Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 μM under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity.

Rehabilitation of Concrete Pavements Utilizing Rubblization and Crack and Seat Methods (Phase II): Performance Evaluation of Rubblized Pavements in Iowa, TR-550, 2008

This Phase II follow-up study of IHRB Project TR-473 focused on the performance evaluation of rubblized pavements in Iowa. The primary objective of this study was to evaluate the structural condition of existing rubblized concrete pavements across Iowa through Falling Weight Deflectometer (FWD) tests, Dynamic Cone Penetrometer (DCP) tests, visual pavement distress surveys, etc. Through backcalculation of FWD deflection data using the Iowa State University's advanced layer moduli backcalculation program, the rubblized layer moduli were determined for various projects and compared with each other for correlating with the long-term pavement performance. The AASHTO structural layer coefficient for rubblized layer was also calculated using the rubblized layer moduli. To validate the mechanistic-empirical (M-E) hot mix asphalt (HMA) overlay thickness design procedure developed during the Phase I study, the actual HMA overlay thicknesses from the rubblization projects were compared with the predicted thicknesses obtained from the design software. The results of this study show that rubblization is a valid option to use in Iowa in the rehabilitation of portland cement concrete pavements provided the foundation is strong enough to support construction operations during the rubblization process. The M-E structural design methodology developed during Phase I can estimate the HMA overlay thickness reasonably well to achieve long-lasting performance of HMA pavements. The rehabilitation strategy is recommended for continued use in Iowa under those conditions conducive for rubblization.

Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods, [and] Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes

Rapport de synthèse1. Partie de laboratoireCette première étude décrit le développement et la validation, selon les standards internationaux, de deux techniques de mesure des concentrations sanguines de voriconazole, un nouvel agent antifongique à large spectre: 1) la chromatographic en phase liquide à haute pression et 2) le bio-essai utilisant une souche mutante de Candida hypersensible au voriconazole. Ce travail a aussi permis de mettre en évidence une importante et imprévisible variabilité inter- et intra-individuelle des concentrations sanguines de voriconazole malgré l'utilisation des doses recommandées par le fabriquant. Ce travail a été publié dans un journal avec "peer-review": "Variability of voriconazole plasma levels measured by new high- performance liquid chromatography and bioassay methods" by A. Pascual, V. Nieth, T. Calandra, J. Bille, S. Bolay, L.A. Decosterd, T. Buclin, P.A. Majcherczyk, D. Sanglard, 0. Marchetti. Antimicrobial Agents Chemotherapy, 2007; 51:137-432. Partie CliniqueCette deuxième étude a évalué de façon prospective l'impact clinique des concentrations sanguines de voriconazole sur l'efficacité et sécurité thérapeutique chez des patients atteints d'infections fongiques. Des concentrations sanguines élevées étaient significativement associés à la survenue d'une toxicité neurologique (encéphalopathie avec confusion, hallucinations et myoclonies) et des concentrations sanguines basses à une réponse insuffisante au traitement antifongique (persistance ou progression des signes cliniques et radiologiques de l'infection). Dans la majorité des cas, un ajustement de la dose de voriconazole, sur la base des concentrations mesurées, a abouti à une récupération neurologique complète ou à une résolution de l'infection, respectivement. Ce travail a été publié dans un journal avec "peer-review": " Voriconazole Therapeutic Drug Monitoring in Patients with Invasive Mycoses Improves Efficacy and Safety Outcomes" by A. Pascual, T. Calandra, S. Bolay, T. Buclin, J. Bille, and O. Marchetti. Clinical Infectious Diseases, 2008 January 15; 46(2): 201-11.Ces deux études, financées de façon conjointe par un "grant" international de la Société suisse d'infectiologie et la Société internationale de maladies infectieuses et par la Fondation pour le progrès en microbiologie médicale et maladies infectieuses (FAMMID, Lausanne), ont été réalisées au sein du Service des Maladies Infectieuses, Département de Médecine, au CHUV, en étroite collaboration avec la Division de Pharmacologie Clinique, Département de Médecine, au CHUV et l'Institut de Microbiologie du CHUV et de l'Université de Lausanne.

