The ability of the brain to change structurally and functionally with experience is called brain plasticity. High levels of pro-inflammatory cytokines impair normal memory formation and consolidation. To better understand the role of pro-inflammatory cytokines in learning, the contribution of the cytokine interleukin-6 (IL-6) to a motor skill learning task investigated. The Fmr1 Knockout (KO) mouse, an animal model of Fragile X Syndrome, has demonstrated impaired neural plasticity and learning. Fmr1 KO and control wild-type (WT) mice were trained on the dowel and flat beam runways to study motor skill learning and motor activity respectively. The cerebellum from the animals was examined for IL-6 protein using ELISA. No significant differences in the levels of IL-6 in the cerebellum of the Fmr1 KO and WT normal mice were found. The expression of IL-6 was not altered by the behavioural training. These results suggest lack of association between IL-6, and FMRP and motor skill learning. / October 2016

La cornification est la dernière étape de la différenciation terminale de l'épiderme. Elle est caractérisée par de profonds remaniements morphologiques et biochimiques du kératinocyte et aboutit à la formation d'une couche cornée solide, résistante, imperméable et hydratée, responsable de la fonction " barrière " de l'épiderme. Certaines génodermatoses rares, appelées ichtyoses, sont dues à des mutations de gènes impliqués dans la cornification. Le " Peeling Skin Disease " (PSD, OMIM 270300) est une ichtyose inflammatoire généralisée, caractérisée par une importante desquamation, de l'eczéma et un prurit souvent sévère et insomniant. Cette maladie chronique entraine une altération importante de la qualité de vie du patient. A ce jour, aucune thérapie efficace n'est disponible. Le PSD est dû à des mutations homozygotes du gène Cornéodesmosine (CDSN), qui code une protéine adhésive de l'épiderme essentielle à la cohésion du stratum corneum (SC) et à l'homéostasie de la barrière épidermique. La physiopathologie du PSD est encore mal connue. Le décollement du SC conduit à une rupture de la barrière épidermique, qui déclenche à son tour érythème, atopie et prurit, par des mécanismes non élucidés. Afin de décortiquer ces mécanismes, j'ai utilisé deux modèles murins d'invalidation du gène Cdsn (knock-out, KO) dans l'épiderme. Le premier mime le stade précoce du PSD (décollement du SC chez l'embryon E18.5 Cdsnep-/-) et le second, qui est inductible, reproduit le stade chronique (défaut persistant de la barrière épidermique chez la souris adulte Cdsniep-/-). J'ai réalisé l'étude comparative du transcriptome cutané de ces deux modèles à l'aide de puces à ADN. Des signatures d'expression génique distinctes, en lien avec une réponse de restauration de la barrière cutanée, ont été obtenues : induction principalement de gènes de l'inflammation et de la prolifération (Cdsnep-/-) vs des gènes de défenses de l'hôte et de la cornification (Cdsniep-/-). En particulier, une forte expression de gènes codant des inhibiteurs de protéases à cystéine de la famille des stéfines A (cystatine A chez l'homme) et des protéases à sérine de la famille des kallikréines (KLKs), caractérise le modèle adulte Cdsniep-/-. Ceci a été secondairement confirmé dans l'épiderme de patients atteints de PSD. Parmi les KLKs, KLK13 est apparue la plus fortement exprimée, contrairement à KLK5 dont l'expression reste faible et stable. KLK13 pourrait donc intervenir dans la réponse inflammatoire et/ou la desquamation, mécanismes dans lesquels jusqu'à présent seule KLK5 a été décrite comme jouant un rôle central. Une surexpression de KLK13 avait déjà été décrite dans l'épiderme de patients atteints de PSD et au niveau de lésions psoriasiques, ce qui conforte notre hypothèse. Ainsi, mes résultats mettent en lumière KLK13, dont la fonction dans l'épiderme est encore très peu connue. En parallèle, dans le cadre d'un travail collaboratif, j'ai participé à une étude centrée sur la composante inflammatoire de la maladie, réalisée à l'aide de notre modèle de souris adultes Cdsniep-/-. Les résultats obtenus montrent un développement simultané des voies inflammatoires de type Th2 