Chez l’homme, des données cliniques décrivent une association entre des pathologies hépatiques et des désordres de la fertilité masculine. Plusieurs modèles expérimentaux de cholestase ont permis de confirmer ce lien et de souligner un impact sur la physiologie testiculaire. De manière intéressante, une telle corrélation existe aussi bien à l’âge adulte que dans des modèles animaux en période pré-pubertaire. Pour autant, le lien moléculaire pouvant expliquer cette association physiopathologique n’a pas été exploré. L’ensemble des hépatopathies a pour dénominateur commun une augmentation des taux plasmatiques d’acides biliaires et ce dès les stades les plus précoces de la maladie. Dans ce contexte, l’hypothèse de l’impact délétère des acides biliaires sur la fonction reproductrice reste à définir. Notre projet de recherche s’articule autour de l’analyse d’un modèle murin d’atteinte hépatique induite par un régime supplémenté en acide cholique. Nos résultats principaux montrent que : 1) lors d’une exposition pubertaire, l’activation supra-physiologique des signalisations Fxrα conduit à un défaut de maturation sexuelle associé à une altération de la fonction endocrine du testicule ; 2) dans un contexte d’exposition à l’âge adulte, l’activation excessive du récepteur membranaire Tgr5 par les acides biliaires est associées à une hypofertilité. Celle-ci s’accompagne d’une altération de la spermatogenèse consécutive à un détachement progressif de l’épithélium séminifère et à une apoptose spécifique des spermatides ; 3) enfin, nos conclusions démontrent pour la première fois l’impact transgénérationnel de l’exposition aux acides biliaires. Sur deux générations successives, les descendants des mâles adultes nourris par un régime supplémenté en acide cholique présentent des anomalies développementales et métaboliques. Dépendantes de l’action de Tgr5, ces dernières sont attribuées à des altérations de l’épigénome des spermatozoïdes issus des mâles exposés aux acides biliaires. En conclusion, nos données démontrent que, dans des conditions cholestatiques, les acides biliaires altèrent les fonctions de reproduction notamment par leurs impacts sur les fonctions testiculaires. Au regard du nombre croissant de personnes souffrant de troubles hépatiques, ces effets délétères des acides biliaires pourraient contribuer à l’augmentation de l’incidence de l’infertilité masculine. Des molécules agonistes des signalisations FXRα et TGR5 sont aujourd’hui envisagées dans le cadre du traitement de pathologies courantes de notre société. Dans ce contexte, notre étude permettra d’alerter les instances sanitaires quant aux conséquences de l’accès à de tels traitements sur la fertilité et la santé des générations futures. / Clinical data describe an association between liver diseases and disorders of male fertility. Several experimental models of cholestasis have confirmed this link and highlight an impact on testicular physiology. Interestingly, such correlation exists in adult as well as in during pre-pubertal animals. However, the molecular links have not been explored yet. The increase of plasma bile acids levels is a common feature of liver diseases. In this context, the hypothesis of the deleterious impact of bile acids on reproductive function remains to be defined. For that purpose, we used a mouse model of liver injury induced by a diet supplemented with cholic acid. Main results show that: 1) supra-physiological activation of Fxra, during pubertal period, alters endocrine function of the testis and then sexual maturation. 2) during adult age excessive activation of membrane receptor TGR5 by bile acids leads to subfertility. This is associated with impaired spermatogenesis due to a detachment of the seminiferous epithelium and specific apoptosis of spermatids. 3) Finally, we show for the first time the transgenerational impact of bile acid exposure. Two generations of progenies from males exposed to bile acid-diet show developmental and metabolic abnormalities. These effects, mediated by TGR5, are correlated with alterations of the spermatozoa epigenome. In conclusion, our data demonstrate that bile acids affect reproductive functions with impacts on testicular functions. In line with the increasing number of people with liver diseases, the deleterious effects of bile acids may contribute to the incidence of male infertility. Interestingly, agonists of FXRα and TGR5 are now considered in the treatment of several diseases. In this context, our study might alert health authorities regarding the potential consequences of these treatments on fertility and health futures generations.

