La Possession – 8 rue Évariste-de-Parny

Le site étudié est localisé au no 8 de la rue Évariste-de-Parny dans le centre ancien de la ville de La Possession, sur la parcelle BM 126. Cette rue correspond à l’axe historique reliant Saint-Denis à Saint-Paul durant la période moderne et c’est à son embouchure qu’était situé le débarcadère principal de La Possession permettant de rejoindre Saint-Denis, mais aussi de faire la liaison en chaloupe avec les navires de haut bord. La parcelle, d’une superficie de 1 728 m2, est entourée d’un mur..

HIV-1 tropism determination using a phenotypic Env recombinant viral assay highlights overestimation of CXCR4-usage by genotypic prediction algorithms for CRRF01_AE and CRF02_AG

Background: Human Immunodeficiency virus type-1 (HIV) entry into target cells involves binding of the viral envelope (Env) to CD4 and a coreceptor, mainly CCR5 or CXCR4. The only currently licensed HIV entry inhibitor, maraviroc, targets CCR5, and the presence of CXCX4-using strains must be excluded prior to treatment. Co-receptor usage can be assessed by phenotypic assays or through genotypic prediction. Here we compared the performance of a phenotypic Env-Recombinant Viral Assay (RVA) to the two most widely used genotypic prediction algorithms, Geno2Pheno([coreceptor]) and webPSSM. Methods: Co-receptor tropism of samples from 73 subtype B and 219 non-B infections was measured phenotypically using a luciferase-tagged, NL4-3-based, RVA targeting Env. In parallel, tropism was inferred genotypically from the corresponding V3-loop sequences using Geno2Pheno([coreceptor]) (5-20% FPR) and webPSSM-R5X4. For discordant samples, phenotypic outcome was retested using co-receptor antagonists or the validated Trofile (R) Enhanced-Sensitivity-Tropism-Assay. Results: The lower detection limit of the RVA was 2.5% and 5% for X4 and R5 minority variants respectively. A phenotype/genotype result was obtained for 210 samples. Overall, concordance of phenotypic results with Geno2Pheno([coreceptor]) was 85.2% and concordance with webPSSM was 79.5%. For subtype B, concordance with Geno2pheno([coreceptor]) was 94.4% and concordance with webPSSM was 79.6%. High concordance of genotypic tools with phenotypic outcome was seen for subtype C (90% for both tools). Main discordances involved CRF01_AE and CRF02_AG for both algorithms (CRF01_AE: 35.9% discordances with Geno2Pheno([coreceptor]) and 28.2% with webPSSM; CRF02_AG: 20.7% for both algorithms). Genotypic prediction overestimated CXCR4-usage for both CRFs. For webPSSM, 40% discordance was observed for subtype A. Conclusions: Phenotypic assays remain the most accurate for most non-B subtypes and new subtype-specific rules should be developed for non-B subtypes, as research studies more and more draw conclusions from genotypically-inferred tropism, and to avoid unnecessarily precluding patients with limited treatment options from receiving maraviroc or other entry inhibitors

Saint-Paul – L’Ermitage-les-Bains, Bruniquel Hôpital, Camp des engagés

Le site étudié est localisé sur la commune de Saint-Paul, à l’Ermitage-les-Bains, sur le site sucrier de Bruniquel, nom de son second propriétaire. L’usine des Filaos, son premier nom, a été construite en 1865 par Joseph Lelièvre. Dotée des dernières avancées techniques et architecturales, elle marquait un phénomène de concentration industrielle, tandis que d’autres domaines étaient touchés par la crise économique. Des vestiges en sont conservés sur le terrain, dont des élévations, notamment ..

