Steroid substrate-induced epimerase mechanism in the active site of the human 11β-hydroxysteroid dehydrogenase type 1

Cytochrome P4507B1 7[alpha]-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5[alpha]-androstane-3[beta],17[beta]-diol (Adiol). 11[beta]-Hydroxysteroid dehydrogenase type 1 (11[beta]-HSD1) interconverts 7[alpha]- and 7[beta]- forms. Whether the inter-conversion proceeds through oxido-reductive steps or epimerase activity is investigated. Experiments using ^3^H-labeled 7[beta]-hydroxy-DHEA, 7[beta]-hydroxy-EpiA and 7[beta]-hydroxy-Adiol show the ^3^H-label to accumulate in 7-oxo-DHEA trap but neither in 7-oxo-EpiA nor 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids dock in the active site of 11[beta]-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7[alpha]- or 7[beta]-hydroxylated derivatives results from either turned or flipped forms. 11[beta]-HSD1 incubation in H~2~^18^O medium with each 7-hydroxysteroid did not incorporate ^18^O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7[alpha]- and 7[beta]-hydroxy-DHEA through 7-oxo-DHEA. Epimerisation may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser170

Techno-economic and Life Cycle Assessment of methane production via biogas upgrading and power to gas technology

International audienceTo decrease the use of fossil fuels and face the energetic demand, the integration of renewable energy is a necessary step. Part of this renewable energy can be supplied by the production of electricity from photovoltaic panels and windfarms. The massive use of these intermittent energies will lead to overproduction periods, and there is consequently a need to convert this surplus of electricity into a storable form of energy. Power-togas (PtG) technology consists in using electricity to convert water into hydrogen by electrolysis, and then to synthetize methane from carbon dioxide and hydrogen. Techno-economic and Life Cycle Assessment of methane production via the combination of anaerobic digestion and PtG technology have been applied to sewage sludge valorization. Process studies and equipment design have been addressed considering already available technologies. Sensitivity analyses have been done on biogas upgrading technologies, electricity prices, annual operation time and composition of the electricity mix with also a comparison between PtG and direct injection. It appears that the more the electricity is expensive, the longer the operation time of the methanation process must be to be competitive with injection of methane from biogas. Reduction of electricity consumption of the electrolysis step decreases production costs. Even if the current context does not feature adapted conditions to ensure an economically viable chain, the evolution of the energetic context in the next few years as well as the expected technological improvements will contribute to overall cost reduction. From an environmental point of view, continuous PtG generates more greenhouse gases than direct injection, but intermittent operation with use of renewable electricity can significantly reduce GHG emissions. From an endpoint impacts perspective, impact from continuous PtG are higher than biogas upgrading, but much lower than fossil energy. Future development of low electricity consumption of the electrolysis process, and integration of renewable credits from CO 2 valorization can increase the competitiveness of this technology

Evidence for a Nonallelic Heterogeneity of Epidermodysplasia Verruciformis with Two Susceptibility Loci Mapped to Chromosome Regions 2p21–p24 and 17q25

Epidermodysplasia verruciformis is a rare genodermatosis associated with a high risk of skin cancer. This condition is characterized by an abnormal susceptibility to specific related human papillomavirus genotypes, including the oncogenic HPV5. Epidermodysplasia verruciformis is usually considered as an autosomal recessive disease. We recently mapped a susceptibility locus for epidermodysplasia verruciformis (EV1) to chromosome 17qter within the 1 cM interval between markers D17S939 and D17S802. We report here the genotyping for 10 microsatellite markers spanning 29 cM around EV1 in two consanguineous epidermodysplasia verruciformis families from Colombia (C2) and France (F1) comprising five patients and two patients, respectively. Using homozygosity mapping, linkage with 17qter markers was observed for family C2 only. Multipoint linkage analysis yielded maximum multipoint LOD-score values above 10 between markers D17S1839 and D17S802 encompassing the EV1 locus. A genome-wide search performed in family F1 yielded evidence for linkage between epidermodysplasia verruciformis and the chromosomal 2p marker D2S365. Nine additional microsatellite markers spanning 15 cM in this region were analyzed. Assuming an autosomal recessive inheritance with a complete penetrance, the expected maximum two-point LOD-score value of 1.8 was obtained for three markers and multipoint linkage analysis yielded a maximum LOD-score value of 3.51 between markers D2S2144 and D2S392. Haplotype analysis allowed to map a candidate region for a second epidermodysplasia verruciformis susceptibility locus (EV2) within the 8 cM interval between markers D2S171 and D2S2347 of the 2p21–p24 region. In contrast, linkage with 2p markers was excluded for family C2 and for the three families in which we mapped EV1 previously. The disclosure of two susceptibility loci for epidermodysplasia verruciformis provides evidence for a nonallelic heterogeneity in this disease

