Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex.

A-kinase anchoring proteins (AKAPs) target the cAMP-regulated protein kinase (PKA) to its physiological substrates. We recently identified a novel anchoring protein, called AKAP-Lbc, which functions as a PKA-targeting protein as well as a guanine nucleotide exchange factor (GEF) for RhoA. We demonstrated that AKAP-Lbc Rho-GEF activity is stimulated by the alpha subunit of the heterotrimeric G protein G12. Here, we identified 14-3-3 as a novel regulatory protein interacting with AKAP-Lbc. Elevation of the cellular concentration of cAMP activates the PKA holoenzyme anchored to AKAP-Lbc, which phosphorylates the anchoring protein on the serine 1565. This phosphorylation event induces the recruitment of 14-3-3, which inhibits the Rho-GEF activity of AKAP-Lbc. AKAP-Lbc mutants that fail to interact with PKA or with 14-3-3 show a higher basal Rho-GEF activity as compared to the wild-type protein. This suggests that, under basal conditions, 14-3-3 maintains AKAP-Lbc in an inactive state. Therefore, while it is known that AKAP-Lbc activity can be stimulated by Galpha12, in this study we demonstrated that it is inhibited by the anchoring of both PKA and 14-3-3.

Mapping HIV/STI behavioural surveillance in Europe.

BACKGROUND: Used in conjunction with biological surveillance, behavioural surveillance provides data allowing for a more precise definition of HIV/STI prevention strategies. In 2008, mapping of behavioural surveillance in EU/EFTA countries was performed on behalf of the European Centre for Disease prevention and Control. METHOD: Nine questionnaires were sent to all 31 member States and EEE/EFTA countries requesting data on the overall behavioural and second generation surveillance system and on surveillance in the general population, youth, men having sex with men (MSM), injecting drug users (IDU), sex workers (SW), migrants, people living with HIV/AIDS (PLWHA), and sexually transmitted infection (STI) clinics patients. Requested data included information on system organisation (e.g. sustainability, funding, institutionalisation), topics covered in surveys and main indicators. RESULTS: Twenty-eight of the 31 countries contacted supplied data. Sixteen countries reported an established behavioural surveillance system, and 13 a second generation surveillance system (combination of biological surveillance of HIV/AIDS and STI with behavioural surveillance). There were wide differences as regards the year of survey initiation, number of populations surveyed, data collection methods used, organisation of surveillance and coordination with biological surveillance. The populations most regularly surveyed are the general population, youth, MSM and IDU. SW, patients of STI clinics and PLWHA are surveyed less regularly and in only a small number of countries, and few countries have undertaken behavioural surveys among migrant or ethnic minorities populations. In many cases, the identification of populations with risk behaviour and the selection of populations to be included in a BS system have not been formally conducted, or are incomplete. Topics most frequently covered are similar across countries, although many different indicators are used. In most countries, sustainability of surveillance systems is not assured. CONCLUSION: Although many European countries have established behavioural surveillance systems, there is little harmonisation as regards the methods and indicators adopted. The main challenge now faced is to build and maintain organised and functional behavioural and second generation surveillance systems across Europe, to increase collaboration, to promote robust, sustainable and cost-effective data collection methods, and to harmonise indicators.

Géotourisme et utilisation de sites naturels d'intérêt pour les sciences de la Terre: les régions de Crans-Montana-Sierre (Valais, Alpes suisses) et Chamonix-Mont-Blanc (Haute-Savoie, Alpes françaises)

