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1
Byrne, Christopher. "Muscle function after exercise-induced muscle damage." Thesis, Bangor University, 2001. https://research.bangor.ac.uk/portal/en/theses/muscle-function-after-exerciseinduced-muscle-damage(2bbf5fe1-f35b-4b7b-9790-ff3a04b86875).html.
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Muscle function after exercise-induced muscle damage has traditionally been evaluated by measures of isometric strength at a single joint angle or muscle length. The thesis investigates the effect of muscle damage on other muscle function parameters such as, isometric strength as a function of muscle length, concentric strength as a function of angular velocity, strength across muscle actions, the stretch-shortening cycle, power output, and fatigability. Study 1 The first part of this study aimed to determine how the muscle length at which strength is measured affects reductions in isometric strength following eccentric exercise-induced muscle damage. The damaging exercise protocol consisted of 100 maximal voluntary eccentric actions of the knee extensors, performed in the prone position through a range of motion from 40° to 140° (0° = full extension) at an angular velocity of 90 deg's-1. Isometric strength of the knee extensors was measured at short muscle length (10° knee flexion) and optimal length (80°). A significantly greater relative loss of strength was observed at short versus optimal muscle length (76.3 ± 2.5% vs. 82.1 ± 2.7% of pre-exercise values, P<0.05) over the seven day testing period following eccentric exercise. The second part of the study investigated isometric strength at optimal length and concentric strength at slow (30 deg's 1) and fast (180 deg's 1) angular velocities of movement. No differences were apparent in the magnitude and rate of recovery of strength across isometric (82.1 ± 2.7%) and slow (86.6 ± 2.0%) and fast (84.3 ± 1.5%) concentric muscle actions. Both the popping sarcomere hypothesis of 2 muscle damage and a failure in excitation-contraction coupling are possible explanations for the reduction in strength being affected by the muscle length at which it is measured. Both would be expected to affect strength to a greater extent at short versus optimal muscle lengths. Study 2 The second study investigated knee extensor muscle strength during isometric, concentric and eccentric muscle actions and vertical jump performance under conditions of squat jump (SJ), countermovement jump (CMJ) and drop jump (DJ). These measures were taken before, 1 hour after, and on days 1,2,3,4 and 7 following a damaging exercise protocol consisting of 100 barbell squats (10 sets x 10 reps @ 70% body mass load). Strength was significantly reduced for four days, however, no differences were observed in the magnitude or rate of recovery of isometric strength at 80° knee flexion and concentric and eccentric strength at 90 deg's'. Vertical jump performance was significantly reduced for three days and was dependent on the type of jump being performed. The relative decline in SJ performance was significantly greater than that in CMJ performance (91.6 ± 1.1% vs. 95.2 ± 1.3% of pre-exercise values, P<0.05) and the relative decline in SJ was significantly greater than that in DJ performance (91.6 ± 1.1% vs. 95.2 ± 1.4%, P<0.05). No differences were observed in the relative decline in CMJ and DJ performance (95.2 ± 1.3% vs. 95.2 ± 1.4%, P> 0.05). The stretch-shortening cycle (SSC) of muscle function is utilised in CMJ and DJ but not in SJ. The SSC has a clear purpose: to allow the final phase (concentric action) to take place with greater force or power output, as compared to the condition where the movement is initiated by a concentric action alone. 3 Utilisation of the SSC in performance seems to attenuate the detrimental performance effects of exercise-induced muscle damage. Study 3 The third and final study investigated the effects of exercise-induced muscle damage on maximal power output and knee extensor fatigability under isometric and dynamic conditions. Under isometric conditions, strength was assessed at 40° and 80° knee flexion and fatigability was assessed by a sustained 60s maximum voluntary contraction (MVC) at each joint angle. For dynamic conditions, maximum power output and fatigue were assessed during a maximal 30s cycle ergometer test. These measures were taken before, 1 hour after, and on days 1,2,3, and 7 following a damaging exercise protocol consisting of 100 eccentric squats (10 sets x 10 reps @ 80% concentric 1 RM). Isometric strength was significantly reduced (P < 0.05) for seven days but no significant differences were observed in the magnitude of strength loss and the pattern of recovery between the two joint angles. Fatigability was quantified as the slope (b) of a linear regression line fitted to the torque and power decay during the 60s MVC and the 30s cycle test, respectively. Prior to muscle damage, subjects were significantly less fatigable (P < 0.05) at 40° (b = -2.39 ± 0.26) versus 80° (b = -5.50 ± 0.72). After muscle damage, subjects became significantly less fatigable at both 40° and 80° with recovery taking three days at 401 and seven days at 80°. Before damaging exercise, a greater rate of fatigue was observed under dynamic (b = -12.75 ± 2.3) versus isometric (80°) conditions (b = -5.50 ± 0.72). Isometric and dynamic fatigue 4 followed a similar temporal pattern after damaging exercise. When the effects of muscle damage on strength at 801 and maximal power output were compared, differences in the extent of performance loss and the time course of recovery were observed. At 1 hour post-exercise, strength was affected to a greater extent (30% reduction) than power (13% reduction) and whereas strength followed a linear recovery pattern, power suffered further decrements at day 1 (18%) and day 2 (16%) before starting to recover. The results indicate that under conditions of voluntary activation muscle becomes weaker but less fatigable under isometric and dynamic conditions following exercise-induced muscle damage. The lower starting torque / power output and the slower rate of decline in torque / power output observed in post-damage fatigue curves may be a phenomenon of selective type II fibre damage. Evidence suggests that type II fibres are selectively damaged during eccentric exercise and therefore post-damage fatigue curves may be missing their contribution to performance. The different recovery patterns observed for isometric and dynamic performance may indicate an inability to maintain central motor drive during complex dynamic tasks when damage is present.
2
Ohtsuki, Akimichi. "Organic Chemical Approaches to DNA Function and Damage." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/142392.
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Li, Xiaoling. "Investigation of tissue transglutaminase function in apoptosis." Thesis, Nottingham Trent University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251281.
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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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Nafria, Javier Garcia. "Structure-function studies on proteins involved in DNA damage prevention." Thesis, University of York, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547327.
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Burrage, Joseph. "Analysis of the function of LSH in DNA damage repair." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/9416.
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DNA damage from both normal metabolic activities and environmental factors such as UV and radiation can cause as many as 1 million individual lesions to the DNA per cell per day (Lodish et al 2004). Cells respond to this continuous damage by employing many, highly efficient DNA repair mechanisms and undergo apoptosis when normal DNA repair fails. Of the many types of DNA damage that can occur, double strand breaks (DSBs) are the most toxic (Featherstone & Jackson 1999). A single unrepaired DSB is enough to induce cellular apoptosis and several mechanisms have developed to repair DSBs. The recognition, signalling and repair of DSBs involve large multi-‐subunit complexes that bind to both the DNA and modified histone tails, which require modification of the chromatin in order to access their bind sites and function effectively (Allard et al 2004). Consequently several chromatin-‐remodelling proteins have been implicated in DSB repair (van Attikum et al 2004, Chai et al 2005). LSH (Lymphoid specific helicase) is a putative chromatin-‐remodelling enzyme that interacts with DNA methyltransferases and has been connected to DNA methylation (Myant & Stancheva, 2008). Knockouts of LSH or its homologues in A. thaliana and M. musculus show a reduction in DNA methylation of 60-‐70% (Jeddeloh et al 1999, Dennis et al 2001). However in addition to this phenotype, knockout A. thaliana also have an increased sensitivity to DNA damage (Shaked et al 2006). A homologue of LSH has also been identified in S. cerevisiae, which interacts with known repair proteins (Collins et al 2007) and may be involved in DSB repair. Although the majority of Lsh-‐/-‐ mice die shortly after birth, 40% of the line produced by Sun et al survive and show unexplained premature aging (Sun et al 2004). As premature aging is a hallmark of increased acquisition of DNA damage there is the possibility of a conserved role for LSH in mammalian DNA damage repair. Here I show that LSH depleted mammalian cells have an increased sensitivity specifically to DSB inducing agents and show increased levels of apoptosis. Further analysis shows that cells lacking LSH repair DSBs slower, indicating a novel role for LSH in mammalian repair of DSB. I performed an in depth analysis of the DSB defects in LSH depleted cells in an attempt to elucidate the function of LSH in DSB repair. I found that LSH depleted cells can correctly recognise DSBs but recruit downstream signalling and repair factors, such as γH2AX, less efficiently. I show that reduced recruitment of downstream DSB repair factors is not accompanied by extended cell cycle checkpoint signalling. This suggests that LSH depleted cells continue through the mitosis with unrepaired DSBs, which most likely leads to apoptosis and the increased sensitivity to DSB inducing agents. These experiments also showed that recruitment of DSB signalling and repair factors is not impaired equally at all breaks, and I present a model system created to quantitatively compare individually breaks between WT and LSH depleted cells to identify DSB that require LSH for efficient repair. I also preformed an analysis of Lsh-/- MEFs containing WT or catalytic null mutant LSH rescue constructs and I show that WT but not catalytic null LSH can restore efficient DSB repair. These studies identify a novel role for LSH in mammalian DSB repair and demonstrate the importance of its catalytic activity.
