Dissertations / Theses on the topic 'Structural remodeling'
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Wang, Jingwen M. Eng Massachusetts Institute of Technology. "Trabecular topology : computational structural design inspired by bone remodeling." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111530.
Full textAbstract:
Thesis: M. Eng., Massachusetts Institute of Technology, Department of Civil and Environmental Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 59-60).
Bone remodeling is the process by which the internal morphology of bones in a healthy person or animal will adapt to the loads under which it is placed. This process makes bone stronger and performs better under daily loadings. It also gives a special topology to the trabecular bone. This thesis proposes a new computational structural design approach inspired by the trabecular bone topology and remodeling process and it can be applied to the 2D, 3D and building-scale structures. It reveals the importance of the connectivity in the structures and provides a innovative bio-inspired method for the future structural topology design.
by Jingwen Wang.
M. Eng.
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Li, Li. "Electrophysiological, structural and molecular remodeling of chronically infarcted rabbit heart." online version, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1130882699.
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Атаман, Юрій Олександрович, Юрий Александрович Атаман, Yurii Oleksandrovych Ataman, O. A. Vorozhko, and O. S. Voloshin. "Structural and functional features of myocardial remodeling in professional athletes." Thesis, Сумський державний університет, 2018. http://essuir.sumdu.edu.ua/handle/123456789/71676.
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Hota, Swetansu Kumar. "STRUCTURAL AND FUNCTIONAL ANALYSIS OF THE ISW2 CHROMATIN REMODELING COMPLEX." OpenSIUC, 2011. https://opensiuc.lib.siu.edu/dissertations/431.
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Chromatin remodelers utilize the energy derived from ATP hydrolysis to mobilize nucleosomes. ISWI remodelers mobilize and evenly space nucleosomes to regulate gene expression. ISW2, an ISWI remodeler in yeast, has been shown to reposition nucleosome near promoter regions and represses both mRNA and antisense non coding RNA transcription. ISW2 is composed of four subunits and the catalytic Isw2 subunit consists of several conserved domains. The highly conserved ATPase domain is present at the N-terminus whereas the conserved HAND, SANT and SLIDE domain are towards the carboxyl terminal end of Isw2. Nucleosome mobilization by ISW2 requires both extranucleosomal DNA and the N-terminal tail of histone H4. DNA crosslinking and peptide mapping revealed that the ATPase domain contacts nucleosome two helical turns away (SHL2) from dyad to a site close to the H4 tail, whereas the HAND, SANT and SLIDE domain contact a 30bp stretch of DNA comprising the edge of nucleosome and ~20bp of extranucleosomal DNA. The ATPase domain and the C-terminal domains were investigated for their role in regulation of ISW2 activity both in-vitro and in-vivo. It appears that there are distinct modes of ISW2 regulation by these domains. Mutation of a patch of five acidic amino acids on the region of ATPase domain that contact SHL2 was found to be crucial for both ISW2 remodeling and nucleosome stimulated ATPase activity. Acidic patch mutant ISW2 was unable to mobilize nucleosome or hydrolyze ATP in absence of H4 tail. This indicates that the region of ATPase domain contacting nucleosome at SHL2 and H4 tail act in two separate and independent pathways to regulate ISW2 remodeling. Both HAND and SLIDE domain were shown to crosslink entry/exit site and linker DNA respectively. The roles of C-terminal domains were investigated either by deletion of the individual domain or mutation of conserved basic residues on the surface of these domains that are suspected to interact extranucleosomal with DNA. Deletion of HAND domain had minimal effect on in vitro ISW2 activity, however whole genome transcription analysis revealed one key role of this domain in ISW2 regulation. In absence of HAND domain, ISW2 had minimal role on repression of genes that were RPD3 (co-factor) dependent, however significantly derepressed genes that were RPD3 independent. At these loci, nucleosome positions were altered and ISW2 recruitment was reduced in absence of a functional HAND domain. Thus the HAND domain regulates recruitment and remodeling of ISW2 at those genes where ISW2 acts independent of other cofactors. The SANT domain, C-terminal to HAND domain, appears to control the "step size" of nucleosome remodeling and was found to be required for processive nucleosome remodeling by ISW2. Both H4 tail and SANT domain appear to control two distinct stages of ISW2 remodeling. A long alpha helical spacer separates SANT domain from SLIDE domain. SLIDE domain was found to be the protein-protein interaction domain that interacts with accessory Itc1 subunit to maintain ISW2 complex integrity. The two ways by which SLIDE domain regulate ISW2 is by binding or recruitment of ISW2 to promoter regions and additionally by binding independent regulation of both ATPase and remodeling activity. The remodeling mechanism of ISW2 was further compared with another ISWI type remodeler in yeast, Isw1a; using time resolved nucleosome remodeling combined with high resolution site specific histone DNA crosslinking at six different nucleosomal positions to track the movement of the nucleosomes. Nucleosome remodeled by the same remodeler showed discontinuous nucleosome movement between two tracking points indicating formation of small "bulges". One key difference in remodeling mechanism was that although both ISW2 and Isw1a moved nucleosomes towards longer linker DNA, only Isw1a remodeled nucleosomes "backtracked" ~11bp during remodeling. Backtracking of remodeling was prominently observed at nucleosomal regions in close proximity to translocase binding sites suggesting the potentially different mechanisms shared by similar remodeling complexes.
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Bernardino, Gabriel. "Computational anatomy as a driver of understanding structural and functional cardiac remodeling." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/668213.
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We present a statistical shape analysis framework to identify cardiac shape remodelling while accounting for individual´s natural variability and apply it in two clinical applications: comparing triathletes with controls, and comparing individuals who were born small-for-their-gestational-age (SGA) and controls. We were able to identify the shape remodelling due to the practice of endurance sport: it consisted a dilation of the left ventricle and an increase of the left ventricular myocardial mass. In the right ventricle (RV), the increase of volume was concentrated in the outflow. This changes in shape correlated with a better performance during exercise. In SGA, we found subtle differences in the RV that correlated with worse performance during exercise. These differences were bigger when SGA condition was combined with cardiovascular risk factors: smoking and overweight. Finally, we present a geometry processing technique for parcellating the RV cavity in 3 subvolumes for regional analysis without point-to-point correspondence.Presentamos un framework de análisis estadístico de forma para identificar remodelado cardiaco teniendo en cuenta la variabilidad natural de cada individuo. Utilizamos este framework en dos aplicaciones clínicas: triatletas e individuos nacidos pequeños-para-su-edad-gestacional (SGA). Identificamos el remodelado cardiaco en el caso de los triatletas: consistente en una dilatación del ventrículo izquierdo y un aumento de la masa miocárdica. En el ventrículo derecho (RV) la dilatación estaba concentrada en el tracto de salida. Este remodelado correlaciona con una mejor respuesta al ejercicio. En el análisis de SGA, encontramos sutiles cambios en el RV que correlacionaban con una peor respuesta al ejercicio. Estos cambios de forma fueron mayores si SGA se encontraba combinada con otros factores de riesgo cardiaco: tabaco y sobrepeso. Finalmente, presentamos una parcelación de la cavidad del RV en 3 subvolumenes para el análisis regional del RV cuando no es posible la correspondencia punto-a-punto.
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Lang, Claudia. "Structural analysis and therapeutic modulation of axonal remodeling following spinal cord injury." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-147615.
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Yang, Xiaofang. "Functional and Structural Dissection of the SWI/SNF Chromatin Remodeling Complex: A Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/330.
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The yeast SWI/SNF complex is the prototype of a subfamily of ATP-dependent chromatin remodeling complexes. It consists of eleven stoichiometric subunits including Swi2p/Snf2p, Swi1p, Snf5p, Swi3p, Swp82p, Swp73p, Arp7p, Arp9p, Snf6p, Snf11p, and Swp29p, with a molecular weight of 1.14 mega Daltons. Swi2p/Snf2p, the catalytic subunit of SWI/SNF, is evolutionally conserved from yeast to human cells. Genetic evidence suggests that SWI/SNF is required for the transcriptional regulation of a subset of genes, especially inducible genes. SWI/SNF can be recruited to target promotors by gene specific activators, and in some cases, SWI/SNF facilitates activator binding. Biochemical studies have demonstrated that purified SWI/SNF complex can hydrolyze ATP, and it can use the energy from ATP hydrolysis to generate superhelical torsion, mobilize mononucleosomes, enhance the accessibility of endonucleases to nucleosomal DNA, displace H2A/H2B dimers, induce dinucleosome and altosome formation, or evict nucleosomes. A human homolog of Swi2p/Snf2p, BRG1, is the catalytic subunit of the human SWI/SNF complex. Interestingly, isolated BRG1 alone is able to remodel a mononucleosome substrate. Importantly, mutations in mammalian SWI/SNF core subunits are implicated in tumorigenesis. Therefore, it remains interesting to characterize the role(s) of each subunit for SWI/SNF function. In this thesis project, I dissected SWI/SNF chromatin remodeling function by investigating the role of the SANT domain of the Swi3p subunit. Swi3p is one of the core components of SWI/SNF complex, and it contains an uncharacterized SANT domain that has been found in many chromatin regulatory proteins. Earlier studies suggested that the SANT domain of Ada2p may serve as the histone tail recognition module. For Swi3p, a small deletion of eleven amino acids from the SANT domain caused a growth phenotype similar to that of other swi/snf mutants.