Résumé : Au travers de l'étude des régions de Crans-Montana-Sierre (Valais, Suisse) et de Chamonix-Mont-Blanc (Haute-Savoie, France), cette recherche considère les liens existants entre activités touristiques et sciences de la Terre. Ainsi, les sites géologiques et géomorphologiques pris en compte sont perçus comme ayant non seulement une valeur scientifique, mais aussi un intérêt scénique, culturel et économique. D'un point de vue (géo)touristique, différents modèles d'analyse sont proposés pour expliciter les composantes de l'offre et de la demande et comprendre le cycle de vie des objets étudiés. L'offre que constituent ces sites est tout d'abord présentée afin d'évaluer leurs différents potentiels, ainsi que l'utilisation spatio-temporelle, didactique et économique qui en est faite. Ensuite, les logiques d'acteurs sont analysées au travers des phases de valorisation, d'exploitation et de transformation, dans le but de comprendre les facteurs et les projets d'utilisation les concernant. Enfin, la demande des différents publics cibles, de même que leurs caractéristiques socio-touristiques et (géo)didactiques, sont discutées. Pour ce faire, des méthodes d'inventaire, d'évaluation, d'entretien et de questionnaire ont été utilisées, à différentes échelles d'analyse. On constate d'abord que le pôle des valeurs scénique et économique présente une plus forte mise à contribution, par rapport à l'utilisation didactique. De plus, le niveau de protection des sites ne restreint généralement pas leur exploitation, au contraire du facteur risque. Du point de vue des publics cibles, une forte demande d'explications didactiques est exprimée, s'orientant vers une approche multithématique des potentiels à mettre en valeur; des biens et services de base sont ainsi demandés. Enfin, force est de constater que seuls de grands projets peuvent rendre les activités (géo)touristiques rentables. A l'avenir, sachant que le géotourisme peut répondre à une demande touristique liée au rêve et à l'émotion, l'approche de l'offre devrait intégrer une réflexion en didactique des sciences de la Terre, d'autant que cette forme de tourisme tend à devenir une composante du développement économique régional, notamment en dehors de la saison d'hiver. Idéalement, l'utilisation touristique de la géodiversité devrait s'accompagner d'une politique de protection dynamique, combinant préservation et mise en valeur. A terme, le but ultime de cette entreprise est notamment d'élargir la notion de patrimoine culturel, pour favoriser une approche transdisciplinaire du paysage Abstract : Based on the study of the areas of Crans-Montana-Sierre (Valais, Switzerland) and Chamonix-Mont-Blanc (Haute-Savoie, France), this study considers the links between tourism activities and Earth science. Thus, the studied geological and geomorphological sites have not only a scientific va1ue, but also scenic, cultural and economic value. From a point of view of tourism, different models of analysis are examined in order to explain the components of the supply and the demand, and to understand the life cycles of the considered objects. The primary product of these sites is first presented, in order to assess their different potential as well as their didactic, economic, spatial and temporal use. The stakeholders' behaviour is then analysed to understand the factors and projected use, with the help of the optimisation, exploitation and transformation phases. Finally, the demand of the different target markets as well as their socio-tourist and (geo)didactic characteristics are discussed. To complete this study, methods of census, assessment, interviewing and questionnaire surveying are used, at different scales of analysis. The main results appear to demonstrate that the scenic and economic values present a higher value relative to the didactic use. Moreover, the required conservation measures for the studied sites do not generally restrict the use, on the contrary to the "risk" factor. From the point of view of the target market, a relevant requirement for explanatory commentary is expressed and tends towards an approach optimising different themes to utilise potential; basic popular goods and services are also requested. Finally, it is clearly demonstrated that only relevant projects are able to make this kind of activity profitable. For the future, geotourism may be marketed to a tourist demand for imagination and emotion. Consequently, the product approach should integrate a reflection on Earth science popularisation given that this branch of tourism tends to receive a component of the economic and regional development, notably during the summer period. However, the use of geodiversity should include a concept of dynamic management, taking into account conservation as well as tourism development. Thus, the final aim of this process is to r,r'iden the notion of cultural heritage, in order to stimulate a multidisciplinary approach to the landscape.

Application des méthodes géophysiques à l'étude de deux sites (Kappelen et Grenchen) de l'aquifère poreux complexe du Seeland

