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Santos, Tapia Celia. "Understanding chromosomal instability-induced senescence." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/671915.
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Aneuploidy, defined as a chromosome number that deviates from a multiple of the haploid set, is a common feature in human cancer, and around 70% of human solid tumours are aneuploid. The resulting metabolic imbalance is proposed to play a fundamental role in the compromised fitness of these cells and lead to malignant transformation by causing proteotoxic stress and affecting cell cycle proliferation and growth. However, most of the molecular pathways and cellular behaviours underlying aneuploid-induced tumorigenesis remain uncharacterized. Drosophila larval epidermal primordia have proved useful model systems to demonstrate the contribution of aneuploidy-induced metabolic stress to tumour growth. By depleting different Spindle Assembly Checkpoint (SAC) genes in the epithelial cells, we induce chromosomal instability and generate aneuploidy. When prevented from undergoing programmed cell death (PCD), these cells give rise to a neoplasic overgrowth. Here we propose that CIN-induced aneuploidy in epithelial cells activates low levels of the c-Jun N-terminal kinase (JNK) and the DNA damage response (DDR). This induces a G1 stall that prevents the accumulation of damage. However, when due to CIN these cells become highly aneuploid, they delaminate from the epithelium and acquire a senescent behaviour. This senescent behaviour is dependent on high levels of JNK and DDR signalling, and induce the secretion of wide variety of factors - also known as the senescence-associated secretory phenotype (SASP) -, and a permanent G2 arrest, among other senescent features. In addition, we have identified two target effectors, Fizzy-related and String, that are miss-regulated and could act downstream JNK and the DDR to induce the G2 arrest. Finally, we were able to explore two different ways to target CIN-aneuploid cells based on their basal levels of replicative stress: genetic (CycE/Dap overexpression) and chemical (Hydroxyurea), which significantly affect tissue growth and impair tumour progression.La aneuploidía, que se define como un número de cromosomas diferente al haploide, es una característica muy común en cáncer ya que se encuentra en alrededor de 68% de los tumores sólidos. Esta resulta en un desequilibrio metabólico que compromete la función celular induciendo estrés proteotóxico y afectando el crecimiento celular, dando lugar a así a una transformación maligna de estas células. Sin embargo, muchos de los mecanismos moleculares detrás de esta transformación generada por la aneuploidía son aún desconocidos. En este trabajo, usamos el epitelio del ala de Drosophila como tejido modelo para demostrar la contribución de la aneuploidía al crecimiento tumoral. Mediante la inhibición de genes del checkpoint del huso mitótico, inducimos inestabilidad cromosómica y aneuploidía que, tras bloquear la muerte celular, da lugar a un sobrecrecimiento tumoral. Cuando las células no tienen aún altos niveles de aneuploidía, activan bajos niveles de la quinasa c-Jun N-terminal (JNK) y activan la respuesta a daño en el DNA (DDR). Esto induce un arresto temporal en G1 que previene la acumulación de más daño. Sin embargo, debido a la inestabilidad cromosómica, estas células continúan proliferando y acumulan altos niveles de aneuploidía, delaminan del epitelio y adquieren un comportamiento senescente. Este depende de la activación de altos niveles de JNK y la DDR y tiene como consecuencia la secreción de distintos factores (SASP) y un arresto permanente en G2, entre otras características senescentes. Además, hemos podido identificar dos factores involucrados en el arresto, Tribbles and String, que podrían actuar en respuesta a JNK y a la DDR para hacer efectivo el arresto en G2. Finalmente, exploramos dos maneras distintas de afectar los tumores CIN aprovechando que sufren daño en el DNA: genéticamente (mediante la sobre-expresión de CycE/Dap) y químicamente (mediante el tratamiento con hidroxiurea), afectando ambas el crecimiento del tejido e inhibiendo la progresión tumoral.
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Papadopoulou, Charikleia. "Replication stress-induced epigenetic instability." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708935.
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Li, Maoxin. "Seepage induced instability in widely graded soils." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/862.
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Internal instability of a widely graded cohesionless soil refers to a phenomenon in which its finer particles migrate within the void network of its coarser particles, as a result of seepage flow. Onset of internal instability of a soil is governed by a combination of geometric and hydromechanical constraints. Much concern exists for embankment dams and levees built using soils with a potential for internal instability. Migration of finer particles to a boundary where they can exit, by washing out, may cause erosion or piping failure and, occasionally, induce collapse of these soil structures. There is a need, in professional practice, to better understand the phenomenon and to develop improved methods to evaluate the susceptibility of a soil.
A series of permeameter tests was performed on six widely-graded cohesionless materials. The objectives are to assess the geometric indices proposed for evaluation of susceptibility, and examine hydromechanical factors influence the onset of internal instability. A modified slurry mixing technique, with discrete deposition, was found satisfactory for reconstitution of the homogeneous saturated test specimens. The onset of internal instability was founded to be triggered by a combination of effective stress and hydraulic gradient. The finding yields a hydromechanical envelope, unique for a particular gradation shape, at which internal instability initiated.
Three commonly used geometric criteria were comprehensively evaluated with reference to these experimental data and also a database compiled from the literature. The relative conservatism of each criterion was examined and a modified semi-empirical geometric rule then proposed based on the capillary tube model. A theoretical framework for plotting the hydromechanical envelope was established based on an extension of the α concept of Skempton and Brogan, and subsequently verified by test data. Finally, a novel unified approach was proposed to assess the onset of internal instability, based on combining geometric and hydromechanical indices of a soil.
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Krivets, V. V., K. J. Ferguson, and J. W. Jacobs. "Turbulent mixing induced by Richtmyer-Meshkov instability." AMER INST PHYSICS, 2017. http://hdl.handle.net/10150/625211.
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Richtmyer-Meshkov instability is studied in shock tube experiments with an Atwood number of 0.7. The interface is formed in a vertical shock tube using opposed gas flows, and three-dimensional random initial interface perturbations are generated by the vertical oscillation of gas column producing Faraday waves. Planar Laser Mie scattering is used for flow visualization and for measurements of the mixing process. Experimental image sequences are recorded at 6 kHz frequency and processed to obtain the time dependent variation of the integral mixing layer width. Measurements of the mixing layer width are compared with Mikaelian's [1] model in order to extract the growth exponent. where a fairly wide range of values is found varying from theta approximate to 0.2 to 0.6.
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Pornprompanya, Methasit. "Instability of excitation waves induced by electrical fields." [S.l. : s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975449834.
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Ivanochko, Danton. "ATRX Protects Cells Against Replication-Induced Genomic Instability." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/35123.
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Expansive proliferation of neural progenitor cells (NPCs) is a prerequisite to the temporal waves of neuronal differentiation that generate the six-layered cerebral cortex. NPC expansion places a heavy burden on proteins that regulate chromatin packaging and genome integrity, which is further reflected by the growing number of developmental disorders caused by mutations in chromatin regulators. Accordingly, mutations in ATRX, a chromatin remodelling protein required for heterochromatin maintenance at telomeres and simple repeats, cause the ATR-X syndrome. Here, we demonstrate that proliferating ATRX-null cells accumulate DNA damage, while also exhibiting sensitivity to hydroxyurea-induced replication fork stalling. Specifically, PARP1 hyperactivation and replication-dependent double strand DNA breakage indicated replication fork protection defects, while DNA fiber assays confirmed that ATRX was required to protect replication forks from degradation. Interestingly, inhibition of the exonuclease MRE11 by the small molecule mirin could prevent degradation. Thus, ATRX is required to limit replication stress during NPC expansion.
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Hosseini, Seyed M., Ardeshir Hanifi, and Dan Henningson. "Effect of freestream turbulence on roughness-induced crossflow instability." KTH, Stabilitet, Transition, Kontroll, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-123192.
