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1
Valkhoff, Nienke Jeltje Marjoke. "Stabilization by competing instability mechanisms." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/37776.
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Akl, Sherif Adel. "Wellbore instability mechanisms in clays." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/64569.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, February 2011."February 2011." Cataloged from PDF version of thesis.
Includes bibliographical references (p. 331-341).
This dissertation investigates the stability of wellbores drilled in Ko-consolidated clays using non-linear finite element method (FEM) and effective stress soil models to characterize the behavior of clay and unconsolidated shale formations. Two constitutive models are used: Modified Cam Clay (MCC; Roscoe and Burland, 1968), and MIT-E3 (Whittle and Kavvadas, 1994). These soil models are incorporated in the commercial finite element program ABAQUS TM through user material subroutines (Hashash, 1992). The wellbores are modeled by a quasi-3D finite element model to approximate the far field stresses and plane strain boundary conditions. The constitutive models are calibrated to the behavior of Resedimented Boston Blue Clay (RBBC), an analog shale material which is Ko-consolidated to stress levels ranging from 0.15MPa to 10.0 MPa. The thesis comprises three major parts. Part one analyzes the short-term wellbore instability during drilling in low permeability formations. The part focuses on the relationship between the mud pressure inside the wellbore and the undrained shear deformations within the formations. The analyses predict critical mud pressure values necessary to maintain wellbore stability at different deviation angles and stress histories. The MIT-E3 model predicted higher deformations at reference mud pressure and estimated higher values of mud pressures than the underbalanced limit to prevent failure in highly deviated wellbores in NC clays. The second part validates the numerical analyses by comparing model predictions to results of an extensive program of model borehole tests. The lab experiments are performed on high pressure Thick- Walled Cylinder (TWC devices) using RBBC as analog testing material (Abdulhadi, 2009). The MIT-E3 predictions demonstrated a very good match with results from the experiments. The results from the analyses illustrated the effect of the device boundary conditions on specimen behavior and validated approximate analytical methods for interpreting TWC results. Part three studies the effects of consolidation on long-term wellbore stability. Non-linear coupled consolidation analyses are performed to simulate the post-drilling, time-dependent deformations and pore pressures around the wellbore. The analyses consider two different boundary conditions on seepage at the cavity. The analyses show that consolidation generates extensive volumetric strains around the wellbore and cavity deformations can aggravate stability conditions in highly deviated wellbores.
by Sherif Adel Akl.
Ph.D.
3
Perkins, Adam Christopher. "Mechanisms of instability in Rayleigh-Bénard convection." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42768.
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In many systems, instabilities can lead to time-dependent behavior, and instabilities can act as mechanisms for sustained chaos; an understanding of the dynamical modes governing instability is thus essential for prediction and/or control in such systems. In this thesis work, we have developed an approach toward characterizing instabilities quantitatively, from experiments on the prototypical Rayleigh-Bénard convection system. We developed an experimental technique for preparing a given convection pattern using rapid optical actuation of pressurized SF6, a greenhouse gas. Real-time analysis of convection patterns was developed as part of the implementation of closed-loop control of straight roll patterns. Feedback control of the patterns via actuation was used to guide patterns to various system instabilities. Controlled, spatially localized perturbations were applied to the prepared states, which were observed to excite the dominant system modes. We extracted the spatial structure and growth rates of these modes from analysis of the pattern evolutions. The lifetimes of excitations were also measured, near a particular instability; a critical wavenumber was found from the observed dynamical slowing near the bifurcation. We will also describe preliminary results of using a state estimation algorithm (LETKF) on experimentally prepared non-periodic patterns in a cylindrical convection cell.
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Thirthagiri, Eswary. "Mechanisms of genomic instability in oral cancer." Thesis, University of Bristol, 2005. http://hdl.handle.net/1983/dc1b9061-be5b-4839-a266-de82fd1da5cf.
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Hackett, Jennifer. "Telomere dysfunction and mechanisms of genomic instability." Available to US Hopkins community, 2003. http://wwwlib.umi.com/dissertations/dlnow/3080673.
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Chan, Kara Y. "MECHANISMS OF TRINUCLEOTIDE REPEAT INSTABILITY DURING DNA SYNTHESIS." UKnowledge, 2019. https://uknowledge.uky.edu/toxicology_etds/29.
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Genomic instability, in the form of gene mutations, insertions/deletions, and gene amplifications, is one of the hallmarks in many types of cancers and other inheritable genetic disorders. Trinucleotide repeat (TNR) disorders, such as Huntington’s disease (HD) and Myotonic dystrophy (DM) can be inherited and repeats may be extended through subsequent generations. However, it is not clear how the CAG repeats expand through generations in HD. Two possible repeat expansion mechanisms include: 1) polymerase mediated repeat extension; 2) persistent TNR hairpin structure formation persisting in the genome resulting in expansion after subsequent cell division. Recent in vitro studies suggested that a family A translesion polymerase, polymerase θ (Polθ), was able to synthesize DNA larger than the template DNA. Clinical and in vivo studies showed either overexpression or knock down of Polθ caused poor survival in breast cancer patients and genomic instability. However, the role of Polθ in TNR expansion remains unelucidated. Therefore, we hypothesize that Polθ can directly cause TNR expansion during DNA synthesis. The investigation of the functional properties of Polθ during DNA replication and TNR synthesis will provide insight for the mechanism of TNR expansion through generations.
7
Lieuwen, Tim C. "Investigation of combustion instability mechanisms in premixed gas turbines." Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/20300.
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Ozols, Agris. "Low-dose studies of genomic instability-mechanisms and targets." Thesis, Queen Mary, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.271260.
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Lee, A. J. X. "An investigation of chromosomal instability survival mechanisms in cancer." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1344056/.
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Chromosomal instability (CIN) describes ongoing numerical and structural chromosomal aberrations in cancer cells, leading to intra-tumour heterogeneity and is frequently associated with polyploidy and aneuploidy. CIN is a frequent event in solid tumours and previous evidence has implicated CIN with acquired multidrug resistance, intrinsic taxane resistance and poor patient prognosis. In this thesis, I have attempted to explore mechanisms required for the initiation of CIN and the tolerance of this pattern of genome instability. Firstly, I have attempted to identify clinically relevant therapeutics that may have specific activity in CIN+ tumour cell lines. Focusing on a panel of colorectal cancer cell lines, classified as either CIN+ or CIN-, and treating them individually with kinase inhibitor and cytotoxic agent libraries, I demonstrated that CIN+ cell lines displayed significant intrinsic multidrug resistance. Next, I addressed if specific means to target CIN+ cells could be identified through pharmacological and RNA interference (RNAi) screens. No compounds were observed to be preferentially cytotoxic towards CIN+ cells in the pharmacological screen. A whole genome RNAi screen was performed to identify CIN+ specific survival pathways using isogenic cell line models of CIN. No genes were identified that conferred preferential cell death when silenced in CIN+ cells, despite sufficient statistical power to detect such targets. Using integrative genomics techniques and cell cycle data from this RNAi screen, I endeavoured to identify clinically relevant initiators of aneuploidy in colorectal cancer, that revealed both known and potential novel regulators of polyploidy. Finally, I endeavoured to identify a mechanistic basis for the taxane-sensitising phenotype associated with the silencing of the ceramide transporter, CERT, which may reveal means to target CIN+ cells. I demonstrated that CERT silencing sensitises paclitaxel-treated cells to cell death in a LAMP2-dependent manner that is associated with autophagy flux and may target death of multinucleated cells specifically.
10
Barsoum, Nader N. "Analysis and computation of instability mechanisms in rotating electrical machinery." Thesis, University of Newcastle Upon Tyne, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328149.
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Zhu, Ting 1971. "Atomistic characterization of stress-driven configurational instability and its activation mechanisms." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/17954.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2004.Includes bibliographical references (p. 145-156).
Cleavage decohesion and shear dislocation nucleation are two basic modes of localized deformation in crystal lattices, which normally result from instability of the atomic configuration driven by mechanical forces. The critical state of instability and its thermal activation mechanisms can be quantitatively determined by analyzing the energetics of the lattice system. In this thesis, the unit processes of configurational instability of crystal lattices under various non-uniform structural and/or chemical environments are characterized by systematically probing the atomistic potential energy landscape of each system using the state of the art configurational space sampling schemes. The problems studied are homogeneous dislocation nucleation in a perfect crystal by nanoindentation, dislocation emission and cleavage decohesion at atomically sharp crack tips, and chemically-enhanced bond breaking in a wet silica nanorod. These processes are studied in a unified manner such that two important types of properties are determined: one is the athermal load at which the instability takes place instantaneously without the aid of thermal fluctuations, and the other is the stress-dependent activation energy used for an estimate of the kinetic rate of transition. Along the way, important aspects concerning the atomistic characterization of configurational instability are revealed. Of particular note is extending the continuum instability criterion to detect atomic defect nucleation. We demonstrate that a local instability criterion can be applied to identify dislocation nucleation in the case of indentation, considering that the relatively small strain gradient beneath the indenter will lead to a mode of long wavelength phonon instability suitable for a study
(cont.) by the local continuum approach. In addition, the chemical effect on stress-driven lattice instability is revealed via the study on reactivity of a silica nanorod with water. We identify distinct competing mechanisms of hydrolysis which are rate-controlling at different load regimes. The ensuing stress-mediated switch of rate-limiting steps of hydrolysis quantitatively demonstrates the impact of finding the detailed molecular mechanisms on a realistic estimate of the activation rate when configurational instability occurs within a chemically reactive environment. Implications regarding the analysis of chemically-assisted brittle fracture are also discussed.
by Ting Zhu.
Ph.D.
12
Ghaffarzadeh, K. "Carrier transport and instability mechanisms in oxide semiconductor thin film transistors." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1333220/.