In chapter I, I have reviewed recent findings in the function of chromatin remodeling complexes and discuss the molecular mechanism of their action.
In chapter II, I characterized the role of the SANT domain of Swi3p. I found that deletion of the SANT domain caused a defect in a genome-wide transcriptional profile, SWI/SNF recruitment, and more interestingly impairment of the SANT domain caused the dissociation of SWI/SNF into several subcomplexes: 1) Swi2p/Arp7p/Arp9p, 2) Swi3p/Swp73p/Snf6p, 3) Snf5p, and 4) Swi1p. Artificial tethering of SWI/SNF onto a LacZ reporter promoter failed to activate the reporter gene in the absence of the SANT domain, although Swi2p can be recruited to the LacZ promoter. We thus demonstrated that the Swi3p SANT domain is critical for Swi3p function and serves as a protein scaffold to integrate these subcomplexes into an intact SWI/SNF complex.
In Chapter III, I first characterized the enzymatic activity of the subcomplexes, especially the minimal complex of Swi2p/Arp7p/Arp9p. We found that this minimal subcomplex is fully functional for chromatin remodeling in assays including cruciform formation, restriction enzyme accessibility in mononucleosomal and nucleosomal array substrates, and mononucleosome mobility shift. However, it is defective in ATP-dependent removal of H2A/H2B dimers. Moreover, we found that Swi3p and the N-terminal acidic domain of Swi3p strongly interact with GST-H2A and H2B but not GST-H3 or H4 tails. We purified a SWI/SNF mutant (SWI/SNF-Δ2N) that lacks 200 amino acids within the N-terminal acidic domain of Swi3p. Intriguingly, SWI/SNF-Δ2N failed to catalyze ATP-dependent dimer loss, although this mutant SWI/SNF contains all the subunits and has intact ATP-dependent activity in enhancing restriction enzyme accessibility. These data help to further understand the molecular mechanism of SWI/SNF, and show that H2A/H2B dimer loss is not an obligatory consequence of ATP-dependent DNA translocation, but requires the histone chaperone function of the Swi3p subunit. Based on these findings, we proposed a new model of the structural and functional organization of the SWI/SNF chromatin remodeling machinery: SWI/SNF contains at least four distinct modules that function at distinct stages of the chromatin remodeling process. 1) Swi1p and Snf5p modules directly interact with gene specific activators and function as the recruiter; 2) Swi2p/Arp7p/Arp9p generates energy from ATP hydrolysis and disrupts histone/DNA interactions; and 3) Swi3p/Swp73p/Snf6p may play dual roles by integrating each module into a large remodeling complex, as well as functioning as a histone H2A/H2B chaperone to remove dimers from remodeled nucleosomes.
Chapter IV is a perspective from current work in this project. I first discuss the interest in further characterizing the essential role of Snf6p, based on its activation of LacZ reporter on its own. Using in vitro translated protein and co-IP studies, I tried to pinpoint the requirement of the SANT domain for SWI/SNF assembly. I found that Swi3p directly interacts with Swp73p, but not with other subunits. When Swi3p is first incubated with Swp73p, Swi3p also interacts with Snf6p, indicating that Swi3p indirectly interacts with Snf6p, therefore forming a subcomplex of Swi3p/Swp73p/Snf6p. This subcomplex can also be reconstituted using in vitro co-translation. Consistent with the TAP preparation of this subcomplex, partial deletion of the SANT domain of Swi3p does not affect the assembly of Swi3p/Swp73p/Snf6p in vitro. However, the assembly of SWI/SNF complex was not detected in the presence of eight essential in vitro translated subunits or from co-translation of all the subunits. I have discussed the interest in further characterizing the histone chaperone role of the Swi3p N-terminal acidic domain and the role of other core subunits of SWI/SNF such as Snf6p for transcriptional regulation.
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Sen, Payel. "STRUCTURAL AND FUNCTIONAL DELINEATION OF SUBUNITS AND DOMAINS IN THE SACCHAROMYCES CEREVISIAE SWI/SNF COMPLEX." OpenSIUC, 2011. https://opensiuc.lib.siu.edu/dissertations/432.
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Chromatin remodelers are ATP-dependent multisubunit assemblies that regulate transcription and other processes by altering DNA-histone contacts. The mechanism of action is based on the transduction of energy released by ATP hydrolysis to translocation on DNA and ultimately the movement of histones in cis or trans. Though the critical ATP burning and translocation activities are fulfilled by a conserved ATPase domain in the catalytic subunit, there are accessory domains and subunits that are speculated to regulate these activities. Important questions in the field center around the identification of these domains and subunits, whether they affect complex formation, substrate affinity or a critical step in remodeling. If they do affect remodeling, what is the structural basis of the regulatory activity. In this study, these questions have been addressed using the prototype remodeler SWI/SNF from budding yeast. ySWI/SNF is a 12 subunit complex that includes the catalytic subunit Swi2/Snf2. It affects 6% of the yeast genome being primarily involved in gene activation. We employed a systematic protein or domain deletion strategy and characterized the mutant complexes in vitro and in vivo. A key finding was that SWI/SNF is organized in distinct structural modules and that the Snf2 module regulates most of its activities. Snf2 is a central subunit in this module and the function of conserved regions within Snf2 were studied. The N terminus preceding the HSA and ATPase domain has three major roles - complex assembly, recruitment and regulation of catalytic activity. A novel SnAC domain located C terminal to ATPase domain was identified to play critical role in coupling ATP hydrolysis to nucleosome movement by acting as a histone anchor. Finally the tandem AT-hooks between SnAC and bromodomain serve as DNA binding domains but also affect ATPase activity and nucleosome mobilization independent of its binding activity. Taken together, this study provides a comprehensive overview of the function of regulatory domains in SWI/SNF.
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Manning, Benjamin J. "ATP-Dependent Heterochromatin Remodeling: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/795.
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Eukaryotic DNA is incorporated into the nucleoprotein structure of chromatin. This structure is essential for the proper storage, maintenance, regulation, and function of the genomes’ constituent genes and genomic sequences. Importantly, cells generate discrete types of chromatin that impart distinct properties on genomic loci; euchromatin is an open and active compartment of the genome, and heterochromatin is a restricted and inactive compartment. Heterochromatin serves many purposes in vivo, from heritably silencing key gene loci during embryonic development, to preventing aberrant DNA repeat recombination. Despite this generally repressive role, the DNA contained within heterochromatin must still be repaired and replicated, creating a need for regulated dynamic access into silent heterochromatin. In this work, we discover and characterize activities that the ATP-dependent chromatin remodeling enzyme SWI/SNF uses to disrupt repressive heterochromatin structure.
First, we find two specific physical interactions between the SWI/SNF core subunit Swi2p and the heterochromatin structural protein Sir3p. We find that disrupting these physical interactions results in a SWI/SNF complex that can hydrolyze ATP and slide nucleosomes like normal, but is defective in its ability to evict Sir3p off of heterochromatin. In vivo, we find that this Sir3p eviction activity is required for proper DNA replication, and for establishment of silent chromatin, but not for SWI/SNF’s traditional roles in transcription. These data establish new roles for ATP-dependent chromatin remodeling in regulating heterochromatin.
Second, we discover that SWI/SNF can disrupt heterochromatin structures that contain all three Sir proteins: Sir2p, Sir3p and Sir4p. This new disruption activity requires nucleosomal contacts that are essential for silent chromatin formation in vivo. We find that SWI/SNF evicts all three heterochromatin proteins off of chromatin. Surprisingly, we also find that the presence of Sir2p and Sir4p on chromatin stimulates SWI/SNF to evict histone proteins H2A and H2B from nucleosomes. Apart from discovering a new potential mechanism of heterochromatin dynamics, these data also establish a new paradigm of chromatin remodeling enzyme regulation by nonhistone proteins present on the substrate.