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The effect of freestream turbulence on generation of crossflow disturbances over swept wings is investigated through direct numerical simulations. The set up follows the experiments performed by Downs et al. in their TAMU experi- ment. In this experiment the authors use ASU(67)-0315 wing geometry which promotes growth of crossflow disturbances. Distributed roughness elements are locally placed near the leading edge with a span-wise wavenumber, to ex- cite the corresponding crossflow vortices. The response of boundary layer to external disturbances such as roughness heights, span-wise wavenumbers, Rey- nolds numbers and freestream turbulence characteristics are studied. It must be noted that the experiments were conducted at a very low level of freestream turbulence intensity (T u). In this study, we fully reproduce the freestream isotropic homogenous turbulence through a DNS code using detailed freestream spectrum data provided by the experiment. The generated freestream fields are then applied as the inflow boundary condition for direct numerical simulation of the wing. The geometrical set up is the same as the experiment along with application of distributed roughness elements near the leading edge to precipi- tate stationary crossflow disturbances. The effects of the generated freestream turbulence are then studied on the initial amplitudes and growth of the bound- ary layer perturbations. It appears that the freestream turbulence damps out the dominant stationary crossflow vortices.QC 20130604
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Al-Mayah, Ammar Hassan Jasim. "Radiation-induced genomic instability and cellular communication : mechanistic investigations." Thesis, Oxford Brookes University, 2012. https://radar.brookes.ac.uk/radar/items/573581b4-6468-4c41-8fab-17bfdcf489d6/1/.
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Communication between irradiated and un-irradiated (bystander) cells can cause damage in cells that are not directly targeted by ionizing radiation (IR); a process known as the bystander effect (BE). BE can also lead to genomic instability GI) within the progeny of bystander cells, similar to the progeny of directly irradiated cells. The molecular factors that mediate this cellular communication can be transferred between cells via gap junctions or be released into the extracellular media/microenvironment of cells and tissue following irradiation. Although GI is thought to be a critical step in the onset and progression of cancer, BE response contributions in such processes are still not clear. Therefore, this study was designed to investigate the risks or benefits associated with the induction of non-targeted effects especially BE following exposure to low LET X-ray radiation using two different cell types. Additionally, the project aims to achieve an increased understanding of the mechanisms of non-targeted effects of ionizing radiation by examining the molecular signalling via exosomes within the irradiated, bystander and progeny of irradiated and bystander cell population. Different cell combinations were established between tumour (MCF7) and nontumour (HMT-3522S1) human breast epithelial cells using a 6-well plate co-culture system. The cells were irradiated with two doses of X-ray; 0.1 Gy (a diagnostic procedure relevant dose) and 2 Gy (therapeutic dose) and a sham-irradiation dose of 0 Gy (for control groups of experiment). The co-culturing time was 4 hours for all cell combination, whereupon a media transfer approach as used to induce BE within the cells in the exosome part of this study. The early and late cellular damage responses were evaluated by the following biological endpoints: cytogenetic/chromosomal analysis, apoptotic analysis, telomere length and telomerase activity measurements. In addition to these biological endpoints, the comet assay was utilised to estimate the initial and delayed DNA damage within the cells that had been treated with exosomes, previously extracted from the irradiated, bystander and control cell media. The results showed that 2 Gy direct irradated MCF7 and HMT cells were both able to induce early and late chromosomal damage in the bystander MCF7 and HMT cells. Furthermore, these bystander cells exhibited early and delayed telomeric instability, which could prompt further GI at later time-points. In comparison, 0.1 Gy direct irradiated MCF7 cells were only able to induce initial and delayed chromosomal damage within the bystander MCF7, which also demonstrated a high level of telomeric instability at early and late time-points. While, bystander HMT cells did not show chromosomal damage after 1, 12 and 24 generations/population doublings following co-culture with 0.1 Gy direct irradiated MCF7 or HMT cells. 0.1 Gy bystander HMT cells did reveal a high level of apoptosis at early and late time points, which might be due the removal of cells with a high level of chromosomal damage. Interestingly, the 0.1 Gy bystander HMT cells exhibited significant levels of telomeric instability at early and late time points, which could contribute to chromosomal instability at later time-points. The investigation in to the mechanisms of molecular signalling via exosomes showed that the exosomes of irradiated cell conditioned media (ICCM) from MCF7 cells had the ability to induce BE within MCF7 and HMT cells similar to the effects of ICCM following 2 Gy X-ray. The exosomes that were isolated from the MCF7 bystander cell media had a similar effect as the ICCM on the MCF7 and HMT bystander cells. These exosome-bystander cells also showed GI within their progeny after 24 generations and retained the ability to induce cellular damage to fresh un-irradiated MCF7 cells, demonstrating an underlying mechanism for propagating the delayed damage responses. The inhibition of the exosome’s cargo molecules by RNase treatment and protein denaturating (boiling of exosmes) significantly abrogated BE and GI in both MCF7 and HMT bystander cells following 2 Gy X-ray. Thus data demonstrated crucial roles for exosome RNA and protein molecules in the non-targeted effects of IR induction. In summary, our investigations demonstrate that BE has detrimental consequences within the tumour and non-tumour breast epithelial cells (MCF7 and HMT3522S1) following low and high doses of X-ray irradiation, and these detrimental consequences are frequently mediated by exosomes that contain RNA and protein molecules. Inhibition of these molecules can abrogate BE and GI following a radiotherapy dose, which can potentially have an application in clinical radiotherapy.
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Bright, Scott James. "The role of lysosomes in radiation induced genomic instability." Thesis, Oxford Brookes University, 2013. https://radar.brookes.ac.uk/radar/items/a72f01e0-a29b-41a8-ad4c-e54ae04ed7ee/1/.
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Our understanding of ionizing radiation and its associated biological effects has recently under- gone a paradigm shift from a DNA-centric model to one inclusive of non-targeted effects (NTE), so called for the lack of direct radiation interaction with DNA. Two effects encompassed within the NTE paradigm are termed genomic instability (GI) and bystander effects (BE). GI can be described as an increase in rate of genetic alterations many cell generations after the initial radi- ation exposure. BE can be defined as the manifestation of radiation like effects in un-irradiated cells that have communicated with cells that have been irradiated either through inter-signalling utilising gap junctions or the secretion of a soluble diffusion signalling factor. The exact mechanisms that underlie these processes are still under investigation but a wealth of evidence suggests that a number of mechanisms are involved. These include; cytokine signalling, oxidative stress, inflammation and sub-cellular alterations, in addition to factors such as genetic background and radiation quality/dose. This study was designed to investigate lysosomal involvement in radiation induced NTE, whether it be downstream of one of the above mentioned mechanisms, or independent of their involve- ment. To this end the primary human fibroblast cell line, HF19, was exposed to X-rays at therapeutic and diagnostic doses of 2 and 0.1 Gy respectively. Bystander groups were also established by media transfer techniques. Cells were analysed over the first 24 hours and then at 1 and 20 population doublings, initially for detection of GI and BE and thus confirm the suitability of the system. The lysosomes were then analysed for permeability and their distri- bution within the cell. Oxidative stress was also measured in a bid to correlate this event with lysosomal perturbations. Finally lysosomal contents, in particular DNaseIIα, were analysed for their cellular location along with analysis of nuclear membrane permeability which we surmised would facilitate the redistribution of lysosomal enzymes. The results demonstrated that HF19 cells were susceptible to the induction of GI and BE. The latter was noted within the first hour following irradiation in both 0.1 and 2 Gy bystander groups. High levels of chromosomal instability were also induced in both 0.1 and 2 Gy directly irradiated groups, 1 population doubling after exposure. Chromosomal instability was still noted at 20 population doublings mainly in the 2 Gy although the 0.1 Gy group did show elevated levels. A similar pattern was observed in the bystander group. However we were unable to detect sustained production of the bystander signal at 20 population doublings. Lysosomal properties were also characterised and measured at corresponding time points; large alterations were observed in the first 24 hours following irradiation, furthermore, the lysosomes appeared more permeable at 20 population doublings especially in bystander groups, however, these changes did not correlate with increases in oxidative stress. As a result we further exam- ined cells for changes in the distribution of lysosomal enzymes, in particular DNaseIIα, however no significant changes were observed. Nuclear permeability was additionally investigated as to whether increased permeability facilitated enzyme redistribution; however permeability ap- peared reduced rather than increased. In summary, our investigations have demonstrated and confirmed that HF19 cells are susceptible to the induction of GI and BE following low LET X-ray exposure. The results suggest that the mechanism of radiation induced GI and BE responses can be correlated with alterations in lysosomal membrane permeability which appears independent of oxidative stress. We also demonstrated that if lysosomes are involved in NTE it is unlikely to be through direct action of DNaseIIα but rather from enzymes such as acid sphingomylinase. To conclude, radiation was able to alter lysosomes and nuclear permeability at delayed time points which was correlated with GI , however it appears DNaseIIα is not involved. It also appears that an early effect of the bystander signal may have antioxidant property.
