 0.35 mu M, respectively. Moreover, the compound was found to trigger apoptosis in HL60 cells, inducing DNA fragmentation and caspase-3, -6, and -9 activations. The apoptsosis-induced by RT-04 is probably related to the diminished Bcl-2 expression, observed by RT-PCR, in HL60-treated cells. In vivo studies demonstrated that the RT-04 treatment (2.76 mg/kg given for three consecutive days) produces no significant toxic effects for bone marrow and spleen CFU-GM. However, higher doses (5.0 and 10 mg/kg) produced a dose-dependent reduction in the number of CFU-GM of RT-04-treated mice. These results suggest that RT-04 is able to induce apoptosis in HL60 cells by Bcl-2 expression down-modulation. Further studies are necessary to better clarify the effects of this compound on bone marrow normal cells. (C) 2008 Elsevier Ltd. All rights reserved.

Nasal immunization of mice with Lactobacillus casei expressing the Pneumococcal Surface Protein A: induction of antibodies, complement deposition and partial protection against Streptococcus pneumoniae challenge

Strategies for the development of new vaccines against Streptococcus pneumoniae infections try to overcome problems such as serotype coverage and high costs, present in currently available vaccines. Formulations based on protein candidates that can induce protection in animal models have been pointed as good alternatives. Among them, the Pneumococcal Surface Protein A (PspA) plays an important role during systemic infection at least in part through the inhibition of complement deposition on the pneumococcal surface, a mechanism of evasion from the immune system. Antigen delivery systems based on live recombinant lactic acid bacteria (LAB) represents a promising strategy for mucosal vaccination, since they are generally regarded as safe bacteria able to elicit both systemic and mucosal immune responses. In this work, the N-terminal region of clade I PspA was constitutively expressed in Lactobacillus casei and the recombinant bacteria was tested as a mucosal vaccine in mice. Nasal immunization with L. casei-PspA 1 induced anti-PspA antibodies that were able to bind to pneumococcal strains carrying both clade 1 and clade 2 PspAs and to induce complement deposition on the surface of the bacteria. In addition, an increase in survival of immunized mice after a systemic challenge with a virulent pneumococcal strain was observed. (C) 2008 Elsevier Masson SAS. All rights reserved.

Does speed matter? : the impact of the EU membership incentive on rule adoption in minority language rights protection

Denna avhandling tar sin utgångspunkt i ett ifrågasättande av effektiviteten i EU:s konditionalitetspolitik avseende minoritetsrättigheter. Baserat på den rationalistiska teoretiska modellen, External Incentives Model of Governance, syftar denna hypotesprövande avhandling till att förklara om tidsavståndet på det potentiella EU medlemskapet påverkar lagstiftningsnivån avseende minoritetsspråksrättigheter. Mätningen av nivån på lagstiftningen avseende minoritetsspråksrättigheter begränsas till att omfatta icke-diskriminering, användning av minoritetsspråk i officiella sammanhang samt minoriteters språkliga rättigheter i utbildningen. Metodologiskt används ett jämförande angreppssätt både avseende tidsramen för studien, som sträcker sig mellan 2003 och 2010, men även avseende urvalet av stater. På basis av det \"mest lika systemet\" kategoriseras staterna i tre grupper efter deras olika tidsavstånd från det potentiella EU medlemskapet. Hypotesen som prövas är följande: ju kortare tidsavstånd till det potentiella EU medlemskapet desto större sannolikhet att staternas lagstiftningsnivå inom de tre områden som studeras har utvecklats till en hög nivå. Studien visar att hypotesen endast bekräftas delvis. Resultaten avseende icke-diskriminering visar att sambandet mellan tidsavståndet och nivån på lagstiftningen har ökat markant under den undersökta tidsperioden. Detta samband har endast stärkts mellan kategorin av stater som ligger tidsmässigt längst bort ett potentiellt EU medlemskap och de två kategorier som ligger närmare respektive närmast ett potentiellt EU medlemskap. Resultaten avseende användning av minoritetsspråk i officiella sammanhang och minoriteters språkliga rättigheter i utbildningen visar inget respektive nästan inget samband mellan tidsavståndet och utvecklingen på lagstiftningen mellan 2003 och 2010.

A stopping rule while searching for optimal solution of facility-location

Solutions to combinatorial optimization, such as p-median problems of locating facilities, frequently rely on heuristics to minimize the objective function. The minimum is sought iteratively and a criterion is needed to decide when the procedure (almost) attains it. However, pre-setting the number of iterations dominates in OR applications, which implies that the quality of the solution cannot be ascertained. A small branch of the literature suggests using statistical principles to estimate the minimum and use the estimate for either stopping or evaluating the quality of the solution. In this paper we use test-problems taken from Baesley's OR-library and apply Simulated Annealing on these p-median problems. We do this for the purpose of comparing suggested methods of minimum estimation and, eventually, provide a recommendation for practioners. An illustration ends the paper being a problem of locating some 70 distribution centers of the Swedish Post in a region.