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The growing demand for amorphous oxide semiconductor thin film transistors (TFT) necessitates the development of a physics-based field-effect mobility model that links the terminal characteristics of TFTs to their material properties. This need is particularly acute since existing approaches fail to explicitly account for the unique carrier transport properties of oxide semiconductors. The first part of this thesis specifically addresses this challenge. Here, it is shown that the electron conduction mechanism in the above-threshold regime of amorphous oxide semiconductor TFTs is controlled by both percolation and trap-limited conduction. In the limit where trap-limited conduction prevails, the characteristic temperature of tail states controls the field-effect mobility; whereas in the limit where percolation prevails, the properties of conduction’s band potential fluctuation govern it. Irrespective of the operation regime, the fieldeffect mobility is found to follow a power law form. The value of the trap density plays a critical role in determining the transition voltage. This is because a high value leads to Fermi level pinning, and thus trap-limited conduction dominates; whereas a low value results in percolation since the Fermi level becomes able to cross the conduction band edge for trap density of <1020 cm-3eV-1. The threshold voltage (VT) stability of TFTs is a critical figure-of-merit that largely determines the lifetime of active matrix backplanes. This, coupled with the growing demand on the TFTs to perform analogue functions, necessitates the study of the instability mechanisms in oxide semiconductor TFTs. The second part of this thesis specifically addresses this challenge. Here, electrical and/or optical stress/recovery measurements reveal the presence of charge trapping and persistent photoconductivity (PPC) in passivated HfInZnO/SiOx and GaInZnO/InZnO/SiOx TFT systems. In the absence of light, charge trapping is found dominant; whereas in the presence of light, PPC is. The PPC keeps the active channel in a state of high conductivity long after the removal of the light source, causing the TFT to act as though n-doped. This results in a negative VT shift, irrespective of bias magnitude and polarity. The origin of the PPC is attributed to the ionisation of oxygen vacancy sites, mainly based on the observations of its temperature- and wavelength-dependence. Interestingly, the gate voltage is found to control the decay of the PPC, giving rise to a memory action. This is explained in terms of the dependence of the rate of the PPC recovery reaction, Vo +++2e /rightarrow Vo, on carrier concentration.
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VENEZIANO, Lorena. "MECHANISMS OF CHROMOSOMAL INSTABILITY: RELATIONSHIP BETWEEN TUMOR SUPPRESSORS AND SAC GENES." Doctoral thesis, Università degli Studi di Palermo, 2017. http://hdl.handle.net/10447/219878.
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Caratteristica comune di molti tumori solidi è l’aneuploidia, conseguenza dell’instabilità cromosomica (CIN). Tuttavia non sono ancora chiari i meccanismi alla base dell’aneuploidia e i percorsi che permettono la sua tolleranza. Lo Spindle Assembly Checkpoint (SAC) è un meccanismo di sorveglianza cellulare che controlla la stabilità genomica durante la mitosi. Alterazioni nei membri del SAC generano aneuploidia, ma non è ancora chiaro se questi difetti sono sufficienti per promuovere la tumori-genesi. In questo processo, infatti, il contesto genetico della cellula gioca un ruolo importante. È risaputo che i difetti di p53 aiutano le cellule a proliferare velocemente tollerando la CIN. Al contrario, l’attivazione di una p53-wt contrasta l’aneuploidia. Poco si sa, invece, circa il ruolo del tumor suppressor p14ARF nel contrastare l’aneuploidia.
In questa tesi ho voluto valutare la relazione tra alcuni geni del SAC, la cui deplezione induce aneuploidia, e i geni tumor suppressor. Inizialmente, per indagare sul ruolo di p14ARF nel contrastare l’aneuploidia, l’ho espresso ectopicamente in cellule HCT116 (quasi diploidi) dopo aver ridotto, in contemporanea, l’espressione del gene MAD2, elemento cruciale del SAC. Il silenziamento post-trascrizionale di MAD2 ha indotto alti livelli di aneuploidia e di mitosi anomale, che sono diminuiti con l’espressione contemporanea di p14ARF. Inoltre, l’espressione ectopica di p14ARF in cellule MAD2-deplete ha attivato un percorso apoptotico, associato a un incremento della proteina p53. Questa risposta non è stata rilevata in cellule HCT116 p53KO, suggerendo che p14ARF contrasta l’aneuploidia attivando un’apoptosi p53-dipendente. Poi, ho voluto approfondire la relazione tra la proteina motrice Cenp-E, che funziona solo nell’attivazione del SAC, e l’aneuploidia in cellule umane. A tal fine, ho utilizzato due diversi tipi cellulari, fibroblasti primari umani IMR90 e cellule HCT116 che non esprimono la proteina p14ARF, analizzando gli effetti della deplezione di Cenp-E fino a quattro settimane. I due tipi cellulari hanno risposto in maniera differente poiché l’aneuploidia è più tollerata dalle cellule che non esprimono p14ARF piuttosto che dai fibroblasti primari. Inoltre, l’osservazione che la riduzione dell’aneuploidia nelle IMR90 coincide con l’incremento di p14ARF e che la sua espressione ectopica riduce l’aneuploidia nelle HCT116 conferma l’abilità del gene di contrastare l’aneuploidia. Infine, per approfondire questi risultati, ho generato cellule HCT116 che esprimono una proteina p14ARF funzionale, in cui ho valutato gli effetti della deplezione di Cenp-E. In conclusione, questi risultati suggeriscono che p14ARF potrebbe avere un ruolo importante nel contrastare l’aneuploidia attivando un’apoptosi p53-dipendente e che, in maniera più generale, è coinvolto nell’ostacolare l’aneuploidia indotta da differenti stimoli.The majority of solid tumors are characterized by aneuploidy that is believed to be the consequence of chromosomal instability (CIN). The mechanisms leading to aneuploidy and the pathway (s) that allows its tolerance are not completely understood. The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism that works to maintain the genomic balance in mitosis. Alterations of SAC components can induce aneuploidy but it is not clear if these defects are sufficient for tumorigenesis. In this process the genetic background of the cell plays an important role. It is known that p53 defects allow cells to quickly proliferate tolerating CIN. On the contrary, activation of wt-p53 counteracts aneuploidy. Less is known about the role of the p14ARF tumor suppressor to counteract aneuploidy. In this thesis, I investigate the relationship between some of the SAC genes that if depleted induce aneuploidy and tumor suppressor genes. First, to investigate the role of p14ARF to counteract aneuploidy it was ectopically expressed in HCT116 cells (near diploid) after MAD2 depletion a crucial component of the SAC. MAD2 posttranscriptional silencing induced high levels of aneuploid cells and aberrant mitosis that decreased when p14ARF was simultaneously expressed. In addition, p14ARF ectopic expression in MAD2-depleted cells induced apoptosis associated with increased p53 protein levels. This response was not detected in HCT116 p53KO cells suggesting that p14ARF counteracts aneuploidy activating apoptosis p53-dependent. Second, I wanted to probe the relationship between the motor protein CENP-E, which works only in the SAC signaling, and aneuploidy in human cells. To this aim I used two types of cells, human primary fibroblasts (IMR90) and near diploid cells (HCT116) lacking p14ARF, and analyzed the effects of CENP-E depletion up to four weeks. These experiments showed a different response for the two cell types. Aneuploidy was tolerated for longer times in cells lacking p14ARF expression rather than in primary cells. In addition the observations that the reduction of aneuploidy in IMR90 cells was proportional to the increase of p14ARF gene expression, and that its ectopic expression in HCT116 cells reduced aneuploidy confirm the ability of p14ARF to counteract aneuploidy. Third, to improve these results I generated HCT116 cells expressing a functional p14ARF to assess the effects of CENP-E depletion. Collectively, these results suggest that the tumor suppressor p14ARF may have an important role to contrast aneuploidy activating a p53-dependent apoptosis pathway and that it is generally involved to counterbalance aneuploidy induced by different stimuli.
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Nano, Maddalena. "Identification of the molecular mechanisms generating genetic instability in polyploid cells." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066263.
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La polyploïdie se caractérise par une duplication du génome entier. Elle inhibe efficacement la prolifération cellulaire et joue pourtant un rôle clé dans les étapes précoces de la tumorigénèse. Comment est-elle capable de promouvoir une instabilité génétique dans les cellules cancéreuses est une question en suspens. J'ai établi un système modèle affectant la cytocinèse pour étudier les conséquences de la polyploïdie dans les cellules souches neuronales (CSN) et dans le disque imaginal de l'aile de drosophile. Les cellules polyploïdes du disque sont rapidement éliminées, les CSN polyploïdes continuent de proliférer. Les CSN polyploïdes sont caractérisées par une instabilité génétique précoce et deux facteurs en sont responsables: les erreurs mitotiques et des dommages à l'ADN. Ces dommages sont issus en partie de l'incapacité des cellules à restreindre leur progression dans le cycle cellulaire après une réplication incomplète de l'ADN. J'ai trouvé que de multiples domaines nucléaires au sein de la même CSN polyploïde pouvaient présenter une asynchronie de leur progression dans le cycle cellulaire. Les domaines nucléaires en retard dans leur progression sont les cibles des lésions à l'ADN au moment de l'entrée en mitose. Les lésions sont réduites après surexpression de Chk1, une kinase de la voie ATR de réponse aux dommages à l'ADN. De plus, la prolifération incontrôlée des CSN polyploïdes génétiquement instables est responsable de leur potentiel tumorigénique dans les essais de transplantation. Mes résultats montrent que la tolérance à la polyploïdie dépend du tissu et qu'une série d'événements contribue à l'instabilité génétique dans les CSN polyploïdesPolyploidy, which derives from whole-genome duplication events, is normally a potent inhibitor of cell proliferation, but plays important roles during the early steps of tumorigenesis. However, how the gain of multiple sets of chromosomes promotes the generation of unbalanced karyotypes typical of cancer cells remains to be investigated. Using a number of conditions that affect cytokinesis, I established a model system to study the consequences of polyploidy in the neural stem cells (NSCs) of Drosophila and in the wing disc (WD). Importantly, while polyploidy is rapidly eliminated from the WD, polyploid NSCs continue to proliferate. Polyploid NSCs are characterized by early-onset genetic instability and two sources account for the generation of unstable karyotypes: mitotic errors and high-levels of DNA damage. DNA damage in polyploid NSCs arises, at least in part, from the inability of polyploid cells to restrain cell cycle progression in response to incomplete DNA replication. Surprisingly, I found that multiple nuclear domains in the same polyploid NSC can exhibit asynchrony in cell cycle progression, with delayed nuclear domains experiencing acute DNA damage at mitotic entry. I show that DNA damage in polyploid NSCs can be reduced over-expressing Chk1, the main downstream kinase engaged by ATR in the DNA damage response. I also show that uncontrolled proliferation of genetically unstable polyploid NSCs holds tumorigenic potential in transplantation assays. Overall, my results show that the tolerance to polyploidy is tissue dependent and that a complex network of events contributes to the generation of unbalanced karyotypes in polyploid NSCs
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Nano, Maddalena. "Identification of the molecular mechanisms generating genetic instability in polyploid cells." Electronic Thesis or Diss., Paris 6, 2017. http://www.theses.fr/2017PA066263.
