New materials, optimized for increased strength, ductility, and other desirable properties, have the potential to improve every aspect of modern living. To achieve these optimums, the necessary technological advancements are impeded mainly by the limits of available material models. Innovations in this field rely on research into the nature of material behavior. While a typical model of material behavior in the region near yield involves the initial linear elastic response, followed by yield and isotropic hardening, this fails to explain various important phenomena that manifest in a range of materials, such as pre-yield nonlinearity, anelasticity, yield point phenomena, hardening stagnation, and the Bauschinger effect. These effects have been explained over the past century with the theories of Cottrell atmospheres, the Orowan by-pass mechanism, and back stress. This manuscript compares data from experimental observation in tantalum to these theories to better understand the micromechanisms occurring near yield. Understanding deformation in this region has significant implications in structural and mechanical engineering, as well has having direct applications in the forming of metals. Forty-four dogbone-shaped samples were cut from 99.99% pure tantalum and pulled in load-unload-load and multi-cycle loop tensile tests at room temperature. The specimens were either single crystal, whose orientations were chosen based on desired active slip mode determined by Schmid factors, or bicrystal, based on the orientation of the single grain boundary. Sample behavior was simulated in both crystal plasticity and General Mesoscale finite element models to assist in interpreting results and in suggesting plausible micromechanisms. The experimental results and crystal plasticity simulations suggest alternate explanations to some of the discussed mechanical theories of near-yield deformation. The combined experimental / modeling approach indicates that other slip systems, besides the conventionally assumed {110}, are activated upon yield; particularly the {112} system. The breakaway model traditionally associated with the yield point phenomenon may also be better explained through a different mechanism; back stress development during deformation is shown to result in the observed behavior. Lastly, as is well-known, the Taylor formulation, upon which most crystal plasticity models are based, does not adequately predict yield stress behavior in the presence of grain boundaries; once again, an internal stress mechanism matches much better with the experimental results on single and bicrystals. While not all observations could be fully explained by simply adding internal stress generation to a standard crystal plasticity model, this work anticipates further studies to enable more accurate predictive modeling capabilities and increase understanding of the mechanisms driving the fundamental material properties necessary for future progress.

L'application d'un temps de maintien, même de faible durée, lors d'un chargement cyclique, modifie de façon très sensible à la fois le comportement contrainte-déformation et le nombre de cycles à amorçage dans l'alliage base titane TI-6242. Ceci est lié à un régime de fluage cyclique, conduisant à de la déformation progressive d'une part, et à une forte interaction fatigue-temps de maintien pour ce qui concerne le nombre de cycles à amorçage. Les différents phénomènes sont pour le moment assez mal analysés, si bien qu'il n'est pas possible d'effectuer une conception optimale des pièces, de larges marges de sécurité étant nécessaires. Le but du travail est de mieux comprendre les mécanismes locaux qui régissent le comportement et l'amorçage des fissures, dans le but de suggérer des microstructures optimales, et de calibrer des modèles macroscopiques utilisables en bureau d'études. En s'appuyant sur une base expérimentale fournie par Snecma et l'ENSMA, une approche multiéchelles a été mise en place pour représenter les hétérogénéités locales qui ont un rôle significatif sur les comportements observés. Dans les calculs des microstructures, faisant intervenir une étape d'évaluation statistique, on se focalise sur la représentation explicite des ”plumes”, grains de taille exceptionnelle, qui sont à l'origine des premières microfissures en raison du contraste cristallin qu'ils introduisent avec l'environnement. Une revue des différentes configurations de plumes, afin de retenir celles qui sont le plus critique, a été établie. Cette analyse a permis de mettre en évidence la présence de plumes simples, doubles ou triples, les domaines se présentant sous formes de bandes. Les configurations à étudier comportent comme paramètres critiques l'orientation géométrique de la bande par rapport à la direction du chargement macroscopique, mais surtout l'orientation cristallographique au sein de cette (ces) bande(s). Des calculs systématiques ont été effectués afin de mener une étude statistique et de déterminer les configurations les plus sensibles. / The application of a dwell period, even of short length, during a cyclic loading, simultaneously changes the stress-strain behaviour and the number of cycles to failure in a very sensitive way. This phenomenon is connected to a cyclic creep regime, generating progressive deformation, and to a strong interaction between the fatigue process and dwell periods for the number of cycles to failure. All these phenomena are poorly analysed nowadays, so that engineers hardly perform optimal design of the components, since large security margins are necessary. The aim of the work is to better understand the local mechanisms which govern both behaviour and crack initiation, having in view optimal microstructures, and to calibrate manageable macroscopic models for the design department. Using an experimental data set given by Snecma and ENSMA, a multiscale approach has been developed to represent the local heterogeneities that play a significant role on observed behaviour. In the calculations of microstructures that are performed for a statistical evaluation, the focus is made on the explicit representation of the so called "plumes", that are grains of exceptional size, which are at the origin of the first microcracks due to crystal contrast they introduce with the environment. A review of various "plume" configurations is made, in order to investigate the most critical ones. This analysis allowed to shed the light on the presence of simple, double or triple "plumes", the domains being in band shapes. The critical parameters are the geometric arrangement of the band with respect to the direction of the macroscopic loading, but essentially the crystal orientation within this (these) band(s). Systematic calculations were carried out in order to do a statistical study and to determine the most critical configurations.

