Molecular alterations in nucleotide excision repair genes in malignant glioma and their relevance to malignant progression and drug resistance

Recently, it has become apparent that DNA repair mechanisms are involved in the malignant progression and resistance to therapy of gliomas. Many investigators have shown that increased levels of O6-methyl guanine DNA alkyltransferase, a DNA monoalkyl adduct repair enzyme, are correlated with resistance of malignant glioma cell lines to nitrosourea-based chemotherapy. Three important DNA excision repair genes ERCC1 (excision repair cross complementation group 1), ERCC2 (excision repair cross complementation group 2), and ERCC6 (excision repair cross complementation group 6) have been studied in human tumors. Gene copy number variation of ERCC1 and ERCC2 has been observed in primary glioma tissues. A number of reports describing a relationship between ERCC1 gene alterations and resistance to anti-cancer drugs have been also described. The levels of ERCC1 gene expression, however, have not been correlated with drug resistance in gliomas. The expression of ERCC6 gene transcribes has been shown to vary with tissue types and to be highest in the brain. There have been no comprehensive studies so far, however, of ERCC6 gene expression and molecular alterations in malignant glioma. This project examined the ERCC1 expression levels and correlated them with cisplatin resistance in malignant glioma cell lines. We also examined the molecular alterations of ERCC6 gene in primary glioma tissues and cells and analyzed whether these alterations are related to tumor progression and chemotherapy resistance. Our results indicate the presence of mutations and/or deletions in exons II and V of the ERCC6 gene, and these alterations are more frequent in exon II. Furthermore, the mutations and/or deletions in exon II were shown to be associated with increased malignant grade of gliomas. The results on the Levels of ERCC1 gene transcripts showed that expression levels correlate with cisplatin resistance. The increase in ERCC1 mRNA induced by cisplatin could be down-regulated by cyclosporin A and herbimycin A. The results of this study are likely to provide useful information for clinical treatment of human gliomas. ^

Gender differences in life circumstances, monthly income, risky sexual and drug behaviors among injection drug users in Dar es Salaam, Tanzania

This study investigated the gender difference between male and female injection drug users’ (IDUs) life circumstances, income and risky sexual and drug behaviors. The study sample comprised of 318 male and 249 female injection drug users in Dar es Salaam, Tanzania. There were gender differences between male and female IDUs in terms of life circumstances and sexual behaviors. There were no differences in the drug behaviors among the two sexes. Women were more likely to be 21-25 years of age, have had more sexual partners in the last 30 days, traded sex for money, and have been sexually abused as a child. On the other hand, the males were more likely to be 26-30 years of age and have never used a condom during sex in the last 30 days. Regardless of the differences in sexual risk behaviors by gender, both male and female injection drug users in Dar es Salaam are at risk of HIV/AIDS, blood borne and other sexually transmitted diseases associated with drug use.^

Specialized managed care for children with cystic fibrosis: Resource use patterns and rate design for a high cost Medicaid population

Objective. This research study had two goals: (1) to describe resource consumption patterns for Medi-Cal children with cystic fibrosis, and (2) to explore the feasibility from a rate design perspective of developing specialized managed care plans for such a special needs population.^ Background. Children with special health care needs (CSHN) comprise about 2% of the California Medicaid pediatric population. CSHN have rare but serious health problems, such as cystic fibrosis. Medicaid programs, including Medi-Cal, are enrolling more and more beneficiaries in managed care to control costs. CSHN, however, do not fit the wellness model underlying most managed care plans. Child health advocates believe that both efficiency and quality will suffer if CSHN are removed from regionalized special care centers and scattered among general purpose plans. They believe that CSHN should be "carved out" from enrollment in general plans. One alternative is the Specialized Managed Care Plan, tailored for CSHN.^ Methods. The study population consisted of children under age 21 with CF who were eligible for Medi-Cal and California Children's Services program (CCS) during 1991. Health Care Financing Administration (HCFA) Medicaid Tape-to-Tape data were analyzed as part of a California Children's Hospital Association (CCHA) project.^ Results. Mean Medi-Cal expenditures per month enrolled were $2,302 for 457 CF children, compared to about \$1,270 for all 47,000 CCS special needs children and roughly $60 for almost 2.6 million ``regular needs'' children. For CF children, inpatient care (80\%) and outpatient drugs (9\%) were the major cost drivers, with {\it all\/} outpatient visits comprising only 2\% of expenditures. About one-third of CF children were eligible due to AFDC (Aid to Families with Dependent Children). Age group explained about 17\% of all expenditure variation. Regression analysis was used to select the best capitation rate structure (rate cells by age and eligibility group). Sensitivity analysis estimated moderate financial risk for a statewide plan (360 enrollees), but severe risk for single county implementation due to small numbers of children.^ Conclusions. Study results support the carve out of CSHN due to unique expenditure patterns. The Specialized Managed Care Plan concept appears feasible from a rate design perspective given sufficient enrollees. ^