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Manning, Benjamin J. "ATP-Dependent Heterochromatin Remodeling: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/795.
Full textAbstract:
Eukaryotic DNA is incorporated into the nucleoprotein structure of chromatin. This structure is essential for the proper storage, maintenance, regulation, and function of the genomes’ constituent genes and genomic sequences. Importantly, cells generate discrete types of chromatin that impart distinct properties on genomic loci; euchromatin is an open and active compartment of the genome, and heterochromatin is a restricted and inactive compartment. Heterochromatin serves many purposes in vivo, from heritably silencing key gene loci during embryonic development, to preventing aberrant DNA repeat recombination. Despite this generally repressive role, the DNA contained within heterochromatin must still be repaired and replicated, creating a need for regulated dynamic access into silent heterochromatin. In this work, we discover and characterize activities that the ATP-dependent chromatin remodeling enzyme SWI/SNF uses to disrupt repressive heterochromatin structure.
First, we find two specific physical interactions between the SWI/SNF core subunit Swi2p and the heterochromatin structural protein Sir3p. We find that disrupting these physical interactions results in a SWI/SNF complex that can hydrolyze ATP and slide nucleosomes like normal, but is defective in its ability to evict Sir3p off of heterochromatin. In vivo, we find that this Sir3p eviction activity is required for proper DNA replication, and for establishment of silent chromatin, but not for SWI/SNF’s traditional roles in transcription. These data establish new roles for ATP-dependent chromatin remodeling in regulating heterochromatin.
Second, we discover that SWI/SNF can disrupt heterochromatin structures that contain all three Sir proteins: Sir2p, Sir3p and Sir4p. This new disruption activity requires nucleosomal contacts that are essential for silent chromatin formation in vivo. We find that SWI/SNF evicts all three heterochromatin proteins off of chromatin. Surprisingly, we also find that the presence of Sir2p and Sir4p on chromatin stimulates SWI/SNF to evict histone proteins H2A and H2B from nucleosomes. Apart from discovering a new potential mechanism of heterochromatin dynamics, these data also establish a new paradigm of chromatin remodeling enzyme regulation by nonhistone proteins present on the substrate.
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Reglin, Bettina, Timothy W. Secomb, and Axel R. Pries. "Structural Control of Microvessel Diameters: Origins of Metabolic Signals." FRONTIERS MEDIA SA, 2017. http://hdl.handle.net/10150/626059.
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Diameters of microvessels undergo continuous structural adaptation in response to hemodynamic and metabolic stimuli. To ensure adequate flow distribution, metabolic responses are needed to increase diameters of vessels feeding poorly perfused regions. Possible modes of metabolic control include release of signaling substances from vessel walls, from the supplied tissue and from red blood cells (RBC). Here, a theoretical model was used to compare the abilities of these metabolic control modes to provide adequate tissue oxygenation, and to generate blood flow velocities in agreement with experimental observations. Structural adaptation of vessel diameters was simulated for an observed mesenteric network structure in the rat with 576 vessel segments. For each mode of metabolic control, resulting distributions of oxygen and deviations between simulated and experimentally observed flow velocities were analyzed. It was found that wall-derived and tissue-derived growth signals released in response to low oxygen levels could ensure adequate oxygen supply, but RBC-derived signals caused inefficient oxygenation. Closest agreement between predicted and observed flow velocities was obtained with wall-derived growth signals proportional to vessel length. Adaptation in response to oxygen-independent release of a metabolic signal substance from vessel walls or the supplied tissue was also shown to be effective for ensuring tissue oxygenation due to a dilution effect if growth signal substances are released into the blood. The present results suggest that metabolic signals responsible for structural adaptation of microvessel diameters are derived from vessel walls or from perivascular tissue.
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Fröhlich, Chris [Verfasser]. "Structural insights into oligomerization and mitochondrial remodeling of dynamin 1-like protein / Chris Fröhlich." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1043957839/34.
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Kourlioros, Antonios. "Structural remodeling, inflammation and the role of statins in atrial fibrillation following cardiac surgery." Thesis, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547611.
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Gong, Wei, and 龔蔚. "A structural equation model to unveil the effect of human behaviour to the satisfaction of sustainable refurbishment for high-rise residential buildings." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208029.
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Improving the energy performance of existing building refurbishment has been identified as one of the key measures to reduce greenhouse gases (GHGs) emissions and combat climate change. According to Environmental Protection Department, buildings in Hong Kong take up almost 90% of urban electricity consumption. Sustainable building refurbishment not only can help decrease energy consumption but may also improve building’s overall condition, and thus prolong its life, uplift the living conditions, ensure better health and safety as well as minimize the negative effects to environment.
To respond to the energy emission reduction, many researchers focus on technical improvements through various refurbishment methods. However, there is a research gap in determining the appropriate refurbishment solutions for high-rise residential buildings in developed cities like Hong Kong. The challenge is aggravated as there are a number of owners and occupants in multi-storey residential buildings and their behaviour can be very different. Albeit more and more attentions have been attributed to human behaviours and occupant satisfaction, little has been done to examine their effects to the choices and success of sustainable refurbishment solutions. This study aims to systematically analyse the effect of human behaviour to the satisfaction of sustainable refurbishment by setting up a unified model so as to maximize the opportunity for emission reduction without sacrificing the satisfaction of owners and occupants.
Literature review was first conducted to attain the knowledge of sustainable refurbishment and human behaviour. Then, a list of potential sustainable building refurbishment method items was compiled under five criteria through literature review. In order to further examine the suitability of sustainable building refurbishment methods in Hong Kong scenario from the perspective of owners and occupants, a questionnaire survey was administered. Following that, literature review and interviews were carried out to identify a set of critical success factors (CSFs) of electing sustainable refurbishment strategies as well as key performance indicators (KPIs) of a sustainable building refurbishment scheme. Based on that, another questionnaire survey was conducted to examine the occupants’ perception to the relative importance of the identified CSFs and KPIs. Finally, a structural equation model was set up to unveil the relationships between occupants’ satisfaction and project success, and the findings were validated through expert interviews. The results shows that disruption is the most important factors affecting occupants’ decisions, followed by Management and Organization; Comfort; Cost; and Health and Safety. The technological and environmental accomplishments are proven to be the most important KPIs to the success of a sustainable building refurbishment project. The model developed can help decision-makers select on suitable sustainable building refurbishment methods to meet the social expectations of occupants while achieving the carbon emission target.published_or_final_version
Civil Engineering
Master
Master of Philosophy
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Prasad, Punit. "MECHANISMS OF CHROMATIN REMODELING BY ISWI FAMILY OF REMODELERS: A FUNCTIONAL AND STRUCTURAL INSIGHT INTO THE ROLE OF THE Itc1 SUBUNIT OF ISW2 REMODELING COMPLEX." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/dissertations/208.