No description available.

Sonic hedgehog (Shh) is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. When cells receive the Shh signal a cascade of effects begin which in turn regulate downstream target genes. The genes controlled by Sonic hedgehog provide messages instructing cells how to differentiate or when to divide. Disruption of the hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. Patched, the receptor for Shh, acts as a tumour suppressor and is mutated in naevoid basal cell carcinoma syndrome (NBCCS). NBCCS patients display a susceptibility to tumour formation, particularly for basal cell carcinoma (BCC). The discovery of Patched mutations in sporadic BCCs and other tumour types further highlights the importance of this pathway to human cancer. The identification of genes regulated by hedgehog is crucial for understanding how disruption of this pathway leads to neoplastic transformation. It is assumed that the abnormal expression of such genes plays a large role in directing cells to divide at inappropriate times. Only a small number of genes controlled by Shh have been described in vertebrate tissues. In the work presented in this thesis a Sonic hedgehog responsive embryonic mouse cell line, C3H/10T1/2, was used as a model system for hedgehog target gene discovery. Known downstream target genes were profiled to determine their induction kinetics, building up a body of knowledge on the response to Shh for this cell type. During this work, it was discovered that C3H/10T1/2 cells do not become fully competent to respond to Shh stimulation until the cells reach a critical density, a factor that had to be taken into account when determining timepoints of interest for further investigation. Several techniques were employed to identify genes that show expression changes between Shh stimulated and control cells. In one of these techniques, RNA from cell cultures activated with Shh was used to interrogate cDNA microarrays, and this provided many insights into the downstream transcriptional consequences of hedgehog stimulation. Microarrays consist of thousands of spots of DNA of known sequence gridded onto glass slides. Experiments using this technology allow the expression level of thousands of genes to be measured simultaneously. Independent stimulation methods combined with northern blotting were used to investigate individual genes of interest, allowing genuine targets to be confirmed and false positives eliminated. This resulted in the identification of eleven target genes. Seven of these are induced by Sonic hedgehog (Thrombomodulin (Thbd), Glucocorticoid induced leucine zipper (Gilz), Brain factor 2 (Bf2), Nuclear receptor subfamily 4, group A, member 1 (Nr4a1), Insulin-like growth factor 2 (Igf2), Peripheral myelin protein 22 (Pmp22), Lim and SH3 Protein 1 (Lasp1)), and four are repressed (Secreted frizzled related proteins 1 and 2 (Sfrp1 and Sfrp2), Macrophage inflammatory protein-1 gamma (Mip-1?), and Anti-mullerian hormone (Amh)). The majority of these represent novel downstream genes not previously reported as targets of Shh. The new target genes have a diverse range of functions, and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery. The identification of novel Sonic hedgehog responsive genes provides candidates whose abnormal expression may be decisive in initiating tumour formation and future studies will investigate their role in development and disease. It is expected that such findings will provide vital clues to the aetiology of various human cancers, and that an understanding of their roles may ultimately provide greater opportunities in the future design of anti-tumour therapies.

<p>Mutation of the p53 gene appears to be an early event in skin cancer development. The present study is based on morphology and represents a cellular and genetic investigation of p53 alterations in normal human skin and basal cell cancer.</p><p>Using double immunofluorescent labelling, we have demonstrated an increase in thymine dimers and p53 protein expression in the same keratinocytes following ultraviolet radiation. Large inter-individual differences in the kinetics of thymine dimer repair and subsequent epidermal p53 response were evident in both sunscreen-protected and non-protected skin. The formation of thymine dimers and the epidermal p53 response were partially blocked by topical sunscreen. We have optimized a method to analyze the p53 gene in single cells from frozen tissue sections. In chronically sun-exposed skin there exist clusters of p53 immunoreactive keratinocytes (p53 clones) in addition to scattered p53 immunoreactive cells. Laser assisted microdissection was used to retrieve single keratinocytes from immunostained tissue sections, single cells were amplified and the p53 gene was sequenced. We have shown that p53 mutations are prevalent in normal skin. Furthermore, we detected an epidermal p53 clone which had prevailed despite two months of total protection from ultraviolet light. Loss of heterozygosity in the PTCH and p53 loci as well as in the sequenced p53 gene was determined in basal cell cancer from sporadic cases and in patients with Gorlin syndrome. Allelic loss in the PTCH region was prominent in both sporadic and hereditary tumors, while loss of heterozygosity in the p53 locus was rare in both groups. p53 mutations found in the hereditary tumors differed from the typical mutations found in sporadic cases. In addition, we found genetically linked subclones with partially different p53 and/or PTCH genotypes in individual tumors. Our data show that both genes are important in the development of basal cell cancer.</p>

