La présente recherche se propose d’examiner les multiples intérêts de faire intégrer l’approche psychanalytique dans un cadre spécifique de prise en charge pour des sujets toxicomanes : la communauté thérapeutique (CT). A partir de mon expérience clinique au Liban avec des sujets addictés, rencontrés dans une CT, j’expose les écueils de cette modalité de soin basée uniquement sur l’approche comportementale. Je décris aussi la clinique de la toxicomanie comme “clinique du semblable”. Cette clinique repose sur des processus identificatoires qui prennent appui sur un trépied : le regard social vis-à-vis du phénomène toxicomaniaque, un certain discours scientifique concernant les addictions, mais surtout sur le fonctionnement psychique propre aux sujets toxicomanes. Le point nodal de ma réflexion se trouve dans le fait qu’à la rencontre d’un soignant qui n’a pas nécessairement été usager de drogue lui-même, la plupart des patients addictés arguent qu’il n’est pas semblable à eux, donc il ne comprendrait jamais leur souffrance. Cette situation peut être considérée comme une forme de résistance, mais elle me permet de concevoir la fonction de la drogue sous l’angle de la problématique identificatoire. Je me propose donc, en me basant sur la psychanalyse, à déconstruire un pseudo-savoir constitué autour d’un phénomène complexe, savoir qui tend à figer les toxicomanes dans des notions qui mènent à des pratiques controversées (notamment en CT). J’essaye ainsi de recentrer la question de l’usage de drogue sur le patient addicté lui-même, avec ses failles et ses fantasmes identificatoires qui l’incitent à s’agréger aux communautés de personnes ayant des comportements bien codifiés. / This research intend to examine the multiple interests to integrate the psychoanalytic approach in a specific context of care for drug addicts : the therapeutic community (TC). Based on my clinical experience in Lebanon with drug abusers that I have met in CT, I expose the pitfalls of this form of care founded exclusively on the behavioral approach. I also describe the drug addiction as “clinic of the similar”. This clinic is based on identification processes that rely upon a tripod : the social opinions regarding the drug dependency phenomenon, some scientific discourse about addiction, but especially on the dependent subjects own psychological functioning. The central hub of my proposition is located in the fact that when they meet a caregiver who has not necessarily been drug user himself, most addicted patients argue that he is not similar to them, so he would never understand their pain. This situation can be considered as a form of resistance, but it allows me to conceive the function of the drug in terms of identificatory issues. I use psychoanalytic theory to deconstruct a pseudo-knowledge built around the complex phenomenon of drug addiction. This knowledge tends to freeze addicts in concepts that lead to controversial practices (including CT). I try to refocus the question of the substance abuse on the addicted patient himself, with his identification problems and fantasies that incite him to join a community of people having behaviors well codified.

Memoria para optar al título de Químico Farmacéutico / El daño ocasionado por la ocurrencia de un infarto cardíaco es complejo, generando la muerte celular cardíaca entre otros efectos deletéreos tanto en el periodo isquémico de falta de oxígeno y nutrientes, así como también en la posterior reperfusión sanguínea. Frente a esta condición patológica los fibroblastos cardíacos son capaces de reaccionar, secretando y renovando la matriz extracelular; lo que los convierte en elementos celulares claves en la cicatrización y remodelado del tejido cardiaco dañado post-infarto al miocardio. Esto hace necesario el intentar preservar la viabilidad de estas células para una correcta cicatrización y mantención de la función cardíaca. En relación a esto se ha reportado el uso de factores de crecimiento como elementos cardioprotectores frente al daño ocasionado por I/R, entre los cuales destaca el factor de crecimiento análogo a insulina de tipo I (IGF-1); cuyas propiedades cardioprotectoras han sido reportadas frente a I/R. Sin embargo, estos efectos citoprotectores en corazón, otorgados por IGF-1 solo han sido estudiados en cardiomiocitos, por lo que sus efectos en fibroblastos cardíacos son aun desconocidos. Nuestro trabajo estudió la capacidad de IGF-1 de proteger a los fibroblastos cardíacos de ratas neonatas sometidos a un modelo in vitro de I/R e indagó en las vías de transducción implicadas con esta protección. El tratamiento con IGF-1 (10 ng/mL) previno la pérdida de viabilidad y apoptosis de fibroblastos cardiacos ocasionado por el daño por I/R. Más aun, esta protección se observó al incubar con IGF-1 durante el momento de reperfusión e I/R, pero no así en el período isquémico, lo que sugiere que la muerte de los fibroblastos cardiacos es causada principalmente por el daño por reperfusión. Akt fue rápidamente fosforilado por IGF-1 tanto en isquemia como en reperfusión, mientras que ERK 1/2 sólo se fosforiló en el momento de reperfusión. La utilización de los inhibidores LY29002 y PD98059, neutralizó la protección conferida por IGF-1. Por lo que nuestros