An overview of the ciao multiparadigm language and program development environment and its design philosophy

We describe some of the novel aspects and motivations behind the design and implementation of the Ciao multiparadigm programming system. An important aspect of Ciao is that it provides the programmer with a large number of useful features from different programming paradigms and styles, and that the use of each of these features can be turned on and off at will for each program module. Thus, a given module may be using e.g. higher order functions and constraints, while another module may be using objects, predicates, and concurrency. Furthermore, the language is designed to be extensible in a simple and modular way. Another important aspect of Ciao is its programming environment, which provides a powerful preprocessor (with an associated assertion language) capable of statically finding non-trivial bugs, verifying that programs comply with specifications, and performing many types of program optimizations. Such optimizations produce code that is highly competitive with other dynamic languages or, when the highest levéis of optimization are used, even that of static languages, all while retaining the interactive development environment of a dynamic language. The environment also includes a powerful auto-documenter. The paper provides an informal overview of the language and program development environment. It aims at illustrating the design philosophy rather than at being exhaustive, which would be impossible in the format of a paper, pointing instead to the existing literature on the system.

An overview of ciao and its design philosophy

We provide an overall description of the Ciao multiparadigm programming system emphasizing some of the novel aspects and motivations behind its design and implementation. An important aspect of Ciao is that, in addition to supporting logic programming (and, in particular, Prolog), it provides the programmer with a large number of useful features from different programming paradigms and styles and that the use of each of these features (including those of Prolog) can be turned on and off at will for each program module. Thus, a given module may be using, e.g., higher order functions and constraints, while another module may be using assignment, predicates, Prolog meta-programming, and concurrency. Furthermore, the language is designed to be extensible in a simple and modular way. Another important aspect of Ciao is its programming environment, which provides a powerful preprocessor (with an associated assertion language) capable of statically finding non-trivial bugs, verifying that programs comply with specifications, and performing many types of optimizations (including automatic parallelization). Such optimizations produce code that is highly competitive with other dynamic languages or, with the (experimental) optimizing compiler, even that of static languages, all while retaining the flexibility and interactive development of a dynamic language. This compilation architecture supports modularity and separate compilation throughout. The environment also includes a powerful autodocumenter and a unit testing framework, both closely integrated with the assertion system. The paper provides an informal overview of the language and program development environment. It aims at illustrating the design philosophy rather than at being exhaustive, which would be impossible in a single journal paper, pointing instead to previous Ciao literature.

Analysis and optimized design of a distributed multi-stage EMC filter for an interleaved three-phase PWM-rectifier system for aircraft applications

Different possible input filter configurations for a modular three-phase PWM rectifier system consisting of three interleaved converter cells are studied. The system is designed for an aircraft application where MIL-STD-461E conducted EMI standards have to be met and system weight is a critical design issue. The importance of a LISN model on the simulated noise levels and the effect of interleaving and power unbalance between the different converter modules is discussed. The effect of the number of filter stages and the degree of distribution of the filter stages among the individual converter modules on the weight and losses of the input filter is studied and optimal filter structures are proposed.

