Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).

Cellular and physiological responses to changes in dioxygen levels in metazoans are mediated via the posttranslational oxidation of hypoxia-inducible transcription factor (HIF). Hydroxylation of conserved prolyl residues in the HIF-alpha subunit, catalyzed by HIF prolyl-hydroxylases (PHDs), signals for its proteasomal degradation. The requirement of the PHDs for dioxygen links changes in dioxygen levels with the transcriptional regulation of the gene array that enables the cellular response to chronic hypoxia; the PHDs thus act as an oxygen-sensing component of the HIF system, and their inhibition mimics the hypoxic response. We describe crystal structures of the catalytic domain of human PHD2, an important prolyl-4-hydroxylase in the human hypoxic response in normal cells, in complex with Fe(II) and an inhibitor to 1.7 A resolution. PHD2 crystallizes as a homotrimer and contains a double-stranded beta-helix core fold common to the Fe(II) and 2-oxoglutarate-dependant dioxygenase family, the residues of which are well conserved in the three human PHD enzymes (PHD 1-3). The structure provides insights into the hypoxic response, helps to rationalize a clinically observed mutation leading to familial erythrocytosis, and will aid in the design of PHD selective inhibitors for the treatment of anemia and ischemic disease

Peroxy radical behavior during the Transport and Chemical Evolution over the Pacific (TRACE-P) campaign as measured aboard the NASA P-3B aircraft

Peroxy radical concentrations were measured aboard the NASA P-3B aircraft during the Transport and Chemical Evolution over the Pacific (TRACE-P) campaign in the spring of 2001 and varied in ways that depended on radical production rates and reactive nitrogen concentrations. Measurements of HO2, HO2 + RO2, and OH during this study allowed calculation of radical ratios, examination of functional relationships of these ratios on controlling variables, and comparison with numerical model estimations. Radical production terms show changes in relative contributions at low, middle, and high total production rates that are understandable in terms of systematic variations in the controlling components (trace gas concentrations and photolysis rate coefficients). Ozone tendency calculations indicate net ozone production in the western Pacific basin because the concentrations of critical precursor trace gases (e.g., NOx, hydrocarbons) are highest there. The dependence of ozone tendency follows the concentration of NO systematically. Peroxy radical levels on the two aircraft (HO2 + RO2 on the P-3B and HO2 on the DC-8) during two relatively short prescribed intercomparison periods were in good agreement in one instance and poorer in another given reasonable assumptions about the apportioning of radicals between HO2 and RO2. Recommended changes to CH2O photolysis quantum yields, HO2 self reaction, and O(1D) quenching kinetics lead to small changes (<5%) in calculated peroxy radical levels for TRACE-P conditions. There is evidence from this campaign that peroxy radicals are lost by interaction with aerosols and cloud droplets

Techniques d'évaluation de l'œdème des membres inférieurs en recherche clinique

L'œdème des membres inférieurs est une manifestation essentielle de la maladie veineuse chronique et du lymphoedème des membres inférieurs : deux pathologies vasculaires fréquemment rencontrées au sein de la population et pouvant avoir des répercutions socio-économiques importantes. Paramètre objectif pouvant être mesuré, reflet de la sévérité de ces maladies et sensible aux traitements, l'œdème des membres inférieurs apparaît ainsi comme un critère pertinent de jugement de l'efficacité des thérapeutiques vasculotropes lors d'essais cliniques en angiologie. Devant un tel intérêt, l'œdème doit être évalué par des méthodes adaptées et précises. De nombreuses techniques peuvent être utilisées à cette fin, chacune possédant ses propres avantages et inconvénients et agissant selon un principe bien particulier. Cependant, malgré la grande variété de techniques disponibles, il est aujourd'hui difficile de déterminer la " méthode idéale " qui pourrait permettre une harmonisation de l'évaluation des thérapies utilisées lors de telles pathologies.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Probing molecular mechanisms of M13 bacteriophage adhesion

M13 bacteriophages can provide a versatile platform for nanobiotechnology because of their unique biological and physicochemical properties. Polypeptides on their surfaces can be finely tuned on demand through genetic engineering, enabling tailored assembly of multiple functional components through specific interactions. Their versatility has been demonstrated by synthesizing various unprecedented hybrid materials for energy storage, biosensing, and catalysis. Here we select a specific type of genetically engineered M13 bacteriophage (DSPH) to investigate the origin of interactions. The interaction forces between the phage-coated surface and five different functionalized self-assembled monolayers are directly measured using a surface forces apparatus. We confirm that the phages have strong adhesion energies in acidic environments due to ??-?? stacking and hydrophobic interactions, while hydrogen bonding interactions remain relatively weak. These results provide quantitative and qualitative information of the molecular interaction mechanisms of DSPH phages, which can be utilized as a database of the bacteriophage interactions