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Maisse, Carine. "Regulation and function of the DeltaNp73 isoforms after DNA damage." Paris 6, 2004. http://www.theses.fr/2004PA066598.
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Les cellules d’un organisme subissent chaque jour des stress dus à l’environnement (rayons UV, agents chimiques, métaux lourds) pouvant conduire à des lésions du patrimoine génétique ou à un déséquilibre de l’état RedOx. De nombreux systèmes cellulaires permettent tout d’abord d’identifier le dommage puis d’induire éventuellement la réparation de l’ADN ou la mort de la cellule si le dommage subi est irréversible. Une cellule cancéreuse est le résultat d’échecs cumulés des systèmes de contrôle intra et extra-cellulaires et de mort programmée. Identifiée en 1979, la protéine p53 est un facteur de transcription muté dans 50% des cancers. Elle joue un rôle central dans la régulation de la prolifération cellulaire, de la réparation de l’ADN et de l’apoptose après stress, génotoxique ou non. Etonnamment, p53 semblait jouer seule ce rôle prépondérant qui lui a valu la dénomination de "gardienne du génome", et, pendant 20 ans, toutes tentatives pour caractériser d'éventuels homologues sont restées vaines. En 1997, p73, un homologue de p53, fut identifiée dans la bande p36 du chromosome 1, une région dont la délétion est souvent associée à de nombreux neuroblastomes. La caractérisation de p73 fut accueillie avec enthousiasme et sa grande homologie avec p53 semblait pouvoir expliquer les 50% de cancers présentant une p53 non mutée. L'année suivante, un deuxième homologue fut identifié et caractérisé: p63. Les trois membres de la famille p53 présentent une grande homologie, notamment dans le domaine de liaison à l'ADN : p73 et p63 sont en effet capables d'activer l'expression de nombreux gènes cibles de p53 et d'induire l'apoptose ou de bloquer le cycle cellulaire. Toutefois, 6 ans après leur découverte, p73 et p63 semblent de plus en plus différents de leur "parente" p53. La génération et l'étude de souris déficientes pour les membres de la famille illustrent ces différences : si les souris manquant p53 atteignent normalement l'âge adulte et développent spontanément des tumeurs, les souris manquant p73 ou p63 présentent de graves troubles du développement embryonnaire, indiquant un rôle majeur dans la différenciation cellulaire. Si p73 et p63 présentent une structure globale comparable à p53 (un domaine de transactivation, un domaine de liaison à l’ADN et un domaine d’oligomérisation, impliqué dans la tétramérisation de la protéine nécessaire à son activité transcriptionnelle), elles possèdent en effet un prolongement du domaine C-terminal, absent de la séquence de p53, et qui semble impliqué dans leurs propriétés propres. La maturation des transcrits de p73 et p63 donne lieu à différents splicing variants (6 pour p73 et au moins 3 pour p63) en C-terminal, dont les fonctions transcriptionnelles et le pattern d'expression sont différents. De plus, les formes les plus longues des deux protéines présentent un domaine SAM (Sterile Alpha Motif), commun à de nombreuses protéines impliquées dans le développement. Ce domaine est souvent muté dans des syndromes humains impliquant p63, ce qui laisse présager un rôle important dans la régulation de l'activité de p63 et p73. Par ailleurs, des formes tronquées en N-terminal ont été décrites dans la souris : ces formes sont nommées ΔΝ, elles ne possèdent pas le domaine de transactivation, au contraire des formes longues (TA). Ainsi, ΔΝp73 et ΔΝp63 agissent dans la souris comme dominants négatifs des fonctions pro-apoptotiques de TAp73 et TAp63. Il a été établi par la suite que ΔΝp73 et ΔΝp63 sont transcrites à partir d'un second promoteur, localisé dans le troisième intron de la forme longue. L'étude présentée ici décrit la première caractérisation de la forme ΔΝp73 humaine, la régulation de son expression et de son activité. De même que ΔΝp73 murine, la forme humaine inhibe les fonctions pro-apoptotiques de TAp73 et p53, via interactions protéines/protéines ou compétition pour les sites de liaison sur les promoteurs cibles. De plus, la présence d’un élément de réponse à p53 situé dans le promoteur de ΔΝp73 caractérise une boucle de régulation négative qui s’ajoute à la boucle de régulation MDM2/p53. ΔΝp73 agissant comme un oncogène, il semble donc que le ratio ΔΝ/TA ou ΔΝ/p53 soit fondamental à l’équilibre cellulaire et que sa dérégulation puisse être impliquée dans la formation tumorale, ce ratio pouvant être contrôlé au niveau transcriptionnel ou post-traductionel de la protéine ΔΝp73. L’étude du promoteur de ΔΝp73 a mis en évidence de nombreux éléments de réponse à différents facteurs de transcription. De récents travaux ayant associé une augmentation de ΔΝp73 à certains types de neuroblastomes, nous nous sommes particulièrement intéressés à N-Myc, facteur de transcription également amplifié dans certains neuroblastomes. Nous n’avons pu toutefois mettre en évidence une activation transcriptionnelle directe de ΔΝp73 de la part de N-Myc, mais d’autres éléments de réponse restent encore à caractériser, notamment NFκB et p300, tous deux impliqués dans la régulation de l’apoptose. Par ailleurs, l’étude de modifications post-traductionnelles de ΔΝp73 a mis en évidence une rapide dégradation de la protéine après dommages à l’ADN induits par rayons Ultra-Violets ou traitement par drogues, libérant ainsi p53 et TAp73 de son inhibition et permettant ainsi l’apoptose ou l’arrêt du cycle cellulaire. De plus, notre étude a mis en évidence une très brève hémie-vie de la forme ΔΝ par rapport aux formes contenant le domaine de transactivation. Ainsi, le ratio ΔΝ/formes longues pourrait également dépendre d’une fine régulation de la dégradation des deux protéinesIn our search for the underlying causes of cancer, TP53 is the most intensively studied gene. P53 plays a central role for balancing the antagonistic processes of proliferation and apoptosis. As a sequence-specific transcription factor, p53 regulates the expression of genes involved in cell cycle arrest and apoptosis in response to genotoxic damage or cellular stress. Failure of p53 function consequently leads to uncontrolled cell growth, a defining feature of cancer cells. Given the importance of p53 as a tumor suppressor, it is therefore no wonder that p53 is the most frequent site of genetic alterations found in human cancers. The recent discovery of two TP53-related genes, TP73 and TP63 with striking sequence homology, was therefore a big surprise, raising the possibility that other tumor suppressors exist which share the power of p53 in preventing cancer formation. The three members of the p53 family share significant homology both at the genomic and at the protein level. The highest level of identity is reached in the DBD (DNA-Binding Domain), suggesting that they can bind to the same DNA sequence and transactivate the same promoters. In fact, p73 and p63 are able to activate some p53 targets and to induce apoptosis, but they appear more and more different from their relative. The study of the respective knock-out mice gives a good illustration of these differences : while p53-null mice develop normally but present spontaneous tumors, the p73 and p63-null mice present severe developmental troubles but no spontaneous tumors, indicating that they may have more complex functions. Conversely to p53, p73 and p63 contain additional C-terminal extensions. In both proteins, these extensions show alternative splicing, which results in at least six C-terminal variants for p73 and three for p63. These isoforms have different transcription and biological properties, and their expression patterns change among normal tissues. Moreover, the α variants of p73 and p63 have close to their C terminus a SAM (Sterile Alpha Motif) domain, which is thought to be responsible for regulating p53-like functions, and is implicated in various human syndromes where p63 is mutated. In addition to the C-terminal variants aminoterminous truncated variants of p73 and p63 exist : ΔNp73 and ΔΝp63. These N-terminally truncated isoforms lack the transactivation domain (TA), which is coded by the first 3 exons, and derive from the use of an alternative promoter (P2) located in intron 3 and an additional exon (exon 3'). While TAp73 isoforms work as transcription factors and can induce irreversible cell cycle arrest and apoptosis like p53, the ΔNp73 isoforms that lack the transactivation domain are incapable of directly inducing gene expression and do not induce growth arrest or cell death. However, the ΔNp73 forms have a very important regulatory role, since they exert a dominant negative effect on p53 and TAp73 by blocking their transactivation activity, and hence their ability to induce apoptosis. The relative levels of expression of the ΔNp73 isoforms can therefore determine the function of both TAp73 and p53. It is most interesting that the ΔNp73 promoter (P2) contains a very efficient p53/p73 responsive element and consequently, p53 and TAp73 efficiently induce ΔNp73 expression. Moreover, upon strong DNA damage, induced by UV irradiation or drug treatment, ΔNp73 is rapidly degraded, releasing the block exerted on p53 and TAp73 and thus allowing cell cycle arrest and apoptosis to proceed. Hence, ΔNp73 is part of a dominant negative feedback loop that regulates the function of both p53 and TAp73 and this regulation can be overcome in case of strong DNA damage
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De, Moura Miguez Araujo Sofia Jorge. "Interactions and function of nucleotide excision repair protein complexes." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322320.