resultados demuestran que el tratamiento con IGF-1 durante la reperfusión previene la muerte de los fibroblastos cardiacos sometidos a I/R mediante la activación de las vías PI3K/Akt y MEK-ERK 1/2 / Myocardial infarction causes complex injury, involving cell death among other detrimental effects in both ischemia and reperfusion periods. To face this pathological condition, cardiac fibroblasts are key cellular elements, capable of extracellular matrix secretion and renewal, allowing the healing and remodeling of damaged heart tissue post-myocardial infarction. It necessary then, to preserve the viability of these cells for a proper healing and maintenance of cardiac function. In regards to this, it has been demonstrated the use of several growth factors to protect cardiac cells from the effects of acute ischemia/reperfusión. Among these, insulin-like growth factor (IGF-1) has showed several cardioprotective properties in hearts exposed to ischemia/reperfusion. However these cytoprotective effects granted by IGF-1 have been studied only in cardiomyocytes, while their effects on cardiac fibroblasts remain unknown. In this study we have determined the ability of IGF-1 to protect cardiac fibroblasts against simulated in vitro I/R injury and investigated the potential mechanisms underlying this protection. Treatment with IGF-1 (10 ng/mL) promoted a increase in cell survival against I/R dependent cell death and a decrease in apoptosis induced by this injury. Furthermore, the IGF-1 induced protection was observed with treatment at the time of reperfusion but not with IGF-1 at the time of ischemia, suggesting that cardiac fibroblast death is induced by reperfusion injury. Akt was rapidly phosphorylated by IGF-1 at both ischemia and reperfusion, but ERK 1/2 was only phosphorylated by IGF-1 at the onset of reperfusion. IGF-1 induced protection was abolished when LY294002 and PD98059 were used, suggesting that the protection is mediated via a Akt and ERK 1/2 dependent pathways. Thus, the results suggest that IGF-1 treatment at reperfusion prevents cardiac fibroblast death induced by simulated in vitro I/R via the activation of PI3K/Akt and MEK-ERK 1/2 pathways

Tesis entregada a la Universidad de Chile para optar al grado de Doctor en Bioquímica / La autofagia es un proceso fisiológico clave para la sobrevida celular durante la privación de nutrientes (estrés nutricional), diferenciación celular y desarrollo. La autofagia se define como un proceso dinámico y programado que procede con el secuestro de proteínas citoplasmáticas y organelos dentro de vacuolas de doble membrana, que se contactan y fusionan con los lisosomas para formar los autolisosomas. Diferentes vías transduccionales regulan la autofagia, siendo la vía de la fosfatidilinositol 3-kinasa (PI3-K) una de las más importantes. La PI3-K clase III se requiere en los estadios tempranos de la generación del autofagosoma, mientras que la de clase I tiene un efecto inhibitorio dependiente de la proteína kinasa mTOR. En los últimos años, la autofagia también se ha definido como un proceso de muerte programada. El factor de crecimiento análogo a insulina tipo-1 (IGF-1), tiene diversas acciones sobre el corazón, destacando sus efectos prohipertrófico e inotrópico. Nuestro Laboratorio y otros grupos de investigación han demostrado que IGF-1 protege a los cardiomiocitos de la apoptosis inducida por distintas formas de estrés. Las acciones prohipertróficas y antiapoptóticas del IGF-1 son mediadas por un receptor de membrana que posee actividad tirosina kinasa intrínseca y una red transduccional compleja, integrada por las siguientes vías de señalización: a) PI3-K/PKB/mTOR, b) Raf/MEK/ERK y c) calcio. En la literatura existen evidencias contradictorias respecto a las acciones del IGF-1 sobre la autofagia y sus mecanismos en varios tipos celulares. Dado que prácticamente se desconoce si este factor de crecimiento regula la autofagia cardiaca, en esta tesis se postuló como hipótesis que “IGF-1 inhibe la autofagia cardiaca inducida por estrés nutricional”. Los objetivos específicos propuestos fueron:  Estudiar in vitro si la vía transduccional PKB/mTOR es activada por IGF-1 en cardiomiocitos expuestos a estrés nutricional.  Investigar in vitro el efecto del IGF-1 en el metabolismo y viabilidad del cardiomiocito expuesto a estrés nutricional.  Determinar in vitro si IGF-1 regula negativamente la autofagia inducida por estrés nutricional.  Estudiar in vivo el papel del IGF-1 en la autofagia inducida por estrés nutricional. Los modelos experimentales utilizados fueron cultivos primarios de cardiomiocitos de ratas neonatas expuestos a dos formas de estrés nutricional (privación de suero/glucosa o privación de suero/aminoácidos) y ratones transgénicos LID (“Liver IGF-1 deficiency”) y controles, ayunados por 48 h. Los ratones LID presentan una deficiencia selectiva en el gen de IGF-1 en el hígado que determina niveles plasmáticos de IGF-1 muy bajos en comparación a sus controles. Los resultados mostraron que el estrés nutricional por privación de suero/glucosa estimuló temprana y progresivamente la autofagia en cultivos primarios de cardiomiocitos determinada por el procesamiento de la proteína endógena LC3-I, efecto que no se observó en los cardiomiocitos