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Kim, Hyun-Min. "Genome instability induced by triplex forming mirror repeats in S.cerevisiae." Diss., Georgia Institute of Technology, 2009. http://hdl.handle.net/1853/33874.
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The main goal of this research is to understand molecular mechanisms of GAA/TTC-associated genetic instability in a model eukaryotic organism, S. cerevisiae. We demonstrate that expanded GAA/TTC repeats represent a threat to eukaryotic genome integrity by triggering double-strand breaks and gross chromosomal rearrangements. The fragility potential strongly depends on the length of the tracts and orientation of the repeats relative to the replication origin and to block replication fork progression. MutSbeta complex and endonuclease activity of MutLalpha play an important role in facilitation of fragility. In addition to GAA/TTC triplex forming repeats, non-GAA polypurine polypyrimidine mirror repeats that are prone to the formation of similar structures were found to be hotspots for rearrangements in humans and other model organisms. These include H-DNA forming sequences located in the major breakpoint cluster region at BCL2, intron 21 of PKD1, and promoter region of C-MYC. Lastly, we have investigated the effect of the triplex-binding small molecules, azacyanines, on GAA-mediated fragility using the chromosomal arm loss assay. We have found that in vivo, azacyanines stimulate (GAA/TTC)-mediated arm loss in a dose dependent manner in actively dividing cells. Azacyanines treatment enhances the GAA-induced replication arrest. We discovered that also, azacyanines at concentrations that induce fragility also inhibit cell growth. Over 60% of yeast cells are arrested at G2/M stage of the cell cycle. This implies an activation of DNA-damage checkpoint response.
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Miraskari, Seyed Mohammad. "Identification of the fluid induced instability phenomenon in journal bearings." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61283.
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The demand for high pressure injection of natural gas in underground has been an incentive for a growing interest in the design and manufacture of multistage compressors. Many of such compressors suffer from violent sub-synchronous whirl. If the spin-speed of the rotors exceed the “threshold speed of instability,” the rotor-bearing system experiences sub-synchronous whirling known as oil whirl/whip. For rotors supported on journal bearings, oil whirl is the most common cause of instability. Existing models fall short in predicting the nature of sub-synchronous instabilities in journal bearings with a finite length. In this thesis, a new nonlinear rotor-bearing model is introduced to characterize the phenomenon of oil whirl for rotors supported on finite length journal bearings.
As a first step in constructing a rotor-bearing model, this research introduces a modified scheme for performance predictions of cavitated journal bearings. The resulting algorithms are then used throughout the thesis to obtain solutions to the Reynolds equation in original and perturbed form in order to calculate journal induced pressure and pressure gradients. The pressure gradients are used as a basis for the calculation of bearing linear and nonlinear dynamic coefficients. Dynamic coefficients are widely used to represent the journal bearing reaction forces exerted on the rotating shaft. These coefficients are implemented to construct mathematical models of the system that are suitable for studying dynamics and stability. Analytical treatments are introduced wherever possible to provide a means for verification purposes.
The linear and nonlinear stability of flexible shafts supported on finite length journal bearings is studied. As linear models are not suitable for bifurcation analysis, a simple yet versatile nonlinear rotor-bearing model is proposed such that the journal force is represented by first and higher order dynamic coefficients. Results show that the implementation of nonlinear coefficients can enable the application of nonlinear analysis methods. Nonlinear stability analysis is carried out by implementing a variety of techniques including the Hopf bifurcation theorem and eigenvalue analysis of the Monodromy matrices. The versatility of the techniques used made it possible to study the existence and directions of Hopf bifurcations for rotors supported on finite length journal bearings.Applied Science, Faculty of
Mechanical Engineering, Department of
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Whiteside, James Roy. "Persistent genomic instability and bystander effects induced by ultraviolet radiation." Thesis, Lancaster University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444640.
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Schalbetter, Stephanie. "Genome instability induced by structured DNA and replication fork restart." Thesis, University of Sussex, 2012. http://sro.sussex.ac.uk/id/eprint/38853/.
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DNA replication is a central mechanism to all forms of life. Errors occurring during DNA replication can result in mutagenesis and genome rearrangements, which can cause various diseases. In this work I have investigated the stability of direct tandem repeats (TRs) in the context of replication and replication-associated repair mechanisms. During DNA replication the replication fork encounters many obstacles, such as DNA-protein barriers, secondary DNA structures and DNA lesions. How and if replication resumes or restarts in these circumstances in order to complete genome replication is not well understood and the fidelity of replication in response to such obstacles remains unclear. I have developed TR assays to assess replication errors in the context of replication fork restart and secondary structures. The results suggest that structured DNA (G4) can cause instability of TRs in the context of normal replication and that restarted replication can be intrinsically error-prone. Surprisingly, the mutagenic effect of G4-DNA on TR stability was not elevated in the context of replication fork restart. Therefore, deletions of TRs containing G4-DNA are not more susceptible to the compromised fidelity of a restarted replication fork. Structures such as stalled replication forks can induce checkpoint responses to maintain genome stability. The stabilisation of replication forks is central in the response to replication stress. These protective mechanisms include the regulation of enzymatic activities. Mus81-Eme1 is a structure-specific endonuclease which is regulated by the DNA replication checkpoint, but has also been shown to be required for replication fork restart in certain circumstances. In collaboration with Professor Neil McDonald I analysed a novel domain identified in Mus81-Eme1. Mutagenesis of key residues deduced from the protein structure and comparison of their genetic analysis to known phenotypes of Mus81-Eme1 suggests distinct requirements for this domain.
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Novoa, Carolina. "RecQ-like helicase SGS1 counteracts DNA : RNA hybrid induced genome instability." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/60964.
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Dividing cells are constantly under threat from both endogenous and exogenous DNA damaging stresses that can lead to mutations and structural variations in DNA. One contributor to genome instability is three-stranded DNA:RNA hybrid structures called R-loops. Though R-loops are known to induce DNA damage and DNA replication stress, it is unclear whether they are recognized and processed by an established DNA repair pathway prior to inducing DNA breaks. Canonically, DNA repair proteins work downstream of R-loop-induced DNA damage to stimulate repair and suppress genome instability. Recently, the possibility that some DNA repair pathways actively destabilize R-loops, thus preventing unscheduled DNA damage has emerged. Here we identify the helicase SGS1 as a suppressor of R-loop stability. Our data reveals that SGS1 depleted cells accumulate R-loops. In addition, we define a role for transcription in genome instability of cells lacking SGS1, which is consistent with an R-loop based mechanism. Hyper-recombination in SGS1 mutants is dependent on transcript length, transcription rate, and active DNA replication. Also, rDNA instability in sgs1Δ can be suppressed by ectopic expression of RNaseH1, a protein that degrades DNA:RNA hybrids. Interestingly, R-loops are known to form at rDNA loci. We favour a model in which SGS1 contributes to the stabilization of stalled replication forks associated with transcription complexes, and unresolved DNA:RNA hybrids. Finally, we showed that knockdown of the human Sgs1 orthologue BLM in HCT116 cells also led to the accumulation of more R-loops than control HCT116 cells. In summary, our data supports the idea that some DNA repair proteins involved in replication fork stabilization might also prevent and process R-loops.Science, Faculty of
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Crawford-Flett, Kaley A. "An improved hydromechanical understanding of seepage-induced instability phenomena in soil." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46709.