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Zhang, Muyu [Verfasser], Bernd [Akademischer Betreuer] Markert, and Rüdiger [Akademischer Betreuer] Schmidt. "Auto-correlation-function-based damage index for damage detection and system identification / Muyu Zhang ; Bernd Markert, Rüdiger Schmidt." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1130327329/34.
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Chapman, J. R. "Molecular analysis of mediator-protein function in the DNA damage response." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597474.
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I report the identification of phosphorylation sites in MDC1 that are phosphorylated by ATM in response to ionizing radiation (IR), and demonstrates that these motifs are required for the efficient recruitment of BRCA1 and 53BP1 into IRIF. We identified the E3 Ubiquitin ligase RNF8 as critical for this process, and show that upon phosphorylation, these MDC1 sites are bound directly by the FHA domain of RNF8, directing it to generate ubiquitinated proteins at DSB sites. We demonstrate that it is the formation of these ubiquitin conjugates at DSB sites that facilitate BRCA1 and 53BP1 recruitment into IRIF. I report a novel interaction-surface in MDC1 that is phosphorylated constitutively by the protein kinase CK2. These phosphorylation sites in MDC1 are bound directly by NBS1, in a manner dependent on its FHA and tandem BRCT domains. I demonstrate that this interaction surface on MDC1 is essential for promoting MDC1-NBS1 interactions and NBS1 retention on chromatin flanking DSB sites. We have elucidated the structure of the FHA-tandem-BRCT domains of Schizosaccharomyes pombe Nbs1 by X-ray crystallography. Phosphorylated MDC1 Ser-Asp-Thr-Asp (pSDpTD)-like motifs are evolutionarily conserved NBS1 binding motifs In vitro. I identified similar CK2-consensus sites conserved in the fission yeast DNA repair protein Ctp1 (CtIP). Nbs1 FHA domain-mediated binding of these Ctp1 sites is crucial for MRN-dependent functions in yeast. These findings suggest that the unique and specialist domain architecture of NBS1 underpins an evolutionary conserved adaptor-function mode for MRN-dependent responses to DNA damage.
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Twigg, Jeremy Philip. "DNA damage in human spermatozoa : free radicals, sperm function and ICSI." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.391610.
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Hurley, Michael V. "Muscle function, inhibition and rehabilitation following traumatic and degenerative joint damage." Thesis, King's College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321690.
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Xie, Jenny X. "Regulation of BACH1/FANCJ Function in DNA Damage Repair: A Dissertation." eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/435.
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The DNA damage response (DDR) pathway is a complicated network of interacting proteins that function to sense and remove DNA damage. Upon exposure to DNA damage, a signaling cascade is generated. The damage is either removed, restoring the original genetic sequence, or apoptosis is activated. In the absence of DDR, cells are unable to effectively process DNA damage. Unprocessed DNA damage can lead to chromosomal changes, gene mutations, and malignant transformation. Thus, the proteins involved in DDR are critical for maintaining genomic stability.
One essential DDR protein is the BRCA1 Associated C-terminal Helicase, BACH1. BACH1 was initially identified through its direct association with the BRCT domain of the Breast Cancer Associated Gene, BRCA1. Similar to BRCA1, germline mutations in BACH1were identified in patients with early onset breast cancer. Interestingly, the disease-associated mutations in BACH1 were shown to have altered helicase activity in vitro, providing a direct link between BACH1 helicase activity and disease development. The correlation between BACH1 and cancer predisposition was further confirmed by the identification of BACH1 as the cancer syndrome Fanconi anemia (FA) gene product, FANCJ. Similar to other FA proteins, suppression of FANCJ leads to decreased homologous recombination, enhanced sensitivity to DNA interstrand crosslinking (ICL) agents, and chromosomal instability.
In an effort to further understand the function of FANCJ in DDR, FANCJ was shown to directly associate with the mismatch repair (MMR) protein MLH1. This interaction is facilitated by lysines 141 and 142 within the helicase domain of FANCJ. Importantly, the FANCJ/MLH1 interaction is critical for ICL repair. Furthermore, in an attempt to dissect the binding site of FANCJ on MLH1, we discovered an HNPCC associated MLH1 mutation (L607H) that has intact mismatch repair, but lacks FANCJ interaction. In contrast to the MLH1 interaction, the FANCJ/BRCA1 interaction was not required for correcting the cellular defects in FANCJ null cells. Thus, in an effort to understand the functional significance of the FANCJ/BRCA1 interaction, we discovered that FANCJ promotes Pol η dependent translesion synthesis (TLS) bypass when uncoupled from BRCA1. In this thesis, we provide evidence suggesting that FANCJ and MLH1 are functionally linked and that the interaction of these proteins is critical for repair choice.
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Smith, Peter Alan. "A study of the transient effects of high energy laser light on visual function." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243277.
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Kysela, Boris. "Ionizing radiation-induced DNA damage and repair in relation to biological function." Thesis, Brunel University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384841.
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Archer, Sophie. "Innate immune cell migration and function in response to damage associated signals." Thesis, University of Bath, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665383.
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Tissue damage initiates the release of a complex, interacting collection of chemical signals. The coordinated function of these signals gives rise to an inflammatory event, whereby circulating immune cells are recruited to clear pathogens. Invertebrate models of tissue damage have revealed a key role for damage-associated signals, specifically hydrogen peroxide (H2O2), in attracting immune cells to sites of tissue damage. The Src family kinase (SFK), Lyn, is oxidised by H2O2 in zebrafish wound models, and subsequent activation of Lyn triggers directed cell motility. In mammalian systems, H2O2 is an important second messenger, however, its role as a damage signal and its association with SFK signalling remains unclear. The aims of this thesis are to investigate how immune cell function and migration in response to damage-associated signals transfers into other models. To address this, we have used an in vivo Drosophila melanogaster embryonic wounding model and in vitro assays of human innate cell function and migration. The migration of Drosophila hemocytes in response to a wound was impaired in embryos lacking functional Src42A or Shark kinase. However, hemocyte motility was impaired in embryos bathed in exogenous H2O2. In vitro, H2O2 inhibited human innate cell motility, chemotaxis, actin reorganisation and phagocytosis, but activated intracellular signalling pathways and did not affect receptor expression or cell viability. Exogenous ATP activated chemokinesis and rapid actin reorganisation. The in vitro effects of immune-related ligands were inhibited by pharmacological inhibition of SFK, Syk, and PI3K signalling. In particular, inhibition of class IA PI3K isoforms p110β and p110δ, but not p110α, disrupted monocyte MCP-1-mediated actin reorganisation and spreading. SFKs are required for Drosophila immune cell migration to a wound and for human innate cell migration to chemoattractants. While endogenous ROS production is important for immune cell function, exogenous H2O2 may negatively modulate downstream mediators of chemokine signalling. H2O2 and ATP are distinct in their abilities to activate immune cells and initiate chemokinesis. Intracellular kinases regulate basal and chemoattractant-mediated motility and are therefore attractive targets for therapeutic management of inflammatory disease.