et Th17, ainsi qu'une contre-régulation entre ces deux axes au cours de la maladie chez la souris. En conclusion, mon travail contribue à mieux comprendre les mécanismes physiopathologiques du PSD. Notamment, le modèle adulte Cdsniep-/- apparaît comme particulièrement pertinent pour étudier la maladie humaine. L'exploration du rôle, dans le contexte du PSD, des gènes candidats identifiés pourrait déboucher sur la découverte de nouvelles cibles thérapeutiques. Enfin, nos résultats seront certainement bénéfiques à l'étude d'autres maladies dermatologiques inflammatoires rares (syndrome de Netherton, syndrome SAM) ou fréquentes (psoriasis, dermatite atopique), qui présentent un défaut de barrière épidermique. / Cornification is the final step of epidermal differentiation. It is characterized by structural and biochemical modifications of keratinocytes and leads to the formation of a solid, resistant, impermeable and moisturized cornified layer, responsible for the "barrier" function of the epidermis. Some rare genodermatoses, called ichthyoses, are caused by mutations of genes involved in cornification. The Peeling Skin Disease (PSD, OMIM 270300) is a generalized inflammatory ichthyosis characterized by important desquamation, eczema and severe itching. This chronic disease severely affects patients 'quality of life and no specific therapy is currently available. PSD is due to homozygous mutations in the Corneodesmosin (CDSN) gene, which codes an adhesive epidermal protein crucial for the cohesion of the stratum corneum (SC) and the epidermal barrier homeostasis. The pathophysiology of PSD is still poorly understood. The detachment of the SC leads to an impairment of the epidermal barrier which could in turn trigger erythema, atopic manifestations and pruritus by so far unidentified mechanisms. In order to dissect these mechanisms, I used two epidermis-specific Cdsn-deficient mouse models (knock-out, KO). The first mimics the early phase of PSD (detachment of the SC in Cdsnep-/- E18.5 embryos) and the second, inducible, reproduces the chronic phase (permanent permeability defect in Cdsniep-/- adult mice). I performed a comparative analysis of the skin transcriptome between these two models using DNA microarrays. Distinct molecular signatures related to a skin barrier repair response were highlighted: increased expression of inflammatory and proliferative genes (Cdsnep-/-) vs antimicrobial defense and cornification genes (Cdsniep-/-). In particular, a strong expression of genes coding for inhibitors of cysteine proteases from the stefin A family (cystatin A in humans), and serine proteases of the kallikrein (KLK) family, was distinguishable in Cdsniep-/- mice. This was secondarily confirmed in the epidermis of PSD patients. Among the KLKs, KLK13 was the most strongly up-regulated, contrary to KLK5 whose expression remains low and constant. Thus, KLK13 could take part into the inflammatory response and/or the desquamation when until now only KLK5 was described as playing a central role in these mechanisms. An up-regulation of KLK13 has already been described in the epidermis from PSD patients and from chronic psoriatic plaques, reinforcing our hypothesis. Thus, my results highlight KLK13, whose epidermal function is still poorly characterized. At the same time, I was part of a collaborative study focusing on the inflammatory component of the disease carried out with our Cdsniep-/- adult mouse model. The results showed a simultaneous development of type 2 and type 17 T lymphocytes responses as well as a counter-regulation between these two inflammatory axes. In conclusion, my work contributes to a better understanding of PSD pathophysiology. Notably, the Cdsniep-/- adult mouse model seems especially relevant to study the human disease. A further exploration, in the context of PSD, of the role of the candidate genes we identified could lead to the discovery of new therapeutic targets. Finally, our results will certainly be helpful for the understanding of other inflammatory skin diseases with epidermal barrier defects, whether they are rare (Netherton syndrome, SAM syndrome) or frequent (psoriasis, atopic dermatitis).

