DNA is a highly unstable molecule. Endogenous souces of DNA damage, such as reactive oxygen species (ROS), can cause DNA damage and it has been estimated that 20000 lesions occur in a cell per day. BER is the major pathway for the repair of these lesions and therefore maintains genome stability, thus preventing the development of human diseases such as neurodegenerative diseases and cancer. Therefore, if BER cannot accomplish the repair, accumulation of DNA damage occurs, triggering different cellular responses, such as cell cycle delay and senescence. The ARF tumour suppressor protein, the gene of which is frequently mutated in many human cancers, plays an important role in the cellular stress response by orchestrating upregulation of p53 protein. Moreover, ARF expression is upregulated in senescent cells, suggesting that ARF induction might be triggerred in response to persistent DNA damage. Although ARF has been reported to be important in the regulation of proteins involved in the DNA damage response, its role is still controversial. Here, it has been shown that ARF gene transcription is induced by DNA strand breaks (SBs) and that ARF protein accumulates in response to persistent DNA damage generated by disabling BER. These data suggest that PARP1-dependent poly(ADP-ribose) synthesis at the sites of SBs initiates DNA damage signal transduction by reducing the cellular concentration of NAD⁺, thus inhibiting SIRT1 activity and consequently activating E2F1-dependent ARF transcription. These findings suggest a vital role for ARF in DNA damage signalling, and furthermore explain the critical requirement for ARF inactivation in cancer cells, which are frequently deficient in DNA repair and accumulate DNA damage.

No description available.

This thesis explores methods by which carbon fibre reinforced polymers may be fficiently designed with the inclusion of damage tolerance criteria. An efficient method of modelling the compression after impact (CAI) strength of composite materials is selected, and this forms the basis of analysis performed. The CAI model is initially used as the objective in an optimisation routine using a simple genetic algorithm. This indicates features of a damage tolerant composite laminate, namely that plies near the surface are less axially sti® in the loading direction than those nearer the laminate midplane, with a lower Poisson's ratio than the full laminate. This delays sublaminate buckling under laminate uniaxial compression, thus restricting delamination propagation. The designs produced by the optimisation are verified experimentally. In order to improve the computational efficiency of the CAI model a simple surrogate modelling technique for sublaminate buckling is presented. This allows a complete database of results to be produced for a given set of ply angles, in this case standard 0/90/§45± plies. This is used in the full analysis of a collection of layups produced elsewhere to be fully uncoupled, but without the stipulation of midplane symmetry. The surrogate method is shown to reduce computation time by over 99%, and produce results with an average error of less than 0.1% compared to exhaustive analysis. The analysis of the damage tolerance of fully uncoupled laminates shows that the relaxation of midplane symmetry as a design rule gives the designer far more flexibility in layup, and may allow for more damage tolerant laminates to be selected. Finally, the CAI model is incorporated into a stiffened panel design optimisation problem as a constraint. Firstly the panel is optimised using the in¯nite strip analysis tool VICONOPT, with three stiffener geometries. The objective function is minimum mass for a panel subject to compressive and out-of-plane loading, with buckling and strain allowable constraints applied. Damage tolerance constraints are then applied in place of a strain allowable, using a bi-level optimisation approach. This method is shown to allow efficient inclusion of damage tolerance as a constraint in stiffened panel design, although it does not account for interactions in global buckling and local sublaminate buckling which may reduce the strength of the panel. Results indicate that the inclusion of damage tolerance analysis in stiffened panel design shows little benefit for low load panels, but can give significant reductions in mass (up to 30%) for higher load panels.