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Hill, Sarah J. "Familial ALS Proteins Function in Prevention/repair of Transcription-Associated DNA Damage." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:27007760.
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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no defined molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43; and we propose a disease mechanism in which loss of function of one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms.
In support of this hypothesis, we found that depletion of FUS and TDP43 leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. This indicates that these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, we observed that both FUS and TDP43 co-localize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein BRCA1, and that FUS and TDP43 participate in the prevention or repair of R-loop associated DNA damage.
Ideally, gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage will shed light on the mechanisms underlying ALS pathogenesis.
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Ninic, Dejan Mechanical & Manufacturing Engineering Faculty of Engineering UNSW. "Fatigue in automatic transmissions." Awarded by:University of New South Wales. School of Mechanical and Manufacturing Engineering, 2006. http://handle.unsw.edu.au/1959.4/28056.
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A novel method of predicting the multiaxial high-cycle fatigue strength of metallic components is proposed and verified for various steel, aluminium and cast iron alloys. The proposed Fatigue Damage Function shows superior multiaxial fatigue strength prediction compared to the established methods of Gough and Pollard, McDiarmid and Carpinteri and Spagnoli. A new material property, the Normal Stress Sensitivity Factor, is also introduced and its applicability is verified according to published test results of sixteen different structural alloys. To highlight the effectiveness of the proposed criterion, for industrial applications, a case study has been conducted on heat-treated and not heat-treated automatic transmission output shafts.
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Kennedy, Jessica Ashley. "Structure-Function Analysis of the DNA Damage Repair Complex STR in Saccharomyces cerevisiae." Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5713.
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The RecQ family of helicases has been termed the “Caretakers of the Genome,” and rightfully so. These proteins are highly conserved from bacteria to humans and have been implicated in functions from homologous recombinatorial repair to damage checkpoint response to telomere maintenance and more. Mutant genes of three of the human RecQ helicases lead to syndromes characterized by a high incidence of cancer, premature aging and early death. Despite their implications in several biological functions and importance to the integrity of the human genome and suppression of cancer, many aspects of the RecQ family structure and function remain unknown. To date, much is known about the catalytic function of the helicase domain and accompanying domains, but considerably less is known about the non-catalytic N-terminus in these proteins, which, in many cases, including those human orthologs involved in disease, can make up about half of the total protein length. While experiments have been able to identify protein partners that interact with the N-terminal region, few are able to narrow the binding sites to minimally functional parts and fewer still describe any detail regarding the structural features of these binding areas. In fact, some reviews have generally described the N-terminus as “featureless,” a concept we challenge in our studies.
Many of the N-termini of these RecQs have long been known to contain large stretches of acidic residues, a feature of intrinsically disordered regions. These regions/proteins are rich in charged and polar residues, lack compactness that makes crystallography possible, and have flexible and dynamic conformations that are prevalent in “high specificity, low affinity” interactions. Disordered proteins are well-known to be hot spots for protein/protein interactions and post-translational modifications, amongst other functions. Considering these facts, and recognizing the ties between these and what we know about the N-termini of the RecQs, we hypothesized that these proteins likely have long disordered termini. In Chapter 3, we confirm the presence of disorder at the Top3/Rmi1 binding site on Sgs1, the Saccharomyces cerevisiae RecQ helicase. We show that even in a disordered state, this binding region is not “featureless,” but in fact contains a transient alpha-helical molecular recognition element that is necessary to facilitate complex formation between Sgs1, Top3 and Rmi1. Loss of helical structure at this site leads to increased genomic instability and sensitivity to DNA damaging agents. Based on these results, we suggest that there are likely many more such elements in the N-terminus that that are important for other Sgs1 protein/protein interactions and provide an estimate for the number of interactions in this region.
In Chapter 4, we evaluate the prevalence of disorder in a set of Chromatin Processes proteins in an effort to establish a role for disorder with regards to maintaining chromatin integrity. In our bioinformatics study, we found that disorder is overrepresented in the Chromatin Processes proteins, and that a major driving force for disorder in these proteins is protein/protein interaction and post-translational modification. We also show a biological connection to disorder and increased protein/protein interaction by investigating these parameters in the context of the DNA damage checkpoint response and in complex formations. Mediators between highly structured kinases in the checkpoint were the most interactive proteins and over half of all predicted interaction sites occurred in disordered areas. Complexed proteins often contained one protein with a high number of disordered sites and a high number of predicted interactions, while the rest were considerably more ordered.
Chapter 5 explores a Sgs1 interaction partner, Rmi1 and uses bioinformatics to design structurally-based point mutations in an effort to further elucidate Rmi1 function in yeast, which remains largely unknown outside of its enhancement of Top3/Sgs1 catalytic function. Using AGADIR, which predicts alpha-helical structure and is particularly useful in our hands for guided-mutagenesis in disordered regions, we identified several point mutations that lead to Δrmi1 phenotypes or intermediate growth on hydroxyurea. We hypothesize that these mutants are important in maintaining Rmi1 stability.
Together, these studies suggest an important change in how the field approaches further studies into the RecQ helicases; traditional methods of primary sequence comparisons and crystal structures limit the study of disordered regions that are still functionally important. Future care should be given to consider the conservation of structure or structural elements in the RecQs over strict alignments when comparing functional regions between orthologs. Our studies also suggest that it is highly likely that structural motifs for important protein interactions in RecQs are being overlooked because they are not readily obvious using traditional methods. By understanding these motifs and the interactions they facilitate, we may be able to more easily identify polymorphisms in patients with genomically unstable conditions like cancer and, having better understood the biological process these structures facilitate, design drugs to counteract detrimental effects.
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Ajina, Sara. "Changes in connectivity, structure and function following damage to the primary visual cortex." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:2e274261-c71a-4ad1-82cf-2fe6bbdbf673.
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Residual vision, or blindsight, following damage to the primary visual cortex was first identified almost a century ago. However, the mechanism and pathways underlying this ability, as well as the extent of visual function, remain unclear and are a continuing source of speculation. The work presented here goes some way to try to address these questions, investigating 18 patients with V1 damage and homonymous visual field loss acquired in adulthood. Six experimental chapters explore the extent and potential for visual function after V1 damage, and apply novel neuroimaging paradigms and techniques to try to uncover the mechanisms and pathways that might be involved. A combination of psychophysics, functional and structural MRI was used to investigate responses to blind field stimulation in the dorsal and ventral streams. In addition, diffusion MRI tractography was performed and related to psychophysical performance, so that the three main pathways implicated in blindsight could be evaluated. Lastly, a small rehabilitation study was carried out to assess the effect of training in the blind hemifield, and to investigate whether there is any transfer of learning between the dorsal and ventral visual streams. The results from this work reinforce the suggestion that blindsight may be more common than was first thought, and may extend across a number of characteristics involving both visual streams. It is also suggested that visual function need not be completely unconscious, but that certain salient stimuli can elicit both non-visual and crude visual experience. The use of parametric functional imaging paradigms has enabled a number of properties of non-striate inputs to the extrastriate cortex to be revealed. Together with tractography, this points to an important role for the ipsilateral lateral geniculate nucleus in blindsight function. It is hoped that future work will build upon this, and that it may be possible to target these residual pathways in the rehabilitation of patients with V1 damage.
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Maisel, Simon F. "Repetitive anodal tDCS of perilesional cortex impairs recovery of function after parietal damage." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12501.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Unilateral spatial neglect is a common disorder, most often occurring after right hemispheric stroke and resulting in severe functional impairment and a poor prognosis of recovery. Previous research has shown that there are several methods of rehabilitation, one of the newer techniques being non-invasive brain stimulation. Specifically, transcranial direct current stimulation has been show to change neuronal activity in a polarity dependent manner. In this study we investigated whether passive anodal repetitive transcranial direct current stimulation of the perilesional parietal cortex ameliorated the symptoms of unilateral spatial neglect. Three cats were given focal right posterior parietal cortex lesions to produce neglect. After the plateau of spontaneous recovery of function, subjects received passive anodal transcranial direct current stimulation (2 mA for 20 min a day for 50 days). No overall collective effects of tDCS on visual performance were seen in the contralesional nor ipsilesional visual hemi-field. Yet when visual field quadrants were analyzed, tDCS exerted a deteriorative effect on performance in the right peripheral visual quadrant. These data show that passive anodal transcranial direct current stimulation in the perilesional cortex may come with a cost of function in performance to stimuli in the intact visual field. Future research is necessary to further investigate these effects.
