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1
Saitou, Yuuichirou. "Regulatory mechanism of damage-dependent homologous recombination." Kyoto University, 2015. http://hdl.handle.net/2433/199392.
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Kyoto University (京都大学)0048
新制・課程博士
博士(人間・環境学)
甲第19068号
人博第721号
新制||人||173(附属図書館)
26||人博||721(吉田南総合図書館)
32019
京都大学大学院人間・環境学研究科相関環境学専攻
(主査)教授 小松 賢志, 教授 宮下 英明, 准教授 三浦 智行
学位規則第4条第1項該当
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Karras, Georgios Ioannis. "Mechanism and function of RAD6-mediated DNA damage tolerance." Diss., lmu, 2010. http://nbn-resolving.de/urn:nbn:de:bvb:19-129233.
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Vanichkitrungruang, Siriluck. "Mechanism of damage to fibronectin by myeloperoxidase derived oxidants." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/19752.
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Atherosclerosis is characterised by lipid deposition in the arterial wall and chronic low-grade inflammation. Leukocytes migrate to the area of injury and release the heme enzyme myeloperoxidase (MPO) into the extracellular matrix (ECM). This enzyme converts H2O2 to hypohalous acids (e.g.HOCl from Cl-, HOSCN from SCN-). There is considerable evidence that these oxidants, particularly HOCl, damage cells and the ECM, and contribute to cardiovascular disease. HOCl is a highly damaging oxidant, whereas HOSCN is less reactive and generates reversible modifications. The ECM contains multiple proteins, including fibronectin (FN), which are critical to matrix assembly and cell function. FN possesses multiple functionally-important epitopes including a cell binding fragment (CBF) and a heparin binding fragment (HBF). The co-localisation of FN and MPO in the ECM, makes FN a likely target for MPO-derived oxidants. Therefore, this project aimed to elucidate the effects of HOCl and HOSCN on FN, and whether the increasing SCN- concentrations modulated ECM damage induced by HOCl. Exposure of human plasma FN to HOCl resulted in fragmentation and aggregation of the protein, formation of modified amino acids, and alterations to the CBF and HBF. Human coronary artery endothelial cells exposed to modified FN showed poor adhesion, impaired cell spreading, reduced metabolic activity and altered gene expression. In contrast, reagent HOSCN generated limited modifications. Studies using an enzymatic MPO/H2O2 system with either Cl- or SCN-, showed that MPO/H2O2/Cl- gave extensive FN modifications, whereas MPO/H2O2/SCN- induced only minor changes. When both Cl- and SCN- were present as competing substrates, increasing concentrations of SCN- decreased the extent of chemical and structural modifications detected on FN supporting the hypothesis that increasing the concentration of SCN- may mitigate damage generated by the MPO/Cl-/H2O2 system and potentially modulate disease development.
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Geranmayeh, Vaneghi Rashid. "Progressive Damage Mechanism of Rocks Subjected to Cyclic Loading." Thesis, Curtin University, 2020. http://hdl.handle.net/20.500.11937/81962.
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This thesis investigates the effect of cyclic loading conditions on the strength and deformation behaviour of rock materials under uniaxial compression. Two microstructurally and mineralogically different rocks are considered in this experimental investigation. Variations in loading stress level, stress amplitude and frequency are considered to derive novel conclusions on the damage mechanism and fatigue strength. The investigation revealed the greater susceptibility of hard rocks to cyclic loading compared to soft rocks.
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Dawson, Lisa Frances. "A novel mechanism regulating DNA-damage repair in Mycobacterium tuberculosis." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1444620/.
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The intracellular pathogen Mycobacterium tuberculosis (M. tuberculosis) resides in macrophages and is the causative agent of human tuberculosis. Infected macrophages produce reactive oxygen and nitrogen intermediates, known to damage DNA therefore DNA damage repair is thought to be important in survival of M. tuberculosis in the host. The expression of many bacterial DNA repair genes is often regulated by the SOS response, in which RecA is an integral part however, in M. tuberculosis the majority of genes in the DNA-damage regulon are regulated independently of the RecA/LexA system. In this study two potential mechanisms for this alternative mode of gene regulation were investigated. The first hypothesis addressed was that regulation of expression following DNA-damage is controlled by an alternative sigma factor. Sigma factors are protein subunits of RNA polymerase, which confer specificity of binding to particular promoters. The function/expression of alternative sigma factors is usually regulated by various mechanisms. The sigma factor SigG is the most highly induced of all 13 sigma factors of M. tuberculosis in response to DNA-damage in both wild-type and ArecA strains. A knockout of sigG in M. tuberculosis was constructed, and found to be more susceptible to mitomycin C stress than wild-type H37Rv and attenuated in mice. ruvC was shown to possesses 2 transcriptional start sites, and although neither were regulated by SigG, the PI promoter appeared to be dual regulated by LexA and the RecA/LexA independent mechanism. Microarray analysis revealed that SigG was not significantly involved in regulation of the RecA/LexA independent DNA-damage regulon, but that SigG directly or indirectly regulated expression of 127 genes in the absence of DNA-damage. The other possible mode of RecA/LexA independent regulation was via a repressor/activator protein. Gel shifts assays using M. tuberculosis cell free extracts were used to attempt to identify a repressor or activator protein that bound to the operator of the recA PI promoter, known to be induced independently of RecA, but failed to detect specific binding. Published microarray data revealed that Rv2017, a predicted regulatory protein, was upregulated in both wild-type and ArecA strains of M. tuberculosis in response to DNA-damage. Therefore, a gene inactivation knockout of Rv2017 was constructed and analysed in M. tuberculosis. The ARv2017 strain was hyposensitive to mitomycin C stress and preliminary mouse in-vivo infection data suggested that the ARv2017 strain may be hypervirulent. Microarray data revealed that Rv2017 plays a direct/indirect role in regulation of a large regulon, including some genes in the DNA-damage repair regulon.
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Parsons, Jason Luke. "The mechanism of genotoxicity of potassium bromate." Thesis, University of Birmingham, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364521.
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Yang, Xin. "The development of creep damage constitutive equations for high chromium steel based on the mechanism of cavitation damage." Thesis, University of Huddersfield, 2018. http://eprints.hud.ac.uk/id/eprint/34682/.
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Due to increasing electrical energy power supply, thermal efficiency and the desire to reduce CO2 emissions, creep-resistant high chromium steels are becoming widely developed and applied for components of electric power plants under high pressure at high temperature. The limited design factors such as strain histories, damage evolution and lifetime are important factors when creating the components of a power plant. Obtaining a long-term (100,000h, over 11 years) creep data is time consuming and costly, hence long-term creep data is very limited, and the extrapolation using the conventional empirical methods may not be reliable due to limited data (Chen et al., 2011; Shrestha et al., 2013; Ghosh et al., 2013). To design against failures, creep damage constitutive equations have the advantage of traceability from the physics based constitutive equation to the fundamental microstructural and damage behaviour. Thus, creep modelling constitutive equations for materials of the critical components of, for example, power plants and other safety critical systems, are a key issue in the research of materials. In the past decade, a range of creep damage constitutive equations have been developed to describe creep damage behaviour for high chromium steel, however, some models are only based on creep deformation (creep microstructural degradation) and are not really concerned with cavitation damage, which is a dominant factor in creep rupture; most of them are proposed based on high stress levels of high chromium steel and extended to a low stress level, the modelling results fail to explore the phenomenon of stress breakdown. Besides, the cavitation damage equations were developed on experimental data of pure metal and super alloy, the fundamental nature of the evolution of creep cavitation damage is still unclear and necessary to solve for high chromium steel. Thus, the aim of this research project was to develop a novel creep damage constitutive equation for high chromium steel based on the mechanism of cavitation damage under a wide range of stress levels. This research made contributions to the specialised knowledge on the following three aspects. Firstly, a modified hyperbolic sine law, which describes the relationship between minimum creep strain and applied stress, was applied to high chromium steel. Through which we found that the modelling results fitted better with published experimental data by NIMS in comparison with conventional functions such as power law, hyperbolic sine law and linear power law. The other two aspects of innovation in the development of creep damage constitutive equation had been achieved. Secondly, using the quantitatively analysed results of the cavity size distribution along grain boundary by the superior 3D technology of X-ray micro-tomography, a novel creep cavitation damage equation was developed and applied to describe the evolution of cavity along grain boundary in the creep process for high chromium steel. Thirdly, the novel creep damage constitutive equations, that coupled appropriate creep deformation mechanisms with the new cavitation damage equation, were successfully applied to high chromium steel under a wide range of stress level according to comparisons made between the modelling results of novel creep damage constitutive equations, classic uniaxial KRH constitutive equations and experimental data for P91 steel at 600°C and also applied to P91 steel at 625°C.
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Smart, Kevin Arthur. "The mechanism by which hyperammonaemia may cause hepatic encephalopathy." Thesis, King's College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267312.
