Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia

Context Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH). Objective StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported. Design To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature. Setting Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain. Patients Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age. Results StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (~30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol. Conclusions StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.

Impedance-pH reflux patterns can differentiate non-erosive reflux disease from functional heartburn patients

Symptom association is important to distinguish non-erosive reflux disease [NERD; abnormal oesophageal acid exposure time (AET) and/or positive symptom association] from functional heartburn (FH; normal AET and negative symptom association). Asymptomatic patients during reflux monitoring are challenging as symptom association cannot be assessed.

Functional polymorphism in ABCA1 influences age of symptom onset in coronary artery disease patients

ATP-binding-cassette-transporter-A1 (ABCA1) plays a pivotal role in intracellular cholesterol removal, exerting a protective effect against atherosclerosis. ABCA1 gene severe mutations underlie Tangier disease, a rare Mendelian disorder that can lead to premature coronary artery disease (CAD), with age of CAD onset being two decades earlier in mutant homozygotes and one decade earlier in heterozygotes than in mutation non-carriers. It is unknown whether common polymorphisms in ABCA1 could influence age of symptom onset of CAD in the general population. We examined common promoter and non-synonymous coding polymorphisms in relation to age of symptom onset in a group of CAD patients (n = 1164), and also carried out in vitro assays to test effects of the promoter variations on ABCA1 promoter transcriptional activity and effects of the coding variations on ABCA1 function in mediating cellular cholesterol efflux. Age of symptom onset was found to be associated with the promoter - 407G > C polymorphism, being 2.82 years higher in C allele homozygotes than in G allele homozygotes and intermediate in heterozygotes (61.54, 59.79 and 58.72 years, respectively; P = 0.002). In agreement, patients carrying ABCA1 haplotypes containing the -407C allele had higher age of symptom onset. Patients of the G/G or G/C genotype of the -407G > C polymorphism had significant coronary artery stenosis (>75%) at a younger age than those of the C/C genotype (P = 0.003). Reporter gene assays showed that ABCA1 haplotypes bearing the -407C allele had higher promoter activity than haplotypes with the -407G allele. Functional analyses of the coding polymorphisms showed an effect of the V825I substitution on ABCA1 function, with the 825I variant having higher activity in mediating cholesterol efflux than the wild-type (825V). A trend towards higher symptom onset age in 825I allele carriers was observed. The data indicate an influence of common ABCA1 functional polymorphisms on age of symptom onset in CAD patients.

Spinal Muscular Atrophy: position and functional importance of the branch site preceding SMN exon 7

In spinal muscular atrophy, the SMN1 gene is deleted or destroyed by mutation, while the neigbouring, nearly identical SMN2 gene acts as a partial functional substitute. However, due to a single nucleotide exchange, the seventh exon of SMN2 is mostly excluded from the mature mRNA, and the resulting shorter protein is non-functional. Here, we map the previously uncharacterised intron 6 branch point by RT-PCR. Moreover we show that exon 7 inclusion can be either abolished or improved by mutations in this branch site region.

Functional analysis of anionic phospholipids in cell metabolism in {\it Escherichia coli\/}

The major goal of this work was to understand the function of anionic phospholipid in E. coli cell metabolism. One important finding from this work is the requirement of anionic phospholipid for the DnaA protein-dependent initiation of DNA replication. An rnhA mutation, which bypasses the need for the DnaA protein through induction of constitutive stable DNA replication, suppressed the growth arrest phenotype of a $pgsA$ mutant in which the synthesis of anionic phospholipid was blocked. The maintenance of plasmids dependent on an $oriC$ site for replication, and therefore DnaA protein, was also compromised under conditions of limiting anionic phospholipid synthesis. These results provide support for the involvement of anionic phospholipids in normal initiation of DNA replication at oriC in vivo by the DnaA protein. In addition, structural and functional requirements of two major anionic phospholipids, phosphatidylglycerol and cardiolipin, were examined. Introduction into cells of the ability to make phosphatidylinositol did not suppress the need for the naturally occurring phosphatidylglycerol. The requirement for phosphatidylglycerol was concluded to be more than maintenance of the proper membrane surface charge. Examination of the role of cardiolipin revealed its ability to replace the zwitterionic phospholipid, phosphatidylethanolamine, in maintaining an optimal membrane lipid organization. This work also reported the DNA sequence of the cls gene, which encodes the CL synthase responsible for the synthesis of cardiolipin. ^

How Do Software Architects Specify and Validate Quality Requirements?

Software architecture is the result of a design effort aimed at ensuring a certain set of quality attributes. As we show, quality requirements are commonly specified in practice but are rarely validated using automated techniques. In this paper we analyze and classify commonly specified quality requirements after interviewing professionals and running a survey. We report on tools used to validate those requirements and comment on the obstacles encountered by practitioners when performing such activity (e.g., insufficient tool-support; poor understanding of users needs). Finally we discuss opportunities for increasing the adoption of automated tools based on the information we collected during our study (e.g., using a business-readable notation for expressing quality requirements; increasing awareness by monitoring non-functional aspects of a system).