expuestos al estrés nutricional por privación de suero/aminoácidos. El estrés nutricional por privación de suero/glucosa también incrementó la distribución punteada de LC3-GFP, disminuyó la fluorescencia de LC3-GFP en los cardiomiocitos transducidos con el adenovirus LC3-GFP pero no modificó los niveles de la proteína proautofágica beclin-1. La privación de suero/glucosa produjo una caída significativa en los niveles intracelulares de ATP y un aumento de la muerte celular, la cual que no tuvo las características bioquímicas de apoptosis. Sin embargo, el bloqueo de la inducción de autofagia con el inhibidor selectivo de PI3-K clase III 3-metiladenina incrementó la muerte de los cardiomiocitos expuestos a ambos tipos de estrés nutricional. Los dos tipos de estrés nutricionales disminuyeron tempranamente (1 h) los niveles basales de las formas fosforiladas de las proteínas PKB, p70-S6K y ERK, observándose sólo una recuperación paulatina de la fosforilación de ERK1 en los cardiomiocitos expuestos a privación de suero/glucosa. IGF-1 inhibió la autofagia, la muerte y recuperó los niveles intracelulares de ATP en los cardiomiocitos expuestos a estrés nutricional por privación de suero/glucosa. Este efecto fue selectivo ya que IGF-1 no recuperó los niveles intracelulares de ATP y la viabilidad de los cardiomiocitos privados de suero y aminoácidos. Por otra parte, IGF-1 estimuló las fosforilaciones de la PKB y p70-S6K en cardiomiocitos expuestos a estrés nutricional por privación de suero/glucosa, revelando que la vía transduccional mTOR está activa. Sin embargo, el efecto del IGF-1 sobre p70-S6K no se observó en los cardiomiocitos privados de suero y aminoácidos. En un modelo in vivo de estrés nutricional en el ratón, el ayuno por 48 h indujo autofagia en el corazón, siendo este efecto mayor en los ratones transgénicos LID en comparación a los controles silvestres. Además, estos ratones LID sometidos a estrés nutricional por 48 h presentaron mayor fosforilación de la proteína AMPK en el tejido cardiaco, efecto que podría estar asociado a una mayor inducción de autofagia. Finalmente, los resultados obtenidos con el desarrollo de esta tesis permiten concluir que IGF-1 es un regulador negativo de la autofagia del cardiomiocito inducida por privación de nutrientes / Autophagy is a key physiological process for cell survival during nutrient deprivation, cell differentiation and development. Autophagy is a dynamic and programmed process that involves the engulfment of cytoplasmic proteins and organelles within a double membrane vacuole, which are fused with lysosomes to form the autolysosomes. Autophagy is regulated by different signaling pathways being the most important the PI3-K pathway. PI3-K class III is required in the early steps of autophagosome formation, while PI3-K class I has an mTOR protein kinase-mediated inhibitory effect. In recent years autophagy has also been identified as a type II programmed cell death. Insulin-like growth factor type 1 (IGF-1) has different actions on the heart, being the most important its pro-hypertrophic and positive inotropic effects. Moreover, our laboratory and other research groups have shown that IGF-1 protects cardiac myocytes from apoptosis induced by different cell stresses. Pro-hypertrophic and antiapoptotic IGF-1 actions are mediated by a membrane receptor with intrinsic tyrosine kinase activity and a complex signaling network, integrated by a) PI3-K/PKB/mTOR, b) Raf/MEF/ERK and c) Ca2+. In the literature conflicting evidence exists about the IGF-1 effects on autophagy and the mechanisms involved. Moreover, no information is available whether this growth factor regulates cardiac autophagy. Therefore, this thesis proposed as hypothesis that "IGF-1 inhibits the nutritional stress-induced cardiac autophagy". The specific aims were:  To study in vitro whether PKB/mTOR transductional pathway is activated by IGF-1 in cardiac myocytes exposed to nutritional stress.  To investigate IGF-1 in vitro effects on metabolism and viability in cardiac myocytes exposed to nutritional stress.  To determine in vitro whether IGF-1 negatively regulates nutritional stress-induced autophagy.  To study in vivo the role of IGF-1 on nutritional stress-induced autophagy. The experimental models were primary cultures of neonatal rat cardiac myocytes exposed to two forms of nutritional stresses (serum/glucose or serum/aminoacid deprivation), and transgenic mice LID (Liver IGF-1 Deficiency) on control mice starved for 48 h. The LID mice have a selective liver deficiency in IGF-1 gene that results in a lower IGF-1 plasma level than in control mice. Our results showed that nutritional stress by serum/glucose deprivation stimulated an early and progressive autophagy in primary cultures of neonatal rat cardiac myocytes, as determined by the processing of endogenous protein LC3-I. This effect was not observed in cardiac myocytes exposed to nutritional stress by serum/aminoacid deprivation. Nutritional stress by serum/glucose deprivation increased GFP-LC3 dot pattern and decreased GFP-LC3 fluorescence in cardiac myocytes transduced with an adenovirus overexpressing GFP-LC3, but any change was observed in the levels of the pro-autophagic protein beclin-1. The serum/glucose