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Barr, Alexis. "Characterising the function of CDK5RAP2 in the vertebrate centrosome." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/228639.
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The centrosome is the major microtubule organising centre in vertebrate cells. CDK5RAP2 is a human protein that localises to the centrosome. At the start of this thesis work, the function of CDK5RAP2 was uncharacterised. Significantly, cdk5rap2 is one of several centrosomal genes that are mutated in the developmental disorder Primary Microcephaly, where affected individuals have smaller brains than expected for the age- and sex-adjusted mean. Orthologues of CDK5RAP2 in the fruit fly (Centrosomin/Cnn) and in fission yeast (Mod20p) have been well characterised and are known to have important roles in maintaining centrosome structure and in regulating microtubule nucleation. CDK5RAP2 shares two evolutionarily conserved domains with Cnn, known as CNN motif 1 and 2. Using the chicken B-cell line, DT40, I have used gene-targeting methods to disrupt both of these domains in CDK5RAP2. This revealed a function for CDK5RAP2 in attaching centrosomes to mitotic spindle poles. Centrosome attachment to spindle poles is mediated by a binding partner of CDK5RAP2, AKAP450. AKAP450 also localises to centrosomes and provides anchorage sites for spindle poles in the centrosome. Disruption of the CNN1 and CNN2 domains of CDK5RAP2 causes mislocalisation of AKAP450 from the centrosome and detachment of centrosomes from spindle poles. My studies in DT40 and in human cell lines revealed that CDK5RAP2 and AKAP450 also cooperate during interphase to maintain the two centrioles in the centrosome as a pair. In addition to a structural role in the centrosome, I also find that CNN motif 1 of CDK5RAP2 plays a role in the cellular response to DNA damage. In the absence of CNN motif 1, cells no longer efficiently arrest the cell cycle in response to damage. Centrosome-mediated mitotic spindle alignment and the DNA damage response have both been implicated in microcephaly. Therefore, defects in these functions of CDK5RAP2 may explain how mutations in cdk5rap2 may lead to microcephaly.
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Cromie, Lillian. "The influence of reactive oxygen species on human lymphoid cell function in vitro." Thesis, University of Ulster, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281431.
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Brooks, William Samuel. "Localization and function of G2E3." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2008r/brooks.pdf.
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Gürler, Hakan [Verfasser]. "Effects of cryopreservation on mitochondrial function and DNA damage of bovine sperm / Hakan Gürler." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/104671029X/34.
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Ghospurkar, Padmaja Laxman. "Characterization of RPA2 N-terminal Function in the DNA Damage Response in Saccharomyces Cerevisiae." Diss., North Dakota State University, 2015. http://hdl.handle.net/10365/24843.
Full textAbstract:
In response to DNA damage, two general but fundamental processes occur in the
cell: (1) a DNA lesion is recognized and repaired, and (2) concomitantly, the cell halts
the cell cycle to provide a window of opportunity for repair to occur. A key factor
involved in the DNA damage response is the heterotrimeric protein complex Replication
Protein A (RPA), which is not only essential for the repair of damaged DNA, but also is
post-translationally modified on at least two of the three subunits in response to DNA
damage by checkpoint kinases. Of particular interest is the 32-kDa subunit, called Rpa2,
which is hyper-phosphorylated on its serine/threonine-rich N-terminus following DNA
damage in human cells. This unstructured N-terminus is often referred to as the
phosphorylation domain (PD) and is conserved amongst eukaryotic Rpa2 subunits,
including Rfa2 in Saccharomyces cerevisiae. In this work we aim to characterize the
function of Rfa2 N-terminus (Rfa2 NT) in DNA damage response and develop yeast as a
tool to study human RPA.
With the help of mutagenesis we developed Rfa2 NT extreme mutants, which
showed that the phosphorylation of Rfa2 NT is dispensable in DNA damage response.
However, the presence of Rfa2 NT is essential for cells to survive in stressed condition
indicating an uncharacterized function. We further discovered seven S/T sites are
responsible for the damage sensitive phenotype of Rfa2 NT extreme mutants. And the
phosphorylation affects protein interaction of RFA complex.
Although, the phosphorylation event of Rfa2 NT is dispensable in S. cerevisiae
the cells have conserved the ability to phosphorylate Rfa2 N terminus. With the help
Rfa2 NT fusion mutants we showed that S. cerevisiae could phosphorylate N terminus
from seven different eukaryotic species. Hence, we successfully developed yeast as a tool
to study Rpa2 phosphorylation amongst various eukaryotic species.NIJ 2004RGCX-K001
National Institutes of Health NIH NCRR-COBRE 5P20RR015566
National Science Foundation NSF-CAREER-1253723
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Lomax, Martine Elizabeth. "The evaluation of p53 function in cells from members of cancer prone families." Thesis, King's College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298202.
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Zhang, Fang. "Flood Damage and Vulnerability Assessment for Hurricane Sandy in New York City." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374108651.
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Ochodnický, Peter. "Vascular endothelial and myogenic function in renal disease focus on individual susceptibility to organ damage /." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2006. http://irs.ub.rug.nl/ppn/289761514.
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Silva, Garcia Maria [Verfasser]. "A novel function of DPP9 in DNA damage repair via BRCA2 regulation / Maria Silva Garcia." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://d-nb.info/1222264986/34.
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Levadoux, Marilyne. "A novel approach to the study of metallothionein function in oxidative stress and DNA damage." Thesis, University of Aberdeen, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323398.
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Metallothioneins (MTs) have a major role in metal metabolism and may also protect DNA against oxidants. MT protein has been found localized in the nucleus during S-phase. The mRNA encoding for the MT-1 isoform is found localized around the nucleus and associated with the cytoskeleton; this is due to targeting signals within the 3'untranslated region (3'UTR). Using cells transfected with gene constructs differing in their 3'UTRs, the role of perinuclear mRNA localization in facilitating MT synthesis close to its site of function and subsequent import of protein into the nucleus has been investigated, as well as the role of MT protein in the nucleus. We transfected CHO cells, which have a low constitutive level of MT expression, with either the full MT-gene (MTMT) or with MR 5'UTR and coding region linked to the 3'UTR of glutathione peroxidase (MTGSH). Immunocytochemistry showed that MT protein was localized in the perinuclear cytoplasm in the MTMT cells whereas no distinct localization was found in the MTGSH cells. The cells were then synchronised in S-phase by serum depletion/repletion. After serum repletion, MT was found in the nucleus of MTMT cells but not in the MTGSH cells. This suggests that perinuclear localization of MT-1 mRNA and its association with the cytoskeleton is necessary for MT protein localization, particularly for the shuttling of MT protein into the nucleus during S-phase. Functional studies demonstrated that the extent of oxidative stress and DNA damage was lower in the MTMT than the MTGSH, showing that a loss of MT protein localization led to a reduced protection of the cell. Therefore, it seems that perinuclear localization of mRNAs coding for MT is necessary for subsequent transport and targeting of proteins into the nucleus and that the localization of the protein within the cell is important for its function.
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Bennett, Brian Thomas. "Human Rad51: Regulation of Cellular Localization and Function in Response to DNA Damage: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/224.
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Repair of DNA double-strand breaks via homologous recombination is an essential pathway for vertebrate cell development and maintenance of genome integrity throughout the organism’s lifetime. The Rad51 enzyme provides the central catalytic function of homologous recombination while many other proteins are involved in regulation and assistance of Rad51 activity, including a group of five proteins referred to as Rad51 paralogs (Rad51B, Rad51C, Rad51D, Xrcc2, Xrcc3). At the start of my work, cellular studies of human Rad51 (HsRad51) had shown only that it forms distinct nuclear foci in response to DNA damage. Additionally, no information regarding the cellular localization, potential DNA damage-induced redistribution or cellular functions for any of the Rad51 paralog proteins was available. Therefore, the goals of this work were to (1) present a more complete description of the cellular localization and DNA damage-induced redistribution of Rad51 and the two paralog proteins known to specifically associate with Rad51, Rad51C and Xrcc3, and (2) to define specific functional roles for Rad51C and Xrcc3 in mediating Rad51 activity. I focused on the use of cellular, RNAi and immunofluorescence methods to study endogenous Rad51, Rad51C and Xrcc3 in human cells.