Predominance of the heterozygous CCR5 delta‐24 deletion in African individuals resistant to HIV infection might be related to a defect in CCR5 addressing at the cell surface

Introduction The chemokine receptor CCR5 is the main co-receptor for R5-tropic HIV-1 variants. We have previously described a novel 24-base pair deletion in the coding region of CCR5 among individuals from Rwanda. Here, we investigated the prevalence of hCCR5 Delta 24 in different cohorts and its impact on CCR5 expression and HIV-1 infection in vitro. Methods We screened hCCR5 Delta 24 in a total of 3232 individuals which were either HIV-1 uninfected, high-risk HIV-1 seronegative and seropositive partners from serodiscordant couples, Long-Term Survivors, or HIV-1 infected volunteers from Africa (Rwanda, Kenya, Guinea-Conakry) and Luxembourg, using a real-time PCR assay. The role of the 24-base pair deletion on CCR5 expression and HIV infection was assessed in cell lines and PBMC using mRNA quantification, confocal analysis, flow and imaging cytometry. Results and Discussion Among the 1661 patients from Rwanda, 12 individuals were heterozygous for hCCR5 Delta 24 but none were homozygous. Although heterozygosity for this allele may not confer complete resistance to HIV-1 infection, the prevalence of the mutation was 2.41% (95%CI: 0.43; 8.37) in 83 Long-Term Survivors (LTS) and 0.99% (95%CI: 0.45; 2.14) in 613 HIV-1 exposed seronegative members as compared with 0.35% (95% Cl: 0.06; 1.25) in 579 HIV-1 seropositive members. The prevalence of hCCR5 Delta 24 was 0.55% (95%CI: 0.15; 1.69) in 547 infants from Kenya but the mutation was not detected in 224 infants from Guinea-Conakry nor in 800 Caucasian individuals from Luxembourg. Expression of hCCR5 Delta 24 in cell lines and PBMC showed that the hCCR5 Delta 24 protein is stably expressed but is not transported to the plasma membrane due to a conformational change. Instead, the mutant receptor was retained intracellularly, colocalized with an endoplasmic reticulum marker and did not mediate HIV-1 infection. Co-transfection of hCCR5 Delta 24 and wtCCR5 did not indicate a transdominant negative effect of CCR5 Delta 24 on wtCCR5. Conclusions Our findings indicate that hCCR5 Delta 24 is not expressed at the cell surface. This could explain the higher prevalence of the heterozygous hCCR5 Delta 24 in LTS and HIV-1 exposed seronegative members from serodiscordant couples. Our data suggest an East-African localization of this deletion, which needs to be confirmed in larger cohorts from African and non-African countries

Cytopathic effects of the cytomegalovirus-encoded apoptosis inhibitory protein vMIA

Replication of human cytomegalovirus (CMV) requires the expression of the viral mitochondria–localized inhibitor of apoptosis (vMIA). vMIA inhibits apoptosis by recruiting Bax to mitochondria, resulting in its neutralization. We show that vMIA decreases cell size, reduces actin polymerization, and induces cell rounding. As compared with vMIA-expressing CMV, vMIA-deficient CMV, which replicates in fibroblasts expressing the adenoviral apoptosis suppressor E1B19K, induces less cytopathic effects. These vMIA effects can be separated from its cell death–inhibitory function because vMIA modulates cellular morphology in Bax-deficient cells. Expression of vMIA coincided with a reduction in the cellular adenosine triphosphate (ATP) level. vMIA selectively inhibited one component of the ATP synthasome, namely, the mitochondrial phosphate carrier. Exposure of cells to inhibitors of oxidative phosphorylation produced similar effects, such as an ATP level reduced by 30%, smaller cell size, and deficient actin polymerization. Similarly, knockdown of the phosphate carrier reduced cell size. Our data suggest that the cytopathic effect of CMV can be explained by vMIA effects on mitochondrial bioenergetics

Impact of the HIV-1 env Genetic Context outside HR1–HR2 on Resistance to the Fusion Inhibitor Enfuvirtide and Viral Infectivity in Clinical Isolates