deprivation induced a significant decrease in intracellular ATP levels and an increase in cell death, which lacks the apoptotic biochemical features. However, inhibition of the induction of autophagy by 3-MA increased cell death in cardiac myocytes exposed to both types of nutritional stresses. Both types of nutritional stresses produced an early decrease (1 h) in phosphorylated forms of PKB, p70-S6K and ERK. Only a gradual recovery of ERK1 phosphorylation in cardiac myocytes exposed to deprivation of serum/glucose was observed. IGF-1 inhibited both autophagy and cell death, and recovered intracellular ATP levels in cardiac myocytes exposed to nutritional stress by serum/glucose deprivation. This effect was selective to this stress because IGF-1 did not recover intracellular ATP levels and viability in serum/aminoacid deprived cardiac myocytes. Moreover, IGF-1 stimulated PKB and p70-S6K phosphorylation in cardiac myocytes exposed to nutritional stress by serum/glucose deprivation, suggesting that mTOR transductional pathway was active. However, IGF-1 effect on p70-S6K was not observed in serum/aminoacid deprived cardiac myocytes. In an in vivo nutritional stress model produced by 48 h fasting, cardiac autophagy was induced. This induction was higher in transgenic LID mice as compared to control mice. In addition, the levels of phosphorylation of AMPK increased in cardiac tissue from 48 h fasted LID mice, effect that could be associated with a larger autophagy induction. Finally, these results allow us to conclude that IGF-1 inhibits nutrient deprivation-induced cardiac autophagy

The predominating theories on non-product-related attributes stretch only so far to explain why some brands do not manage to succeed on foreign markets where the product needs are essentially similar to their domestic markets. Therefore, the aim of this paper is to cast new light on the theoretical field of non-product-related attributes, by unveiling which non-product- related attributes affect consumer brand preferences on similar markets. This is done by studying consumer expectations on cosmetics brands in general and brand attitudes towards a Finnish cosmetics brand, on the Swedish market. The results suggest that most of the non-product-related attributes that are covered by predominating theories are still relevant for the formation of consumer preferences, but that new important attributes have also emerged. It was also found that the level of importance varies from attribute to attribute, and that some factors affect consumer preferences more than others. The findings serve as a basis for re-evaluating and expanding the theory of non-product- related attributes, and can help brands to succeed on similar markets.

Orientador: Alagacone Sri Ranga / Banca: Sandra Augusta Santos / Banca: Cleonice Fátima Bracciali / Resumo: Dentre as diversas fórmulas de quadratura interpolatórias estão aquelas que utilizam em sua construção as propriedades dos polinômios ortogonais Pn, ou ainda dos polinômios similares Bn. Consideramos, aqui, fþormulas de quadratura envolvendo polinôomios em x da forma .n(x, .) = Pn-1(.)Pn(x) - Pn(.)Pn-1(x), e da forma Gn(x, u) = Bn-1(u)Bn(x) - Bn(u)Bn-1(x). Abordamos ainda certas fþormulas de quadratura que visam aproximar a integral de um produto de duas funções k e f sendo k Lebesgue integrþavel e f Riemann integrþavel. O principal objetivo deste trabalho þe analisar propriedades das fþormulas de quadratura utilizando-se .n e obter propriedades anþalogas para o caso onde utiliza-se Gn, bem como estudar o erro e as propriedades de convergência das fórmulas envolvendo k e f. Propriedades dos pesos das fórmulas de quadratura nos diversos casos são analisadas, a convergência das fórmulas associadas a k e f são estudadas mediante determinadas escolhas de pontos. / Abstract: Among the many well known quadrature formulas one finds those interesting interpolatory quadrature formulas that take advantage of the properties of orthogonal polynomials Pn or similar polynomials Bn. Here, we consider the interpolatory quadrature rules based on the zeros of the polynomials øn(x, î) = Pn.1(î)Pn(x).Pn(î)Pn.1(x), and Gn(x, u) = Bn.1(u)Bn(x) . Bn(u)Bn.1(x) where î and u are arbitrary parameters. One of the objective of this dissertation is to study some of the known properties of quadrature rules based on øn(x, î) and consider the analogous properties of the quadrature rules based on Gn(x, u).We also look at the convergence properties of those quadrature rules that serve to approximate integrals of the product of functions k and f, where k is a Lebesgue integrable function and f needs to be a Riemann integrable function. / Mestre

