Study of tumor suppressor genes p53 and Rb in acute myelogenous leukemia

Loss of antiproliferative function of p53 by point mutation occurred frequently in various solid tumors. However, the genetic change of p53 by deletion or point mutation was a rare event (6%) in the cells of 49 AML patients analyzed by single-stranded conformation polymorphism and sequencing. Despite infrequent point mutation, abundant levels of p53 protein were detected in 75% of AML patients studied by immunoprecipitation with p53 specific antibodies. Furthermore, p53 protein in most cases had an altered conformation as analyzed by the reactivity to PAb240 which recognizes mutant p53; p53 protein in mitogen stimulated normal lymphocytes also had similar altered conformation. This altered conformation may be another mechanism for inactivation of p53 function in the growth stimulated environment. Some evidence indicated that posttranslational modification by phosphorylation may contribute to the conformational change of p53.^ Retinoblastoma (Rb) gene inactivation by deletion, rearrangement or mutation has also been implicated in many types of solid tumors. Our studies showed that absence or low levels of Rb protein were observed in more than 20% of AML patients at diagnosis, and the low levels of Rb correlated with shorter survival of patients. The absence of Rb protein was due to gene inactivation in some cases and to abnormal regulation of Rb expression in others. ^

Patent foramen ovale and closure technique with the amplatzer occluder.

Proof that percutaneous closure of the patent foramen ovale (PFO) is superior to medical treatment is still incomplete. Paradoxical embolism is a rare event occurring over decades rather than years. None of the 4 randomized trials published carried enough patients or was followed up for long enough to reach superiority endpoints. All data, however, point to a benefit of PFO closure. Free wall erosion (exceedingly rare) and triggering of atrial fibrillation (in about 1% of patients) are the only noteworthy complications. They are outweighed by the supposedly prevented events of paradoxical embolisms, such as stroke, transient ischemic attacks, myocardial infarctions, or other systemic embolisms. Medical treatment with perhaps the exception of lifelong oral anticoagulation provides less protection. During a 10-year follow-up of a comparative study the annual mortality was significantly lower in the patients with PFO closure (0.4%) than in those with medical treatment (1.1%, P < 0.03). PFO closure can be accomplished in less than 1 hour with immediate resumption of physical activity. It represents thus a kind of mechanical vaccination.

Cosmogenic activation of xenon and copper

Rare event search experiments using liquid xenon as target and detection medium require ultra-low background levels to fully exploit their physics potential. Cosmic ray induced activation of the detector components and, even more importantly, of the xenon itself during production, transportation and storage at the Earth's surface, might result in the production of radioactive isotopes with long half-lives, with a possible impact on the expected background. We present the first dedicated study on the cosmogenic activation of xenon after 345 days of exposure to cosmic rays at the Jungfraujoch research station at 3470m above sea level, complemented by a study of copper which has been activated simultaneously. We have directly observed the production of 7Be, 101Rh, 125Sb, 126I and 127Xe in xenon, out of which only 125Sb could potentially lead to background for a multi-ton scale dark matter search. The production rates for five out of eight studied radioactive isotopes in copper are in agreement with the only existing dedicated activation measurement, while we observe lower rates for the remaining ones. The specific saturation activities for both samples are also compared to predictions obtained with commonly used software packages, where we observe some underpredictions, especially for xenon activation.

Alterations in the ras oncogene and the p53 tumor suppressor gene in ultraviolet radiation-induced skin carcinogenesis