In my initial studies we showed for the first time that Xrcc3 forms distinct foci in both the nucleus and cytoplasm independent of DNA damage, that the distribution of these foci did not change significantly throughout the time course of DNA damage and repair, and that Xrcc3 focus formation is independent of Rad51. Additionally, and unlike most previously published images of nuclear Rad51, we found that the majority of DNA damage-induced nuclear Rad51 foci do not colocalize with gamma H2AX, a histone marker used to indicate the occurrence of DNA double strand breaks.
As a consequence of these initial outcomes, a significant amount of effort was devoted to developing and optimizing immunofluorescence methods. Importantly, we developed a purification method for commercially available monoclonal antibodies against Rad51C and Xrcc3 that significantly improved their reactivity and specificity. My next study concentrated on Rad51C. Similar to Xrcc3, we found for the first time that Rad51C forms distinct nuclear and cytoplasmic foci independent of DNA damage and Rad51. An additional and surprising outcome was our discovery that Rad51C plays an important role in regulating the ubiquitination and proteasome-mediated degradation of Rad51. While biochemical functions for Rad51 paralog proteins had been suggested in the literature, this was the first demonstration of a specific biochemical function for Rad51C that contributes directly to the Rad51 activity in the homologous recombination pathway. Our improved immunofluorescence methods allowed us to see the accumulation of Rad51, Rad51C and Xrcc3 at the nuclear periphery early in response to DNA damage, suggesting the existence of a DNA damage-dependent trafficking mechanism that promoted movement of these proteins from the cytoplasm to the nucleus. This led to further studies in which we show distinct co-localization of cytoplasmic Rad51 with actin as well as alpha and beta tubulin. Using both immunofluorescence and sub-cellular fractionation methods our recent results strongly suggest that trafficking of Rad51 to the nucleus in response to DNA damage is regulated at least in part by its association with cytoskeletal proteins, and involves movement of both existing pools of Rad51 and newly synthesized protein.
In a particularly exciting development, in collaboration with Leica Microsystems and Dr. Joerg Bewersdorf at The Jackson Laboratory, Bar Harbor, ME., I have been able to exploit a new technology, 4Pi microscopy, to provide the first images of endogenous nuclear proteins using this method.
Results presented in this thesis have added significantly to a more complete understanding of cellular localization Rad51, Rad51C and Xrcc3, and have provided important insights into possible mechanisms of cellular trafficking of Rad51 in response to response to DNA damage. Additionally, we have defined a specific function for Rad51C in its regulation of Rad51 ubiquitination. These findings open several new avenues of investigation for furthering our understanding of the cellular and molecular functions of proteins with critical roles in the maintenance of genome integrity in human cells.
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Macabuag, Joshua. "Tsunami damage prediction for buildings : development of methods for empirical and analytical fragility function derivation." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10047419/.
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Over the past two decades, tsunami have been the cause of 33% of total deaths and 35% of total economic losses due to natural disasters globally, and currently 6 out of 10 of the most populous megacities in the world are at risk of being severely affected by tsunami. Quantifying tsunami risk is therefore centrally important for land use and emergency planning in the DRR sector, for human and financial loss estimation in the insurance sector, and for performance-based design in the engineering sector. Tsunami fragility functions are statistical models that relate a measure of tsunami intensity (e.g. inundation depth) to probabilities of damage exceedance for a number of damage states, and form a key component of tsunami risk models. This thesis presents improved derivation methods for empirical fragility functions (those derived from observed damage data from past tsunami), and research towards methodologies for deriving analytical fragility functions (those constructed from structural analysis in the absence of past damage data). First, a critical review of the literature related to the prediction of building damage due to tsunami is presented. This review highlights that it is unclear which of the many available statistical methods available provide optimal empirical fragility functions. It is also seen that analytical methods are required for damage prediction in the vast majority of at-risk areas, however few such functions exist. Hence tsunami loads on buildings and methods of structural analysis under tsunami loading are critically reviewed so as to identify and justify the loading and analysis assumptions to be employed throughout this thesis. A methodology for deriving optimal empirical tsunami fragility functions for a given dataset is then developed and demonstrated using a unique, disaggregated building damage dataset from the 2011 Japan Tsunami. The proposed methodology identifies the key Tsunami Intensity Measures (TIMs) and improved statistical methods to be used for fragility function derivation. A number of techniques novel in the field of empirical fragility function derivation are introduced: Multiple Imputation, K-fold Cross-Validation, and semi-parametric models. Furthermore, a preliminary methodology is also presented for quantifying debris-related effects on fragility functions. Methods for structural analysis for the derivation of analytical fragility functions are then developed. First an investigation is carried out on how time-dependent effects, ductility and overstrength (a structure’s ability tomaintain a load greater than its yield value) affect structural damage analysis. This is then extended to develop a simplified method for estimating tsunami-induced structural damage under tsunami loading, suitable for use in the large number of analyses required to derive analytical fragility functions of populations of buildings. By introducing advanced methods for selecting optimal TIMs and statistical models, and by furthering the field of structural analysis under tsunami loading, this research has the potential to influence how both empirical and analytical tsunami fragility curves are constructed in the future.
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Yang, Yu-Ying. "The Effects of Exogenous Ubiquinone on Mitochondrial Function, Oxidative Damage, and Lifespan in Caenorhabditis elegans." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278098162.
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Croft, Richard P. "The epidemiology, risk factors and response to treatment by corticosteroids of acute nerve function impairment in leprosy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325251.
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Can, Geylani. "S-phase checkpoint activity and function throughout the cell cycle." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/268506.
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DNA damage or replication stress during S-phase can activate the S-phase checkpoint which executes a variety of responses, such as the inhibition of origin firing and replication fork stabilisation. Deregulation of the S-phase checkpoint leads to genomic instability, which has been implicated in diseases such as cancer. In this thesis, I aimed to address whether the S-phase checkpoint is regulated outside of S-phase, and how the S-phase checkpoint targets its substrates in budding yeast. Although this checkpoint has thus far been associated exclusively with S-phase, it remains unknown whether its responses such as inhibition of origin firing can also occur in other phases of the cell cycle. To investigate this, the targets of the S-phase checkpoint for the inhibition of origin firing were analysed outside of S-phase upon DNA damage. Interestingly, I showed that the S-phase checkpoint effector kinase Rad53 phosphorylates its targets to inhibit origin firing outside of S-phase upon DNA damage when there is no replication. I then set out to test whether inhibition of origin firing by Rad53 outside of S-phase might be important for faithful DNA replication. Having shown that the checkpoint response is not specific for any cell cycle phases, I then tested how the specificity of Rad53 for its substrates might be determined. After demonstrating that the essential replication protein Cdc45 is required for Rad53 to phosphorylate the initiation factor Sld3, the key residues of Cdc45 necessary for Rad53 interaction were identified. A Cdc45 allele was produced by mutating the identified residues. This allele of Cdc45 is a separation-of-function mutant which prevents Sld3 phosphorylation upon DNA damage, but retains its function in DNA replication. Because Cdc45 travels with the replication fork, it is possible that Cdc45 also targets Rad53 to the replication fork to stabilise it upon replication stress. Overall, this thesis provides evidence that the S-phase checkpoint can function throughout the cell cycle and that Cdc45 targets Rad53 to some of its substrates, and possibly plays a role in replication fork stabilisation.
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Miller, Halie Kay. "Characterization of the Lone Extracytoplasmic Function Sigma Factor, óS, and its Role in the Staphylococcus aureus Virulence and Stress Responses." Scholar Commons, 2012. http://scholarcommons.usf.edu/etd/4164.