A search for heavy Majorana neutrinos is performed using an event signature defined by two same-sign muons accompanied by two jets. This search is an extension of previous searches, (L3, DELPHI, CMS, ATLAS), using 19.7 fb-1 of data from the 2012 Large Hadron Collider experimental run collected by the Compact Muon Solenoid experiment. A mass window of 40-500 GeV/c2 is explored. No excess events above Standard Model backgrounds is observed, and limits are set on the mixing element squared, |VμN|2, as a function of Majorana neutrino mass. The Hadronic Forward (HF) Detector's performance will degrade as a function of the number of particles delivered to the detector over time, a quantity referred to as integrated luminosity and measured in inverse femtobarns (fb-1). In order to better plan detector upgrades, the CMS Forward Calorimetry Task Force (FCAL) group and the CMS Hadronic Calorimeter (HCAL) group have requested that radiation damage be simulated and the subsequent performance of the HF subdetector be studied. The simulation was implemented into both the CMS FastSim and CMS FullSim simulation packages. Standard calorimetry performance metrics were computed and are reported. The HF detector can expect to perform well through the planned delivery of 3000 fb-1.

DNA repair mechanisms constitute an essential cellular response to DNA damage arising either from metabolic processes or from environmental sources such as ultraviolet radiation. Repair of these lesions may be via direct reversal, or by processes such as nucleotide excision repair (NER), a coordinated pathway in which lesions and the surrounding nucleotides are excised and replaced via DNA resynthesis. The importance of repair is illustrated by human disease states such as xeroderma pigmentosum and Cockayne's syndrome which result from defects in the NER system arising from mutations in XP- genes or XP- and CS- genes respectively Little detail is known of DNA damage repair processes in plants, despite the economic and ecological importance of these organisms. This study aimed to expand our knowledge of the process of NER in plants, largely via a polymerase chain reaction (PCR)-based approach involving amplification, cloning and characterisation of plant genomic DNA and cDNA. Homologues of the NER components XPF/RAD1 and XPD/RAD3 were isolated as both genomic and complete cDNA sequences from the model dicotyledonous plant Arabidopsis thaliana. The sequence of the 3'-untranslated region of atXPD was also determined. Comparison of genomic and cDNA sequences allowed a detailed analysis of gene structures, including details of intron/exon processing. Variable transcript processing to produce three distinct transcripts was found in the case of atXPF. In an attempt to validate the proposed homologous function of these cDNAs, assays to test complementation of resistance to ultraviolet radiation in the relevant yeast mutants were performed. Despite extensive amino acid sequence conservation, neither plant cDNA was able to restore UV-resistance. As the yeast RAD3 gene product is also involved in vivo in transcription, and so is required for viability, the atXPD cDNA was tested in a complementation assay for this function in an appropriate yeast mutant. The plant cDNA was found to substantially increase the viability of the yeast mutant. The structural and functional significance of these results is discussed comparatively with reference to yeast, human and other known homologues. Other putative NER homologues were identified in A. thaliana database sequences, including those of ERCC1/RAD10 and XPG/ERCC5/RAD2, and are now the subjects of ongoing investigations. This study also describes preliminary investigations of putative REVS and RAD30 translesion synthesis genes from A. thaliana.

Graduation date: 2003

Les expériences conduites auprès du futur accélérateur LHC au CERN nécessitent la construction des détecteurs les plus grands et les plus complexes jamais conçus. En particulier, le trajectographe de la collaboration CMS utilisera uniquement des détecteurs micropiste silicium et ce, en très grandes quantités. Ce dernier dépend donc de manière capitale de la qualité de toute la production des senseurs et la collaboration CMS a ainsi décidé de mettre en place un vaste programme de contrôle de cette qualité. Cette thèse présente une partie des travaux réalisés à l'UCL dans ce cadre. La discussion porte en particulier sur résistance aux radiations des senseurs en silicium, testée de manière routinière à Louvain-la-Neuve. Le texte débute par une présentation du détecteur CMS et des dégâts radiatifs subits par les détecteurs micropiste silicium. Les dispositifs expérimentaux mis en place auprès des cyclotrons et dans le laboratoire de l'institut de Physique nucléaire sont ensuite détaillés. Finalement, les résultats des tests systématiques sont résumés, et discutés au regard des critères posés par la collaboration