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Barber, Ruth Caroline. "Radiation-induced instability at mouse expanded simple tandem repeat (ESTR) loci." Thesis, University of Leicester, 2002. http://hdl.handle.net/2381/34456.
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Expanded Simple Tandem Repeat (ESTR) loci provide a useful system to assess the effect of exposure to ionising radiation on the germline of male mice; however, little is known about the mutation mechanism(s) at these loci. Information about mutation processes at these loci may provide important clues concerning the damaging effects of irradiation at the DNA level. A number of approaches have been used to investigate possible mutation mechanisms. No correlation was observed between the levels of meiotic recombination and ESTR mutation rate in the germline of exposed male mice, ruling out the possibility that radiation induced mutation at ESTR loci resulted from an increase in meiotic crossing-over. The analysis of the murine scid mutation on ESTR mutation rate demonstrated that the process of non-homologous end-joining (NHEJ) is important in the stability of ESTR loci in the germline of non-exposed mice, but was unable to ascertain whether the activation of NHEJ could provide a plausible explanation for radiation-induced increases in ESTR mutation rate. A transgenerational study of the descendants of directly exposed male mice provided evidence for a long-term effect of ionising radiation on ESTR stability in the mouse germline. ESTR instability was observed in the germline of the offspring and grandoffspring of the initially irradiated males, with no evidence for a decrease in mutation rate. This analysis also provided additional information about the inheritance of ESTR instability in the mouse germline, demonstrating the possibility that the transmission of instability was epigenetic in nature, and showing that the effect could be observed after exposure to both high- or low-LET sources of irradiation. The data also showed transgenerational effects in three different mouse strains, and that there were no differences in the inheritance of ESTR instability between the male and female germlines. The work presented here provides the basis for a number of new and exciting directions to further analyse radiation-induced mutation at ESTR loci.
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Guo, Zenglin. "Morton Effect Induced Instability in Mid-Span Rotorâ Hydrodynamic Bearing Systems." Diss., Virginia Tech, 2011. http://hdl.handle.net/10919/37923.
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The Morton Effect in the rotor - bearing systems may lead to an unstable operation. Up to the present, most of the established research efforts have been focused on the overhung rotor systems. In this dissertation, a systematic study on the Morton Effect induced instability in mid-span rotor systems is presented.
First, the mechanism study is conducted. The simplified rotor models with isotropic linear bearing supports are adopted for the derivation of analytical expressions. The threshold speeds of instability in simple forms are obtained for the systems with the thermal imbalance acting concurrent with or perpendicular to the direction of the response displacement. For a perspective view of the system stability, a stability map for the damped rigid mid-span rotors with the thermal imbalance having arbitrary phase difference has been generated. It shows that the stable operating regions of the system are bounded by two curves of threshold of instability. The results show that the Morton Effect induced instability thresholds are actually affected by both the magnitude and relative phase of the thermal imbalance. The mechanism of the Morton Effect induced thermal instability of mid-span rotors supported by linear isotropic bearings can be explained through the fact that the Morton Effect introduces either negative stiffness or negative cross-coupled stiffness.
Next, the steady-state response performance under the influence of the Morton Effect is discussed. The results show that the Morton Effect has a comprehensive impact on both the amplitude and phase lag of the steady-state unbalance response. It may shift both curves in a manner dependent on the relative magnitude and direction of the thermal imbalance.
Then, the mid-span rotors supported by the hydrodynamic journal bearings are analyzed.
The models to calculate the thermal bending of the shaft and the temperature distribution across the journal surface are established. The calculations of the temperature difference and its equivalent thermal imbalance are conducted and discussed with the comparison to the analytical results. It shows that the thermal imbalance may increase to the level of the mechanical imbalance and its influence on the system stability should be then included. The suggested thermal bending model also explains that the mid-span rotors are less liable to be influenced by the Morton Effect than are the overhung configurations, because of the restraining effect between the two supports. The simulation results of a symmetric mid-span rotor - hydrodynamic journal bearing system show that the inclusion of the Morton Effect may lead to an unstable operation of the system. Considering the existence of the oil film self-induced vibration due to the dynamic characteristics of fluid film bearings, the Morton Effect may make a further negative impact on the instabilities of the rotor system under some working conditions.
Finally, the predictive solution method for the general mid-span rotors is discussed. The computer code, VT-MAP, is developed for the predictions of the Morton Effect induced instability of rotor systems in either mid-span and overhung configurations.Ph. D.
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Abdulrehem, Mahmoud M. Gad. "Low dimensional description of pedestrian-induced instability of the millennium bridge." College Park, Md.: University of Maryland, 2008. http://hdl.handle.net/1903/8736.
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Thesis (M.S.) -- University of Maryland, College Park, 2008.Thesis research directed by: Dept. of Electrical and Computer Engineering. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Dunn, Daniel D. "Attacker-Induced Traffic Flow Instability in a Stream of Automated Vehicles." DigitalCommons@USU, 2015. https://digitalcommons.usu.edu/etd/4455.
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Highway systems world wide continue to see an ever increased number of vehicles and subsequently a rise in congested traffic. This results in longer commute times, wasted energy as vehicles idle in stop and go traffic, and increases the risk of accidents. In short, increased congestion costs time and money. These issues have prompted much research into Automated Highway Systems (AHS). In AHS vehicles using computer algorithms can safely travel at much smaller inter-vehicle distances than human drivers are capable of. This increases the capacity of existing highway systems. Sensors aboard each vehicle make this possible by monitoring their surroundings. Vehicles equipped with Adaptive Cruise Control (ACC) are capable of this type of close proximity travel. ACC packages are becoming common as a standard package on many mid-priced vehicles.
Another form of automation, Cooperative Adaptive Cruise Control (CACC), which utilizes wireless communication between vehicles, has been proposed and will likely become available within the next couple decades. CACC allows each vehicle to communicate their intended speed or position changes to surrounding vehicles, further decreasing the possibility of collisions.
These automation methods are proposed to reduce driver stress, increase highway throughput, and decrease accident rates. However, the fact that vehicles are being automated creates new opportunities for malicious individuals to wreak havoc on society.
This research investigates the possibility that some vehicles on the highway might be under the control of malicious individuals who have modified their automated control systems to negatively affect vehicles around them. These malicious actors might also exploit the wireless communication of CACC vehicles and hack their control algorithms, causing them to become unstable. These hacked vehicles could become passive participants in the attack unbeknownst to the driver of the vehicle. The result of such attacks could be congested traffic, rapid changes in acceleration causing drivers discomfort, or multi-vehicle collisions. Such attacks could effectively negate the benefits of implementing AHS.
The goal of this work is to bring to light possible weaknesses in the proposed systems so they can be rectified before becoming an issue to the public at large.
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Schäfer, Urs [Verfasser]. "Turbulence and planetesimal formation induced by the streaming instability : Turbulenz und Planetesimalenstehung hervorgerufen durch die Streaming Instability / Urs Schäfer." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2020. http://d-nb.info/122113535X/34.