Genomic modifications occur slowly across generations, whereas short-term epigenetic transgenerational inheritance of adaptive phenotypes may be immediately beneficial to large numbers of individuals, acting as a bridge for survival when adverse environments occur. In this study we used dietary exposure to crude oil as an example of an environmental stressor to assess its effects from the molecular to the organismal levels in piscine and avian animal models. In addition, we assessed the role of the parental exposures on their offspring F1 generation. The research developed in this dissertation has contributed to several areas of investigation including molecular biology, animal physiology, and evolutionary biology. The quantitative information from these studies may be utilized to supplement information regarding the proximate and ultimate effects of environmental stressors on fish and bird populations. Furthermore, this information may be used as additional support for understanding the conservation of the responses from the molecular to the whole organismal levels across the vertebrate taxa, as well as their implications for population survival and maintenance. Additionally, the zebrafish (Danio rerio), the Siamese fighting fish (Betta splendens) and the king quail (Coturnix chinensis) have proven to be excellent models to start building a strong basis for understanding the effects of environmental stressors and transgenerational epigenetic phenomena using a multi-level approach. Furthermore, as more raw data and information is discovered, the concatenation of development, organismal variation, epigenetics inheritance, natural selection, speciation and evolution is being slowly decrypted.

This thesis presents the results of a historical investigation of the arrival and presence of Vietnamese immigrants in Prague between 1974 and 1993. Methodologically, the research is based on interviews with witnesses of the program of socialist internationalism and on the study of the Czechoslovak government administrative documents from the period between 1974, ie. the year the signing of the Agreement between the Government Czechoslovak Socialist Republic and the Socialist Republic of Vietnam about employing Vietnamese citizens in Czechoslovak organizations1 , with a milestone in 1989 as the collapse of the communist regime, and the year 1993, as the separation of Slovakia and the establishment of an independent Czechoslovak Republic This work is not only based on the assumption that this program influenced the integration of the first generation in Czechoslovak society, but it also shows an indirect influence on the second generation coming after the Velvet Revolution, due to the program's effect on the emergence of Vietnamese social networks. The research aims to uncover the factors that influence the adaptation of the first and second generations in the majority environment and to indicate the effect that the normative framework of the program had on the formation of ethnic social networks. It...

In this essay, the aim is to analyse the representation of collective and cultural trauma within the narrative of Tommy Orange's novel There There, as well as how the novel is redressing the experience of traumatisation, leading a way towards healing. To do this, the essay will focus on six of the novel's characters as well as the title, prologue and interlude. By using concepts of colonial and transgenerational trauma as well as survivance to approach the novel, the essay will argue that, as it makes the trauma visible, the narrative shows that healing can still be possible after traumatisation.

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Western studies have established that men from African descent are disproportionally affected by prostate cancer (PCa). Annual incidence rates in this population vary from 1.5 to 2 times when compared to their counterparts from other racial groups. They also record the worse outcomes in terms of prognosis. Additionally, with the rise of PCa in Subsaharan Africa, new cancer control policies and programs are increasingly demanded. Understanding therefore, factors that underpin racial inequality in distribution and especially why the disease preferentially niches in African males can help better address PCa in both Western and Subsaharan countries. There is also the potential to develop new therapeutic options. A genetic susceptibility was first hypothesized, however available data suggest that they only account for less than 20% of the cases. Current findings from epidemiological and molecular investigations suggest an important role of complex and dynamic environmental interactions involving the different levels of calcium regulation. Using a multi-method design, this research aims at developing an integrative mechanistic model of PCa. We argue that given the versatile and ubiquitous role calcium plays in nutrition, physical environment, and in key cellular processes, that mineral cation is central to prostate tumorigenesis and in shaping its populational distribution. Thus a tree-level investigation was conducted: (i) a critical analysis and synthesis of empirical evidence on calcium interactions with cancer mechanisms (ii) a population-wide prospective cohort study of calcium intake patterns in a group of Subsaharan males in Côte d’Ivoire, namely the African Prostate Cancer Study (APCS) (iii) a proteomics research investigating the responses of prostate cancer cell lines when exposed to a high affinity synthetic calcium binding peptide. This monograph describes the research methods, instruments design and validation and the preliminary findings of the ongoing research, portions of which have already been published, presented at two international cancer seminars or under review. Findings at this stage include: mechanistic models of prostate cancer differential distribution and outcomes, a novel calcium questionnaire specific to African diet, synthesis of a high affinity calcium-binding peptide (Peptide#1). New concepts and constructs related to prostatic carcinogenesis have been developed as well.

