Transcriptional regulation of gene expression in eukaryotes has evolved over millions of years. The regulatory pathways of nuclear receptors represent an evolutionarily ancient, but conserved mechanism with associated accessory proteins, many of them forming a functional nexus known as the Mediator complex involved in transcription. Despite the versatility of the pathway, e.g. through the adoption of new regulatory functions in phylogenetically more recent Metazoa, we hypothesise that the intrinsic potential of the NR-Mediator axis to directly translate a stimulus to a biological response is conserved across species, and additional regulation could also be achieved through secondary functions of its essential members. To support the hypothesis, we assessed the ligand-binding capability of retinoic X receptor in Trichoplax adhaerens and provided evidence to support the concept that this capability was already present at the base of metazoan evolution. With regards to the potential secondary functions, we took inspiration from previous research and identified the Mediator subunit 28 (MED28) as the only known member having documented nuclear and cytoplasmic dual roles, and thus possessing the potential to transmit signals from the cellular structural states to the nucleus. Due to the lack of...

The mammalian central nervous system is not able to regenerate neurons lost upon injury. In contrast, anamniote vertebrates show a remarkable regenerative capacity and are able to replace damaged cells and restore function. Recent studies have shown that in naturally regenerating vertebrates, such as zebrafish, inflammation is a key processes required for the initiation of regeneration. These findings are in contrast to many studies in mammals, where the central nervous system has long been viewed as an immune-privileged organ with inflammation considered one of the key negative factors causing lack of neuronal regeneration. In this review, we discuss similarities and differences between naturally regenerating vertebrates, and those with very limited to non-existing regenerative capacity. We will introduce neural stem and progenitor cells in different species and explain how they differ in their reaction to acute injury of the central nervous system. Next, we illustrate how different organisms respond to injuries by activation of their immune system. Important immune cell types will be discussed in relation to their effects on neural stem cell behavior. Finally, we will give an overview on key inflammatory mediators secreted upon injury that have been linked to activation of neural stem cells and regeneration. Overall, understanding how species with regenerative potential couple inflammation and successful regeneration will help to identify potential targets to stimulate proliferation of neural stem cells and subsequent neurogenesis in mammals and may provide targets for therapeutic intervention strategies for neurodegenerative diseases.

博士(心理学) / Doctor of Philosophy in Psychology / 同志社大学 / Doshisha University

The cause and effect paradigm underlying medical research has led to an enhanced etiological understanding of many diseases and the development of many lifesaving drugs, but the paradigm does not always include an understanding of the pathways involved. Causal mediation analysis extends the cause and effect relationship to the cause and effect through a mediator, an intermediate variable on the causal pathway. The total effect of an exposure on an outcome is decomposed into two parts: 1) the indirect effect of the exposure on the outcome through the mediator and 2) the direct effect of the exposure on the outcome through all other pathways. In this dissertation, I describe various counterfactual causal mediation frameworks with identifiability assumptions that all lead to the Mediation Formula. The indirect and direct effects can be estimated from observable data using a semi-parametric algorithm derived from the Mediation Formula that I generalize to different types of mediators and outcomes. With an increased interest in causal mediation analysis, thoughtful consideration is necessary in the application of the Mediation Formula to real-world data challenges. Here, I consider three motivating causal mediation questions in the areas of HIV curative research and cardio-respiratory fitness. HIV curative treatments typically target the viral reservoir, cells infected with latent HIV. Quantifying the effect of an HIV curative treatment on viral rebound over a set time horizon mediated by reductions in the viral reservoir can inform future directions for improving curative treatments. In cardiorespiratory fitness research, metabolites, molecules involved with cellular respiration, are believed to mediate the effect of physical activity on cardiorespiratory fitness. I propose three novel adaptations to the semi-parametric estimation algorithm to address three data challenges: 1) Numerical integration and optimization of the observed data likelihood for mediators with an assay lower limit (left-censored mediators); 2) Pseudo-value approach for time-to-event outcomes on a restricted mean survival time scale; 3) Elastic net regression for high-dimensional mediators. My novel approaches provide estimation frameworks that can be applied to a broad spectrum of research questions. I provide simulation studies to assess the properties of the estimators and applications of the methodologies to the motivating data. / 2025-06-16T00:00:00Z

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付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 新制・課程博士 / 博士(医学) / 甲第23789号 / 医博第4835号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 松田 道行, 教授 寺田 智祐 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