Thesis advisor: Julia E. Grigsby / We use the Birman-Ko-Lee presentation of the braid group to show that all closures of strongly quasipositive braids whose normal form contains a positive power of the dual Garside element δ are fibered. We classify links which admit such a braid representative in geometric terms as boundaries of plumbings of positive Hopf bands to a disk. Rudolph constructed fibered strongly quasipositive links as closures of positive words on certain generating sets of Bₙ and we prove that Rudolph’s condition is equivalent to ours. We compute the sutured Khovanov homology groups of positive braid closures in homological degrees i = 0,1 as sl₂(ℂ)-modules. Given a condition on the sutured Khovanov homology of strongly quasipositive braids, we show that the sutured Khovanov homology of the closure of strongly quasipositive braids whose normal form contains a positive power of the dual Garside element agrees with that of positive braid closures in homological degrees i ≤ 1 and show this holds for the class of such braids on three strands. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Mathematics.

Fragile X syndrome (FXS) is the leading single gene cause of intellectual disability and Autism Spectrum Disorder (ASD). It is caused by epigenetic silencing of the fragile X mental retardation gene (FMR1), causing a loss of Fragile-X Mental Retardation Protein (FMRP). Over the last 2 decades, much has been learned about the pathophysiology related to the loss of FMRP from mouse models of FXS. The recent generation of a rat model of FXS opens the door to: validate phenotypes across mammalian species, address cognitive dysfunction using paradigms that are more difficult to address in mice and explore candidate therapeutics more accurately. This thesis explored the validity of a new rat model for FXS (Fmr1 KO rat). I showed that Fmr1 KO rats exhibit normal spatial navigation memory, social interactions and anxiety levels. On the contrary, when subjects were tested in a battery of spontaneous exploration tasks: object recognition (OR), object-context (OC), object-place (OP), and object-place-context (OPC) recognition, which assess associative memory, Fmr1 KO rats showed a severe deficit in remembering the most complex (episodic-like) associations. Following these results, I sought to explore the development of associative memory from postnatal day 25 (P25) to adulthood (P71). Subjects were tested in the four spontaneous exploration tasks, previously mentioned, 8 times between P25 and P71 to assess the development of their ability to discriminate novel from familiar associations between objects, contexts and places. Fmr1 KO rats’ ability to discriminate novel from familiar object-place (spatial) and object-place-context (episodic-like) associations was significantly impaired (OP was delayed, and OPC ability did not develop). In the last part of this thesis I examined whether early therapeutic intervention with lovastatin can restore the cognitive deficits I observed. Subjects were fed either a diet containing lovastatin (“lovachow”) or an identically looking control diet, between P29 and P64, and tested in the four spontaneous exploration tasks, previously mentioned. Fmr1 KO rats demonstrated a developmental profile of associative memory indistinguishable from that of WT animals. At P64, lovachow was replaced with standard laboratory chow and the animals were tested 1 and 3 months later. Surprisingly, lovastatin treated Fmr1 KO animals maintained the ability to perform the OPC task even at 3 months after the end of treatment, whereas Fmr1 KO animals on control chow showed no improvement with age. The findings of this work indicate that transgenic rats can complement existing mouse models of FXS, providing valuable insights into the effects of FMRP loss on cognitive function. Furthermore, the results from the treatment study show that not only can lovastatin treatment prevent the emergence of cognitive deficits associated with Fragile X Syndrome but also that lovastatin (and perhaps pharmaceutical interventions more generally) may prevent the developmental deficits in neuronal circuit formation which can be maintained into adulthood.

Xenotransplantation is the final frontier of using vascularised organs or cellular grafts to treat end-organ disease and offers a potential solution to the worldwide shortage of human tissue available for transplantation. The main immunological barrier to xenografting from pig-to-primate is the antigen, Galactose-α1,3-Galactose (Gal) which is found in all species except humans and other higher primates. Even with the major advancement of deleting Gal from the potential pig donor species with the aid of cloning technology, complete elimination may be elusive as alternative genes yet to be fully characterised, may still produce Gal at low levels. Thus, the human immune response against Gal may continue to be a barrier to successful xenotransplantation. The aim of this project was to develop small animal models of the important components of xenograft rejection that largely relate to the anti-Gal immune response. These include models of hyperacute, acute vascular and chronic xenograft-like rejection that in turn, provide new insights in the immune mechanisms of the rejection processes. The role of antibody and both innate and cognate cellular immunity are explored. Both vascularised heart grafts and non-vascularised skin graft models are examined as rejection of solid organs may differ from cellular transplantation. The project also provides a platform for future studies in testing genetic and pharmacotherapeutic strategies to overcome the rejection processes uncovered.

Multiculturalism is one of the major trends in the choral education of the Twenty-first Century. Choral conductors attempt to capture diverse repertories from around the world. Japan, a country not very distant from Taiwan, is full of splendid choral development and composing achievements. Ko Matsushita is a Japanese choral conductor, composer, and educator. He is the conductor of ten choirs that have won many international choral competitions in the last decade. He also won the Carl Orff Composer Award two times. Matsushita was awarded the honor of the Robert Edler Prize in 2005 for his outstanding work in promoting choral music. Anthology of Love is a suite for female chorus with piano accompaniment. It was premiered in October 2003, and was published by KAWAI in August 2004. This suite contains four pieces: Somewhere or Other, Malayan Love Songs, A Poem for April, and Last Song of a Poet. These songs trace four different stages of love in human life: innocent, attractive, matured, and heroic love. All the Japanese lyrics in this work are taken from Shuntaro Tanikawa¡¦s poem collections. The piano accompaniment can play an important part in the music but requires a performer with advanced technique to deliver that result. This thesis consists of five chapters. Chapter One is the Introduction. Chapter Two discusses the background of Matsushita: Part One is a biographic sketch of Matsushita¡¦s life; Part Two introduces the musical style and characteristics of Matsushita¡¦s female choral works. Chapter Three focuses on the origin of lyrics and analysis of these four pieces. Chapter Four supplies rehearsal techniques and teaching suggestions for conductors. The diction fundamentals of Japanese and pronunciation of the lyrics are also included in this chapter. Chapter Five is the Conclusion. There are three appendices at the end of this thesis. Appendix A supplies four letters from Matsushita. Appendix B is a list of Matsushita¡¦s published choral works. Appendix C contains the translation and the Romanization of the Japanese lyrics for these four pieces.