Monospecific stands of invasive plant species are found in nearly all known ecosystems and can cause permanent lasting ecosystem damage via deleterious effects in soils. These deleterious soil effects are a proposed mechanism which drives invasions by plants and are known to be influenced by kin recognition in plants. Uncovering whether invasive species utilize kin recognition to facilitate their own ecological persistence via soil conditioning will allow us to better understand the drivers of plant invasions and help combat them. In my master’s thesis, I examined the role of kin recognition and kin selection on soil effects. I grew groups of Potentilla recta in groups of maternal half-sibs or strangers to condition the soil. I then grew a second generation of plants in that conditioned soil to determine the impacts of soil conditioning effects on plant performance. I found soil conditioning by groups of plants affected the performance of a second generation of plants based on the relatedness of the conditioning plants. Further, these soil effects of conditioning selectively benefit future individuals of a subsequent generation based on their relatedness. Moreover, these soil effects only existed in soil that has not been sterilized, indicating these soil effects depended on soil microbes. / Thesis / Master of Biological Science (MBioSci) / Invasive plants form dense stands of same-species individuals that can cause lasting deleterious effects to the soil. These deleterious soil effects have been proposed as a mechanism driving plant invasions. In my master’s thesis, I examined the role of kin recognition and kin selection on soil effects. I first grew groups of Potentilla recta in groups of maternal half-sibs or strangers to condition the soil, and then grew a second generation of plants in that conditioned soil to determine the impacts on plant performance. I found that soil influenced by groups of related plants affect increased the performance of a second generation of plants, particularly if the second generation was related to the first. Moreover, these soil effects only existed in soil that has not been sterilized, indicating these soil effects depended on soil microbes. I found that these soil effects of conditioning selectively benefited future individuals of a subsequent generation based on their relatedness.

Plants are sessile organisms and have developed varied mechanisms to tolerate stress. One such mechanism is DNA methylation, which plays a vital role within and across generational stress adaptation. To understand the role of DNA methylation in transgenerational stress adaptation, we exposed Arabidopsis thaliana for four generations of sub-lethal doses of glyphosate, trifloxysulfuron, clipping, and shading, which we further classified into the broader categories of stress ecological (shading and clipping) and herbicides (glyphosate and trifloxysulfuron). We analyzed phenotypic and whole-genome bisulfite sequencing data and found that the Arabidopsis phenotype adapts more rapidly to herbicide stress as compared to ecological stresses. DNA methylation changes for glyphosate were minimal after four generations of stress whereas the other three stresses showed dynamic change in the DNA methylation patterns. To understand within generation stress response, Sorghum bicolor was exposed to the same stresses at sub-lethal doses and we analyzed its phenotypic, whole genome bisulfite sequencing, and gene expression responses. Ecological stresses had higher negative impact on S. bicolor plant growth as compared to herbicide stresses. Similarly, we found higher differentially expressed genes for clipping as compared to both herbicides. All four stresses changed the methylome in a unique way; where we found 998 differentially methylated regions (DMR) for trifloxysulfuron, 193 for shading, 141 for clipping and 60 for glyphosate. Out of these DMR's some occurred genic region, which could potentially change gene expression and help plants withstand stress. Overall, DNA methylation can potentially help plants to withstand stress due to their dynamic and specific response to a variety of stresses both transgenerational and within generation. This information to better understand stress adaptation mechanisms in plants and used to develop stress-resilient crops. / Doctor of Philosophy / Environmental and anthropogenic stresses can negatively impact plant growth and development. Plants can have stress memory through epigenetic changes which helps them withstand stress in future generations. Epigenetics is the field of science where changes on the DNA and not sequence, that can be an addition or deletion of a methyl group, modification of histones, or production of small RNAs. We wanted to understand short and long-term effects of common anthropogenic and ecological stresses on how DNA methylation changes can help plants to withstand stress. We used the model plant Arabidopsis thaliana and the non-model crop/weed Sorghum bicolor. We exposed plants to sub-lethal doses of two herbicides, clipping, and shade stress, at levels high enough to cause significant visible injury but still allowed them to recover and reproduce for a single generation for S. bicolor and four generations for A. thaliana. We found that A. thaliana rapidly more adapts to herbicide stress as compared to ecological stresses. DNA methylation changes for glyphosate were minimal after four generations of stress whereas the other three stresses showed dynamic changes in the DNA methylation patterns. Each stressed impacted S. bicolor phenotype, DNA methylation, and gene expression in unique ways. We found ecological stresses greatly affected the phenotype of the S. bicolor plants as compared to herbicide stresses. Overall, our results showed that stress can cause DNA methylation changes and in transgenerational stress DNA methylation can potentially play a role in stress adaptation. This information could be useful for scientists to further understand stress resilience in plants.