This research investigates the performance of an existing structural damage detection method (SDIM) when only experimentally-obtained measurement information can be used to calculate the frequency response functions used to detect damage. The development of a SDIM that can accurately identify damage while processing measurements containing realistic noise levels and overcoming experimental modeling errors would provide a robust method for identifying damage in the larger, more complex structures found in practice. The existing SDIM program, GaDamDet, uses an advanced genetic algorithm, along with a two-dimensional finite element model of the structure, to identify the location and the severity of damage using the linear vibration information contained in frequency response functions (FRF) as response signatures. Datagen is a Matlab program that simulates the three-dimensional dynamic response of the four-story, two-bay by two-bay UBC test structure built at the University of British Columbia. The dynamic response of the structure can be obtained for a range of preset damage cases or for any user-defined damage case. Datagen can be used to provide the FRF measurement information for the three-dimensional test structure. Therefore, using the FRF measurements obtained from the UBC test structure allows for a more realistic evaluation of the performance of the SDIM provided by GaDamDet as the impact on performance of more realistic noise and model errors can be investigated. Previous studies evaluated the performance of the SDIM using only simulated FRF measurements obtained from a two-dimensional structural model. In addition, the disparity between the two-dimensional model used by the SDIM used to identify damage and the measurements obtained from the three-dimensional test structure is analyzed. The research results indicate that the SDIM is able to accurately detect structural damage to individually damaged members or to within a damaged floor, with few false damages identified. The SDIM provides an easy to use, visual, and accurate algorithm and its performance compares favorably to performance of the various damage detection algorithms that have been proposed by researchers to detect damage in the three-dimensional structural benchmark problem.

Patent laws state that upon infringement, patentees are entitled to "damages adequate to compensate for the infringement but in no event less than a reasonable royalty." The key issue that plagues patent laws is that the current damage statute is too vague and provides little guidance to the United States court system in the determination of proper patent damages. A growing concern is that patent infringement awards are drifting away from its compensatory nature, and that damage awards are often excessive or inconsistently applied. Reformation is necessary to incorporate provisions in patent law that will establish a cohesive framework in the accounting for infringement damages.