L'aquifère du Seeland représente une richesse en ressources hydriques qu'il est impératif de préserver contre tout risque de détérioration. Cet aquifère prolifique est constitué principalement de sédiments alluviaux post-glaciaires (graviers, sables et limons). Il est soumis aux contraintes environnementales des pratiques d'agriculture intensive, du réseau routier, des villes et de leurs activités industrielles. La connaissance optimale de ces ressources est donc primordiale pour leur protection. Dans cette optique, deux sites Kappelen et Grenchen représentatifs de l'aquifère du Seeland ont été étudiés. L'objectif de ce travail est de caractériser d'un point de vue hydrogéophysique l'aquifère au niveau de ces deux sites, c'est-à-dire, comprendre la dynamique des écoulements souterrains par l'application des méthodes électriques de surface associées aux diagraphies en intégrant des méthodes hydrogéologiques. Pour le site de Kappelen, les méthodes électriques de surface ont permis d'identifier les différents faciès géoélectriques en présence et de mettre en évidence leur disposition en une structure tabulaire et horizontale. Il s'agit d'un aquifère libre constitué d'une série de graviers allant jusqu'à 15 m de profondeur reposant sur de la moraine argileuse. Les diagraphies électriques, nucléaires et du fluide ont servis à la détermination des caractéristiques pétrophysiques et hydrauliques de l'aquifère qui contrôlent son comportement hydrodynamique. Les graviers aquifères de Kappelen présentent deux minéraux dominants: quartz et calcite. Les analyses minéralogiques indiquent que ces deux éléments constituent 65 à 75% de la matrice. La porosité totale obtenue par les diagraphies nucléaires varie de 20 à 30 %, et de 22 à 29 % par diagraphies électrique. Avec les faibles valeurs de Gamma Ray ces résultats indiquent que l'aquifère des graviers de Kappelen est dépourvu d'argile minéralogique. La perméabilité obtenue par diagraphies du fluide varie de 3.10-4 à 5.10-2 m/s, et par essais de pompage de 10-4 à 10-2 m/s. Les résultats des analyses granulométriques indiquent une hétérogénéité granulométrique au niveau des graviers aquifères. La fraction de sables, sables très fins, silts et limons constitue de 10 à 40 %. Ces éléments jouent un rôle important dans le comportement hydraulique de l'aquifère. La porosité efficace de 11 à 25% estimée à partir des résultats des analyses granulométriques suppose que les zones les plus perméables correspondent aux zones les plus graveleuses du site. Etablie sur le site de Kappelen, cette méthodologie a été utilisée sur le site de Grenchen. Les méthodes électriques de surface indiquent que l'aquifère captif de Grenchen est constitué des sables silteux comprenant des passages sableux, encadrés par des silts argileux imperméables. L'aquifère de Grenchen est disposé dans une structure relativement tabulaire et horizontale. Son épaisseur totale peut atteindre les 25 m vers le sud et le sud ouest ou les passages sableux sont les plus importants. La détermination des caractéristiques pétrophysiques et hydrauliques s'est faite à l'aide des diagraphies. Les intensités Gamma Ray varient de 30 à 100 cps, les plus fortes valeurs n'indiquent qu'une présence d'éléments argileux mais pas de bancs d'argile. Les porosités totales de 15 à 25% et les densités globales de 2.25 à 2.45 g/cm3 indiquent que la phase minérale (matrice) est composée essentiellement de quartz et de calcaire. Les densités de matrice varient entre 2.65 et 2.75 g/cm3. La perméabilité varie de 2 10-6 à 5 10-4 m/s. La surestimation des porosités totales à partir des diagraphies électriques de 25 à 42% est due à la présence d'argiles. -- The vast alluvial Seeland aquifer system in northwestern Switzerland is subjected to environmental challenges due to intensive agriculture, roads, cities and industrial activities. Optimal knowledge of the hydrological resources of this aquifer system is therefore important for their protection. Two representative sites, Kappelen and Grenchen, of the Seeland aquifer were investigated using surface-based geoelectric methods and geophysical borehole logging methods. By integrating of hydrogeological and hydrogeophysical methods, a reliable characterization of the aquifer system at these two sites can be performed in order to better understand the governing flow and transport process. At the Kappelen site, surface-based geoelectric methods allowed to identify various geoelectric facies and highlighted their tabular and horizontal structure. It is an unconfined aquifer made up of 15 m thick gravels with an important sandy fraction and bounded by a shaly glacial aquitard. Electrical and nuclear logging measurements allow for constraining the petrophysical and hydrological parameters of saturated gravels. Results indicate that in agreement with mineralogical analyses, matrix of the probed formations is dominated by quartz and calcite with densities of 2.65 and 2.71 g/cc, respectively. These two minerals constitute approximately 65 to 75 % of the mineral matrix. Matrix density values vary from 2.60 to 2.75 g/cc. Total porosity values obtained from nuclear logs range from 20 to 30 % and are consistent with those obtained from electrical logs ranging from 22 to 29 %. Together with the inherently low natural gamma radiation and the matrix density values obtained from other nuclear logging measurements, this indicates that at Kappelen site the aquifer is essentially devoid of clay. Hydraulic conductivity values obtained by the Dilution Technique vary between 3.10-4 and 5.10-2 m/s, while pumping tests give values ranging from 10-4 to 10-2 m/s. Grain size analysis of gravel samples collected from boreholes cores reveal significant granulometric heterogeneity of these deposits. Calculations based on these granulometric data have shown that the sand-, silt- and shale-sized fractions constitute between 10 and 40 % of the sample mass. The presence of these fine elements in general and their spatial distribution in particular are important as they largely control the distribution of the total and effective porosity as well as the hydraulic conductivity. Effective porosity values ranging from 11 to 25% estimated from grain size analyses indicate that the zones of higher hydraulic conductivity values correspond to the zones dominated by gravels. The methodology established at the Kappelen site was then applied to the Grenchen site. Results from surface-based geoelectric measurements indicate that it is a confined aquifer made up predominantly of shaly sands with intercalated sand lenses confined impermeable shally clay. The Grenchen confined aquifer has a relatively tabular and horizontal structure with a maximum thickness of 25 m in the south and the southwest with important sand passages. Petrophysical and hydrological characteristics were performed using electrical and nuclear logging. Natural gamma radiation values ranging from 30 to 100 cps indicate presence of a clay fraction but not of pure clay layers. Total porosity values obtained from electrical logs vary form 25 to 42%, whereas those obtained from nuclear logs values vary from 15 to 25%. This over-estimation confirms presences of clays. Density values obtained from nuclear logs varying from 2.25 to 2.45 g/cc in conjunction with the total porosity values indicate that the dominating matrix minerals are quartz and calcite. Matrix density values vary between 2.65 and 2.75 g/cc. Hydraulic conductivity values obtained by the Dilution Technique vary from 2 10-6 to 5 10-4 m/s.

