Gain-of-function haplotype in the epithelial calcium channel TRPV6 is a risk factor for renal calcium stone formation

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.

How reliable is an undetectable viral load?

OBJECTIVES: An article by the Swiss AIDS Commission states that patients with stably suppressed viraemia [i.e. several successive HIV-1 RNA plasma concentrations (viral loads, VL) below the limits of detection during 6 months or more of highly active antiretroviral therapy (HAART)] are unlikely to be infectious. Questions then arise: how reliable is the undetectability of the VL, given the history of measures? What factors determine reliability? METHODS: We assessed the probability (henceforth termed reliability) that the n+1 VL would exceed 50 or 1000 HIV-1 RNA copies/mL when the nth one had been <50 copies/mL in 6168 patients of the Swiss HIV Cohort Study who were continuing to take HAART between 2003 and 2007. General estimating equations were used to analyse potential factors of reliability. RESULTS: With a cut-off at 50 copies/mL, reliability was 84.5% (n=1), increasing to 94.5% (n=5). Compliance, the current type of HAART and the first antiretroviral therapy (ART) received (HAART or not) were predictive factors of reliability. With a cut-off at 1000 copies/mL, reliability was 97.5% (n=1), increasing to 99.1% (n=4). Chart review revealed that patients had stopped their treatment, admitted to major problems with compliance or were taking non-HAART ART in 72.2% of these cases. Viral escape caused by resistance was found in 5.6%. No explanation was found in the charts of 22.2% of cases. CONCLUSIONS: After several successive VLs at <50 copies/mL, reliability reaches approximately 94% with a cut-off of 50 copies/mL and approximately 99% with a cut-off at 1000 copies/mL. Compliance is the most important factor predicting reliability.

Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress.

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-beta expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-beta signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-beta was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-beta is a regulator of the compensatory cardiac response to pressure overload-induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors.

Elderly age is not a negative predictive factor for virological response to therapy with pegylated interferon-α and ribavirin in chronic hepatitis C virus patients

BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.

Explaining Economic Growth: Factor Accumulation, Total Factor Productivity Growth, and Production Efficiency Improvement

This paper examines cross-country patterns of economic growth by estimating a stochastic frontier production function for 80 developed and developing countries and decomposing output change into factor accumulation, total factor productivity growth, and production efficiency improvement. In addition, this paper incorporates the quality of inputs in analyzing output growth, where the productivity of capital depends on its average age, while the productivity of labor depends on its average level of education. Our growth decomposition involves five geographic regions - Africa, East Asian, Latin America, South Asia, and the West. Factor growth, especially capital accumulation, generally proves much more important than either the improved quality of factors or total factor productivity growth in explaining output growth. The quality of capital positively and significantly affects output growth in all groups. The quality of labor, however, only possesses a positive and significant effect on output growth in Africa, East Asia, and the West. Labor quality owns a negative and significant effect in Latin America and South Asia.

Association between glycemic index and glycemic load and the risk of incident coronary heart disease among whites and African Americans with and without type 2 diabetes: The Atherosclerosis Risk in Communities study

Several studies have examined the association between high glycemic index (GI) and glycemic load (GL) diets and the risk for coronary heart disease (CHD). However, most of these studies were conducted primarily on white populations. The primary aim of this study was to examine whether high GI and GL diets are associated with increased risk for developing CHD in whites and African Americans, non-diabetics and diabetics, and within stratifications of body mass index (BMI) and hypertension (HTN). Baseline and 17-year follow-up data from ARIC (Atherosclerosis Risk in Communities) study was used. The study population (13,051) consisted of 74% whites, 26% African Americans, 89% non-diabetics, 11% diabetics, 43% male, 57% female aged 44 to 66 years at baseline. Data from the ARIC food frequency questionnaire at baseline were analyzed to provide GI and GL indices for each subject. Increases of 25 and 30 units for GI and GL respectively were used to describe relationships on incident CHD risk. Adjusted hazard ratios for propensity score with 95% confidence intervals (CI) were used to assess associations. During 17 years of follow-up (1987 to 2004), 1,683 cases of CHD was recorded. Glycemic index was associated with 2.12 fold (95% CI: 1.05, 4.30) increased incident CHD risk for all African Americans and GL was associated with 1.14 fold (95% CI: 1.04, 1.25) increased CHD risk for all whites. In addition, GL was also an important CHD risk factor for white non-diabetics (HR=1.59; 95% CI: 1.33, 1.90). Furthermore, within stratum of BMI 23.0 to 29.9 in non-diabetics, GI was associated with an increased hazard ratio of 11.99 (95% CI: 2.31, 62.18) for CHD in African Americans, and GL was associated with 1.23 fold (1.08, 1.39) increased CHD risk in whites. Body mass index modified the effect of GI and GL on CHD risk in all whites and white non-diabetics. For HTN, both systolic blood pressure and diastolic blood pressure modified the effect on GI and GL on CHD risk in all whites and African Americans, white and African American non-diabetics, and white diabetics. Further studies should examine other factors that could influence the effects of GI and GL on CHD risk, including dietary factors, physical activity, and diet-gene interactions. ^

Stochastic homogenization of the laser intensity to improve the irradiation uniformity of capsules directly driven by thousands laser beams

Illumination uniformity of a spherical capsule directly driven by laser beams has been assessed numerically. Laser facilities characterized by ND = 12, 20, 24, 32, 48 and 60 directions of irradiation with associated a single laser beam or a bundle of NB laser beams have been considered. The laser beam intensity profile is assumed super-Gaussian and the calculations take into account beam imperfections as power imbalance and pointing errors. The optimum laser intensity profile, which minimizes the root-mean-square deviation of the capsule illumination, depends on the values of the beam imperfections. Assuming that the NB beams are statistically independents is found that they provide a stochastic homogenization of the laser intensity associated to the whole bundle, reducing the errors associated to the whole bundle by the factor  , which in turn improves the illumination uniformity of the capsule. Moreover, it is found that the uniformity of the irradiation is almost the same for all facilities and only depends on the total number of laser beams Ntot = ND × NB.