Les estimacions de danys ambientals en cadenes de processos necessiten l'avaluació d'impactes ambientals en dues perspectives: orientades cap a cadenes de processos i orientades localment. Per a ambdues perspectives s'han desenvolupat eines específiques d'avaluació: l'Avaluació del Cicle de Vida (ACV o LCA) i l'Avaluació del Risc Ambiental (ERA). L'ACV és una eina, bastant nova, orientada cap a cadenes de processos, per avaluar el perfil ambiental dels productes, enfocada cap al cicle de vida complet d'aquests. A la fase de l'Avaluació de l'Impacte del Cicle de Vida (LCIA) s'avaluen els resultats del Inventari del Cicle de Vida (LCI) d'un sistema de producte, per entendre millor el seu significat ambiental. L'ERA és una eina per avaluar el risc de substàncies químiques específiques. A l'anàlisi d'exposició, s'avalua el risc d'un procés en un lloc concret. L'Anàlisi de Vies d'Impacte (IPA) és un mètode semblant que s'ha desenvolupat per a l'avaluació dels danys ambientals en termes de paràmetres d'impactes físics, com per exemple els casos de càncer. A l'IPA normalment aquests paràmetres es converteixen en costs externs. No obstant això, els individus podrien preferir altres esquemes de valoració.Els productes es fabriquen en una cadena ramificada de processos. Existeixen mètodes específics per a l'avaluació ambiental de productes que no s'haurien d'emprar directement per a l'avaluació d'un número de processos industrials amb una unitat funcional comuna, ja que el nivell de sofisticació en l'avaluació pot ser més elevat per a cadenes de processos industrials amb un número limitat de processos inclosos que per a productes complexos. S'han realitzat pocs esforços, per explorar sistemàticament les incerteses inherents, interfases i tipus de possibilitats d'integració i comunicació dels mètodes d'avaluació ambientals citats, orientats per un costat a cadenes de processos i per l'altre els orientats localment, en el cas de cadenes de processos industrials. Per això l'objectiu d'aquesta tesi, és trobar un compromís adequat entre els mètodes d'avaluació d'impacte ambiental, orientats a cadenes de processos i els orientats localment i, convertir les estimacions de danys ambientals en resultats significatius, com els costs ambientals.La tesi ofereix un algoritme matemàtic i un esquema que permet la diferenciació espaial a diferents nivells de detall i proposa una integració de l'ACV, l'IPA i els costs ambientals. La metodologia establerta "Estimacions de Danys Ambientals per a Cadenes de Processos Industrials" posa els punts mitjos i els punts finals en un marc comú. S'aplica i se segueix desenvolupant un mètode per a l'avaluació d'impactes depenents del lloc com una manera per aconseguir un compromís entre les avaluacions del dany específic de lloc i els indicadors potencials del cicle de vida. El mètode utilitza classes genèriques d'impacte que corresponen a diverses distribucions de receptors i condicions de dispersió basades en un raonament estadístic. Una part del desenvolupament de la metodologia consisteix en l'anàlisi de les incerteses en el LCI i l'IPA per la simulació de Monte Carlo. Aquesta aplicació paral.lela permet mostrar que les incerteses de l'inventari són menys importants que les dels danys.Els mètodes presentats i la metodologia desenvolupada s'han aplicat amb èxit per diferents camins al cas pràctic d'incineració de residus i, especialment, al seu impacte sobre la salut humana. La comparació dels resultats derivats, mitjançant indicadors d'impacte de punt final, amb els obtinguts per a l'indicador de punt mitjà, indica que per la situació del cas pràctic l'indicador de punt mitjà desestima l'impacte ambiental dels processos de transport. S'ha establert la base per a la creació d'una nova generació de models de gestió integrada de residus que inclou l'optimització de la ubicació de plantes de tractament de residus i de la difusió de les rutes de transports corresponents. / Las estimaciones de daños ambientales en cadenas de procesos necesitan la evaluación de impactos ambientales en dos perspectivas: orientadas hacia cadenas de procesos y orientadas localmente. Para las dos perspectivas se han desarrollado herramientas específicas de evaluación: el Análisis del Ciclo de Vida (ACV o LCA) y la Evaluación del Riesgo Ambiental (ERA). El ACV es una herramienta, bastante nueva, orientada hacia cadenas de procesos, para evaluar el perfil ambiental de los productos, enfocada hacia el ciclo de vida completo de éstos. En la fase de la Evaluación del Impacto del Ciclo de Vida (LCIA) se evalúan los resultados del Inventario del Ciclo de Vida (LCI) de un sistema de producto, para entender mejor su significado ambiental. La ERA es una herramienta para evaluar el riesgo de substancias químicas específicas. En el análisis de exposición, se evalúa el riesgo de un proceso en un lugar concreto. El Análisis de Vías de Impacto (IPA) es un método similar que se ha desarrollado para la evaluación de los daños ambientales en forma de parámetros de impactos físicos, como casos de cáncer. En el IPA normalmente estos parámetros están convertidos en costes externos. Los productos se fabrican en una cadena ramificada de procesos. Existen métodos específicos para la evaluación ambiental de productos que no se deberían aplicar directamente para la evaluación de un número de procesos industriales con una unidad funcional comuna, ya que el nivel de sofisticación en la evaluación puede ser más elevado para cadenas de procesos industriales con un número limitado de procesos incluidos que para productos complejos. Se han realizado pocos esfuerzos, para explorar sistemáticamente las incertidumbres inherentes y los tipos de posibilidades de integración y comunicación de los métodos de evaluación ambiental citados, orientados de un lado a cadenas de procesos y del otro lado orientados