Full textAbstract:
La polyploïdie se caractérise par une duplication du génome entier. Elle inhibe efficacement la prolifération cellulaire et joue pourtant un rôle clé dans les étapes précoces de la tumorigénèse. Comment est-elle capable de promouvoir une instabilité génétique dans les cellules cancéreuses est une question en suspens. J'ai établi un système modèle affectant la cytocinèse pour étudier les conséquences de la polyploïdie dans les cellules souches neuronales (CSN) et dans le disque imaginal de l'aile de drosophile. Les cellules polyploïdes du disque sont rapidement éliminées, les CSN polyploïdes continuent de proliférer. Les CSN polyploïdes sont caractérisées par une instabilité génétique précoce et deux facteurs en sont responsables: les erreurs mitotiques et des dommages à l'ADN. Ces dommages sont issus en partie de l'incapacité des cellules à restreindre leur progression dans le cycle cellulaire après une réplication incomplète de l'ADN. J'ai trouvé que de multiples domaines nucléaires au sein de la même CSN polyploïde pouvaient présenter une asynchronie de leur progression dans le cycle cellulaire. Les domaines nucléaires en retard dans leur progression sont les cibles des lésions à l'ADN au moment de l'entrée en mitose. Les lésions sont réduites après surexpression de Chk1, une kinase de la voie ATR de réponse aux dommages à l'ADN. De plus, la prolifération incontrôlée des CSN polyploïdes génétiquement instables est responsable de leur potentiel tumorigénique dans les essais de transplantation. Mes résultats montrent que la tolérance à la polyploïdie dépend du tissu et qu'une série d'événements contribue à l'instabilité génétique dans les CSN polyploïdesPolyploidy, which derives from whole-genome duplication events, is normally a potent inhibitor of cell proliferation, but plays important roles during the early steps of tumorigenesis. However, how the gain of multiple sets of chromosomes promotes the generation of unbalanced karyotypes typical of cancer cells remains to be investigated. Using a number of conditions that affect cytokinesis, I established a model system to study the consequences of polyploidy in the neural stem cells (NSCs) of Drosophila and in the wing disc (WD). Importantly, while polyploidy is rapidly eliminated from the WD, polyploid NSCs continue to proliferate. Polyploid NSCs are characterized by early-onset genetic instability and two sources account for the generation of unstable karyotypes: mitotic errors and high-levels of DNA damage. DNA damage in polyploid NSCs arises, at least in part, from the inability of polyploid cells to restrain cell cycle progression in response to incomplete DNA replication. Surprisingly, I found that multiple nuclear domains in the same polyploid NSC can exhibit asynchrony in cell cycle progression, with delayed nuclear domains experiencing acute DNA damage at mitotic entry. I show that DNA damage in polyploid NSCs can be reduced over-expressing Chk1, the main downstream kinase engaged by ATR in the DNA damage response. I also show that uncontrolled proliferation of genetically unstable polyploid NSCs holds tumorigenic potential in transplantation assays. Overall, my results show that the tolerance to polyploidy is tissue dependent and that a complex network of events contributes to the generation of unbalanced karyotypes in polyploid NSCs
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Martinez, Ramon, Hans-K. Schackert, Jens Plaschke, Gustavo Baretton, Hella Appelt, and Gabriele Schackert. "Molecular Mechanisms Associated with Chromosomal and Microsatellite Instability in Sporadic Glioblastoma multiforme." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133546.
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Objective: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas. Methods: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors. Results: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN. Conclusions: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBMDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Martinez, Ramon, Hans-K. Schackert, Jens Plaschke, Gustavo Baretton, Hella Appelt, and Gabriele Schackert. "Molecular Mechanisms Associated with Chromosomal and Microsatellite Instability in Sporadic Glioblastoma multiforme." Karger, 2004. https://tud.qucosa.de/id/qucosa%3A27514.
Full textAbstract:
Objective: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas.
Methods: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors.
Results: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN.
Conclusions: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBM.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Nayak, Sushma [Verfasser], and Anne [Akademischer Betreuer] Régnier-Vigourox. "Mechanisms of Chromosomal Instability in Glioblastoma / Sushma Nayak ; Betreuer: Anne Régnier-Vigourox." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180613821/34.
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Zhang, Yu. "Mechanisms of chromosomal instability induced by unstable DNA repeats in yeast S.cerevisiae." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/52185.
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DNA repetitive sequences capable of adopting non-B DNA structures are a potent source of instability in eukaryotic genomes. They are strong inducers of chromosomal fragility and genome rearrangements that cause various hereditary diseases and cancers. In addition, a subset of repeats also has an ability to expand, which leads to more than 20 human genetic diseases that are collectively known as repeat expansion diseases. However, the mechanisms underlying the potential of these structure-prone motifs to break and expand are largely unknown.
In this study, a systematic genome-wide screen was employed in yeast Saccharomyces cerevisiae to investigate the contributing factors of the instability of two representative non-B DNA-forming repeats: the triplex-adopting GAA/TTC tracts and the inverted repeats that can form hairpin and cruciform structures.
The GAA/TTC screen revealed that DNA replication and transcription initiation are the two major pathways governing the GAA/TTC stability in yeast, as corresponding mutants strongly induce both fragility and large-scale expansions of the repeats. The inverted repeats screen and follow-up experiments revealed that both replication-dependent and -independent pathways are involved in maintaining the stability of palindromic sequences.
We propose that similar mechanisms could operate in the human cells to mediate the deleterious metabolism of GAA and inverted repeats.
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Speth, Raymond L. 1981. "Fundamental studies in hydrogen-rich combustion : instability mechanisms and dynamic mode selection." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/61525.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 121-127).
Hydrogen-rich alternative fuels are likely to play a significant role in future power generation systems. The emergence of the integrated gasification combined cycle (IGCC) as one of the favored technologies for incorporating carbon capture into coal-based power plants increases the need for gas turbine combustors which can operate on a range of fuels, particularly syngas, a hydrogen-rich fuel produced by coal gasification. Lean premixed combustion, the preferred high-efficiency, low-emissions operating mode in these combustors, is susceptible to strong instabilities even in ordinary fuels. Because hydrogen-rich fuels have combustion properties which depend strongly on composition, avoiding the dynamics that energize combustion instability across all operating conditions is a significant challenge. In order to explore the effect of fuel composition on combustion dynamics, a series of experiments were carried out in two optically-accessible laboratory-scale combustors: a planar backward-facing step combustor and an axisymmetric swirlstabilized combustor. Fuels consisting of carbon monoxide and hydrogen, or propane and hydrogen were tested over a range of equivalence ratios and at various inlet temperatures. Dynamic pressure and chemiluminescence measurements were taken for each case. High-speed video and stereographic particle imaging velocimetry were used to explore the dynamic interactions between the flame and the flow field of the combustor. Stable, quasi-stable, and unstable operating modes were identified in each combustor, with each mode characterized by a distinct dynamic flame shape and acoustic response which is dependent on the composition of the reactants and the inlet temperature. In both combustors, the quasi-stable and unstable modes are associated with acoustically driven flame-vortex interactions in the combustion-anchoring region. In the planar combustor, the flame is convoluted around a large wake vortex, which is periodically shed from the step. In the swirl-stabilized combustor, the flame shape is controlled by the dynamics of the inner recirculation zone formed as a result of vortex breakdown. In both cases, the unstable mode is associated with velocity oscillation amplitudes that exceed the mean flow velocity. The apparent similarity between the response curves and flame dynamics in the two combustors indicate that the intrinsic local dynamics--instead of global acoustics--govern the flame response. Analysis shows that for each combustor, the pressure response curves across a range of operating conditions can be collapsed onto a single curve by introducing an appropriate similarity parameter that captures the flame response to the vortex. Computations are performed for stretched flames in hydrogen-rich fuels and the results are used to explain the observed similarity and to define the form of the similarity parameter. This similarity parameter works equally well for both experiments across fuel compositions and different inlet conditions, demonstrating that it fundamentally embodies the reciprocity between the flow and the combustion process that drives the instability. A linear model of the combustor's acoustics shows that the onset of combustion instability at a particular frequency can be related to a time delay between the velocity and the exothermic response of the flame that is inversely proportional to the local burning velocity. This analysis captures the impact of the fuel composition and operating temperature on the mode selection through an appropriately-weighted strained flame consumption speed, further emphasizing the influence of local transport-chemistry interactions on the system response. This new result confirms the role of turbulent combustion dynamics in driving thermoacoustic instabilities.
by Raymond Levi Speth.
Ph.D.
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Zong, Zhixin. "Studies on the mechanisms of solid state and solution instability of drugs." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/2795.