Thesis (doctoral)--Charles University, Prague, 1974. / Letter from the author dated 30th October 1985, including errata inserted. Includes bibliographical references (p. 480-488) and index.

Xenotransplantation is the final frontier of using vascularised organs or cellular grafts to treat end-organ disease and offers a potential solution to the worldwide shortage of human tissue available for transplantation. The main immunological barrier to xenografting from pig-to-primate is the antigen, Galactose-α1,3-Galactose (Gal) which is found in all species except humans and other higher primates. Even with the major advancement of deleting Gal from the potential pig donor species with the aid of cloning technology, complete elimination may be elusive as alternative genes yet to be fully characterised, may still produce Gal at low levels. Thus, the human immune response against Gal may continue to be a barrier to successful xenotransplantation. The aim of this project was to develop small animal models of the important components of xenograft rejection that largely relate to the anti-Gal immune response. These include models of hyperacute, acute vascular and chronic xenograft-like rejection that in turn, provide new insights in the immune mechanisms of the rejection processes. The role of antibody and both innate and cognate cellular immunity are explored. Both vascularised heart grafts and non-vascularised skin graft models are examined as rejection of solid organs may differ from cellular transplantation. The project also provides a platform for future studies in testing genetic and pharmacotherapeutic strategies to overcome the rejection processes uncovered.

Thesis (M. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 62-63).

The regulation of neural precursor cells (NPCs), which encompass neural progenitor and neural stem cells (NSCs), is fundamental for proper brain development and function. These cells are regulated by orchestrated signalling within their local environment. Aberrant aspects of cell proliferation, differentiation, survival, or integration have been linked to various neurological diseases including Fragile X syndrome (FXS)—a disorder characterized by intellectual and social changes due to the silencing of the gene encoding FMRP. The biology of hippocampal NPCs in FXS during early postnatal development has not been studied, despite high FMRP expression levels in the hippocampus at the end of the first postnatal week. In this thesis, the Fmr1-knockout (KO) mouse model was used to study hippocampal cell biology during early postnatal development. A tissue culture assay, used to study the effect of astrocyte-secreted factors on the proliferation of NSCs, indicated that astrocyte secreted factors from Fmr1-KO brains enhanced the proliferation of wild type, but not Fmr1-KO NSCs (Chapter 3). Next, the proliferation and cell cycle profiles of NPCs in vitro and in vivo studied with immunocytochemistry, Western blotting, and flow cytometry revealed decreased proliferation of NPCs in the Fmr1-KO hippocampus (Chapter 4). Finally, cells isolated from the P7 dentate gyrus and characterized by flow cytometry, showed a reduced proportion of NSCs and an increased proportion of neuroblasts—neuronal committed progenitors—in Fmr1-KO mice. Together, these results indicate that hippocampal NPCs show aberrant proliferation and neurogenesis during early postnatal development. This could indicate stem-cell depletion, increased quiescence, or a developmental delay in relation to lack of FMRP and uncovers a new role for FMRP in the early postnatal hippocampus. In turn, elucidating the mechanisms that underlie FXS will aid in the development of targeted treatments. / Thesis / Doctor of Philosophy (PhD) / Fragile X syndrome is the leading inherited cause of intellectual impairment and autism spectrum disorder. The syndrome is caused by a defect in one gene. This gene has been suggested to play a role in regulating the birth of new brain cells termed neural precursor cells. The importance of neural precursor cells stems from their ability to generate neurons and glia, the main cells in the brain. In this thesis, I focus on studying neural precursor cells from the hippocampus, a brain region important for learning and memory. A mouse model was used to compare neural precursor cells from healthy and Fragile X mice during early postnatal development. I found that neural precursor cells do not divide as much as they should in the Fragile X mouse hippocampus. The results help to determine the causes for learning and memory deficits in Fragile X and potentially open avenues for intervention.