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ISWI type remodelers mobilize and space nucleosomes. These ATP-dependent remodeling complexes have a relatively small number of subunits (2-4) as compared to other classes of remodelers such as SWI/SNF, RSC and INO80/SWR-C. The accessory subunits of some of the ISWI remodelers from yeast have been shown to contact extensively extranucleosomal or linker DNA and appear to be involved in regulating the movement of nucleosomes along DNA. In the ISW2 complex, the Itc1 (accessory) and Isw2 (catalytic) subunits make up the minimal active complex. ISW2 moves mononucleosomes to the center of DNA as a function of the length of extranucleosomal DNA. This same property is also responsible for the nucleosome spacing activity of ISW2 observed in nucleosomal arrays. The Itc1 subunit has been shown to contact the linker DNA starting at the entry site of the nucleosome and extending over at least 59 bp of linker DNA. The role of the Itc1 subunit in regulating the remodeling activity of the ISW2 complex was investigated by deleting different regions of Itc1 and monitoring the effects on complex assembly, ATPase activity and nucleosome mobilization activities of ISW2. A key finding was that a domain of 322 amino acids at the C-terminus of Itc1 was crucial for regulating nucleosome movement. Deletion of this domain causes ISW2 to move nucleosomes from one end to the other of DNA without pausing or stopping at a central position unlike wild type (WT) ISW2. The missing domain appears to be responsible for sensing linker DNA length to stall or stop remodeling when linker DNA is shortened to certain lengths. Loss of another region of 122 amino acids near the C-terminus was found to adversely affect the processivity of the ISW2 complex. The regions of Itc1 contacting the different parts of linker DNA were mapped by site-directed DNA cross-linking and peptide mapping. The mapping data along with molecular modeling provided an idea of the spatial arrangement of Itc1 with linker DNA like that previously obtained for the Isw2 subunit. The domain of Itc1 that interacts with Isw2 and is required for complex assembly was also identified. Next, we have used an approach of arresting nucleosome movement by placing DNA gaps that block translocation to study the changes in contacts of Itc1 with linker DNA upon ATP hydrolysis and remodeling. Results from such experiments highlighted massive conformational changes in both Itc1 and Isw2, which cause bending of the extranucleosomal DNA and assist to "pump" it inside the nucleosome for DNA translocation. ISW1 complexes have a common catalytic subunit but different accessory subunits. Considering the vital role that accessory subunits play in modulating the catalytic activities of remodelers, a comparative analysis of the remodeling properties of ISW1a, ISW1b and ISW2 complexes with various nucleosomal substrates was done. The analysis revealed significant differences in substrate specificities and translocation mechanisms among these three remodelers. The most intriguing observation was that ISW1a requires two sites on DNA to initiate translocation, unlike other known remodeling complexes. One of the sites is at SHL2, signature of all remodelers characterized to date, whereas the other unique site is 10 bp from the nucleosome edge on the extranucleosomal DNA. These mechanistic differences exhibited by different complexes of the same family underscore the importance of auxiliary subunits as regulators of enzyme function.
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Nguyen, Vu Quang. "Structural insights into the assembly and dynamics of the ATP-dependent chromatin-remodeling complex SWR1." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11606.
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The ATP-dependent chromatin remodeling complex SWR1 exchanges a variant histone H2A.Z-H2B dimer for a canonical H2A-H2B dimer at nucleosomes flanking histone-depleted regions, such as promoters. This localization of H2A.Z is conserved throughout eukaryotes. SWR1 is a 1 Mega-Dalton complex containing 14 different polypeptides, including the AAA+ ATPases Rvb1 and Rvb2. Using electron microscopy, we obtained the three-dimensional structure of SWR1 and mapped its major functional components. Our data show that SWR1 contains a single hetero-hexameric Rvb1/2 ring that, together with the catalytic subunit Swr1, brackets two independently assembled multi-subunit modules. We also show that SWR1 undergoes a large conformational change upon engaging a limited region of the nucleosome core particle. Our work suggests an important structural role for the Rvb1/2 ring and a distinct substrate-handling mode by SWR1, thereby providing the first structural framework for understanding the complex dimer-exchange reaction.
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Böhnke, Ann-Kristin [Verfasser]. "Structural remodeling of L-type calcium channel subunits in human and murine atherosclerosis / Ann Kristin Böhnke." Bonn : Universitäts- und Landesbibliothek Bonn, 2012. http://d-nb.info/1047622653/34.
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Kotiya, Akhilesh A. "Mechanical characterisation and structural analysis of normal and remodeled cardiovascular soft tissue." Texas A&M University, 2008. http://hdl.handle.net/1969.1/85903.
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Characterization of multiaxial mechanical properties of cardiovascular soft tissue
is essential in order to better understand their growth and remodeling in homeostatic
conditions and in response to injury or pathological conditions. Though numerous
phenomenological models have been proposed to characterize such multiaxial
mechanical behavior, the approach has certain drawbacks regarding experimental
determination of the model coefficients. We propose a method that aims to overcome
these drawbacks. The approach makes use of orthogonal polynomials to fit the biaxial
test data and suggests a way to derive the strain energy function from these analytical fits
by way of minimizing the deviation of the behavior from hyperelastic ideal. Using the
proposed method, a strain energy function for a lymphatic vessel is derived and the
method is compared with traditional ones that used non-orthogonal polynomials as
independent variables in the functional form for strain energy. The unique coefficient
values obtained using the proposed method, for the first time gives us an opportunity to
attribute a physical characteristic of the material to the coefficient values. The method
also provides a way to assess two different material behaviors by way of comparing their
deviation from the hyperelastic behavior when a similar test protocol is used to collect
the data, over a similar deformation range and the order of polynomial function is chosen
so as to give a similar error of fit. The behavior of mesenteric lymph vessels from
normal cows, cows subjected to sham surgery and those subjected to 3 days of
edematous conditions by venous occlusion are compared using this method. To be able
to better understand the changes in mechanical behavior, morphological analysis of the
vessels was carried out and the geometric and structural changes in these vessels were
studied. We found that the behavior of bovine mesenteric lymph vessels subjected to a high flow condition shows a small difference in their mechanical behavior as compared
to the vessels from normal a cow and a cow subjected to sham surgery. The geometry
and structure of these vessels also showed marked differences from the other two. The
thickness to radius ratio increased and a rise in percentage of area occupied by smooth
muscle cells and medial collagen was observed. Though not all the differences were
statistically significant, we conclude that the behavior and the morphology are
suggestive of the remodeling of the vessel in response to altered hemodynamic
conditions and require further investigation.
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Barrio, Garcia Clara [Verfasser], and Roland [Akademischer Betreuer] Beckmann. "Structural view on 60S ribosome biogenesis : remodeling and quality control mechanisms / Clara Barrio Garcia ; Betreuer: Roland Beckmann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1115144901/34.
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Shah, Claudio S. [Verfasser]. "Structural and mechanistic analysis of membrane remodeling by Eps15-homology domain-containing protein 2 / Claudio S. Shah." Berlin : Freie Universität Berlin, 2013. http://d-nb.info/1044891912/34.
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Lang, Claudia Nicole [Verfasser], and Hans [Akademischer Betreuer] Straka. "Structural analysis and therapeutic modulation of axonal remodeling following spinal cord injury / Claudia Lang. Betreuer: Hans Straka." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1025822056/34.
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Gomez-Arroyo, Jose. "Metabolic Remodeling and Mitochondrial Dysfunction in Maladaptive Right Ventricular Hypertrophy Secondary to Pulmonary Arterial Hypertension." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3257.
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Right ventricular dysfunction is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the development of chronic left heart failure, data describing such metabolic remodeling in failing right ventricular tissue remain incomplete. In the present dissertation we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy. Two different rat models of RV hypertrophy were studied. The model of right ventricular failure (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor- coactivator-1α, peroxisome proliferator- activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor- coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor- coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in right ventricular failure tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from right ventricular failure tissue had a significantly reduced ADP- stimulated (state 3) rate for complex I. Conversely, functional right ventricular hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor- coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-right ventricular tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated right ventricular pressure-overload. We conclude that right ventricular dysfunction, but not functional right ventricular hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.
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Bratu, Ioana. "Long growth, structural remodeling, surfactant levels, and lung function after reversible fetal lamb tracheal occlusion in congenital diaphragmatic hernia." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33383.
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The effects of reversible fetal tracheal occlusion (TO), and antenatal glucocorticoids on lung growth, structure, surfactant levels, and function were assessed in a lamb hypoplastic lung model of congenital diaphragmatic hernia (CDH). CDH, CDH+TO, CDH+TO+release of the tracheal occlusion one week before delivery (TR), and unoperated twin controls were compared. TO+/-TR partially normalized the hypoplastic lungs of CDH: they accelerated growth of both lungs and led to structural maturity. Only TO thinned the medial area of small pulmonary arteries closer to control values. Despite TO, TR, and glucocorticoids, lungs from lambs with CDH have dysfunctional type II cells with decreased surfactant levels. Nonetheless, CDH+TO lambs showed normal oxygenation, ventilation, and compliance over untreated CDH, with a clear survival advantage over an eight hour resuscitation. TR one week before delivery had no added benefit in terms of lung function. It appears that surfactant independent mechanisms such as pulmonary growth and structural changes are of foremost importance in relating to improved compliance, oxygenation, and ventilation of CDH+TO animals.
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Harrer, Nadine [Verfasser], and Peter [Akademischer Betreuer] Becker. "Probing the conformation of ISWI-type chromatin remodeling enzymes by an integrative structural approach / Nadine Harrer ; Betreuer: Peter Becker." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1185979174/34.
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Exler, Josef H. [Verfasser], and Gernot [Akademischer Betreuer] Längst. "Nuclear architecture and structural dynamics : molecular basis of chromatin remodeling induced by human ISWI machines / Josef H. Exler. Betreuer: Gernot Längst." Regensburg : Universitätsbibliothek Regensburg, 2010. http://d-nb.info/1022819739/34.
