Part I: Target identification studies are one of the most difficult but rewarding challenges in chemical biology. Part I of this thesis describes target identification studies for 5-nitrofuran containing hits. The 5-nitrofurans used in this study were identified in a phenotypic screen for compounds that induced melanocyte cells death in zebrafish. Chapter 1 provides brief overviews on three related areas of the project: 1) the use of zebrafish as a model organism in drug discovery; 2) phenotypic screening using zebrafish and 3) the strategies used in target identification studies. Chapter 2 describes the synthesis of and SAR studies on two series of 5-nitrofuran containing analogues. The design and preparation of biotinylated chemical probes based on the SAR data is also described. These chemical tools are then used in affinity chromatography studies and genetic validation of a potential target (zebrafish Aldh2) of the 5-nitrofuran compounds is reported. Chapter 3 provides a review of the biological and chemical processes that human ALDHs are known to mediate. In addition, small molecules that modulate ALDH2 activity are reviewed. A detailed study of the interaction between 5-nitrofurans and human ALDH2 including in vitro enzymatic assays is described leading to the conclusion that the 5- nitrofurans under study are substrates of human ALDH2. Further mechanism of action investigations using model reactions are also presented. Chapter 4 introduces the use of 5-nitrofuran containing drugs in the clinic and highlights the reported side-effects. Further investigation of the interaction between ALDH2 and 5- nitrofurans in zebrafish and yeast using ALDH2 inhibitors is described. Based on these results, a combination therapy strategy is proposed. Finally, the trypanocidal activity of the newly synthesised 5-nitrofurans is discussed. Experimental details and future work for Part I are presented in Chapters 5 and 6 respectively. Part II: Human sirtuins are associated with various biological functions and diseases, including cancer and neurodegeneration. Previous work from the Westwood Lab has led to the discovery of the tenovins that act as inhibitors of SIRT1 and SIRT2. Part II of the thesis reports the development of potent fixed ring tenovin analogues with high SIRT2 selectivity. Chapter 7 provides a brief review of the biology of human SIRT2 and the reported SIRT2 inhibitors available to date. This is followed by a short summary of the previous work on the tenovins in the Westwood Lab and the design of the fixed ring tenovin analogues. Chapter 8 describes the synthesis of three series of fixed ring tenovin analogues. SAR data is generated based on in vitro enzymatic assays against both SIRT1 and SIRT2 and the prepared analogues showed relatively high potency and selectivity against SIRT2. Further cell-based deacetylation assay are also discussed. All the experimental details are reported in Chapter 9 and Chapter 10 provides with conclusions and proposed future work.

No description available.

Ce travail est une contribution à l'analyse du comportement à l'endommagement des matériaux ductiles. L'endommagement ductile désigne le processus de dégradation progressive des propriétés physiques et mécaniques d'un matériau lorsqu'il subit, sous l'effet d'un chargement et avant rupture, une déformation plastique importante à température ambiante ou peu élevée. L'objectif de ce travail est de déterminer un critère de propagation de fissures pour simuler la déchirure des matériaux ductiles en se basant sur les modèles d'endommagements locaux. Nous avons mené une campagne expérimentale sur 3 matériaux structurellement très différents: un acier 12NC6, un aluminium 2024T351 et un polymère PA66. Le modèle de croissance des cavités Rice-Tracey s'est révélé très limité à décrire la rupture des matériaux testés, nous avons alors proposé une modification de ce modèle en l'enrichissant de paramètres micromécaniques permettant de prendre en compte l'effet de la croissance et des interactions entre les cavités. Le modèle proposé a été implanté dans un code de calcul par éléments finis pour simuler l'amorçage d'une fissure et sa propagation au cours du chargement. Nous avons validé ce modèle analytique à l'aide des résultats expérimentaux des trois matériaux. Les résultats numériques obtenus en termes de courbes R et «charge-déplacement» comparés aux résultats expérimentaux ont permis de valider le modèle sur les trois matériaux étudiés. / The purpose of this thesis is to contribute to the study of ductile fracture of materials on micromechanical models based on local approach. Ductile fracture of metals occurs mainly by nucleation, growth and coalescence of voids. Concerning the local approach of ductile fracture, the emphasis is laid on the micromechanical model of Rice-Tracey. The latter based on growth cavities is verified in order to describe the ductile tearing in stainless steel NiCr(12NC6), 2024T351 aluminium alloy and polymer PA66. The experimental study is carried out on compact tension ct , central crack panel ccp, single edge notched tension sent and tensile axisymetric notched specimens to characterize ductile failure in different materials. The comparison of the experimental results with the classical Rice-Tracey model shows that it cannot make a good prediction using "j -da" curve. On the basis of fitting procedure and numerical simulation a correction of coefficients is introduced to improve the Rice-Tracey model. A methodology of identification of parameters is presented. Ductile crack growth, defined by the" j -da" curve, has been correctly simulated using the numerical calculations by adjusting the three parameters of " modified Rice-Tracey model in the calibration procedure. The proposed model is implemented into a finite element code. Close agreement between the computed results aj'ld experimentally measured values justifies the usefulness of the present modified model.

