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No. of bitstreams: 2 Tese - Rodolpho de Campos Braga - 2015.pdf: 15048949 bytes, checksum: 8c5fe5ec8f286e33101963872c33d8d5 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-09-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / In view of the alarming scenario of visceral leishmaniasis in Brazil and in the world, especially due to the increasing number of cases of drug resistance and due to the few drugs available, it is essential to search for new therapeutic alternatives for this parasitosis. The complete sequencing of the genome of the main species of Leishmania opened great possibilities in understanding these diseases and initiated the post-genomic era of drug discovery against kinetoplastids. In this context, the enzyme 14 a-sterol demethylase (CYP51) of Leishmania is especially involved in the biosynthesis of ergosterol, the main sterol membrane and vital to the parasite. Furthermore, it was recently shown that inhibition of CYP51 of L. donovani is essential for the growth of the parasite, and therefore, is a validated target for the development of new leishmanicidal drugs. The aim of this work was the development and implementation of integrated strategies in medicinal chemistry to identify new bioactive compounds against L. infantum using CYP51 enzyme as molecular target. For this, we compiled, integrated and prepared the largest publicly available data sets related to CYP51 and phenotypic assays for Leishmania infantum amastigotes. Virtual screening models (VS) were constructed and extensively validated and applied to filter over 1 million of commercial compounds. The best models for VS were ROCS (LBDD) and pharmacophore (SBDD), with an area under the ROC curve (AUC) values of 0.86-0.90. The consensus between the two models had greater performance, with AUC of 0.93 and high recognition ability active ligands in the top 1% hits. Quantitative structure-activity relationship (QSAR) models robust and predictive were generated and validated for L. infantum (amastigote forms). The models were able to discriminate inactive active compounds with correct classification rate (CCR) values of 0.77 to 0.95 when evaluated for the external validation set. After the virtual screening, QSAR models were used to assist in the final selection of the compounds to be experimentally evaluated. This strategy allowed the identification of 12 compounds that were selected and acquired for in vitro assays against Leishmania (L.) infantum (MHOM / BR / 1972 / LD) in promastigote and amastigote forms, and determination of selectivity/cytotoxicity in NCTC in mammalian cells. Of the twelve compounds tested, six of them showed 50% inhibitory concentration (IC50) values raging from 3.48 to 58.94 μM and were more potent than the standard drug meglumine antimoniate, which is the drug of choice for the treatment of all forms of leishmaniasis. Three most promising compounds (LabMol-007, LabMol-009 and LabMol-012), had activity in leishmanicidal as amastigote and selectivity index promising (IC50 < 5.21 μM and selectivity index > 6.8) and were selected as new hits. We analyzed the parasite metabolic changes in the presence of known CYP51 inhibitors and new inhibitors using HR-MAS NMR 1H . We observed major changes in the energetic metabolism, amino acids catabolism, sterol biosynthesis, purine biosynthesis and thiol-redox system of the parasite. The three hit compounds identified in this work will continue in the drug development process, being necessary to carry out in vivo studies, elucidation of the mechanism of action, hit optimization, as well as the study of pharmacokinetic properties and toxicity. / Tendo em vista o quadro alarmante da leishmaniose visceral no Brasil e no mundo, especialmente devido ao crescente número de casos de resistência e aos poucos medi- camentos disponíveis, é imprescindível a busca de novas alternativas terapêuticas para esta parasitose. O sequenciamento completo do genoma das principais espécies de Leish- mania abriu grandes possibilidades no entendimento desses organismos e iniciou a era pós-genômica da descoberta de fármacos contra tripanossomatídeos. Nesse contexto, destaca-se a enzima 14 a-esterol desmetilase (CYP51) de Leishmania, que é especial- mente envolvida na biossíntese do ergosterol, principal esterol de membrana e vital para o parasito. Além disso, recentemente foi demonstrado que a inibição da CYP51 de L. donovani é essencial para o crescimento do parasito, sendo, portanto, um alvo validado para o desenvolvimento de novos fármacos leishmanicidas. O objetivo geral deste trabalho foi o desenvolvimento e a aplicação de estratégias integradas em Química Medicinal para a identificação de novas substâncias bioativas contra L. infantum, utilizando a enzima CYP51 como alvo molecular. Para isso, foram compilados, integrados e preparados os maiores conjuntos de dados disponíveis publicamente relacionados a CYP51 e a ensaios fenotípicos para Leishmania spp. Modelos de triagem virtual (VS) foram construídos, exaustivamente validados e aplicados para filtrar uma quimioteca com mais de 1 milhão de compostos comerciais. Os melhores modelos para a VS foram o ROCS (LBDD) e o farmacofórico (SBDD), com valores de área sob a curva ROC (AUC) de 0,86-0,90. O consenso entre esses dois modelos foi superior com valor de AUC de 0,93 e alta capacidade de reconhecimento de ligantes ativos no topo de 1% hits. Modelos de relação quantitativa entre estrutura e atividade (QSAR) robustos e preditivos foram gerados e validados para um conjunto de dados de compostos com atividade contra L. infantum (formas amastigota). Os modelos de QSAR foram capazes de discriminar compostos ati- vos de inativos com uma taxa de acerto (CCR) de 0,77-0,95, quando avaliados utilizando o conjunto de validação externa. Após a triagem virtual, os modelos de QSAR foram usados para auxiliar na seleção final dos compostos a avaliados experimentalmente. Essa estratégia permitiu a identificação de 12 compostos que foram selecionados e adquiridos para realização de ensaios de atividade biológica in vitro contra Leishmania (L.) infantum (MHOM/BR/1972/LD) em formas promastigotas e amastigotas, e determinação de sele- tividade/citotoxidade em células mamíferas NCTC. Dos doze compostos testados, seis deles apresentaram valores de concentração inibitória de 50% (IC50) entre 3,48-58,94 μM e foram mais potentes que o fármaco padrão antimoniato de meglumina, que é o fármaco de primeira escolha para o tratamento de todas as formas de leishmaniose. Três compostos mais (LabMol-007, LabMol-009 e LabMol-012) tiveram atividade em leishmanicida na forma amastigota e índice de seletividade bastante promissores (IC50 < 5,21 μM e índice de seletividade > 6,8) e foram selecionados como novos hits. Analisou-se as alterações metabólicas do parasito na presença inibidores conhecidos de CYP51 e dos novos inibi- dores, empregando-se RMN HR-MAS 1H. Foram observadas alterações principais nas vias de metabolismo energético, catabolismo de aminoácidos, biossíntese de esteróis, metabolismo purinas e no sistema tiol-redox do parasito. Os três hits identificados neste trabalho prosseguirão no processo de desenvolvimento de novos fármacos, sendo necessá- ria a realização de estudos in vivo, elucidação do mecanismo de ação, otimização dos hits, além do estudo de propriedades farmacocinéticas e toxicidade.