Full textAbstract:
The overarching objective of this thesis is to demonstrate a systematic approach for addressing the instability issues associated with low limit degradants by developing quantitative degradation models that incorporate key instability determinants into predictive equations. Chlorhexidine was used as model compound in aqueous solution to demonstrate the application of the predictive models to issues of formulation design and manufacturing. Chorhexidine degrades to p-chloroaniline, a well-established toxicant, by various pH-dependent pathways. In acidic conditions, the direct formation of p-chloroaniline from chlorhexidine is the major pathway whereas the indirect formation of p-chloroaniline via p-chlorophenylurea is the main alkaline pathway. Rate laws and mechanisms for each pathway were presented. Shelf life predictions equations for chlorhexidine formulations were derived based on the kinetics of p-chloroaniline appearance as a function of formulation strength, solution pH, bulk chlorhexidine purity and storage temperature. The pH range for optimal shelf-life was 5.0 to 5.5. Simple extraction procedures used during formulation preparation were identified to improve bulk chlorhexidine purity and thereby extend product shelf-life. Gabapentin degrades directly to gabapentin-lactam in the solid-state. The established limit on gabapentin-lactam in gabapentin pharmaceutical formulations is <0.5% w/w thus gabapentin instability was studied as a model compound for solid state formulation applications. Mechanical stress associated with drug product manufacturing in unit operations such as milling increased the subsequent lactamization rate upon storage due to increased gabapentin crystal disorder. The effect of environment moisture was to decrease the rate of gabapentin-lactam formation due to competitive recovery of gabapentin crystallinity which was accelerated by humidity. A degradation model that combined both physical and chemical instability pathways including autocatalytic branching, spontaneous intra-molecular cyclization and moisture-induced physical transformation steps was shown to be consistent with lactamization kinetics as a function of both environmental (temperature and humidity) and manufacturing-related effects. This kinetic model was used to predict the shelf-life of gabapentin tablets prepared under various exemplary manufacturing conditions thereby demonstrating the ability of the model to link manufacturing variation and shelf-life stability in for solid-state drug formulations.
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Dere, Ruhee J. "The molecular mechanisms involved in the genetic instability of the CCTG. CAGG repeats associated with myotonic dystrophy type 2." Texas A&M University, 2005. http://hdl.handle.net/1969.1/3783.
Full textAbstract:
Myotonic dystrophy type 2 (DM2) is caused by the extreme expansion (from <
30 repeats in normal individuals to ~ 11,000 for the full mutation in certain patients) of
the repeating tetranucleotide CCTGÂCAGG sequence in the intron of the zinc finger
protein 9 (ZNF9) gene. The genetic instabilities of the CCTGÂCAGG repeats were
investigated to evaluate the molecular mechanisms responsible for these massive
expansions. The effects of replication, recombination, repair and transcription on the
genetic instabilities have been investigated in COS-7 cells and E. coli model systems. A
replication assay was established in COS-7 cells wherein the CCTGÂCAGG repeats
cloned proximal to the SV40 origin of replication resulted in expansions and deletions in
a length and orientation-specific manner, whereas the repeats cloned distal to the same
origin were comparatively stable. These results fit with our data obtained from
biochemical studies on synthetic oligonucleotides since these biochemical studies
revealed that the d(CAGG)26 oligomer had a marked propensity to adopt a hairpin
structure as opposed to its complementary d(CCTG)26 that lacked this capacity. Furthermore, a genetic assay in E. coli was used to monitor the intramolecular frequency
of recombination. This assay revealed that the tetranucleotide repeats were indeed hot
spots for recombination. Moreover, studies conducted in SOS-repair mutants showed
that recombination frequencies were much lower in a SOS¯ strain as compared to a SOS+
strain. However, experiments conducted to ascertain the level of induction of the SOS
response revealed that the SOS pathway was not stimulated in our studies. These results
revealed that although breaks may occur within the repeats, the damage is most likely
repaired without induction of the SOS response contrary to previous beliefs.
Thus, a complex interplay of replication, recombination, and repair is likely
responsible for the expansions observed in DM2.
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Grant, David. "Failure mechanisms and instrumentation systems for an induced slope failure project." Thesis, University of Southampton, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243134.
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Grant, David. "Instrumentation systems for and failure mechanisms of an induced slope failure project." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243025.
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Modise, Thero. "Genomic Instability and Gene Dosage Obscures Clues to Virulence Mechanisms of F. tularensis species." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/72885.
Full textAbstract:
The pathogen Francisella tularensis subsp. tularensis has been classified as a Center for Disease Control (CDC) select agent. However, little is still known of what makes the bacteria cause dis-ease, especially the highly virulent type A1 strains. The work in this dissertation focused on type A1 strains from the Inzana laboratory, including a wildtype virulent strain TI0902, an avirulent chemical mutant strain TIGB03 with a Single Nucleotide Polymorphism in the wbtK gene, and several complemented mutants, [wbtK+]TIGB03, with dramatic differences in virulence and growth rates. One of the complemented clones (Clone12 or avp-[wbtK+]TIGB03-C12) was aviru-lent, but protected mice against challenge of a lethal dose of TI0902 and was considered as a possible vaccine strain.
Whole genome sequencing was performed to identify genetic differences between the virulent, avirulent and protective strains using both Roche/454 and Illumina next-generation sequencing technologies. Additionally, RNASeq analysis was performed to identify differentially expressed genes between the different strains. This comprehensive genomic analysis revealed the critical role of transposable elements in inducing genomic instability resulting in large du-plications and deletions in the genomes of the chemical mutant and the complemented clones that in turn affect gene dosage and expression of genes known to regulate virulence. For exam-ple, whole genome sequencing of the avirulent chemical mutant TIGB03 revealed a large 75.5 kb tandem duplication flanked by transposable elements, while the genome of a virulent Clone01 (vir-[wbtK+]TIGB03-C1) lost one copy of the 75.5 kb tandem duplicated region but gained a tandem duplication of another large 80kb region that contains a virulence associated transcription factor SspA. RNAseq data showed that the dosage effect of this extra region in Clone1 suppresses expression of MglA regulated genes. Since MglA regulates genes that are known to be crucial for virulence, including the well-studied Francisella Pathogenicity Island (FPI), these results suggest that gene dosage effects arising from large duplications can trigger unknown virulence mechanisms in F. tularensis subsp. tularensis. These results are important especially when designing live vaccine strains that have repeated insertion elements in their genomes.Ph. D.
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Stanger, Jonathan Jeffrey. "Charge Transfer Mechanisms in Electrospinning." Thesis, University of Canterbury. Physics and Astronomy, 2008. http://hdl.handle.net/10092/1667.
Full textAbstract:
Electrospinning is a method of producing nano structured material from a polymer solution or melt using high strength electric fields. It is a process that has yet to find extensive industrial application yet shows promise if obstacles such as low rate of production overcome perhaps by more complete theoretical modelling. This work examines the effects of adding an ionic salt to a solution of poly(vinyl alcohol) in water. The direct effect was an increase the charge density and electric current. It was found that an increase in charge density decreases the mass deposition rate and forms a thinner initial jet. When the sign of the charge on the polymer solution was changed from positive to negative the charge density increased and the initial jet diameter and mass deposition rate also decreased. It was proposed that a smaller radius of curvature is formed by the Taylor cone at higher charge densities resulting in a smaller “virtual orifice”. The extent of the bending instability was explored and it was found that adding ionic salt results in a decrease in the bending instability resulting in thicker fibres. Changing the sign of the charge on the polymer solution from positive to negative resulted in an increase in the bending instability and resulted in thinner fibres. The charge transfer mechanisms used in different electrospinning models are explored and some assumptions not explicitly stated are discussed. From this discussion a generalized equation describing the charge transport mechanisms is proposed.
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Diemuodeke, Ogheneruona Endurance. "Modelling of Liquid Breakup Mechanisms in Engineering Systems." Thesis, Cranfield University, 2014. http://dspace.lib.cranfield.ac.uk/handle/1826/9289.
Full textAbstract:
Effective design of liquid fuel injection systems is a function of good understanding of liquid breakup mechanisms. A transient liquid breakup model is developed on the classical interfacial breakup theory by modifying the classical linear perturbation process to include time-dependent base and perturbed flow parameters. The non-isothermal condition on liquid jet instability and breakup is theoretically modelled; with the particular consideration of a spatially variation of surface tension along the liquid-gas interface. The model combines the classical interface hydrodynamic instability and breakup theory and heat-transfer through semi-infinite medium. Analytical liquid breakup model, which combines transient and non-isothermal effects on liquid jet breakup, is suggested. The suggested model could be simplified to the transient breakup model and the non-isothermal breakup model equivalents. A novel mechanistic model, which is based on a simple momentum balance between the injected jet and the aerodynamic drag force, is suggested for breakup length. A new model, which combines energy criterion and dual-timescale for turbulent shear in droplet dispersion, is suggested for droplet breakup criteria on the basis of critical Webber number. All developed models showed good predictions of available experimental data, and established empirical correlation, within the operational conditions of contemporary ICEs, specifically diesel engines. Continued research in these areas could benefit the development of the next generation of liquid fuel injectors and combustors – by accounting for transient effects and non-isothermal conditions in liquid jet breakup, and turbulent shear in droplet breakup.
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Colosio, A. "MECHANISMS MEDIATING REPLICATION FORK COLLAPSE AND PROCESSING IN CHECKPOINT DEFECTIVE CELLS." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/234147.