L’étude proposée dans ce mémoire porte sur le processus de visite des adolescents de 14-16 ans au Musée des beaux-arts de Montréal. Je mobilise principalement les concepts de « médiateurs » et « médiations », entendus selon la définition proposée par Hennion (1988, 2000). En effet, Hennion propose de voir la médiation non comme un pont entre deux entités, vision commune de la médiation, mais comme un processus en construction. Ainsi, le médiateur est un élément qui va capter l’attention du jeune visiteur et la médiation est l’action qui va se développer dans cette relation médiateur-visiteur. L’analyse vise plus particulièrement à identifier les médiateurs qui agissent durant cette visite et à comprendre les médiations qui se mettent en place. Cette étude a été réalisée au moyen d’entrevues semi-structurées et d’observations participantes, auprès de six adolescents, âgés de 14 à 16 ans. Une première entrevue permettait de connaître les antécédents de ces jeunes à l’égard des musées et de comprendre suite à quelles mises en condition ils se rendaient à l’exposition. Une observation, par groupe de deux participants, a ensuite été menée lors de l’exposition du Musée des beaux-arts de Montréal : Il était une fois l’impressionnisme. Une histoire de l’impressionnisme : chefs-d’œuvre de la peinture française du Clark. Ces observations ont permis de repérer les moments qui ont capté l’attention des participants durant leur visite. Enfin, une seconde entrevue a été l’occasion de revenir sur leur expérience de visite et de dégager les médiations qui se sont mises en place. Sur les bases de ce terrain, ce mémoire met en avant un ensemble de médiateurs (les autres visiteurs, l’environnement physique, l’œuvre et le récit) et de médiations (rêver, comprendre, se projeter, admirer, comparer et refuser) qui se sont développées chez ces adolescents. Suite à cela, ce mémoire propose une explication du processus de visite tel qu’analysé chez ces adolescents à travers la représentation de la « spirale coquillage ». Cette représentation souligne le fait que le processus de visite n’est pas un phénomène linéaire mais se fait par la confrontation des antécédents de l’adolescent avec sa nouvelle expérience de visite. Il s’agit donc d’un processus circulaire qui se base sur ses antécédents pour construire progressivement de nouvelles strates, qui conditionneront ses prochaines expériences au musée. / The study presented in this thesis focuses on the visiting process of teenagers from 14 to 16 years old at the Montreal Museum of Fine Arts. I am principally drawing on concepts of “mediators” and “mediations”, following the definition given by Hennion (1988, 2000). Indeed, Hennion suggests that mediation should not be seen as a bridge between two entities, which is the common vision of mediation, but rather as a process under construction. Thus, the mediator is an element that will capture the young visitor's attention and mediation is the action that will develop in this mediator-visitor relationship. The analysis more specifically aims to identify the mediators acting during this visit and to understand the mediations that get constituted. This study was conducted with six teenagers between 14 and 16 years old. A first interview enabled me to become acquainted with the background of the young visitors regarding museums, and to understand in which conditions they were going to the exhibit. An observation, done in binomial groups, was then carried out during Once upon a time Impressionism. A story of impressionism: great French paintings from the Clark, the exhibit held at the Montreal Museum of Fine Arts. These observations allowed me to spot the moments that attracted the teenagers' attention during the visit. Finally, a second interview gave the opportunity to go over their visiting experience and to bring out the mediations that occurred. On the basis of this fieldwork, this thesis foregrounds a set of mediators (the other visitors, the environment, the works and stories) and mediations (dreaming, understanding, planning, admiring, comparing and refusing) that teenagers have developed. Following this, the thesis offers an explanation of the visiting process as analyzed with these teenagers through the representation of the “shell spiral''. This representation emphasizes the fact that the visiting process is not a linear phenomenon, but is created through the confrontation of the teenager's background with his new visiting experience. It is thus a circular process that relies on the teenager's background to progressively build new strata that will condition his future museum experiences.

Nutrient availability regulates eukaryotic cell growth. This study focuses on two signaling pathways, involved in sensing amino acids and carbon sources, which allow cells to respond appropriately to their presence. The first part of this study shows that Ssy1, a plasma membrane localized sensor in the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway, can detect 19 common L-amino acids with different potencies and affinities based on the physiochemical structure of amino acids. Substituents around alpha carbon are critical for amino acid sensing by Ssy1. Furthermore, a high concentration of cysteine is toxic to cells. Inactivation of SPS signaling confers resistance to cysteine. The second part focuses on the regulation of Hap4, the regulatory subunit of the Hap2/3/4/5 transcriptional factor complex. Many components of the 25-subunit Mediator complex negatively regulate HAP4 expression. Srb8 undergoes post-translational modification in response to changes of the carbon source. Gal11 and Med3 positively regulate HAP4 expression.

