Langerhan’s cells (LCs) are the immune sentinels of the skin, sampling the cutaneous microenvironment and presenting captured antigen to T cells. A sheet-like proliferation of LCs is termed Langerhan’s cell histiocytosis (LCH), an enigmatic and poorly understood disorder with a widely varied clinical spectrum and disease course. In non-pulmonary LCH all cases reported to date have been monoclonal. Clonality argues for LCH as a neoplastic rather than reactive disorder. After initial investigation of the limitations of formalin fixed paraffin embedded tissues for downstream analysis, lesions of LCH were collected from 4 sites across Scotland. To further define the spectrum of LCH, clonality was assessed using an X inactivation assay based on the polymorphous region of the Human Androgen Receptor. To improve understanding of the assay, a study on post-mortem material was undertaken. This demonstrated a unique insight into patterns of X inactivation across different tissues of the same individual and highlighted potential pitfalls in interpretation. An important question was whether lesions of LCH associated with haematopoietic neoplasms were polyclonal or monoclonal proliferations? For the first time, associations of LCH with B-cutaneous lymphoid hyperplasia (B-CLH), lymphomatoid papulosis (LyP) and mycosis fungoides (MF) are reported. In two female cases, the LCs were polyclonal providing some reassurance that such lesions are reactive in nature and should not be regarded as potential second neoplasms. In a more expanded study a wide variety of primary LCH lesions were assessed for clonality. Significant limitations were posed by the quality of the material available; in 2 cases the lesions were found to be polyclonal. This is the first time such a result has been reported. Monoclonality was identified in 2 other cases including one of pulmonary LCH. The findings reported herein suggest that clonality and hence neoplasia cannot be assumed in all cases of primary non-pulmonary LCH. The possible functions of LCs in cutaneous lymphoma were explored. In T-cell lymphoma 2 cases reported here suggest a role for LCs in disease progression. In contrast, LCs play no significant part in the development or progression of cutaneous B-cell proliferations although other types of dendritic cells probably have an important role. By studying proliferations of LCs in a variety of settings, this work has extended knowledge of the spectrum of LCH. Displaying similar histopathological appearances, lesions of LCH may be best defined by clonality as well as cytokine expression and level of maturation. In future, such markers may be employed as prognostic indicators allowing individualised and targeted management.

<p>Mechanisms of sex chromosome dosage compensation vary widely between different vertebrate species. All eutherians, including humans, other primates, and rodents, undergo random X chromosome inactivation in early female embryos, a process by which the majority of the genes on one X chromosome in the female are silenced (inactive X, Xi) to create a transcription level matching that of the single X chromosome in males. Random inactivation of the placental embryo is initiated from a region on the X chromosome called the X-inactivation center (XIC in humans and Xic in mice), thus implicating this region as the key chromosomal element in distinguishing random from imprinted X inactivation during mammalian evolution. This invites a comparative genomic approach to explore the organization and evolution of this region throughout mammalian lineages</p><p>Patterns of X inactivation are genetically determined, as indicated by non-random patterns of inactivation in mice heterozygous for the X-linked X controlling element (Xce) locus, the molecular and genomic basis of which is unknown. Using QTL mapping in Xce heterozygous mice, we previously identified a 1.85Mb candidate region for Xce. This candidate region contains the X inactivation center (Xic), including the critical X inactivation genes Xist and Tsix. To explore the genomic organization of this region in C57BL/6J (B6), we identified extensive large (>5Kb) inverted and non-inverted segmental duplications lying greater than 350Kb proximal to Xist. Investigating these segmental duplications further, we then compared copy number and sequence variant differences among strains carrying different Xce alleles to identify candidate variants in a subportion of the interval that correlate with specific Xce alleles. </p><p>The Xce candidate region was then compared to the corresponding region of the X chromosome from several other species. Notably, the segmental duplications within the mouse Xce region are maintained positionally through the other species over at least 105 MYA, although they do not share the same DNA in the copy variant. </p><p>These and future experiments should provide detailed characterization of the Xce candidate region and an opportunity to address the role that these sequence signatures may play in the earliest stages of X inactivation when the two X chromosomes are distinguished from one another.</p> / Dissertation

Thèse de doctorat : Sciences du Vivant. Biologie cellulaire et moléculaire des Plantes : Strasbourg 1 : 2007. / Thèse soutenue sur un ensemble de travaux. Titre provenant de l'écran-titre. Bibliogr. 17 p.

