La schizophrénie est une maladie psychiatrique grave qui affecte approximativement 1 % de la population. Il est clairement établi que la maladie possède une composante génétique très importante, mais jusqu’à présent, les études ont été limitées au niveau de l’identification de facteurs génétiques spécifiquement liés à la maladie. Avec l’avènement des nouvelles avancées technologiques dans le domaine du séquençage de l’ADN, il est maintenant possible d’effectuer des études sur un type de variation génétique jusqu’à présent laissé pour compte : les mutations de novo, c.-à-d. les nouvelles mutations non transmises de manière mendélienne par les parents. Ces mutations peuvent avoir deux origines distinctes : une origine germinale au niveau des gamètes chez les parents ou une origine somatique, donc au niveau embryonnaire directement chez l’individu. L’objectif général de la présente recherche est de mieux caractériser les mutations de novo dans la schizophrénie. Comme le rôle de ces variations est peu connu, il sera également nécessaire de les étudier dans un contexte global au niveau de la population humaine. La première partie du projet consiste en une analyse exhaustive des mutations de novo dans la partie codante (exome) de patients atteints de schizophrénie. Nous avons pu constater que non seulement le taux de mutations était plus élevé qu’attendu, mais nous avons également été en mesure de relever un nombre anormalement élevé de mutations non-sens, ce qui suggère un profil pathogénique. Ainsi, nous avons pu fortement suggérer que les mutations de novo sont des actrices importantes dans le mécanisme génétique de la schizophrénie. La deuxième partie du projet porte directement sur les gènes identifiés lors de la première partie. Nous avons séquencé ces gènes dans une plus grande cohorte de cas et de contrôles afin d’établir le profil des variations rares pour ces gènes. Nous avons ainsi conclu que l’ensemble des gènes identifiés par les études de mutations de novo possède un profil pathogénique, ce qui permet d’établir que la plupart de ces gènes ont un rôle réel dans la maladie et ne sont pas des artéfacts expérimentaux. De plus, nous avons pu établir une association directe avec quelques gènes qui montrent un profil aberrant de variations rares. La troisième partie du projet se concentre sur l’effet de l’âge paternel sur le taux de mutations de novo. En effet, pour la schizophrénie, il est démontré que l’âge du père est un facteur de risque important. Ainsi, nous avons tenté de caractériser l’effet de l’âge du père chez des patients en santé. Nous avons observé une grande corrélation entre l’âge du père et le taux de mutations germinales et nous avons ainsi pu répertorier certaines zones avec un grand nombre de mutations de novo, ce qui suggère l’existence de zone chaude pour les mutations. Nos résultats ont été parmi les premiers impliquant directement les mutations de novo dans le mécanisme génétique de la schizophrénie. Ils permettent de jeter un nouveau regard sur les réseaux biologiques à l’origine de la schizophrénie en mettant sous les projecteurs un type de variations génétiques longtemps laissé pour compte. / Schizophrenia is a severe psychiatric disorder that affects roughly 1% of the general population. It has been clearly demonstrated that the disease possesses a strong genetic component, but thus far, studies have had limited success in identifying key schizophrenia genes. With the advent of new DNA sequencing technologies it is now possible to study a type of genetic variation that has been previously looked over: de novo mutations (new mutations not transmitted by parents) The main aim of the present thesis is to better characterize de novo mutations in schizophrenia. As the role of these variations is not very well known, it was also necessary to study them in a global context in the human population. The first part of our project was to do a comprehensive study of de novo mutations found in the coding section (exome) of patients affected with schizophrenia. We found that the mutation rate was higher than expected. We also observed an aberrant number of nonsense mutations, which suggests a pathogenic profile of mutations. Thus, we strongly suggested that de novo mutations are key players in the genetic mechanism of schizophrenia. The second part of the work builds on the genes bearing mutations identified in the exome sequencing analysis. We sequenced these genes in a larger cohort of cases and controls in order to establish the profile of rare variants for these genes. We were able to conclude that the global mutational profile of the genes identified during de novo mutation studies are indeed pathogenic, which confirms that some of those genes are really involved in the disease and are not sequencing artefacts. Additionally, we were also able to identify some genes that had an aberrant rare variation profile. The third part of the work aimed to characterize the paternal age effect on the de novo mutation rate. Indeed, in schizophrenia, it has been shown numerous times that paternal age is a risk factor for the disease. Thus, we have chosen to characterize this effect in a cohort of healthy subjects. We were able to observe a high correlation between paternal age and an elevated germline mutation rate. We were also able to confirm the existence of genomic regions that present an elevated number of de novo mutations, supporting the notion of mutational hotspots. Our results were amongst the first to be published on the scientific area to directly involve de novo mutations in the genetic mechanism of schizophrenia. Those results bring new clues on the biological networks underlying schizophrenia by investigating a genetic variation type long overlooked.

