Detection in urine of 4-methyl-2-hexaneamine, a doping agent.

Stimulants are banned in-competition for all categories of sports by the World Anti-Doping Agency. A simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay employing electrospray ionisation in positive mode was developed in that work for the quantification in urine specimens of 4-methyl-2-hexaneamine, a primary amine exhibiting sympathomimetic properties. Following a simple pretreatment procedure, the analyte was separated using a gradient mobile phase on reverse phase C8 column. Selected reaction monitoring m/z 116.2-->57.3 was specific for detection of 4-methyl-2-hexaneamine and the assay exhibited a linear dynamic range of 50-700 ng/mL. The validated method has been successfully applied to analyze the target compound in food supplements as well as in urine specimens. The administered drug (40 mg) was detected at the level of 350 ng/mL in the urine up to 4 days.

ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.

BACKGROUND: An ADME (absorption, distribution, metabolism and excretion)-pharmacogenetics association study may identify functional variants relevant to the pharmacokinetics of lopinavir co-formulated with ritonavir (LPV/r), a first-line anti-HIV agent. METHODS: An extensive search of literature and web resources helped select ADME genes and single nucleotide polymorphisms (SNPs, functional and HapMap tagging SNPs) with a proven or potentially relevant role in LPV/r pharmacokinetics. The study followed a two-stage design. Stage 1 (discovery) considered a Caucasian population (n=638) receiving LPV/r, where we selected 117 individuals with low LPV clearance (cases) and 90 individuals with high clearance (controls). Genotyping was performed by a 1536-SNP customized GoldenGate Illumina BeadArray. Stage 2 (confirmation) represented a replication study of candidate SNPs from the stage 1 in 148 individuals receiving LPV/r. The analysis led to formal population pharmacokinetic-pharmacogenetic modeling of demographic, environmental and candidate SNP effects. RESULTS: One thousand three hundred and eighty SNPs were successfully genotyped. Nine SNPs prioritized by the stage 1 analysis were brought to replication. Stage 2 confirmed the contribution of two functional SNPs in SLCO1B1, one functional SNP in ABCC2 and a tag SNP of the CYP3A locus in addition to body weight effect and ritonavir coadministration. According to the population pharmacokinetic-pharmacogenetic model, genetic variants explained 5% of LPV variability. Individuals homozygous rs11045819 (SLCO1B1*4) had a clearance of 12.6 l/h, compared with 5.4 l/h in the reference group, and 3.9 l/h in individuals with two or more variant alleles of rs4149056 (SLCO1B1*5), rs717620 (ABCC2) or rs6945984 (CYP3A). A subanalysis confirmed that although a significant part of the variance in LPV clearance was attributed to fluctuation in ritonavir levels, genetic variants had an additional effect on LPV clearance. CONCLUSION: The two-stage strategy successfully identified genetic variants affecting LPV/r pharmacokinetics. Such a general approach of ADME pharmacogenetics should be generalized to other drugs.

Promoting the development of secure mobile agent applications

Peer-reviewed

Securing dynamic itineraries for mobile agent applications

In this paper we present a novel mechanism for the protection of dynamic itineraries for mobile agent applications. Itineraries that are decided as the agent goes are essential in complex applications based on mobile agents, but no approach has been presented until now to protect them. We have conceived a cryptographic scheme for shielding dynamic itineraries from tampering, impersonation and disclosure. By using trust strategically, our scheme provides a balanced trade-off between flexibility and security. Our protection scheme has been thought always bearing in mind a feasible implementation, and thus facilitates the development of applications that make use of it. An example application based on a real healthcare scenario is also presented to show its operation.

From rifting to passive margin - The examples of the Red Sea, Central Atlantic and Alpine Tethys

Evolution of the Red Sea/Gulf of Suez and the Central Atlantic rift systems shows that an initial, transtensive rifting phase, affecting a broad area around the future zone of crustal separation, was followed by a pre-oceanic rifting phase during which extensional strain was concentrated on the axial rift zone. This caused lateral graben systems to become inactive and they evolved into rift-rim basins. The transtensive phase of diffuse crustal extension is recognized in many intra-continental rifts. If controlling stress systems relax, these rifts abort and develop into palaeorifts. If controlling stress systems persist, transtensive rift systems can enter the pre-oceanic rifting stage, during which the rift zone narrows and becomes asymmetric as a consequence of simple-shear deformation at shallow crustal levels and pure shear deformation at lower crustal and mantle-lithospheric levels. Preceding crustal separation, extensional denudation of the lithospheric mantle is possible. Progressive lithospheric attenuation entails updoming of the asthenosphere and thermal doming of the rift shoulders. Their uplift provides a major clastic source for the rift basins and the lateral rift-rim basins. Their stratigraphic record provides a sensitive tool for dating the rift shoulder uplift. Asymmetric rifting leads to the formation of asymmetric continental margins, corresponding in a simple-shear model to an upper plate and a conjugate lower plate margin, as seen in the Central Atlantic passive margins of the United States and Morocco. This rifting model can be successfully applied to the analysis of the Alpine Tethys palaeo-margins (such as Rif and the Western Alps).