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Gruber, Claudia. "Investigation into the regulatory mechanism of BRCA2 stability." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:e69ab649-f955-48d2-a7c5-48b65f15df45.
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Inherited mutations in the BRCA2 gene predispose individuals to the development of breast and ovarian cancers. The BRCA2 protein plays a fundamental role in the repair of DNA double strand breaks by homologous recombination (HR). BRCA2 mediates the recruitment of the RAD51 recombinase to DNA damage sites, which in turn promotes homologous pairing and strand exchange during HR. It has been reported that increased BRCA2 mRNA levels correlate with poor cancer prognosis, and recently it has been shown that increased levels of BRCA2 suppress HR. As HR is regulated through the cell cycle and can only be employed during S and G2 phases of the cell cycle, in this study, the cell cycle-dependent regulation of BRCA2, as a key player of HR, was investigated. In this study I report that BRCA2 stability is regulated by the ubiquitin-proteasome system (UPS), which has become increasingly evident as an important regulator of DNA repair. In line with this, I found that BRCA2 can be ubiquitylated in vivo and that it interacts with proteins of the UPS. Interestingly, I observed that BRCA2 levels and its ubiquitylation status change during the cell cycle. Using a siRNA-based approach, I identified a candidate E3 ubiquitin ligase, the SCFFBXW7 complex, which is also a known major cell cycle regulator. siRNA-mediated knockdown of FBXW7 led to stabilization of BRCA2 and overexpression of FBXW7 resulted in BRCA2 ubiquitylation in vivo. Furthermore, I have refined the regions that the SCFFBXW7 interacts with on BRCA2, which likely occurs in a phosphorylation-dependent manner. Taken together, these observations suggest that BRCA2 stability is regulated by the UPS in a cell cycle-dependent manner, which may be an important regulatory mechanism for BRCA2 function.
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Chau, P. Y. Pauline. "Mechanism of genomic instability in Prelamin A based premature ageing." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557352.
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Shirazi, Hosseini Dokht Alireza. "Kinetics, mechanism and modulation of accelerated repopulation in mouse epidermis during daily irradiation." Thesis, Queen Mary, University of London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243323.
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Jacob, Molly. "Mechanism of non-steroidal anti-inflammatory drug induced damage in the small bowel." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313890.
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Chatterji, Tonika. "Mechanism of oxidative DNA cleavage by antitumor antibiotic Varacin and insight into the mechanism of alkylative DNA damage by novel antitumor antibiotic Leinamycin /." free to MU campus, to others for purchase, 2001. http://wwwlib.umi.com/cr/mo/fullcit?p3025610.
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Chau, P. Y. Pauline, and 周珮然. "Mechanism of genomic instability in Prelamin A based premature ageing." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39557352.
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Mensah-Osman, Edith J. "Mechanism of DNA damage, cell cycle arrest and apoptosis in indolent B-cell lymphomas." Connect to online resource - WSU on-site and authorized users, 2003.
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Panomwan, Pornpen. "Analysis of the mechanism of DNA damage and replication arrest-induced histone mRNA decay." Thesis, University of Sheffield, 2017. http://etheses.whiterose.ac.uk/17121/.
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Chang, Debbie Jimway. "Defining the molecular mechanism and functions of PCNA ubiquitination in the DNA damage response /." May be available electronically:, 2009. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Maillard, Olivier. "DNA damage recognition mechanism of xeroderma pigmentosum group C protein in human nucleotide excision repair /." [S.l.] : [s.n.], 2007. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253588.
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Azarbayjani, Faranak. "Common mechanism for teratogenicity of antiepileptic drugs : Drug-induced embryonic arrhythmia and hypoxia-reoxygenation damage." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5065-2/.
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Ho, Hsin Shen. "Fundamental mechanism of surface damage associated with the localization of the plastic deformation in fatigue." Compiègne, 2011. http://www.theses.fr/2011COMP1967.
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L’objectif principal que l’on espère atteindre pour ces travaux de recherche est de définir un modèle d’amorçage des fissures en fatigue pour l’alliage durci par précipitation. Les travaux de ma thèse consistent à étudier les effets de différents états métallurgiques (taille des grains, la taille de précipiter et des distributions de taille associés) sur l’irréversibilité de la déformation plastique, pour les éprouvettes sollicitées à une amplitude de déformation plastique constante. Mes travaux consistent en premier temps à obtenir quelques nuances de matériaux par les traitements thermiques. Dans le second temps, les essais de fatigue sont menés jusqu’en phase d’amorçage des fissures. Les analyses et les observations sont faites par la suite avec multiple techniques expérimentales (microscope à force atomique (AFM), microscopie électronique en transmission (MET), microscopie électronique à balayage (MEB) et electron backscattered diffraction (EBSD)). Les résultats partiaux de ma thèse ont montré qu’il existe une corrélation assez prometteuse entre les comportements mécaniques et les comportements d’irréversibilité de la déformation plastique (microreliefs ou extrusions) étudiés par AFM, MEB et MET. Ces comportements ont une dépendance non négligeable sur les états métallurgiques (taille de grain et précipité ainsi que leurs distributions). L’apparition des fissures est favorisée quand les paramètres d’irréversibilités de la déformation plastique (la hauteur d’extrusion critique et le taux critique d’irréversibilité de la déformation cumulée dans une bande) respectent une certaine condition d’amorçage des fissuresThe main objective of this thesis is to investigate the influence of local behaviour related to metallurgical parameters (grains and precipitated sizes) on damage mechanism. In this work, the effects of metallurgical states (grain size, precipitate size and size distributions associated with), under one constant plastic deformation amplitude on irreversibility of plastic deformation are investigated. For this purpose, it is necessary to obtain a range of well controlled precipitate size with a same grain size and inversely. The fatigue tests are conducted until crack initiation phase. The analysis and observations are made subsequently with multiple experimental techniques (atomic force microscope (AFM), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and electron backscattered diffraction (EBSD)). This partial results of my thesis have shown that the correlation that exists between the mechanical behavior and the behavior of the irreversible plastic deformation (microreliefs or extrusions) studied by AFM, SEM and TEM is very promising. Moreover they are found to have a significant dependence on metallurgical states (grain size and precipitate their distributions). When the parameters of the irreversible plastic deformation (extrusion height criticism and critical rate of irreversible strain accumulated in a band) meet certain conditions, the nucleation of cracks is favored
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Cheng, Anchi. "Kinetics and mechanism of lipid mesophase structural changes induced by pressure and X-radiation damage /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu148786179681917.
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Schlientz, Nathan William. "Charge Migration through Duplex DNA: A Study of the Mechanism for Charge Migration and Oxidative Damage." Diss., Available online, Georgia Institute of Technology, 2006, 2006. http://etd.gatech.edu/theses/available/etd-05182006-164757/.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2007.Laren M. Tolbert, Committee Member ; Uzi Landman, Committee Member ; Nicholas V. Hud, Committee Member ; David M. Collard, Committee Member ; Gary B. Schuster, Committee Chair.
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Nandi, Saikat. "Deciphering the molecular mechanism by which Fml1 promotes and constrains homologous recombination." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.561123.
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Homologous Recombination (HR) can promote genome stability through its capacity to faithfully repair DNA gouble 2trand !;!reak2 (DSBs) and preventing the demise of stalled replication forks in part by catalysing template switching to enable DNA polymerase to bypass lesions. Despite these beneficial roles, inappropriate or untimely HR events can have deleterious consequences. HR can cause genome instability by recombining "inappropriate" homologous sequences, especially if the recombination intermediates are resolved to form crossovers. Over the past few years, study of the rare inherited chromosome instability disorder, Eanconi Anaemia (FA), has uncovered a novel DNA damage response pathway. Although the FA pathway is required primarily for interstrand DNA cross link repair, its precise role in DNA repair reactions is still unclear. FA.Qomplementation group M (FANCM) is the sole component within the FA core complex which possesses a DNA helicase/ATPase domain and an endonuclease domain (albeit non-functional), suggesting that FANCM could translocate along DNA and target the FA core complex to blocked replication forks. To further elucidate the role of FANCM in HR, I have purified Fm11, the FANCM orthologue in the fission yeast Schizosaccharomyces pombe and tested its activity on a range of synthetic replication and recombination intermediates in vitro. Fml1 binds both replication forks and Holliday Junctions (HJs) which are key intermediates of HR.
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Lacroix, Gauthier. "On the relationships between microstructure and mechanical properties of TRIP-assisted multiphase steels : strength, ductility, fracture and fatigue." Université catholique de Louvain, 2007. http://edoc.bib.ucl.ac.be:81/ETD-db/collection/available/BelnUcetd-11302007-114213/.