La principale limite en chirurgie hépatobiliaire est représentée par l’insuffisance hépatocellulaire (IHC) posthépatectomie (Hx) ou la dysfonction du greffon (EAD) après transplantation (TH). Peu d’études ont évalué le métabolisme du foie dans son ensemble, du fait du manque de technique utilisable en clinique. La métabolomique HR-MAS-RMN pourrait pallier à ce manque. Le but de cette thèse était d’évaluer l’apport de cette technique en chirurgie hépatobiliaire.En TH (n=42), le profil métabolique (PM) prédisait le risque d’EAD et identifiait le lactate et la phosphocholine comme biomarqueurs permettant d’envisager un matching métabolique. Après Hx majeure (n=45), le PM prédisait la survenue d’un décès par IHC. Ce PM différait du profil cirrhotique en décompensation et était compatible avec celui de système cellulaire prolifératif. Une étude préliminaire montrait que le PM prédisait la récidive à 1 an après hépatectomie. Ce travail montre l’intérêt de la métabolomique par HR MAS RMN pour prédire l’issue d’une Hx ou d’une TH dans un temps compatible avec la clinique. Ces données orientent vers la piste de l’intervention métabolique en chirurgie hépatique. / One of the main limits in liver surgery is the risk of liver failure (LF) after hepatectomy (Hx) or graft dysfunction (EAD) after liver transplantation (LT). Few studies have evaluated global liver metabolism, probably due to the lack of clinically relevant techniques. HR-MAS-NMR metabolomics may fulfill this lack and the goal of this work was to evaluate its capacity to predict early outcomes after hepatectomy and LT. In LT (n=42), metabolic profile predicted EAD and lactate and phosphocholine were potent biomarkers providing means for metabolic matching. In liver biopsies harvested at the end of major Hx (n=45), metabolic profile predicted PHLF. The profile at risk of LF differed from that of decompensated cirrhosis but correlated to that of proliferative multicellular systems. A preliminary study showed that the metabolic profile predicted the risk of liver metastases recurrence at 1 year. This work underlines the potential value of HR-MAS-NMR metabolomics in the prediction of short-term outcomes in liver surgery. It provides clues to be further investigated for future evaluation of metabolic intervention in the field of liver surgery.