O desenvolvimento tecnológico observado nos últimos anos e o avanço na aquisição de dados para os sistemas tanto químicos como biológicos tem gerado um grande número de informações. Como consequência, nos últimos anos, procuram-se ferramentas, fundamentalmente matemáticas, que permitam decodificar este volume imenso de informações, em termos estruturais e biológicos. Embora diversos parâmetros estatísticos e métodos de seleção de modelos e de variáveis tenham sido descritos, mais recentemente, são encontradas propostas de novas ferramentas visando assegurar tanto a qualidade de predição do modelo como a elucidação de algum mecanismo a partir do modelo gerado. Com relação aos estudos de compostos antichagásicos, é grande o número de dados disponíveis, na literatura, nos diferentes aspectos pesquisados.A cruzipaína, também chamada de cruzaína, é a principal cisteína protease do Trypanosoma cruzi e sua inibição tem se mostrado capaz de inibir o desenvolvimento intracelular do protozoário. Neste trabalho foram selecionados da literatura original 90 compostos, incluindo-se 29 alfa-(N)-heterocíclica carboxaldeído tiossemicarbazonas substituídas, com atividade inibitória frente a ribonucleotídeo redutase (IRNR) (série I; compostos I.1. a I.29); 37 tiossemicarbazonas substituídas na cadeia lateral e no anel aromático (série II; compostos II.1 a II.37) e, 61 compostos estruturalmente diferentes (série III; compostos II.1 a III.61, sendo 45 tiossemicarbazonas das quais 37 da série II e, 16 derivados de isatinas). As séries II e III apresentam atividade inibitória frente à cruzaína, uma cisteína protease do T.cruzi. E a série I, embora, apresente atividade inibitória frente a ribonucleotídeo redutase (IRNR) de células H.Ep.-2, é, no entanto, estruturalmente similar às séries II e III. E, ainda mais, os modelos gerados nesta dissertação para a série I foram incluídos na tese de doutorado de H.Ishiki. Cada uma das séries foi dividida em 3 séries de treinamento (A, B e C) com suas correspondentes séries de teste. A seguir, a partir das estruturas representadas em 3 dimensões das moléculas, foram gerados 1497 descritores através do programa DRAGON (v. 3.0) para cada série (I, II e III). Estes descritores foram submetidos a um pré-tratamento de dados, excluindo-se aqueles que não contribuiriam para as análises PLS - Partial Least Squares (mínimos quadrados parciais). Através das análises PLS foram selecionados os descritores mais significativos das equações de regressão linear, que a seguir foram submetidos a uma análise de freqüência, ou seja, foram selecionados os descritores presentes em pelo menos em 2 dos 3 modelos obtidos das séries de treinamento (A, B e C). A partir destes descritores selecionados foram obtidos modelos de QSAR clássico com 5 descritores que foram validados por três filtros. Estes modelos de QSAR validados, apresentaram valores de coeficiente de correlação (r) e do quadrado do coeficiente de predição interna (Qcv2) maiores que 0,9 e 0,7 respectivamente. / It has been observed an enormous improvement in the methods concerning data generation, leading to a large amount of information, especially for chemical and biological systems. Through these developments, it becomes relevant to have reliable methods, mainly new mathematical tools, for structure-activity relationship (SAR) data examination, which means that there is a need for developing datasets screening tools. Although a huge number of descriptors and methods for selection have been described in the literature, it becomes a crucial aspect to develop new concepts and tools that assure selection of relevant information as well as a high predictive power for the generated QSAR models. Concerning antichagasic compounds, in the literature, there is a huge number of data in anti Chagas disease drug research fields. Cruzain, known also as cruzipain, is the major cysteine protease of T. cruzi. The protease is expressed in all life cycle stages of the parasite. Therefore, cruzain is essential for replication of the intracellular parasite. Thus, cruzain is an appealing target for new antitrypanosomal chemotherapy. In this work, it has been taken from selected literature 90 compounds, including 29 substituted alpha-(N)- heterocyclic carboxaldehyde thiosemicarbazones, (set I, compounds I.1 to I. 29) and 37 substituted thiosemicarbazones (set II, compounds II.1 to II.37) and 61 structurally different compounds (set III, compounds II.1 to III.61, namely 45 thiosemicarbazones (37 from set II) and 16 isatin derivatives). Sets II and III showed inhibitory activity against cruzain, a cysteine protease of T. cruzi. Although set I compounds showed inhibitory activity against ribonucleotide reductase enzyme of H.Ep.-2 cells they have been included in this study taking into account that they are structurally similar to sets II and III, studied by H. Ishiki in his PhD thesis. Each set was divided in 3 training sets (A, B and C) with its corresponding test sets. Initially, 1497 descriptors have been obtained by means of DRAGON program (v.3.0) using 3D structures of sets I, II and III compounds. In a second step to reduce the data size, all descriptors have been submitted to a pre-treatment, including the use of different filters, followed by PLS analyses with external validation. Relevant descriptors have been selected using PLS followed by frequency analysis. That means, it has been selected descriptors, which were present at least in 2 or 3 models, generated from training sets (A, B an C). These descriptors have been used to generate QSAR models with up to 5 descriptors. The QSAR models had been validated by three filters. Values of correlation coefficient (r) and the squared correlation coefficient of internal predictions (Qcv2) were higher than 0.9 and 0.7, respectively, for the validated QSAR models.