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In the context of sustainable development, steelmakers and automotive manufacturers decided for some years now to join their efforts to promote the development and use of advanced high strength steels such as the present TRIP steels in order to reduce the fuel consumption and emission of greenhouse gas. These multiphase steels contain some retained austenite, a ductile phase that can transform into hard and brittle martensite during a mechanical solicitation. One the one hand, this transformation improves the mechanical properties during plasticity by bringing about an additional work-hardening. On the other hand, the appearence of a hard and brittle phase can give rise to premature cracking after necking. Knowing the good influence of martensitic transformation on the work-hardening, this Thesis starts with the characterisation of the relationship between transformation rates and testing conditions. It appears that, for each testing condition, there is an optimum austenite stability that leads to a maximum uniform strain. After necking under monotonic loading conditions, the damage mechanisms that takes place in these steels has been characterised. It can be concluded that the TRIP-aided steels that present low or moderate austenite stability behave exactly like Dual-Phase steels, in which martensite replaces retained austenite. However, a very stable retained austenite brings about a significant toughness improvement by providing an additional work-hardening contribution in the necking zone. The mechanical behaviour of these steels has also been characterised under cyclic loading conditions. The results indicate that, for particular loading conditions (i.e. low load levels), the martensitic transformation improves the fatigue properties.
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Shen, Zeng. "Characterisation of low velocity impact response in composite laminates." Thesis, University of Hertfordshire, 2015. http://hdl.handle.net/2299/16334.
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A major concern affecting the efficient use of composite laminates in aerospace industry is the lack of understanding of the effect of low-velocity impact (LVI) damage on the structural integrity. This project aims to develop further knowledge of the response and damage mechanisms of composite laminates under LVI, and to explore the feasibility of assessing the internal impact damage with a visually inspectable parameter. The response and damage mechanisms of composite laminates under LVI have been investigated experimentally and numerically in this project. Various parameters including the laminates thickness, lay-up configuration, repeated impact, and curing temperature have been examined. The concept and the phenomena of delamination threshold load (DTL) have been assessed in details. It was found that DTL exists for composite laminates, but the determination of the DTL value is not straightforward. There is a suitable value of range between the impact energy and the laminates stiffness/thickness, if the sudden load drop phenomenon in the impact force history is used to detect the DTL value. It is suggested that the potential menace of the delamination initiation may be overestimated. The composite laminates tested in this project demonstrate good damage tolerance capacity due to the additional energy absorption mechanism following the delamination initiation. As a result, the current design philosophy for laminated composite structure might be too conservative and should be reassessed to improve the efficiency further. To explore the feasibility of linking the internal damage to a visually inspectable parameter, quasi-static indentation (QSI) tests have been carried out. The dent depth, as a visually inspectable parameter, has been carefully monitored and assessed in relation to the damage status of the composite laminates. It is proposed that the damage process of composite laminates can be divided into different phases based on the difference in the increasing rate of dent depth. Moreover, the internal damage has been examined under the optical microscope (OM) and the scanning electron microscope (SEM). Residual compressive strength of the damaged specimen has been measured using the compression-after-impact (CAI) test. The results further confirm the findings with regard to the overestimated potential menace of the delamination initiation and the proposed damage process assumption. The proposed damage process assumption has great potential to improve the efficiency and accuracy of both the analytical prediction and the structural health monitoring for damages in composite laminates under low-velocity impact.
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Matkar, Smita S. "Mechanism of action of potential anticancer drugs." Scholarly Commons, 2008. https://scholarlycommons.pacific.edu/uop_etds/2368.
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Traditionally, inoperable or metastatic cancers have been treated by causing massive DNA damage in order to induce self-destruction (apoptosis) of the rapidly multiplying cancer cells. Initially, this strategy works for many cancers, in particular those which express normal p53 tumor suppressor protein. However, most cancers eventually aquire mutations in either p53 or other signaling molecules and fail to initiate apoptosis in response to severe DNA damage. During this study three types of compounds were investigated for their DNA damaging and anticancer effects: a pair of novel metal containing compounds, a pair of natural products, and a known synthetic drug which had been used many years ago for completely different indication. It was shown that all stop the growth of cancer cells and that the latter two classes do not require functional p53 because they work equally well in cells with normal (wildtype), mutant or no p53. The two nickel complexes investigated in this dissertation, differ in their ability to cause DNA damage and cell death. The oxidized form of the nickel complex, [Ni(CR-2H)] 2+ causes DNA damage and cell death at a much lower concentration than its reduced counterpart [Ni(CR)] 2+ . The phenanthridine alkaloids, Sanguinarine and Chelerythine cause high levels of DNA strand breaks and extremely rapid apoptosis which is not due to DNA damage because the quick onset precludes extensive signaling. The effects of the phenanthridines were linked to production of large amounts of reactive oxygen species (ROS), in particular hydrogen peroxide (H 2 O 2 ). The importance of ROS for the action of anticancer drugs as well as antibiotics is increasingly being recognized. In addition we also investigated the thioxanthone Lucanthone or Miracil D (which was used for the treatment of parasitic worms more than 50 years ago). It causes DNA strand breaks and apoptosis. Apoptosis occurs on a timescale consistent with signaling. However, p53 does not seem to be involved and alternative mechanisms are being investigated. This work provides new directions for designing novel anticancer drugs that are not subject to the limitations of DNA damaging agents.
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Calcaterra, Jeffrey Ronald. "Life prediction evaluation and damage mechanism identification for SCS-6/Timetal 21S composites subjected to thermomechanical fatigue." Diss., Georgia Institute of Technology, 1996. http://hdl.handle.net/1853/12548.
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Amuzuga, Kwassi. "Damage mechanism related to plasticity around heterogeneous inclusions under rolling contact loading in hybrid bearings ceramic/steel." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSEI154.
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La durée de vie des pièces mécaniques en contact est fortement affectée par la présence d'hétérogénéités dans le matériau, comme des renforts (fibres, particules), des précipités, des porosités, ou encore des fissures. Des hétérogénéités dures et de formes complexes peuvent créer des surcontraintes locales, initiatrices de fissures par fatigue à proximité de la surface de contact. Une analyse quantitative des surcontraintes créées par les hétérogénéités est nécessaire à la compréhension des mécanismes d'endommagement. Cette étude s'applique à des roulements de ligne d'arbre qui font partie des éléments critiques de moteurs en aéronautique. Elle vise à déterminer précisément la distribution du champ de pression sur l'aire effective de contact et à prédire le profil et l'évolution des champs de contraintes/déformations à chaque passage de la charge sur un volume élémentaire représentatif prenant en compte le gradient de dureté, la présence de carbures et l'existence des contraintes initiales d'origine thermochimique. Une partie de l’étude est consacrée au développement d’un solveur du problème de contact roulant élasto-plastique avec présence d’hétérogénéité par les méthodes semi analytiques assurant un excellent gain en temps et ressources de calculs. Ensuite, un algorithme homogénéisation a été conçu pour analyser le comportement effectif d’un massif élasto-plastique hétérogène sous indentation. Enfin une partie expérimentale est dédiée à la caractérisation microstructurale des aciers étudiés dans le but de déterminer leurs propriétés. Les analyses des résultats de cette étude concourent à soutenir que bien que les inclusions de particules non métalliques soient responsables de la haute résistance de ces matériaux, certaines d’entre elles (celles de longueur dépassant les dizaines de micromètre ou celles qui forment des chaines dans une direction particulière) deviennent, au cours des cycles de fatigue, les principales sources d’endommagement depuis l’échelle locale jusqu’à la rupture globale de la structureThe lifetime of contacting mechanical parts is strongly affected by the presence of heterogeneities in their materials, such as reinforcements (fibers, particles), precipitates, porosities, or cracks. Hard heterogeneities having complex forms can create local overstress that initiating fatigue cracks near the contact surface. The presence of heterogeneities influences the physical and mechanical properties of the material at microscopic and macroscopic scales. A quantitative analysis of the over-stresses generated by heterogeneities is necessary to the comprehension of the damage mechanisms. The present study is applied to rolling bearings which are the critical elements of the aero-engine's mainshaft. The performance required for these bearings, led SKF Aerospace to introduce a new technology of hybrid bearing with ceramic rolling elements on high-strength steels having experienced a double surface treatment (carburizing followed by nitriding). The study aims to precisely determine the pressure field distribution on the effective contact area and to predict the profile and the evolution of the stress/strain fields at each loading cycle on a representative elementary volume that takes into account the gradient of hardness, the presence of carbides and the existence of an initial compressive stress from thermochemical origin. A major part of this study is devoted to develop a heterogeneous elastic-plastic rolling contact solver, by semi-analytical methods ensuring an excellent saving of calculation time and resources. Thereafter, a homogenization algorithm was built to analyze the effective behavior of a heterogeneous elastic-plastic half-space subjected to an indentation loading. Finally, an experimental part is dedicated to the microstructure characterization of the studied steels with intent to determine their properties. A description of the carbides behavior inside the matrix during micro-tensile tests was carried out under SEM in-situ observation. In the scheme of all analyses conducted in the present work, it can be argued that, although the heterogeneities (such as carbides or nitrides) are responsible for the high resistance of the studied materials, some of them (those whose length exceeds tens of micrometer or those which form stringers in a particular direction) become, over fatigue cycles, the main sources of damage, from their local scale up to the macroscopic failure of the structure
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Lee, Wen-Hua. "α-tocopherol induces calnexin in renal tubular cells : another protective mechanism against free radical-induced cellular damage." Kyoto University, 2008. http://hdl.handle.net/2433/135837.