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Previously our laboratory had identified a novel component of the Staphylococcus aureus regulatory network, an extracytoplasmic function ó factor, óS, involved in stress response and disease causation. Here we present additional characterization of óS, demonstrating a role for it in protection against DNA damage, cell wall disruption and interaction with components of the innate immune system. Promoter mapping reveals the existence of four unique sigS start sites, one of which appears to be subject to auto-regulation. Transcriptional profiling revealed that sigS expression remains low in a number of S. aureus wild-types, but is upregulated in the highly mutated strain RN4220. Further analysis demonstrates sigS expression is inducible upon exposure to a variety of chemical stressors that elicit DNA damage, including methyl methanesulfonate (MMS) and ciprofloxacin, as well as those that disrupt cell wall stability, such as ampicillin and oxacillin. Ex vivo transcriptional analysis reveals that significant expression of sigS can be induced upon phagocytosis by RAW 264.7 murine macrophage-like cells. Regulation of óS appears to be unique, as the downstream encoded protein, SACOL1828, seemingly acts as a positive activator, rather than as an expected anti-sigma factor. Using a global transposon screen we have elucidated additional genes implicated in the regulation of sigS, including those involved in cell wall stability, cellular detoxification, virulence and DNA base excision repair. Phenotypically, óS mutants display sensitivity to a broad range of DNA damaging agents, such as ultraviolet light, MMS and ethidium bromide. These effects are seemingly mediated via regulation of the purine biosynthesis pathway, as microarray, proteomic and qRT-PCR analysis of óS mutants reveal decreased transcription of all genes involved. Enzymatic profiling of PurA involved in adenine biosynthesis, demonstrates decreased activity in the óS mutant. Finally, we provide further evidence for the role of óS in S. aureus pathogenesis, revealing that sigS mutants display decreased ability to cause localized infections and are impaired in their interactions with components of the human innate immune system. Collectively, our data argues for the important, and perhaps novel, role of óS in the stress and virulence responses of S. aureus.
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Navarro, Serer Judith 1990. "Understanding functional interplay between PARP-1 and PARP-2 in T cell development and function." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/481994.
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T-cell homeostasis must be tightly regulated and maintained in order to guarantee appropriate immune responses and prevent immunopathology. This maintenance depends on MHC-TCR interaction and cytokine-mediated signals among others. However, cell intrinsic factors that modulate essential functions in T-cells must be also integrated to support genomic stability and contribute to the control of T-cell homeostasis.
The present work establishes a coordinated role of poly (ADP-ribose) polymerase-1 (PARP-1) and PARP-2 in maintaining T-lymphocyte number and function, demonstrated by the defective thymocyte maturation and diminished numbers of peripheral CD4+ and CD8+ T cells in mice bearing a T-cell specific deletion of PARP-2 in a PARP-1-deficient background. Moreover, this T-cell lymphopenia is associated with an increased DNA-damage and concomitant cell death, leading to highly aggressive spontaneous T-cell lymphomas in PARP-1/PARP-2 double-deficient mice.
Our findings highlight the importance of understanding the specific involvement of both proteins in key biological processes that could have an impact on the development and exploitation of PARP-inhibitors.L’homeòstasi de la cèl·lula T ha d’estar estrictament regulada per tal de garantir una correcta resposta immunitària i prevenir alhora qualsevol problema immunopatològic. Aquest correcte manteniment depèn, entre d’altres, de la interacció amb el complex MHC-TCR i de les senyals de diferents interleuquines. No obstant, hi ha altres factors intrínsecs que intervenen en la modulació de les funcions vitals de la cèl·lula T i que han d’estar també correctament integrats en tot el sistema per tal de garantir una correcta estabilitat genòmica i contribuir en el control de l’homeòstasi de la cèl·lula T. El present treball estableix el paper coordinat entre els enzims poli (ADP-ribosa) polimerasa-1 (PARP-1) i PARP-2 en el manteniment del nombre i la funció dels limfòcits T, tal i com es demostra amb el defecte en maduració i el descens en el número de cèl·lules CD4+ i CD8+ perifèriques que tenen els ratolins amb deleció de PARP-2 en un background PARP-1 deficient. A més a més, aquesta limfopènia està associada amb un increment del dany en el ADN i una concomitant mort cel·lular, que condueix al desenvolupament espontani de limfomes T molt agressius en els ratolins dobles deficients per PARP-1 i PARP-2. Els nostres resultats posen de manifest la importància de conèixer correctament el paper específic de les dues proteïnes en processos biològics rellevants, ja que podria tenir especial impacte en el desenvolupament i l’explotació dels inhibidors PARP.
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Pessoa-Brandão, Luis. "Genetic and molecular studies of Saccharomyces cerevisiae Cdc7-Dbf4 kinase function in DNA damage-induced mutagenesis /." Connect to full text via ProQuest. IP filtered, 2005.
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Angelin, Karinne Ansiliero. "Dano injusto como pressuposto do dever de indenizar." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/2/2131/tde-10012014-073936/.
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O objetivo desta dissertação é demonstrar que a responsabilidade civil aquiliana, no ordenamento jurídico brasileiro, tem como pressuposto fundamental a causação de dano injusto. Esse objetivo justifica-se porque existem posições doutrinárias, conhecidas como direito de danos, que defendem a desnecessidade do dano injusto para que seja deflagrada a estrutura de responsabilização civil. Analisam-se, para tanto, a estrutura e a finalidade da responsabilidade civil, bem como o seu enquadramento no sistema jurídico brasileiro.The aim of this dissertation is to show that the non-contractual civil liability in the Brazilian legal order has as a fundamental presupposition the causation of the unfair damage. This aim is justifiable because there are doctrinaire opinion, known as damage law, that advocate the unnecessariness of the unfair damage to be triggered the structure of civil liability. It analyzes, therefore, the structure and the goal of the civil liability, as well as its fitting into the Brazilian legal system.
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Hass, Cathy Staloch. "Function of Replication Protein A in DNA repair and cell checkpoints." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/2515.
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Replication Protein A (RPA), the major eukaryotic single-strand DNA (ssDNA) binding protein, is essential for replication, repair, recombination, and checkpoint activation. Defects in RPA-associated cellular activities lead to genomic instability, a major factor in the pathogenesis of cancer. The ssDNA-binding activity of RPA is primarily mediated by two domains in the RPA1 subunit. I characterized mutant forms of RPA to elucidate the contribution of specific residues in the high affinity DNA binding domains to the cellular function of RPA. These studies enhance the understanding of the properties of RPA that contribute to DNA repair and cellular checkpoints.
Mutation of a conserved leucine residue to proline in the high-affinity DNA binding site of RPA (residue L221 in human RPA) has been shown to have a high rate of chromosomal rearrangements in yeast and mice. I characterized the equivalent mutation in human RPA. My studies show that the mutation causes a defect in ssDNA binding and a nonfunctional protein. Combined with the mice studies, the data suggest that haploinsufficiency of RPA causes an increase in DNA damage and in the incidence of cancer.
The ssDNA-interactions of the high affinity binding domains in RPA1 are mediated by several residues including four highly conserved aromatic residues. Mutation of these residues had no effect on DNA replication but caused defects in DNA repair pathways. I conclude that DNA intermediates in different DNA metabolic pathways require different RPA binding functions and that the aromatic residues are indispensable for binding in DNA repair.
These studies illustrate that different DNA metabolic pathways have distinct requirements for RPA function. A decrease in binding to ssDNA of any length has specific consequences in vivo. These data also demonstrate that a single mutation in RPA in a residue that does not even contact ssDNA can result in a non-functional RPA complex. I conclude that even a modest decrease in RPA protein levels is not compatible with long term cell survival. Taken together, these studies highlight the importance of proper regulation of RPA protein levels and its ssDNA binding affinity to proper maintenance of the integrity of the genome.
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Grauer, Christine M. "The effects of zinc status on hepatic poly(ADP-ribose) polymerase function in response to DNA damage." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/mq24472.pdf.
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Befroy, Douglas Eugene. "Osmotic shock : modulation of contractile function, pHâ†i and ischaemic damage in the perfused guinea-pig heart." Thesis, University of Oxford, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326024.
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Li, Kai. "Regulation of WRN Function by Acetylation and SIRT1-Mediated Deacetylation in Response to DNA Damage: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/511.