Resistance mutations to the HIV-1 fusion inhibitor enfuvirtide emerge mainly within the drug's target region, HR1, and compensatory mutations have been described within HR2. The surrounding envelope (env) genetic context might also contribute to resistance, although to what extent and through which determinants remains elusive. To quantify the direct role of the env context in resistance to enfuvirtide and in viral infectivity, we compared enfuvirtide susceptibility and infectivity of recombinant viral pairs harboring the HR1–HR2 region or the full Env ectodomain of longitudinal env clones from 5 heavily treated patients failing enfuvirtide therapy. Prior to enfuvirtide treatment onset, no env carried known resistance mutations and full Env viruses were on average less susceptible than HR1–HR2 recombinants. All escape clones carried at least one of G36D, V38A, N42D and/or N43D/S in HR1, and accordingly, resistance increased 11- to 2800-fold relative to baseline. Resistance of full Env recombinant viruses was similar to resistance of their HR1–HR2 counterpart, indicating that HR1 and HR2 are the main contributors to resistance. Strictly X4 viruses were more resistant than strictly R5 viruses, while dual-tropic Envs featured similar resistance levels irrespective of the coreceptor expressed by the cell line used. Full Env recombinants from all patients gained infectivity under prolonged drug pressure; for HR1–HR2 viruses, infectivity remained steady for 3/5 patients, while for 2/5 patients, gains in infectivity paralleled those of the corresponding full Env recombinants, indicating that the env genetic context accounts mainly for infectivity adjustments. Phylogenetic analyses revealed that quasispecies selection is a step-wise process where selection of enfuvirtide resistance is a dominant factor early during therapy, while increased infectivity is the prominent driver under prolonged therapy

Selectivity and capture of gas mixture in gas hydrates in presence of impurities : study by vibrational spectroscopy and neutron diffraction

Les hydrates de gaz sont présents dans de nombreux environnements naturels : sédiments marins, carotte de glace polaire ou encore aérosols atmosphérique. Ils représentent de grands enjeux dans le domaine des applications techniques et industrielles, allant de l’exploitation des hydrates de gaz naturel au sein des sédiments marins, jusqu’au stockage et au transport du gaz naturel sous forme solide. Au cours de cette étude, un intérêt particulier est donné à l’influence des minéraux sur la formation des hydrates de gaz. Les aluminosilicates (feldspath de sodium, calcium et potassium) sont des minéraux répandus aussi bien sur Terre que sur les différents corps astraux tels que les planètes, les lunes ou encore les météorites et comètes. Ces minéraux sont chargés en alcalins et possèdent une grande surface de réaction pouvant influencer la formation des hydrates de gaz. L’utilisation de la diffraction des neutrons, couplée à la spectroscopie Raman, a permis de mettre en évidence que les substituts alcalins agissent comme inhibiteurs de la cinétique de formation des hydrates de gaz tout en modifiant la sélectivité des hydrates mixtes. En effet, la mobilité des cations alcalins, au contact de molécules d’eaux et de CO2 gazeux entraine la précipitation de carbonate, dont la formation rentre en compétition avec celle des hydrates de gaz. Le deuxième objectif de ce travail était de comprendre l’influence de ces substituts sur la formation d’hydrates de gaz dans des conditions astrophysiques. Ces données étant peu présent dans la littérature, l’objectif principale de cette partie d’étude était alors d’étudier la formation d’hydrate pur et mixte dans des conditions de très basse pression et basse température. Il en ressort que, dans ces conditions extrêmes, il est nécessaire de former des interfaces entre différentes couches de glace amorphe afin de permettre la formation d’hydrate de gaz.Gas hydrates are present in many natural environments like marine sediments, polar ice cores and atmospheric aerosols. They represent major challenges in the field of technical and industrial applications, ranging from the exploitation of natural gas hydrates in marine sediments to the storage and transport of natural gas in solid form. During this study, particular interest is given to the influence of minerals on the formation of gas hydrates. Aluminosilicates (sodium feldspar, calcium and potassium) are minerals that are found on Earth as well as on various astral bodies such as planets, moons, meteorites and comets. These minerals are loaded with alkalis and have a large specific surface of reaction that can influence the formation of gas hydrates. The use of neutronic diffraction, coupled with Raman spectroscopy, has shown that alkaline surrogates act as inhibitors of gas hydrate formation kinetics while modifying the selectivity of mixed hydrates. Indeed, the mobility of alkaline cations, in contact with water molecules and gaseous CO2, leads to the precipitation of carbonate, whose formation competes with that of gas hydrates. The second objective of this work was to understand the influence of these surrogates on the formation of gas hydrates under astrophysical conditions. As these data are not widely available in the literature, the main objective of this part of the study was to understand the formation of pure and mixed hydrate under very low pressure and low temperature conditions. It appears that, under these extreme conditions, it is necessary to form interfaces between different amorphous ice layers in order to allow the formation of gas hydrate