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Lesho, Jeffrey Carl. "Embedded damage sensor using triboluminescence as a transduction mechanism for detecting failure of a material under load." Available to US Hopkins community, 2002. http://wwwlib.umi.com/dissertations/dlnow/3068181.
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Wu, Wing-Fung. "Structural studies of the molecular mechanism of DNA damage-dependent poly(ADP-ribosyl)ation by human PARP-1." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648786.
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Chen, Xiaochao. "Mechanism of cellular uptake of HIV-TAT peptide & effects of TAT-SOD against ultraviolet induced skin damage." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/10641.
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TAT peptide is one of the best-characterised cell penetrating peptides (CPPs) derived from the transactivator of transcription protein from the human immunodeficiency virus 1 (HIV-1). TAT peptide is able to cross the cell membrane and deliver various biomolecules into cells with low immunogenicity and no toxicity. However, the exact mechanism of internalization still remains a subject of controversy. Lamellar neutron scattering was used to determine the location of TAT peptide in the negativelycharged phospholipids bilayers. The results reveal two locations, one in the peripheral aqueous phase between the adjacent bilayers and the second one below the glycerol backbone region of the lipid bilayer. A concentrationindependent membrane thinning above a peptide concentration threshold (1mol%) and a contiguous transbilayer water channel at the largest peptide concentration (10mol%) were also found. This evidence led to the suggestion that the toroidal pore model might be involved in the transmembrane mechanism at high peptide concentration. Another set of neutron diffraction experiments examined the interaction between the TAT peptide and neutral phospholipids showed that TAT peptide preferentially intercalated into the hydrophobic core and the glycerol backbone region of the neutral lipid bilayer at the lowest peptide concentration investigated (0.1mol%), indicating that the insertion did not require negatively-charged phospholipids. There was also clear evidence for the concentration-dependent reorientation of TAT peptide. A plasmid containing the human copper-zinc SOD gene linked with the coding sequence for a 11-aa HIV-TAT peptide (pGEX-TAT-SOD, 513bp) was constructed and used to express a recombinant fusion protein in Escherichia coli strain BL21 (DE3). High-level expression of TAT-SOD soluble protein with a GST tag (44-kDa) was achieved under optimal expression conditions and a small-scale glutathione affinity column or large-scale ion-exchange chromatography used for its purification. The potential protective effect of TAT-SOD against UV-induced cell damage was studied on UVC-irradiated MDCK epithelial cells. Before any further clinical study, the UV full-length absorption of TAT-SOD protein was measured. The results showed the potential UV protective effect of TAT-SOD was not due to the physical absorption of UV irradiation. In a preclinical study with five healthy volunteers, the penetration of TAT-SOD through human stratum corneum on the inner upper arm was identified by the tape stripping and specific SOD activity analysis. Significant increases on SOD activity were found on the outer layers of stratum corneum in TAT-SOD treated group, compared to placebo treated control, indicating that the TAT peptide assisted SOD to penetrate into the human stratum corneum . In a clinical study with ten healthy volunteers, eight showed a significant increase of minimal erythema dose (MED) with TAT-SOD pre-treatment. The median blood flow value of ten subjects at the UVB-irradiated site decreased with TAT-SOD pretreatment. Taken together, this evidence showed that TATvi SOD did have a marked protective effect against UVB induced skin damage. In a second clinical study, five healthy volunteers were challenged with a series of UVB doses. Skin punch biopsies were taken from four test sites on the lower back for H&E and immunohistochemical staining analysis. UVB-induced apoptotic sunburn cell (SBC) formation, p53 up-regulation and thymine dimer formation in epidermis were not attenuated by pretreatment with TAT-SOD. These data suggest that transdermal superoxide scavenger TAT-SOD reduced the UVB-induced inflammation, but did not abrogate the direct DNA damage of UVB irradiation on the skin. However, the hope of TAT-SOD could reduce UVA indirect DNA damage remains.
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Raghuraman, Nandini. "Prepubertal bisphenol A exposure in the rat mammary gland mechanism of action for carcinogenesis /." Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/raghuraman.pdf.
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Heckmann, Irina [Verfasser], and Stefan [Akademischer Betreuer] Jentsch. "DNA damage-induced degradation of elongating RNA polymerase II by a SUMO-dependent mechanism / Irina Heckmann ; Betreuer: Stefan Jentsch." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1173087567/34.
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Casley, Christopher Stuart. "Amyloid beta peptide-induced oxidative stress and mitochondrial respiratory chain damage : a mechanism for cell death in Alzheimer's disease?" Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252296.
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Williams, Sarah. "Molecular mechanism of regulation of the cellular protein levels of endonuclease III homologue (NTH1) in response to DNA damage." Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3026978/.
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Deoxyribonucleic acid (DNA) is the store of genetic material, needed for cellular survival and replication. Cellular DNA is under constant attack from genotoxic agents, arising endogenously or exogenously in relation to the cell. Maintaining the stability of the genome is imperative to ensure accurate inheritance of the genetic code for future progeny and ensures that crucial biological processes are undisturbed. To uphold the integrity of the genome, cells have developed numerous DNA surveillance and repair mechanisms. The base excision repair (BER) pathway is one of the pathways that has evolved to remove minor types of DNA damage. The main sub-pathway of BER involves recognition and removal of the oxidised DNA base lesion, incision of the phosphodiester backbone, followed by insertion of the correct complementary nucleotide, before the nick in the DNA backbone is restored. During BER, the recognition of damaged bases relies on DNA glycosylase enzymes. Human endonuclease III (NTH1) is a DNA glycosylase enzyme which specifically recognises oxidised base lesions, caused by reactive oxygen species (ROS). Crucially, NTH1 excises thymine glycol (Tg), which is a particularly mutagenic base lesion. Regulation of enzymes implicated in the BER pathway is important to prevent excessive DNA damage. Reports have demonstrated the importance of post translational modifications (PTMs) in controlling the levels, activity and interactivity of BER proteins. Ubiquitylation is a PTM that has been implicated in the regulation of several BER enzymes. Ubiquitylation is completed by the ubiquitin proteasome pathway (UPP); whereby E3 ligase enzymes attach of moieties of ubiquitin to lysine residues of substrate proteins. The attachment of multiple moieties of ubiquitin (polyubiquitylation) is associated with the regulation of protein levels, whereas, the attachment of singular subunits of ubiquitin (monoubiquitylation) can have variable consequences. Despite this understanding, evidence of PTMs that target human NTH1 are deficient. A proteomic study demonstrated that NTH1 is subject to ubiquitylation dependent regulation, but the specific UPP enzymes involved were not identified. The overarching aim of this project was to understand the molecular mechanisms employed by human cells to regulate levels of NTH1 via ubiquitylation, with specific emphasis on discovering the E3 ligase enzymes involved. Using a well refined purification technique, human cell extracts were fractionated using a series of column chromatography columns. Candidate E3 ligase activity was examined using in vitro ubiquitylation assays of chromatography fractions, with recombinant NTH1 as the substrate protein. Eventually, mass spectrometry analysis of an isolated ubiquitylated fraction, identified tripartite motif containing 26 (TRIM26) as the only candidate E3 ligase enzyme present in the active fraction. We strengthened this finding by repeating ubiquitylation assays using recombinant TRIM26. Together, these findings identify TRIM26 as the major E3 in human cell extracts that catalyses the ubiquitylation of NTH1. Following this, site directed mutagenesis identified lysine 67 as the major site of TRIM26 dependent ubiquitylation of NTH1. Aside to this, the cellular implications of TRIM26 dependent regulation of NTH1 were investigated. Elevated levels of cellular NTH1 following proteasome inhibition confirmed that NTH1 levels may be regulated in cells by ubiquitylation dependent degradation. However, depletion of cellular TRIM26 via siRNA had no significant impact on the steady state levels of the glycosylase. Fractionation of cellular extracts confirmed that cellular NTH1 is located primarily in the nucleus and may be associated with chromatin. Depletion of TRIM26 resulted in no alteration in the cellular distribution of the glycosylase. Since TRIM26 dependent ubiquitylation did not appear to regulate the steady state levels of NTH1, further examination using hydrogen peroxide as a DNA damaging agent showed that DNA damage responsive levels of NTH1 protein expression increased following TRIM26 depletion. The clonogenic assay demonstrated that cells had increased survival capacity in the absence of TRIM26. Importantly, this observation was recapitulated with a partial overexpression of NTH1. Similarly, the alkaline single gel electrophoresis (comet) assay, in combination with an siRNA mediated depletion of TRIM26, concluded that cells with reduced TRIM26 levels have improved ability to manage oxidative stress. Once more, a similar level of improved DNA repair kinetics could be achieved by partially overexpressing NTH1. Overall, I successfully purified and identified TRIM26 as the major E3 ligase that ubiquitylates NTH1. The major site of TRIM26 dependent ubiquitylation is lysine 67; as substitution of this residue substantially impeded in vitro ubiquitylation via TRIM26. Cellular studies confirmed that levels of NTH1 may be regulated by ubiquitylation dependent degradation, although, TRIM26 dependent ubiquitylation was not implicated in the regulation of steady state levels of NTH1. Rather, it appears that TRIM26 may be implicated in the regulation of DNA damage responsive levels of NTH1. Interestingly, a separate investigation in our laboratory previously identified TRIM26 as one of the major E3 ligase enzymes involved in regulation of the steady state levels of another BER glycosylase, endonuclease VIII-like protein 1 (NEIL1). Excitingly, the outcomes of this work have now been peer-reviewed and accepted for publication in the Molecular and Cellular Biology scientific journal (see appendix). In summary, an increasingly dynamic role of TRIM26 is now becoming apparent; whereby, the E3 ligase is involved in the regulation of multiple BER glycosylases with different effects in relation to the DNA damage response. Despite this increased perception, the cellular mechanism which dictates the outcome of ubiquitylation of either glycosylase under the regulation of TRIM26 remains to be fully understood and demands further inspection.