La schizophrénie est une maladie psychiatrique grave qui affecte approximativement 1 % de la population. Il est clairement établi que la maladie possède une composante génétique très importante, mais jusqu’à présent, les études ont été limitées au niveau de l’identification de facteurs génétiques spécifiquement liés à la maladie. Avec l’avènement des nouvelles avancées technologiques dans le domaine du séquençage de l’ADN, il est maintenant possible d’effectuer des études sur un type de variation génétique jusqu’à présent laissé pour compte : les mutations de novo, c.-à-d. les nouvelles mutations non transmises de manière mendélienne par les parents. Ces mutations peuvent avoir deux origines distinctes : une origine germinale au niveau des gamètes chez les parents ou une origine somatique, donc au niveau embryonnaire directement chez l’individu. L’objectif général de la présente recherche est de mieux caractériser les mutations de novo dans la schizophrénie. Comme le rôle de ces variations est peu connu, il sera également nécessaire de les étudier dans un contexte global au niveau de la population humaine. La première partie du projet consiste en une analyse exhaustive des mutations de novo dans la partie codante (exome) de patients atteints de schizophrénie. Nous avons pu constater que non seulement le taux de mutations était plus élevé qu’attendu, mais nous avons également été en mesure de relever un nombre anormalement élevé de mutations non-sens, ce qui suggère un profil pathogénique. Ainsi, nous avons pu fortement suggérer que les mutations de novo sont des actrices importantes dans le mécanisme génétique de la schizophrénie. La deuxième partie du projet porte directement sur les gènes identifiés lors de la première partie. Nous avons séquencé ces gènes dans une plus grande cohorte de cas et de contrôles afin d’établir le profil des variations rares pour ces gènes. Nous avons ainsi conclu que l’ensemble des gènes identifiés par les études de mutations de novo possède un profil pathogénique, ce qui permet d’établir que la plupart de ces gènes ont un rôle réel dans la maladie et ne sont pas des artéfacts expérimentaux. De plus, nous avons pu établir une association directe avec quelques gènes qui montrent un profil aberrant de variations rares. La troisième partie du projet se concentre sur l’effet de l’âge paternel sur le taux de mutations de novo. En effet, pour la schizophrénie, il est démontré que l’âge du père est un facteur de risque important. Ainsi, nous avons tenté de caractériser l’effet de l’âge du père chez des patients en santé. Nous avons observé une grande corrélation entre l’âge du père et le taux de mutations germinales et nous avons ainsi pu répertorier certaines zones avec un grand nombre de mutations de novo, ce qui suggère l’existence de zone chaude pour les mutations. Nos résultats ont été parmi les premiers impliquant directement les mutations de novo dans le mécanisme génétique de la schizophrénie. Ils permettent de jeter un nouveau regard sur les réseaux biologiques à l’origine de la schizophrénie en mettant sous les projecteurs un type de variations génétiques longtemps laissé pour compte. / Schizophrenia is a severe psychiatric disorder that affects roughly 1% of the general population. It has been clearly demonstrated that the disease possesses a strong genetic component, but thus far, studies have had limited success in identifying key schizophrenia genes. With the advent of new DNA sequencing technologies it is now possible to study a type of genetic variation that has been previously looked over: de novo mutations (new mutations not transmitted by parents) The main aim of the present thesis is to better characterize de novo mutations in schizophrenia. As the role of these variations is not very well known, it was also necessary to study them in a global context in the human population. The first part of our project was to do a comprehensive study of de novo mutations found in the coding section (exome) of patients affected with schizophrenia. We found that the mutation rate was higher than expected. We also observed an aberrant number of nonsense mutations, which suggests a pathogenic profile of mutations. Thus, we strongly suggested that de novo mutations are key players in the genetic mechanism of schizophrenia. The second part of the work builds on the genes bearing mutations identified in the exome sequencing analysis. We sequenced these genes in a larger cohort of cases and controls in order to establish the profile of rare variants for these genes. We were able to conclude that the global mutational profile of the genes identified during de novo mutation studies are indeed pathogenic, which confirms that some of those genes are really involved in the disease and are not sequencing artefacts. Additionally, we were also able to identify some genes that had an aberrant rare variation profile. The third part of the work aimed to characterize the paternal age effect on the de novo mutation rate. Indeed, in schizophrenia, it has been shown numerous times that paternal age is a risk factor for the disease. Thus, we have chosen to characterize this effect in a cohort of healthy subjects. We were able to observe a high correlation between paternal age and an elevated germline mutation rate. We were also able to confirm the existence of genomic regions that present an elevated number of de novo mutations, supporting the notion of mutational hotspots. Our results were amongst the first to be published on the scientific area to directly involve de novo mutations in the genetic mechanism of schizophrenia. Those results bring new clues on the biological networks underlying schizophrenia by investigating a genetic variation type long overlooked.