localmente, en el caso de cadenas de procesos industriales. Por eso el objetivo de esta tesis, es: encontrar un compromiso adecuado entre los métodos de evaluación de impacto ambiental, orientados a cadenas de procesos y los orientados localmente y, convertir las estimaciones de daños ambientales en resultados significativos, como los costes ambientales.La tesis ofrece un algoritmo matemático y un esquema que permite la diferenciación espacial a diferentes niveles de detalle y propone una integración del ACV, IPA y costes ambientales. La metodología establecida "Estimaciones de Daños Ambientales para Cadenas de Procesos Industriales" pone los puntos medios y los puntos finales en un marco común. Se continúa el desarrollo de un método para la evaluación de impactos dependientes del lugar como una manera para conseguir un compromiso entre les evaluaciones del daño específico de lugar y los indicadores potenciales del ciclo de vida. El método utiliza clases genéricas de impacto que corresponden a diversas distribuciones de receptores y condiciones de dispersión basadas en un razonamiento estadístico. Como parte del desarrollo de metodología, se analizan las incertidumbres en el LCI y IPA mediante la simulación de Monte Carlo.Los métodos presentados y la metodología desarrollada se han aplicado con éxito por diferentes caminos al caso práctico de incineración de residuos y especialmente a su impacto sobre la salud humana. La comparación de los resultados derivados mediante indicadores de impacto de punto final con los obtenidos para el indicador de punto medio, indica que para la situación del caso práctico el indicador de punto medio desestima el impacto ambiental de los procesos de transporte. Se ha establecido la base para la creación de una nueva generación de modelos de gestión integrada de residuos que incluye la optimización de la ubicación de plantas de tratamiento y de las rutas de transportes correspondientes. / Environmental damage estimations in industrial process chains need the assessment of environmental impacts in two perspectives: process chain-orientated and site-orientated. For both perspectives environmental assessment tools exist: Life Cycle Assessment (LCA) and Environmental Risk Assessment (ERA). LCA is a fairly new chain-orientated tool to evaluate the environmental performance of products focussing on its entire life cycle. In the Life Cycle Impact Assessment (LCIA) phase a product system's Life Cycle Inventory (LCI) results are evaluated to better understand their environmental relevance. ERA is a tool to assess the risk of chemicals. In the exposure analysis the risk of a process at one location is evaluated. The Impact Pathway Analysis (IPA) is a method related to ERA that has been developed for the assessment of environmental damages by the terms of physical impact parameters like cancer cases. Usually in the IPA the physical impact parameters are converted into external environmental costs, but depending on personal values individuals may prefer other existing weighting schemes to express different types of environmental damages.Products are manufactured in a ramified chain of processes. While specific tools exist for the environmental assessment of products and processes, this is not the case for the assessment of a number of industrial processes with a common functional unit such as end-of-life cycles. However, the level of sophistication in the assessment can be much higher for industrial process chains with a quite limited number of processes involved than for the life cycles of complex products. Only little efforts have been made so far to systematically explore the inherent uncertainties, interfaces and possibilities for integration and communication of the chain-orientated and site-orientated environmental assessment methods in the case of such industrial process chains. Therefore, the objective of this thesis is to find an adequate trade-off between process chain-orientated and site-orientated environmental impact assessment and to convert environmental damage estimates in meaningful results like environmental costs.The thesis proposes a mathematical framework and a flowchart that allows spatial differentiation at different levels of detail based on the integration of LCA, ERA and IPA with environmental costs. This methodology called "Environmental Damage Estimations in Industrial Process Chains" puts the conventional potential midpoint LCIA indicators in a common framework with damage endpoint IPA indicators. As a trade-off between site-specific damage assessments and potential life cycle indicators a currently existing site-dependent impact assessment is further developed and integrated in the methodology proposed. The site-dependent impact assessment method is based on statistical reasoning and uses representative generic impact classes corresponding to receptor distribution and dispersion conditions. As part of the methodology development, uncertainties in the LCI and IPA are analysed using Monte Carlo Simulation. This parallel analysis permits to show that the uncertainties in the inventory analysis are less important than those in the damage assessment.The presented methods and the developed methodology were successfully applied in several ways to a case study on waste incineration with a special focus on human health. In a comparison of the results obtained by endpoint indicators with midpoint indicators it was found that for the situation of the case study apparently the midpoint indicators underestimate the environmental impact of the transport processes. A new generation of integrated waste management tools seems to be feasible that takes into account the setting of the waste treatment installations and the sites affected by the transport routes, allowing in this way an overall environmental optimisation