Mutation of the p53 gene appears to be an early event in skin cancer development. The present study is based on morphology and represents a cellular and genetic investigation of p53 alterations in normal human skin and basal cell cancer. Using double immunofluorescent labelling, we have demonstrated an increase in thymine dimers and p53 protein expression in the same keratinocytes following ultraviolet radiation. Large inter-individual differences in the kinetics of thymine dimer repair and subsequent epidermal p53 response were evident in both sunscreen-protected and non-protected skin. The formation of thymine dimers and the epidermal p53 response were partially blocked by topical sunscreen. We have optimized a method to analyze the p53 gene in single cells from frozen tissue sections. In chronically sun-exposed skin there exist clusters of p53 immunoreactive keratinocytes (p53 clones) in addition to scattered p53 immunoreactive cells. Laser assisted microdissection was used to retrieve single keratinocytes from immunostained tissue sections, single cells were amplified and the p53 gene was sequenced. We have shown that p53 mutations are prevalent in normal skin. Furthermore, we detected an epidermal p53 clone which had prevailed despite two months of total protection from ultraviolet light. Loss of heterozygosity in the PTCH and p53 loci as well as in the sequenced p53 gene was determined in basal cell cancer from sporadic cases and in patients with Gorlin syndrome. Allelic loss in the PTCH region was prominent in both sporadic and hereditary tumors, while loss of heterozygosity in the p53 locus was rare in both groups. p53 mutations found in the hereditary tumors differed from the typical mutations found in sporadic cases. In addition, we found genetically linked subclones with partially different p53 and/or PTCH genotypes in individual tumors. Our data show that both genes are important in the development of basal cell cancer.

The investigation of genetic alterations in cancer-relatedgenes is useful for research, prognostic and therapeuticpurposes. However, the genetic heterogeneity that often occursduring tumour progression can make correct analysischallenging. The objective of this work has been to develop,evaluate and apply techniques that are sufficiently sensitiveand specific to detect and analyse genetic alterations in skintumours as well as in normal skin. Initially, a method based on laser-assisted microdissectionin combination with conventional dideoxy sequencing wasdeveloped and evaluated for the analysis of the p53 tumoursuppressor gene in small tissue samples. This method was shownto facilitate the analysis of single somatic cells fromhistologic tissue sections. In two subsequent studies themethod was used to analyse single cells to investigate theeffects of ultraviolet (UV) light on normal skin. Single p53immunoreactive and nonimmunoreactive cells from differentlayers of sunexposed skin, as well as skin protected fromexposure, were analysed for mutations in the p53 gene. Theresults revealed the structure of a clandestine p53 clone andprovided new insight into the possible events involved innormal differentiation by suggesting a role for allele dropout.The mutational effect of physiological doses of ultravioletlight A (UVA) on normal skin was then investigated by analysingthe p53 gene status in single immunoreactive cells at differenttime-points. Strong indications were found that UVA (even atlow doses) is indeed a mutagen and that its role should not bedisregarded in skin carcinogenesis. After slight modifications, the p53 mutation analysisstrategy was thenused to complement an x-chromosomeinactivation assay for investigation of basal cell cancer (BCC)clonality. The conclusion was that although the majority ofBCC’s are of monoclonal origin, an occasional tumour withapparently polyclonal origin exists. Finally, apyrosequencing-based mutation detection method was developedand evaluated for detection of hot-spot mutations in the N-rasgene of malignant melanoma. More than 80 melanoma metastasissamples were analysed by the standard approach of single strandconformation polymorphism analysis (SSCP)/DNA sequencing and bythis pyrosequencing strategy. Pyrosequencing was found to be agood alternative to SSCP/DNA sequencing and showed equivalentreproducibility and sensitivity in addition to being a simpleand rapid technique. <b>Keywords:</b>single cell, DNA sequencing, p53, mutation,UV, BCC, pyrosequencing, malignant melanoma, N-ras