INTRODUÇÃO: O câncer colorretal é um dos cânceres mais incidentes no mundo. As maiores incidências são descritas em homens e aumentam com a idade. Porém, estudos recentes reportaram aumento da incidência entre os mais jovens. Apesar das maiores incidências serem descritas em países desenvolvidos, estes apresentam tendência de estabilidade ou declínio. Em países com tendência de aumento, a mudança no padrão alimentar é a principal hipótese para este aumento. A mortalidade apresenta tendência de queda, principalmente em países que investiram em diagnóstico precoce e tratamento oportunos. OBJETIVO: Estudar as desigualdades na incidência e mortalidade do câncer colorretal no Município de São Paulo e Brasil. MÉTODOS: Esta tese está dividida em três manuscritos. MANUSCRITO 1: Simulação e comparação de técnicas de correção de dados incompletos de idade para o cálculo de taxas de incidência. A partir de seis bases com diferentes proporções de dados incompletos para idade (5 até 50%), foram comparados dois métodos de correção. Verificou-se que bases com 5% ou mais de dados incompletos para idade apresentaram taxas de incidência subestimadas. O fator de correção retificou as subestimativas das taxas padronizadas, entretanto, esta técnica não permitiu corrigir taxas específicas por idade. A imputação múltipla foi útil na correção das taxas padronizadas e específicas em bancos com até 30% de dados incompletos. Bases com 5% ou mais de dados incompletos necessitam de aplicação de correção. A imputação múltipla mostrou-se superior ao fator de correção, pois permitiu corrigir as taxas de incidência específicas. MANUSCRITO 2: Descrição e análise das taxas de mortalidade por câncer de colorretal no Brasil, segundo sexo e Unidades da Federação e indicadores socioeconômicos. As tendências das taxas de mortalidade foram estimadas por modelo de regressão linear. No Brasil,ocorreu aumento da tendência da taxa de mortalidade em todos os estados para o sexo masculino e em 21 estados para o sexo feminino. Ao ajustar por taxa de mortalidade por causas mal definidas, Produto Interno Bruto e Coeficiente de Gini, a tendência de aumento manteve-se significativa (p<0,05) no Brasil e em sete estados em homens e em nove estados em mulheres. O aumento da taxa de mortalidade por câncer colorretal em algumas Unidades Federativas e no Brasil pode estar relacionada ao aumento da incidência, ao atraso no diagnóstico e no tratamento. MANUSCRITO 3: descrição e análise das taxas de incidência e mortalidade por câncer colorretal no município de São Paulo, segundo sexo e faixa etária. Foram calculadas as razões das taxas padronizadas de incidência e mortalidade, estimada a mudança percentual anual média (AAPC) e o efeito idade-período-coorte. As razões das taxas de incidência e mortalidade foram superiores a 1 em homens a partir dos 50 anos e para o total da população. Ao comparar com indivíduos de 30 a 39 anos, em ambos os sexos, as razões das taxas foram maiores que 1 após 40 anos. Verificou-se tendência de aumento da incidência em mulheres (AAPC 0,9%) e da mortalidade em homens (AAPC 1,0%) e em mulheres (AAPC 0,2%). O modelo idade-período-coorte apresentou melhor ajuste para a incidência, em ambos os sexos (p<0,001). A mortalidade em homens foi explicada pelo modelo idade-drift (p<0,001). No Munícipio de São Paulo, a tendência crescente da incidência pode estar relacionada à