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Singh, Mahavir. "Biochemical and structural investigations of the retinoblastoma protein, its binding partners, and the BRG1 protein - a subunit of human SWI, SNF remodeling complexes." [S.l.] : [s.n.], 2006. http://deposit.ddb.de/cgi-bin/dokserv?idn=979981875.
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Santos, Karine [Verfasser], Markus [Akademischer Betreuer] Wahl, Ralf [Akademischer Betreuer] Ficner, Detlef [Akademischer Betreuer] Doenecke, Marina [Akademischer Betreuer] Rodnina, Kai [Akademischer Betreuer] Tittmann, and Dirk [Akademischer Betreuer] Fasshauer. "Structural and functional studies of the spliceosomal RNP remodeling enzyme Brr2 / Karine Santos. Gutachter: Markus Wahl ; Ralf Ficner ; Detlef Doenecke ; Marina Rodnina ; Kai Tittmann ; Dirk Fasshauer. Betreuer: Markus Wahl." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://d-nb.info/1044362049/34.
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Santos, Karine Verfasser], Markus [Akademischer Betreuer] Wahl, Ralf [Akademischer Betreuer] Ficner, Detlef [Akademischer Betreuer] [Doenecke, Marina [Akademischer Betreuer] Rodnina, Kai [Akademischer Betreuer] Tittmann, and Dirk [Akademischer Betreuer] Fasshauer. "Structural and functional studies of the spliceosomal RNP remodeling enzyme Brr2 / Karine Santos. Gutachter: Markus Wahl ; Ralf Ficner ; Detlef Doenecke ; Marina Rodnina ; Kai Tittmann ; Dirk Fasshauer. Betreuer: Markus Wahl." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2013. http://d-nb.info/1044362049/34.
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El, Masri Rana. "Remodeling of heparan sulfate : functional and structural characterization of human endosulfatase HSulf-2 The sweet side of extracellular sulfatases Expression and purification of recombinant extracellular sulfatase HSulf-2 allows deciphering of enzyme sub-domain coordinated role for the binding and 6-O-desulfation of heparan sulfate." Thesis, Université Grenoble Alpes (ComUE), 2019. http://www.theses.fr/2019GREAV037.
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Les Héparanes Sulfates (HS) sont de polysaccharides complexes impliqués dans de nombreux processus biologiques. La structure des HS est contrôlée à la surface cellulaire par une famille particulière d‟endosulfatases extracellulaires, les Sulfs. Les Sulfs modifient dramatiquement les propriétés fonctionnelles des HS et sont impliqués dans de nombreux processus physiopathologiques, notamment le cancer. Ces enzymes se composent de deux domaines: un domaine catalytique (CAT) contenant le site actif et un domaine basique hydrophile (HD) responsable de la liaison aux HS. Le but de mon projet de thèse est de caractériser les propriétés structurales et fonctionnelles de la forme humaine HSulf-2, qui demeure à ce jour très mal connues. Dans ce cadre, nous avons tout d‟abord étudié les mécanismes de reconnaissance enzyme/substrat et caractérisé deux nouveaux motifs de reconnaissance des HS sur ces enzymes, responsable de leur activité. En utilisant des oligosaccharides naturels et synthétiques, nous avons aussi démontré que le domaine HD n'est pas essentiel pour la reconnaissance des HS, mais est permet une désulfatation processive et orientée du polysaccharide. De plus, nous avons identifié un tétrasaccharide comme étant la taille oligosaccharidique minimale requise pour l'activité de HSulf-2. Nos résultats nous ont permis de proposer un nouveau modèle décrivant le processus de désulfatation du HS par HSulf-2. D'autre part, nous avons montré que HSulf-2 est un protéoglycane, car il contient une modification post-traductionnelle unique (chaîne CS de Chondoitin Sulfate) sur son domaine HD. Cette chaîne diminue l'activité enzymatique et la liaison aux HS in vitro. Dans le microenvironnement tumoral, en utilisant un modèle de tumeur mammaire orthotopique murin, nous avons montré que la chaîne CS est libérée par protéolyse, conduisant à l'activation de HSulf-2, augmentant la capacité des tumeurs à se développer et à se transformer en métastase. Finalement, nous avons réalisé une étude structurale des Sulfs. Nous avons choisi d‟étudier séparément les deux domaines (CAT et HD). Des essais de cristallogenèse ont été menés pour le domaine CAT afin de résoudre sa structure par cristallographie aux rayons X, mais n‟ont pu aboutir. En ce qui concerne le HD, nous avons mis en place un protocole de production et de purification de HD d‟une manière recombinante et nous avons initiés une étude par RMN ainsi que d'autres techniques biophysiques afin de caractériser structuralement le domaine et d'identifier les sites de liaison aux HS. Nos résultats préliminaires suggèrent que la HD est un domaine non structuré, à l'exception de ses parties N- et C-terminales. L‟ensemble de ces travaux devrait nous permettre de mieux comprendre ces importants mécanismes de régulation des HS et de d‟envisager de nouvelles stratégies anticancéreuses ciblant les SulfsHeparan Sulfate (HS) are complex polysaccharides involved in many biological processes. The structure of HS is regulated at the cell surface by unique extracellular endosulfatases, the Sulfs. Sulfs dramatically change HS functional properties, thereby being implicated in many physiopathological processes including cancer. Sulfs features two domains: a catalytic domain (CAT) that comprises the active site, and an hydrophilic basic domain (HD) responsible for HS binding. The aim of my PhD project is to characterize the structural and the functional properties of the human for HSulf-2, which remains poorly understood. In this context, we have first studied the enzyme/substrate recognition mechanisms. We identified two novel HS binding motifs on these enzymes implicated in their activity. In addition, using natural and synthetic oligosaccharides, we demonstrated that the HD is not essential for HS recognition, but is directs the processive and orientated desulfation of the polysaccharide. Moreover, we showed that a tetrasaccharide is the minimal oligosaccharide size required for HSulf-2 activity. Our results enabled us to propose a new model depicting the desulfation process of HS by the Sulfs. Second, we have shown that HSulf-2 is a proteoglycan, given that it harbors a unique PTM (Chondroitin Sulfate, CS chain) on its HD domain. This chain decreases enzyme activity and HS binding in vitro. In the tumoral microenvironment, using a murine orthotropic mammary tumor model, we showed that the CS chain is lost by proteolytic processing, leading to the activation of HSulf-2, and the promotion of tumor growth, vascularization and metastasis. Finally, we have undertaken the structural characterization of the Sulfs. For this, we decided to study separately the two domains found in these enzymes (CAT and HD). Crystallogenesis assays were undertaken for the CAT domain to solve its structure by X-ray crystallography, but were unsuccessful. Regarding the HD, we set up a protocol of production and purification of recombinant HD and we initiated NMR studies and other biophysics analyses in order to structurally characterize the domain and to identify the HS binding sites. Our preliminary results suggest that the HD is an unstructured domain, except for its N- and C-terminal parts. Overall, our data provide significant insights into this critical regulatory step of HS function
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Grüne, Tim. "Structural studies on ISWI, an ATP-dependent nucleosome remodelling factor." Université Joseph Fourier (Grenoble), 2003. http://www.theses.fr/2003GRE10107.
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Saeed, Yawer. "Structural and functional remodelling of the atrioventricular node with ageing." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/structural-and-functional-remodelling-of-the-atrioventricular-node-with-ageing(9a72ee2b-89e0-4d08-a731-22282c10af74).html.