Full textAbstract:
ABSTRACT
An accurate DNA replication is essential to prevent genome instability events, such as mutations and chromosomal rearrangements that are hallmarks of neoplastic transformation and cancer onset. A dedicated branch of the DNA damage checkpoint maintains the integrity of replicating chromosomes by stabilising replication forks in the presence of genotoxic agents, thus ensuring cell viability. Upon fork collapse, budding yeast checkpoint mutants experiencing replication stress accumulate aberrant replication intermediates, such as gapped and hemireplicated molecules, as well as four-branched structures known as reversed forks. Aberrant replication intermediates are potentially harmful for the cells since they are thought to trigger unscheduled recombination events that cause genome rearrangements. In this PhD thesis, I examined checkpoint-dependent mechanisms controlling fork stability, and I provide in vivo evidence that positive supercoiling accumulating ahead of replication forks is the main mechanical force driving fork reversal. Thus, DNA topology is a critical determinant of replication fork stability in vivo. Furthermore, a 2D-gel screening for enzymatic activities involved in the metabolism of collapsed forks, revealed a novel role for the Sae2 and Dna2 endonucelases in replication intermediates processing.
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Webster, Gregory Daniel. "Level and Instability of Global and Domain-Specific Self-Esteem as Differential Predictors of Aggression." W&M ScholarWorks, 2001. https://scholarworks.wm.edu/etd/1539626333.
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Grabsch, Heike Irmgard. "Clinicopathological and molecular factors related to chromosomal instability and its underlying genetic mechanisms in gastric cancer." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551249.
Full textAbstract:
The majority of gastric cancer (GC) patients present at advanced stage and have a poor prognosis. Poor survival might be related to the unavailability of molecular markers to determine patient management. Most GC are considered genetically unstable (microsatellite unstable (MSI)) and/or chromosomal unstable (CIN). Recent studies suggest that CIN cancers are multi-drug resistant. First drugs targeting specific characteristics of CIN cancer have shown activity in vitro. Thus, there is an urgent need to fully understand the mechanisms leading to and maintaining CIN in GC as this might identify new treatment targets. It has been proposed that CIN might be caused by an impaired DNA damage response (DDR). The current study characterised the type of genetic instability present in GC measuring DNA ploidy (CIN surrogate marker) as well as MSI and investigated in parallel the expression of all key DDR proteins and their downstream signalling pathways regulating cell cycle progression in a retrospectively collected series of GC using immunohistochemistry and tissue microarray technology. GC were also screened for KRAS and BRAF mutations as the RAS signalling pathway had been implicated in generating genetic instability in colorectal cancer. This is the first study to identify a significant overlap between MSI and CIN in a subset of GC with poor prognosis. DNA double strand breaks were rare in GC making deregulated DNA damage response unlikely as the major mechanism leading to CIN in GC. The identification of GC with low proliferative index, low DNA repair activity and poor survival suggested that a subset of GC may switch from proliferation to invasion, identifying a potential additional cause for GC resistance against cytotoxic drugs warranting further studies. KRASIBRAF mutations were rare in GC, related to MSI but not to CIN. Results from this exploratory study require and warrant validation in a larger independent cohort.
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CHOUDHARY, RAMVEER. "MECHANISMS CONTROLLING THE INTEGRITY OF CONVERGING FORKS DURING REPLICATION TERMINATION." Doctoral thesis, Università degli Studi di Milano, 2018. http://hdl.handle.net/2434/559540.
Full textAbstract:
During S phase, natural fork pausing elements including replication termination zones (TERs) and transcribed genes, can easily lead to genotoxicity and chromosome fragility at fragile sites (CFs), known as hotspots for DNA breaks and chromosomal rearrangements, particularly in cancer cells. However, the key factors and pathways protecting the integrity of CFSs are not well understood. In order to elucidate these mechanisms, we used yeast as a model system, and combined genetic and genomic studies aimed at identifying fragile sites genome-wide.
We found that centromeres, rDNA, telomeres and TERs represent hot spots for copy number variation (CNV) in wild-ype yeast cells exposed to replication stress. We found that top2 contributes to relieve the topological stress and extensive fork pausing during termination at TERs. We also observed that fragility at these sites is greatly enhanced in checkpoint mutants (Tel1-ATM1 and Mec1-ATR1), likely due to their inability to uncouple transcription from gene gating, thus leading to topological stress in front of replication forks. TER fragility in checkpoint defective cells can be partially rescued by Top2 and Condensin complex inactivation.
We further demonstrated that Pif1 family helicase, Rrm3, regulate extensive fork pausing at TERs and endogenous pausing sites by suppressing RNA:DNA hybrid (R-loops) accumulation. Alongside, a RNA:DNA helicase Senataxin1 (Sen1) coordinates replication and transcription collision at TERs and endogenous fork pausing. Absence of Sen1 accumulates CNVs at TERs and double-strand DNA breaks. We show that programmed fork pausing and resolution of R-loops are key processes for TER integrity. Accordingly, sen1 rrm3 double mutants, accumulate gaps and RNA:DNA hybrids at TERs and fail to fuse replicons; moreover, these mutants exhibit unscheduled condensation events at TERs leading to chromosome entangling. Taken together, our data strongly suggests that, the replication checkpoint, Sen1 and Rrm3, coordinate replication termination to prevent accumulation of unsolved topological constrains and premature recruitment of Condensins and Top2.
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Cheng, Boqian. "The mechanisms underlying flow-induced instability of cylinder arrays in cross-flow : an investigation of system parameters." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28437.
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The main aim of this thesis is the study of the two mechanisms underlying fluidelastic instability in cylinder arrays subjected to cross-flow: the negative fluid damping and the fluid stiffness-controlled mechanisms, especially with regard to the effect of fluidelastic coupling between cylinders and the effect of system parameters in each case.An in-line square array with pitch-to-diameter ratio P/d = l.5 has been tested in both water- (with low mass ratio, $m/pd sp2$ = 6.5) and air-flow (with high mass ratio, $m/pd sp2$ = 860). The effect of fluidelastic coupling between cylinders on the critical flow velocity for fluidelastic instability was investigated via frequency detuning experiments, including an extreme case of one flexible cylinder in an otherwise rigid cylinder array. The water tunnel experimental results showed that fluidelastic coupling between cylinders in water-flow has little effect on the critical flow velocity for fluidelastic instability, whereas the wind tunnel experimental results demonstrated that fluidelastic coupling between cylinders in airflow has a significant effect on the critical flow velocity. Therefore, for the cases with low mass ratio parameter the negative fluid damping mechanism dominated the fluidelastic instability of the array; however, for cases with high mass ratio, fluidelastic instability of the array was controlled by fluid stiffness effects.
An in-line square array with P/d = l.5 was also tested in the wind tunnel, with cylinders with high and low levels of mechanical damping. The experimental results showed that fluidelastic coupling between cylinders with low mechanical damping has a more significant effect on the critical flow velocity for fluidelastic instability than with high mechanical damping in airflow (with high mass ratio, $m/pd sp2$ = 860); hence, fluid stiffness-controlled mechanism becomes more important for fluidelastic instability of the array with low mechanical damping in airflow. Next, an in-line square array with P/d = 3.0 was tested in the wind tunnel. The results showed that one flexible cylinder becomes unstable when positioned in row 2 of the array; however, it does not become unstable when positioned in rows 3 or 4. This suggests that P/d has a large effect on fluidelastic instability behaviour of in-line square arrays.
Finally, a new constrained-mode approach, with a one-cylinder-kernel, has been developed for the instability analysis of both in-line and staggered arrays. The approach was developed to reduce the computational effort when a fully flexible cylinder array has to be analyzed, in order to take into account fluidelastic coupling; between cylinders.
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Smith, Michael James. "Implications of anthocyanin instability and metabolism : impact on discovery of intake biomarkers and in vitro mechanisms of action." Thesis, University of East Anglia, 2016. https://ueaeprints.uea.ac.uk/61980/.
Full textAbstract:
Anthocyanins are polyphenol pigments responsible for the blue/red colouring of many fruits and vegetables whose consumption is associated with reduced risk of cardiovascular disease. Due to instability at neutral pH and reported low bioavailability of anthocyanins, the focus has shifted to their phenolic metabolites to explain the observed bioactivity. The hypothesis of the present study was that greater sensitivity and higher throughput could be achieved by developing existing analytical methodology, metabolite biomarkers of anthocyanin intake could be identified, and physiologically relevant anthocyanin metabolite profiles could reduce expression of proinflammatory cytokines in vitro. Stability of cyanidin-3-glucoside and 17 metabolites in serum was assessed. Unlike the parent anthocyanin, metabolite recovery was unaffected by either pH or freeze/thaw cycling suggesting that acidification and aliquoting of samples may be unnecessary for quantifying anthocyanin metabolites only. HPLC-ESI-MS/MS methodology was developed to increase sensitivity and sample throughput. Initial and developed methods were validated against FDA guidelines and found to have acceptable linearity, specificity and sensitivity with limits of detection of 9.5 ± 13.0 nM and 96.7 ± 541.7 nM respectively. Accuracy and precision were acceptable at 50 μM but outside guidelines at 1.56 μM and 0.098 μM for both methods. Biomarkers of anthocyanin intake were explored using samples from a 13C-labelled cyanidin-3-glucoside trial to compare 13C-labelled metabolites against 12C metabolites from the background diet. Gallic acid was consistently found above background levels in urine and represented the best biomarker candidate. Finally, effect of anthocyanin metabolite profiles on proinflammatory cytokines in CD40L and TNF-α-stimulated HUVEC was investigated. Incubation with metabolite profiles reduced expression of sVCAM-1 by 47-58% and IL-6 by 16-37% following TNF-α stimulation. In conclusion, the present thesis develops methodology for the quantification of anthocyanin metabolites in biological matrices and provides insight into their use as biomarkers of anthocyanin intake and role in maintaining cardiovascular health.
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Palanca-Wessels, Maria Corinna. "In vitro analysis of cultured Barrett's esophagus cells : insights into mechanisms of genomic instability and possible therapeutic strategies /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/4995.
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Paisie, Carolyn Anne. "Definition of mechanisms of mutation generation in tissues and embryonic stem cellsof the constitutive Fhit knockout mouse." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1436542716.