alimentação inadequada e ao aumento do diagnóstico e a da mortalidade por diagnóstico e tratamento inoportunos. / INTRODUCTION: Colorectal cancer is one of the most common cancers worldwide. The highest incidence rates are described in men and with increasing age. However, recent studies have reported an increase in incidence among younger people. Although the highest incidence are described in developed countries, they show a tendency of stability or decline. In countries with increasing trends, the change in dietary pattern is the main hypothesis for this increase. Mortality is declining, especially in countries that have invested in diagnosis and treatment. OBJECTIVE: To study the inequalities in the incidence and mortality from colorectal cancer in the city of São Paulo and Brazil. METHODS: This thesis is divided into three manuscripts. MANUSCRIPT 1: Simulation and comparison of incomplete data correction techniques for the calculation of incidence rates. From six databases with different proportions of incomplete data for age (5 to 50%), two correction methods were compared. Databases with 5% or more of incomplete data for age were found to have underestimated rates. The correction factor mitigated the underestimation of the standardized rates; however, this technique did not allow the correction of age-specific rates. Multiple imputation was useful in correcting standardized and age-specific rates in datasets with up to 30% incomplete data. Databases with 5% or more of incomplete data need to be corrected. Multiple imputation technique was a superior method in comparison to the correction factor. MANUSCRIPT 2: description and analysis of mortality rates from colorectal cancer in Brazil, according to sex and States, according to socioeconomic indicators. For the trend analysis, the linear regression models were chosen through linear regression In Brazil, there was an increase in the mortality rate in all states for males and in 21 states for females. When the mortality rate was controlled for ill-defined causes, Gross Domestic Product and Gini Index, the increasing trend of mortality remained significant (p-value <0.05) in Brazil and in seven states in men and in nine states in women. The increase in the colorectal cancer mortality rate in some States and in Brazil may be related to the possible increase in incidence delayed diagnosis and treatment. MANUSCRIPT 3: description and analysis of incidence and mortality rates for colorectal cancer in the city of São Paulo, according to sex and age group. The incidence and mortality rate ratios were estimated. Joinpoint regression was performed to obtain average annual percent change (AAPC) and age-period-cohort analysis was used to examine the incidence trends. The incidence and mortality rates ratio were higher than 1 in men aged 50 and over. When comparing individuals aged 30 to 39 in both sexes, the rates ratios were higher than 1 after 40 years. There was an upward trend in incidence in women only (AAPC 0.9%) and mortality in men (AAPC 1.0%) and women (AAPC 0.2%). The age-period-cohort model provided the best fit to incidence in both sexes (p <0.001). Mortality in men was explained by the age-drift model (p <0.001). In the city of São Paulo, the increasing trend in incidence may be related to inadequate diet and increased diagnosis and mortality due to untimely diagnosis and treatment.