Complexation to macromolecules with a large number of sites

This paper presents an approach based on the saddle-point approximation to study the equilibrium interactions between small molecules and macromolecules with a large number of sites. For this case, the application of the Darwin–Fowler method results in very simple expressions for the stoichiometric equilibrium constants and their corresponding free energies in terms of integrals of the binding curve plus a correction term which depends on the first derivatives of the binding curve in the points corresponding to an integer value of the mean occupation number. These expressions are simplified when the number of sites tends to infinity, providing an interpretation of the binding curve in terms of the stoichiometric stability constants. The formalism presented is applied to some simple complexation models, obtaining good values for the free energies involved. When heterogeneous complexation is assumed, simple expressions are obtained to relate the macroscopic description of the binding, given by the stoichiomeric constants, with the microscopic description in terms of the intrinsic stability constants or the affinity spectrum. © 1999 American Institute of Physics.

Web-pohjaisen videoeditorin toteutus ja Object-Relational Mapping

Tässä insinöörityössä esitellään Stadian verkkoviestinnän VIDEOS-hankkeeseen liittyvän web-pohjaisen videoeditorin kehitys ja käytetyt teknologiat. Fooga-nimiseksi nimetty videoeditorin käyttämät tekniikat ovat Ruby, Ruby on Rails, FFmpeg, Mencoder, ImageMagick ja FLVTool2. Ruby on olio-pohjainen skriptikieli, Ruby on Rails on websovelluskehys ja muut tekniikat ovat komentorivipohjaisia työkaluja, jotka tarjoavat tärkeimmät toiminnallisuudet Foogalle. Tavoitteina oli tämän työn yhteydessä ohjelmoida Foogaan perustoiminnallisuudet, jotka mahdollistavat minimaaliset käyttömahdollisuudet kevääseen 2007 mennessä. Kehitystyö jatkuu vuoteen 2009 asti tarjoamalla samalla mahdollisuuden usealle insinöörityölle tekniikan ja liikenteen koulutusohjelmasta. Tämän lisäksi tässä insinöörityössä perehdytään Object-Relational Mapping-tekniikan perusteisiiin ja verrataan Ruby on Railsin ja Javan ORM-ominaisuuksia. Ruby on Railsin osalta esitellään ActiveRecord-luokka ja Javan osalta Hibernate, jonka johdantona on DAO/DTO-sunnittelumalli.

Identifying the index lesion with template prostate mapping biopsies.

PURPOSE: The natural history of prostate cancer might be driven by the index lesion. We determined the percent of men in whom the index lesion could be defined using transperineal template prostate mapping biopsies. MATERIALS AND METHODS: Included in study were consecutive men undergoing transperineal template prostate mapping biopsies with biopsies grouped into 20 zones. Men with clinically significant disease in only 1 prostate area were considered to have an identifiable index lesion. We evaluated the impact of using 2 definitions of clinically significant disease (Gleason grade pattern 4 and/or lesion volume 0.5 cc or greater) and 2 clustering rules (stringent and tolerant) to define the index lesion. RESULTS: Included in study were 391 men with a median age of 62 years (IQR 58-67) and a median prostate specific antigen of 6.9 ng/ml (IQR 4.8-10.0). Of the men 269 (69%) were previously diagnosed with prostate cancer. By deploying a median of 1.2 cores per ml (IQR 0.9-1.7) cancer was diagnosed in 82.9% of the men (324 of 391) with a median of 6 positive cores (IQR 2-9), a median maximum cancer core length of 5 mm (IQR 3-8) and a total cancer core length per zone of 7 mm (IQR 3-13). Insignificant disease was found in 26.3% to 42.9% of cases. When a stringent spatial relationship was used to define individual lesions, 44.4% to 54.6% of patients had 1 index lesion and 12.7% to 19.1% had more than 1 area with clinically significant disease. These proportions changed to 46.6% to 59.2% and 10.5% to 14.5%, respectively, when less stringent spatial clustering was applied. CONCLUSIONS: Transperineal template prostate mapping biopsies enable the index lesion to be localized in most men with clinically significant disease. This information may be important to select appropriate candidates for targeted therapy and to plan a tailored treatment strategy in men undergoing radical therapy.