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Gogolin, Sina [Verfasser]. "MYCN-dependent and -independent mechanisms targeting drug-induced DNA damage response and chromosomal instability in neuroblastoma cells / Sina Gogolin." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2013. http://d-nb.info/1030142882/34.
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Lees, Hayley Diane. "Molecular mechanisms of premature ageing in a worm model of human Werner syndrome." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:080df619-828b-4248-b03f-c4aeb31f1672.
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Investigating the biological basis of ageing is both fascinating and medically relevant, as we strive to understand both how organisms age, and how our knowledge might be put to good use in an increasingly long-lived human population. Despite the complexity of ageing biology, it is very striking that longevity, in a wide variety of organisms, can be modified by manipulating single genes. In this thesis, I investigate phenotypes associated with mutations in C. elegans homologues of human WRN, the gene mutated in the progeroid Werner syndrome (WS). Mutant phenotypes in the worm recapitulate aspects of the pathophysiology observed in WS patients, including premature ageing, genomic instability, and sensitivity to DNA damaging agents. wrn-1 overexpression, on the other hand, appears to enhance longevity, suggesting that wrn-1 acts as a bona fide anti-gerontogene. The combination of wrn-1 mutations with mutation in the worm p53 homologue, cep-1, unexpectedly triggers a novel and very striking enhanced lifespan and healthspan phenotype, termed synthetic super-viability (SSV). The SSV phenotype is modulated by various environmental inputs such as temperature stress. The data presented here can be incorporated into a model in which stress sensing (involving p53) is the crucial determinant of longevity outcomes. Several theories of ageing incorporate the idea that 'that which does not kill us, makes us stronger' - encapsulated in a biological sense in the idea of hormesis, a physiological shift in response to stress. Here, this hypothesis is expanded to include the notion that intrinsic responses to stress may themselves act to limit lifespan - too much of a good thing can be bad.
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Gomez, Giraldo Evelio Andres. "Observations of energy transfer mechanisms associated with internal waves." University of Western Australia. Centre for Water Research, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0045.
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[Truncated abstract] Internal waves redistribute energy and momentum in stratified lakes and constitute the path through which the energy that is introduced at the lake scale is cascaded down to the turbulent scales where mixing and dissipation take place. This research, based on intensive field data complemented with numerical simulations, covers several aspects of the energy flux path ranging from basin-scale waves with periods of several hours to high frequency waves with periods of few minutes. It was found that, at the basin-scale level, the horizontal shape of the lake at the level of the metalimnion controls the period and modal structure of the basin-scale natural modes, conforming to the dispersion relationship of internal waves in circular basins. The sloping bottom, in turn, produces local intensification of the wave motion due to focusing of internal wave rays over near-critical slopes, providing hot spots for the degeneration of the basin-scale waves due to shear instabilities, nonlinear processes and dissipation. Different types of high-frequency phenomena were observed in a stratified lake under different forcing conditions. The identification of the generation mechanisms revealed how these waves extract energy from the mean flow and the basin-scale waves. The changes to the stratification show that such waves contribute to mixing in different ways . . . Detailed field observations were used to develop a comprehensive description of an undocumented energy flux mechanism in which shear-instabilities with significant amplitudes away from the generation level are produced in the surface layer due to the shear generated by the wind. The vertical structure of these instabilities is such that the growing wave-related fluctuations strain the density field in the metalimnion triggering secondary instabilities. These instabilities also transport energy vertically to the thermocline where they transfer energy back to the mean flow through interaction with the background shear.
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Vogt, Damian. "Experimental Investigation of Three-Dimensional Mechanisms in Low-Pressure Turbine Flutter." Doctoral thesis, KTH, Energy Technology, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-205.
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The continuous trend in gas turbine design towards lighter, more powerful and more reliable engines on one side and use of alternative fuels on the other side renders flutter problems as one of the paramount challenges in engine design. Flutter denotes a self-excited and self-sustained aeroelastic instability phenomenon that can lead to material fatigue and eventually damage of structure in a short period of time unless properly damped. The design for flutter safety involves the prediction of unsteady aerodynamics as well as structural dynamics that is mostly based on in-house developed numerical tools. While high confidence has been gained on the structural side unanticipated flutter occurrences during engine design, testing and operation evidence a need for enhanced validation of aerodynamic models despite the degree of sophistication attained. The continuous development of these models can only be based on the deepened understanding of underlying physical mechanisms from test data.
As a matter of fact most flutter test cases treat the turbomachine flow in two-dimensional manner indicating that the problem is solved as plane representation at a certain radius rather than representing the complex annular geometry of a real engine. Such considerations do consequently not capture effects that are due to variations in the third dimension, i.e. in radial direction. In this light the present thesis has been formulated to study three-dimensional effects during flutter in the annular environment of a low-pressure turbine blade row and to describe the importance on prediction of flutter stability. The work has been conceived as compound experimental and computational work employing a new annular sector cascade test facility. The aeroelastic response phenomenon is studied in the influence coefficient domain having one blade oscillating in various three-dimensional rigid-body modes and measuring the unsteady response on several blades and at various radial positions. On the computational side a state-of-the-art industrial numerical prediction tool has been used that allowed for two-dimensional and three-dimensional linearized unsteady Euler analyses.
The results suggest that considerable three-dimensional effects are present, which are harming prediction accuracy for flutter stability when employing a two-dimensional plane model. These effects are mainly apparent as radial gradient in unsteady response magnitude from tip to hub indicating that the sections closer to the hub experience higher aeroelastic response than their equivalent plane representatives. Other effects are due to turbomachinery-typical three-dimensional flow features such as hub endwall and tip leakage vortices, which considerably affect aeroelastic prediction accuracy. Both effects are of the same order of magnitude as effects of design parameters such as reduced frequency, flow velocity level and incidence. Although the overall behavior is captured fairly well when using two-dimensional simulations notable improvement has been demonstrated when modeling fully three-dimensional and including tip clearance.
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Moritz, Benjamin [Verfasser], and Peter [Akademischer Betreuer] Becker. "Prevention and prediction of production instability of CHO-K1 cell lines by the examination of epigenetic mechanisms / Benjamin Moritz. Betreuer: Peter Becker." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/107914031X/34.
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Quinlan, John Mathew. "Investigation of driving mechanisms of combustion instabilities in liquid rocket engines via the dynamic mode decomposition." Diss., Georgia Institute of Technology, 2015. http://hdl.handle.net/1853/54343.
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Combustion instability due to feedback coupling between unsteady heat release and natural acoustic modes can cause catastrophic failure in liquid rocket engines and to predict and prevent these instabilities the mechanisms that drive them must be further elucidated. With this goal in mind, the objective of this thesis was to develop techniques that improve the understanding of the specific underlying physical processes involved in these driving mechanisms. In particular, this work sought to develop a small-scale, optically accessible liquid rocket engine simulator and to apply modern, high-speed diagnostic techniques to characterize the reacting flow and acoustic field within the simulator. Specifically, high-speed (10 kHz), simultaneous data were acquired while the simulator was experiencing a 170 Hz combustion instability using particle image velocimetry, OH planar laser induced fluorescence, CH* chemiluminescence, and dynamic pressure measurements. In addition, this work sought to develop approaches to reduce the large quantities of data acquired, extracting key physical phenomena involved in the driving mechanisms. The initial data reduction approach was chosen based on the fact that the combustion instability problem is often simplified to the point that it can be characterized by an approximately linear constant coefficient system of equations. Consistent with this simplification, the experimental data were analyzed by the dynamic mode decomposition method. The developed approach to apply the dynamic mode decomposition to simultaneously acquired data located a coupled hydrodynamic/combustion/acoustic mode at 1017 Hz. On the other hand, the dynamic mode decomposition's assumed constant operator approach failed to locate any modes of interest near 170 Hz. This led to the development of two new data analysis techniques based on the dynamic mode decomposition and Floquet theory that assume that the experiment is governed by a linear, periodic system of equations. The new periodic-operator data analysis techniques, the Floquet decomposition and the ensemble Floquet decomposition, approximate, from experimental data, the largest moduli Floquet multipliers, which determine the stability of the periodic solution trajectory of the system. The unstable experiment dataset was analyzed with these techniques and the ensemble Floquet decomposition analysis found a large modulus Floquet multiplier and associated mode with a frequency of 169.6 Hz. Furthermore, the approximate Rayleigh criterion indicated that this mode was unstable with respect to combustion instability. Overall, based on the positive finding that the ensemble Floquet decomposition was able to locate an unstable combustion mode at 170 Hz when the operator's time period was set to 1 ms, suggests that the dynamic mode decomposition based 1017 Hz mode parametrically forces the 170 Hz mode, resulting in what could be characterized as a parametric combustion instability.
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Petit, Tom. "Compréhension et modélisation d’essais de ténacité avec pop-in : application à l’aluminium 6061-T6 et influence de l’irradiation neutronique." Thesis, Paris Sciences et Lettres (ComUE), 2018. http://www.theses.fr/2018PSLEM019/document.