A rapid increase of the ultraviolet radiation (UVR)-related skin cancer incidence has attracted more and more public attention during the last few decades. Prevention and treatment of UVR-related skin cancer has become an important public health issue in the United States. Recent studies indicate that mutations in ras and/or p53 genes may be involved in UVR-induced skin tumor development but the precise molecular mechanism remains unclear. In this study, alterations of H-ras and p53 genes were investigated in different stages of carcinogenesis in a chronic UVR (solar simulator) exposure-induced Sencar mouse skin carcinogenesis model in order to clarify the role of the alterations of these genes during the skin carcinogenesis process and to further understand the mechanisms by which UVR causes skin cancer.^ Positive ras-p21 staining in cell membranes and cytosol were detected in 18/33 (55%) of squamous cell carcinomas (SCCs), but were not detected in UV-exposed skin, papillomas, or spindle cell tumors (SCTs). Positive staining of the malignant progression marker K13 was found in 17/33 (52%) of SCCs only. A significant positive correlation was observed between the K13 and the ras-p21 expression. Polymerase chain reaction (PCR)-based single strand conformation polymorphism (SSCP) analysis and gene sequencing analysis revealed three point mutations, one (codon 56) in UV-exposed non-tumor bearing skin and the other two (codons 21 and 13) in SCCs. No UV-specific mutation patterns were found.^ Positive p53 nuclear staining was found in 10/37 (27%) of SCCs and 12/24 (50%) of SCTs, but was not detected in normal skin or papillomas. PCR-based SSCP and sequencing analysis revealed eight point mutations in exons 5 and 6 (four in SCTs, two in SCCs, and two in UV-exposed skin) including six C-T or C-A transitions. Four of the mutations occurred at a dipyrimidine (CC) sequence. The pattern of the mutations indicated that the mutagenic lesions were induced by UVR.^ These results indicate that overexpression of ras-p21 in conjunction with aberrant expression of K13 occurred frequently in UVR-induced SCCs in Sencar mouse skin. The point mutation in the H-ras gene appeared to be a rare event in UVR skin carcinogenesis and may not be responsible for overexpression of ras-p21. UVR-induced P53 gene alteration is a frequent event in UVR-induced SCCs and later stage SCT tumors in Sencar mice skin, suggesting the p53 gene mutation plays an important role in skin tumor malignant progression. ^

Evaluating alternative industrial network organizations and information systems

Purpose – The purpose of this paper is to present a simulation‐based evaluation method for the comparison of different organizational forms and software support levels in the field of supply chain management (SCM). Design/methodology/approach – Apart from widely known logistic performance indicators, the discrete event simulation model considers explicitly coordination cost as stemming from iterative administration procedures. Findings - The method is applied to an exemplary supply chain configuration considering various parameter settings. Curiously, additional coordination cost does not always result in improved logistic performance. Influence factor variations lead to different organizational recommendations. The results confirm the high importance of (up to now) disregarded dimensions when evaluating SCM concepts and IT tools. Research limitations/implications – The model is based on simplified product and network structures. Future research shall include more complex, real world configurations. Practical implications – The developed method is designed for the identification of improvement potential when SCM software is employed. Coordination schemes based only on ERP systems are valid alternatives in industrial practice because significant investment IT can be avoided. Therefore, the evaluation of these coordination procedures, in particular the cost due to iterations, is of high managerial interest and the method provides a comprehensive tool for strategic IT decision making. Originality/value – Reviewed literature is mostly focused on the benefits of SCM software implementations. However, ERP system based supply chain coordination is still widespread industrial practice but associated coordination cost has not been addressed by researchers.