A depressão é hoje a doença mental mais comum do mundo, afetando mais de 121 milhões de pessoas. Além disso, estima-se que em aproximadamente uma década ela se torne a 2º doença responsável pela perda prematura de vida entre todas as idades e sexos. Diferentes propostas foram feitas no intuito de se compreender os mecanismos pelos quais essa doença incide, contudo a etiologia dos transtornos depressivos ainda não é totalmente entendida. Existem consideráveis evidências de que a administração perinatal de lipopolissacarídeo (LPS), uma endotoxina bacteriana, promove efeitos persistentes no desenvolvimento e comportamento da prole de camundongos, os quais podem-se manter até a idade adulta. Ainda, esses eventos podem ter implicações evolucionárias ligadas a alterações transgeracionais. Tendo em vista que a ativação do sistema imune pode estar relacionada com os transtornos depressivos, o presente trabalho expos pré-natalmente ao LPS uma geração de camundongos avaliando os efeitos comportamentais dessa exposição em três gerações subsequentes levando-se em consideração os comportamentos depressivos e não depressivos de cada geração avaliada. Para isso camundongos fêmeas, após terem o comportamento selecionado pelo teste de suspensão da cauda (TSC), foram cruzadas com machos de mesmo comportamento recebendo 100g/kg de LPS ou solução salina no 15º dia de prenhez. Após os nascimentos, as gerações subsequentes tiveram o comportamento em questão avaliado pelo TSC, bem como a atividade geral em campo aberto. Além disso, a interação materno-filhote foi avaliada, uma vez que alterações na mesma poderiam contribuir para os efeitos do tratamento com a endotoxina. Ainda, foi-se realizado um desafio com LPS na geração filial 3, na qual o nível de citocinas e a expressão do comportamento doentio foram avaliadas. Os resultados mostraram que (i) a administração do LPS na geração parental não afetou o comportamento depressivo e não depressivo nas três gerações avaliadas, dado que animais com comportamento depressivo tiveram mais filhotes com o mesmo comportamento em todas as gerações. (ii) Foram observadas alterações no comportamento materno da geração parental, possivelmente ligadas a motivação materna desses animais. (iii) Foram encontradas alterações transgeracionais na atividade geral de camundongos machos e fêmeas das gerações filiais 1 e 2. Tais alterações foram mais x expressivas nos machos e, havendo diferenças entre o comportamento. Esses dados apontam que a exposição a endotoxina possui diferentes consequências de acordo com o comportamento e, (iv) os animais da geração filial 3 quando desafiados com a endotoxina apresentaram maior comportamento doentio e maiores níveis de citocinas. Esses dados apontam para um forte componente genético na transmissão do comportamento, além de, uma influencia epigenética na modulação do mesmo. Ainda, foi possível concluir que a inflamação gerada pela administração pré-natal do LPS atua de forma distinta entre os sexos, bem como o histórico comportamental, no caso, o comportamento depressivo e não depressivo estudados nesse trabalho / Depression disorders are to be considered the most common mental illness affecting more than 121 million people worldwide. It is estimated that approximately one decade it becomes the 2nd disease most responsible for premature loss of life of all ages and sexes. Different proposals to understand this disorders have been made in the past years, however its etiology it is still yet fully understood. There is considerable evidence that the administration of lipopolysaccharide (LPS), a bacterial endotoxin, promotes persistent effects on development and behavior of the offspring of mice, which are maintained into adulthood. Still, these events may have evolutionary implications related to transgenerational changes. Given that activation of the immune system may be related to depressive disorders, this study aimed to expose a generation of mice to LPS evaluating the behavioral effects on three subsequent generations taking into account the depressive-like and non depressive-like behaviors assessed on each generation by the tail suspension test (TST). For this, female mice after behavior selected by the tail suspension test (TST) were crossed with males of the same behavior and exposed to 100g/kg of LPS or saline solution on day 15th of pregnancy. After births, the subsequent generations were also evaluated on the TST and in the open field for general activity. In addition, the maternal interaction was also evaluated, since changes on this parameter could contribute to the treatment effects of the endotoxin. Yet, has been performed a challenge with LPS in the generation branch 3, wherein the level of expression of cytokines and sickness behavior were evaluated. The results showed that (i) the administration of LPS in the parental generation did not affect the depressive-like behaviors on the three generations evaluated, since animals with depressive-like and non depressive-like behavior had more offspring with the same behavior in all generations. (ii) Changes were observed in maternal behavior of the parental generation which is possibly related to a change in motivational state of those animals. (iii) Transgenerational alterations were found in the general activity of male and female mice of the filial generation 1 and 2. These changes were more significant in males and differences between depressive-like e non depressive-like behaviors were also observed. Together, these data indicate that the exposure to endotoxin has different consequences according to the animal historical behavior and, xii finally, (iv) the animals of filial generation 3 when challenged with endotoxin had higher sickness behavior and higher levels of cytokines when evaluated in the open field test. These data point to a strong genetic component in the transmission of behavior and, besides, a possible influence of epigenetic mechanism of the same. Furthermore it was possible to concluded that inflammation state created by the prenatal LPS exposure acts differently according to the animal historical behavior, in this case, the depressive-like and non depressive-like behavior studied, and also acting differently according to the sexes