Response threshold models, stochastic learning automata and ant colony optimization-based decentralized self-coordination algorithms for heterogeneous multi-tasks distribution in multi-robot systems

In recent decades, there has been an increasing interest in systems comprised of several autonomous mobile robots, and as a result, there has been a substantial amount of development in the eld of Articial Intelligence, especially in Robotics. There are several studies in the literature by some researchers from the scientic community that focus on the creation of intelligent machines and devices capable to imitate the functions and movements of living beings. Multi-Robot Systems (MRS) can often deal with tasks that are dicult, if not impossible, to be accomplished by a single robot. In the context of MRS, one of the main challenges is the need to control, coordinate and synchronize the operation of multiple robots to perform a specic task. This requires the development of new strategies and methods which allow us to obtain the desired system behavior in a formal and concise way. This PhD thesis aims to study the coordination of multi-robot systems, in particular, addresses the problem of the distribution of heterogeneous multi-tasks. The main interest in these systems is to understand how from simple rules inspired by the division of labor in social insects, a group of robots can perform tasks in an organized and coordinated way. We are mainly interested on truly distributed or decentralized solutions in which the robots themselves, autonomously and in an individual manner, select a particular task so that all tasks are optimally distributed. In general, to perform the multi-tasks distribution among a team of robots, they have to synchronize their actions and exchange information. Under this approach we can speak of multi-tasks selection instead of multi-tasks assignment, which means, that the agents or robots select the tasks instead of being assigned a task by a central controller. The key element in these algorithms is the estimation ix of the stimuli and the adaptive update of the thresholds. This means that each robot performs this estimate locally depending on the load or the number of pending tasks to be performed. In addition, it is very interesting the evaluation of the results in function in each approach, comparing the results obtained by the introducing noise in the number of pending loads, with the purpose of simulate the robot's error in estimating the real number of pending tasks. The main contribution of this thesis can be found in the approach based on self-organization and division of labor in social insects. An experimental scenario for the coordination problem among multiple robots, the robustness of the approaches and the generation of dynamic tasks have been presented and discussed. The particular issues studied are: Threshold models: It presents the experiments conducted to test the response threshold model with the objective to analyze the system performance index, for the problem of the distribution of heterogeneous multitasks in multi-robot systems; also has been introduced additive noise in the number of pending loads and has been generated dynamic tasks over time. Learning automata methods: It describes the experiments to test the learning automata-based probabilistic algorithms. The approach was tested to evaluate the system performance index with additive noise and with dynamic tasks generation for the same problem of the distribution of heterogeneous multi-tasks in multi-robot systems. Ant colony optimization: The goal of the experiments presented is to test the ant colony optimization-based deterministic algorithms, to achieve the distribution of heterogeneous multi-tasks in multi-robot systems. In the experiments performed, the system performance index is evaluated by introducing additive noise and dynamic tasks generation over time.

Fracture strength of drilled wafers: study of the stress concentration factor and determination of the weibull distribution of the fracture stress

In the photovoltaic field, the back contact solar cells technology has appeared as an alternative to the traditional silicon modules. This new type of cells places both positive and negative contacts on the back side of the cells maximizing the exposed surface to the light and making easier the interconnection of the cells in the module. The Emitter Wrap-Through solar cell structure presents thousands of tiny holes to wrap the emitter from the front surface to the rear surface. These holes are made in a first step over the silicon wafers by means of a laser drilling process. This step is quite harmful from a mechanical point of view since holes act as stress concentrators leading to a reduction in the strength of these wafers. This paper presents the results of the strength characterization of drilled wafers. The study is carried out testing the samples with the ring on ring device. Finite Element models are developed to simulate the tests. The stress concentration factor of the drilled wafers under this load conditions is determined from the FE analysis. Moreover, the material strength is characterized fitting the fracture stress of the samples to a three-parameter Weibull cumulative distribution function. The parameters obtained are compared with the ones obtained in the analysis of a set of samples without holes to validate the method employed for the study of the strength of silicon drilled wafers.

Evaluación estocástica de huecos de tensión en sistemas eléctricos: estudio de sensibilidad, estimación de índices y localización óptima de medidores

