Le chikungunya : une arbovirose ré-émergente (Thèse d'exercice de Pharmacie)

Currently reemergence in the world, chikungunya virus is an arbovirus causing the occurrence of epidemics in countries not previously affected. Mainly transmitted to humans by mosquitoes Aedes albopictus and Aedes aegypti this arbovirus concerned by its development. The possible mutations of the virus, different genotypes, climate change, the political context (war, globalization ...) and reservoirs of viruses difficult to identify are all factors making the control very complicated of viral dissemination. Paradoxically this development, despite the lack of treatment and vaccine, chikungunya disease is becoming better understood. This overall progress of knowledge is one of optimism for the future. However currently, individual and collective prevention remains the most effective way to fight against the spread of the virus. Therefore, vector control is the major asset of this taken into preventive care. As the first contact the pharmacist has a major role to play in prevention

Establishment of mouse and rat hepatoma cell clones showing stable expression of rabbit cytochrome P450 IA2

AbstractCytochrome P450 IA2, a liver-specific member of the 3-methylcholanthrene-inducible family, is never detected in established cell lines. With the aim of isolating cells stably producing this protein, we have used rat and mouse hepatoma cells as recipients in transfection experiments involving rabbit cytochrome P450 IA2 cDNA. We report here the isolation of five hepatoma cell clones expressing functional P450 IA2. The level of expression is comparable to that found in COS cells transiently transformed by other P450 cDNAs. It ranges between 0.4 and 1.6 pmol P450 IA2/mg total cell protein

Examining inhibition during spoken word production in aphasia

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Effects of Phonomotor Treatment on the Reading Abilities of Individuals with Aphasia and Phonological Alexia

A left hemisphere stroke often results in aphasia characterized by impaired reading (Cherney, 2004; Webb & Love, 1983) and phonological processing abilities (Blumstein, Baker, & Goodglass, 1977; den Ouden & Bastiaanse, 2005). Research has shown that treatment focused at the level of the phoneme improves reading abilities in persons with aphasia (PWA) and phonological alexia (Conway et al., 1998; Kendall et al., 1998; Kendall et al., 2003). These findings are theoretically supported by a connectionist model of phonology (Nadeau, 2001), and a multimodal model of phonological processing and reading (Alexander & Slinger, 2004)

Dynamics of Elastic Capsules in Cross-Junction and T-Junction Microfluidic Channels

In this dissertation, we investigate via numerical computations the dynamicsof elastic capsules (made from a thin strain-hardening elastic membrane) in two microfluidic channels of cross-junction and T-junction geometries. For the cross-junction microfluidic channel, we consider an initially spherical capsule with a size smaller than the cross-section of the square channels comprising the cross-junction, and investigate the effects of the capsule size, flow rate, and lateral flow rates on the transient dynamics and deformation of low-viscosity and equiviscous capsules. In addition, we also study the effects of viscosity ratio on the transient capsule dynamics and deformation. Our investigation shows that the intersecting lateral flows at the cross-junction act like a constriction. Larger capsules, higher flow rates and higher intersecting lateral flows result in stronger hydrodynamic forces that cause a significant capsule deformation, i.e., the capsule’s length increases while its height decreases significantly. The capsule obtains different dynamic shape transitions due to the asymmetric shape of the cross-junction. Larger capsules take more time to pass through the cross-junction owning to the higher flow blocking. As the viscosity ratio decreases, the capsule’s transient deformation increases and tail formation develops transiently, especially for low-viscosity capsules owing to the normal-stress effects of the surrounding fluid on the capsule’s interface. However, the viscosity ratio does not affect much the capsule velocity due to a weak inner circulation. Our findings suggest that the tail formation of low-viscosity capsule may promote membrane breaking and thus drug release of pharmaceutical capsules in the microcirculation. Furthermore, we investigate via numerical computations the motion of an elastic capsule (made from an elastic membrane obeying the strain-hardening Skalak law) flowing inside a microfluidic T-junction device. In particular, we consider the effects of the capsule size, flow rate, lateral flow rate, and fluid viscosity ratio on the motion of the capsule in the T-junction micro-channel. As the capsule’s initial lateral position increases, the capsule moves faster and reaches different final lateral positions. As the capsule size increases, the gap between the capsule’s surface and the channel wall decreases. This results in the development of stronger hydrodynamic forces and a decrease in the capsule velocity due to flow blocking. As the capsule size increases, there is a small lateral migration towards the micro-channel centerline, which is the low-shear region of the T-junction micro-channel. This migration is in agreement with experimental and numerical studies on non-inertial lateral migration of vesicles in bounded Poiseuille flow by Coupier et al. [13] who showed that the combined effects of the walls and of the curvature of the velocity profile induce a lateral migration toward the centerline of the channel. As the capillary number Ca increases, the stronger hydrodynamic forces cause the capsule to extend along the flow direction (i.e., the capsule’s length Lx increases as the capsule enters the T-junctions and decreases as the capsule exits the T-junction). There is a small lateral migration away from the micro-channel centerline as the flow rate Ca increases. The capsule lateral position zc, main-flow velocity Ux and migration velocity Uz are practically not affected by the fluids viscosity ratio λ. As the channel’s lateral flow rate increases, the capsule migrates downwards towards the bottom of the device. Our findings on the lateral migration in the T-junction micro-channel suggest that there is a great potential for designing a T-junction microfluidic device that can be used to manipulate artificial and biological capsules