Metodología de análisis estadístico de roturas en redes de distribución de agua

La presente Tesis plantea una metodología de análisis estadístico de roturas de tubería en redes de distribución de agua, que analiza la relación entre las roturas y la presión de agua y que propone la implantación de una gestión de presiones que reduzca el número de roturas que se producen en dichas redes. Las redes de distribución de agua se deterioran y una de sus graves consecuencias es la aparición de roturas frecuentes en sus tuberías. Las roturas llevan asociados elevados costes sociales, económicos y medioambientales y es por ello por lo que las compañías gestoras del agua tratan de reducirlas en la medida de lo posible. Las redes de distribución de agua se pueden dividir en zonas o sectores que facilitan su control y que pueden ser independientes o aislarse mediante válvulas, como ocurre en las redes de países más desarrollados, o pueden estar intercomunicados hidráulicamente. La implantación de una gestión de presiones suele llevarse a cabo a través de las válvulas reductoras de presión (VPR), que se instalan en las cabeceras de estos sectores y que controlan la presión aguas abajo de la misma, aunque varíe su caudal de entrada. Los métodos más conocidos de la gestión de presiones son la reducción de presiones, que es el control más habitual, el mantenimiento de la presión, la prevención y/o alivio de los aumentos repentinos de presión y el establecimiento de un control por alturas. A partir del año 2005 se empezó a reconocer el efecto de la gestión de presiones sobre la disminución de las roturas. En esta Tesis, se sugiere una gestión de presiones que controle los rangos de los indicadores de la presión de cabecera que más influyan en la probabilidad de roturas de tubería. Así, la presión del agua se caracteriza a través de indicadores obtenidos de la presión registrada en la cabecera de los sectores, debido a que se asume que esta presión es representativa de la presión de operación de todas las tuberías porque las pérdidas de carga son relativamente bajas y las diferencias topográficas se tienen en cuenta en el diseño de los sectores. Y los indicadores de presión, que se pueden definir como el estadístico calculado a partir de las series de la presión de cabecera sobre una ventana de tiempo, pueden proveer la información necesaria para ayudar a la toma de decisiones a los gestores del agua con el fin de reducir las roturas de tubería en las redes de distribución de agua. La primera parte de la metodología que se propone en esta Tesis trata de encontrar los indicadores de presión que influyen más en la probabilidad de roturas de tuberías. Para conocer si un indicador es influyente en la probabilidad de las roturas se comparan las estimaciones de las funciones de distribución acumulada (FDAs) de los indicadores de presiones, considerando dos situaciones: cuando se condicionan a la ocurrencia de una rotura (suceso raro) y cuando se calculan en la situación normal de operación (normal operación). Por lo general, las compañías gestoras cuentan con registros de roturas de los años más recientes y al encontrarse las tuberías enterradas se complica el acceso a la información. Por ello, se propone el uso de funciones de probabilidad que permiten reducir la incertidumbre asociada a los datos registrados. De esta forma, se determinan las funciones de distribución acumuladas (FDAs) de los valores del indicador de la serie de presión (situación normal de operación) y las FDAs de los valores del indicador en el momento de ocurrencia de las roturas (condicionado a las roturas). Si las funciones de distribución provienen de la misma población, no se puede deducir que el indicador claramente influya en la probabilidad de roturas. Sin embargo, si se prueba estadísticamente que las funciones proceden de la misma población, se puede concluir que existe una relación entre el indicador analizado y la ocurrencia de las roturas. Debido a que el número de valores del indicador de la FDA condicionada a las roturas es mucho menor que el número de valores del indicador de la FDA incondicional a las roturas, se generan series aleatorias a partir de los valores de los indicadores con el mismo número de valores que roturas registradas hay. De esta forma, se comparan las FDAs de series aleatorias del indicador con la FDA condicionada a las roturas del mismo indicador y se deduce si el indicador es influyente en la probabilidad de las roturas. Los indicadores de presión pueden depender de unos parámetros. A través de un análisis de sensibilidad y aplicando un test estadístico robusto se determina la situación en la que estos parámetros dan lugar a que el indicador sea más influyente en la probabilidad de las roturas. Al mismo tiempo, los indicadores se pueden calcular en función de dos parámetros de cálculo que se denominan el tiempo de anticipación y el ancho de ventana. El tiempo de anticipación es el tiempo (en horas) entre el final del periodo de computación del indicador de presión y la rotura, y el ancho de ventana es el número de valores de presión que se requieren para calcular el indicador de presión y que es múltiplo de 24 horas debido al comportamiento cíclico diario de la presión. Un análisis de sensibilidad de los parámetros de cálculo explica cuándo los indicadores de presión influyen más en la probabilidad de roturas. En la segunda parte de la metodología se presenta un modelo de diagnóstico bayesiano. Este tipo de modelo forma parte de los modelos estadísticos de prevención de roturas, parten de los datos registrados para establecer patrones de fallo y utilizan el teorema de Bayes para determinar la probabilidad de fallo cuando se condiciona la red a unas determinadas características. Así, a través del teorema de Bayes se comparan la FDA genérica del indicador con la FDA condicionada a las roturas y se determina cuándo la probabilidad de roturas aumenta para ciertos rangos del indicador que se ha inferido como influyente en las roturas. Se determina un ratio de probabilidad (RP) que cuando es superior a la unidad permite distinguir cuándo la probabilidad de roturas incrementa para determinados intervalos del indicador. La primera parte de la metodología se aplica a la red de distribución de la Comunidad de Madrid (España) y a la red de distribución de Ciudad de Panamá (Panamá). Tras el filtrado de datos se deduce que se puede aplicar la metodología en 15 sectores en la Comunidad de Madrid y en dos sectores, llamados corregimientos, en Ciudad de Panamá. Los resultados demuestran que en las dos redes los indicadores más influyentes en la probabilidad de las roturas son el rango de la presión, que supone la diferencia entre la presión máxima y la presión mínima, y la variabilidad de la presión, que considera la propiedad estadística de la desviación típica. Se trata, por tanto, de indicadores que hacen referencia a la dispersión de los datos, a la persistencia de la variación de la presión y que se puede asimilar en resistencia de materiales a la fatiga. La segunda parte de la metodología se ha aplicado a los indicadores influyentes en la probabilidad de las roturas de la Comunidad de Madrid y se ha deducido que la probabilidad de roturas aumenta para valores extremos del indicador del rango de la presión y del indicador de la variabilidad de la presión. Finalmente, se recomienda una gestión de presiones que limite los intervalos de