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Introduction: Factors that influence atrioventricular (AV) nodal conduction are complex and not well understood. Multiple studies have been performed to explain the mechanisms responsible for AV nodal conduction but the AV node (AVN) remains a "riddle". With ageing there is an increase in the incidence of AV nodal dysfunction leading to AV block. Methodology: I have performed electrophysiological (EP) and immunohistochemistry experiments on male Wistar-Hanover rats aged 3 months (equivalent to 20 year old humans; n=24) and 2 years (equivalent to 70 year old humans; n=15). AH interval, Wenkebach cycle length (WCL) and AV node effective refractory period (AVNERP) were measured. I used cesium (Cs+ = 2 mM) to block HCN channels responsible for the funny current "If " (and therefore the membrane clock), and ryanodine (2 μM) to block RyR2 channels responsible for Ca2+ release from the sarcoplasmic reticulum (and therefore the Ca2+ clock) in the two age groups. Protein expression in each group (from n=9 young and n=8 old rats) from different regions of the AV conduction axis: inferior nodal extension (INE), compact node (CN), proximal penetrating bundle (PPB) and distal penetrating or His bundle (His) were studied using immunofluorescence and confocal microscopy. The expression of the gap junction channels Cx43 and Cx40 and ion channel’s including HCN4 (responsible for If current), Nav1.5 (major cardiac Na+ channel responsible for INa) and Cav1.3 (L-type Ca2+ channel), and calcium handling proteins, RyR2 and SERCA 2a (involved in Ca2+ release and reuptake from cardiac sarcoplasmic reticulum, SR) were studied. Semi-quantitative signal intensity of these channels was measured using Volocity software. Structural characteristics of the tissue were studied using histology (Masson’s trichome stain and picrosirius red stain for collagen). Statistical analysis was performed with Prism 6.0. Electrophysiological measurements were performed using Spike2.Results: Without drugs to block the If current and Ca2+ release from the SR, there was a significant prolongation of the AH interval (P<0.005), WCL (P<0.005) and AVNERP (P<0.001) with ageing. In young rats (but not old rats), Cs+ prolonged the AH interval (P<0.001), WCL (P<0.01) and AVNERP (P<0.01). Ryanodine prolonged the AH interval (P<0.01) and WCL (P<0.01) in young and old rats. Immunofluorescence revealed that with ageing: Cx43 is downregulated in the PPB and His (P<0.05); Cx40 is upregulated in the INE and CN (P<0.05); HCN4 is downregulated in the His bundle (P=0.05); Nav1.5 is downregulated in the CN and PB (P<0.05); RyR2 is downregulated in the CN and PPB (P<0.05); SERCA2a and Cav1.3 is upregulated in the PPB (P<0.05). Histology confirmed that with ageing that the cells of CN, PPB and His are more loosely packed and irregularly arranged. There is cellular hypertrophy, decrease in the number of nuclei and increase in the collagen content with ageing. The clinical study has shown that elderly patients with syncope and cardiac conduction system disease are at risk of high mortality and recurrent transient loss of consciousness. Conclusion: For the first time, we have shown that both HCN and RyR2 channels play an important role in AV nodal conduction. With ageing the expression of HCN4 and the role of If in AV nodal conduction decreases, whereas the role of Ca2+ clock in AV nodal conduction was unchanged, although the expression of RyR2 and SERCA2a changes. The clinical study suggests that AV nodal disease is associated with significant morbidity and higher mortality among elderly patients who present with transient loss of consciousness.
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Yang, Quansheng. "MECHANISM OF RNA REMODELING BY DEAD-BOX HELICASES." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1173812791.
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Aguilar, Gurrieri Carmen. "Etudes structurales sur l'assemblage du nucléosome." Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV017/document.
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Au sein du noyau, l'ADN est organise en chromatine dont l'unité de base est le nucléosome. La structure de la chromatine est très dynamique, ce qui est nécessaire pour la plupart des opérations qui se produisent dans l'ADN telles que la réplication, la transcription, la réparation et la recombinaison. Le nucléosome est constitué de deux dimères H2A/H2B et deux dimères H3/H4 associés avec 147 paires de bases d'ADN. La protéine Nap1 est un chaperon d'histone H2A/H2B impliquée dans l'assemblage et démontage des nucléosomes. Nap1 protège les interactions non spécifiques entre l'ADN chargé négativement et les dimères H2A/H2B chargés positivement, afin de permettre la formation de la structure ordonnée des nucléosomes. Lors de l'assemblage des nucléosomes, les dimères d'histones H3/H4 sont déposés en premier lieu, suivi par le dépôt de dimères H2A/H2B. Lors du démontage du nucléosome, les dimères H2A/H2B sont retirés avant le retrait des dimères H3/H4. La determination de la structure du complexe Nap1-H2A/H2B pourra permettre une meilleure compréhension du processus d'assemblage du nucléosome. Dans cette étude, nous voulons comprendre comment le chaperon Nap1 cible spécifiquement les dimères d'histones H2A/H2B pour l'assemblage des nucléosomes. Notre objectif est de caractériser la structure et la fonction du complexe de Nap1-H2A/H2B. Ainsi nous nous sommes tout d'abord intéresse à la stoechiometrie de ce complexe. Nous avons trouvé qu'un dimère de Nap1 s'associe à un dimère H2A/H2B (Nap1_2-H2A/H2B). D'autre part, l'analyse par spectrométrie de masse non-dénaturante a montré que ce complexe de base peut s'oligomériser et contenir jusqu'à 6 copies de Nap1_2-H2A/H2B. L'analyse de ce complexe par spectrométrie de masse non-dénaturant a montré que ce complexe peu oligomériser dans un grand complexe contenant jusqu'à 6 copies de Nap1_2-H2A/H2B. Nous avons également obtenu la première structure cristalline à basse résolution de ce complexe. L'analyse du même complexe par microscopie électronique à coloration négative a révélé la présence en solution du même oligomère que dans l'unité asymétrique du cristal, qui contient aussi 6 copies de Nap1_2-H2A/H2B. Ainsi, nous avons pu mettre en évidence de nouvelles interfaces d'interaction entre les différents composants de ce complexe qui nous permettent de mieux comprendre le processus d'assemblage des nucléosomes. Le remodelage de la chromatine permet l'expression des gènes eucaryotes. Ce remodelage nécessite des enzymes telles que des histone acétyltransférases (HAT) et les chaperons d'histones. Les HATs acétylent les chaînes latérales des lysines. Il a été proposé que les HATs et les histones chaperons agissent en synergie pour moduler la structure de la chromatine pendant la transcription. La HAT p300 a été proposé d'interagir avec l'histone chaperon Nap1. Nous avons entrepris de caractériser cette interaction. Malheureusement, nos expériences n'ont pas pu détecter d'interaction directe entre ces protéinesAssembly of chromatin is an essential process that concerns most DNA transactions in eukaryotic cells. The basic repeating unit of chromatin are nucleosomes, macromolecular complexes that consist of a histone octamer that organizes 147 bp of DNA in two superhelical turns. Although, the structures of nucleosomes are known in detail, their assembly is poorly understood. In vivo, nucleosome assembly is orchestrated by ATP-dependent remodelling enzymes, histone-modifying enzymes and a number of at least partially redundant histone chaperones. Histone chaperons are a structurally diverse class of proteins that direct the productive assembly and disassembly of nucleosomes by facilitating histone deposition and exchange. The currently accepted model is that nucleosome assembly is a sequential process that begins with the interaction of H3/H4 with DNA to form a (H3/H4)2 tetramer-DNA complex. The addition of two H2A/H2B dimers completes a canonical nucleosome. High-resolution structures of histone chaperons in complex with H3/H4 histones have resulted in detailed insights into the process of nucleosome assembly. However, our understanding of the mechanism of nucleosome assembly has been hampered by the as yet limited number of co-crystal structures of histone–chaperone complexes. In particular it remains unclear how histone chaperons mediate H2A/H2B deposition to complete nucleosome assembly. In this work, we have investigated the role of the H2A/H2B chaperon Nap1 (Nucleosome assembly protein 1) in nucleosome assembly. We have determined the crystal structure of the complex between Nap1 and H2A/H2B and analysed the assembly by various biophysical methods. The structure shows that a Nap1 dimer binds to one copy of H2A/H2B (Nap1_2-H2A/H2B). A large ~550 kDa macromolecular assembly containing 6 copies of the Nap12-H2A/H2B complex is seen in the asymmetric crystallographic unit. We confirmed by both non-denaturing mass spectroscopy and negative stain electron microscopy studies that this assembly is the predominant form of the Nap1_2-H2A/H2B complex in solution. We further investigated the potential interplay between p300-mediated histone acetylation and nucleosome assembly. Together, the structure and associated functional analysis provide a detailed mechanism for the Nap1 chaperon activity, its role in H2A/H2B deposition and in nucleosome assembly
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Carlsson, Lena. "The muscle cytoskeleton of mice and men : Structural remodelling in desmin myopathies." Doctoral thesis, Umeå universitet, Anatomi, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-83451.