Using error type on confrontation naming as an indicator of improved linguistic processing following phonomotor treatment

This paper presents initial data on the influence of phonomotor treatment on word retrieval accuracy and error type from pre- and post-treatment confrontation naming probe responses produced by 10 individuals with aphasia. This study is part of a Phase II clinical rehabilitation research program which trains real- and non-words, comprised of low phonotactic probability and high neighborhood density phoneme sequences, to improve word retrieval in 30 subjects with left hemisphere lesion and aphasia. The treatment program is a logical advance on existing Phase I and Phase II clinical rehabilitation research (Kendall et al 2003, Kendall et al 2006a, Kendall et al 2006b, Kendall et al 2006c, Kendall et al 2008) and is motivated by a parallel distributed processing model of phonology (Nadeau, 2001)

Improvement of the phase regulation between two amplifiers feeding the inputs of the 3dB combiner in the ASDEX-Upgrade ICRH system

The present ICRF system at ASDEX Upgrade uses 3dB combiners to forward the combined power of a generator pair to a single line. Optimal output performance is achieved when the voltages at the two input lines of a combiner are equal in amplitude and the phase in quadrature. If this requirement is not met, a large amount of power is lost in the dummy loads of the combiner. To minimize losses, it is paramount to reach this phase relationship in a fast and stable way. The current phase regulation system is based on analog phase locked loops circuits. The main limitation of this system is the response time: several tens of milliseconds are needed to achieve a stable state. In order to get rid of the response time limitation of the current system, a new system is proposed based on a multi-channel direct digital synthesis device which is steered by a microcontroller and a software-based controller. The proposed system has been developed and successfully tested on a test-bench. The results show a remarkable improvement in the reduction of the response times. Other significant advantages provided by the new system include greater flexibility for frequency and phase settings, lower cost and a noticeable size reduction of the system

Developing a standardized measure of short-term memory and syntactic complexity: results from subtests of the CRTT-R

Short-term memory (STM) effects have shown to be distinguishable from other working memory components supporting complex computations/central executive functions. To develop a measure capable of assessing the effects of STM and linguistic computations on sentence processing,  effects of syntactic complexity and padding were investigated with the Computerized Revised Token Test –Revised in individuals with aphasia and control participants.  Off-line measures revealed clear effects of both factors.  The expected interaction of complexity and padding  and overadditive effects for individuals with aphasia were not found. An effect of complexity on word errors in passive sentences for individuals was shown

Single Mutations in Cytochrome P450 Oxidoreductase Can Alter the Specificity of Human Cytochrome P450 1A2-Mediated Caffeine Metabolism

Funding Information: F.E. and M.K.: UID/BIM/0009/2020 of the Portuguese Fundação para a Ciência e a Tecnologia (FCT) and HLTH-2022-STAYHLTH-02/grant agreement 101095679 of the European Horizon´s research and innovation program. Publisher Copyright: © 2023 by the authors.A unique cytochrome P450 (CYP) oxidoreductase (CPR) sustains activities of human microsomal CYPs. Its function requires toggling between a closed conformation enabling electron transfers from NADPH to FAD and then FMN cofactors and open conformations forming complexes and transferring electrons to CYPs. We previously demonstrated that distinct features of the hinge region linking the FAD and FMN domain (FD) modulate conformer poses and their interactions with CYPs. Specific FD residues contribute in a CYP isoform-dependent manner to the recognition and electron transfer mechanisms that are additionally modulated by the structure of CYP-bound substrate. To obtain insights into the underlying mechanisms, we analyzed how hinge region and FD mutations influence CYP1A2-mediated caffeine metabolism. Activities, metabolite profiles, regiospecificity and coupling efficiencies were evaluated in regard to the structural features and molecular dynamics of complexes bearing alternate substrate poses at the CYP active site. Studies reveal that FD variants not only modulate CYP activities but surprisingly the regiospecificity of reactions. Computational approaches evidenced that the considered mutations are generally in close contact with residues at the FD–CYP interface, exhibiting induced fits during complexation and modified dynamics depending on caffeine presence and orientation. It was concluded that dynamic coupling between FD mutations, the complex interface and CYP active site exist consistently with the observed regiospecific alterations.publishersversionpublishe