INTRODUÇÃO: O câncer colorretal é um dos cânceres mais incidentes no mundo. As maiores incidências são descritas em homens e aumentam com a idade. Porém, estudos recentes reportaram aumento da incidência entre os mais jovens. Apesar das maiores incidências serem descritas em países desenvolvidos, estes apresentam tendência de estabilidade ou declínio. Em países com tendência de aumento, a mudança no padrão alimentar é a principal hipótese para este aumento. A mortalidade apresenta tendência de queda, principalmente em países que investiram em diagnóstico precoce e tratamento oportunos. OBJETIVO: Estudar as desigualdades na incidência e mortalidade do câncer colorretal no Município de São Paulo e Brasil. MÉTODOS: Esta tese está dividida em três manuscritos. MANUSCRITO 1: Simulação e comparação de técnicas de correção de dados incompletos de idade para o cálculo de taxas de incidência. A partir de seis bases com diferentes proporções de dados incompletos para idade (5 até 50%), foram comparados dois métodos de correção. Verificou-se que bases com 5% ou mais de dados incompletos para idade apresentaram taxas de incidência subestimadas. O fator de correção retificou as subestimativas das taxas padronizadas, entretanto, esta técnica não permitiu corrigir taxas específicas por idade. A imputação múltipla foi útil na correção das taxas padronizadas e específicas em bancos com até 30% de dados incompletos. Bases com 5% ou mais de dados incompletos necessitam de aplicação de correção. A imputação múltipla mostrou-se superior ao fator de correção, pois permitiu corrigir as taxas de incidência específicas. MANUSCRITO 2: Descrição e análise das taxas de mortalidade por câncer de colorretal no Brasil, segundo sexo e Unidades da Federação e indicadores socioeconômicos. As tendências das taxas de mortalidade foram estimadas por modelo de regressão linear. No Brasil,ocorreu aumento da tendência da taxa de mortalidade em todos os estados para o sexo masculino e em 21 estados para o sexo feminino. Ao ajustar por taxa de mortalidade por causas mal definidas, Produto Interno Bruto e Coeficiente de Gini, a tendência de aumento manteve-se significativa (p<0,05) no Brasil e em sete estados em homens e em nove estados em mulheres. O aumento da taxa de mortalidade por câncer colorretal em algumas Unidades Federativas e no Brasil pode estar relacionada ao aumento da incidência, ao atraso no diagnóstico e no tratamento. MANUSCRITO 3: descrição e análise das taxas de incidência e mortalidade por câncer colorretal no município de São Paulo, segundo sexo e faixa etária. Foram calculadas as razões das taxas padronizadas de incidência e mortalidade, estimada a mudança percentual anual média (AAPC) e o efeito idade-período-coorte. As razões das taxas de incidência e mortalidade foram superiores a 1 em homens a partir dos 50 anos e para o total da população. Ao comparar com indivíduos de 30 a 39 anos, em ambos os sexos, as razões das taxas foram maiores que 1 após 40 anos. Verificou-se tendência de aumento da incidência em mulheres (AAPC 0,9%) e da mortalidade em homens (AAPC 1,0%) e em mulheres (AAPC 0,2%). O modelo idade-período-coorte apresentou melhor ajuste para a incidência, em ambos os sexos (p<0,001). A mortalidade em homens foi explicada pelo modelo idade-drift (p<0,001). No Munícipio de São Paulo, a tendência crescente da incidência pode estar relacionada à alimentação inadequada e ao aumento do diagnóstico e a da mortalidade por diagnóstico e tratamento inoportunos. / INTRODUCTION: Colorectal cancer is one of the most common cancers worldwide. The highest incidence rates are described in men and with increasing age. However, recent studies have reported an increase in incidence among younger people. Although the highest incidence are described in developed countries, they show a tendency of stability or decline. In countries with increasing trends, the change in dietary pattern is the main hypothesis for this increase. Mortality is declining, especially in countries that have invested in diagnosis and treatment. OBJECTIVE: To study the inequalities in the incidence and mortality from colorectal cancer in the city of São Paulo and Brazil. METHODS: This thesis is divided into three manuscripts. MANUSCRIPT 1: Simulation and comparison of incomplete data correction techniques for the calculation of incidence rates. From six databases with different proportions of incomplete data for age (5 to 50%), two correction methods were compared. Databases with 5% or more of incomplete data for age were found to have underestimated rates. The correction factor mitigated the underestimation of the standardized rates; however, this technique did not allow the correction of age-specific rates. Multiple imputation was useful in correcting standardized and age-specific rates in datasets with up to 30% incomplete data. Databases with 5% or more of incomplete data need to be corrected. Multiple imputation technique was a superior method in comparison to the correction factor. MANUSCRIPT 2: description and analysis of mortality rates from colorectal cancer in Brazil, according to sex and States, according to socioeconomic indicators. For the trend analysis, the linear regression models were chosen through linear regression In Brazil, there was an increase in the mortality rate in all states for males and in 21 states for females. When the mortality rate was controlled for ill-defined causes, Gross Domestic Product and Gini Index, the increasing trend of mortality remained significant (p-value <0.05) in Brazil and in seven states in men and in nine states in women. The increase in the colorectal cancer mortality rate in some States and in Brazil may be related to the possible increase in incidence delayed diagnosis and treatment. MANUSCRIPT 3: description and analysis of incidence and mortality rates for colorectal cancer in the city of São Paulo, according to sex and age group. The incidence and mortality rate ratios were estimated. Joinpoint regression was performed to obtain average annual percent change (AAPC) and age-period-cohort analysis was used to examine the incidence trends. The incidence and mortality rates ratio were higher than 1 in men aged 50 and over. When comparing individuals aged 30 to 39 in both sexes, the rates ratios were higher than 1 after 40 years. There was an upward trend in incidence in women only (AAPC 0.9%) and mortality in men (AAPC 1.0%) and women (AAPC 0.2%). The age-period-cohort model provided the best fit to incidence in both sexes (p <0.001). Mortality in men was explained by the age-drift model (p <0.001). In the city of São Paulo, the increasing trend in incidence may be related to inadequate diet and increased diagnosis and mortality due to untimely diagnosis and treatment.