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Le pop-in est un phénomène d’instabilité de propagation de fissure observé lors d’essais de ténacité sur certains matériaux. Ce phénomène a été observé sur l’alliage d’aluminium 6061-T6 qui a été identifié pour constituer des éléments de structure essentiels du cœur du réacteur de recherche Jules Horowitz. Cette thèse a été initiée pour comprendre l’origine de ce phénomène sur l’aluminium 6061-T6 et en proposer une modélisation à bases physiques qui pourra être utilisée pour l’exploitation et l’interprétation des essais de ténacité, notamment à l’état irradié.Les différentes pistes identifiées dans la littérature ont été testées expérimentalement. Des revenus (4/8/12/16 h) ont été appliqués afin d’obtenir différents comportements mécaniques. Des essais de traction avec corrélation d’images ont montré que les pop-ins observés ne sont pas dus à un effet PLC. Ils ne correspondent pas non plus à une hétérogénéité microstructurale ; ils ne sont pas liés à des mécanismes d’endommagement, car la rupture est typiquement ductile, qu’un pop-in soit intervenu ou non. Ces mécanismes et les différentes microstructures ont été comparés par le biais de plusieurs techniques (MEB, EBSD, EDS, Sonde Atomique Tomographique, tomographie, laminographie et nanolaminographie par rayonnement synchrotron). Les pop-ins sont donc uniquement le résultat d’une accélération de la rupture ductile.En réalité, ils sont dus à une interaction entre deux paramètres : une résistance réduite du matériau à la propagation de fissure (i.e. un faible module de déchirement) et une complaisance importante du dispositif d’essai (i.e. une faible raideur). Afin d’investiguer ce deuxième paramètre, un dispositif innovant a été conçu, permettant de faire varier la raideur de la machine d’essai lors d’essais de ténacité. Deux critères analytiques, l’un basé sur la courbe force-ouverture, l’autre sur l’intégrale J, ont été établis, permettant de quantifier les conditions d’amorçage et d’arrêt de pop-in de façon fiable.Pour prendre en compte le rôle central du durcissement vis-à-vis de la propagation ductile, un nouveau critère de germination piloté par les contraintes a été introduit dans un unique modèle GTN. Cela permet de simuler et de reproduire par éléments finis les différentes courbes de ténacité J-Δa en modifiant uniquement la loi élastoplastique. En rajoutant des ressorts dans les modélisations et avec un pilotage adapté, les pop-ins sont simulés avec succès, et restent exploitables avec les critères analytiques.Des études sur éprouvettes irradiées réalisées dans des enceintes blindées ont montré que l’augmentation des pop-ins avec l’irradiation résultait de la diminution du module de déchirement, elle-même due au durcissement. De même qu’à l’état non irradié, les pop-ins apparaissent donc à cause de l’interaction du module de déchirement avec le dispositif d’essai, et non pas à cause d’une gamme d’élaboration industrielle non maitriséePop-in is a phenomenon of crack propagation instability observed during toughness tests on some materials. This phenomenon has been observed on the 6061-T6 aluminum alloy, which has been identified as an essential structural element of the core of the Jules Horowitz research reactor. This thesis was initiated to understand the origin of this phenomenon on 6061-T6 aluminum and to propose a physics-based modeling, usable for the exploitation and interpretation of toughness tests, especially in the irradiated state.The different origins identified in the literature have been experimentally tested. Different aging times (4/8/12/16h) were applied to obtain different mechanical behaviors. Tensile tests with image correlation have shown that the observed pop-ins are not due to a PLC effect. Nor do they correspond to microstructural heterogeneity; they are not linked to different fracture mechanisms, because the rupture is typically ductile, whether a pop-in is involved or not. These mechanisms and the different microstructures were compared using several techniques (SEM, EBSD, EDS, Atom Probe Tomography, tomography, synchrotron laminography and nanolaminography). Pop-ins are therefore only the result of an acceleration of the ductile fracture.In fact, they are due to an interaction between two parameters: the reduced material crack growth toughness (i.e. the low tearing modulus), and the significant compliance of the test device (i.e. the low stiffness). In order to investigate this second parameter, an innovative setup has been designed to vary the machine stiffness during toughness tests. Two analytical criteria, one based on the load-opening curve, the other on the J-integral, have been established, making it possible to reliably quantify the conditions for initiation and arrest of pop-in.To take into account the central role of hardening for ductile propagation, a new stress-controlled nucleation criterion has been introduced into a single GTN model. This makes it possible to simulate and capture by finite elements the various J-Δa toughness curves by modifying only the elastoplastic law. By adding springs in the models and with an adapted control, the pop-ins are successfully simulated, and remain exploitable with the analytical criteria.Studies on irradiated specimens carried out in hot cells have shown that the increase in pop-ins with irradiation results from the decrease in the tearing modulus, itself due to hardening. As in the non-irradiated state, pop-ins thus appear solely because of the interaction between the tearing modulus and the test device stiffness, and not because of a range of industrial development not mastered
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Smart, Una Margaret. "Chaos in the Rayleigh-Taylor instability." Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317526.
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Zhou, Yang. "Numerical instability investigations for thin membranes." Doctoral thesis, KTH, Strukturmekanik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-209155.
Full textAbstract:
Membrane structures are commonly used in many fields. The studies of these structures are of increasing interest. The projects in this thesis focus on the evaluations of equilibrium states for pressurized membranes under different problem settings, using finite element methods, and the corresponding instability behaviors. The first part of the current work discusses the instability behavior of a thin, planar, circular and initially horizontal membrane subjected to downwards or upwards fluid pressure. The membrane structures exhibit large deformations under pressure. The method for evaluating fluid pressure from gravity was developed in finite element context, and used in numerical simulations. Limit and bifurcation points have been detected for different loading parameters and conditions. The effects on instabilities of parameters, the initial states of the membrane, and the chosen mesh are discussed. The second part of the current work discusses instability behavior of a thin, spherical and closed membrane containing gas and fluid, when placed on a horizontal rigid and non-friction plane. A multi-parametric loading is described. By adding practically relevant controlling equations, different classes of equilibrium paths were followed using a generalized path following algorithm. Stability conclusions were made, according to the considered load parameters and the constraints. A generalized eigenvalue analysis was used to evaluate the stability behavior including the constraint effects. Fold line evaluations were performed to analyze the parametric dependence. A solution surface approach is used to visualize the mechanical response under this multi-parametric setting. The third part of the current work focuses on instability response of a truncated sphere, containing gas and fluid, and in contact with two vertical rigid and non-friction planes. Different penalty formulations were used and compared. The effects of contact implementations on instability behaviors were investigated. Bifurcation points induced by contacts have been observed. Multi-parametric problems were defined, and generalized paths were followed. The multi-parametric stability was evaluated using generalized eigenvalue analysis, based on the mass and total differential matrices. The effects of augmenting equations on bifurcation points and limit points are discussed. The fourth part of the current work analyses the instability response of a truncated sphere, completely filled with fluid, placed on a horizontal plane and spinning around the vertical axis. The loads from fluid pressure and the constraints, e.g., fluid volume, were formulated to generate a symmetric differential matrix. Several mesh patterns with different symmetries were used to simulate the model, and the obtained results are compared. Various problem settings were considered, and generalized paths were followed. The effects of symmetry aspects of the chosen meshes on instability behaviors are discussed, as are the effects of parameters.QC 20170616
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Skryabin, Dmitry Vladimirovich. "Modulational instability of optical solitary waves." Thesis, University of Strathclyde, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366995.
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Taute, Katja. "Microtubule mechanics and the implications for their assembly." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-86861.
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Microtubules are cytoskeletal protein polymers relevant to a wide range of cell functions. In order to polymerize, the constituent tubulin subunits need to bind the nucleotide GTP, but its subsequent hydrolysis to GDP in the microtubule lattice induces depolymerization. The resulting behaviour of stochastic switching between growth and shrinkage is called dynamic instability. Both dynamic instability and microtubule mechanical properties are integral to many cell functions, yet are poorly understood.
The present study uses thermal fluctuation measurements of grafted microtubules
with different nucleotide contents to extract stiffnesses, relaxation times, and drag coefficients with an unprecedented precision. Both the stiffness and the relaxation time data indicate that stiffness is a function of length for GDP microtubules stabilized with the chemotherapy drug taxol. By contrast, measurements on microtubules polymerized with the non-hydrolizable GTP-analogue GMPCPP show a significantly higher, but constant, stiffness. The addition of taxol is shown to not significantly affect the properties of these microtubules, but a lowering of the GMPCPP content restores the length-dependent stiffness seen for taxol microtubules.
The data are interpreted on the basis of a recent biopolymer model that takes into account the anisotropic architecture of microtubules which consist of loosely coupled protofilaments arranged in a tube. Using taxol microtubules and GMPCPP microtubules as the respective analogues of the GDP and GTP state of microtubules, evidence is presented that shear coupling between neighbouring protofilaments is at least two orders of magnitude stiffer in the GTP state than in the GDP state. Previous studies of nucleotide effects on tubulin have focussed on protofilament bending, and the present study is the first to be able to show a dramatic effect on interprotofilament bonds. The finding’s profound implications for dynamic instability are discussed.
In addition, internal friction is found to dominate over hydrodynamic drag for microtubules shorter than ∼ 4 μm and, like stiffness, to be affected by the bound nucleotide, but not by taxol.
Furthermore, the thermal shape fluctuations of free microtubules are imaged, and the intrinsic curvatures of microtubules are shown for the first time to follow a spectrum reminiscent of thermal bending. Regarding the extraction of mechanical data, this assay, though previously described in the literature, is shown to suffer from systematic flaws.
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Schneider, Alexandra Patrizia. "Aerodynamic and aeroelastic investigation of a composite fan for ultra-high-bypass-ratio aircraft engines." Electronic Thesis or Diss., Ecully, Ecole centrale de Lyon, 2024. http://www.theses.fr/2024ECDL0018.