Spectral analysis and limit behaviours in a spring-mass system

We consider a model for a damped spring-mass system that is a strongly damped wave equation with dynamic boundary conditions. In a previous paper we showed that for some values of the parameters of the model, the large time behaviour of the solutions is the same as for a classical spring-mass damper ODE. Here we use spectral analysis to show that for other values of the parameters, still of physical relevance and related to the effect of the spring inner viscosity, the limit behaviours are very different from that classical ODE

Analysis and Forecast of Housing Needs in Iowa Technical Report, January 22, 2013

The research and analysis summarized in this report prepared by Gruen Gruen + Associates (“GG+A”) provides an information base about population, household, housing, and employment conditions and trends affecting the current and future housing needs of Iowans. It also provides a synthesis of how the housing needs of Iowans have changed over the past decade and how needs are likely to continue to change over the present decade (2010-2020), given forecast employment and population growth in Iowa.

Combining digital elevation model analysis and run-out modeling to characterize hazard posed by a potentially unstable rock slope at Turtle Mountain, Alberta, Canada

Turtle Mountain in Alberta, Canada has become an important field laboratory for testing different techniques related to the characterization and monitoring of large slope mass movements as the stability of large portions of the eastern face of the mountain is still questionable. In order to better quantify the volumes potentially unstable and the most probable failure mechanisms and potential consequences, structural analysis and runout modeling were preformed. The structural features of the eastern face were investigated using a high resolution digital elevation model (HRDEM). According to displacement datasets and structural observations, potential failure mechanisms affecting different portions of the mountain have been assessed. The volumes of the different potentially unstable blocks have been calculated using the Sloping Local Base Level (SLBL) method. Based on the volume estimation, two and three dimensional dynamic runout analyses have been performed. Calibration of this analysis is based on the experience from the adjacent Frank Slide and other similar rock avalanches. The results will be used to improve the contingency plans within the hazard area.

Investigation of AASHTOWare Pavement ME Design/DARWin-ME Performance Prediction Models for Iowa Pavement Analysis and Design, 2015

The Mechanistic-Empirical Pavement Design Guide (MEPDG) was developed under National Cooperative Highway Research Program (NCHRP) Project 1-37A as a novel mechanistic-empirical procedure for the analysis and design of pavements. The MEPDG was subsequently supported by AASHTO’s DARWin-ME and most recently marketed as AASHTOWare Pavement ME Design software as of February 2013. Although the core design process and computational engine have remained the same over the years, some enhancements to the pavement performance prediction models have been implemented along with other documented changes as the MEPDG transitioned to AASHTOWare Pavement ME Design software. Preliminary studies were carried out to determine possible differences between AASHTOWare Pavement ME Design, MEPDG (version 1.1), and DARWin-ME (version 1.1) performance predictions for new jointed plain concrete pavement (JPCP), new hot mix asphalt (HMA), and HMA over JPCP systems. Differences were indeed observed between the pavement performance predictions produced by these different software versions. Further investigation was needed to verify these differences and to evaluate whether identified local calibration factors from the latest MEPDG (version 1.1) were acceptable for use with the latest version (version 2.1.24) of AASHTOWare Pavement ME Design at the time this research was conducted. Therefore, the primary objective of this research was to examine AASHTOWare Pavement ME Design performance predictions using previously identified MEPDG calibration factors (through InTrans Project 11-401) and, if needed, refine the local calibration coefficients of AASHTOWare Pavement ME Design pavement performance predictions for Iowa pavement systems using linear and nonlinear optimization procedures. A total of 130 representative sections across Iowa consisting of JPCP, new HMA, and HMA over JPCP sections were used. The local calibration results of AASHTOWare Pavement ME Design are presented and compared with national and locally calibrated MEPDG models.