1. Summary Identification of corpses and skeletal findings The topic of my graduation thesis is the identification of corpses and skeletal findings. In this work I have described methods which are currently being used for an individual identification of people, and I have also paid a special attention to methods that are regarded as predecessors of modern currently-used methods. In each chapter of my thesis, I described different kinds of methods and I have also attached some short cases, just to illustrate the real work of police forensic experts after location of the corpse or the skeleton. In the initial part of my work I have also attached the Glossary of Terms that explains some complicated technical terms. Although some of the methods which I have described in my work are used in many other branches, I have focused on the use of these methods in the forensic practice (criminal investigation) with the possible collaboration of experts in the identification work in mass accidents and disasters. Nowadays, one of the fastest growing and most accurate methods of the identification with the widest spectrum of applications is the DNA analysis method, so I decided to devote a substantial part of my work to this method. I have described her historical development, her practical use and how this method really...

Este trabalho investigou as identificações que os adolescentes estabelecem com as imagens que consomem cotidianamente, sejam elas originadas dos meios de comunicação em massa ou dos livros didáticos. Considerou-se a hipótese de que essas identificações muitas vezes não se dão de forma consciente, devido à profusão e à padronização das imagens da cultura visual contemporânea e à especifidade dos textos imagéticos. Além disso, a linguagem visual é presentacional, isto é, revela-se ao leitor dentro de um campo onde não existe um início ou um fim, apresentando-se integral e instantaneamente ao espectador e diferenciando-se, desta forma, dos textos verbais. Para tanto, foram utilizados dois tipos de pesquisa complementares: pesquisa bibliográfica e pesquisa de campo. Em relação à pesquisa bibliográfica, foram consultados autores que discutiram como as particularidades da modernidade e da contemporaneidade implicaram na aquisição de identidades e identificações pelos sujeitos, na produção e veiculação de imagens em geral e, ainda, nas concepções sobre a adolescência. Paralelamente, por meio de uma pesquisa participativa com 71 estudantes do 1º ano do Ensino Médio de uma escola técnica estadual da zona norte de São Paulo, cujas idades variavam entre 14 e 16 anos, investigou-se como os adolescentes estabeleceram identificações com as imagens de sua cultura visual e como um trabalho contínuo de leitura de imagens num ambiente escolar pode levar os estudantes a desenvolver autonomia no consumo dos textos imagéticos e no reconhecimento de suas identificações com os mesmos. O tipo de pesquisa de campo utilizado foi a pesquisa-ação participativa, onde os participantes, pesquisadora e pesquisados, eram respectivamente, professora e seus alunos. Os instrumentos usados para a coleta de dados foram questionários, entrevistas, análise das imagens coletadas pelos estudantes, leituras de imagens em grupo, discussões sobre essas imagens e análise dos discursos dos adolescentes. Também foram entrevistados os professores das cinco disciplinas cujos livros didáticos tiveram imagens selecionadas pelos estudantes. Os resultados obtidos indicam que o trabalho específico com leitura de imagens pode propiciar maior compreensão e aprofundamento dos significados atribuídos às imagens selecionadas pelos adolescentes, provocando reflexões sobre os múltiplos processos de identificação que se estabelecem, bem como os diversos conceitos representados por essas imagens. / This study investigated the identifications that adolescents establish with the images they consume daily, whether it originates from the mass media or textbooks. It was considered the hypothesis that these identifications often are not conscious, because of the profusion of images and standardization of contemporary visual culture and specificity of imagistic texts: visual language is presentational, i.e., it is revealed to the reader in an area where there is no beginning or end, presenting full and instantly to the viewer and differing, this way, from verbal texts. For this, we used two complementary kinds of research: literature and field research. About the literature, we consulted authors who discussed how the particularities of modernity and contemporary involved in the acquisition of identities and identifications by subjects, in the production and placement of images in general and also in the conceptions of adolescence. At the same time, through a participatory research with 71 students from the 1st year of high school at a state technical school in the northern zone of São Paulo, whose ages ranged between 14 and 16 years old, it was investigated how teenagers established identifications with images of their visual culture, and as a continuous work to read images in a school environment can make students to develop autonomy in the consumption of imagistic texts and recognition of their identifications with these texts. The kind of field research used was a participatory action research where participants, researcher and researched, were respectively a teacher and her students. The instruments used for data collection were questionnaires, interviews, analysis of images selected by students, in group readings of images, discussions of these images and analysis of teenagers talking. Teachers of the five disciplines whose textbooks had images selected for students were also interviewed. The results indicate that the specific work of reading images enables a greater understanding and deepening about the meanings of images selected for teenagers, causing reflections on the established process of identification and on the concepts that the images represent.