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The muscle fibre cytoskeleton of skeletal and heart muscle cells is composed mainly of intermediate filaments (IFs), that surround the myofibrils and connect the peripheral myofibrils with the sarcolemma and the nuclear membrane. Desmin is the first muscle specific IF protein to be produced in developing muscles and is the main IF protein in mature muscles. In skeletal muscle, desmin is particularly abundant at myotendinous and neuromuscular junctions. In the heart an increased amount of desmin is found at intercalated discs and in Purkinje fibres of the conduction system. Interactions between the IFs themselves, and between IFs and other structures such as Z-discs and the sarcolemma, are mediated by intermediate filament associated proteins (IFAPs). A transgenic mice model, which lacks the desmin gene have been developed to study the function of desmin. In these mice, morphological abnormalities are observed in both heart and skeletal muscles. Similar defects have been observed in human myopathies, caused by different mutations in the desmin gene. In the present thesis, skeletal and heart muscles of both wild type and desmin knock-out (K/O) mice have been investigated. Furthermore the cytoskeletal organisation in skeletal muscles from human controls and from a patient with desmin myopathy was examined. In the desmin K/O mice, no morphological alterations were observed during embryogenesis. These mice postnatally developed a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. Ruptures of the sarcolemma appear to be the primary event leading to muscle degeneration and fibrosis both in cardiac and affected skeletal muscles. In the heart the muscle degeneration gave rise to calcifications, whereas in skeletal muscles regeneration of affected muscle was seen. In mature wild type mice, the IF proteins synemin and paranemin, and the IFAP plectin were present together with desmin at the myofibrillar Z-discs, the sarcolemma, the neuromuscular junctions and the myotendinous junctions. Nestin was only found in these junctional regions. In desmin K/O mice, all four proteins were detected at neuromuscular and myotendinous junctions. The normal network of synemin and paranemin were not observed, whereas the distribution of plectin was preserved. In normal human muscles, synemin, paranemin, plectin and αB-crystallin were colocalised with desmin in between the myofibrils, at the sarcolemma and at myotendinous and neuromuscular junctions. In the human desmin myopathy, the distribution of desmin varied considerably. A normal pattern was seen in some fibres areas, whereas other regions either contained large subsarcolemmal and intermyofibrillar accumulations of desmin or totally lacked desmin. Nestin, synemin, paranemin, plectin and αB-crystallin also exhibited an abnormal distribution. They were often aggregated in the areas that contained accumulations of desmin. In cultured satellite cells from the patient, a normal network of desmin was present in early passages, whereas aggragates of desmin occurred upon further culturing. In the latter, also the nestin network was disrupted, whereas vimentin showed a normal pattern. αB-crystallin was only present in cells with a disrupted desmin network. Plectin was present in a subset of cells, irrespective of whether desmin was aggregated or showed a normal network. From the present study it can be concluded that an intact desmin network is needed to maintain the integrity of muscle fibres. Desmin may be an important component in the assembly of proteins, which connect the extrasarcomeric cytoskeleton with the extracellular matrix.
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Alayoubi, Samha. "Load-dependent electrophysiological and structural cardiac remodelling studied in ultrathin myocardial slices." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/44552.
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Introduction: Myocardial slices are becoming an established system to study cardiac electrophysiology and pharmacological research and development. Unlike other preparations, cardiac slices are a multicellular preparation that has an intermediate, adequate complexity required for this research. Previous studies have successfully obtained slices from human biopsies and animal models, where the electrical and structural parameters could be maintained for several hours - a process which is comparable to other preparation types. Therefore, we aimed to use left ventricular myocardial slices obtained from rat models of mechanical unloading (HAHLT) and from two models of overload (TAC and SHR), to investigate electrophysiological and structural alterations in these models. Methods: Mechanical unloading was achieved by heterotopic abdominal heart and lung transplantation (HAHLT, 8 weeks) and overload was induced by thoracic aortic constriction (TAC, 10 and 20 weeks) in male Lewis rats. Spontaneous hypertensive rats (SHR) were also used as a second model of overload and were primarily induced by hypertension (3, 12 and 20 months). Brown Norway and Wistar Kyoto rats were used as the control groups for SHR. Myocardial slices from the left ventricle (LV) free wall were cut (300-350 μm thick) tangentially to the epicardial surface using a high-precision slow-advancing Vibratome and were point-stimulated using a multi-electrode array system (MEA), therefore, acquiring field potentials (FPs). Field potential duration (FPD) and conduction velocity (CV) were analysed locally and transmurally across the LV free wall. In addition, FPD heterogeneity within each slice was calculated. For the SHR group, the same slices used for the MEA recording were preserved and used subsequently to measure Cx43, Nav1.5 protein levels and fibrosis. Results: Slices obtained from normal rat hearts that are chronically unloaded were found to develop atrophy at a whole heart level. They showed an increase in FPD and its heterogeneity with preserved conduction properties when compared to controls. In TACs, an in vivo whole heart function assessment confirmed hypertrophy with no signs of cardiac dysfunction. Slices from TAC rats showed an increase in FPD at both 10 and 20 weeks after banding. FPD heterogeneity was increased at 10 weeks but normalised at 20 weeks. Changes in CV properties were observed in this group, showing a faster CV and longitudinal conduction velocity (CVL) at 10 weeks and no change at 20 weeks. Transverse conduction velocity (CVT) was unchanged in the TAC group. In SHRs, however, hypertrophy was confirmed and signs of dysfunction in the aged group (20 months) were observed due to the decrease in EF by 18%, especially when compared to the 12 months group. FPD and its heterogeneity was unchanged in SHR when compared to controls. Disease and age-related abnormalities in CV properties were observed in SHR and these were associated with changes in Cx43, Nav1.5 protein level and fibrosis. Conclusion: Myocardial slices are a suitable multicellular preparation to study electrophysiological remodelling obtained from different rat models of cardiovascular disease. In addition, it was possible to investigate the changes in CV and FPD transmurally in rats using this type of preparation method. Thus, this study supports the use of this multicellular preparation in understanding the mechanisms of cardiac disease and the testing of new treatments and therapeutic targets.
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Birkhold, Annette Isabell [Verfasser], Georg N. [Akademischer Betreuer] Duda, Peter [Akademischer Betreuer] Fratzl, Marc [Gutachter] Kraft, Georg N. [Gutachter] Duda, and Peter [Gutachter] Fratzl. "A 4D imaging approach to monitor bone remodeling : development, design, validation and first applications of a tomography-based medical image processing method and tool for enhanced visualization and quantification of patho-physiological dynamic structural processes in bone / Annette Isabell Birkhold ; Gutachter: Marc Kraft, Georg N. Duda, Peter Fratzl ; Georg N. Duda, Peter Fratzl." Berlin : Technische Universität Berlin, 2016. http://d-nb.info/1156180007/34.
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Udugama, Maheshi Imalka. "THE UNIQUE STRUCTURE AND MECHANISM OF INO80 - AN ATP DEPENDENT REMODELER OF THE HISTONE EXCHANGER FAMILY." OpenSIUC, 2010. https://opensiuc.lib.siu.edu/dissertations/235.
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INO80, a member of the multi-subunit SWI2/SNF2 superfamily, is involved in transcription regulation, DNA repair and replication. Not much is known about its substrate specificity and remodeling mechanism or how it differs in comparison to SWI/SNF or ISWI. Site-directed mapping of histone-DNA contacts showed that INO80 generally remodels mononucleosomes by moving them to the center of DNA. The length of extranucleosomal DNA was found to play an important role in nucleosome binding as well as remodeling by INO80 much like ISW2 and ISW1a. INO80 preferentially binds to nucleosomes containing >20bp of extranucleosomal DNA. Similarly, INO80 remodeling of mononucleosomes with different lengths of extranucleosomal DNA showed that at least 33bp of extranucleosomal DNA on one side of the nucleosome was required for initiation of remodeling. These data suggest that INO80 behaves much like ISW2 and ISW1a complexes based on their requirement for extranucleosomal DNA. INO80 does not unravel or displace nucleosomes like SWI/SNF. There are several key aspects of how INO80 interacts with and remodels nucleosomes that are quite distinct from SWI/SNF, ISW2, and ISW1a. Previously SWI/SNF and ISW2 were shown to initiate nucleosome movement by translocating along nucleosomal DNA two helical turns from the dyad axis. Nucleosome movement by INO80 instead requires translocation by the complex along nucleosomal DNA near the entry/exit site at the dimer-tetramer interface. Sliding interference of INO80 by the presence of nicks indicated that torsional strain at the site of translocation is required for nucleosome mobilization by INO80. Hydroxyl radical footprinting of the INO80-nucleosome complex shows found that INO80 interactioninteracts with extranucleosomal DNA at, the entry-exit site and to lesser extent at the dyad axis, but it lacks the protection found indoes not contact 2 helical turns from the dyad like ISW2 and SWI/SNF at two helical turns from the dyad axis as determined by photoaffinity cross-linking studies. The catalytic subunit (Ino80) rather than being found associated 2 helical turns from the dyad, was bound to extranucleosomal DNA and nucleosomal DNA near the entry-exit site. Other subunits (Arp8p, Arp5p and Nhp10) were also found to be contacting both nucleosomal and extranucleosomal DNA. Site-specific histone cross-linking studies revealed that Ino80, Arp5 and Arp4 interact extensively with the histone dimer of the nucleosome in comparison to H3-H4 tetramer. Although N-terminal histone tails are often important for chromatin remodeling, INO80 shows no requirement of histone tails for its nucleosome binding and mobilizing activities. The deviation of INO80 from the canonical model of how ATP-dependent remodelers interact and mobilize nucleosome is apparently due to its unique role as a member of the remodeling complexes that promote the exchange of H2A/H2B dimer from core nucleosome particle.