Business/IT Alignment in Practice: Lessons Learned From a Requirements Project at P&G

One of the main objectives of the alignment of Business and IT in both small and large organizations is to improve the chances for an IT department to provide services that result in business success. An essential phase for this alignment is the definition of business requirements. In this paper we describe the successful use of a blend of industrial and academic requirements methods for an IT system development at Procter and Gamble, (P&G), UK. We identify two main elements for the success of this phase: (1) the combination of methods from P&G and academia, (2) the focus of P&G’s IT department on providing business solutions. This shift is accompanied by a move from writing specifications of IT systems towards defining business requirements. We dis-cuss how these elements explain the success of this phase and propose research directions that may ease the introduction and use of requirements definition methods in organizations

How to translate therapeutic recommendations in clinical practice guidelines into rules for critiquing physician prescriptions? Methods and application to five guidelines

<p>Abstract</p> <p>Background</p> <p>Clinical practice guidelines give recommendations about what to do in various medical situations, including therapeutical recommendations for drug prescription. An effective way to computerize these recommendations is to design critiquing decision support systems, <it>i.e</it>. systems that criticize the physician's prescription when it does not conform to the guidelines. These systems are commonly based on a list of "if conditions then criticism" rules. However, writing these rules from the guidelines is not a trivial task. The objective of this article is to propose methods that (1) simplify the implementation of guidelines' therapeutical recommendations in critiquing systems by automatically translating structured therapeutical recommendations into a list of "if conditions then criticize" rules, and (2) can generate an appropriate textual label to explain to the physician why his/her prescription is not recommended.</p> <p>Methods</p> <p>We worked on the therapeutic recommendations in five clinical practice guidelines concerning chronic diseases related to the management of cardiovascular risk. We evaluated the system using a test base of more than 2000 cases.</p> <p>Results</p> <p>Algorithms for automatically translating therapeutical recommendations into "if conditions then criticize" rules are presented. Eight generic recommendations are also proposed; they are guideline-independent, and can be used as default behaviour for handling various situations that are usually implicit in the guidelines, such as decreasing the dose of a poorly tolerated drug. Finally, we provide models and methods for generating a human-readable textual critique. The system was successfully evaluated on the test base.</p> <p>Conclusion</p> <p>We show that it is possible to criticize physicians' prescriptions starting from a structured clinical guideline, and to provide clear explanations. We are now planning a randomized clinical trial to evaluate the impact of the system on practices.</p