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Werner syndrome (WS) is an autosomal recessive disorder associated with premature aging and cancer predisposition. WS cells show increased genomic instability and are hypersensitive to DNA-damaging agents. WS is caused by mutations of the WRN gene. WRN protein is a member of RecQ DNA helicase family. In addition to a conserved 3’–5’ helicase activity, the WRN protein contains unique 3’–5’ exonuclease activity. WRN recognizes specific DNA structures as substrates that are intermediates of DNA metabolism. WRN physically and functionally interacts with many other proteins that function in telomere maintenance, DNA replication, and DNA repair. The function of WRN is regulated by post–translational modifications that include phosphorylation, acetylation, and sumoylation.
SIRT1 is a NAD-dependent histone deacetylase (HDAC) that deacetylates histones and a numbers of cellular proteins. SIRT1 regulates the functions of many proteins, which are important for apoptosis, cell proliferation, cellular metabolism, and DNA repair. SIRT1 is also regulated by other proteins or molecules from different levels to activate or inhibit its deacetylase activity.
In this study, we found that SIRT1 interacts with and deacetylates WRN. We further identified the major acetylation sites at six lysine residues of the WRN protein and made a WRN acetylation mutant for functional analysis. We found that WRN acetylation increases its protein stability. Deacetylation of WRN by SIRT1 reverses this effect. CREB-binding protein (CBP) dramatically increased the half-life of wild-type WRN, while this increase was abrogated with the WRN acetylation mutant. We further found that WRN stability is regulated by the ubiquitination pathway, and that WRN acetylation by CBP dramatically reduces its ubiquitination level.
We also found that acetylation of WRN decreases its helicase and exonuclease activities, and that SIRT1 reverses this effect. Acetylation of WRN alters its nuclear distribution. Down-regulation of SIRT1 increases WRN acetylation level and prevents WRN protein translocating back to nucleolus after DNA damage. Importantly, we found that WRN protein is strongly acetylated and stabilized in response to mitomycin C (MMC) treatment. H1299 cells that were stably expressing WRN acetylation mutant display significantly higher sensitivity to MMC than the cells expressing wild-type WRN. Taken together, these data demonstrated that acetylation pathway plays an important role in regulating WRN function in response to DNA damage. A model has been proposed based on our discoveries.
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Taura, Akiko. "Recovery of hair cell function after damage induced by gentamicin in organ culture of rat vestibular maculae." Kyoto University, 2007. http://hdl.handle.net/2433/135651.
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Farukh, Farukh. "Experimental and numerical analysis of deformation and damage in thermally bonded nonwoven material." Thesis, Loughborough University, 2013. https://dspace.lboro.ac.uk/2134/12812.
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Grahn, Tonje. "Risk assessment of natural hazards : Data availability and applicability for loss quantification." Doctoral thesis, Karlstads universitet, Institutionen för miljö- och livsvetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kau:diva-48324.
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Quantitative risk assessments are a fundamental part of economic analysis and natural hazard risk management models. It increases the objectivity and the transparency of risk assessments and guides policymakers in making efficient decisions when spending public resources on risk reduction. Managing hazard risks calls for an understanding of the relationships between hazard exposure and vulnerability of humans and assets. The purpose of this thesis is to identify and estimate causal relationships between hazards, exposure and vulnerability, and to evaluate the applicability of systematically collected data sets to produce reliable and generalizable quantitative information for decision support. Several causal relationships have been established. For example, the extent of lake flood damage to residential buildings depends on the duration of floods, distance to waterfront, the age of the house and in some cases the water level. Results also show that homeowners private initiative to reduce risk, prior to or during a flood, reduced their probability of suffering building damage with as much as 40 percent. Further, a causal relationship has been established between the number of people exposed to quick clay landslides and landslide fatalities. Even though several relationships were identified between flood exposure and vulnerability, the effects can only explain small parts of the total variation in damages, especially at object level. The availability of damage data in Sweden is generally low. The most comprehensive damage data sets in Sweden are held by private insurance companies and are not publicly available. Data scarcity is a barrier to quantitative natural hazard risk assessment in Sweden. More efforts should therefore be made to collect data systematically for modelling and validating standardized approaches to quantitative damage estimation.Natural hazard damages have increased worldwide. Impacts caused by hydrological and meteorological hazards have increased the most. An analysis of insurance payments in Sweden showed that flood damages have been increasing in Sweden as well. With climate change and increasing populations we can expect this trend to continue unless efforts are made to reduce risk and adapt communities to the threats. Economic analysis and quantitative risk assessments of natural hazards are fundamental parts of a risk management process that can support policymakers' decisions on efficient risk reduction. However, in order to develop reliable damage estimation models knowledge is needed of the relationships between hazard exposure and the vulnerability of exposed objects and persons. This thesis has established causal relationships between residential exposure and flood damage on the basis of insurance data. I also found that private damage-reducing actions decreased the probability of damage to buildings with almost 40 percent. Further, a causal relationship has been established between the number of people exposed to quick clay landslides and fatalities. Even though several relationships have been identified between flood exposure and vulnerability, the effects can explain only small parts of the total variation in damages, especially at object level, and more effort is needed to develop quantitative models for risk assessment purposes.
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Lozada, Santiago Enerlyn Meliza. "GENOTOXIN-INDUCED ACETYLATION OF THE WERNER SYNDROME PROTEIN (WRN) AND EFFECT ON ITS DNA METABOLIC FUNCTION." UKnowledge, 2011. http://uknowledge.uky.edu/gradschool_diss/817.
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Loss of function of the WRN protein causes the genetic disorder Werner Syndrome that is characterized by increased cancer and premature aging. WRN belongs to the RecQ helicase family that plays key roles in preventing genome instability. In response to treatment with genotoxins, WRN is subject to post-translational modification. The relationship of post-translational modification of WRN with its function in DNA metabolism is unknown. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA replication. Consistent with this notion, WS cells are sensitive to DNA replication inhibitors and DNA damaging agents that tend to block replication fork progression. The cells exhibit an extended S phase, as well as defects in normal bi-directional progression of replication forks diverging from the majority of replication origins. To elucidate the relationship between post-translational modifications of WRN with its function in DNA metabolism, here the acetylation of WRN was studied. In our studies, we provide evidence that WRN acetylation is a dynamic process that strongly correlates to blockage of replication by persistent DNA damage. We also determined the effect of WRN acetylation on its specificity and enzymatic functions. In addition, our studies reveal how agents that block replication regulate the nature of WRN interactions with RPA, a factor known to bind to single-stranded DNA generated at blocked replication forks. Our results demonstrated that WRN and RPA form a stable direct association under normal physiological conditions and treatments that block replication fork progression increase their association, further supporting the idea that WRN is involved in DNA replication through its action at blocked or stalled replication forks. Thus, these studies point to both 1) an important role for acetylation of WRN and 2) its interaction with RPA in the putative function of WRN in response to blocked replication. Overall, our results impact knowledge regarding the relationship between DNA damage, genome instability and the development and progression of aging and cancer.
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Frey, Erin N. "ACID-SENSING ION CHANNELS: TARGETS FOR NEUROPEPTIDE MODULATION AND NEURONAL DAMAGE." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1365777374.
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Powers, Kyle Thomas. "Structure and function of the disordered regions within translesion synthesis DNA polymerases." Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6625.
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Normal DNA replication is blocked by DNA damage in the template strand. Translesion synthesis is a major pathway for overcoming these replication blocks. In this process, multiple non-classical DNA polymerases form a complex at the stalled replication fork called the mutasome. This complex is structurally organized by the replication accessory factor PCNA and the non-classical DNA polymerase Rev1. One of the non-classical DNA polymerases within the mutasome then catalyzes replication through the damage. Each non-classical DNA polymerase has one or more cognate lesions, which the enzyme bypasses with high accuracy and efficiency. Thus, the accuracy and efficiency of translesion synthesis depends on which non-classical DNA polymerase within the mutasome is chosen to bypass the damage. In this thesis, I discuss how the most appropriate polymerase is chosen. In so doing, I examine the components of the mutasome; the structural motifs that mediate the protein interactions in the mutasome; the methods used to study translesion synthesis; the definition of a cognate lesion; the intrinsically disordered regions that tether the polymerases to PCNA and to one another; the multiple architectures that the mutasome can adopt, such as PCNA tool belts and Rev1 bridges; and the kinetic selection model in which the most appropriate polymerase is chosen via a competition among the multiple polymerases within the mutasome. Taken together, this thesis provides and inclusive review of the current state of what is known about translesion synthesis with conclusions at its end suggesting what major questions remain and ideas of how to answer them.