Cette thèse présente une approche multicompartimentée en métabolomique appliquée au diagnostic des tumeurs indéterminées de la thyroïde et à la caractérisation de l’effet du fructo-oligosaccharide sous condition de régime hyperlipidique chez la souris. L’objectif était de montrer qu’une telle approche permettrait de visualiser de façon plus globale des modulations du métabolisme induites, et par conséquent, d’améliorer la pertinence des marqueurs discriminants identifiés. Dans le cas de l'analyse nutritionnelle, l’analyse mono-compartimentée des différentes organes/segments intestinaux des souris ont permis de mettre en évidence les voies métaboliques affectées par le régime hyperlipidique mais pas d’observer un effet significatif du prébiotique FOS. Dans le cas du cancer de la thyroïde, l’étude multicompartimentée n’a pas pu être mise en place dans de bonnes conditions (problème de prélèvement d’échantillons). Cependant, l’analyse métabolomique monocompartimentée basée sur l’analyse HR-MAS des ponctions prélevées à l’aiguille fine a mené à une discrimination significative entre les lésions bénignes et malignes avec une prédictivité similaire aux tests moléculaires actuellement disponibles. En parallèle, nous avons exploré la technique HR-MAS à rotation lente dans le but de préserver l’intégrité des tissus au cours des expériences. L’utilisation de cette technique s’accompagne d’un certain nombre d’inconvénients que nous avons contournés en utilisant des séquences RMN particulières, et en mettant en place un protocole robuste de préparation d’échantillons. Enfin, nous avons évalué le filtre T1ρ et son application en métabolomique comme alternative au filtre T2. / This thesis presents a multicompartmental metabolomics approach applied to the diagnosis of indeterminate thyroid tumours and to the characterization of the effect of fructo-oligosaccharide (FOS), a prebiotic, under high fat diet condition in a mouse model. The aim of this project is to show that such approach could lead to a more global visualization of the induced metabolic modulations, and therefore, improve the identified discriminant markers relevance. Regarding the diet study, the mono-compartmental analysis of the different mouse organs/intestine segments enabled us to identify metabolic pathways affected by the high fat diet whereas the effect of FOS could only be characterized for the feces samples collected at day 28. Regarding the thyroid cancer study, the multi-compartmental approach could not have been continued due to sample handling issues. However, the classical metabolomics analysis of the fine-needle aspiration biopsies (FNAB) from patients with benign or malignant tumours led to a clear discrimination between both groups with a predictivity similar to that of commercial diagnosis tests. In the meantime, we explored the slow-spinning NMR HR-MAS technique in order to preserve the integrity of the tissues during the experiments. The use of this technique is accompanied by a number of drawbacks that we have avoided using special NMR sequences, and putting in place a robust protocol for sample preparation. Finally, we evaluated the T1ρ filter and its applications to metabolomics as an alternative to T2 filter.

Ce travail a pour finalité d'analyser l'évolution de la GRH au sein des entreprises marocaines vers l'avènement d'une nouvelle tendance « Talents », en prenant le cas du secteur bancaire. Ce secteur connaît actuellement un contexte concurrentiel rude, notamment en présence d'une conjoncture économique difficile, une crise financière internationale, et un turn-over important. Nous avons choisi une méthodologie qualitative qui fait appel à des échanges, des entretiens en face à face, et aussi téléphoniques, réalisés sur le terrain. Cette thèse vise à comprendre l'approche « Talents » non seulement du point de vue de l'entreprise, mais également de la discerner telle que nous pouvons l'apercevoir chez le salarié. En effet, l'évolution actuelle de la mondialisation peut être repérée dans plusieurs domaines, et principalement dans les marchés financiers. Cela entraine certes des changements dans le fonctionnement de ce secteur. D'où l'apparition des nouvelles pratiques RH. L'objectif principal de la présente recherche est de voir si la gestion des talents peut s'imposer au sein des entreprises marocaines comme une nouvelle pratique de la GRH. Pour ce faire, nous allons tout d'abord déterminer la politique actuelle mise en place par les banques en termes de GRH, puis nous allons essayer de discerner la place de la nouvelle tendance « Talents » au sein de celles-ci, et enfin, nous allons analyser les résultats obtenus, et confirmer ou infirmer les hypothèses formulées à la lumière de notre étude empirique. Les résultats de ce travail peuvent faire l'objet de recommandations pratiques aux banques marocaines, afin de revoir leur politique RH, et de faire face aux enjeux actuels. / The purpose of this work is to analyze the evolution of HRM in the Moroccan companies to the advent of a new trend "Talents", taking the case of the banking sector. This sector is currently experiencing a severe competitive environment, particularly in the presence of a difficult economic environment, international financial crisis, and high turnover. We chose a qualitative methodology that involves exchanges, face-to-face discussion or phone interview. This thesis aims to understand the "Talents" not only in terms of business approach, but also to discern it as we can perceive it from the employee. Indeed, the current evolution of globalization can be spotted in several areas, especially in the financial markets. This certainly leads to changes in the functioning of this sector. Hence the appearance of new HR practices. The main objective of this research is to see if the talent management may be required in Moroccan companies as a new practice of HRM. To do this, we will first determine the current policy implemented by banks in terms of HRM, then we will try to discern the place of the new trend "Talents" in them, and finally, we will analyze the results and confirm or refute the hypotheses that have been mad of our empirical study. The results of this work may be of practical recommendations to Moroccan banks to review their HR policies, and cope the current issues.