los indicadores influyentes en la probabilidad de roturas que incrementen dicha probabilidad. La metodología propuesta puede aplicarse a otras redes de distribución y puede ayudar a las compañías gestoras a reducir el número de fallos en el sistema a través de la gestión de presiones. This Thesis presents a methodology for the statistical analysis of pipe breaks in water distribution networks. The methodology studies the relationship between pipe breaks and water pressure, and proposes a pressure management procedure to reduce the number of breaks that occur in such networks. One of the manifestations of the deterioration of water supply systems is frequent pipe breaks. System failures are one of the major challenges faced by water utilities, due to their associated social, economic and environmental costs. For all these reasons, water utilities aim at reducing the problem of break occurrence to as great an extent as possible. Water distribution networks can be divided into areas or sectors, which facilitates the control of the network. These areas may be independent or isolated by valves, as it usually happens in developing countries. Alternatively, they can be hydraulically interconnected. The implementation of pressure management strategies is usually carried out through pressure-reducing valves (PRV). These valves are installed at the head of the sectors and, although the inflow may vary significantly, they control the downstream pressure. The most popular methods of pressure management consist of pressure reduction, which is the common form of control, pressure sustaining, prevention and/or alleviation of pressure surges or large variations in pressure, and level/altitude control. From 2005 onwards, the effects of pressure management on burst frequencies have become more widely recognized in the technical literature. This thesis suggests a pressure management that controls the pressure indicator ranges most influential on the probability of pipe breaks. Operating pressure in a sector is characterized by means of a pressure indicator at the head of the DMA, as head losses are relatively small and topographical differences were accounted for at the design stage. The pressure indicator, which may be defined as the calculated statistic from the time series of pressure head over a specific time window, may provide necessary information to help water utilities to make decisions to reduce pipe breaks in water distribution networks. The first part of the methodology presented in this Thesis provides the pressure indicators which have the greatest impact on the probability of pipe breaks to be determined. In order to know whether a pressure indicator influences the probability of pipe breaks, the proposed methodology compares estimates of cumulative distribution functions (CDFs) of a pressure indicator through consideration of two situations: when they are conditioned to the occurrence of a pipe break (a rare event), and when they are not (a normal operation). Water utilities usually have a history of failures limited to recent periods of time, and it is difficult to have access to precise information in an underground network. Therefore, the use of distribution functions to address such imprecision of recorded data is proposed. Cumulative distribution functions (CDFs) derived from the time series of pressure indicators (normal operation) and CDFs of indicator values at times coincident with a reported pipe break (conditioned to breaks) are compared. If all estimated CDFs are drawn from the same population, there is no reason to infer that the studied indicator clearly influences the probability of the rare event. However, when it is statistically proven that the estimated CDFs do not come from the same population, the analysed indicator may have an influence on the occurrence of pipe breaks. Due to the fact that the number of indicator values used to estimate the CDF conditioned to breaks is much lower in comparison with the number of indicator values to estimate the CDF of the unconditional pressure series, and that the obtained results depend on the size of the compared samples, CDFs from random sets of the same size sampled from the unconditional indicator values are estimated. Therefore, the comparison between the estimated CDFs of random sets of the indicator and the estimated CDF conditioned to breaks allows knowledge of if the indicator is influential on the probability of pipe breaks. Pressure indicators depend on various parameters. Sensitivity analysis and a robust statistical test allow determining the indicator for which these parameters result most influential on the probability of pipe breaks. At the same time, indicators can be calculated according to two model parameters, named as the anticipation time and the window width. The anticipation time refers to the time (hours) between the end of the period for the computation of the pressure indicator and the break. The window width is the number of instantaneous pressure values required to calculate the pressure indicator and is multiple of 24 hours, as water pressure has a cyclical behaviour which lasts one day. A sensitivity analysis of the model parameters explains when the pressure indicator is more influential on the probability of pipe breaks. The second part of the methodology presents a Bayesian diagnostic model. This kind of model belongs to the class of statistical predictive models, which are based on historical data, represent break behavior and patterns in water mains, and use the Bayes’ theorem to condition the probability of failure to specific system characteristics. The Bayes’ theorem allows comparing the break-conditioned FDA and the unconditional FDA of the indicators and determining when the probability of pipe breaks increases for certain pressure indicator ranges. A defined probability ratio provides a measure to establish whether the probability of breaks increases for certain ranges of the pressure indicator. The first part of the methodology is applied to the water distribution network of Madrid (Spain) and to the water distribution network of Panama City (Panama). The data filtering method suggests that the methodology can be applied to 15 sectors in Madrid and to two areas in Panama City. The results show that, in both systems, the most influential indicators on the probability of pipe breaks are the pressure range, which is the difference between the maximum pressure and the minimum pressure, and pressure variability, referred to the statistical property of the standard deviation. Therefore, they represent the dispersion of the data, the persistence of the variation in pressure and may be related to the fatigue in material resistance. The second part of the methodology has been applied to the influential indicators on the probability of pipe breaks in the water distribution network of Madrid. The main conclusion is that the probability of pipe breaks increases for the extreme values of the pressure range indicator and of the pressure variability indicator. Finally, a pressure management which limits the ranges of the pressure indicators influential on the probability of pipe breaks that increase such probability is recommended. The methodology presented here is general, may be applied to other water distribution networks, and could help water utilities reduce the number of system failures through pressure management.