Context. Bug tracking systems play an important role in software maintenance. They allow users to submit bug reports. However, it has been observed that often a bug report submitted is a duplicate (when several users submit bug reports for the same problem, these reports are called duplicated issue reports) which results in considerable duplicate bug reports in a bug tracking system. Solutions for automating the process of duplicate bug reports detection can increase the productivity of software maintenance activities, as new incoming bug reports are directly compared with the existing bug reports to identify their similar bug reports, which is no need for the human to spend time reading, understanding, and searching. Although recently there has been considerable research on such solutions, there is still much room for improvement regarding accuracy and recall rate during the duplicate detection process. Besides, very few tools were evaluated in an industrial setting. Objectives. In this study, firstly, we aim to characterize automated duplicate bug report detection methods by exploring categories of all those methods, identifying proposed evaluation methods, specifying performance difference between the categories of methods. Then we propose a method leveraging recent advances on using semantic model – Doc2vec and present an overall framework - preprocessing, training a semantic model, calculating and ranking similarity, and retrieving duplicate bug reports of the proposed method. Finally, we apply an experiment to evaluate the performance of the proposed method and compare it with the selected best methods for the task of duplicate bug report detection Methods. To classify and analyze all existing research on automated duplicate bug report detection, we conducted a systematic mapping study. To evaluate our proposed method, we conducted an experiment with an identified number of bug reports on the internal bug report database of Axis Communication AB. Results. We classified automated duplicate bug report detection techniques into three categories - TOP N recommendation and ranking approach, binary classification approach, and decision-making approach. We found that recall-rate@k is the most common evaluation metric, and found that TOP N recommendation and ranking approach has the best performance among the identified approaches. The experimental results showed that the recall rate of our proposed approach is significantly higher than the combination of TF-IDF with Word2vec and the combination of TF-IDF with LSI. Our combination of Doc2vec and TF-IDF approach, has a recall rate@1-10 of 18.66%-42.88% in the TROUBLE data, which is an improvement of 1.63%-9.42% to the state-of-art. Conclusions. In this thesis, we identified and classified 44 automated duplicate bug report detection research papers by conducting a systematic mapping study. We provide an overview of the state-of-art, identifying evaluation metrics, investigating the scientific evidence in the reported results, and identifying needs for future research. We implemented a bug tracking system with a duplicate bug report detection module where a list of Top-N related bug reports (along with a numerical value representing a similar score) is created. After conducting the experiment, we found that our proposed approach - the combination of Doc2vec and TF-IDF approach produces the best recall rate.Keywords: Similar

The chicken eggshell possesses physical and chemical barriers to protect the embryo from pathogens. The avian eggshell cuticle is the outmost layer of the eggshell whose protein constituents remain largely unknown. Since eggs with incomplete or absent cuticle are more susceptible to bacterial contamination, we hypothesize that cuticle protein components play an important role in microbial resistance. In our study, at least 47 proteins were identified by LC/MS/MS in the non-calcified cuticle layer. Similar to Kunitz-like protease inhibitor (also annotated as ovocalyxin-25, OCX-25) and ovocalyxin-32 (OCX-32) were two of most abundant proteins of the cuticle proteins. Some proteins that have antimicrobial activity were also detected in the proteomic results, such as lysozyme C, ovotransferrin, ovocalyxin-32, cystatin, ovoinhibitor. This study represents the first comprehensive report of the cuticle proteome. Since the sequence similarity of the kunitz motif in OCX-25 is similar to that of BPTI, it is predicted that it will have the same trypsin inhibitory and antimicrobial activity against Gram-positive and/or Gram-negative bacteria. In order to test the antimicrobial property and trypsin inhibitor activity of OCX-25, cuticle proteins were extracted by 1N HCl. Antimicrobial activity was monitored using the Bioscreen C instrument; and antimicrobial activity was identified primarily against Staphylococcus aureus. Trypsin inhibitor activity was studied by using a specific trypsin assay, and the assay indicated that the cuticle proteins could inhibit the reaction of trypsin and substrate. Therefore, the current research has provided some insight into the antimicrobial and enzymatic aspects of the cuticle proteins, and its function for egg protection. Eggshell membranes are another important component of the chicken eggshell.Due to its insoluble and stable properties, there are still many questions regarding formation and constituents of the eggshell membranes. The purpose of our study was to identify eggshell membrane proteins, particularly these responsible for its structural features, by examining the transcriptome of the white isthmus during its formation. Bioinformatics tools were applied to analyze the differentially expressed genes as well as their encoded proteins. Some interesting proteins were encoded by the over-expressed genes in the white isthmus during the formation of eggshell membranes, such as Collagen X, and similar to spore coat protein SP75. These proteins may have potential applications. Our study provides a detailed description of the chicken white isthmus transcriptome during formation of the eggshell membranes; it could lead to develop the strategies to improve food safety of the table egg.

Utbildning skapar de grundläggande förutsättningarna för invandrare att integreras ekonomiskt och socialt i ett samhälle. Denna uppsats undersöker vilken roll integrationspolitisk inriktning  har i integrationsprocessen inom utbildning genom att jämföra två länder där frågan om integration ständigt är aktuell, Sverige och Australien. Studien följer en mest-lika design som bygger på att Sverige och Australien antas vara mycket lika vad gäller integrationspolitiken inom utbildning men trots detta påvisar olika integrationsutfall. Syftet med uppsatsen är att undersöka eventuella skillnader i ländernas integrationspolitiska inriktning som kan tänkas förklara de olika integrationsutfallen. Som metod för att fullgöra syftet används både kvalitativ textanalys och intervjuer. Uppsatsen når slutsatsen att Australien i en högre grad en Sverige tycks fokusera på integrationspolitik avseende interkulturellt lärande och att detta i sin tur utgör en möjlig förklaring till att Australien påvisar bättre integrationsutfall än Sverige.