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Shi, Yuquan Shi Yu-Quan. "Studies of programmed cell death and genetic instability induced by X-rays /." [S.l.] : [s.n.], 2000. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=13701.
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Ulker, Mehmet Baris Can. "Dynamics of Saturated Porous Media: Wave Induced Response and Instability of Seabed." NCSU, 2009. http://www.lib.ncsu.edu/theses/available/etd-08042009-161500/.
Full textAbstract:
Problems in fields ranging from geomechanics to biomechanics require response of saturated porous media subjected to dynamic loading. An engineering problem requiring the true behavior of saturated porous medium should consider the coupling of both fluid and solid phases yielding the simultaneous analysis of flow of pore fluid and deformation of solid skeleton. Depending on the nature of loading vis-Ã -vis the characteristics of the media, different formulations; fully-dynamic (FD), partially-dynamic (PD), quasi-static (QS) are possible. In this study, analytical solutions and numerical models are developed for the response of plane strain saturated porous media, and wave-induced response of seabed in free field and around a breakwater under pulsating/breaking waves. For each formulation, the results are presented with pore-pressure, shear and normal stress distributions within porous medium. The response is studied for various conditions and regions of applicability of formulations are identified in non-dimensional and actual parametric spaces. This can be used for a specific case with known loading and medium characteristics and may help engineers identify the necessary formulation to be used in a given problem. Effect of seabed-wave parameters and inertial terms on standing/breaking wave-induced pulsating/impact response of seabed-caisson system were investigated. The selection of the adequate formulation is decided depending upon the response variable and ranges of physical parameters. While FD formulation yields the minimum response in cyclic wave, for impacting wave it yields variable distributions in between the other two formulations. The areas of instantaneous liquefaction were identified inside the domain through contours of mean effective stress for both types of waves. Liquefied regions are concentrated at the front toe of rubble under cyclic wave which can initiate a vertical-horizontal movement and rotation towards the seabed causing structural failure. Liquefied areas in case of breaking waves are much larger compared to cyclic waves. Additional analyses made introducing a constitutive model for the inelastic behavior of soil to evaluate the nonlinear dynamic response of seabed reveal the importance of the inclusion of material nonlinearity effects.
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Estey, Tia Brie. "Protein instability associated with PLGA delivery systems and UV-induced protein oxidation /." Connect to full text via ProQuest. IP filtered, 2006.
Find full textAbstract:
Thesis (Ph.D. in Pharmaceutical Sciences) -- University of Colorado, 2006.Typescript. Includes bibliographical references (leaves 144-161). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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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.
Full textAbstract:
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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Winfield, Mark O. "Tissue culture induced chromosome instability in cell suspensions of wheat (Triticum spp.)." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284143.
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Kaynia, Narges. "Instability-induced transformation of interfacial layers in composites and its multifunctional applications." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103494.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 237-241).
Inspired by the undulating patterns found in different plant and biological cells in nature, this thesis explores the deformation-induced wrinkling instability transformation in the microstructure of composites with thin interfacial layers. The hybrid microstructure of a composite material has an essential influence on the effective properties and behavior of the composite. Hence, in this research, the principles and mechanics of interfacial layer instabilities are purposely designed to achieve sudden pattern transformations in the composite structure to generate new controlled multifunctional behavior. The wrinkling instability transformation is investigated in multilayered and networked composites consisting of relatively stiff interfacial layers or cells embedded in a soft matrix. Through analytical modeling, finite element simulations, and physical experiments, a comprehensive study is performed to elucidate: i) the conditions governing wrinkling, ii) the effect of wrinkling on local deformations, iii) the energy stored and dissipated in wrinkling composites, and iv) the change in the effective mechanical behavior of the composites. It is concluded that these properties are directly dependent on the composite's material and geometrical properties, and that composites can be designed to exhibit enhanced energy absorption (including energy storage and dissipation), stress mitigation effects, bilinear and multi-linear elastic stress-strain behavior, switchable effective stiffness, and can be used for energy harvesting applications. Design guidelines are presented to assist the process of deploying instability-transformation to tune, control, and switch the mechanical properties of multifunctional composite materials. Instability principles such as buckling and wrinkling are favorable mechanisms as they can be designed to be elastic and therefore reversible. The ability to alter and transform the microstructure enables on-demand tunability and active control of the composite's properties and attributes.
by Narges Kaynia.
Ph. D.
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Kuenze, Christopher Zinder Steven. "The effects of functional ankle instability and induced fatigue on ankle stiffness." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2574.
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Thesis (M.A.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Oct. 5, 2009). "... in partial fulfillment of the requirements for the degree of Master of Arts in the Department of Exercise and Sport Science." Discipline: Exercise and Sports Science; Department/School: Exercise and Sport Science.
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Jiang, Zhongliang. "Epigenetic Instability Induced by DNA Base Lesion via DNA Base Excision Repair." FIU Digital Commons, 2017. https://digitalcommons.fiu.edu/etd/3566.
Full textAbstract:
DNA damage can cause genome instability, which may lead to human cancer. The most common form of DNA damage is DNA base damage, which is efficiently repaired by DNA base excision repair (BER). Thus BER is the major DNA repair pathway that maintains the stability of the genome. On the other hand, BER mediates DNA demethylation that can occur on the promoter region of important tumor suppressor genes such as Breast Cancer 1 (BRCA1) gene that is also involved in prevention and development of cancer. In this study, employing cell-based and in vitro biochemical approaches along with bisulfite DNA sequencing, we initially discovered that an oxidized nucleotide, 5’,2-cyclo-2-deoxyadenosine in DNA duplex can either cause misinsertion by DNA polymerase β (pol β) during pol β-mediated BER or inhibit lesion bypass of pol β resulting in DNA strand breaks. We then explored how a T/G mismatch resulting from active DNA demethylation can affect genome integrity during BER and found that pol β can extend the mismatched T to cause mutation. We found that AP endonuclease 1 (APE1) can use its 3'-5' exonuclease to remove the mismatched T before pol β can extend the nucleotide preventing a C to T mutation. The results demonstrate that the 3'-5' exonuclease activity of APE1 can serve as a proofreader for pol β to prevent mutation. We further explored the effects of exposure of environmental toxicants, bromate and chromate on the DNA methylation pattern on the promoter region of BRCA1 gene with bisulfite DNA sequencing. We found that bromate and chromate induced demethylation of 5-methylcytosines (5mC) at the CpG sites as well as created additional methylation at several unmethylated CpG sites at BRCA1 gene in human embryonic kidney (HEK) 293 cells. We further demonstrated that the demethylation was mediated by pol β nucleotide misinsertion and an interaction between pol β and DNA methyltransferase 1 (DNMT1) suggesting a cross-talk between BER and DNA methyltransferases. We suggest that DNA base damage and BER govern the interactions among the environment, the genome and epigenome, modulating the stability of the genome and epigenome and disease development.
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Alnujaie, Ali H. "Flow-induced Vibration of Double Wall Carbon Nanotubes Conveying Pulsating Fluid." University of Akron / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=akron1555409894074253.
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Ryabtseva, Elena. "Analysis of a Magnetic-Field-Induced Periodic Instability in a Liquid Crystal Film." Kent State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=kent1248126599.
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Elango, Rajula. "Break-induced replication repair pathway promotes mutagenesis and genomic instability in Saccharomyces cerevisiae." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5933.