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Afsar, Nilufer. "Effect Of Cold Stress On Antioxidant Mechanism Of Winter And Spring Type Barley ( Hordeum Vulgare L.) Cultivars." Master's thesis, METU, 2007. http://etd.lib.metu.edu.tr/upload/3/12608514/index.pdf.
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In this study, effect of cold stress on physiology and biochemistry of two Turkish barley cultivars, winter type Tarm-92 and spring type Zafer-160, was studied. For chilling stress treatment, cultivars were exposed to +4 ºC for 1, 3 and 7 days, and for freezing stress application acclimated cultivars (+4 º
C for 3 days) were treated with -3 º
C and -7 º
C. After freezing stress treatment, a recovery period was applied for 4 days at 4 º
C. Following analyses were performed on leaf and root tissues: growth parameters (length, wet-dry weights), malondialdehyde (MDA) content, proline content, hydrogen peroxide content (H2O2) electrolyte leakage, PS II fluorescence (Fv/Fm), antioxidant enzyme activities such as catalase (CAT: EC 1.11.1.6), ascorbate peroxidase (APX: EC 1.11.1.11) and glutathione reductase (GR: EC 1.6.4.2). It was observed that effect of cold was more at freezing temperatures than chilling temperature. Cold dependent damage was more obvious as the duration of chilling temperature increased. Growth retardation, membrane damage, leaf catalase deactivation were more apparent and leaf glutathione reductase activity increase was less in spring type cultivar Zafer than in winter type Tarm. These results indicated that winter type barley cultivar is more cold tolerant than spring type barley.
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Aswani, A. D. "The importance and mechanism of mitochondrial damage associated molecular patterns (DAMPs) in the pathogenesis of trauma haemorrhage induced inflammation and organ injury." Thesis, Queen Mary, University of London, 2016. http://qmro.qmul.ac.uk/xmlui/handle/123456789/18405.
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Trauma is a leading cause of death worldwide with 5.8 million deaths occurring yearly. Almost 40% of trauma deaths are due to bleeding and occur in the first few hours after injury. Of the remaining severely injured patients up to 25% develop a dysregulated immune response leading to multiple organ failure (MOF). Despite improvements in trauma care, the morbidity and mortality of this condition remains very high. Massive traumatic injury can overwhelm endogenous homeostatic mechanisms even with prompt treatment. The underlying mechanisms driving MOF are also not fully elucidated. As a result, successful therapies for trauma-related MOF are lacking. Trauma causes tissue damage that releases a large number of endogenous damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs released in trauma, such as mitochondrial DNA (mtDNA), could help to explain part of the immune response in trauma given the structural similarities between mitochondria and bacteria. MtDNA, like bacterial DNA, contains an abundance of highly stimulatory unmethylated CpG DNA motifs that signal through Toll-like receptor (TLR)-9 to produce inflammation. MtDNA has been shown to be highly damaging when injected into healthy animals causing acute organ injury to develop. Elevated circulating levels of mtDNA have been reported in trauma patients but an association with clinically meaningful outcomes has not been established in a large cohort. The first aim of this PhD thesis was to determine whether mtDNA released after trauma haemorrhage is sufficient for the development of MOF. Secondly, I then aimed to determine the extent of mtDNA release with varying degrees of tissue injury and haemorrhagic shock in a clinically relevant rodent model. My final aim was to determine whether neutralising mtDNA at a clinically relevant time point in vivo would reduce the severity of organ injury in this model.
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Kong, Weixi. "Oxidative DNA Damage and DNA Binding Induced by 2, 2-Bis (Bromomethyl)-1, 3-Propanediol: Possible Mode of Action Implicated in its Carcinogenicity." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/223375.
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The studies in this dissertation research were conducted to investigate the possible mode of action by which a brominated flame retardant, 2, 2-Bis (bromomethyl)-1, 3-propanediol (BMP) causes genotoxicity. Binding of BMP to DNA and BMP induced DNA strand breaks were investigated in SV-40 immortalized human uroepithelial cells (UROtsa) as an in vitro model for the bladder (a tissue that developed cancer after two year exposure to BMP in rodents). Results showed binding of [¹⁴C]-BMP equivalents to DNA increased with increased exposure time and concentration of [¹⁴C]-BMP. Comet analysis indicated BMP significantly increased the extent of DNA strand breaks at 1 and 3 h of incubation. However, strand breaks were repaired by 6 h of incubation. The DNA damaging effects of BMP at 1 h was concentration dependent. Compared with the parent compound, BMP-glucuronide (the predominant metabolite of BMP) bound less to DNA and produced less DNA strand breaks in UROtsa cells. Evidences that the BMP induced strand breaks were the result of an oxidative stress include: a concentration and time dependent increase in ROS generation; increased expression of Nrf2 and HSP70; complete attenuation of BMP induced DNA strand breaks by the antioxidant, NAC; and the presence of the oxidized base 8-OHguanine. UROtsa cells appear to be target cells for BMP because, as compared to rat hepatocytes (non-target cells), these cells lack the ability to detoxify BMP via glucuronidation and also because they are deficient in glutathione, a major intracellular antioxidant molecule. Both of these genotoxic events, DNA binding and oxidative DNA damage may, in part, contribute to BMP carcinogenicity observed in rodents. The relevance of current results to humans is remained to be established.
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Black, Jennifer. "Discerning the Mechanism of Gamma Delta T Cell-Mediated Damage in Multiple Sclerosis: the Potential Role of Antibodies in Disease Pathogenesis." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/31925.
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Background: Both the innate and adaptive immune systems contribute to autoimmune injury in multiple sclerosis (MS). We have been particularly interested in elucidating the role of the innate γδ T-cell population in MS pathogenesis. In particular, some γδ T-cells that express Fc receptors (FcR), such as CD16, that bind antibody are more prominent with MS disease progression and have been shown to exert cytolysis via antibody-dependent cellular cytotoxicity (ADCC). We postulated that if there were also relevant and detectable antibodies in MS patients that might engage these FcR-bearing γδ T-cells then this might be a purported mechanism of neuro-axonal injury. A search for antibodies specific to axonal elements in MS revealed the presence of antibodies to neurofascin (Nfasc).
Methods: Anti-Nfasc antibody titres, and concentrations of the light and heavy chains of neurofilament (NfL and NfH, respectively), markers of neuro-axonal injury, were measured in the sera and cerebrospinal fluid (CSF) of MS patients using enzyme-linked immunosorbent assays (ELISA), including those that underwent autologous hematopoietic stem cell transplantation (aHSCT), both prior to and yearly for 3 years thereafter. HeLa cells were transfected with the axonal variant of Nfasc, Nfasc-186, and were utilized as targets in ADCC assays involving γδ T-cells as the effectors, and anti-Nfasc antibodies that were enriched from MS patient sera.
Results: Positive anti-Nfasc antibody titres were detected in of 22% and 25% of MS patient sera and CSF, respectively. The most elevated serum titres were in secondary progressive MS (SPMS), and highest CSF titres in relapsing-remitting MS (RRMS) (p<0.05 and p<0.0001, respectively, vs. other neurological disease [OND] controls). Patient serum and CSF antibody titres correlated and, in the CSF, the titres correlated positively with the concentration of NfL. Though NfL and NfH concentrations declined markedly following aHSCT in the CSF, anti-Nfasc antibody titres failed to decline. When co-cultured with CD16+ γδ T-cells in the presence of MS patient-derived anti-Nfasc antibodies, the percent specific cytolysis of the Nfasc-transfected HeLa cells was significantly greater than that of the non-transfected control HeLa cells, at 18% and 1%, respectively, indicating cytolytic kill via ADCC.
