Reversing Gut Damage in HIV Infection: Using Non-Human Primate Models to Instruct Clinical Research

International audienceAntiretroviral therapy (ART) has led to dramatic improvements in the lives of HIV-infected persons. However, residual immune activation, which persists despite ART, is associated with increased risk of non-AIDS morbidities. Accumulating evidence shows that disruption of the gut mucosal epithelium during SIV/HIV infections allows translocation of microbial products into the circulation, triggering immune activation. This disruption is due to immune, structural and microbial alterations. In this review, we highlighted the key findings of gut mucosa studies of SIV-infected macaques and HIV-infected humans that have revealed virus-induced changes of intestinal CD4, CD8 T cells, innate lymphoid cells, myeloid cells, and of the local cytokine/chemokine network in addition to epithelial injuries. We review the interplay between the host immune response and the intestinal microbiota, which also impacts disease progression. Collectively, these studies have instructed clinical research on early ART initiation, modifiers of microbiota composition, and recombinant cytokines for restoring gut barrier integrity

Seismic stratigraphic framework and depositional history for Cretaceous and Cenozoic contourite depositional systems of the Mozambique Channel, SW Indian Ocean

International audienceThis study describes previously unrecognized contourite depositional systems (CDSs) in the Mozambique Channel which constrain palaeoceanographic models for this area. The stratigraphic stacking patterns record nine seismic units (SU1 to SU9) separated by eight major discontinuities (a to h, oldest to youngest). Key seismic markers in CDS evolutionary history occur during Aptian-Albian (~122 Ma), late Cenomanian (94 Ma), early (38.2–36.2 Ma) and late (25–23 Ma) Oligocene, and early-middle Miocene (~17–15 Ma) epochs. These record onset (~122 to 94 Ma), growth (94 to 25–23 Ma), maintenance (25–23 to 17–15 Ma), and burial (17–15 Ma to the actual time) stages for CDSs. CDSs first develop during the onset stage which coincides with the opening and deepening of the African-Southern Ocean gateway (at 122 and 100 Ma, respectively). The growth stage, beginning in the late Cenomanian (94 Ma), correlates with the opening and deepening of the Equatorial Atlantic gateway. During the growth stage, two major shifts in sedimentary stacking pattern occur which coincide with palaeoceanographic changes during the early (38.2–36.2 Ma) and late (25–23 Ma) Oligocene. These in turn coincide with the onset and local enhancement of Antarctic water masses. CDS growth continued until the early-middle Miocene during the maintenance stage (~17–15 Ma). Most CDS growth ceased at the end of the maintenance stage. Circulation of the North Atlantic water mass into the Southern Hemisphere led to a deepening of Antarctic water masses in the area

LILAC pilot study : effects of metformin on mTOR activation and HIV reservoir persistence during antiretroviral therapy

Background: Chronic inflammation and residual HIV transcription persist in people living with HIV (PLWH) receiving antiretroviral therapy (ART), thus increasing the risk of developing non-AIDS co-morbidities. The mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism and HIV transcription, and therefore represents an interesting novel therapeutic target. Methods: The LILAC pilot clinical trial, performed on non-diabetic ART-treated PLWH with CD4+ /CD8+ T-cell ratios <0.8, evaluated the effects of metformin (12 weeks oral administration; 500-850 mg twice daily), an indirect mTOR inhibitor, on the dynamics of immunological/virological markers and changes in mTOR activation/phosphorylation in blood collected at Baseline, Week 12, and 12 weeks after metformin discontinuation (Week 24) and sigmoid colon biopsies (SCB) collected at Baseline and Week 12. Findings: CD4+ T-cell counts, CD4+ /CD8+ T-cell ratios, plasma markers of inflammation/gut damage, as well as levels of cell-associated integrated HIV-DNA and HIV-RNA, and transcriptionally-inducible HIV reservoirs, underwent minor variations in the blood in response to metformin. The highest levels of mTOR activation/ phosphorylation were observed in SCB at Baseline. Consistently, metformin significantly decreased CD4+ Tcell infiltration in the colon, as well as mTOR activation/phosphorylation, especially in CD4+ T-cells expressing the Th17 marker CCR6. Also, metformin decreased the HIV-RNA/HIV-DNA ratios, a surrogate marker of viral transcription, in colon-infiltrating CD4+ T-cells of 8/13 participants

PhenoExplorer: An Interactive Web-based Platform for Exploring (Epi)Genome-Wide Associations Using a Swiss Population-based Study

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes

Residual vascular risk in diabetes – will the SPPARM alpha concept hold the key?

No abstract available

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

The African margin of the Mozambique channel, the turbiditic system : a source to sink approach during the Meso-Cenozoic.

Le système Zambèze localisé sur le versant est de l'Afrique est caractérisé par un système turbiditique de très grande dimension (x 100 km) et est associé à terre au troisième plus grand bassin versant d'Afrique (1 320 000 km2) après ceux du Nil et du Congo. A ce jour, peu d'études ont porté sur l'évolution du système terre - mer depuis le bassin versant en érosion jusqu'au bassin en sédimentation. Ce travail s'attachera à : [1] caractériser et à discuter l'origine des déformations enregistrées dans le système sédimentaire Zambèze depuis 155 Ma, [2] quantifier les bilans érosion - sédimentation du système du Zambèze, pour une meilleure compréhension du routage sédimentaire.The Zambezi system located on the eastern slope of Africa is characterized by a turbiditic system of very large size (x 100 km) and is associated onshore to the third largest watershed in Africa (1,320,000 km2) after those of the Nile and Congo. Few studies have examined the evolution of the land - sea system from the eroding catchment to the sedimentation basin. This work will focus on: [1] characterize and discuss the origin of the deformations recorded in the Zambezi sedimentary system since 155 Ma, [2] quantify the erosion-sedimentation balances of the Zambezi system, for a better understanding of the sedimentary routin

La marge africaine du canal du Mozambique, le système turbiditique du Zambèze : une approche « Source to Sink » au Méso – Cénozoïque

The Zambezi system located on the eastern slope of Africa is characterized by a turbiditic system of very large size (x 100 km) and is associated onshore to the third largest watershed in Africa (1,320,000 km2) after those of the Nile and Congo. Few studies have examined the evolution of the land - sea system from the eroding catchment to the sedimentation basin. This work will focus on: [1] characterize and discuss the origin of the deformations recorded in the Zambezi sedimentary system since 155 Ma, [2] quantify the erosion-sedimentation balances of the Zambezi system, for a better understanding of the sedimentary routingLe système Zambèze localisé sur le versant est de l'Afrique est caractérisé par un système turbiditique de très grande dimension (x 100 km) et est associé à terre au troisième plus grand bassin versant d'Afrique (1 320 000 km2) après ceux du Nil et du Congo. A ce jour, peu d'études ont porté sur l'évolution du système terre - mer depuis le bassin versant en érosion jusqu'au bassin en sédimentation. Ce travail s'attachera à : [1] caractériser et à discuter l'origine des déformations enregistrées dans le système sédimentaire Zambèze depuis 155 Ma, [2] quantifier les bilans érosion - sédimentation du système du Zambèze, pour une meilleure compréhension du routage sédimentaire