The Open Door Mission: Measuring and predicting outcomes of one community-based substance abuse treatment program

The objectives of this study were to identify and measure the average outcomes of the Open Door Mission's nine-month community-based substance abuse treatment program, identify predictors of successful outcomes, and make recommendations to the Open Door Mission for improving its treatment program.^ The Mission's program is exclusive to adult men who have limited financial resources: most of which were homeless or dependent on parents or other family members for basic living needs. Many, but not all, of these men are either chemically dependent or have a history of substance abuse.^ This study tracked a cohort of the Mission's graduates throughout this one-year study and identified various indicators of success at short-term intervals, which may be predictive of longer-term outcomes. We tracked various levels of 12-step program involvement, as well as other social and spiritual activities, such as church affiliation and recovery support.^ Twenty-four of the 66 subjects, or 36% met the Mission's requirements for success. Specific to this success criteria; Fifty-four, or 82% reported affiliation with a home church; Twenty-six, or 39% reported full-time employment; Sixty-one, or 92% did not report or were not identified as having any post-treatment arrests or incarceration, and; Forty, or 61% reported continuous abstinence from both drugs and alcohol.^ Five research-based hypotheses were developed and tested. The primary analysis tool was the web-based non-parametric dependency modeling tool, B-Course, which revealed some strong associations with certain variables, and helped the researchers generate and test several data-driven hypotheses. Full-time employment is the greatest predictor of abstinence: 95% of those who reported full time employment also reported continuous post-treatment abstinence, while 50% of those working part-time were abstinent and 29% of those with no employment were abstinent. Working with a 12-step sponsor, attending aftercare, and service with others were identified as predictors of abstinence.^ This study demonstrates that associations with abstinence and the ODM success criteria are not simply based on one social or behavioral factor. Rather, these relationships are interdependent, and show that abstinence is achieved and maintained through a combination of several 12-step recovery activities. This study used a simple assessment methodology, which demonstrated strong associations across variables and outcomes, which have practical applicability to the Open Door Mission for improving its treatment program. By leveraging the predictive capability of the various success determination methodologies discussed and developed throughout this study, we can identify accurate outcomes with both validity and reliability. This assessment instrument can also be used as an intervention that, if operationalized to the Mission’s clients during the primary treatment program, may measurably improve the effectiveness and outcomes of the Open Door Mission.^

La divulgación científica de análisis sensorial de vinos en soporte web

En esta tesis se trabaja sobre la hipótesis de que el componente didáctico del discurso divulgativo queda delimitado por estrategias discursivas originadas en el tratamiento modal y actualizadas en los niveles funcional, situacional, semántico y formal-gramatical. El objetivo es caracterizar tales estrategias para identificar tendencias en la realización lingüísticodiscursiva del componente didáctico. El corpus se ha formado teniendo en cuenta soporte (web), formato (hipertexto) y dominio disciplinar (Análisis Sensorial de Vinos). La metodología es, fundamentalmente, cualitativo-ejemplar, basada en el modelo multinivel propuesto por Ciapuscio (2003) para el análisis de textos especializados. Los resultados sugieren que en el nivel funcional, el componente didáctico se distingue por el predominio de los términos positivos de las categorías modales epistémica (función informar) y ética (función dirigir); en el nivel situacional, por tres tipos de construcciones discursivas: la del enunciador experto, la del enunciatario lego y la de la pertenencia del lego a la comunidad especializada; en el nivel semántico, por la estandarización de partes textuales y por el predominio tanto de axiologización eufórica ética y cognoscitiva, como de secuencias expositivas y de procedimientos explicativos causales, descriptivos e ilustrativos; en el nivel formal, por recursos paratextuales e hipertextuales que refuerzan la actualización del componente didáctico.

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

Impact of product-related environmental regulations / voluntary requirements on Thai firms

The rules governing the trade of goods in global markets have shifted toward non-tariff measures related to environmental and chemical safety. Unlike traditional environmental/safety requirements, the scope of modern regulations covers products’ environmental performance and chemical safety. To comply with these modern regulations, production practices along the entire supply chain must be realigned to manage certain chemical substances incorporated into the final product. This paper examines the implications of product-related environmental and chemical safety regulations on different firms operating in Thailand.

Domain-Specific Multi-Modeling of Security Concerns in Service-Oriented Architectures

As a common reference for many in-development standards and execution frameworks, special attention is being paid to Service-Oriented Architectures. SOAs modeling, however, is an area in which a consensus has not being achieved. Currently, standardization organizations are defining proposals to offer a solution to this problem. Nevertheless, until very recently, non-functional aspects of services have not been considered for standardization processes. In particular, there exists a lack of a design solution that permits an independent development of the functional and non-functional concerns of SOAs, allowing that each concern be addressed in a convenient manner in early stages of the development, in a way that could guarantee the quality of this type of systems. This paper, leveraging on previous work, presents an approach to integrate security-related non-functional aspects (such as confidentiality, integrity, and access control) in the development of services.

Multi Domain-Specific Modeling of the Security Concerns of Service-Oriented Architectures

Service-Oriented Architectures (SOA), and Web Services (WS), the technology generally used to implement them, achieve the integration of heterogeneous technologies, providing interoperability, and yielding the reutilization of pre-existent systems. Model-driven development methodologies provide inherent benefits such as increased productivity, greater reuse, and better maintainability, to name a few. Efforts on achieving model-driven development of SOAs already exist, but there is currently no standard solution that addresses non-functional aspects of these services as well. This paper presents an approach to integrate these non-functional aspects in the development of web services, with an emphasis on security.

The dicode workbench: A flexible framework for the integration of information and web services

Aiming to address requirements concerning integration of services in the context of ?big data?, this paper presents an innovative approach that (i) ensures a flexible, adaptable and scalable information and computation infrastructure, and (ii) exploits the competences of stakeholders and information workers to meaningfully confront information management issues such as information characterization, classification and interpretation, thus incorporating the underlying collective intelligence. Our approach pays much attention to the issues of usability and ease-of-use, not requiring any particular programming expertise from the end users. We report on a series of technical issues concerning the desired flexibility of the proposed integration framework and we provide related recommendations to developers of such solutions. Evaluation results are also discussed.