Summary: Anti-Nfasc antibodies were detectable in the sera and CSF of MS patients, and rarely in OND controls, suggesting they are relevant to MS. Higher titres in the serum support peripheral synthesis, while higher CSF titres in the relapsing phase, that correlate with serum titres, imply that antibodies access the CNS during periods of active inflammation that are associated with disruption of the blood-CSF barrier. CSF anti-Nfasc antibody titres correlated strongly with the release of NfL, suggesting that axonal injury could be related to the presence of Nfasc-specific antibodies. Following aHSCT, CSF NfL and NfH release were reduced without concomitant CSF anti-Nfasc antibody reductions, suggesting that the presence alone of anti-Nfasc antibodies is not enough to cause axonal injury. Indeed, when co-cultured with CD16+ γδ T-cells in the presence of MS patient-derived anti-Nfasc antibodies, the percent specific cytolysis of the Nfasc-transfected HeLa cells was significantly greater than that of the non-transfected control HeLa cells, proving that FcR-bearing γδ T-cells can cause axonal damage by lysing axonal membranes via ADCC, when armed with axon-specific antibodies such as anti-Nfasc. This is the first report of γδ T-cell-mediated cytolysis by ADCC using both γδ T-cells and antibodies derived from MS patients.
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Cosa, Gonzalo. "Study on the mechanism of photodegradation of pharmaceutical products and analogues, development of a novel fluorescence technique for DNA-damage detection." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6286.
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This thesis focuses on different aspects of photobiology. The first chapters address the photophysical and photochemical characterization of two pharmaceutical products, fenofibric acid and ketoprofen, both containing the benzophenone chromophore. These studies have been performed with the aim of better understanding the photostability of these drugs. These compounds are shown to undergo efficient photodecarboxylation in basic solutions, with concomitant formation of carbanions. Time-resolved studies lead us to propose a singlet mediated reaction in the case of ketoprofen, whereas the photoreactivity of fenofibric acid results from the triplet state of this compound; further, dramatic solvent dependence is encountered in the photochemical reactions of the latter drug and its photoproducts. In the case of ketoprofen photodegradation, the photogenerated benzylic carbanion can be monitored, and lifetime measurements at different temperatures and in different solvents have been performed to determine its dynamic parameters. The decay of this carbanion, resulting from protonation by water, is found to occur within a few hundred nanoseconds; and the protonation rate is shown to be dependent on the solvent and the degree of substitution of the carbanion center. The case of alpha-diketones as potential photosensitizers is also addressed with the example study of a di-thienyl alpha-diketone; i.e., 2,2 '-thenil. Direct spectroscopic evidence is given for the formation of a molecular oxygen-triplet adduct (Bartlett-Schenck intermediate), a previously described, though never isolated, reactive oxygen species about which little is known. The formation and yield of this intermediate are discussed in terms of the energy of its triplet precursors. The subsequent chapters in this thesis deal with two other biologically relevant problems where photochemistry and photophysics are employed as a tool in order to better understand the systems under study. Thus the properties of the adrenaline derived radical are evaluated, as a case study for the catecholamine group in general. Absolute rate constants for tert-butoxyl radical scavenging and triplet benzophenone quenching are reported, and a reactivity comparison is established with other intermediates involved in the reaction of melanin formation via catecholamines. A second aspect involves the development of a novel technique to assess DNA-damage, based on fluorescence of dye-DNA complexes. The rigidity imposed by the DNA base pairs on intercalating chromophores is exploited. Its retardation effect on the relaxation of a photoexcited DNA-stain probe is employed to determine the amounts of DNA existing as double and single stranded form; which is ultimately an expression of the damage the DNA has suffered.
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Azzam, Aussama. "On the Mechanical Modeling and Analysis of the Dynamical Fiber Pullout Mechanism Taking into Account the Damage and Viscoelasticity of the Bond." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-197897.
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Textile reinforcement concrete (TRC) is a new building material in increasing usage in modern engineering applications. The experimental investigations of TRC reveal a multiple cracking behavior which corresponds to concrete cracking and fiber pullout mechanisms. The aim of the presented research work is the mechanical analysis of the fiber pullout mechanism under dynamical loading conditions. Appropriate constitutive material models are proposed for the matrix-fiber interface taking into consideration two main mechanical characteristics, damage behavior and rate-dependent effects. These material models are the elastic damage model, the viscoelastic model and two developed viscoelastic damage material models. Moreover, an analytical model of the fiber pullout mechanism is provided, where the governing differential equation of motion is formulated and closed analytical solutions are derived under a dynamical excitation of a harmonic pullout displacement function at the fiber tip. These analytical solutions are derived for two material models of the interface, the elastic damage and the viscoelastic material models. Furthermore, the dynamical responses are also sought for the case of a linearly increasing pullout displacement function of a definite velocity. For the latter dynamical loads a numerical DISCRETE MODEL with an iterative solving scheme is formulated for the pullout problem to solve the corresponding nonlinear differential equation of motion. Moreover, comparisons between the obtained results regarding the different proposed material models of the interface are provided. The elastic damage model can be used with a dynamical increasing factor (DIF) on the bond strength and the stiffness of the interface with respect to the shear slip rate. On the other hand, the developed viscoelastic damage material models characterize the rate-dependent effects of the dynamical pullout through the viscous and the viscoelastic parts of the corresponding constitutive relations of these models. The second part of this doctorial thesis deals with the mechanical analysis of the uniaxial tensile behavior of TRC specimen under dynamical tensile loading. A corresponding analytical model is firstly formulated. Furthermore, a tested TRC tensile specimen and the corresponding fiber crack bridging behavior (cracked stage) are also analyzed by means of the Finite Element modeling approach by conducting 3-dimensional heterogeneous modelsTextil bewehrter Beton (Textilbeton) ist ein neues Baumaterial mit zunehmender Verwendung in modernen Ingenieuranwendungen. Die experimentellen Untersuchen an Textilbeton zeigen Mehrfachrissbildung, die zu Betonriss- und Faserauszugsmechanismen korrespondieren. Das Ziel dieser Forschungsarbeit ist die mechanische Untersuchung des Faserauszugsmechanismus unter dynamischer Belastung. Hierzu werden geeignete Materialmodelle für das Matrix-Faser-Interface vorgeschlagen, die zwei mechanische Phänomene, nämlich das Schädigungsverhalten und den Dehnraten-Effekt, berücksichtigen. Diese Materialmodelle sind das elastische Schädigungsmodell, das viskoelastische Modell und zwei entwickelte viskoelastische Schädigungsmodelle. Zudem wird ein analytisches Modell zum Faserauszugsmechanismus bereitgestellt, wobei die beschreibende Bewegungsgleichung aufgestellt und geschlossene, analytische Lösungen unter dynamischer Erregung durch eine harmonische Auszugsverschiebung am Faserende gefunden werden. Diese analytischen Lösungen werden für zwei Materialmodelle, das elastische Schädigungsmodell und das viskoelastische Modell, hergeleitet. Außerdem wird die dynamische Antwort für den Fall einer linear ansteigenden Auszugsverschiebung mit konstanter Geschwindigkeit gesucht. Zu dieser dynamischen Belastung wurde für die numerische Lösung der entsprechenden nichtlinearen Differentialgleichung ein diskretesModell (DISCRETE MODEL) entwickelt und mit einem iterativen Lösungsverfahren gelöst. Darüber hinaus wurde ein Vergleich zwischen den Ergebnissen, die bei Verwendung der unterschiedlichen vorgeschlagenen Materialgesetze für das Interface erhalten wurden, durchgeführt. Das elastische Schädigungsmodell kann zum einen mit einem von der Schlupfrate abhängigen dynamischen Vergrößerungsfaktor (DIF) für die Verbundfestigkeit bzw. die Steifigkeit des Interface verwendet werden. Zum anderen werden die Dehnraten-Effekte durch die viskosen und viskoelastischen Anteile in den entwickelten viskoelastischen Schädigungsmodellen abgebildet. Der zweite Teil dieser Dissertation behandelt die mechanische Untersuchung des uniaxialen Zugverhaltens von Textilbeton unter dynamischer Zugbelastung. Ein zugehöriges analytisches Modell wird zuerst formuliert. Zudem werden der Mehrfachrissbildungszustand und der Faserrissüberbrückungsmechanismus an einem Textilbetonprobekörper mittels einer Finite-Elemente-Analyse an einem dreidimensionalen, heterogenen Modell untersucht
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Lau, Wing Yin. "Pain assessment and possible mechanism of delayed onset muscle soreness." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2014. https://ro.ecu.edu.au/theses/1275.