Shake-table tests of a reinforced concrete frame designed following modern codes: seismic performance and damage evaluation

This paper presents shake-table tests conducted on a two-fifths-scale reinforced concrete frame representing a conventional construction design under current building code provisions in the Mediterranean area. The structure was subjected to a sequence of dynamic tests including free vibrations and four seismic simulations in which a historical ground motion record was scaled to levels of increasing intensity until collapse. Each seismic simulation was associated with a different level of seismic hazard, representing very frequent, frequent, rare and very rare earthquakes. The structure remained basically undamaged and within the inter-story drift limits of the "immediate occupancy" performance level for the very frequent and frequent earthquakes. For the rare earthquake, the specimen sustained significant damage with chord rotations of up to 28% of its ultimate capacity and approached the upper bound limit of inter-story drift associated with "life safety". The specimen collapsed at the beginning of the "very rare" seismic simulation. Besides summarizing the experimental program, this paper evaluates the damage quantitatively at the global and local levels in terms of chord rotation and other damage indexes, together with the energy dissipation demands for each level of seismic hazard. Further, the ratios of column-to-beam moment capacity recommended by Eurocode 8 and ACI-318 to guarantee the formation of a strong column-weak beam mechanism are examined.

Evaluation of configurations of supply networks supported by it systems

Los sistemas transaccionales tales como los programas informáticos para la planificación de recursos empresariales (ERP software) se han implementado ampliamente mientras que los sistemas analíticos para la gestión de la cadena de suministro (SCM software) no han tenido el éxito deseado por la industria de tecnología de información (TI). Aunque se documentan beneficios importantes derivados de las implantaciones de SCM software, las empresas industriales son reacias a invertir en este tipo de sistemas. Por una parte esto es debido a la falta de métodos que son capaces de detectar los beneficios por emplear esos sistemas, y por otra parte porque el coste asociado no está identificado, detallado y cuantificado suficientemente. Los esquemas de coordinación basados únicamente en sistemas ERP son alternativas válidas en la práctica industrial siempre que la relación coste-beneficio esta favorable. Por lo tanto, la evaluación de formas organizativas teniendo en cuenta explícitamente el coste debido a procesos administrativos, en particular por ciclos iterativos, es de gran interés para la toma de decisiones en el ámbito de inversiones en TI. Con el fin de cerrar la brecha, el propósito de esta investigación es proporcionar métodos de evaluación que permitan la comparación de diferentes formas de organización y niveles de soporte por sistemas informáticos. La tesis proporciona una amplia introducción, analizando los retos a los que se enfrenta la industria. Concluye con las necesidades de la industria de SCM software: unas herramientas que facilitan la evaluación integral de diferentes propuestas de organización. A continuación, la terminología clave se detalla centrándose en la teoría de la organización, las peculiaridades de inversión en TI y la tipología de software de gestión de la cadena de suministro. La revisión de la literatura clasifica las contribuciones recientes sobre la gestión de la cadena de suministro, tratando ambos conceptos, el diseño de la organización y su soporte por las TI. La clasificación incluye criterios relacionados con la metodología de la investigación y su contenido. Los estudios empíricos en el ámbito de la administración de empresas se centran en tipologías de redes industriales. Nuevos algoritmos de planificación y esquemas de coordinación innovadoras se desarrollan principalmente en el campo de la investigación de operaciones con el fin de proponer nuevas funciones de software. Artículos procedentes del área de la gestión de la producción se centran en el análisis de coste y beneficio de las implantaciones de sistemas. La revisión de la literatura revela que el éxito de las TI para la coordinación de redes industriales depende en gran medida de características de tres dimensiones: la configuración de la red industrial, los esquemas de coordinación y las funcionalidades del software. La literatura disponible está enfocada sobre todo en los beneficios de las implantaciones de SCM software. Sin embargo, la coordinación de la cadena de suministro, basándose en el sistema ERP, sigue siendo la práctica industrial generalizada, pero el coste de coordinación asociado no ha sido abordado por los investigadores. Los fundamentos de diseño organizativo eficiente se explican en detalle en la medida necesaria para la comprensión de la síntesis de las diferentes formas de organización. Se han generado varios esquemas de coordinación variando los siguientes parámetros de diseño: la estructura organizativa, los mecanismos de coordinación y el soporte por TI. Las diferentes propuestas de organización desarrolladas son evaluadas por un método heurístico y otro basado en la simulación por eventos discretos. Para ambos métodos, se tienen en cuenta los principios de la teoría de la organización. La falta de rendimiento empresarial se debe a las dependencias entre actividades que no se gestionan adecuadamente. Dentro del método heurístico, se clasifican las dependencias y se mide su intensidad basándose en factores contextuales. A continuación, se valora la idoneidad de cada elemento de diseño organizativo para cada dependencia específica. Por último, cada forma de organización se evalúa basándose en la contribución de los elementos de diseño tanto al beneficio como al coste. El beneficio de coordinación se refiere a la mejora en el rendimiento logístico - este concepto es el objeto central en la mayoría de modelos de evaluación de la gestión de la cadena de suministro. Por el contrario, el coste de coordinación que se debe incurrir para lograr beneficios no se suele considerar en detalle. Procesos iterativos son costosos si se ejecutan manualmente. Este es el caso cuando SCM software no está implementada y el sistema ERP es el único instrumento de coordinación disponible. El modelo heurístico proporciona un procedimiento simplificado para la clasificación sistemática de las dependencias, la cuantificación de los factores de influencia y la identificación de configuraciones que indican el uso de formas organizativas y de soporte de TI más o menos complejas. La simulación de eventos discretos se