Three essays in incomplete contracts

General Introduction These three chapters, while fairly independent from each other, study economic situations in incomplete contract settings. They are the product of both the academic freedom my advisors granted me, and in this sense reflect my personal interests, and of their interested feedback. The content of each chapter can be summarized as follows: Chapter 1: Inefficient durable-goods monopolies In this chapter we study the efficiency of an infinite-horizon durable-goods monopoly model with a fmite number of buyers. We find that, while all pure-strategy Markov Perfect Equilibria (MPE) are efficient, there also exist previously unstudied inefficient MPE where high valuation buyers randomize their purchase decision while trying to benefit from low prices which are offered once a critical mass has purchased. Real time delay, an unusual monopoly distortion, is the result of this attrition behavior. We conclude that neither technological constraints nor concern for reputation are necessary to explain inefficiency in monopolized durable-goods markets. Chapter 2: Downstream mergers and producer's capacity choice: why bake a larger pie when getting a smaller slice? In this chapter we study the effect of downstream horizontal mergers on the upstream producer's capacity choice. Contrary to conventional wisdom, we find anon-monotonic relationship: horizontal mergers induce a higher upstream capacity if the cost of capacity is low, and a lower upstream capacity if this cost is high. We explain this result by decomposing the total effect into two competing effects: a change in hold-up and a change in bargaining erosion. Chapter 3: Contract bargaining with multiple agents In this chapter we study a bargaining game between a principal and N agents when the utility of each agent depends on all agents' trades with the principal. We show, using the Potential, that equilibria payoffs coincide with the Shapley value of the underlying coalitional game with an appropriately defined characteristic function, which under common assumptions coincides with the principal's equilibrium profit in the offer game. Since the problem accounts for differences in information and agents' conjectures, the outcome can be either efficient (e.g. public contracting) or inefficient (e.g. passive beliefs).

Étude et implémentation d'un modèle de conscience d'agent

La thèse essaie de montrer comment il est possible d'offrir une implémentation fonctionnelle d'un agent doté d'une conscience (psychologique). Une première étape étudie les différentes approches, définitions et théories de la conscience proposées par la littérature. Cette étude dégage plus particulièrement un modèle psychologique qui offre une modélisation des fonctionnalités de la conscience, de ses éléments constitutifs et des relations entre ces éléments. Cet effort de formalisation permet d'identifier les corrélations computionnelles du modèle ouvrant ainsi la voie à une implémentation fonctionnelle de la conscience. Une seconde étape réuni les outils et méthodes informatiques existants en vue de procéder à une telle implémentation. En particulier, celle-ci repose sur un modèle de communication permettant d'élaborer une machine virtuelle basée sur des processus concurrents synchronisés. La troisième étape consiste à implémenter les corrélations computationnelles dont l'une est une fonction de délibération qui, après une analyse itérative de son état et de son environnement (machine à état), aboutit à la sélection d'une action. Une deuxième fonction est la formation de contextes, autrement dit l'apprentissage d'automatismes, consistant à compiler la délibération. Cette compilation s'opère grâce à un processus concurrent reflétant le processus de délibération, dotant ainsi l'agent de la capacité d'observer son propre fonctionnement. La thèse se conclut en proposant quelques axes de recherches et d'applications futures susceptibles de prolonger le travail.

Effect of water velocity on the uptake of polychlorinatedd biphenyls (PCBs) by silicone rubber (SR) and low-density polyethylene (LDPE) passive samplers: an assessment of the efficiency of performance reference compounds (PRCs) in river-like flow conditions

One aim of this study is to determine the impact of water velocity on the uptake of indicator polychlorinated biphenyls (iPCBs) by silicone rubber (SR) and low-density polyethylene (LDPE) passive samplers. A second aim is to assess the efficiency of performance reference compounds (PRCs) to correct for the impact of water velocity. SR and LDPE samplers were spiked with 11 or 12 PRCs and exposed for 6 weeks to four different velocities (in the range of 1.6 to 37.7 cm s−1) in river-like flow conditions using a channel system supplied with river water. A relationship between velocity and the uptakewas found for each iPCB and enables to determine expected changes in the uptake due to velocity variations. For both samplers, velocity increases from 2 to 10 cm s−1, 30 cm s−1 (interpolated data) and 100 cm s−1 (extrapolated data) lead to increases of the uptake which do not exceed a factor of 2, 3 and 4.5, respectively. Results also showed that the influence of velocity decreased with increasing the octanol-water coefficient partition (log Kow) of iPCBs when SR is used whereas the opposite effect was observed for LDPE. Time-weighted average (TWA) concentrations of iPCBs in water were calculated from iPCB uptake and PRC release. These calculations were performed using either a single PRC or all the PRCs. The efficiency of PRCs to correct the impact of velocity was assessed by comparing the TWA concentrations obtained at the four tested velocities. For SR, a good agreement was found among the four TWA concentrations with both methods (average RSD b 10%). Also for LDPE, PRCs offered a good correction of the impact of water velocity (average RSD of about 10 to 20%). These results contribute to the process of acceptance of passive sampling in routine regulatory monitoring programs.

ACACIA: an agent-based program for simulating behavior to reach long-term goals

We present ACACIA, an agent-based program implemented in Java StarLogo 2.0 that simulates a two-dimensional microworld populated by agents, obstacles and goals. Our program simulates how agents can reach long-term goals by following sensorial-motor couplings (SMCs) that control how the agents interact with their environment and other agents through a process of local categorization. Thus, while acting in accordance with this set of SMCs, the agents reach their goals through the emergence of global behaviors. This agent-based simulation program would allow us to understand some psychological processes such as planning behavior from the point of view that the complexity of these processes is the result of agent-environment interaction.