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Muscle pain is felt during exercise or daily activities for several days after performing unaccustomed exercise, which is referred to as delayed onset muscle soreness (DOMS). Many people experience DOMS, but its underlying mechanisms are not fully understood. One of the challenges in the investigation of DOMS is its subjective nature, which makes the assessment ambiguous, thus establishing a standardised protocol is necessary. The present thesis scrutinised muscle pain assessments (Study 1, Study 2), developed a new assessment of muscle pain focusing on muscle fascia (Study 3), and investigated why DOMS is reduced after the second than the first bout of eccentric exercise (Study 4). From these studies, DOMS was thought to be more associated with connective tissue than muscle fibre damage and inflammation.
In Study 1, the relationship between pain level assessed by a visual analogue scale (VAS) and pain sensitivity assessed by pressure pain threshold (PPT) was examined. Thirty-one healthy young men performed 10 sets of 6 maximal isokinetic eccentric contractions with their non-dominant arm. Before and 1 - 4 days after the exercise, muscle pain perceived upon palpation of the biceps brachii at three sites (5, 9, and 13 cm above the elbow crease) was assessed by VAS with a 100 mm line (0 = no pain, 100 = extremely painful), and PPT of the same sites was determined by an algometer. The VAS increased after exercise and peaked two days post-exercise, while the PPT decreased most at 1 day post-exercise and did not return to baseline for 4 days following exercise (P
Muscle pain induced by elbow flexor eccentric exercise was investigated using different assessments in Study 2. Ten untrained men performed 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors with one arm. Maximal voluntary isometric contraction torque (MVC), range of motion (ROM) and serum creatine kinase (CK) activity were measured before, immediately after, and 1 to 5 days after exercise as indirect markers of muscle damage. PPT of 50 sites over an exercised upper arm, VAS with a 100-mm line for pain level upon static pressure by a cuff and fingers, and palpation of the biceps brachii at three sites (3, 9, and 15 cm above the elbow crease) and different palpation methods (longitudinal, transverse and circular movements) on the mid-belly of biceps were assessed. Large decreases in MVC and ROM, and significant increases in serum CK activity indicated muscle damage. A significant difference (P
In Study 3, changes in the electrical pain threshold (EPT) of the biceps brachii fascia, biceps brachii muscle and brachialis fascia following eccentric elbow flexor contractions, and the relationship between EPT and VAS or PPT were investigated. Ten healthy untrained men performed two eccentric exercise bouts (ECC1, ECC2) consisting of 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors with the same arm separated by 4 weeks. Changes in MVC, ROM, VAS and PPT were smaller (P
The purpose of Study 4 was to investigate the magnitude of muscle lengthening during the first and second bout of eccentric exercise bouts and whether the muscle length changes are associated with the magnitude of DOMS and changes in other indirect markers of muscle damages between bouts. Ten healthy untrained men performed two eccentric exercise bouts (ECC1, ECC2) consisting of 10 sets of 6 maximal isokinetic eccentric contractions of the elbow flexors using the same arm separated by 4 weeks. Changes in MVC, ROM, muscle thickness, ultrasound echo intensity, serum CK activity and muscle soreness (VAS) were smaller (P
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Kychygina, Ganna. "Interaction between telomeres and the nuclear envelope in human cells : dynamics and molecular mechanism." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS259.
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Le matériel génétique contenant l'information des cellules humaines se présente sous forme de chromosomes linéaires dont l'extrémité est protégée par une structure appelée télomères. Les télomères correspondent à une séquence d'ADN répétée, recouverte de protéines spécifiques, qui permettent aux cellules d'étiqueter l'extrémité de leurs chromosomes afin de les différencier des cassures internes de l'ADN nécessitant une réparation. Ainsi, ils jouent un rôle prépondérant dans la protection du génome. Les chromosomes sont organisés et compartimentés dans le noyau de la cellule. Cette organisation est primordiale, la proximité des chromosomes à la membrane nucléaire qui délimite ce noyau est essentielle pour de nombreuses fonctions régulatrices du génome, comme l'activation et la répression des gènes contenant les informations. A chaque division cellulaire, cette organisation est perdue après le désassemblage de la membrane nucléaire et la condensation de la chromatine qui va permettre de correctement répartir les chromosomes entre les cellules filles. Après la division, les noyaux des cellules filles se reforment, la membrane nucléaire est rétablie, et les chromosomes sont repositionnés comme dans la cellule mère. Ce mécanisme de mémoire spatiale est encore inconnu mais est vital au maintien de la stabilité du génome. Une large proportion de télomères sont ancrés à la membrane nucléaire en fin de division, et y restent durant la reformation du noyau. Le laboratoire s'intéresse à cette association afin de caractériser son rôle pendant cette phase clé du cycle cellulaire. Nous cherchons à comprendre ce fonctionnement chez les cellules normales et les cellules de patients atteints de pathologies associées au vieillissement accéléré. Ce projet de thèse à pour but de comprendre l'impact d'une déformation de la membrane nucléaire sur le matériel génétique, et sur l'intégrité des télomères qui protègent l'information génétique. Nous utilisons des techniques de pointe de microscopie, et de biologie cellulaire et moléculaire afin de mieux comprendre le lien entre l'organisation du noyau et le maintien de la stabilité du génomeThe material that contains genetic information of human cells consists in linear chromosomes. The extremities of chromosomes are protected by a specific structure called telomeres. Telomeres are made of repeated DNA sequence, covered by special proteins that prevent cells to recognize extremities of their chromosomes as internal DNA break, thus not to perform unnecessary repair that will result in genome instability. Therefore, telomeres play a major role in genome protection. Chromosomes are spatially organized in the cell nucleus. This organization is important as positioning of chromosomes in the nucleus ensures proper regulatory functions of the genome, such as activation or repression of genes. During the cell division process, this organization is lost after nuclear membrane disassembly and the condensation of DNA, to allow correct segregation of chromosomes between daughter cells. After cell division, the nuclei of daughter cells are reformed, and nuclear membrane is reconstructed. The chromosomes are then relocated as in the mother cell. This mechanism of spatial memory is not well understood yet, but is key to maintain stability of the genome. A large proportion of telomeres are anchored to the nuclear membrane at the end of mitosis, and stay during nuclear envelope reformation. Our laboratory focuses on characterizing the role of telomere anchoring during this important phase of cell cycle. In particular, we want to understand this mechanism in normal cells and cells from patients with premature aging disease. This thesis aims to understand the impact of nuclear envelope abnormalities on the genetic material, in particular on telomere integrity, as telomeres protect genetic information. Here, we use microscopy approaches and techniques of molecular and cellular biology to better understand the link between nuclear organisation and genome stability maintenance
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Wood, Timothy Paul. "Identification of key mechanism in the cytotoxic effect of two novel anti-cancer compounds on breast cancer cells." Diss., University of Pretoria, 2012. http://hdl.handle.net/2263/24532.
Full textAbstract:
Organometallic chemotherapeutic agents, many of which target DNA, have been shown to be effective in the treatment of cancer. With that said though, these compounds have a number of side affects such as nephrotoxicity. Two novel compounds, Ferrocene [ferrocenoyltrichloroacetone] and Rhodium-ferrocene [(1.5 cyclooctadiene)(1-ferrocenyl- 4,4,4-trichloro-1,3-butanedionate], synthesised by the research group of J Swarts (University of the Free State) were evaluated to determine their mechanism of action and their potential use as novel therapeutic agents. It is hypothesized, by merit of their chemical structures, that these compounds’ anti-cancer activity is due to their interaction with DNA. Both drugs were evaluated from a cellular to a molecular level, in vitro, to validate this hypothesis. Linearised DNA was exposed to both drugs and digested with a variety of restriction enzymes. It was found that the compounds bind to the PstI restriction site; thereby inhibiting the enzyme’s restriction activity. From this point it was necessary to show that the compounds are able to interact with DNA in a cellular system. By exposing a transformed breast epithelial cell line (MCF-12A) and a cancerous breast epithelial cell line (MCF-7) to the compounds, for various times, followed by flow cytometric analyses, it was found that both affect progression through the cell cycle. Cells accumulated at various phases of the cell cycle, as a result of checkpoint gene activation. Further flow cytometric analyses showed that both drugs induce necrosis in MCF-7 cells. The “normal” cell line however did not show this response as it is believed that cell cycle arrest and repair mechanisms were initiated, which would delay cell death. Gene expression analyses were performed by reverse transcriptase real-time PCR in which panels of cell cycle related genes as well as DNA damage associated genes were probed in two separate array formats. These studies revealed that a number of DNA damage and repair genes are activated; specifically those associated with excision repair and free-radical induced DNA damage. Members of the RAD family as well as the genes GADD45A, XPC and OGG1 were found to be upregulated as a result of Ferrocene treatment. This could be expected as it was shown that ferrocene binds to DNA, and it logically then follows that this would lead to excision repair being attempted by the cell. Similar gene expression patterns were found following Rhodium-ferrocene treatment with the up-regulation of genes such as OGG1, ATM and GADD45G, albeit to a lesser extent. It is hypothesised that the larger molecule may not interact as effectively with DNA, due to steric hinderance. Arrest mechanisms, for both drugs, were more pronounced in the “normal” cell line and it is believed that this is due to the fact that many of these genes have been inactivated in the cancerous cell line. We have shown, on multiple levels, that both compounds’ therapeutic action is as a result of their interaction with the cell’s DNA. This interaction leads to cell death in both the transformed and the cancerous cell line. In order to clarify these mechanisms it is suggested that proteomic and metabolomic studies should be performed.Dissertation (MSc)--University of Pretoria, 2012.