I. GENERALIDADES 1.1. Introducción Entre los diversos tipos de perturbaciones eléctricas, los huecos de tensión son considerados el problema de calidad de suministro más frecuente en los sistemas eléctricos. Este fenómeno es originado por un aumento extremo de la corriente en el sistema, causado principalmente por cortocircuitos o maniobras inadecuadas en la red. Este tipo de perturbación eléctrica está caracterizado básicamente por dos parámetros: tensión residual y duración. Típicamente, se considera que el hueco se produce cuando la tensión residual alcanza en alguna de las fases un valor entre 0.01 a 0.9 pu y tiene una duración de hasta 60 segundos. Para un usuario final, el efecto más relevante de un hueco de tensión es la interrupción o alteración de la operación de sus equipos, siendo los dispositivos de naturaleza electrónica los principalmente afectados (p. ej. ordenador, variador de velocidad, autómata programable, relé, etc.). Debido al auge tecnológico de las últimas décadas y a la búsqueda constante de automatización de los procesos productivos, el uso de componentes electrónicos resulta indispensable en la actualidad. Este hecho, lleva a que los efectos de los huecos de tensión sean más evidentes para el usuario final, provocando que su nivel de exigencia de la calidad de energía suministrada sea cada vez mayor. De forma general, el estudio de los huecos de tensión suele ser abordado bajo dos enfoques: en la carga o en la red. Desde el punto de vista de la carga, se requiere conocer las características de sensibilidad de los equipos para modelar su respuesta ante variaciones súbitas de la tensión del suministro eléctrico. Desde la perspectiva de la red, se busca estimar u obtener información adecuada que permita caracterizar su comportamiento en términos de huecos de tensión. En esta tesis, el trabajo presentado se encuadra en el segundo aspecto, es decir, en el modelado y estimación de la respuesta de un sistema eléctrico de potencia ante los huecos de tensión. 1.2. Planteamiento del problema A pesar de que los huecos de tensión son el problema de calidad de suministro más frecuente en las redes, hasta la actualidad resulta complejo poder analizar de forma adecuada este tipo de perturbación para muchas compañías del sector eléctrico. Entre las razones más comunes se tienen: - El tiempo de monitorización puede llegar a ser de varios años para conseguir una muestra de registros de huecos estadísticamente válida. - La limitación de recursos económicos para la adquisición e instalación de equipos de monitorización de huecos. - El elevado coste operativo que implica el análisis de los datos de los medidores de huecos de tensión instalados. - La restricción que tienen los datos de calidad de energía de las compañías eléctricas. Es decir, ante la carencia de datos que permitan analizar con mayor detalle los huecos de tensión, es de interés de las compañías eléctricas y la academia poder crear métodos fiables que permitan profundizar en el estudio, estimación y supervisión de este fenómeno electromagnético. Los huecos de tensión, al ser principalmente originados por eventos fortuitos como los cortocircuitos, son el resultado de diversas variables exógenas como: (i) la ubicación de la falta, (ii) la impedancia del material de contacto, (iii) el tipo de fallo, (iv) la localización del fallo en la red, (v) la duración del evento, etc. Es decir, para plantear de forma adecuada cualquier modelo teórico sobre los huecos de tensión, se requeriría representar esta incertidumbre combinada de las variables para proveer métodos realistas y, por ende, fiables para los usuarios. 1.3. Objetivo La presente tesis ha tenido como objetivo el desarrollo diversos métodos estocásticos para el estudio, estimación y supervisión de los huecos de tensión en los sistemas eléctricos de potencia. De forma específica, se ha profundizado en los siguientes ámbitos: - En el modelado realista de las variables que influyen en la caracterización de los huecos. Esto es, en esta Tesis se ha propuesto un método que permite representar de forma verosímil su cuantificación y aleatoriedad en el tiempo empleando distribuciones de probabilidad paramétricas. A partir de ello, se ha creado una herramienta informática que permite estimar la severidad de los huecos de tensión en un sistema eléctrico genérico. - Se ha analizado la influencia la influencia de las variables de entrada en la estimación de los huecos de tensión. En este caso, el estudio se ha enfocado en las variables de mayor divergencia en su caracterización de las propuestas existentes. - Se ha desarrollado un método que permite estima el número de huecos de tensión de una zona sin monitorización a través de la información de un conjunto limitado de medidas de un sistema eléctrico. Para ello, se aplican los principios de la estadística Bayesiana, estimando el número de huecos de tensión más probable de un emplazamiento basándose en los registros de huecos de otros nudos de la red. - Plantear una estrategia para optimizar la monitorización de los huecos de tensión en un sistema eléctrico. Es decir, garantizar una supervisión del sistema a través de un número de medidores menor que el número de nudos de la red. II. ESTRUCTURA DE LA TESIS Para plantear las propuestas anteriormente indicadas, la presente Tesis se ha estructurado en seis capítulos. A continuación, se describen brevemente los mismos. A manera de capítulo introductorio, en el capítulo 1, se realiza una descripción del planteamiento y estructura de la presente tesis. Esto es, se da una visión amplia de la problemática a tratar, además de describir el alcance de cada capítulo de la misma. En el capítulo 2, se presenta una breve descripción de los fundamentos y conceptos generales de los huecos de tensión. Los mismos, buscan brindar al lector de una mejor comprensión de los términos e indicadores más empleados en el análisis de severidad de los huecos de tensión en las redes eléctricas. Asimismo, a manera de antecedente, se presenta un resumen de las principales características de las técnicas o métodos existentes aplicados en la predicción y monitorización óptima de los huecos de tensión. En el capítulo 3, se busca fundamentalmente conocer la importancia de las variables que determinen la frecuencia o severidad de los huecos de tensión. Para ello, se ha implementado una herramienta de estimación de huecos de tensión que, a través de un conjunto predeterminado de experimentos mediante la técnica denominada Diseño de experimentos, analiza la importancia de la parametrización de las variables de entrada del modelo. Su análisis, es realizado mediante la técnica de análisis de la varianza (ANOVA), la cual permite establecer con rigor matemático si la caracterización de una determinada variable afecta o no la respuesta del sistema en términos de los huecos de tensión. En el capítulo 4, se propone una metodología que permite predecir la severidad de los huecos de tensión de todo el sistema a partir de los registros de huecos de un conjunto reducido de nudos de dicha red. Para ello, se emplea el teorema de probabilidad condicional de Bayes, el cual calcula las medidas más probables de todo el sistema a partir de la información proporcionada por los medidores de huecos instalados. Asimismo, en este capítulo se revela una importante propiedad de los huecos de tensión, como es la correlación del número de eventos de huecos de tensión en diversas zonas de las redes eléctricas. En el capítulo 5, se desarrollan dos métodos de localización óptima de medidores de huecos de tensión. El primero, que es una evolución metodológica del criterio de observabilidad; aportando en el realismo de la pseudo-monitorización de los huecos de tensión con la que se calcula el conjunto óptimo de medidores y, por ende, en la fiabilidad del método. Como una propuesta alternativa, se emplea la propiedad de correlación de los eventos de huecos de tensión de una red para plantear un método que permita establecer la severidad de los huecos de todo el sistema a partir de una monitorización parcial de dicha red. Finalmente, en el capítulo 6, se realiza una breve descripción de las principales aportaciones de los estudios realizados en esta tesis. Adicionalmente, se describen diversos temas a desarrollar en futuros trabajos. III. RESULTADOS En base a las pruebas realizadas en las tres redes planteadas; dos redes de prueba IEEE de 24 y 118 nudos (IEEE-24 e IEEE-118), además del sistema eléctrico de la República del Ecuador de 357 nudos (EC-357), se describen los siguientes puntos como las observaciones más relevantes: A. Estimación de huecos de tensión en ausencia de medidas: Se implementa un método estocástico de estimación de huecos de tensión denominado PEHT, el cual representa con mayor realismo la simulación de los eventos de huecos de un sistema a largo plazo. Esta primera propuesta de la tesis, es considerada como un paso clave para el desarrollo de futuros métodos del presente trabajo, ya que permite emular de forma fiable los registros de huecos de tensión a largo plazo en una red genérica. Entre las novedades más relevantes del mencionado Programa de Estimación de Huecos de Tensión (PEHT) se tienen: - Considerar el efecto combinado de cinco variables aleatorias de entrada para simular los eventos de huecos de tensión en una pseudo-monitorización