A fuzzy rule-based decision support system for Duodopa treatment in Parkinson

A decision support system (DSS) was implemented based on a fuzzy logic inference system (FIS) to provide assistance in dose alteration of Duodopa infusion in patients with advanced Parkinson’s disease, using data from motor state assessments and dosage. Three-tier architecture with an object oriented approach was used. The DSS has a web enabled graphical user interface that presents alerts indicating non optimal dosage and states, new recommendations, namely typical advice with typical dose and statistical measurements. One data set was used for design and tuning of the FIS and another data set was used for evaluating performance compared with actual given dose. Overall goodness-of-fit for the new patients (design data) was 0.65 and for the ongoing patients (evaluation data) 0.98. User evaluation is now ongoing. The system could work as an assistant to clinical staff for Duodopa treatment in advanced Parkinson’s disease.

Rule versus interaction function : evaluating regional aggregations of commuting flows in Sweden

The aim of this paper is to evaluate the performance of two divergent methods for delineating commuting regions, also called labour market areas, in a situation that the base spatial units differ largely in size as a result of an irregular population distribution. Commuting patterns in Sweden have been analyzed with geographical information system technology by delineating commuting regions using two regionalization methods. One, a rule-based method, uses one-way commuting flows to delineate local labour market areas in a top-down procedure based on the selection of predefined employment centres. The other method, the interaction-based Intramax analysis, uses two-way flows in a bottom-up procedure based on numerical taxonomy principles. A comparison of these methods will expose a number of strengths and weaknesses. For both methods, the same data source has been used. The performance of both methods has been evaluated for the country as a whole using resident employed population, self-containment levels and job ratios for criteria. A more detailed evaluation has been done in the Goteborg metropolitan area by comparing regional patterns with the commuting fields of a number of urban centres in this area. It is concluded that both methods could benefit from the inclusion of additional control measures to identify improper allocations of municipalities.

Towards Presidential Rule in Ukraine : Hybrid Regime Dynamics under Semi-Presidentialism

This article sets out to analyse recent regime developments in Ukraine in relation to semi-presidentialism. The article asks: to what extent and in what ways theoretical arguments against semi-presidentialism (premier-presidential and president-parliamentary systems) are relevant for understanding the changing directions of the Ukrainian regime since the 1990s? The article also reviews the by now overwhelming evidence suggesting that President Yanukovych is turning Ukraine into a more authoritarian hybrid regime and raises the question to what extent the president-parliamentary system might serve this end. The article argues that both kinds of semi-presidentialism have, in different ways, exacerbated rather than mitigated institutional conflict and political stalemate. The return to the president-parliamentary system in 2010 – the constitutional arrangement with the most dismal record of democratisation – was a step in the wrong direction. The premier-presidential regime was by no means ideal, but it had at least two advantages. It weakened the presidential dominance and it explicitly anchored the survival of the government in parliament. The return to the 1996 constitution ties in well with the notion that President Viktor Yanukovych has embarked on an outright authoritarian path.

The ex-Ante non-optimality of the Dempster-Schafer updating rule for ambiguous beliefs

The most widely used updating rule for non-additive probalities is the Dempster-Schafer rule. Schmeidles and Gilboa have developed a model of decision making under uncertainty based on non-additive probabilities, and in their paper “Updating Ambiguos Beliefs” they justify the Dempster-Schafer rule based on a maximum likelihood procedure. This note shows in the context of Schmeidler-Gilboa preferences under uncertainty, that the Dempster-Schafer rule is in general not ex-ante optimal. This contrasts with Brown’s result that Bayes’ rule is ex-ante optimal for standard Savage preferences with additive probabilities.

Nash equilibrium under knightian uncertainty: breaking down backward induction (extensively revised version)

We define Nash equilibrium for two-person normal form games in the presence of uncertainty, in the sense of Knight(1921). We use the fonna1iution of uncertainty due to Schmeidler and Gilboa. We show tbat there exist Nash equilibria for any degree of uncertainty, as measured by the uncertainty aversion (Dow anel Wer1ang(l992a». We show by example tbat prudent behaviour (maxmin) can be obtained as an outcome even when it is not rationaliuble in the usual sense. Next, we break down backward industion in the twice repeated prisoner's dilemma. We link these results with those on cooperation in the finitely repeated prisoner's dilemma obtained by Kreps-Milgrom-Roberts-Wdson(1982), and withthe 1iterature on epistemological conditions underlying Nash equilibrium. The knowledge notion implicit in this mode1 of equilibrium does not display logical omniscience.

Nash equilibrium under knightian uncertainty: breaking-down backward induction

We present two alternative definitions of Nash equilibrium for two person games in the presence af uncertainty, in the sense of Knight. We use the formalization of uncertainty due to Schmeidler and Gilboa. We show that, with one of the definitions, prudent behaviour (maxmin) can be obtained as an outcome even when it is not rationalizable in the usual sense. Most striking is that with the Same definition we break down backward induction in the twice repeated prisoner's dilemma. We also link these results with the Kreps-Milgrom-Roberts-Wilson explanation of cooperation in the finitely repeated prisoner's dilemma.