Genetics
unrestricted
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Niu, Jiani. "A Study on Damage Evolution Mechanism of Hex-Chrome Free Coating/Aluminum System and a Proposed 2D Transmission Line Model Based on Experimental Results." University of Akron / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=akron1415641540.
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Stok, Kathryn. "Determination of the crack propagation mechanism and fracture toughness of articular cartilage." Thesis, Queensland University of Technology, 2001. https://eprints.qut.edu.au/36140/1/36140_Stok_2001.pdf.
Full textAbstract:
The articular cartilage that is found in joints of the mammalian skeleton is prone to failure when subject to excessive or repetitive mechanical loading. Since articular cartilage protects the underlying bone from high contact stresses, it is imperative that this material remains healthy and functions correctly over a human lifetime. The onset of disease, such as osteoarthritis can severely impact the capacity of the articular cartilage to function effectively. It has been shown that although joints can withstand large loads, structural variation in the joint due to injury (via sporting injuries or incorrect use) will lead to articular cartilage damage and osteoarthritis. The cost of treating this disease in Australia is now about $624 million. With an understanding of the mechanical response of articular cartilage to load, then its relationship to osteoarthritis can be recognised. Classical fracture mechanics is used to study the failure of materials and to also design against material fracture for an assumed
initial crack size. In this work the validity of classical fracture mechanics is examined for its use in understanding articular cartilage crack resistance.
A miniature tensile testing machine is used together with a visual data capture system to run a series of fracture tests on articular cartilage. An artificial crack is introduced into the surface of the articular cartilage, enabling investigation of the mechanical response
of the healthy tissue to structural damage. The artificial crack is wholly contained within the articular surface, and upon loading in tension propagates through the surface and midzone matrix to failure.
Both mechanical stress-strain and visual data of the propagating crack is gathered and used to identify trends in the fracture response of articular cartilage. Visual observation of the cracked cartilage reveals an unorthodox crack growth mechanism, whereby there
is transverse stretch of the opening crack, rather than a radial downward growth usually observed in traditional fracture mechanics. The transverse opening, c, is accompanied by a radial pulling, h, of the deep matrix, due to a fibril strain-locking effect occurring at
the crack root. Further results reveal that it is in fact the fracture of the articular surface which is most important in the ability of the tissue to resist cracking, since once the articular surface has fractured the ability of the general matrix to carry the load is
severely limited. The transverse stretch, c is shown to equal the upward radial pull, h. Therefore crack
growth in articular cartilage can be identified by a transverse (or widening) crack configuration, along a 'wavefront' movement of the deep matrix toward the notch root. The poroelastic critical stress and critical crack length, employing the aforementioned crack configuration, are used to define poroelastic fracture toughness. The results reveal a poroelastic fracture toughness for articular cartilage, Kp1c = 1.83 (s.d 0.8) MPa ~
and Gp1c = 0.74 (s.d 0.54). This result for Gp1c compares well with the work of ChinPurcell and Lewis, who quote fracture toughness for their study of articular cartilage as J = 0.14-1.2kN/m (where J and Gp1c can be considered equivalent). This work demonstrates that classical fracture mechanics can be used to define the crack
resistance of articular cartilage.
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Pu, Xiaoxue. "Thermomechanical study of the gigacycle fatigue behavior of pure iron and carbon-manganese steels : influence of chemical composition and microstructure on damage and crack initiation mechanism." Thesis, Paris 10, 2019. http://www.theses.fr/2019PA100051.
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Ce travail tente de mieux comprendre les dommages par fatigue dans les aciers à ferrite-perlite dans la fatigue à très grand nombre de cycles (VHCF). Les influences de deux paramètres, le pourcentage de phase perlite et le pourcentage d'atomes interstitiels libres dans une solution solide, sont étudiées pour comprendre les mécanismes de dissipation en fatigue à 20 kHz. Une thermographie infrarouge in situ est réalisée pour enregistrer les changements de température, tandis que des observations au microscope sont menées pour étudier le mécanisme de dissipation. Pour les matériaux de BCC, sous fortes amplitudes de contrainte, une augmentation soudaine de la température se produit sans initiation de fissure ni fracture. L’augmentation inévitable de la température jusqu’à des centaines de degrés aux fortes amplitudes de contrainte est principalement due à la mobilité des dislocations vis, qui est l’une des clés permettant d’expliquer le comportement en fatigue observée de la structure du BCC sous un chargement haute fréquence. Par conséquent, les PSB en surface et les micro-vides dans la matrice émergent en masse, accompagnant cette élévation abrupte de la température. Ces phénomènes sont considérés comme une transition du mécanisme de déformation du régime thermique au régime athermique. À faible amplitude, peu de PSB ou de rugosité de surface sont encore observés. Il a été constaté que les PSB sur le fer armco étaient susceptibles d’apparaître avant 1x107 cycles et que le seuil de PSB était inférieur à la limite de fatigue conventionnelle. La présence d'atomes interstitiels libres dans les aciers entraîne l'apparition d'une augmentation secondaire de la température dans la domain de la température stabilisée à 100-200 °C. Ce comportement semble être lié à l'interaction des dislocations coins avec des atomes interstitiels libres. De plus, on pense que le phénomène remarquable de durcissement-adoucissement-durcissement après l'élévation soudaine de la température jusqu'à plus de 300 °C est l'interaction de dislocations à vis multipliées et d'atomes interstitiels libresThis work attempts to a better understanding of the fatigue damage in ferrite-pearlite steels in the Very High Cycle Fatigue (VHCF) domain. The influences of two parameters, pearlite phase percentage and free interstitial atoms percentage in solid solution, are investigated to understand dissipative mechanisms under 20 kHz high frequency fatigue loading. In-situ infrared thermography is carried out to record the temperature changes, while fractography studies and microscope observations are conducted to investigate the dissipative mechanism on the surface of specimens.For body centered cubic (BCC) materials, under high stress amplitudes, a sudden increase of the temperature occurs without a crack initiation and fracture. The inevitable temperature increase up to hundreds of degrees at high stress amplitudes, is caused mainly by the screw dislocations mobility, which is the key to explaining the observed fatigue behavior and thermal response of BCC structure under high frequency loading. Therefore, PSBs on surface and micro-voids in matrix emerge massively, accompanying with this abrupt temperature increase. These phenomena are considered as transition of deformation mechanism from thermal regime to athermal regime. At low amplitudes, few PSBs or surface roughness are still observed on the specimen surface. Through the cycles of PSB appearance on armco-iron, it’s found that PSBs are inclined to appear before 1x10(7)cycles, and PSB threshold lies below the conventional fatigue limit. The increase of pearlite phase content weakens the temperature elevation, and strengthens the fatigue properties. The presence of free interstitial atoms in steels results in appearence of a secondary temperature increase in the stabilized temperature part (100-200 degree). This behavior seems to be related to the interaction of edge dislocations with free interstitial atoms. Moreover, the remarkable hardening-softening-hardening phenomenon after the sudden temperature elevation to above 300 degree is thought as the interaction of multiplicated screw dislocations and free interstitial atoms
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Silva, Wagner Moulin [Verfasser], Christos [Akademischer Betreuer] Aneziris, Christos [Gutachter] Aneziris, and Peter [Gutachter] Quirmbach. "Microsilica-bonded magnesia-based refractory castables : bonding mechanism and control of damage due to magnesia hydration / Wagner Moulin Silva ; Gutachter: Christos Aneziris, Peter Quirmbach ; Betreuer: Christos Aneziris." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2011. http://nbn-resolving.de/urn:nbn:de:bsz:105-qucosa-77492.
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Moulin, Silva Wagner [Verfasser], Christos [Akademischer Betreuer] Aneziris, Christos [Gutachter] Aneziris, and Peter [Gutachter] Quirmbach. "Microsilica-bonded magnesia-based refractory castables : bonding mechanism and control of damage due to magnesia hydration / Wagner Moulin Silva ; Gutachter: Christos Aneziris, Peter Quirmbach ; Betreuer: Christos Aneziris." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2011. http://d-nb.info/1220698601/34.
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