Tesis para optar al grado de Doctor en Bioquímica / Las enfermedades cardiovasculares son la primera causa de muerte en todos los países desarrollados, incluyendo Chile. En los últimos años se ha sugerido que la pérdida de cardiomiocitos debido a muerte celular es un factor importante en el desarrollo de la insuficiencia cardiaca. Sin embargo, no existe claridad acerca del mecanismo por el cual se produce la muerte de los cardiomiocitos y de su desaparición del tejido cardiaco. En el corazón se produce estrés hiperosmótico durante eventos de isquemia/reperfusión cardiaca. Existe un pobre conocimiento acerca de las vías de señalización cardiaca que conllevan a la muerte celular como una consecuencia del estrés osmótico. Nosotros hemos demostrado que el estrés hiperosmótico (sorbitol 600 mOsm) induce una rápida apoptosis en cardiomiocitos en cultivo. El futuro desarrollo de esta área requiere la identificación de moléculas que protejan a los cardiomiocitos de la muerte celular. En este aspecto, el agente más promisorio corresponde al factor de crecimiento análogo a insulina tipo 1 (IGF-1). Algunas células poseen eficientes mecanismos reguladores involucrados en la mantención de la homeostasis, sin embargo el cardiomiocito es especialmente vulnerable a la apoptosis inducida por estrés hiperosmótico debido a que regula su volumen muy lentamente. Aunque existe cierta caracterización molecular de los eventos desencadenados en la apoptosis inducida por sorbitol, se desconoce la participación del Ca2+ y de factores transcripcionales en este proceso. El propósito de esta tesis fue estudiar los mecanismos de señalización que regulan la apoptosis del cardiomiocito inducida por estrés hiperosmótico. Con este objetivo, se estudió la actividad y regulación transduccional del factor transcripcional CREB en respuesta a IGF-1 y/o estrés hiperosmótico. CREB es un importante mediador de la sobrevida celular promovida por IGF-1 en otros tipos celulares. Por lo tanto se investigó la participación de CREB en la señalización antiapoptótica gatillada por IGF-1 en este modelo de estrés hiperosmótico. Además, se estudiaron los efectos del estrés hiperosmótico en cultivos primarios de cardiomiocitos, en términos de cambios en los niveles intracelulares de Ca2+ y en las actividades enzimáticas de la proteína kinasa dependiente de Ca2+/CaM (Calmodulina quinasa II, CaMKII) y la proteína fosfatasa Calcineurina (Cn). Los resultados presentados en este estudio demostraron que tanto el estrés hiperosmótico como IGF-1 conllevan a la activación de CREB, a través de su fosforilación, aunque probablemente por vías distintas. La activación de CREB por estrés hiperosmótico dependió de Ca2+ i y las vías MAPK, ya que BAPTA-AM e inhibidores de las vías p38-MAPK y ERK impidieron el aumento de su fosforilación. Por otro lado, la preincubación de cardiomiocitos con BAPTA-AM o inhibidores de las vías p38-MAPK, ERK, PI3-K, Cn and CaMKII disminuyeron significativamente la fosforilación de CREB inducida por IGF-1. El estrés hiperosmótico bloqueó la activación de CREB inducida por IGF-1, con un patrón de activación similar al de el estímulo apoptótico. Finalmente, los resultados indicaron que CREB participa en la señalización antiapoptótica del IGF-1 en cardiomiocitos expuestos a estrés hiperosmótico, pero no en la respuesta de sobrevida celular frente al estímulo osmótico. El efecto protector de IGF-1 frente a estrés hiperosmótico fue bloqueado por la expresión de una forma inactiva de CREB, como se demuestra con la mayoría de los parámetros apoptóticos evaluados en este estudio; sin embargo, la apoptosis inducida con este modelo experimental no presentó cambios significativos tras la sobreexpresión de CREB inactivo. Los resultados, además, demostraron que el estrés hiperosmótico llevó a aumentos rápidos y transitorios de los niveles de Ca2+ i, como resultado tanto del influjo de este ión desde el medio extracelular como de su liberación desde depósitos intracelulares. Este aumento del Ca2+ i estuvo mediado al menos, por entrada de Ca2+ por canales de Ca2+ de tipo L y la liberación desde reservorios de Ca2+ activada por IP3. Los resultados también mostraron que la liberación de Ca2+ desde depósitos intracelulares inducida por el estrés hiperosmótico depende de la activación de Fosfolipasa C (PLC). El estrés hiperosmótico no produjo un aumento de las actividades enzimáticas CaMKII y Cn. El pretratamiento de los cardiomiocitos con KN62 (inhibidor de CaMKII) y CsA (inhibidor de Cn) no modificó significativamente la apoptosis inducida por estrés hiperosmótico, evaluada en términos de viabilidad celular, fragmentación del DNA, activación de caspasa-3 y -9 y externalización de fosfatidilserina. Estos resultados sugieren que dichas vías de señalización probablemente no estarían involucradas en la regulación de la apoptosis desencadenada por el estrés hiperosmótico inducido por sorbitol. De este trabajo de tesis se puede concluir que: 1) CREB participaría en la señalización antiapoptótica del IGF-1 en cardiomiocitos expuestos a estrés