xviii, 210 p. : ill. (some col.) / The current dissertation investigated segmental and prosodic aspects of first- (L1) and second-language (L2) speech production. Forty Korean-speaking adults and children varying in L2 experience (6 months-inexperienced vs. 6 years-experienced) as well as twenty age-matched native English speaking adults and children participated. Experienced children born in the U.S. were first exposed to English much earlier than inexperienced children. Group differences were investigated for insight into the effect of differing language experience on speech production. For segmental aspects, spectral quality and duration of English and Korean vowels (Chapter II), the effect of English coda consonant voicing on vowel and consonant closure duration (Chapter III), and language-specific voice onset time (VOT) in English and Korean stops (Chapter IV) were examined. All Korean groups except the experienced children differed from the native English speakers in vowel spectral quality and coda voicing production. The experienced children showed native-like production of both English and Korean vowels and also used VOT to distinguish Korean aspirated and English voiceless stops. These results suggest that the experienced children have separate phonological representations for their two languages. For prosodic aspects, stressed and unstressed vowels in English multisyllabic words (Chapter V) and Korean four-syllable phrases (Chapter VI) were elicited. The results of stressed and unstressed vowel production revealed that the Korean adults were able to acquire English prosody in a native-like manner, except for reduced vowel quality. Contrary to the little L1-L2 interaction in prosody for adults, Korean experienced children's production suggested a strong influence of English acquisition on the development of Korean prosody in terms of fundamental frequency, intensity, and duration patterns. Different degrees of L1-L2 interaction between Korean experienced children's production of segments and prosody are discussed from the developmental standpoint of simultaneous bilingual children's language shift from the mother tongue to English. In addition to children's greater plasticity of language acquisition, external (e.g., peer pressure, language input) and internal (e.g., ethnic self-identity) factors are likely to have created a language learning environment different from that of the Korean adults. As a result, the degree and direction of L1-L2 interaction varied by linguistic domains, depending on the age of the learner and the language experience. / Committee in charge: Susan Guion-Anderson, Chairperson; Melissa Redford, Member; Vsevolod Kapatsinski, Member; Kaori Idemaru, Outside Member

No description available.

Pension schemes are facing more difficulties on matching their underlying liabilities with assets, mainly due to faster mortality improvements for their underlying populations, better environments and medical treatments and historically low interest rates. Given most of the pension schemes are relatively much smaller than the national population, modelling and forecasting the small populations' longevity risk become urgent tasks for both the industrial practitioners and academic researchers. This thesis starts with a systematic analysis on the influence of population size on the uncertainties of mortality estimates and forecasts with a stochastic mortality model, based on a parametric bootstrap methodology with England and Wales males as our benchmark population. The population size has significant effect on the uncertainty of mortality estimates and forecasts. The volatilities of small populations are over-estimated by the maximum likelihood estimators. A Bayesian model is developed to improve the estimation of the volatilities and the predictions of mortality rates for the small populations by employing the information of larger population with informative prior distributions. The new model is validated with the simulated small death scenarios. The Bayesian methodologies generate smoothed estimations for the mortality rates. Moreover, a methodology is introduced to use the information of large population for obtaining unbiased volatilities estimations given the underlying prior settings. At last, an empirical study is carried out based on the Scotland mortality dataset.

Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FTIR microspectroscopy. In the first part of this study, global structural and compositional changes in BM-MSCs during beta thallasemia major (

Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FTIR microspectroscopy. In the first part of this study, global structural and compositional changes in BM-MSCs during beta thallasemia major (

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