Introduction: The purpose of a player development pathway is to realise the most effective methods to support young individuals to maximise their potential (MacNamara & Collins, 2015). Within a modern football academy setting, the essential developmental characteristics are often termed environmental, psychological, sociological, physiological, technical, and tactical attributes (Sarmento et al., 2018). Although these factors have been explained to independently facilitate the acquisition of expert performance, fully-integrated multidisciplinary evidence from an English context is unknown. Therefore, the aim of this study was two-fold; firstly, to analyse these respective features to determine what outcomes support greater age-specific performance within the Foundation Development Phase (FDP; under-9 to 11s) and Youth Development Phase (YDP; under-12 to 16s) at an English professional football academy. Following this investigation, this thesis examined what characteristics facilitated age-specific development across two football seasons within the same group. Methods: During the first season, a total of 98 outfield academy players (FDP n=40; YDP n=58) participated. Two professional coaches from each age group (n=14) ranked their players from top to bottom in relation to current ability from a holistic perspective. This created a linear classification with a group of ‘high-performers’ (top third) and ‘low-performers’ (bottom third) within both the FDP and YDP. Results were standardised using z-scores and the assumptions were tested using a two-tailed independent samples t-test. A total of 87 outfield players who progressed into the second season were further analysed within their respective phase (FDP n=36; YDP n=51). A combination of 34 holistic factors, that discriminated high- and low-performers in the initial investigation, were measured at two time points across two football seasons with the Participation History Questionnaire (PHQ), Psychological Characteristics for Developing Excellence Questionnaire (PCDEQ), socio-economic status, growth and maturation data, physical performance, technical tests, match analysis statistics, perceptual-cognitive expertise (PCE), and game test situations. Development was measured by comparing the delta change between the overall player profile scores from two seasonal reports. Stepwise regression analyses were conducted to assess the predictive capability of these variables on overall development. Results: Multiple factors from environmental, psychological, sociological, physiological, technical, and tactical examinations significantly discriminated high- and low-performers, within both the FDP and YDP. Following these initial findings, developmental results illustrated significant technical and tactical characteristics within the FDP, whilst significant environmental, physiological, technical, and tactical attributes were observed within the YDP. When focussing on these factors combined, total touches change (p=0.023), taking advantage of openings quality (p=0.003), and PCE ‘post’ score change (p=0.029) explained a combined 11.5% of the variance within the FDP. Within the YDP, PCE ‘at’ score (p=0.21), total sports played change (p=0.008), and total match-play hours (p=0.009) explained a combined 34.1% of the variance. Discussion: Identifying talented players as young as 8 years of age is a complex and holistic process. Thus, academy coaches and practitioners must understand the significant features, such as practice history and multi-sport engagement, psychological characteristics, socio-economic factors, physical performance abilities, technical attributes, and tactical decision making when identifying and recruiting individuals. From a talent development viewpoint, results from the FDP support the importance of technical and tactical development during middle childhood compared to other influential factors. From a YDP perspective, results support the significance of the environment players are exposed to, whilst also illustrating the importance of PCE as a key ingredient within adolescence, to support greater overall development. Therefore, professional football academies are encouraged to deliver technical and tactical specific developmental activities within the FDP, whilst offering a substantial games programme, alongside other opportunities to participate in multi-sport activities across both age phases, to support superior development. Further evidence is needed within an English context, through collaboration with other academy environments, to support these findings, whilst greater longitudinal data is also required to understand which of these characteristics are necessary to ultimately achieve senior professional status.