The main concept of Body-Coupled Communication (BCC) is to transmit the electrical information through the human body as a communication medium by means of capacitive coupling. Nowadays the current research of wireless body area network are expanding more with the new ideas and topologies for better result in respect to the low power and area, security, reliability and sensitivity since it is first introduced by the Zimmerman in 1995. In contrast with the other existing wireless communication technology such as WiFi, Bluetooth and Zigbee, the BCC is going to increase the number of applications as well as solves the problem with the cell based communication system depending upon the frequency allocation. In addition, this promising technology has been standardized by a task group named IEEE 802.15.6 addressing a reliable and feasible system for low power in-body and on-body nodes that serves a variety of medical and non medical applications. The entire BAN project is divided into three major parts consisting of application layer, digital baseband and analog front end (AFE) transceiver. In the thesis work a strong driver circuit for BCC is implemented as an analog front end transmitter (Tx). The primary purpose of the study is to transmit a strong signal as the signal is attenuated by the body around 60 dB. The Driver circuit is cascaded of two single-stage inverter and an identical inverter with drain resistor. The entire driver circuit is designed with ST65 nm CMOS technology with 1.2 V supply operated at 10 MHz frequency, has a driving capability of 6 mA which is the basic requirement. The performance of the transmitter is compared with the other architecture by integrating different analysis such as corner analysis, noise analysis and eye diagram. The cycle to cycle jitter is 0.87% which is well below to the maximum point and the power supply rejection ratio (PSRR) is 65 dB indicates the good emission of supply noise. In addition, the transmitter does not require a filter to emit the noise because the body acts like a low pass filter. In conclusion the findings of the thesis work is quite healthy compared to the previous work. Finally, there is some point to improve for the driver circuit in respect to the power consumption, propagation delay and leakage power in the future.

In this study, we synthesized amphiphilic block copolymer Poly(ethylene glycol)-b-Poly(£`-caprolactone) (PEO-b-PCL), and the mesoporous silica and phenolic were synthesized by using EISA (evaporation induced self-assembly) strategy. The mesoporous carbon also obtained after carbonization. After incorporating the precursors into the mesoporous channels through incipient wetness impregnation and further hydrogen reduction, 3D body-centered cubic (BCC) metal network/silica, metal nanowires/silica, metal/phenolic, and metal/carbon nanocomposites could be obtained. Moreover, metal replica was obtained through HF etching. Transmission electron microscope (TEM) and the small angle X-ray scattering (SAXS) patterns indicate that the parent ordered mesoporous structure was well-maintained during the synthesis process. The X-ray diffraction (XRD) and selected-area electron diffraction (SAED) demonstrate that Pd and Ag were reduced within the channels of mesoporous materials. The pore size distribution and BET surface area of mesoporous materials and metal/mesoporous materials composite were recorded by N2 isotherm adsorption-desorption experiment. In the future, we expect that the mesoporous metal and mesoporous nanocomposite with specific morphologies behave excellent performance in various applications, such as catalysis, gas sensors, nano electronic/optical devices and medical diagnosis.

<p>The investigation of genetic alterations in cancer-relatedgenes is useful for research, prognostic and therapeuticpurposes. However, the genetic heterogeneity that often occursduring tumour progression can make correct analysischallenging. The objective of this work has been to develop,evaluate and apply techniques that are sufficiently sensitiveand specific to detect and analyse genetic alterations in skintumours as well as in normal skin.</p><p>Initially, a method based on laser-assisted microdissectionin combination with conventional dideoxy sequencing wasdeveloped and evaluated for the analysis of the p53 tumoursuppressor gene in small tissue samples. This method was shownto facilitate the analysis of single somatic cells fromhistologic tissue sections. In two subsequent studies themethod was used to analyse single cells to investigate theeffects of ultraviolet (UV) light on normal skin. Single p53immunoreactive and nonimmunoreactive cells from differentlayers of sunexposed skin, as well as skin protected fromexposure, were analysed for mutations in the p53 gene. Theresults revealed the structure of a clandestine p53 clone andprovided new insight into the possible events involved innormal differentiation by suggesting a role for allele dropout.The mutational effect of physiological doses of ultravioletlight A (UVA) on normal skin was then investigated by analysingthe p53 gene status in single immunoreactive cells at differenttime-points. Strong indications were found that UVA (even atlow doses) is indeed a mutagen and that its role should not bedisregarded in skin carcinogenesis.</p><p>After slight modifications, the p53 mutation analysisstrategy was thenused to complement an x-chromosomeinactivation assay for investigation of basal cell cancer (BCC)clonality. The conclusion was that although the majority ofBCC’s are of monoclonal origin, an occasional tumour withapparently polyclonal origin exists. Finally, apyrosequencing-based mutation detection method was developedand evaluated for detection of hot-spot mutations in the N-rasgene of malignant melanoma. More than 80 melanoma metastasissamples were analysed by the standard approach of single strandconformation polymorphism analysis (SSCP)/DNA sequencing and bythis pyrosequencing strategy. Pyrosequencing was found to be agood alternative to SSCP/DNA sequencing and showed equivalentreproducibility and sensitivity in addition to being a simpleand rapid technique.</p><p><b>Keywords:</b>single cell, DNA sequencing, p53, mutation,UV, BCC, pyrosequencing, malignant melanoma, N-ras</p>