Kétamine (perspectives thérapeutiques dans la dépression en situation palliative)

La dépression est fréquente en soins palliatifs, mais reste encore sous-diagnostiquée, et de surcroit tardivement. Dans ces conditions, le long délai d action des antidépresseurs conventionnels (notamment les IRS actuellement recommandés) est à lui seul un facteur identifié de perte de chance. La problématique de la dynamique temporelle en situation palliative nous a enjoint à considérer d autres traitements de la dépression. Ce travail établit d abord une cartographie détaillée de la dépression en situation palliative. Dans un second temps, nous rappelons les connaissances sur la kétamine et ses utilisations actuelles. Enfin, nous réalisons une revue de littérature sur son utilisation dans la dépression. D après les études épidémiologiques, la prévalence de la dépression est élevée et elle a un impact négatif sur la qualité de vie des patients. La dépression influence également le pronostic global et la mortalité. La prise en charge médicale est de moins bonne qualité, notamment en raison de la sévérité plus importante des symptômes physiques et d une moins bonne observance en cas de dépression. Il existe actuellement des recommandations européennes quant à la prévention, au dépistage, au diagnostic et au traitement de la dépression en soins palliatifs. Si les traitements médicamenteux sont recommandés, la prise en charge pluriprofessionnelle précoce reste au coeur des recommandations. La kétamine, molécule connue depuis les années 1950, est actuellement presque essentiellement utilisée en anesthésie et en douleur aigue ou chronique. Un intérêt croissant pour cette molécule existe en psychiatrie dans le cadre des dépressions pharmaco-résistantes. La kétamine possède l avantage d agir très rapidement, son effet pouvant persister jusqu à deux semaines après une administration unique. En soins palliatifs, la molécule est utilisée presque uniquement dans le cadre de la prise en charge des douleurs. La revue de littérature conforte, grâce aux essais randomisés réalisés en psychiatrie, l intérêt de la molécule dans la dépression. Son efficacité est décrite quatre heures après une administration unique, persistant plusieurs jours, voire deux à trois semaines. Les études de cas en situation palliative, principalement en oncologie, sont également encourageantes. Ces constatations nous amènent à considérer l utilisation de la kétamine dans la prise en charge précoce de la dépression en situation palliativeLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Additional file 2: Figure S2. of Reassessment of the capacity of the HIV-1 Env cytoplasmic domain to trigger NF-κB activation

NF-κB induction relative to Env and CD8-EnvCD expression levels. A. NF-κB induction by subtype B and subtype C Envs relative to Env expression levels. NF-κB induction measured in HEK cells co-transfected with the subtype B or subtype C Envs, NF-κB-Luciferase and CMV-Renilla-Luciferase vectors (Fig. 1a and b) was normalized to Env expression levels (MFI, Additional file 1: Figure S1A) to account for differences in Env expression vectors. B. NF-κB induction by CD8-EnvCD relative to expression levels. NF-κB induction measured in HEK cells co-transfected with the CD8-EnvCD constructs, NF-κB-Luciferase and CMV-Renilla-Luciferase vectors (Fig. 2a and b) was normalized to CD8-EnvCD expression levels (MFI, Additional file 1: Figure S1B) to account for differences in expression vectors. It is noteworthy that this second normalization round is subject to differences in antibody affinity for Env, in Env expression kinetics and cycling dynamics, as well as in Env-induced cytotoxicity. This is particularly the case for the subtype B and C primary Envs, while CD8-EnvCD expression levels are less subject to differences in antibody affinity. (PDF 308 kb