aplica en el segundo modelo de evaluación utilizando el paquete de software ‘Plant Simulation’. Con respecto al rendimiento logístico, por un lado se mide el coste de fabricación, de inventario y de transporte y las penalizaciones por pérdida de ventas. Por otro lado, se cuantifica explícitamente el coste de la coordinación teniendo en cuenta los ciclos de coordinación iterativos. El método se aplica a una configuración de cadena de suministro ejemplar considerando diversos parámetros. Los resultados de la simulación confirman que, en la mayoría de los casos, el beneficio aumenta cuando se intensifica la coordinación. Sin embargo, en ciertas situaciones en las que se aplican ciclos de planificación manuales e iterativos el coste de coordinación adicional no siempre conduce a mejor rendimiento logístico. Estos resultados inesperados no se pueden atribuir a ningún parámetro particular. La investigación confirma la gran importancia de nuevas dimensiones hasta ahora ignoradas en la evaluación de propuestas organizativas y herramientas de TI. A través del método heurístico se puede comparar de forma rápida, pero sólo aproximada, la eficiencia de diferentes formas de organización. Por el contrario, el método de simulación es más complejo pero da resultados más detallados, teniendo en cuenta parámetros específicos del contexto del caso concreto y del diseño organizativo. ABSTRACT Transactional systems such as Enterprise Resource Planning (ERP) systems have been implemented widely while analytical software like Supply Chain Management (SCM) add-ons are adopted less by manufacturing companies. Although significant benefits are reported stemming from SCM software implementations, companies are reluctant to invest in such systems. On the one hand this is due to the lack of methods that are able to detect benefits from the use of SCM software and on the other hand associated costs are not identified, detailed and quantified sufficiently. Coordination schemes based only on ERP systems are valid alternatives in industrial practice because significant investment in IT can be avoided. Therefore, the evaluation of these coordination procedures, in particular the cost due to iterations, is of high managerial interest and corresponding methods are comprehensive tools for strategic IT decision making. The purpose of this research is to provide evaluation methods that allow the comparison of different organizational forms and software support levels. The research begins with a comprehensive introduction dealing with the business environment that industrial networks are facing and concludes highlighting the challenges for the supply chain software industry. Afterwards, the central terminology is addressed, focusing on organization theory, IT investment peculiarities and supply chain management software typology. The literature review classifies recent supply chain management research referring to organizational design and its software support. The classification encompasses criteria related to research methodology and content. Empirical studies from management science focus on network types and organizational fit. Novel planning algorithms and innovative coordination schemes are developed mostly in the field of operations research in order to propose new software features. Operations and production management researchers realize cost-benefit analysis of IT software implementations. The literature review reveals that the success of software solutions for network coordination depends strongly on the fit of three dimensions: network configuration, coordination scheme and software functionality. Reviewed literature is mostly centered on the benefits of SCM software implementations. However, ERP system based supply chain coordination is still widespread industrial practice but the associated coordination cost has not been addressed by researchers. Fundamentals of efficient organizational design are explained in detail as far as required for the understanding of the synthesis of different organizational forms. Several coordination schemes have been shaped through the variation of the following design parameters: organizational structuring, coordination mechanisms and software support. The different organizational proposals are evaluated using a heuristic approach and a simulation-based method. For both cases, the principles of organization theory are respected. A lack of performance is due to dependencies between activities which are not managed properly. Therefore, within the heuristic method, dependencies are classified and their intensity is measured based on contextual factors. Afterwards the suitability of each organizational design element for the management of a specific dependency is determined. Finally, each organizational form is evaluated based on the contribution of the sum of design elements to coordination benefit and to coordination cost. Coordination benefit refers to improvement in logistic performance – this is the core concept of most supply chain evaluation models. Unfortunately, coordination cost which must be incurred to achieve benefits is usually not considered in detail. Iterative processes are costly when manually executed. This is the case when SCM software is not implemented and the ERP system is the only available coordination instrument. The heuristic model provides a simplified procedure for the classification of dependencies, quantification of influence factors and systematic search for adequate organizational forms and IT support. Discrete event simulation is applied in the second evaluation model using the software package ‘Plant Simulation’. On the one hand logistic performance is measured by manufacturing, inventory and transportation cost and penalties for lost sales. On the other hand coordination cost is explicitly considered taking into account iterative coordination cycles. The method is applied to an exemplary supply chain configuration considering various parameter settings. The simulation results confirm that, in most cases, benefit increases when coordination is intensified. However, in some situations when manual, iterative planning cycles are applied, additional coordination cost does not always lead to improved logistic performance. These unexpected results cannot be attributed to any particular parameter. The research confirms the great importance of up to now disregarded dimensions when evaluating SCM concepts and IT tools. The heuristic method provides a quick, but only approximate comparison of coordination efficiency for different organizational forms. In contrast, the more complex simulation method delivers detailed results taking into consideration specific parameter settings of network context and organizational design.