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DNA double strand breaks can occur from various sources and the timely and accurate repair of these breaks is critical to maintain the genomic integrity of the cell. Break-induced replication (BIR) is a repair pathway that has been shown to repair DSBs where only one end of the break can locate homology, similar to ends seen at collapsed replication forks or eroded telomeres. BIR progresses by an unusual bubble-like intermediate. The asynchrony between the synthesis of leading and lagging strand synthesis during BIR leads to the accumulation of long single-stranded DNA (ssDNA) behind the bubble. This mechanism leads to the conservative inheritance of newly synthesized DNA. BIR repair can lead to increased mutations, loss of heterozygosity and gross chromosomal rearrangements. In this thesis I investigated the deleterious effects of the ssDNA formed during BIR. Using yeast, Saccharomyces cerevisiae, I showed that the regulation of Rad51 that binds ssDNA during BIR is important to prevent the accumulation of toxic joint intermediates. Here, I demonstrate that a known Rad51-interacting protein, Srs2, plays two key roles in counteracting the accumulation of lethal recombination intermediates. First, Srs2 dislodges Rad51 from long ssDNA formed during DSB repair and therefore prevents promiscuous strand invasions that generate lethal joint molecules. Second, Srs2 helicase dismantles toxic intermediates that have already formed. We also demonstrate that the structure-specific endonucleases, Mus81 and Yen1, can resolve toxic joint molecules formed in the absence of Srs2, thus promoting cell survival.
The other goal of this thesis was to study the effects of ssDNA accumulated during BIR in the formation of base-substitution mutagenesis. I test whether this ssDNA is mutagenic by analyzing BIR with and without the presence of DNA damaging agents, including methyl methanesulfonate (MMS) and APOBEC3A. I observed a hypermutagenic effect of BIR with respect to base- substitutions in both cases. Importantly, BIR synergizes with ssDNA damaging agents to produce mutation clusters similar to those previously observed in cancer. I also report the critical role translesion polymerase Polζ plays in the formation of base-substitutions resulting from BIR. Finally, I have discovered a completely novel, UNG1-dependent mechanism of supposed error-free bypasses of APOBEC-induced DNA lesions during BIR that promotes chromosomal rearrangements.
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Gur, Sourav, Venkateswara Rao N. Manga, Stefan Bringuier, Krishna Muralidharan, and George Frantziskonis. "Evolution of internal strain in austenite phase during thermally induced martensitic phase transformation in NiTi shape memory alloys." Elsevier, 2017. http://hdl.handle.net/10150/623612.
Full textAbstract:
New insight into the temperature dependent evolution of internal strain in the austenite phase during the martensitic phase transformation in NiTi shape memory alloys is provided via classical molecular dynamics simulations that employ well-established interatomic potentials for NiTi. It is shown, for the first time, that the developed strain tensor in the austenite phase is tetragonal in nature, with exponential temperature-dependence. Equally importantly, it is found that the developed internal strain (parallel to the habit plane) in the austenite varies linearly with the evolving martensite phase fraction. Interestingly, the Richard’s equation is found to describe the temperature dependence of the martensite phase fraction as well as the internal strain components parallel to the habit plane in the austenite phase. An analysis of the temperature dependent phonon dispersion of strained austenite revealed the competition between phonon softening of the TA2 branch and internal strain that leads to stabilization of the austenite phase in the two phase regime.
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Requena, Osete Jordi. "Advancing induced pluripotent stem cell (iPSC) technology by assessing genetic instability and immune response." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457970.
Full textAbstract:
Induced pluripotent stem cells (iPSC) can be made from adult somatic cells by reprogramming them with Oct4, Sox2, Klf4 and c-Myc. IPSC have given rise to a new technology to study and treat human disease (Takahashi et al., 2007). However, before iPSC clinical application, we need to step back and address two main challenges:
(i) Genetic stability of iPSC.
(ii) Immune response of iPSC-derived cells.
To address these key issues, the overall mission of this PhD thesis is to advance iPSC technology by addressing two objectives. First, is to replace c-Myc with Cyclin D1 in the reprogramming cocktail (Oct4, Sox2, Klf4 and c-Myc or Cyclin D1) and second, to study the immune response of iPSC-derived cells.
The quality of the starting iPSC determines the quality of the differentiated cells to be transplanted for clinical applications. In terms of genetic stability, aberrant cell reprogramming leads to genetic and epigenetic modifications that are the most significant barriers to clinical applications of patient iPSC derivatives (Gore et al., 2011). Such aberrations can result from the cellular stress that accompanies reprogramming or from the reprogramming factors themselves (Lee et al., 2012a). IPSC made with c-Myc are neoplastic in mouse models and have a higher tumorigenic potential than embryonic stem cells, prompting a search for new pluripotency factors that can replace the oncogenic factors Klf4 and c-Myc (Huangfu et al., 2008; Miura et al., 2009; Okita et al., 2007). We chose Cyclin D1 to replace c-Myc because of previous observation it can be used to reprogram cells to iPSC (Edel et al., 2010) and because of its DNA repair function (Chalermrujinanant et al., 2016). In this thesis we adopt a synthetic mRNA method to demonstrate that Cyclin D1 and c-Myc made iPSC have equal pluripotency using standard methods of characterisation. Moreover, no significant changes in copy number variation were found between starting skin cells and iPSC highlighting it is the method of choice for generating high quality iPSC. Further in- depth analysis revealed that Cyclin D1 made iPSC have reduced genetic instability assessed by: (i) reduced DNA double strand breaks (DSB), (ii) higher nuclear amount of the homologous recombination key protein Rad51, (iii) reduced multitelomeric signals (MTS) and (iv) reduced teratoma growth kinetics in vivo, compared to c-Myc made iPSC. Moreover, we demonstrate that Cyclin D1 iPSC derived neural stem cells engraft successfully, survive long term and differentiate into mature neuron cell types with high efficiency, with no evidence of pathology in a spinal cord injury rat model.
As we move towards the clinic with iPSC-derived cells for cell transplantation, the immunogenic response is thought to be one of the main advantages of iPSC technology for clinical application, because of its perceived lack of immune rejection of autologous cell therapy. We hypothesize that iPSC derived cells are unlikely to provoke an immune response. Here we have performed an analysis of the innate and adaptive immune response of human skin cells (termed F1) reprogramed to iPSC and then compared to iPSC-derived cells (termed F2) using proteomic and methylome arrays. We found little differences between MHCI expression and function; however, we discovered a short isoform of the Toll-like receptor 3 (TLR3), essential for viral dsRNA innate immune
recognition, which is predominantly upregulated in all iPSC derived cells analysed and not seen in normal endogenous cells. High levels of the TLR3 isoform is associated with unresponsiveness to viral stimulation measured by lack of IL6 secretion in iPSC derived neural stem cells. We propose a new model that TLR3 short isoform competes with the full length wild type isoform destabilizing the essentially required TLR3 dimerization process. These differences could result in supressed inflammatory effects for transplanted human iPSC-derived cells in response to viral or bacterial insult. Further work to determine the in vivo effects is warranted and calls for screening of iPSC lines for TLR3 isoform expression levels before clinical use. In conclusion, this thesis has advanced iPSC technology by defining a new method that is a significant advance with novel insights that has immediate impact on current methods to generate iPSC for clinical application and more accurate disease modelling.Les cèl·lules mare pluripotents induïdes (iPSC) es poden derivar de cèl·lules somàtiques adultes mitjançant la reprogramació amb Oct4, Sox2, Klf4 i c-Myc. Les iPSC han donat lloc a una nova tecnologia per estudiar i tractar malalties humanes (Takahashi et al., 2007). No obstant, abans de la aplicació clínica de les iPSC, dos problemes principals han de ser adreçats: (i) Estabilitat genètica de les iPSC. (ii) Resposta immune de les cèl·lules derivades de iPSC. Per adreçar aquests dos qüestions cabdals, la missió principal d’aquest doctorat és avançar la tecnologia de les iPSC adreçant dos objectius. El primer, és la substitució de c-Myc per Ciclina D1 al còctel de reprogramació (Oct4, Sox2, Klf4 and c-Myc o Ciclina D1) i segon, estudiar la resposta immune de les cèl·lules derivades de iPSC. Hem escollit Ciclina D1 per substituir c-Myc atès a observacions prèvies que pot ser emprat per reprogramar (Edel et al., 2010) i donada la seva funció en reparació de l’ADN (Chalermrujinanant et al., 2016). Les iPSC reprogramades amb Ciclina D1 presenten una pluripotència similar a les reprogramades amb c-Myc, l’anàlisi en profunditat mostra però, que les iPSC reprogramades amb Cyclin D1 tenen una reduïda inestabilitat genètica adreçada per: (i) reducció en ruptures de doble cadena de DNA, (ii) major quantitat nuclear de la proteïna clau en la recombinació homòloga Rad51, (iii) reducció en senyals multitelomèriques (MTS) i (iv) reducció en la cinètica de creixement de teratomes in vivo, en comparació amb iPSC reprogramades amb c-Myc. A més a més, demostrem que les cèl·lules mare neuronals derivades d’aquestes iPSC son capaces de implantar-se exitosament, sobreviure a llarg termini i diferenciar a neurones madures sense evidències de patologia en un model de dany medul·lar. També hem realitzat un anàlisi del sistema immune innat i adaptatiu de cèl·lules humanes de la pell (nomenades F1) reprogramades a iPSC i comparades amb cèl·lules derivades de iPSC (nomenades F2). Hem descobert una isoforma curta del Toll-Like Receptor 3 (TLR3), essencial en el reconeixement de RNA de doble cadena d’origen víric, que està predominantment sobreexpresada en totes les cèl·lules derivades de iPSC analitzades i no trobat en cèl·lules endògenes. Nosaltres proposem un nou model per el qual la isoforma curta del TLR3 competeix amb la isoforma llarga wild type desestabilitzant el procés essencial de dimerització del TLR3.