The accurate identification of children from facial photographs could provide a great attribute in the fight against child sexual exploitation, and may also aid in the detection of missing juveniles where comparative material is available. The European Commission is actively pursuing a global alliance for the identification of the victims of child sexual abuse; a task which is considered to be of the utmost importance. Images of child sexual abuse are shared, copied, and distributed online and their origin can be difficult to trace. Current investigations attempting to identify the children within such images appear to focus on the determination of places or geographical regions depicted in these images, from which victims can subsequently be tracked down and identified. Cutting edge technology is also used to detect duplicate images in order to decrease the workload of human operators and dedicate more time to the identification of new victims. Present investigations do not appear to focus on facial information for victim identification. Methods of facial identification already exist for adult individuals, consisting of both automated facial recognition algorithms and manual facial comparison techniques carried out by human operators. Human operator image comparison is presently the only method considered accurate enough to verify a face identity. It is only recently that researchers involved in automated facial recognition have begun to concern themselves with identification spanning childhood. Methods focus on age simulation to match query images with the age of the target database, rather than discrimination of individual faces over age progression. As far as can be determined, this is the first attempt to assess the manual comparison of juvenile faces. This study aimed to create a database of children’s faces from which identification accuracy could be tested using both automated facial recognition and manual facial comparison methods, which already exist for the identification of adults. A state-of-the-art facial recognition algorithm was employed and manual facial comparison was based on current recommendations by the Facial Identification Scientific Working Group (FISWG). It was not known if methods based on adult faces could be successfully extrapolated to juvenile faces, particularly as facial identification is highly susceptible to errors when there is an age difference between images of an individual. In children, the face changes much more rapidly than adults over ageing, due to the rapid growth and development of the juvenile face. The results of this study are in agreement with comparisons of automated and human performance in the identification of adult faces. Overall the automated facial recognition algorithm superseded human ability for identification of juvenile faces, however human performance was higher for the most difficult face pairs. The average accuracy for human image comparison was 61%. There was no significant difference in juvenile identification between individuals with prior experience of adult facial comparison and those with no prior experience. For automated facial recognition a correct identification rate of 71% was achieved at a false acceptance rate of 9%. Despite using methods created for adult facial identification, the results of this study are promising, particularly as they are based on a set of images acquired under uncontrolled conditions, which is known to increase error rates. With further augmentation of the database and investigation into child-specific identification techniques, the ability to accurately identify children from facial images is certainly a future possibility.

Este trabalho investigou as identificações que os adolescentes estabelecem com as imagens que consomem cotidianamente, sejam elas originadas dos meios de comunicação em massa ou dos livros didáticos. Considerou-se a hipótese de que essas identificações muitas vezes não se dão de forma consciente, devido à profusão e à padronização das imagens da cultura visual contemporânea e à especifidade dos textos imagéticos. Além disso, a linguagem visual é presentacional, isto é, revela-se ao leitor dentro de um campo onde não existe um início ou um fim, apresentando-se integral e instantaneamente ao espectador e diferenciando-se, desta forma, dos textos verbais. Para tanto, foram utilizados dois tipos de pesquisa complementares: pesquisa bibliográfica e pesquisa de campo. Em relação à pesquisa bibliográfica, foram consultados autores que discutiram como as particularidades da modernidade e da contemporaneidade implicaram na aquisição de identidades e identificações pelos sujeitos, na produção e veiculação de imagens em geral e, ainda, nas concepções sobre a adolescência. Paralelamente, por meio de uma pesquisa participativa com 71 estudantes do 1º ano do Ensino Médio de uma escola técnica estadual da zona norte de São Paulo, cujas idades variavam entre 14 e 16 anos, investigou-se como os adolescentes estabeleceram identificações com as imagens de sua cultura visual e como um trabalho contínuo de leitura de imagens num ambiente escolar pode levar os estudantes a desenvolver autonomia no consumo dos textos imagéticos e no reconhecimento de suas identificações com os mesmos. O tipo de pesquisa de campo utilizado foi a pesquisa-ação participativa, onde os participantes, pesquisadora e pesquisados, eram respectivamente, professora e seus alunos. Os instrumentos usados para a coleta de dados foram questionários, entrevistas, análise das imagens coletadas pelos estudantes, leituras de imagens em grupo, discussões sobre essas imagens e análise dos discursos dos adolescentes. Também foram entrevistados os professores das cinco disciplinas cujos livros didáticos tiveram imagens selecionadas pelos estudantes. Os resultados obtidos indicam que o trabalho específico com leitura de imagens pode propiciar maior compreensão e aprofundamento dos significados atribuídos às imagens selecionadas pelos adolescentes, provocando reflexões sobre os múltiplos processos de identificação que se estabelecem, bem como os diversos conceitos representados por essas imagens. / This study investigated the identifications that adolescents establish with the images they consume daily, whether it originates from the mass media or textbooks. It was considered the hypothesis that these identifications often are not conscious, because of the profusion of images and standardization of contemporary visual culture and specificity of imagistic texts: visual language is presentational, i.e., it is revealed to the reader in an area where there is no beginning or end, presenting full and instantly to the viewer and differing, this way, from verbal texts. For this, we used two complementary kinds of research: literature and field research. About the literature, we consulted authors who discussed how the particularities of modernity and contemporary involved in the acquisition of identities and identifications by subjects, in the production and placement of images in general and also in the conceptions of adolescence. At the same time, through a participatory research with 71 students from the 1st year of high school at a state technical school in the northern zone of São Paulo, whose ages ranged between 14 and 16 years old, it was investigated how teenagers established identifications with images of their visual culture, and as a continuous work to read images in a school environment can make students to develop autonomy in the consumption of imagistic texts and recognition of their identifications with these texts. The kind of field research used was a participatory action research where participants, researcher and researched, were respectively a teacher and her students. The instruments used for data collection were questionnaires, interviews, analysis of images selected by students, in group readings of images, discussions of these images and analysis of teenagers talking. Teachers of the five disciplines whose textbooks had images selected for students were also interviewed. The results indicate that the specific work of reading images enables a greater understanding and deepening about the meanings of images selected for teenagers, causing reflections on the established process of identification and on the concepts that the images represent.