hiperosmótico, pero no en la muerte inducida por este tipo de estrés; 2) el estrés hiperosmótico produce un aumento de los niveles Ca2+ i como consecuencia del influjo de este ión desde el medio extracelular y de su liberación desde depósitos intracelulares; y finalmente, 3) CaMKII y Cn no participarían en la apoptosis inducida por el estímulo osmótico / Cardiovascular diseases are the leading cause of death in all developed countries, including Chile. In recent years, it has been suggested that loss of cardiomyocytes due to cell death is an important causative factor in the development of heart failure. However, the mechanism by which cardiomyocytes die and then disappear from the tissue is not clear. In the heart, osmotic stress occurs during myocardial ischemia/reperfusion. Cardiac signaling pathways leading to cell death as a consequence of osmotic stress remain poorly understood. We have shown that hyperosmotic stress (sorbitol 600 mOsm) rapidly induces apoptosis in cultured cardiomyocytes. Future development in this area will require the identification of molecules that protect cardiac cells from cell death. The most promising agent is insulin like growth factor-1 (IGF-1). Several cells display efficient regulatory mechanisms involved in maintaining homeostasis, however cardiomyocyte is especially vulnerable to hyperosmotic stress-induced apoptosis since its volume is regulated very slowly. Although there is some molecular characterization of the events engaged in estrés hiperosmótico-induced apoptosis, the involvement of Ca2+ and transcription factors remains unknown. The aim of this thesis was to study of the signaling mechanisms regulating hyperosmotic stress-induced apoptosis of cardiomyocyte. With that purpose, the activity and transductional regulation of transcriptional factor CREB in the response to IGF-1 and/or hyperosmotic stress were studied. Since CREB is an important mediator of IGF-1 promotion of cell survival in other cell types, the participation of CREB in the IGF-1-induced antiapoptotic signaling pathway during hyperosmotic stress was also investigated. In addition effects of sorbitolinduced hyperosmotic stress on primary cardiomyocyte cultures were studied, in terms of changes in Ca2+ intracellular levels, Ca2+/CaM-dependent protein kinase (Calmodulin kinase II, CaMKII) and the protein phosphatase Calcineurin (Cn) enzymatic activities. Data presented in this study showed that CREB activation (phosphorilation) was induced by both hyperosmotic stress and IGF-1, although most likely by different pathways. CREB activation by hyperosmotic stress depended on Ca2+ i and MAPK pathways since BAPTA-AM and p38-MAPK and ERK pathway inhibitors prevented its phosphorylation. In the other hand, pretreatment of cardiomyocytes with BAPTA-AM or p38-MAPK, ERK, PI3-K, Cn and CaMKII pathway inhibitors significantly decreased CREB phosphorylation induced by IGF-1. Hyperosmotic stress prevented CREB activation IGF-1-induced, maintaining the activation pattern of DNA affinity displayed after the apoptotic stimulus. Finally, the results indicated that CREB participates in the IGF-1 antiapoptotic signaling in cardiomyocytes treated with hyperosmotic stress, but not in the cell survival response. The protective effect of IGF-1 towards sorbitol was overridden by the overexpression of an inactive form of CREB, as shown by most of the apoptotic parameters evaluated in this study; however, stress-induced apoptosis with this experimental model remained unchanged by overexpression of inactive CREB. The results also showed that hyperosmotic stress led to fast and transient increases in intracellular Ca2+ levels, which were the result of both Ca2+ influx from the extracellular milieu and the release from intracellular stores. This Ca2+ i increase was mediated in part by Ca2+ inward by L-type Ca2+ channels and release from stores by IP3 receptors. Results also showed that hyperosmotic stress-induced Ca2+ release from intracellular stores was also dependent on PLC activation. Hyperosmotic stress did not induce CaMKII and Cn enzymatic activities. Pretreatment of cardiomyocytes with KN62 (CaMKII inhibitor) and CsA (Cn inhibitor) did not modified significantly hyperosmotic stress-induced apoptosis, evaluated in terms of cell viability, DNA fragmentation, caspases–3 and –9 activation and phosphatidylserine externalization. These results suggested that these two signaling pathways were not likely implicated in the regulation of apoptosis triggered by sorbitol-induced hyperosmotic stress. Conclusions drawn from this thesis work are: 1) CREB most likely is involved in IGF-1 antiapoptotic signal in cardiomyocytes subjected to hyperosmotic stress but not in this type of stress-induced cell death; 2) hyperosmotic stress leads to an increase in intracellular Ca2+ levels due to both influx from the extracellular milieu and release from intracellular stores; and finally, 3) CaMKII and Cn are not likely to be involved in this osmotic stimulus-induced apoptosis / FONDAP 15010006; FONDECYT 1010246; CONICYT