The theoretical part of this thesis describes internal and external ways that can be of use while appointing employees. The thesis is focused on using direct systematic search (Executive Search) in the environment of consulting company CSP Partners Ltd. and its aim is to show the specific features of this method usually used to appoint specialists or managers. Commercial and executive processes of the company are depicted within the text. Using analytical tools this thesis examines the whole HR consulting industry in the context of Czech labor market. Historical development and recent trends are included, ethical dimension as well as motivation of candidates approached using this method are described as well. Many practical notes are involved and the final part describes one of CSP Partners' Ltd. projects in detail.

This thesis deals with talent management. Its aim is to identify the best practices in talent management based on secondary and primary research of selected talent management programs. The theory is focused on definition of strategic HR management and especially talent management as one of its priorities. It is followed by explanation of the basic concepts of talent (such as high-potential, high performing and key employees) and talent management. Further descriptions of talent management process as well as TM challenges are included. The practical part is divided into two main sections. The first one is related to research in four companies and evaluation of their current talent management programs. Due to the fact that Generation Y is still more and more included in talent pool, the second part covers description of work life from its point of view. The final section contains a summary and the best practices.

This diploma thesis concentrates on relationship between employee satisfaction and usage of new methods in Human Resources Management, particularly coaching and talent management. As employee satisfaction becomes one of the most important sources of influence on company's performance, it is also discussed in the theoretical background the relationship between employee satisfaction and company performance. The goal of the thesis is to find relationship between usage of new HRM methods (coaching and talent management) and employee satisfaction. The thesis has four chapters. First two chapters "Measurement Systems in an Organization" and "Methods in HR Management" set a theoretical background for the research. The third chapter concentrates on the research itself: employees of five Russian companies both with and without coaching and talent management, are tested. In the last chapter are compared research outcomes and theoretical approach, as well as, recommendations are given.

Syftet med uppsatsen har varit att identifiera eventuella diskrepanser mellan arbetsgivares och personalvetarstudenters uppfattningar om vilka egenskaper som är viktiga för att erhålla ett Human Resource (HR)-relaterat yrke efter personalvetarstudier. Syftet har också varit att undersöka om den eventuella diskrepansen skiljer sig mellan olika högskolor och universitet i Stockholms omkringliggande område. Detta har undersökts i form av en enkätundersökning, som har skickats ut till arbetsgivare och personalvetarstudenter. Data från enkäten har analyserats med hjälp av t-tester, korrelationer och regressionsanalyser.Studiens huvudsakliga resultat är att det föreligger en diskrepans mellan arbetsgivare och personalvetarstudenter vad gäller deras uppfattningar om vilka egenskaper som är viktiga på arbetsmarknaden, men att diskrepansen inte påverkas av skoltillhörighet. Tydligast var skillnaden vad gäller personliga egenskaper, eftersom det var den kategori där arbetsgivare värderade egenskaperna signifikant högre än studenterna. Studien bidrar med kännedom om en kunskapslucka hos personalvetarstudenter och tillför därmed också kunskap vad gäller vilka åtgärder som kan vidtas för att utveckla kursprogrammen för personalvetarstudier. / The purpose of this study has been to identify potential discrepancy between employers’ and Human Resource (HR) students’ perceptions of what qualities that are critical for securing an entry-level position in the HR profession after finishing their studies. The purpose has also been to examine whether the potential discrepancy differs between universities in the Stockholm metropolitan area. This has been examined by a survey that has been forwarded to employers and HR-students. The survey data has been analysed by means of t-tests, correlations and regression analyses.The main results of this study are that a discrepancy between employers and HR-students prevails, regarding their perceptions of which qualities that are critical in the labour market. The discrepancy is, however, not affected by school affiliation. The most distinct difference was that of personal qualities, where the employers rated these qualities significantly higher than the HR-students. The study thereby contributes to the research area by identifying HR-students' knowledge gap and consequently, which measures that would benefit the HR-educations.

