Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir.     

Live Fast and Die Young: Metal Effects on Condition and Physiology of Wild Yellow Perch from along Two Metal Contamination Gradients

This review summarizes some of the main findings of our work with the Metals in the Environment Research Network examining seasonal and regional effects on metal accumulation, growth, condition, and physiology in wild yellow perch (Perca flavescens) from 10 lakes comprising two metal contamination gradients in the industrial regions of Sudbury, Ontario and Rouyn-Noranda, Québec, Canada. The specific objectives of this review are: (1) to propose threshold tissue metal concentrations to discriminate between fish from contaminated and reference sites; (2) to identify factors that can influence metal accumulation and fish condition; and (3) to define an experimental approach for measuring metal effects in wild yellow perch. Using tissue thresholds appeared useful not only for discriminating fish from clean or contaminated environments, but also provided a simple approach to examine metabolic consequences of tissue metal accumulation. Overall, fish from Sudbury grew faster, expressed higher aerobic capacities, and died younger, but also appeared better at limiting accumulation of some metals than Rouyn-Noranda fish. The condition of the latter fish was clearly more affected by metals than Sudbury fish. Finally, our dataset allows us to propose that yellow perch are highly suitable for ecological risk assessment studies of metal effects in wild fish, but that fish size, season, and region must be considered in sampling design and that several reference sites must be studied for meaningful conclusions to be reached.     

Seasonal and Regional Variations in Metal Contamination and Condition Indicators in Yellow Perch (Perca flavescens) along Two Polymetallic Gradients. II. Growth Patterns,Longevity, and Condition

Wild yellow perch (Perca flavescens) were sampled from five lakes in each of two metal contamination gradients in Sudbury, Ontario, Canada (n = 1324) and Rouyn-Noranda, Québec, Canada (n = 1125) in the spring and summer of 2002 and 2003, respectively, in order to examine growth patterns, longevity, and the influences of season and region on fish condition. Fish from Rouyn-Noranda began rapid growth at a young age, whereas fish from Sudbury lakes showed slow growth rates between ages 0–3, after which growth rates improved. Fish from contaminated lakes grew faster and died younger than fish from reference lakes in both contamination gradients. Fish from Sudbury had lower condition than in Rouyn-Noranda, higher condition occurred in summer than spring, and fish from contaminated lakes had lower condition than those from cleaner lakes. Tissue Zn concentrations were correlated with fish condition and showed strong temporal stability. However, it is more likely that Zn covariates, such as Cd or Cu (which were more temporally variable) influenced condition, suggesting that long-term, broad-scale processes are more important than short-term, lake-specific processes for establishing growth patterns, longevity, and fish condition in metal-contaminated systems. Results from this study reveal that fish condition must be interpreted in the light of regional, seasonal, and other factors that can potentially influence fish growth patterns. Ecological risk assessments that fail to take these factors into account may draw erroneous conclusions about risk to indigenous populations.     

Regulation of autophagy by cytoplasmic p53

Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.     

IMGT, a system and an ontology that bridge biological and computational spheres in bioinformatics

IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr), is the reference in immunogenetics and immunoinformatics. IMGT standardizes and manages the complex immunogenetic data that include the immunoglobulins (IG) or antibodies, the T cell receptors (TR), the major histocompatibility complex (MHC) and the related proteins of the immune system (RPI), which belong to the immunoglobulin superfamily (IgSF) and the MHC superfamily (MhcSF). The accuracy and consistency of IMGT data and the coherence between the different IMGT components (databases, tools and Web resources) are based on IMGT-ONTOLOGY, the first ontology for immunogenetics and immunoinformatics. IMGT-ONTOLOGY manages the immunogenetics knowledge through diverse facets relying on seven axioms, 'IDENTIFICATION', 'DESCRIPTION', 'CLASSIFICATION', 'NUMEROTATION', 'LOCALIZATION', 'ORIENTATION' and 'OBTENTION', that postulate that objects, processes and relations have to be identified, described, classified, numerotated, localized, orientated, and that the way they are obtained has to be determined. These axioms constitute the Formal IMGT-ONTOLOGY, also designated as IMGT-Kaleidoscope. These axioms have been essential for the conceptualization of the molecular immunogenetics knowledge and for the creation of IMGT. Indeed all the components of the IMGT integrated system have been developed, based on standardized concepts and relations, thus allowing IMGT to bridge biological and computational spheres in bioinformatics. The same axioms can be used to generate concepts for multi-scale level approaches at the molecule, cell, tissue, organ, organism or population level, emphasizing the generalization of the application domain. In that way the Formal IMGT-ONTOLOGY represents a paradigm for the elaboration of ontologies in system biology.     