Functional and environmental design of detached, low crest level breakwaters

In this article we research the design of detached breakwaters, a type of coastal defence work designed to combat erosion on beaches in a stable, sustainable fashion. Our aim is to formulate a functional and environmental (nonstructural) method of design that defines the fundamental characteristics of a detached breakwater as a function of the desired effect on the coast whilst meeting social demands and preserving or improving the quality of the littoral environment. We aim to make this method generally applicable by considering relations between variables of different natures (climatic, geomorphologic, and geometric) influencing the changes experienced on the coast after the detached breakwater has been built. We carried out the study of the relations between the different variables on the data from 19 actual, existing detached breakwaters on the Spanish Mediterranean coastline, and we followed a methodology based on the implementation of nondimensional monomials and on a search for relations of dependency between them. Finally, we discussed the results obtained and came up with a proposal for a design method that uses some of the graphic relations found between the variables studied and that achieves the main objective. For example, a case of a detached breakwater’s geometric presizing is solved as a practical demonstration of how the method is applied. La investigación que se presenta en este artículo aborda el diseño de los diques exentos, por constituir estos un tipo de obras de defensa costera con el que poder luchar de una forma estable y sostenible contra muchos de los problemas de erosión que existen en las playas. El objetivo principal de este trabajo es la formulación de un método de diseño funcional y ambiental (no estructural) que permita definir las características fundamentales de un dique exento en función del efecto que se quiera inducir en la costa, satisfaciendo las demandas sociales y preservando o mejorando la calidad del medio ambiente litoral. Además, se busca la aplicabilidad general del método mediante la consideración de relaciones entre variables de distinta naturaleza (climáticas, geomorfológicas y geométricas) que tienen influencia en los cambios que se experimentan en la costa tras la construcción del dique exento. El estudio de las relaciones entre las distintas variables se realiza sobre los datos de una base de diecinueve diques exentos reales, existentes en el litoral mediterráneo español, y sigue una metodología basada en el planteamiento de monomios adimensionales y en la búsqueda de relaciones de dependencia entre ellos. Finalmente, la discusión de los resultados obtenidos conduce a la propuesta de un método de diseño que utiliza algunas de las relaciones graficas encontradas entre las variables estudiadas y con el que se consigue el objetivo principal anteriormente expuesto. Para demostrar la aplicación práctica del método se resuelve un caso de predimensionamiento geométrico de un dique exento a modo de ejemplo.