a largo plazo. Las variables de entrada modeladas en la caracterización de los huecos de tensión en el PEHT son: (i) coeficiente de fallo, (ii) impedancia de fallo, (iii) tipo de fallo, (iv) localización del fallo y (v) duración. - El modelado estocástico de las variables de entrada impedancia de fallo y duración en la caracterización de los eventos de huecos de tensión. Para la parametrización de las variables mencionadas, se realizó un estudio detallado del comportamiento real de las mismas en los sistemas eléctricos. Asimismo, se define la función estadística que mejor representa la naturaleza aleatoria de cada variable. - Considerar como variables de salida del PEHT a indicadores de severidad de huecos de uso común en las normativas, como es el caso de los índices: SARFI-X, SARFI-Curve, etc. B. Análisis de sensibilidad de los huecos de tensión: Se presenta un estudio causa-efecto (análisis de sensibilidad) de las variables de entrada de mayor divergencia en su parametrización entre las referencias relacionadas a la estimación de los huecos de tensión en redes eléctricas. De forma específica, se profundiza en el estudio de la influencia de la parametrización de las variables coeficiente de fallo e impedancia de fallo en la predicción de los huecos de tensión. A continuación un resumen de las conclusiones más destacables: - La precisión de la variable de entrada coeficiente de fallo se muestra como un parámetro no influyente en la estimación del número de huecos de tensión (SARFI-90 y SARFI-70) a largo plazo. Es decir, no se requiere de una alta precisión del dato tasa de fallo de los elementos del sistema para obtener una adecuada estimación de los huecos de tensión. - La parametrización de la variable impedancia de fallo se muestra como un factor muy sensible en la estimación de la severidad de los huecos de tensión. Por ejemplo, al aumentar el valor medio de esta variable aleatoria, se disminuye considerablemente la severidad reportada de los huecos en la red. Por otra parte, al evaluar el parámetro desviación típica de la impedancia de fallo, se observa una relación directamente proporcional de este parámetro con la severidad de los huecos de tensión de la red. Esto es, al aumentar la desviación típica de la impedancia de fallo, se evidencia un aumento de la media y de la variación interanual de los eventos SARFI-90 y SARFI-70. - En base al análisis de sensibilidad desarrollado en la variable impedancia de fallo, se considera muy cuestionable la fiabilidad de los métodos de estimación de huecos de tensión que omiten su efecto en el modelo planteado. C. Estimación de huecos de tensión en base a la información de una monitorización parcial de la red: Se desarrolla un método que emplea los registros de una red parcialmente monitorizada para determinar la severidad de los huecos de todo el sistema eléctrico. A partir de los casos de estudio realizados, se observa que el método implementado (PEHT+MP) posee las siguientes características: - La metodología propuesta en el PEHT+MP combina la teoría clásica de cortocircuitos con diversas técnicas estadísticas para estimar, a partir de los datos de los medidores de huecos instalados, las medidas de huecos de los nudos sin monitorización de una red genérica. - El proceso de estimación de los huecos de tensión de la zona no monitorizada de la red se fundamenta en la aplicación del teorema de probabilidad condicional de Bayes. Es decir, en base a los datos observados (los registros de los nudos monitorizados), el PEHT+MP calcula de forma probabilística la severidad de los huecos de los nudos sin monitorización del sistema. Entre las partes claves del procedimiento propuesto se tienen los siguientes puntos: (i) la creación de una base de datos realista de huecos de tensión a través del Programa de Estimación de Huecos de Tensión (PEHT) propuesto en el capítulo anterior; y, (ii) el criterio de máxima verosimilitud empleado para estimar las medidas de huecos de los nudos sin monitorización de la red evaluada. - Las predicciones de medidas de huecos de tensión del PEHT+MP se ven potenciadas por la propiedad de correlación de los huecos de tensión en diversas zonas de un sistema eléctrico. Esta característica intrínseca de las redes eléctricas limita de forma significativa la respuesta de las zonas fuertemente correlacionadas del sistema ante un eventual hueco de tensión. Como el PEHT+MP está basado en principios probabilísticos, la reducción del rango de las posibles medidas de huecos se ve reflejado en una mejor predicción de las medidas de huecos de la zona no monitorizada. - Con los datos de un conjunto de medidores relativamente pequeño del sistema, es posible obtener estimaciones precisas (error nulo) de la severidad de los huecos de la zona sin monitorizar en las tres redes estudiadas. - El PEHT+MP se puede aplicar a diversos tipos de indicadores de severidad de los huecos de tensión, como es el caso de los índices: SARFI-X, SARFI-Curve, SEI, etc. D. Localización óptima de medidores de huecos de tensión: Se plantean dos métodos para ubicar de forma estratégica al sistema de monitorización de huecos en una red genérica. La primera propuesta, que es una evolución metodológica de la localización óptima de medidores de huecos basada en el criterio de observabilidad (LOM+OBS); y, como segunda propuesta, un método que determina la localización de los medidores de huecos según el criterio del área de correlación (LOM+COR). Cada método de localización óptima de medidores propuesto tiene un objetivo concreto. En el caso del LOM+OBS, la finalidad del método es determinar el conjunto óptimo de medidores que permita registrar todos los fallos que originen huecos de tensión en la red. Por otro lado, en el método LOM+COR se persigue definir un sistema óptimo de medidores que, mediante la aplicación del PEHT+MP (implementado en el capítulo anterior), sea posible estimar de forma precisa las medidas de huecos de tensión de todo el sistema evaluado. A partir del desarrollo de los casos de estudio de los citados métodos de localización óptima de medidores en las tres redes planteadas, se describen a continuación las observaciones más relevantes: - Como la generación de pseudo-medidas de huecos de tensión de los métodos de localización óptima de medidores (LOM+OBS y LOM+COR) se obtienen mediante la aplicación del algoritmo PEHT, la formulación del criterio de optimización se realiza en base a una pseudo-monitorización realista, la cual considera la naturaleza aleatoria de los huecos de tensión a través de las cinco variables estocásticas modeladas en el PEHT. Esta característica de la base de datos de pseudo-medidas de huecos de los métodos LOM+OBS y LOM+COR brinda una mayor fiabilidad del conjunto óptimo de medidores calculado respecto a otros métodos similares en la bibliografía. - El conjunto óptimo de medidores se determina según la necesidad del operador de la red. Esto es, si el objetivo es registrar todos los fallos que originen huecos de tensión en el sistema, se emplea el criterio de observabilidad en la localización óptima de medidores de huecos. Por otra parte, si se plantea definir un sistema de monitorización que permita establecer la severidad de los huecos de tensión de todo el sistema en base a los datos de un conjunto reducido de medidores de huecos, el criterio de correlación resultaría el adecuado. De forma específica, en el caso del método LOM+OBS, basado en el criterio de observabilidad, se evidenciaron las siguientes propiedades en los casos de estudio realizados: - Al aumentar el tamaño de la red, se observa la tendencia de disminuir el porcentaje de nudos monitorizados de dicho sistema. Por ejemplo, para monitorizar los fallos que originan huecos en la red IEEE-24, se requiere monitorizar el 100\% de los nudos del sistema. En el caso de las redes IEEE-118 y EC-357, el método LOM+OBS determina que con la monitorización de un 89.5% y 65.3% del sistema, respectivamente, se cumpliría con el criterio de observabilidad del método. - El método LOM+OBS permite calcular la probabilidad de utilización del conjunto óptimo de medidores a largo plazo, estableciendo así un criterio de la relevancia que tiene cada medidor considerado como óptimo en la red. Con ello, se puede determinar el nivel de precisión u observabilidad (100%, 95%, etc.) con el cual se detectarían los fallos que generan huecos en la red estudiada. Esto es, al aumentar el nivel de precisión de detección de los fallos que originan huecos, se espera que aumente el número de medidores requeridos en el conjunto óptimo de medidores calculado. - El método LOM+OBS se evidencia como una técnica aplicable a todo tipo de sistema eléctrico (radial o mallado), el cual garantiza la detección de los fallos que originan huecos de tensión en un sistema según el nivel de observabilidad planteado. En el caso del método de localización óptima de medidores basado en el criterio del área de correlación (LOM+COR), las diversas pruebas realizadas evidenciaron las siguientes conclusiones: - El procedimiento del método LOM+COR combina los métodos de estimación de huecos de tensión de capítulos anteriores (PEHT y PEHT+MP) con técnicas de optimización lineal para definir la localización óptima de los medidores de huecos de tensión de una red. Esto es, se emplea el PEHT para generar los pseudo-registros de huecos