Self-navigated isotropic three-dimensional cardiac T2 mapping.

PURPOSE: To implement and characterize an isotropic three-dimensional cardiac T2 mapping technique. METHODS: A self-navigated three-dimensional radial segmented balanced steady-state free precession pulse sequence with an isotropic 1.7-mm spatial resolution was implemented at 3T with a variable T2 preparation module. Bloch equation and Monte Carlo simulations were performed to determine the influence of the heart rate, B1 inhomogeneity and noise on the T2 fitting accuracy. In a phantom study, the accuracy of the pulse sequence was studied through comparison with a gold-standard spin-echo T2 mapping method. The robustness and homogeneity of the technique were ascertained in a study of 10 healthy adult human volunteers, while first results obtained in patients are reported. RESULTS: The numerical simulations demonstrated that the heart rate and B1 inhomogeneity cause only minor deviations in the T2 fitting, whereas the phantom study showed good agreement of the technique with the gold standard. The volunteer study demonstrated an average myocardial T2 of 40.5 ± 3.3 ms and a <15% T2 gradient in the base-apex and anterior-inferior direction. In three patients, elevated T2 values were measured in regions with expected edema. CONCLUSION: This respiratory self-navigated isotropic three-dimensional technique allows for accurate and robust in vitro and in vivo T2 quantification. Magn Reson Med 73:1549-1554, 2015. © 2014 Wiley Periodicals, Inc.

Signalling by neurotrophins and hepatocyte growth factor regulates axon morphogenesis by differential β-catenin phosphorylation

Tyrosine phosphorylation of ß-catenin, a component of adhesion complexes and the Wnt pathway, affects cell adhesion, migration and gene transcription. By reducing ßcatenin availability using shRNA-mediated gene silencing or expression of intracellular N-cadherin, we show that ß-catenin is required for axon growth downstream of Brain Derived Neurotrophic Factor (BDNF) and Hepatocyte Growth Factor (HGF) signalling. We demonstrate that receptor tyrosine kinases (RTK) Trk and Met interact with and phosphorylate ß-catenin. Neurotrophins (NT) stimulation of Trk receptors results in phosphorylation of ß-catenin at residue Y654 and increased axon growth and branching. Conversely, pharmacological inhibition of Trk or a Y654F mutant blocks these effects. ß-catenin phospho(P)-Y654 colocalizes with the cytoskeleton at growth cones. However, HGF that also increases axon growth and branching, induces ß-catenin phosphorylation at Y142 and a nuclear localization. Interestingly, dominant negative ΔN-TCF4 abolishes the effects of HGF in axon growth and branching, but not of NT. We conclude that NT and HGF signalling differentially phosphorylate ß-catenin, targeting ß-catenin to distinct compartments to regulate axon morphogenesis by TCF4-transcription-dependent and independent mechanisms. These results place ß-catenin downstream of growth factor/RTK signalling in axon differentiation.

Controlling the spin of metal atoms adsorbed on oxide surfaces: Ni on regular and defective sites of the MgO(001) surface

We have analyzed the relative energy of nonmagnetic and magnetic low-lying electronic states of Ni atoms adsorbed on regular and defective sites of the MgO(001) surface. To this end cluster and periodic surface models are used within density functional theory. For Ni atoms adsorbed on oxygen vacancies at low coverage, the interaction energy between the metal and the support is much larger than on regular sites. Strong bonding results in a diamagnetic adsorbed species and the energy required to reach the high-spin state increases. Moreover, a correlation appears between the low-spin to high-spin energy difference and the interaction energy hypothesizing that it is possible to prepare the surface to tune the high-spin to low-spin energy difference. Magnetic properties of adsorbed thin films obtained upon increasing coverage are more difficult to interpret. This is because the metallic bond is readily formed and dominates over the effect of the atoms directly bound to the vacancy.