DFMA- Analysis and Aspects of Applying Internet Based Collaborative Design for Axial Eccentric Oil-Pump Design

The integrated system of design for manufacturing and assembly (DFMA) and internet based collaborative design are presented to support product design, manufacturing process, and assembly planning for axial eccentric oil-pump design. The presented system manages and schedules group oriented collaborative activities. The design guidelines of internet based collaborative design & DFMA are expressed. The components and the manufacturing stages of axial eccentric oil-pump are expressed in detail. The file formats of the presented system include the data types of collaborative design of the product, assembly design, assembly planning and assembly system design. Product design and assembly planning can be operated synchronously and intelligently and they are integrated under the condition of internet based collaborative design and DFMA. The technologies of collaborative modelling, collaborative manufacturing, and internet based collaborative assembly for the specific pump construction are developed. A seven-security level is presented to ensure the security of the internet based collaborative design system.

When is a child with status epilepticus likely to have Dravet syndrome?

PURPOSE: To identify clinical risk factors for Dravet syndrome (DS) in a population of children with status epilepticus (SE). MATERIAL AND METHODS: Children aged between 1 month and 16 years with at least one episode of SE were referred from 6 pediatric neurology centers in Switzerland. SE was defined as a clinical seizure lasting for more than 30min without recovery of normal consciousness. The diagnosis of DS was considered likely in previously healthy patients with seizures of multiple types starting before 1 year and developmental delay on follow-up. The presence of a SCN1A mutation was considered confirmatory for the diagnosis. Data such as gender, age at SE, SE clinical presentation and recurrence, additional seizure types and epilepsy diagnosis were collected. SCN1A analyses were performed in all patients, initially with High Resolution Melting Curve Analysis (HRMCA) and then by direct sequencing on selected samples with an abnormal HRMCA. Clinical and genetic findings were compared between children with DS and those with another diagnosis, and statistical methods were applied for significance analysis. RESULTS: 71 children with SE were included. Ten children had DS, and 61 had another diagnosis. SCN1A mutations were found in 12 of the 71 patients (16.9%; ten with DS, and two with seizures in a Generalized Epilepsy with Febrile Seizures+(GEFS+) context). The median age at first SE was 8 months in patients with DS, and 41 months in those with another epilepsy syndrome (p<0.001). Nine of the 10 DS patients had their initial SE before 18 months. Among the 26 patients aged 18 months or less at initial SE, the risk of DS was significantly increased for patients with two or more episodes (56.3%), as compared with those who had only one episode (0.0%) (p=0.005). CONCLUSION: In a population of children with SE, patients most likely to have DS are those who present their initial SE episode before 18 months, and who present with recurrent SE episodes.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

A segmentation analysis and segments profile of budget air travelers

Many Spanish destinations are now considering low cost airlines (LCA) important for attracting tourists. However, there is little evidence on the characteristics travelers using low cost airlines and their flight preferences. Typical segmentation of air travelers are business versus leisure travelers and business versus tourist fares. The aim of this paper is to obtain a deeper understanding of the demand of LCA through a segmentation analysis, based on 808 foreign travelers who used Girona airport, that focuses on low cost travelers’ valuations of different flight attributes and trip related characteristics

The role of financial and accounting methods as estimators of intrinsic value: the Tubacex case

En aquest treball estudiem si el valor intrínsec de Tubacex entre 1994-2013 coincideix amb la seva tendència bursàtil a llarg termini, tenint en compte part de la teoria defensada per Shiller. També verifiquem la possible infravaloració de l’acció de Tubacex a 31/12/13. A la primera part expliquem els principals mètodes de valoració d’empreses y a la segona part fem una anàlisi del sector en el que opera Tubacex (acer inoxidable) i calculem el valor de l’acció de Tubacex per mitjà de tres mètodes de valoració (Free Cash Flow, Cash Flow i Valor en Llibres). Apliquem aquests tres mètodes de valoració per verificar si com a mínim algun d’ells coincideix amb la tendència bursàtil a llarg termini.