Histoire politique de l’administration

Marc Olivier Baruch, directeur d’étudesPerrine Simon-Nahum, directrice de recherche au CNRSAlain Chatriot, chargé de recherche au CNRS Droit et histoire de l’État Lire la construction de l’État, dans l’Europe des XIXe et XXe siècles, à travers le prisme du droit, tel était le pari que s’étaient fixé cette année les animateurs du séminaire. Dans la mesure où il n’est pas d’activité sociale qui ne puisse être lue sous un angle juridique, le champ des possibles restait vaste. Pour les besoins de..

Extended high efficacy of the combination sulphadoxine-pyrimethamine with artesunate in children with uncomplicated falciparum malaria on the Benin coast, West Africa

<p>Abstract</p> <p>Background</p> <p>A study carried out in 2003–2005 in Southern Benin showed a day-28 sulphadoxine-pyrimethamine (SP) monotherapy failure rate greater than 40%, while for SP combined with artesunate (SP-AS) the failure rate was 5.3%. Such a large difference could be explained by the relatively short 28-day follow-up period, with a substantial number of recurrent infections possibly occurring after day 28. This paper reports the treatment outcome observed in the same study cohort beyond the initial 28-day follow-up.</p> <p>Methods</p> <p>After the 28-day follow-up, children treated with either chloroquine alone (CQ), SP or SP-AS, were visited at home twice a week until day 90 after treatment. A blood sample was collected if the child had fever (axillary temperature ≥37.5°C). Total clinical failure for each treatment group was estimated by combining all the early treatment failures and late clinical failures that occurred over the whole follow-up period, i.e. from day 0 up to day 90. Pre-treatment randomly selected blood samples were genotyped for the <it>dhfr </it>gene (59) and the <it>dhps </it>gene (437 and 540) point mutations related to SP resistance.</p> <p>Results</p> <p>The PCR-corrected clinical failure at day 90 was significantly lower in the SP-AS group (SP-AS: 2.7%, SP alone: 38.2%; CQ: 41.1%) (Log-Rank p < 0,001). The most prevalent haplotype was <it>dhfr </it>Arg-59 with the <it>dhps </it>Gly-437 mutant and the <it>dhps </it>540 wild type (85.5%). The <it>dhps </it>540 mutation could be found in only three (8.3%) samples.</p> <p>Conclusion</p> <p>Combining artesunate to SP dramatically increased the treatment efficacy, even when extending the follow-up to day 90 post-treatment, and despite the high percentage of failures following treatment with SP alone. Such a good performance may be explained by the low prevalence of the <it>dhps </it>540 mutation, by the rapid parasite clearance with artesunate and by the level of acquired immunity.</p

Synergistic effects between analogs of DNA and RNA improve the potency of siRNA-mediated gene silencing

We report that combining a DNA analog (2′F-ANA) with rigid RNA analogs [2′F-RNA and/or locked nucleic acid (LNA)] in siRNA duplexes can produce gene silencing agents with enhanced potency. The favored conformations of these two analogs are different, and combining them in a 1–1 pattern led to reduced affinity, whereas alternating short continuous regions of individual modifications increased affinity relative to an RNA:RNA duplex. Thus, the binding affinity at key regions of the siRNA duplex could be tuned by changing the pattern of incorporation of DNA-like and RNA-like nucleotides. These heavily or fully modified duplexes are active against a range of mRNA targets. Effective patterns of modification were chosen based on screens using two sequences targeting firefly luciferase. We then applied the most effective duplex designs to the knockdown of the eIF4E binding proteins 4E-BP1 and 4E-BP2. We identified modified duplexes with potency comparable to native siRNA. Modified duplexes showed dramatically enhanced stability to serum nucleases, and were characterized by circular dichroism and thermal denaturation studies. Chemical modification significantly reduced the immunostimulatory properties of these siRNAs in human peripheral blood mononuclear cells

Adding artesunate to sulphadoxine-pyrimethamine greatly improves the treatment efficacy in children with uncomplicated falciparum malaria on the coast of Benin, West Africa