A SNP transferability survey within the genus <Emphasis Type="Italic">Vitis</Emphasis>

Background  

Efforts to sequence the genomes of different organisms continue to increase. The DNA sequence is usually decoded for one individual and its application is for the whole species. The recent sequencing of the highly heterozygous Vitis vinifera L. cultivar Pinot Noir (clone ENTAV 115) genome gave rise to several thousand polymorphisms and offers a good model to study the transferability of its degree of polymorphism to other individuals of the same species and within the genus.     

Photoreactivity of indirubin derivatives

Twenty-nine analogs of indirubin, an isomer of indigo, have been synthesized to optimize its promising kinase inhibitory scaffold. These compounds being also pigmented, have been tested for their photoreactivity. Absorption maxima were between 485 nm and 560 nm. Addition of fetal calf serum induced fluorescence and time dependent absorption modifications. Appropriate illumination induced Reactive Oxygen Species (ROS) production for nineteen compounds out of twenty-nine. The relationship between fluorescence and ROS production is discussed. Six compounds showed an important toxicity on F98 cells, a murine glioma cell line. Three of these were found to be also phototoxic, as four other non-toxic compounds. All but one phototoxic compounds were detected as ROS producers by in vitro tests. Photoreactivity assessment is important to anticipate adverse reactions for compounds that might be clinically developed. The experimental assay was found to be the only way to evaluate the photoreactivity of this family of compounds since no predictive criteria on structures could be found. Combining the vascular tumor growth inhibition induced by kinase inhibitors with the massive local blood flow arrest following photodynamic treatment may be an efficient anti-cancer strategy. These data could orientate further syntheses of either non-photoreactive compounds or compounds displaying both kinase inhibitory activity and strong phototoxicity.     

Antifungal activity of lichen extracts and lichenic acids

Acetone extracts of the threelichen species Evernia prunastri, Hypogymnia physodes and Cladoniaportentosa were investigated for activityagainst eight plant pathogenic fungi: Pythium ultimum, Phytophthorainfestans, Rhizoctonia solani, Botrytis cinerea, Colletotrichumlindemuthianum, Fusarium solani, Stagonospora nodorum and Ustilagomaydis. Particularly, E. prunastriand H. physodes exhibit total or stronginhibition on P. ultimum, U.maydis and P. infestans growth. Incontrast, Cladonia extracts were lessactive to reduce growth of these fungi.Lichenic acids were also examined forantifungal activity. P. infestans growthwas severely inhibited by evernic acid. P.ultimum and P. infestans growth wereslightly but significantly inhibited by evernicacid and (–) usnic acid, respectively. Growthinhibition of U. maydis was also observedfor the latter lichenic acid. These resultsconfirm the previously observed activities oflichen extracts. This suggests that secondarylichen metabolites might be of potential use asantifungal agents.     

Cell model of inflammation

Chemical and physical stimuli trigger a cutaneous response by first inducing the main epidermal cells, keratinocytes, to produce specific mediators that are responsible for the initiation of skin inflammation. Activation modulates cell communication, namely leucocyte recruitment and blood-to-skin extravasation through the selective barrier of the vascular ECs (endothelial cells). In the present study, we describe an in vitro model which takes into account the various steps of human skin inflammation, from keratinocyte activation to the adhesion of leucocytes to dermal capillary ECs. Human adult keratinocytes were subjected to stress by exposure to UV irradiation or neuropeptides, then the conditioned culture medium was used to mimic the natural micro-environmental conditions for dermal ECs. A relevant in vitro model must include appropriate cells from the skin. This is shown in the present study by the selective reaction of dermal ECs compared with EC lines from distinct origins, in terms of leucocyte recruitment, sensitivity to stress and nature of the stress-induced secreted mediators. This simplified model is suitable for the screening of anti-inflammatory molecules whose activity requires the presence of various skin cells.