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IKI, MASAYUKI. "VIBRATION-INDUCED WHITE FINGER AS A RISK FACTOR FOR HEARING LOSS AND POSTURAL INSTABILITY." Nagoya University School of Medicine, 1994. http://hdl.handle.net/2237/16062.
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Paretkar, Dadhichi R. Verfasser], and Eduard [Akademischer Betreuer] [Arzt. "Switchability induced by mechanical instability in bioinspired adhesives / Dadhichi R. Paretkar. Betreuer: Eduard Arzt." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052550967/34.
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Yoshikiyo, Kazunori. "KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents." Kyoto University, 2013. http://hdl.handle.net/2433/180458.
Full textAbstract:
Kazunori Yoshikiyo, Katja Kratz, Kouji Hirota, Kana Nishihara, Minoru Takata, Hitoshi Kurumizaka, Satoshi Horimoto, Shunichi Takeda, and Josef Jiricny "KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents" PNAS 2010 107 (50) 21553-21557; published ahead of print November 29, 2010, doi:10.1073/pnas.1011081107Kyoto University (京都大学)
0048
新制・論文博士
博士(医学)
乙第12772号
論医博第2063号
新制||医||1000(附属図書館)
30755
(主査)教授 小松 賢志, 教授 小川 誠司, 教授 松本 智裕
学位規則第4条第2項該当
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Kang, Ha Eun David. "Design of anti-biofouling Lubricant-Impregnated Surfaces (LIS) robust to cell-growth-induced instability." Thesis, Massachusetts Institute of Technology, 2020. https://hdl.handle.net/1721.1/127162.
Full textAbstract:
Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, May, 2020Cataloged from the official PDF of thesis.
Includes bibliographical references (pages 28-30).
Unwanted deposition of cells on wetted solids, so-called biofouling, is a serious operational and environmental threat in many underwater and biomedical applications. Over the last decade, Lubricant-Impregnated Surfaces (LIS) has been one of the popular remedies, owing to its unique oil layer that separates solid from cellular media giving no chance for cells to foul. However, a critical bottleneck to this solution has been that retention of the oil could never be permanent, which shortened its anti-fouling efficacy. While understanding the root cause of this oil loss significantly helps prevent such failure, the loss mechanism has not received much attention to date. In this study, we show that secretion of biomolecules from aquatic cells and subsequent change in interfacial tension of the surrounding media can delaminate the oil film, resulting in gradual deterioration of anti-biofouling capability of LIS. We establish a correlation between the decrease in interfacial tension and observed wetting transitions of LIS over the fouling test period. We also visualize the cell medium - oil interface to confirm final wetting states of LIS in situ. We further measure mobility of various algae droplets on such surfaces and scale forces to confirm presence of line force specific to each wetting state. Finally, we propose a LIS regime map that helps determine the design of LIS that can resist oil loss in aquatic cellular environments, increasing long-term anti-biofouling efficacy.
by Ha Eun David Kang.
S.M.
S.M. Massachusetts Institute of Technology, Department of Mechanical Engineering
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Paretkar, Dadhichi R. [Verfasser], and Eduard [Akademischer Betreuer] Arzt. "Switchability induced by mechanical instability in bioinspired adhesives / Dadhichi R. Paretkar. Betreuer: Eduard Arzt." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052550967/34.
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Mahmud, Md Rasel Al. "TDP2 suppresses genomic instability induced by androgen in the epithelial cells of prostate glands." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263551.
Full textAbstract:
付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム京都大学
新制・課程博士
博士(医学)
甲第23090号
医博第4717号
京都大学大学院医学研究科医学専攻
(主査)教授 篠原 隆司, 教授 小川 修, 教授 溝脇 尚志
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
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Kanatani, Kentaro. "Interfacial instability induced by lateral vapor pressure fluctuation in bounded thin liquid-vapor layers." 京都大学 (Kyoto University), 2009. http://hdl.handle.net/2433/124394.
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Epanchintsev, Alexey. "Analysis of c-MYC-induced chromosomal instability and generation of a conditional microRNA expression system." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-83910.
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Epanchintsev, Alexey. "Analysis of c-MYC-induced chromosomal instability and generation of a conditional microRNA expression system." kostenfrei, 2007. http://edoc.ub.uni-muenchen.de/8391/.
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Merrifield, Matthew, and University of Lethbridge Faculty of Arts and Science. "Radiation-induced deregulation of PiRNA pathway proteins : a possible molecular mechanism underlying transgenerational epigenomic instability." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Biological Science, c2011, 2011. http://hdl.handle.net/10133/2617.
Full textAbstract:
PiRNAs and their Piwi family protein partners are part of a germline specific epigenetic regulatory mechanism essential for proper spermatogenesis, silencing of transposable elements, and maintaining germline genome integrity, yet their role in the response of the male germline to genotoxic stress is unknown.
Ionizing radiation (IR) is known to cause transgenerational genome instability that is linked to carcinogenesis. Although the molecular etiology of IR-induced transgenerational genomic instability is not fully understood, it is believed to be an epigenetically mediated phenomenon. IR-induced alterations in the expression pattern of key regulatory proteins involved in the piRNA pathway essential for paternal germline genome stability may be directly involved in producing epigenetic alterations that can impact future generations.
Here we show whole body and localized X-irradiation leads to significant altered expression of proteins that are necessary for, and intimately involved in, the proper functioning of the germline specific piRNA pathway in mice and rats. In addition we found that IR-induced alterations to piRNA pathway protein levels were time and dose dependent.ix, 123 leaves : ill. (some col.) ; 29 cm
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Varlamova, Olga [Verfasser], and Jürgen [Akademischer Betreuer] Reif. "Self-organized surface patterns originating from femtosecond laser-induced instability / Olga Varlamova. Betreuer: Jürgen Reif." Cottbus : Universitätsbibliothek der BTU Cottbus, 2014. http://d-nb.info/1047336553/34.
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Zhan, Liangtong. "Field and laboratory study of an unsaturated expansive soil associated with rain-induced slope instability /." View Abstract or Full-Text, 2003. http://library.ust.hk/cgi/db/thesis.pl?CIVL%202003%20ZHAN.