<p>Abstract</p> <p>Background</p> <p>Benin has recently shifted its national antimalarial drug policy from monotherapies to combinations containing artemisinin derivatives. When this decision was taken, the available information on alternatives to chloroquine and sulphadoxine-pyrimethamine, the first- and second-line treatment, was sparse.</p> <p>Methods</p> <p>In 2003 – 2005, before the drug policy change, a randomized, open-label, clinical trial was carried out on the efficacy of chloroquine, and sulphadoxine-pyrimethamine alone or combined with artesunate, with the aim of providing policy makers with the information needed to formulate a new antimalarial drug policy. Children between six and 59 months of age, with uncomplicated malaria and living in the lagoon costal area in southern Benin, were randomly allocated to one of the three study arms and followed up for 28 days.</p> <p>Results</p> <p>Treatment failure (PCR corrected) was significantly lower in the artesunate + sulphadoxine-pyrimethamine group (4/77, 5.3%) than in chloroquine group(51/71, 71.8%) or the sulphadoxine-pyrimethamine alone group (30/70, 44.1%) (p < 0.001). Despite high sulphadoxine-pyrimethamine failure, its combination with artesunate greatly improved treatment efficacy.</p> <p>Conclusion</p> <p>In Benin, artesunate + sulphadoxine-pyrimethamine is efficacious and could be used when the recommended artemisinin-based combinations (artemether-lumefantrine and amodiaquine-artesunate) are not available. However, because sulphadoxine-pyrimethamine is also used in pregnant women as intermittent preventive treatment, its combination with artesunate should not be widely employed in malaria patients as this may compromise the efficacy of intermittent preventive treatment.</p

Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling

SummaryProtein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor+/− mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock

Malaria Incidence and Prevalence Among Children Living in a Peri-Urban Area on the Coast of Benin, West Africa: A Longitudinal Study

Clinical malaria incidence was determined over 18 months in a cohort of 553 children living in a peri-urban area near Cotonou. Three cross-sectional surveys were also carried out. Malaria incidence showed a marked seasonal distribution with two peaks: the first corresponding to the long rainy season, and the second corresponding to the overflowing of Lake Nokoue. The overall Plasmodium falciparum incidence rate was estimated at 84/1,000 person-months, and its prevalence was estimated at over 40% in the two first surveys and 68.9% in the third survey. Multivariate analysis showed that girls and people living in closed houses had a lower risk of clinical malaria. Bed net use was associated with a lower risk of malaria infection. Conversely, children of families owing a pirogue were at higher risk of clinical malaria. Considering the high pyrethroids resistance, indoor residual spraying with either a carbamate or an organophospate insecticide may have a major impact on the malaria burden

CRH – Approches historiques des mondes contemporains (AhMoC)

Stéphane Audoin-Rouzeau, Marc Olivier Baruch, Christophe Prochasson, Paul-André Rosental, directeurs d’étudesLaura Lee Downs, directrice d’étudesJordi Canal, maître de conférencesVincent Duclert, professeur agrégéMarie-Laurence Netter, ingénieure d’étudesAlain Chatriot, chargé de recherche au CNRSPerrine Simon-Nahum, chargée de recherche au CNRS Histoire politique du contemporain Le programme du séminaire reposait cette année sur une série d’interrogations générales relatives à la recherche e..

Approches historiques des mondes contemporains – AhMoC

Stéphane Audoin-Rouzeau, Marc Olivier Baruch, Jacques Julliard, Laura Lee Downs, Christophe Prochasson, Paul-André Rosental, directeurs d’étudesIsabelle Backouche, Jordi Canal, maîtres de conférencesVincent Duclert, professeur agrégéMarie-Laurence Netter, ingénieur d’étudesAlain Chatriot et Perrine Simon-Nahum, chargés de recherche au CNRS L’histoire politique. État des lieux Cette année, le séminaire s’est concentré sur l’historiographie de la gauche. En 2003-2004, on s’était penché sur les ..

S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3

Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for the activation of IRF3 in the cytosolic DNA pathway

Cap-binding protein 4EHP effects translation silencing by microRNAs

Significance miRNAs are important components of gene regulatory networks and affect all aspects of cell biology by controlling the stability and translation efficiency of their target mRNAs. Here, we identified the mRNA cap-binding eIF4E-related protein 4EHP as an effector of miRNA-mediated translation repression. Through screening for protein interactions in cells via the BioID method, we identified 4EHP as a component of the CCR4–NOT/DDX6/4E-T axis. Direct interaction between 4E-T and 4EHP increases the latter’s cap-binding affinity, suggesting that this interaction potentiates its competition with the eIF4F complex for binding to the mRNA 5′ cap. Our findings suggest that 4EHP facilitates the formation of a closed-loop structure between the 3′ UTR of the mRNA and its 5′ cap, which causes repression of mRNA translation.</jats:p