de tensión, y, en base al criterio planteado de optimización (área de correlación), el LOM+COR formula y calcula analíticamente el conjunto óptimo de medidores de la red a largo plazo. A partir de la información registrada por este conjunto óptimo de medidores de huecos, se garantizaría una predicción precisa de la severidad de los huecos de tensión de todos los nudos del sistema con el PEHT+MP. - El método LOM+COR requiere un porcentaje relativamente reducido de nudos del sistema para cumplir con las condiciones de optimización establecidas en el criterio del área de correlación. Por ejemplo, en el caso del número total de huecos (SARFI-90) de las redes IEEE-24, IEEE-118 y EC-357, se calculó un conjunto óptimo de 9, 12 y 17 medidores de huecos, respectivamente. Es decir, solamente se requeriría monitorizar el 38\%, 10\% y 5\% de los sistemas indicados para supervisar los eventos SARFI-90 en toda la red. - El método LOM+COR se muestra como un procedimiento de optimización versátil, el cual permite reducir la dimensión del sistema de monitorización de huecos de redes eléctricas tanto radiales como malladas. Por sus características, este método de localización óptima permite emular una monitorización integral del sistema a través de los registros de un conjunto pequeño de monitores. Por ello, este nuevo método de optimización de medidores sería aplicable a operadores de redes que busquen disminuir los costes de instalación y operación del sistema de monitorización de los huecos de tensión. ABSTRACT I. GENERALITIES 1.1. Introduction Among the various types of electrical disturbances, voltage sags are considered the most common quality problem in power systems. This phenomenon is caused by an extreme increase of the current in the network, primarily caused by short-circuits or inadequate maneuvers in the system. This type of electrical disturbance is basically characterized by two parameters: residual voltage and duration. Typically, voltage sags occur when the residual voltage, in some phases, reaches a value between 0.01 to 0.9 pu and lasts up to 60 seconds. To an end user, the most important effect of a voltage sags is the interruption or alteration of their equipment operation, with electronic devices the most affected (e.g. computer, drive controller, PLC, relay, etc.). Due to the technology boom of recent decades and the constant search for automating production processes, the use of electronic components is essential today. This fact makes the effects of voltage sags more noticeable to the end user, causing the level of demand for a quality energy supply to be increased. In general, the study of voltage sags is usually approached from one of two aspects: the load or the network. From the point of view of the load, it is necessary to know the sensitivity characteristics of the equipment to model their response to sudden changes in power supply voltage. From the perspective of the network, the goal is to estimate or obtain adequate information to characterize the network behavior in terms of voltage sags. In this thesis, the work presented fits into the second aspect; that is, in the modeling and estimation of the response of a power system to voltage sag events. 1.2. Problem Statement Although voltage sags are the most frequent quality supply problem in electrical networks, thistype of disturbance remains complex and challenging to analyze properly. Among the most common reasons for this difficulty are: - The sag monitoring time, because it can take up to several years to get a statistically valid sample. - The limitation of funds for the acquisition and installation of sag monitoring equipment. - The high operating costs involved in the analysis of the voltage sag data from the installed monitors. - The restrictions that electrical companies have with the registered power quality data. That is, given the lack of data to further voltage sag analysis, it is of interest to electrical utilities and researchers to create reliable methods to deepen the study, estimation and monitoring of this electromagnetic phenomenon. Voltage sags, being mainly caused by random events such as short-circuits, are the result of various exogenous variables such as: (i) the number of faults of a system element, (ii) the impedance of the contact material, (iii) the fault type, (iv) the fault location, (v) the duration of the event, etc. That is, to properly raise any theoretical model of voltage sags, it is necessary to represent the combined uncertainty of variables to provide realistic methods that are reliable for users. 1.3. Objective This Thesis has been aimed at developing various stochastic methods for the study, estimation and monitoring of voltage sags in electrical power systems. Specifically, it has deepened the research in the following areas: - This research furthers knowledge in the realistic modeling of the variables that influence sag characterization. This thesis proposes a method to credibly represent the quantification and randomness of the sags in time by using parametric probability distributions. From this, a software tool was created to estimate the severity of voltage sags in a generic power system. - This research also analyzes the influence of the input variables in the estimation of voltage sags. In this case, the study has focused on the variables of greatest divergence in their characterization of the existing proposals. - A method was developed to estimate the number of voltage sags of an area without monitoring through the information of a limited set of sag monitors in an electrical system. To this end, the principles of Bayesian statistics are applied, estimating the number of sags most likely to happen in a system busbar based in records of other sag network busbars. - A strategy was developed to optimize the monitorization of voltage sags on a power system. Its purpose is to ensure the monitoring of the system through a number of monitors lower than the number of busbars of the network assessed. II. THESIS STRUCTURE To describe in detail the aforementioned proposals, this Thesis has been structured into six chapters. Below is are brief descriptions of them: As an introductory chapter, Chapter 1, provides a description of the approach and structure of this thesis. It presents a wide view of the problem to be treated, in addition to the description of the scope of each chapter. In Chapter 2, a brief description of the fundamental and general concepts of voltage sags is presented to provide to the reader a better understanding of the terms and indicators used in the severity analysis of voltage sags in power networks. Also, by way of background, a summary of the main features of existing techniques or methods used in the prediction and optimal monitoring of voltage sags is also presented. Chapter 3 essentially seeks to know the importance of the variables that determine the frequency or severity of voltage sags. To do this, a tool to estimate voltage sags is implemented that, through a predetermined set of experiments using the technique called Design of Experiments, discusses the importance of the parameters of the input variables of the model. Its analysis is interpreted by using the technique of analysis of variance (ANOVA), which provides mathematical rigor to establish whether the characterization of a particular variable affects the system response in terms of voltage sags or not. In Chapter 4, a methodology to predict the severity of voltage sags of an entire system through the sag logs of a reduced set of monitored busbars is proposed. For this, the Bayes conditional probability theorem is used, which calculates the most likely sag severity of the entire system from the information provided by the installed monitors. Also, in this chapter an important property of voltage sags is revealed, as is the correlation of the voltage sags events in several zones of a power system. In Chapter 5, two methods of optimal location of voltage sag monitors are developed. The first one is a methodological development of the observability criteria; it contributes to the realism of the sag pseudo-monitoring with which the optimal set of sag monitors is calculated and, therefore, to the reliability of the proposed method. As an alternative proposal, the correlation property of the sag events of a network is used to raise a method that establishes the sag severity of the entire system from a partial monitoring of the network. Finally, in Chapter 6, a brief description of the main contributions of the studies in this Thesis is detailed. Additionally, various themes to be developed in future works are described. III. RESULTS. Based on tests on the three networks presented, two IEEE test networks of 24 and 118 busbars (IEEE-24 and IEEE-118) and the electrical system of the Republic of Ecuador (EC-357), the following points present the most important observations: A. Estimation of voltage sags in the absence of measures: A stochastic estimation method of voltage sags, called PEHT, is implemented to represent with greater realism the long-term simulation of voltage sags events in a system. This first proposal of this thesis is considered a key step for the development of future methods of this work, as it emulates in a reliable manner the voltage sag long-term records in a generic network. Among the