Full textAbstract:
Les fans modernes à faible vitesse de rotation à très haut taux de dilution (Ultra-High Bypass Ratio, UHBR) opèrent principalement sur la partie plate de la caractéristique de compression, ont des lon-gueurs de l'entrée d'air plus courtes et sont constitués d'aubes en composites flexibles et légères. Ces changements favorisent l'évolution de différents types d'instabilités avec des interactions multi-physiques telles que les vibrations non-synchrones convectives (NSV). Pour permettre de nouvelles avancées technologiques, des données de référence expérimentales sur des géométries représenta-tives sont nécessaires. Dans ce contexte, le projet européen CATANA a été initié à l'Ecole Centrale de Lyon. Le fan ECL5 a été conçu comme une configuration ouverte selon les directives industrielles et testé expérimentalement sur le banc d'essai ECL-B3. Cette thèse présente les résultats expérimen-taux du projet CATANA. L'investigation expérimentale de la configuration de référence ECL5 montre que les objectifs de conception ont été atteints. La machine est opérationnelle sur une large plage de fonctionnement et les performances aérodynamiques au point de design coïncident exactement avec les prédictions numériques. En revanche, les mécanismes d'instabilité sont plus complexes que ceux prédits. Par l'application d'une instrumentation multi-physique synchronisée, l'interaction fluide-structure complexe impliquée est résolue. L'analyse de l'influence des conditions d'entrée et de la symétrie géométrique et structurel du système permet d'identifier la sensibilité des caractéristiques aérodynamiques et structurelles ainsi que du comportement près de la limite de stabilité. L'investiga-tion d'une deuxième configuration de rotor présentant un désaccordage structurel met en lumière l'importance des variations géométriques d'aube à aube. Elles provoquent une asymétrie du champ aérodynamique en tête d'aube et suppriment des perturbations aérodynamiques se propageant de manière cohérente, retardant le NSV. Les résultats présentés dans cette thèse offrent une caractéri-sation complète du fan ECL5 et servent de jeu de données de référence pour la validation des simula-tions numériquesModern low-speed Ultra-High Bypass Ratio (UHBR) fans operate predominantly on the flat part of the compression characteristic, have shorter intake lengths, and employ flexible, lightweight, composite blades. These changes promote the evolution of different types of instabilities with multi-physical interactions such as convective non-synchronous vibration (NSV). To enable further technological ad-vancements, experimental benchmark data on representative geometries required. Within this con-text, the European project CATANA was initiated at Ecole Centrale de Lyon. The open-test-case fan stage ECL5 was designed, following industrial guidelines, and tested experimentally on the facility ECL-B3. This thesis presents the experimental results of the CATANA project. The experimental investiga-tion of the ECL5 reference configuration shows that all design goals have been reached. The machine is operational in a wide range and aerodynamic performance at design condition is exactly coincident with the numerical prediction. In contrast, instability mechanisms are more complex than predicted by the employed numerical methods. Through application of synchronized multi-physical instrumenta-tion, the involved complex fluid-structure interaction is resolved. The analysis of the influence of in-flow conditions and geometrical and structural system symmetry allows to identify the sensitivity of aerodynamic and structural characteristics and the behavior close to the stability limit. The investiga-tion of a second rotor configuration featuring structural mistuning highlights the importance of geo-metrical blade-to-blade variations. They cause an asymmetry of the aerodynamic field at the blade tip and suppress coherently propagating aerodynamic disturbances resulting in a delayed onset of NSV. The results presented in this thesis provide a comprehensive multi-physical characterization of the ECL5 fan stage and serve as a benchmark data set for the validation of numerical simula-tions
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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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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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Pitayu, Laras. "Mitochondrial Disorders Linked to mtDNA instability : From Therapy to Mechanism." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA112233.
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L’instabilité d’ADN mitochondrial (ADNmt) peut être quantitative avec la déplétion de l’ADNmt ou qualitative avec des délétions de l’ADNmt. Ces anomalies sont une des causes les plus commmunes des maladies mitochondriales. Un des gènes qui contrôle la stabilité et le maintien de l’ADNmt est POLG. Ce gène code pour la polymerase gamma mitochondriale. Chez l’homme, les mutations dans le gène POLG sont liées aux maladies mitochondriales telle que; l’insuffisance hépatique, le syndrome d’Alpers, le PEO ou Progressive External Ophtalmoplegia, la neuropathie sensorielle et l’ataxie. Des mutations dans le gène POLG sont aussi associées au syndrome de Parkinson. Aujourd’hui, il n’existe aucune thérapie pour ces maladies. Compte tenu de la conservation évolutive de la fonction mitochondriale de la levure à l’homme, nous avons utilisé deux organismes modèles, Saccharomyces cerevisiae et Caenorhabditis elegans, pour identifier des molecules chimiques capables de compenser l’instabilité de l’ADNmt liée à des mutations du gène POLG dans des fibroblastes d’un patient. Nous avons trouvé trois molécules candidates potentielles: MRS2, MRS3 et MRS4, à partir d’un criblage primaire chez la levure, en utilisant une chimiothèque d’environ 2000 molécules chimiques. MRS3 est la molécule candidate la plus efficace pour la stabilization d’ADNmt chez des mutants POLG de la levure, du champignon filamenteux, du nématode et sur des fibroblastes de patients. MRS3, ou clofilium tosylate (CLO), est un agent antiarrhytmique, médicament pour soigner les troubles du rythme cardiaque. Dans cette étude, nous avons aussi montré que deux autres antiarrhythmiques appartenant à la même classe que CLO avaient un effet positive chez un mutant POLG de C. elegans. En utilisant une approche de chemogénomique chez la levure, nous avons identifié Fis1, un acteur de la fission mitochondriale qui pourrait être impliqué dans la mode d’action de CLO. Fis1 est requise pour la viabilité cellulaire en concentration légèrement toxique de CLO et nécesaire pour la stabilization de l’ADNmt par CLO. L’ensemble de ces résultats ont montré que CLO pourrait être la première molécule chimique qui stimule la réplication de l’ADNmt et qui pourrait être développée pour le traitement des maladies liées à des mutations dans le gène POLG. Ces résultats ont aussi permis de mettre en évidence une nouvelle connexion entre replication de l’ADNmt et la fission mitochondrialeThe instability of mitochondrial DNA (mtDNA) in form of mtDNA depletion (quantitative instability) or large deletion (qualitative instability) is one of the most common cause of mitochondrial diseases.. One of the genes responsible for human mtDNA stability, POLG, is exploited in this study. POLG encodes the human mitochondrial polymerase gamma. In human, POLG mutations are a major cause of mitochondrial disorders including hepatic insufficiency; Alpers syndrome, progressive external ophthalmoplegia, sensory neuropathy and ataxia. They are also associated with Parkinsonism. Currently, there is no effective and disease-specific therapy for these diseases. Based on the conservation of mitochondrial function from yeast to human, we used Saccharomyces cerevisiae and Caenorhabditis elegans as first pass filters to identify chemical compounds that suppresses mtDNA instability in cultured fibroblasts of a POLG-deficient patient. We found three potential candidates, MRS2, MRS3 and MRS4, from a chemical screening of nearly 2000 compounds in yeast. MRS3 is the most efficacious in stabilizing mtDNA in yeast, filamentous fungi, worm and patient fibroblasts. This unsuspected compound, clofilium tosylate (CLO), belongs to a class of antiarrhythmic agents for cardiovascular disease. Two other antiarrhythmic agents (FDA-approved) sharing common pharmacological properties and chemical structure with CLO also show potential benefit for POLG deficiency in C. elegans. Using a chemogenomic approach in yeast, we also discovered that a mitochondrial fission actor Fis1 is implicated in the mechanism of action of CLO. Fis1 is important for cellular viability in a slightly toxic concentration of CLO and is required for the mtDNA stabilizing potency of CLO. Our findings provide evidence of the first mtDNA-stabilizing compound that may be an effective pharmacological alternative for the treatment of POLG-related diseases and uncover a new connection between the mitochondrial fission process and mtDNA replication
Ketidakstabilan DNA mitokondria (mtDNA) dalam bentuk pengurangan kopi mtDNA di dalam sel (ketidakstabilan kuantitatif), atau pun dalam bentuk delesi pada sekuens mtDNA (ketidakstabilan kualitatif) merupakan salah satu penyebab penyakit mitokondria. Salah satu gen yang bertanggung jawab dalam menjamin kestabilan mtDNA adalah POLG. Gen POLG mengkode protein polimerase gamma pada manusia, yang mereplikasi dan mereparasi mtDNA di dalam mitokondria. Mutasi pada gen POLG dapat menyebabkan penyakit kelainan mitokondria pada manusia, seperti gagal ginjal, sindrom Alpers, Progressive External Ophtalmoplegia, neuropati sensorial, ataxia dan bisa dikaitkan dalam beberapa gejala Parkinsonisme. Saat ini, belum ada terapi obat yang dapat mengatasi penyakit – penyakit tersebut. Berdasarkan kesamaan evolutif dari ragi hingga manusia, pada studi ini kami menggunakan Saccharomyces cerevisiae dan Caenorhabditis elegans untuk mengidentifikasi molekul obat yang berpotensi mengatasi ketidakstabilan mtDNA dari fibroblas pasien manusia yang memiliki mutasi gen POLG. Kami mengidentifikasi tiga kandidat potensial, yakni MRS2, MRS3 dan MRS4 dari penapisan kurang lebih 2000 molekul obat dengan menggunakan ragi. MRS3 adalah kandidat yang paling berkhasiat dan mampu mengatasi ketidakstabilan mtDNA pada ragi, Podospora, cacing dan fibroblas manusia. MRS3 adalah alias bagi clofilium tosylate (CLO), sebuah molekul antiaritmia untuk penyakit kardiovaskuler. Pada studi ini, kami juga menguji aktifitas dua molekul antiaritmia lain yang tergabung dalam kelas yang sama dengan CLO, dan menemukan bahwa kedua molekul ini juga berpotensi mengatasi defisit POLG pada cacing C. elegans. Dengan menggunakan metode kemogenomik pada ragi, kami juga mengidentifikasi sebuah aktor prosesus pembelahan mitokondria, Fis1, yang berpotensi terlibat dalam mekanisme seluler CLO. Fis1 dibutuhkan untuk: (1) kelangsungan hidup ragi pada konsentrasi toksik CLO dan (2) efek CLO dalam menstabilkan mtDNA pada ragi. Keseluruhan studi ini membuktikan potensi CLO sebagai molekul penstabil mtDNA yang pertama, yang dapat dikembangkan sebagai salah satu alternatif terapi obat untuk penyakit – penyakit mitokondria terkait mutasi POLG. Melalui studi ini, juga diungkap adanya hubungan antara kestabilan mtDNA dan prosesus pembelahan mitokondria