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Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2003.Includes bibliographical references (leaves 471-490). Also available in electronic version. Access restricted to campus users.
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Suryo, Eko Andi. "Real - time prediction of rainfall induced instability of residual soil slopes associated with deep cracks." Thesis, Queensland University of Technology, 2013. https://eprints.qut.edu.au/63775/1/Eko_Andi_Suryo_Thesis.pdf.
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The early warning based on real-time prediction of rain-induced instability of natural residual slopes helps to minimise human casualties due to such slope failures. Slope instability prediction is complicated, as it is influenced by many factors, including soil properties, soil behaviour, slope geometry, and the location and size of deep cracks in the slope. These deep cracks can facilitate rainwater infiltration into the deep soil layers and reduce the unsaturated shear strength of residual soil. Subsequently, it can form a slip surface, triggering a landslide even in partially saturated soil slopes. Although past research has shown the effects of surface-cracks on soil stability, research examining the influence of deep-cracks on soil stability is very limited. This study aimed to develop methodologies for predicting the real-time rain-induced instability of natural residual soil slopes with deep cracks. The results can be used to warn against potential rain-induced slope failures.
The literature review conducted on rain induced slope instability of unsaturated residual soil associated with soil crack, reveals that only limited studies have been done in the following areas related to this topic: - Methods for detecting deep cracks in residual soil slopes.
- Practical application of unsaturated soil theory in slope stability analysis.
- Mechanistic methods for real-time prediction of rain induced residual soil slope instability in critical slopes with deep cracks.
Two natural residual soil slopes at Jombok Village, Ngantang City, Indonesia, which are located near a residential area, were investigated to obtain the parameters required for the stability analysis of the slope. A survey first identified all related field geometrical information including slope, roads, rivers, buildings, and boundaries of the slope. Second, the electrical resistivity tomography (ERT) method was used on the slope to identify the location and geometrical characteristics of deep cracks. The two ERT array models employed in this research are: Dipole-dipole and Azimuthal. Next, bore-hole tests were conducted at different locations in the slope to identify soil layers and to collect undisturbed soil samples for laboratory measurement of the soil parameters required for the stability analysis. At the same bore hole locations, Standard Penetration Test (SPT) was undertaken.
Undisturbed soil samples taken from the bore-holes were tested in a laboratory to determine the variation of the following soil properties with the depth: - Classification and physical properties such as grain size distribution, atterberg limits, water content, dry density and specific gravity.
- Saturated and unsaturated shear strength properties using direct shear apparatus.
- Soil water characteristic curves (SWCC) using filter paper method.
- Saturated hydraulic conductivity.
The following three methods were used to detect and simulate the location and orientation of cracks in the investigated slope: (1) The electrical resistivity distribution of sub-soil obtained from ERT.
(2) The profile of classification and physical properties of the soil, based on laboratory testing of soil samples collected from bore-holes and visual observations of the cracks on the slope surface.
(3) The results of stress distribution obtained from 2D dynamic analysis of the slope using QUAKE/W software, together with the laboratory measured soil parameters and earthquake records of the area. It was assumed that the deep crack in the slope under investigation was generated by earthquakes.
A good agreement was obtained when comparing the location and the orientation of the cracks detected by Method-1 and Method-2. However, the simulated cracks in Method-3 were not in good agreement with the output of Method-1 and Method-2. This may have been due to the material properties used and the assumptions made, for the analysis. From Method-1 and Method-2, it can be concluded that the ERT method can be used to detect the location and orientation of a crack in a soil slope, when the ERT is conducted in very dry or very wet soil conditions. In this study, the cracks detected by the ERT were used for stability analysis of the slope.
The stability of the slope was determined using the factor of safety (FOS) of a critical slip surface obtained by SLOPE/W using the limit equilibrium method. Pore-water pressure values for the stability analysis were obtained by coupling the transient seepage analysis of the slope using finite element based software, called SEEP/W.
A parametric study conducted on the stability of an investigated slope revealed that the existence of deep cracks and their location in the soil slope are critical for its stability. The following two steps are proposed to predict the rain-induced instability of a residual soil slope with cracks.
(a) Step-1: The transient stability analysis of the slope is conducted from the date of the investigation (initial conditions are based on the investigation) to the preferred date (current date), using measured rainfall data. Then, the stability analyses are continued for the next 12 months using the predicted annual rainfall that will be based on the previous five years rainfall data for the area.
(b) Step-2: The stability of the slope is calculated in real-time using real-time measured rainfall. In this calculation, rainfall is predicted for the next hour or 24 hours and the stability of the slope is calculated one hour or 24 hours in advance using real time rainfall data.
If Step-1 analysis shows critical stability for the forthcoming year, it is recommended that Step-2 be used for more accurate warning against the future failure of the slope.
In this research, the results of the application of the Step-1 on an investigated slope (Slope-1) showed that its stability was not approaching a critical value for year 2012 (until 31st December 2012) and therefore, the application of Step-2 was not necessary for the year 2012.
A case study (Slope-2) was used to verify the applicability of the complete proposed predictive method. A landslide event at Slope-2 occurred on 31st October 2010. The transient seepage and stability analyses of the slope using data obtained from field tests such as Bore-hole, SPT, ERT and Laboratory tests, were conducted on 12th June 2010 following the Step-1 and found that the slope in critical condition on that current date. It was then showing that the application of the Step-2 could have predicted this failure by giving sufficient warning time.
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Ramage, Amy Elizabeth. "Behavioral and neural responses to induced instability: The dynamics of perturbation and adaptation during language processing." Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/279798.
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The current investigation examined perturbation and adaptation during language comprehension in young normal subjects. Using a dynamic system framework, induced instability was studied by increasing perceptual demand (compressed sentences), syntactic demand, or both. Two experiments were conducted, one behavioral and one using fMRI technology, to explore the relations between brain responses and behavior. This study examines if changes in rate of speech, syntax, or both induce an instability, or perturbation, with subsequent adaptation in which subjects regain a previous stable state. Dependent measures in the behavioral study were accuracy and reaction time based indices of perturbation, adaptation, and stability. Results of the behavioral study demonstrated that language comprehension can be perturbed by changes in syntactic complexity or syntactic + perceptual complexity. Further, it was found that subjects adapted to being perturbed. The more complex the stimulus, the longer it took for subjects to adapt. The second experiment used fMRI to measure brain activation associated with perturbation and adaptation of language. Several brain regions showed increases in activation with increasing complexity (i.e., perturbation). Some regions (e.g., the superior parietal lobule) appeared more active when the perturbation was perceptual and others (e.g., the left inferior frontal gyrus) more active when the perturbation was syntactic in nature. These regions either remained active during the adaptation process, or reduced in activation during adaptation suggesting a role specific role in perturbation. These results suggest that subjects develop and maintain a representation of either the syntactic frame (i.e., via priming), a conscious strategy for accommodating syntactic complexity, or rate normalization schema. Thus, the brain regions that remain active during adaptation may be used to maintain the linguistic or perceptual frame. Within a dynamic system framework, the development of these representations, which occurs over a few items, serves as an attractor to which subjects are drawn each time they are perturbed. Like other complex systems, once instability occurs, there needs to be a strong attractor state to pull subjects into stability that permits appropriate performance to continue.
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Park, Hyungjoo. "Development of a Test System to Measure Squeak Propensity of Vehicle Underbody Components." University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592135515122287.
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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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Puckert, Dominik [Verfasser]. "Experimental Investigation on Global Instability and Critical Reynolds Number in Roughness-Induced Laminar-to-Turbulent Transition / Dominik Puckert." München : Verlag Dr. Hut, 2019. http://d-nb.info/1181515130/34.
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