Drosophila is a simple and genetically tractable model system for studying neural circuits. This dissertation consists of two studies, with the broad goal of understanding sensory processing in neural circuits using Drosophila as a model system.

Non-typhoidal Salmonella enterica serovars continue to be the leading cause of foodborne illnesses in United States. Chlorine, chlorine related, and quaternary compounds are generally used for disinfecting carcasses and equipment in processing industries. The current study was aimed at understanding the inactivation kinetics of four Salmonella serovars to chlorine, chlorine dioxide and cetylpyridinium chloride (CPC). The transcriptomic responses to oxidative stress was investigated in stationary and log phase cells of S. Typhimurium. The study was also aimed at understanding the effect of the chemicals on the expression of virulence genes associated with the Salmonella Pathogenecity Island 1 (SPI1). The possible induction of the viable but nonculturable (VBNC) state in Salmonella due to CPC was also investigated. The inactivation parameters for each serovar and the chemical were estimated based on the Hom's model, ln (N/N0) = -k C^n T^m and it appeared that while disinfectant contact time was significant, biocide concentration in the overall disinfection was insignificant. This was true especially for chlorine and CPC with subtle differences observed between the serovars. The inactivation efficacy was, however, dependent on both concentration and the exposure time for chlorine dioxide. The highest degree of inactivation was obtained with chlorine followed by chlorine dioxide and CPC. Transcriptomic responses of S. Typhimurium revealed significant downregulation of several metabolic processes such as tricarboxylic acid cycle, oxidative phosphorylation, and amino acid biosynthesis in both log and stationary phase cells. Several stress related genes such as usp, rpoS and ompR were upregulated in the stationary phase cells. Majority of the virulence genes associated with the SPI1 were found to be downregulated for all the treatments. While treatment with chlorine and CPC caused downregulation of all the virulence genes, treatment with chlorine dioxide caused significant upregulation of few (hilC, invC, sipA and sipB) genes associated with the SPI1. Finally, the induction of VBNC state was not concluded as a result of treatment with CPC. However, significant percentage of cells (45 percent) with intact membrane was established based on the BacLight assayTM.

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A wood surface, which is exposed to a high temperature condition, can experience inactivation. Surface inactivation results in reduced ability of an adhesive to properly wet, flow, penetrate, and cure. Thus, an inactivated wood surface does not bond well with adhesives. The changes in surface chemistry, wettability, and adhesion of inactivated wood surfaces, including heartwood of yellow-poplar (Liriodendron tulipifera) and southern pine (Pinus taeda), were studied. Wood samples were dried from the green moisture content condition in a convection oven at five different temperature levels ranging from 50 to 200 °C. The comparative characterization of the surface was done by X-ray photoelectron spectroscopy (XPS), sessile drop wettability, and fracture testing of adhesive bonds. The oxygen to carbon ratio (O/C) decreased and the C1/C2 ratio increased with drying temperature. The C1 component is related to carbon-carbon or carbon-hydrogen bonds, and the C2 component represents single carbon-oxygen bond. A low O/C ratio and a high C1/C2 ratio reflected a high concentration of non-polar wood components (extractives/VOCs) on the wood surface, which modified the wood surface from hydrophilic to more hydrophobic. Wettability was directly related to the O/C ratio and inversely related to the C1/C2 ratio. Contact angle decreased with time and increased with the temperature of exposure. Southern pine had a lower wettability than yellow-poplar, which was due to a greater concentration of non-polar hydrocarbon-type extractives and heat-generated volatiles on the surface. Solvent extraction prior to drying did not improved wettability, whereas, extraction after drying improved wettability. A contribution of extractives migration and VOCs generation played a significant role in the heat-induced inactivation process of southern pine. The maximum strain energy release rate (Gmax) showed that surface inactivation was insignificant for yellow-poplar when exposed to drying temperatures < 187°C. The southern pine was most susceptible to inactivation at drying temperatures > 156°C, particularly when bonded with phenol-formaldehyde (PF) adhesive. Chemical treatments improved the wettability of inactivated wood surfaces, but an improvement in adhesion was not evident for specimens bonded with polyvinyl-acetate (PVA) adhesive. NaOH surface treatment was most effective for improving adhesion of the PF adhesive bond. / Ph. D.