Color uniformity in spotligths - visual perception and system design

La iluminación con diodos emisores de luz (LED) está reemplazando cada vez en mayor medida a las fuentes de luz tradicionales. La iluminación LED ofrece ventajas en eficiencia, consumo de energía, diseño, tamaño y calidad de la luz. Durante más de 50 años, los investigadores han estado trabajando en mejoras LED. Su principal relevancia para la iluminación está aumentando rápidamente. Esta tesis se centra en un campo de aplicación importante, como son los focos. Se utilizan para enfocar la luz en áreas definidas, en objetos sobresalientes en condiciones profesionales. Esta iluminación de alto rendimiento requiere una calidad de luz definida, que incluya temperaturas ajustables de color correlacionadas (CCT), de alto índice de reproducción cromática (CRI), altas eficiencias, y colores vivos y brillantes. En el paquete LED varios chips de diferentes colores (rojo, azul, fósforo convertido) se combinan para cumplir con la distribución de energía espectral con alto CRI. Para colimar la luz en los puntos concretos deseados con un ángulo de emisión determinado, se utilizan blancos sintonizables y diversos colores de luz y ópticas secundarias. La combinación de una fuente LED de varios colores con elementos ópticos puede causar falta de homogeneidad cromática en la distribución espacial y angular de la luz, que debe resolverse en el diseño óptico. Sin embargo, no hay necesidad de uniformidad perfecta en el punto de luz debido al umbral en la percepción visual del ojo humano. Por lo tanto, se requiere una descripción matemática del nivel de uniformidad del color con respecto a la percepción visual. Esta tesis está organizada en siete capítulos. Después de un capítulo inicial que presenta la motivación que ha guiado la investigación de esta tesis, en el capítulo 2 se presentan los fundamentos científicos de la uniformidad del color en luces concentradas, como son: el espacio de color aplicado CIELAB, la percepción visual del color, los fundamentos de diseño de focos respecto a los motores de luz y ópticas no formadoras de imágenes, y los últimos avances en la evaluación de la uniformidad del color en el campo de los focos. El capítulo 3 desarrolla diferentes métodos para la descripción matemática de la distribución espacial del color en un área definida, como son la diferencia de color máxima, la desviación media del color, el gradiente de la distribución espacial de color, así como la suavidad radial y axial. Cada función se refiere a los diferentes factores que influyen en la visión, los cuales necesitan un tratamiento distinto que el de los datos que se tendrán en cuenta, además de funciones de ponderación que pre- y post-procesan los datos simulados o medidos para la reducción del ruido, la luminancia de corte, la aplicación de la ponderación de luminancia, la función de sensibilidad de contraste, y la función de distribución acumulativa. En el capítulo 4, se obtiene la función de mérito Usl para la estimación de la uniformidad del color percibida en focos. Se basó en los resultados de dos conjuntos de experimentos con factor humano realizados para evaluar la percepción visual de los sujetos de los patrones de focos típicos. El primer experimento con factor humano dio lugar al orden de importancia percibida de los focos. El orden de rango percibido se utilizó para correlacionar las descripciones matemáticas de las funciones básicas y la función ponderada sobre la distribución espacial del color, que condujo a la función Usl. El segundo experimento con factor humano probó la percepción de los focos bajo condiciones ambientales diversas, con el objetivo de proporcionar una escala absoluta para Usl, para poder así sustituir la opinión subjetiva personal de los individuos por una función de mérito estandarizada. La validación de la función Usl se presenta en relación con el alcance de la aplicación y condiciones, así como las limitaciones y restricciones que se realizan en el capítulo 5. Se compararon los datos medidos y simulados de varios sistemas ópticos. Se discuten los campos de aplicación , así como validaciones y restricciones de la función. El capítulo 6 presenta el diseño del sistema de focos y su optimización. Una evaluación muestra el análisis de sistemas basados en el reflector y la lente TIR. Los sistemas ópticos simulados se comparan en la uniformidad del color Usl, sensibilidad a las sombras coloreadas, eficiencia e intensidad luminosa máxima. Se ha comprobado que no hay un sistema único que obtenga los mejores resultados en todas las categorías, y que una excelente uniformidad de color se pudo alcanzar por la conjunción de dos sistemas diferentes. Finalmente, el capítulo 7 presenta el resumen de esta tesis y la perspectiva para investigar otros aspectos. ABSTRACT Illumination with light-emitting diodes (LED) is more and more replacing traditional light sources. They provide advantages in efficiency, energy consumption, design, size and light quality. For more than 50 years, researchers have been working on LED improvements. Their main relevance for illumination is rapidly increasing. This thesis is focused on one important field of application which are spotlights. They are used to focus light on defined areas, outstanding objects in professional conditions. This high performance illumination required a defined light quality including tunable correlated color temperatures (CCT), high color rendering index (CRI), high efficiencies and bright, vivid colors. Several differently colored chips (red, blue, phosphor converted) in the LED package are combined to meet spectral power distribution with high CRI, tunable white and several light colors and secondary optics are used to collimate the light into the desired narrow spots with defined angle of emission. The combination of multi-color LED source and optical elements may cause chromatic inhomogeneities in spatial and angular light distribution which needs to solved at the optical design. However, there is no need for perfect uniformity in the spot light due to threshold in visual perception of human eye. Therefore, a mathematical description of color uniformity level with regard to visual perception is required. This thesis is organized seven seven chapters. After an initial one presenting the motivation that has guided the research of this thesis, Chapter 2 introduces the scientific basics of color uniformity in spot lights including: the applied color space CIELAB, the visual color perception, the spotlight design fundamentals with regards to light engines and nonimaging optics, and the state of the art for the evaluation of color uniformity in the far field of spotlights. Chapter 3 develops different methods for mathematical description of spatial color distribution in a defined area, which are the maximum color difference, the average color deviation, the gradient of spatial color distribution as well as the radial and axial smoothness. Each function refers to different visual influencing factors, and they need different handling of data be taken into account, along with weighting functions which pre- and post-process the simulated or measured data for noise reduction, luminance cutoff, the implementation of luminance weighting, contrast sensitivity function, and cumulative distribution function. In chapter 4, the merit function Usl for the estimation of the perceived color uniformity in spotlights is derived. It was based on the results of two sets of human factor experiments performed to evaluate the visual perception of typical spotlight patterns by subjects. The first human factor experiment resulted in the perceived rank order of the spotlights. The perceived rank order was used to correlate the mathematical descriptions of basic functions and weighted function concerning the spatial color distribution, which lead to the Usl function. The second human factor experiment tested the perception of spotlights under varied environmental conditions, with to objective to provide an absolute scale for Usl, so the subjective personal opinion of individuals could be replaced by a standardized merit function. The validation of the Usl function is presented concerning the application range and conditions as well as limitations and restrictions in carried out in chapter 5. Measured and simulated data of various optical several systems were compared. Fields of applications are discussed as well as validations and restrictions of the function. Chapter 6 presents spotlight system design and their optimization. An evaluation shows the analysis of reflector-based and TIR lens systems. The simulated optical systems are compared in color uniformity Usl , sensitivity to colored shadows, efficiency, and peak luminous intensity. It has been found that no single system which performed best in all categories, and that excellent color uniformity could be reached by two different system assemblies. Finally, chapter 7 summarizes the conclusions of the present thesis and an outlook for further investigation topics.