Identification of material properties for elastic materials is important in mechanics, material sciences, mechanical engineering and biomedical engineering. Although the principle and techniques have been long established, the application in living biology still faces challenges. The biological materials are in general nonlinear, anisotropic, heterogeneous, and subject-specific. The difficulty is compounded sometimes by the requirement of non-destructiveness in medical applications. Recently, the pointwise identification method (PWIM) was proposed to address some of the needs of soft tissue characterization. PWIM is a non-invasive identification method, designed for thin materials; it can sharply characterize arbitrary heterogeneous property distributions. The primary goal of this thesis is to extend the pointwise identification method , originally developed for membranes which by default is of convex shape in pressurized states, to thin structures of arbitrary geometry. This work consists of four parts. The first part investigates the insensitivity of stress solution to material parameters in thin shell structures. This is an important first step, because PWIM hinges on the static determinacy property of the equilibrium problem of membranes. Before introducing the shell element into PWIM, it is necessary to test to what extent the assumption of static determinacy remains reasonable. It is shown that saccular structure which bending stress is small compared to in-plane stress, can still be treated as a statically determined structure. The second part focuses on developing finite element formulations of forward and inverse shell methods for a hyperelastic material model specifically proposed for cerebral aneuryms tissues. This is a preparatory step for the core development. The third part is the development of pointwise identification method for thin shell structures. Methods for stress solution, strain acquisition, and parameter regression will be discussed in detail. The entire process is demonstrated using an example of a geometrically realistic model of aneurysm. The fourth part is testing the applicability on geometrically realistic cerebral aneurysms. Six models were selected in the study; the emphasis is placed on cerebral aneurysm with concave or saddle surface region for which the use of shell theory is a must. The identification results of all six human cerebral aneurysms successfully demonstrate that the shell PWIM can be applied to realistic cerebral aneurysms. Four types of heterogeneous property distributions are considered in the study. It is found that the method can accurately back out the property distributions in all cases. Fiber directions can also be accurately estimated. The robustness of the method at the presentence of numerical noise is also investigated. It is shown that the shell PWIM still works when small perturbations exist in displacements.

Magister Artium (Psychology) - MA(Psych) / This dissertation reviews the construct of projective identification and the ways in which it is used as a powerful form of communication by the patient within the therapeutic relationship. The particular model of projective identification explored in this dissertation is that of Bion (1962)_ who, through his model of containment, brought the subtle interactive processes between the mother and infant into the foreground. This has been used as a metaphor for the therapeutic relationship. Some of the theoretical constructs central to an understanding of projective identification are introduced and discussed. Clinical case material from psychodynamic child psychotherapy is used in an attempt to illustrate the patient's use of and therapist's experience of projective identification. The method used is the single case study and material is drawn from 14 sessions. Through an analysis of the therapist's experiences in the countertransference, with the help of ongoing supervision and personal psychotherapy, it is shown that patient's induce feelings and experiences in the therapist in an attempt to communicate aspects of their internal worlds. Self reflection and retrospective analysis has been highlighted with the hope that this may be useful to future neophyte psychotherapists working psychodynamically.