Introduction à l'hygiène du travail : un support de formation

[Table des matières] A. Cadre et contexte général : Place et démarche de santé au travail ; Place de l'hygiène du travail dans la santé au travail ; Approche pluridisciplinaire et équipe de santé au travail ; Interface avec d'autres acteurs ; Gestion du risque ; Concept général ; Les outils du management ; La notion de risque acceptable. - B. Hygiène et sécurité du travail : Définition et historique de l'hygiène du travail ; Défis et perspectives ; Ethique professionnelle ; Démarche de l'hygiène du travail ; Méthode d'analyse des risques. - C. Identification des dangers : Méthodes ; Etiquetage des produits chimiques. - D. Evaluation des risques : Généralités ; Stratégie ; Normes ; Risques chimiques ; Toxicologie ; Gaz, vapeurs ; Aérosols ; Amiante ; Surveillance biologique ; Laboratoires ; Risques physiques ; Le Bruit ; Les vibrations ; Les radiations ionisantes ; Rayonnement optique et lasers ; Radiofréquence et rayonnements de basse fréquence ; Le stress thermique ; Environnements hypo- et hyperbares ; les risques biologiques ; Facteurs généraux liés à l'ambiance ; Aspects ergonomiques ; Généralités ; Charge physique ; Organisation du travail ; Instruments de mesure. - E. Maîtrise du risque : Organisation de la prévention ; Un nouveau concept de gestion du risque ; Prévention technique ; A la source - substitution ; A l'interface - ventilation ; Sur la cible. Equipements de protection individuelle ; Au niveau du travailleur - Prévention médicale ; Information et formation des travailleurs

13C—methyl formate : observations of a sample of high mass starforming regions including Orion—KL and spectroscopic characterization

We have surveyed a sample of massive star-forming regions located over a range of distances from the Galactic centre for methyl formate, HCOOCH3, and its isotopologues H13COOCH3 and HCOO13CH3. The observations were carried out with the APEX telescope in the frequency range 283.4-287.4 GHz. Based on the APEX observations, we report tentative detections of the 13C-methyl formate isotopologue HCOO13CH3 towards the following four massive star-forming regions: Sgr B2(N-LMH), NGC 6334 IRS 1, W51 e2 and G19.61-0.23. In addition, we have used the 1 mm ALMA science verification observations of Orion-KL and confirm the detection of the 13C-methyl formate species in Orion-KL and image its spatial distribution. Our analysis shows that the 12C/13C isotope ratio in methyl formate toward Orion-KL Compact Ridge and Hot Core-SW components (68.4±10.1 and 71.4±7.8, respectively) are, for both the 13C-methyl formate isotopologues, commensurate with the average 12C/13C ratio of CO derived toward Orion-KL. Likewise, regarding the other sources, our results are consistent with the 12C/13C in CO. We also report the spectroscopic characterization, which includes a complete partition function, of the complex H13COOCH3 and HCOO13CH3 species. New spectroscopic data for both isotopomers H13COOCH3 and HCOO13CH3, presented in this study, has made it possible to measure this fundamentally important isotope ratio in a large organic molecule for the first time.This work was supported by the National Science Foundation under grant 1008800. We are grateful to the Ministerio de Economia y Competitividad of Spain for the financial support through grant No. FIS2011-28738-C02-02 and to the French Government through grant No. ANR-08-BLAN-0054 and the French PCMI (Programme National de Physique Chimie du Milieu Interstellaire). This paper makes use of the following ALMA data: ADS/JAO. ALMA#2011.0.00009.SV.ALMAis a partnership of ESO (representing its member states), NSF (USA), and NINS (Japan), together with NRC (Canada) and NSC and ASIAA (Taiwan), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO, and NAOJ. C.F. thanks Dahbia Talbi, Eric Herbst, and Anthony Remijan for enlightening discussions. Finally, we thank the anonymous referee for helpful comments

Human replication protein A unfolds telomeric G-quadruplexes

G-quadruplex structures inhibit telomerase activity and must be disrupted for telomere elongation during S phase. It has been suggested that the replication protein A (RPA) could unwind and maintain single-stranded DNA in a state amenable to the binding of telomeric components. We show here that under near-physiological in vitro conditions, human RPA is able to bind and unfold G-quadruplex structures formed from a 21mer human telomeric sequence. Analyses by native gel electrophoresis, cross-linking and fluorescence resonance energy transfer indicate the formation of both 1:1 and 2:1 complexes in which G-quadruplexes are unfolded. In addition, quadruplex opening by hRPA is much faster than observed with the complementary DNA, demonstrating that this protein efficiently unfolds G-quartets. A two-step mechanism accounting for the binding of hRPA to G-quadruplexes is proposed. These data point to the involvement of hRPA in regulation of telomere maintenance