Simulation and geometrical design of multi-section tapered semiconductor optical amplifiers at 1.57 µm

Fully integrated semiconductor master-oscillator power-amplifiers (MOPA) with a tapered power amplifier are attractive sources for applications requiring high brightness. The geometrical design of the tapered amplifier is crucial to achieve the required power and beam quality. In this work we investigate by numerical simulation the role of the geometrical design in the beam quality and in the maximum achievable power. The simulations were performed with a Quasi-3D model which solves the complete steady-state semiconductor and thermal equations combined with a beam propagation method. The results indicate that large devices with wide taper angles produce higher power with better beam quality than smaller area designs, but at expenses of a higher injection current and lower conversion efficiency.

The development of architecture and urban design in China and the problem we need to solve = La utilización de la baja tecnología en la arquitectura popular de China y su combinación con el método del diseño arquitectónico moderno

In this article, I will research this topic from these aspects: the material, architectural forms, building technology and space experience, hoping to figure out the characteristic of traditional Chinese architecture and the use of low technology in it, explore a suitable path of the development of Chinese Vernacular Architecture.

Genetic Separation of FK506 Susceptibility and Drug Transport in the Yeast Pdr5 ATP-binding Cassette Multidrug Resistance Transporter

Overexpression of the yeast Pdr5 ATP-binding cassette transporter leads to pleiotropic drug resistance to a variety of structurally unrelated cytotoxic compounds. To identify Pdr5 residues involved in substrate recognition and/or drug transport, we used a combination of random in vitro mutagenesis and phenotypic screening to isolate novel mutant Pdr5 transporters with altered substrate specificity. A plasmid library containing randomly mutagenized PDR5 genes was transformed into appropriate drug-sensitive yeast cells followed by phenotypic selection of Pdr5 mutants. Selected mutant Pdr5 transporters were analyzed with respect to their expression levels, subcellular localization, drug resistance profiles to cycloheximide, rhodamines, antifungal azoles, steroids, and sensitivity to the inhibitor FK506. DNA sequencing of six PDR5 mutant genes identified amino acids important for substrate recognition, drug transport, and specific inhibition of the Pdr5 transporter. Mutations were found in each nucleotide-binding domain, the transmembrane domain 10, and, most surprisingly, even in predicted extracellular hydrophilic loops. At least some point mutations identified appear to influence folding of Pdr5, suggesting that the folded structure is a major substrate specificity determinant. Surprisingly, a S1360F exchange in transmembrane domain 10 not only caused limited substrate specificity, but also abolished Pdr5 susceptibility to inhibition by the immunosuppressant FK506. This is the first report of a mutation in a yeast ATP-binding cassette transporter that allows for the functional separation of substrate transport and inhibitor susceptibility.