main innovations of this voltage sag estimation method are the following: - Consideration of the combined effect of five random input variables to simulate the events of voltage sags in long-term monitoring is included. The input variables modeled in the characterization of voltage sags on the PEHT are as follows: (i) fault coefficient, (ii) fault impedance, (iii) type of fault, (iv) location of the fault, and (v) fault duration. - Also included is the stochastic modeling of the input variables of fault impedance and duration in the characterization of the events of voltage sags. For the parameterization of these variables, a detailed study of the real behavior in power systems is developed. Also, the statistical function best suited to the random nature of each variable is defined. - Consideration of sag severity indicators used in standards as PEHT output variables, including such as indices as SARFI-X, SARFI-Curve, etc. B. Sensitivity analysis of voltage sags: A cause-effect study (sensitivity analysis) of the input variables of greatest divergence between reference parameterization related to the estimation of voltage sags in electrical networks is presented. Specifically, it delves into the study of the influence of the parameterization of the variables fault coefficient and fault impedance in the voltage sag estimation. Below is a summary of the most notable observations: - The accuracy of the input variable fault coefficient is shown as a non-influential parameter in the long-term estimation of the number of voltage sags (SARFI-90 and SARFI-70). That is, it does not require a high accuracy of the fault rate data of system elements for a proper voltage sag estimation. - The parameterization of the variable fault impedance is shown to be a very sensitive factor in the estimation of the voltage sag severity. For example, by increasing the average value of this random variable, the reported sag severity in the network significantly decreases. Moreover, in assessing the standard deviation of the fault impedance parameter, a direct relationship of this parameter with the voltage sag severity of the network is observed. That is, by increasing the fault impedance standard deviation, an increase of the average and the interannual variation of the SARFI-90 and SARFI-70 events is evidenced. - Based on the sensitivity analysis developed in the variable fault impedance, the omission of this variable in the voltage sag estimation would significantly call into question the reliability of the responses obtained. C. Voltage sag estimation from the information of a network partially monitored: A method that uses the voltage sag records of a partially monitored network for the sag estimation of all the power system is developed. From the case studies performed, it is observed that the method implemented (PEHT+MP) has the following characteristics: - The methodology proposed in the PEHT+MP combines the classical short-circuit theory with several statistical techniques to estimate, from data the of the installed sag meters, the sag measurements of unmonitored busbars of a generic power network. - The estimation process of voltage sags of the unmonitored zone of the network is based on the application of the conditional probability theorem of Bayes. That is, based on the observed data (monitored busbars records), the PEHT+MP calculates probabilistically the sag severity at unmonitored system busbars. Among the key parts of the proposed procedure are the following: (i) the creation of a realistic data base of voltage sags through of the sag estimation program (PEHT); and, (ii) the maximum likelihood criterion used to estimate the sag indices of system busbars without monitoring. - The voltage sag measurement estimations of PEHT+MP are potentiated by the correlation property of the sag events in power systems. This inherent characteristic of networks significantly limits the response of strongly correlated system zones to a possible voltage sag. As the PEHT+MP is based on probabilistic principles, a reduction of the range of possible sag measurements is reflected in a better sag estimation of the unmonitored area of the power system. - From the data of a set of monitors representing a relatively small portion of the system, to obtain accurate estimations (null error) of the sag severity zones without monitoring is feasible in the three networks studied. - The PEHT+MP can be applied to several types of sag indices, such as: SARFI-X, SARFI-Curve, SEI, etc. D. Optimal location of voltage sag monitors in power systems: Two methods for strategically locating the sag monitoring system are implemented for a generic network. The first proposal is a methodological development of the optimal location of sag monitors based on the observability criterion (LOM + OBS); the second proposal is a method that determines the sag monitor location according to the correlation area criterion (LOM+COR). Each proposed method of optimal location of sag monitors has a specific goal. In the case of LOM+OBS, the purpose of the method is to determine the optimal set of sag monitors to record all faults that originate voltage sags in the network. On the other hand, the LOM+COR method attempts to define the optimal location of sag monitors to estimate the sag indices in all the assessed network with the PEHT+MP application. From the development of the case studies of these methods of optimal location of sag monitors in the three networks raised, the most relevant observations are described below: - As the generation of voltage sag pseudo-measurements of the optimal location methods (LOM+OBS and LOM+COR) are obtained by applying the algorithm PEHT, the formulation of the optimization criterion is performed based on a realistic sag pseudo-monitoring, which considers the random nature of voltage sags through the five stochastic variables modeled in PEHT. This feature of the database of sag pseudo-measurements of the LOM+OBS and LOM+COR methods provides a greater reliability of the optimal set of monitors calculated when compared to similar methods in the bibliography. - The optimal set of sag monitors is determined by the network operator need. That is, if the goal is to record all faults that originate from voltage sags in the system, the observability criterion is used to determine the optimal location of sag monitors (LOM+OBS). Moreover, if the objective is to define a monitoring system that allows establishing the sag severity of the system from taken from information based on a limited set of sag monitors, the correlation area criterion would be appropriate (LOM+COR). Specifically, in the case of the LOM+OBS method (based on the observability criterion), the following properties were observed in the case studies: - By increasing the size of the network, there was observed a reduction in the percentage of monitored system busbars required. For example, to monitor all the faults which cause sags in the IEEE-24 network, then 100% of the system busbars are required for monitoring. In the case of the IEEE-118 and EC-357 networks, the method LOM+OBS determines that with monitoring 89.5 % and 65.3 % of the system, respectively, the observability criterion of the method would be fulfilled. - The LOM+OBS method calculates the probability of using the optimal set of sag monitors in the long term, establishing a relevance criterion of each sag monitor considered as optimal in the network. With this, the level of accuracy or observability (100%, 95%, etc.) can be determined, with which the faults that caused sags in the studied network are detected. That is, when the accuracy level for detecting faults that cause sags in the system is increased, a larger number of sag monitors is expected when calculating the optimal set of monitors. - The LOM + OBS method is demonstrated to be a technique applicable to any type of electrical system (radial or mesh), ensuring the detection of faults that cause voltage sags in a system according to the observability level raised. In the case of the optimal localization of sag monitors based on the criterion of correlation area (LOM+COR), several tests showed the following conclusions: - The procedure of LOM+COR method combines the implemented algorithms of voltage sag estimation (PEHT and PEHT+MP) with linear optimization techniques to define the optimal location of the sag monitors in a network. That is, the PEHT is used to generate the voltage sag pseudo-records, and, from the proposed optimization criterion (correlation area), the LOM+COR formulates and analytically calculates the optimal set of sag monitors of the network in the long term. From the information recorded by the optimal set of sag monitors, an accurate prediction of the voltage sag severity at all the busbars of the system is guaranteed with the PEHT+MP. - The LOM + COR method is shown to be a versatile optimization procedure, which reduces the size of the sag monitoring system both at radial as meshed grids. Due to its characteristics, this optimal location method allows emulation of complete system sag monitoring through the records of a small optimal set of sag monitors. Therefore, this new optimization method would be applicable to network operators that looks to reduce the installation and operation costs of the voltage sag monitoring system.