<p>The Mediator (Med) complex comprises about 30 subunits and is a transcriptional co-regulator in eukaryotic systems. The core Mediator complex, consisting of the head, middle and tail modules, functions as a bridge between transcription factors and basal transcription machinery, whereas the CDK8 kinase module can attenuate Mediator’s ability to function as either a co-activator or co-repressor. Many Arabidopsis Mediator subunit has been functionally characterized, which reveals critical roles of Mediator in many aspects of plant growth and development, responses to biotic and abiotic stimuli, and metabolic homeostasis. Traditional genetic and biochemical approaches laid the foundation for our understanding of Mediator function, but recent transcriptomic and metabolomic studies have provided deeper insights into how specific subunits cooperate in the regulation of plant metabolism. In Chapter 1, we highlight recent developments in the investigation of Mediator and plant metabolism, with emphasis on the large-scale biology studies of <i>med</i> mutants.</p> <p>We previously found that MED5, an Arabidopsis Mediator tail subunit, is required for maintaining phenylpropanoid homeostasis. A semi-dominant mutation (<i>reduced epidermal fluorescence 4-3</i>, <i>ref4-3</i>) that causes a single amino acid substitution in MED5b functions as a strong suppressor of the pathway, leading to <a>decreased soluble phenylpropanoid accumulation, reduced lignin content and dwarfism</a>. In contrast, loss of MED5a and MED5b (<i>med5</i>) results in increased levels of phenylpropanoids. In Chapter 2, we present our finding that <i>ref4-3</i> requires CDK8, a Mediator kinase module subunit, to repress plant growth even though the repression of phenylpropanoid metabolism in <i>ref4-3 </i>is CDK8-independent. Transcriptome profiling revealed that salicylic acid (SA) biosynthesis genes are up-regulated in a CDK8-dependent manner in <i>ref4-3,</i> resulting in hyper-accumulation of SA and up-regulation of SA response genes. Both growth repression and hyper-accumulation of SA in <i>ref4-3</i> require CDK8 with intact kinase activity, but these SA phenotypes are not connected with dwarfing. In contrast, mRNA-sequencing (RNA-seq) analysis revealed the up-regulation of a DNA J protein-encoding gene in <i>ref4-3</i>, the elimination of which partially suppresses dwarfing. Together, our study reveals genetic interactions between Mediator tail and kinase module subunits and enhances our understanding of dwarfing in phenylpropanoid pathway mutants.</p> <p>In Chapter 3, we characterize other phenotypes of <i>med5</i> and <i>ref4-3</i>, and find that in addition to the up-regulated phenylpropanoid metabolism, <i>med5</i> show other interesting phenotypes including hypocotyl and petiole elongation as well as accelerated flowering, all of which are known collectively as the shade avoidance syndrome (SAS), suggesting that MED5 antagonize shade avoidance in wild-type plants. In contrast, the constitutive <i>ref4-3 </i>mutant protein inhibits the process, and the stunted growth of <i>ref4-3 </i>mutants is substantially alleviated by the light treatment that triggers SAS. Moreover, <i>ref4-3</i> mimics the loss-of-function <i>med5</i> mutants in maintaining abscisic acid (ABA) levels under both normal and drought growth conditions. The phenotypic characterization of <i>med5</i> mutants extend our understanding of the role of Mediator in SAS and ABA signaling, providing further insight into the physiological and metabolic responses that require MED5.</p> <p>In Chapter 4, we explore the function of MED5 and CDK8 in gene expression regulation by investigating the effect of mutations in Mediator including <i>med5</i>, <i>ref4-3</i>, <i>cdk8-1</i> and <i>ref4-3 cdk8-1</i> on genome-wide Pol II distribution. We find that loss of MED5 results in loss of Pol II occupancy at many target genes. In contrast, many genes show enriched Pol II levels in <i>ref4-3</i>, some of which overlap with those showing reduced Pol II occupancy in <i>med5</i>. In addition, Pol II occupancy is significantly reduced when CDK8 is disrupted in <i>ref4-3</i>. Our results help to narrow down the direct gene targets of MED5 and identify genes that may be closely related to the growth deficiency observed in <i>ref4-3</i> plants, providing a critical foundation to elucidate the molecular function of Mediator in transcription regulation.</p>