High efficiency mutagenesis, repair, and engineering of chromosomal DNA using single-stranded oligonucleotides

Homologous DNA recombination is a fundamental, regenerative process within living organisms. However, in most organisms, homologous recombination is a rare event, requiring a complex set of reactions and extensive homology. We demonstrate in this paper that Beta protein of phage λ generates recombinants in chromosomal DNA by using synthetic single-stranded DNAs (ssDNA) as short as 30 bases long. This ssDNA recombination can be used to mutagenize or repair the chromosome with efficiencies that generate up to 6% recombinants among treated cells. Mechanistically, it appears that Beta protein, a Rad52-like protein, binds and anneals the ssDNA donor to a complementary single-strand near the DNA replication fork to generate the recombinant. This type of homologous recombination with ssDNA provides new avenues for studying and modifying genomes ranging from bacterial pathogens to eukaryotes. Beta protein and ssDNA may prove generally applicable for repairing DNA in many organisms.

Stimulation of intrachromosomal homologous recombination in human cells by electroporation with site-specific endonucleases.

In somatic mammalian cells, homologous recombination is a rare event. To study the effects of chromosomal breaks on frequency of homologous recombination, site-specific endonucleases were introduced into human cells by electroporation. Cell lines with a partial duplication within the HPRT (hypoxanthine phosphoribosyltransferase) gene were created through gene targeting. Homologous intrachromosomal recombination between the repeated regions of the gene can reconstruct a functioning, wild-type gene. Treatment of these cells with the restriction endonuclease Xba I, which has a recognition site within the repeated region of HPRT homology, increased the frequency or homologous recombination bv more than 10-fold. Recombination frequency was similarly increased by treatment with the rare-cutting yeast endonuclease PI-Sce I when a cleavage site was placed within the repeated region of HPRT. In contrast, four restriction enzymes that cut at positions either outside of the repeated regions or between them produced no change in recombination frequency. The results suggest that homologous recombination between intrachromosomal repeats can be specifically initiated by a double-strand break occurring within regions of homology, consistent with the predictions of a model.