Gene dosage and stochastic effects determine the severity and direction of uniparental ribosomal RNA gene silencing (nucleolar dominance) in Arabidopsis allopolyploids

Nucleolar dominance is an epigenetic phenomenon in which one parental set of ribosomal RNA (rRNA) genes is silenced in an interspecific hybrid. In natural Arabidopsis suecica, an allotetraploid (amphidiploid) hybrid of Arabidopsis thaliana and Cardaminopsis arenosa, the A. thaliana rRNA genes are repressed. Interestingly, A. thaliana rRNA gene silencing is variable in synthetic Arabidopsis suecica F1 hybrids. Two generations are needed for A. thaliana rRNA genes to be silenced in all lines, revealing a species-biased direction but stochastic onset to nucleolar dominance. Backcrossing synthetic A. suecica to tetraploid A. thaliana yielded progeny with active A. thaliana rRNA genes and, in some cases, silenced C. arenosa rRNA genes, showing that the direction of dominance can be switched. The hypothesis that naturally dominant rRNA genes have a superior binding affinity for a limiting transcription factor is inconsistent with dominance switching. Inactivation of a species-specific transcription factor is argued against by showing that A. thaliana and C. arenosa rRNA genes can be expressed transiently in the other species. Transfected A. thaliana genes are also active in A. suecica protoplasts in which chromosomal A. thaliana genes are repressed. Collectively, these data suggest that nucleolar dominance is a chromosomal phenomenon that results in coordinate or cooperative silencing of rRNA genes.