The aim of this paper is to present the possibilities of the usage of advanced analytical tools to optimize decision-making in personnel practice. The literature review part of the thesis deals with the so-called HR analytics, its development, possibilities of its usage, and the methodological framework on which it is based. The next part of the paper deals with the specific application of HR analytics in the field of employee retention according to the methodological framework of CRISP-DM. The last chapter describes in detail the phenomenon of employee turnover, its consequences, and possible explanatory variables. The empirical part of the paper is framed as a quantitative, applied research and deals with voluntary turnover of employees in a particular company-a large Czech bank. Firstly, the statistical-inference part of the research identifies several statistically significant predictors of employee turnover through binary logistic regression-unemployment rate, number of changed teams, time spent in the company, salary and total income, salary growth rate, team size, extraordinary bonus, and gender. Secondly, in the data-science part, several prediction models are compiled, one using binary logistic regression as well and another based on several machine learning techniques. The models are...

Bakgrund: Ett allt mer gränslöst arbetsliv breder ut sig över flera branscher på svensk arbetsmarknad. Organisationers flexibilitetsformer och flexibla arbetsätt, skapar nya utmaningar för en pressad organisatorisk nyckelgrupp, cheferna. Under hög arbetsbelastning och stress, kan cheferna vara i behov av Work Life Balance för att uppräthålla god hälsa och fortsatt produktivitet samt få ett HR-stöd för att hantera arbetslivet. I en kontext av Covid-19, har det gränslösa arbetslivet accelerarat och skapar den nuvarande kontexten där kunskapen om chefers Work Life Balance behöver bli mer omfattande i Sverige.  Syfte: Tiilsammans med induktivt och tolkande perspektiv, beskriva hur chefer upplever Work Life Balance i en kontext av Covid-19. Metod: Studien har bedrivits med en induktiv ansats där empirin och inte toerin, ligger till grund för studien. Iklädda endast våra förkunskaper under vår tid på HR-programmet, har studien genomförts i en ingående fallstudie med nio chefer som genom kvalitativa semistrukturerade intervjuer åskådliggjort varierande upplevelser av chefer Work Life Balance.  Slutsatser: Utifrån studiens syfte, påvisar vi att merparten av cheferna i studien, upplever en god Work Life Balance utifrån varje chefs egen verklighet som genomsyras av unika individualiteter. Därutöver, har vi brutit ner faktorer som påverkar chefers av Work Life Balance genom en individuell och organisatorisk kontext samt påvisat att HR inte är en primär källa av stöd för chefers Work Life Balance och slutligen, identifierat hur chefer hanterar Work Life Balance. Överlag har Covid-19 inte haft en större inverkan på cheferna i vår studie. Vidare, kan vi konstatera att cheferna har genom sina erfaranheter och egen medvetenhet, personfierat sin egen Work Life Balance genom exempelvis brist på stöd av HR-avdelningarna och således hittat andra vägar för att skapa Work Life Balance. / Background: An increasingly more bounderless type of work-life are expanding over multiple industries on the Swedish labour-market. New organization-forms of flexibility and new ways of structuring work, creates new challenges for a pressured key organizational group, the managers. With high workload and stress, managers may be in the need of Work Life Balance to maintain good health and continued productivity as wells as HR support to manage their work-life. In the context of Covid-19, the bounderless work-life accelerates and creates the current context where the knowledge about manager´s Work Life Balance needs to be more extensive in Sweden.  Purpose: Combined with an inductive and interpretative perspective, describe how managers experiences Work Life Balance in a context of Covid-19.  Method: This study has been conductecwith an inductive approach where the empirical and not the theoretical, is the basis for this study. Dressed in only our prior knowledge during our time on the HR-program, the study was conductted in a case-study with nine manager´s who thorugh qualitative sem-structured interviews illustrates varying experiences of manager´s Work Life Balance.  Conclusions: Based on the purpose of this study, we demonstrate that a major part of the managers have an overall good Work Life Balance based on each manager´s own reality which is permeated by the uniqueness of each manager. Moreover, we have broken down factors that affects manager´s experiences of Work Life Balance from an individual and organizational context as well as examined that HR is not a primary resource of support to manager´s Work Life Balance and finally, identified how manager´s manage their Work Life Balance. Overall, there is no impending effect that Covid-19 has had on manager´s Work Life Balance. Furthermore, we can state that managers have thorugh their experience and own awareness, personfied their own Work Life Balance caused by example lack of support from HR, find other ways into create Work Life Balance.