Mortality and perinatal infectious complications following home birth in Washington State: 2003-2013

Thesis (Master's)--University of Washington, 2016-06

Dapsone-induced agranulocytosis. The role of xenobiotic-metabolizing enzymes demonstrated by a case report [Dapson-induzierte agranulozytose. Die rolle fremdstoffmetabolisierender enzyme am beispiel einer kasuistik]

A 34-year-old female patient with a three year history of generalized granuloma annulare was treated systemically with dapsone (DADPS). Six weeks after the onset of treatment, the patient developed an extensive tonsillitis of the base of the tongue with fever and malaise. Routine laboratory work showed a leukocytopenia with agranulocytosis. Further investigation revealed a marked decrease of the enzyme activity of N-acetyltransferase 2, which plays an important role in dapsone metabolism. Treatment included the cessation of dapsone, antibiotic coverage, and G-CSF leading to the rapid improvement of symptoms and normalization of leukocyte counts. Dapsone-induced angina agranulocytotica is a rare event and is interpreted as an idiosyncratic reaction. Depending on genetic polymorphisms of various enzymes, dapsone can be metabolized to immunologically or toxicologically relevant intermediates. Because of the risk of severe hematologic reactions, dapsone should only be employed for solid indications and with appropriate monitoring.

Estimating buffer overflows in three stages using cross-entropy

In this paper we propose a fast adaptive Importance Sampling method for the efficient simulation of buffer overflow probabilities in queueing networks. The method comprises three stages. First we estimate the minimum Cross-Entropy tilting parameter for a small buffer level; next, we use this as a starting value for the estimation of the optimal tilting parameter for the actual (large) buffer level; finally, the tilting parameter just found is used to estimate the overflow probability of interest. We recognize three distinct properties of the method which together explain why the method works well; we conjecture that they hold for quite general queueing networks. Numerical results support this conjecture and demonstrate the high efficiency of the proposed algorithm.

The impact of supply chain performance measurement systems on dynamic behaviour in supply chains

The amplification of demand variation up a supply chain widely termed ‘the Bullwhip Effect’ is disruptive, costly and something that supply chain management generally seeks to minimise. Originally attributed to poor system design; deficiencies in policies, organisation structure and delays in material and information flow all lead to sub-optimal reorder point calculation. It has since been attributed to exogenous random factors such as: uncertainties in demand, supply and distribution lead time but these causes are not exclusive as academic and operational studies since have shown that orders and/or inventories can exhibit significant variability even if customer demand and lead time are deterministic. This increase in the range of possible causes of dynamic behaviour indicates that our understanding of the phenomenon is far from complete. One possible, yet previously unexplored, factor that may influence dynamic behaviour in supply chains is the application and operation of supply chain performance measures. Organisations monitoring and responding to their adopted key performance metrics will make operational changes and this action may influence the level of dynamics within the supply chain, possibly degrading the performance of the very system they were intended to measure. In order to explore this a plausible abstraction of the operational responses to the Supply Chain Council’s SCOR® (Supply Chain Operations Reference) model was incorporated into a classic Beer Game distribution representation, using the dynamic discrete event simulation software Simul8. During the simulation the five SCOR Supply Chain Performance Attributes: Reliability, Responsiveness, Flexibility, Cost and Utilisation were continuously monitored and compared to established targets. Operational adjustments to the; reorder point, transportation modes and production capacity (where appropriate) for three independent supply chain roles were made and the degree of dynamic behaviour in the Supply Chain measured, using the ratio of the standard deviation of upstream demand relative to the standard deviation of the downstream demand. Factors employed to build the detailed model include: variable retail demand, order transmission, transportation delays, production delays, capacity constraints demand multipliers and demand averaging periods. Five dimensions of supply chain performance were monitored independently in three autonomous supply chain roles and operational settings adjusted accordingly. Uniqueness of this research stems from the application of the five SCOR performance attributes with modelled operational responses in a dynamic discrete event simulation model. This project makes its primary contribution to knowledge by measuring the impact, on supply chain dynamics, of applying a representative performance measurement system.

Costing police custody operations

Presents a simulation study of the costing of police custody operations at a UK police force. The custody operation incorporates the arrest, booking-in, interview, detention and court appearance activities. The Activity Based Costing (ABC) approach is used as a framework to show how costs are generated by the three “drivers” of cost, activity and resource. These relate to the design efficiency of the process, the timing and mix of demand on the process and the cost of resources used to undertake the process respectively. The use of discrete-event simulation allows the incorporation of dynamic (time-dependent) and stochastic (variability) elements in the cost analysis. This enables both the amount and timing of the use of capacity and the generation of cost to be established. The concept of committed and flexible resources directs management decisions to the redeployment of unused capacity or alternatively the identification of additional capacity requirements.