Mammary tumor suppression by transforming growth factor beta 1 transgene expression.

In cell culture, type alpha transforming growth factor (TGF-alpha) stimulates epithelial cell growth, whereas TGF-beta 1 overrides this stimulatory effect and is growth inhibitory. Transgenic mice that overexpress TGF-alpha under control of the mouse mammary tumor virus (MMTV) promoter/enhancer exhibit mammary ductal hyperplasia and stochastic development of mammary carcinomas, a process that can be accelerated by administration of the chemical carcinogen 7,12-dimethylbenz[a]anthracene. MMTV-TGF-beta 1 transgenic mice display mammary ductal hypoplasia and do not develop mammary tumors. We report that in crossbreeding experiments involving the production of mice carrying both the MMTV-TGF-beta 1 and MMTV-TGF-alpha transgenes, there is marked suppression of mammary tumor formation and that MMTV-TGF-beta 1 transgenic mice are resistant to 7,12-dimethylbenz[a]anthracene-induced mammary tumor formation. These data demonstrate that overexpression of TGF-beta 1 in vivo can markedly suppress mammary tumor development.

Parallel implementation of stochastic simulation for large scale cellular processes

Experimental and theoretical studies have shown the importance of stochastic processes in genetic regulatory networks and cellular processes. Cellular networks and genetic circuits often involve small numbers of key proteins such as transcriptional factors and signaling proteins. In recent years stochastic models have been used successfully for studying noise in biological pathways, and stochastic modelling of biological systems has become a very important research field in computational biology. One of the challenge problems in this field is the reduction of the huge computing time in stochastic simulations. Based on the system of the mitogen-activated protein kinase cascade that is activated by epidermal growth factor, this work give a parallel implementation by using OpenMP and parallelism across the simulation. Special attention is paid to the independence of the generated random numbers in parallel computing, that is a key criterion for the success of stochastic simulations. Numerical results indicate that parallel computers can be used as an efficient tool for simulating the dynamics of large-scale genetic regulatory networks and cellular processes

A reduced load approximation accounting for link interactions in a loss network

This paper is concerned with evaluating the performance of loss networks. Accurate determination of loss network performance can assist in the design and dimensioning of telecommunications networks. However, exact determination can be difficult and generally cannot be done in reasonable time. For these reasons there is much interest in developing fast and accurate approximations. We develop a reduced load approximation which improves on the famous Erlang fixed point approximation (EFPA) in a variety of circumstances. We illustrate our results with reference to a range of networks for which the EFPA may be expected to perform badly.

Die load and stresses in press forging

Several axi-symmetric EN3B steel components differing in shape and size were forged on a 100 ton joint knuckle press. A load cell fitted under the lower die inserts recorded the total deformation forces. Job parameters were measured off the billets and the forged parts. Slug temperatures were varied and two lubricants - aqueous colloidal graphite and oil - were used. An industrial study was also conducted to check the results of the laboratory experiments. Loads were measured (with calibrated extensometers attached to the press frames) when adequately heated mild steel slugs were being forged in finishing dies. Geometric parameters relating to the jobs and the dies were obtained from works drawings. All the variables considered in the laboratory study could not, however, be investigated without disrupting production. In spite of this obvious limitation, the study confirmed that parting area is the most significant geometric factor influencing the forging load. Multiple regression analyses of the laboratory and industrial results showed that die loads increase significantly with the weights and parting areas of press forged components, and with the width to thickness ratios of the flashes formed, but diminish with increasing slug temperatures and higher billet diameter to height ratios. The analyses also showed that more complicated parts require greater loads to forge them. Die stresses, due to applied axial loads, were investigated by the photoelastic method. The three dimensional frozen stress technique was employed. Model dies were machined from cast araldite cylinders, and the slug material was simulated with plasticene. Test samples were cut from the centres of the dies after the stress freezing. Examination of the samples, and subsequent calculations, showed that the highest stresses were developed in die outer corners. This observation partly explains why corner cracking occurs frequently in industrial forging dies. Investigation of die contact during the forging operation revealed the development of very high stresses.