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Lukas, Carolin. "Modeling the influence of bone mineralization and remodeling on the structure of bone." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16648.
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Die Struktur des Knochenmaterials wird während des gesamten Lebens durch dynamische Prozessen verändert. Diese sind der Umbauprozess, bei dem existierendes Material entfernt und durch neues, vorerst weiches ersetzt wird. In dieses weiche Material wird im sog. Mineralisierungsprozess Mineral eingelagert und somit die Steifigkeit erhöht. Diese zwei Prozesse führen zu einem heterogenen Knochenmaterial. Das komplexe Zusammenspiel kann durch Knochenkrankheiten beeinflusst werden und zu einem mechanischen Versagen des Materials führen. Wie viel Einfluss dabei allein dem Umbauprozess und dem Mineralisierungsprozess zuzuschreiben sind, konnte bislang nicht geklärt werden. An diese Fragestellungen wird in der vorliegenden Dissertation mit physikalischen und numerischen Methoden herangegangen. Das heterogene Material ist das Ergebnis des Mineralisierungs- und Umbauprozesses und wird abkürzend BMDD (für bone mineralization density distribution) genannt, die für alle gesunden Menschen gleich ist und bei Knochenkrankheiten davon abweicht. Mittels Modellierung wird eine Störung in der Mineralisierung simuliert, die zu Verschiebungen in der BMDD führt. Diese Verschiebungen können verglichen werden mit einem veränderten Umbauprozess. Der unterschiedliche Einfluss der beiden Prozesse liegt im zeitlichen Verlauf. Die Mineralisierungskinetik im Knochen konnte durch die neuartige Auswertung von 3D in vivo micro-CT-Bildern von Mäusen erstmals quantifiziert werden. Die Auswertung bestätigte, die schnellere Mineralisierung im neugeformten und die langsamere in bereits vorhandenem Knochen. Wie der Umbauprozess im kompakten Knochen gesteuert sein kann, wurde mittels Anordnungsmechanismen der Osteone beschrieben. Für einen solchen Knochenbaustein war es verboten innerhalb einer definierten Zone eines anderen Bausteins gebildet zu werden. Diese Zone ließ sich am besten durch einen normalverteilten Radius, mit einer dazugehörigen Variabilität beschreiben.The structure of the bone material is continuously changed during the life by dynamic processes. These are the remodeling process during which the existing material is replaced by new, initially soft material. In this soft material mineral is incorporated during the so called mineralization process, thus increasing the stiffness. These two processes lead to a heterogeneous bone material. Their interplay can be perturbed by bone diseases, which can lead to material failure. It remains unclear to which degree each of these two processes contributes during diseases. Yet, while the remodeling process is known to be mechanically controlled, it is unclear how mechanical stimuli affect the mineralization process. The heterogeneous mineral distribution in trabecular bone is the result of the complex interplay between the mineralization and the remodeling process and is called bone mineralization density distribution (BMDD). The BMDD is similar for all healthy adult humans. A deviation from this healthy distribution is indicative of bone diseases. With a mathematical model the influence of changed mineralization kinetics on the BMDD is investigated and compared to a remodeling change. The different influences lie in the time development. With a novel 3D analysis of in vivo micro-CT of the vertebra in a mouse tail the mineralization kinetics could be quantified for the first time. It could be e.g. shown that the bone is demineralized before it is completely resorbed. An algorithm was developed to understand how the remodeling process can be regulated. The arrangement of the building blocks could be described when such a block could only be placed within a defined zone of another building block. This zone could be best quantified when its radius was normally distributed with a corresponding standard deviation.
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Mitson, Matthew. "The structure and function of the chromatin remodelling domain of ATRX." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.442902.
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Kourliouros, Antonios. "Structural remodelling, inflammation and the role of statins in atrial fibrillation following cardiac surgery." Thesis, St George's, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546798.
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Berair, Rachid. "Airway structural remodelling in asthma : functional relevance and suitability as a target for therapy." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/41264.
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Airway remodelling (AR) in asthma, a collective term describing all the airway microscopic structural changes, has long been known; however, its functional relevance is poorly understood. The lack of non-invasive methods for assessing AR contributes to this scarcity of studies on AR. First, this thesis describes the association of AR with physiological markers of airflow obstruction. This was coupled with attempting to assess the link between proximal and small airway qualitative computed tomography (QCT)-derived markers and AR. Furthermore, to further study the relevance of AR, we describe the effects of fevipiprant, a novel prostaglandin D2 (PGD2) receptor 2 (DP2) antagonist, and bronchial thermoplasty (BT) on various asthma domains including AR. We found that airway smooth muscle (ASM) mass and airway vascularity was closely related to airflow obstruction. Additionally, we have demonstrated that ASM, vascularity and epithelial thickness was associated with QCT-measured proximal airway morphometry changes whereas increased vascularity and goblet cells hyperplasia was related to air trapping. Coupled with improvements is eosinophilic inflammation, asthma symptoms and lung function, we have shown that DP2 antagonism in a randomised controlled trial, resulted in improvement in epithelial integrity and reduction of ASM. Finally, we have shown that while BT treatment did not affect ASM mass, subepithelial fibrosis or lung function, it did improve epithelial integrity and reduced smooth muscle actin expression. Whether these changes contribute to the benefits seen in BT studies needs further research. This thesis has contributed to the development of fevipiprant as a new treatment for asthma, validated methods to assess AR, demonstrated how AR relates to asthma outcomes and shown how fevipiprant and BT impact AR. Further longitudinal studies are also needed to explore the heterogeneity of AR in various asthma phenotypes especially in the context of clinical trials of new therapies using novel non-invasive methods of measuring AR.
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Grytz, Rafael. "Computational modeling and remodeling of human eye tissues as biomechanical structures at multiple scales." Aachen Shaker, 2008. http://d-nb.info/992477573/04.
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West, Philip M. "The double CUE domain of chromatin remodelling factor SMARCAD1." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:615cc567-c79c-4f4a-aed4-82bf67f8adac.
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ATP-dependent chromatin remodellers represent a class of proteins that restructure chromatin through the action of a conserved helicase-like ATPase domain. Remodellers typically have several accessory binding domains alongside the ATPase. These confer target specificity and most commonly recognise histone post-translational modifications. SMARCAD1 is a ubiquitous chromatin remodeller involved with DNA replication and re- pair. It binds directly to PCNA at the site of DNA replication and recruits co-repressor KAP1 in order to silence newly produced chromatin. In contrast to most other chromatin remodellers, SMARCAD1 does not contain several different types of accessory domains. Only two CUE do- mains have been identified in addition to the SMARCAD1 core ATPase domain. CUE domains are a type of helical ubiquitin-binding domain. This thesis presents the findings of an investigation into the structure and function of the SMARCAD1 double CUE domain. The solution NMR structure is presented with results from NMR binding experiments mapped onto the structure. Each CUE domain was found to be an independent helix bundle connected by a dynamic flexible linker. The N-terminal CUE domain, CUE-1, binds ubiquitin and has an adjacent SUMO (a ubiquitin-like protein) binding motif on a protruding extended helix. The C-terminal CUE domain, CUE-2, has a very similar structure to several published CUE domains but does not bind ubiquitin due to a charged substitution at a highly conserved CUE consensus position. The SMARCAD1 double CUE domain binds KAP1 from nuclear extract and is likely to mediate the interaction between SMARCAD1 and KAP1. SMARCAD1 double CUE domain is not involved with PCNA binding.
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Moir, Lyn Margaret. "Airway wall structural remodelling : studies on smooth muscle phemotype and contractility in isolated small bronchioles." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405168.
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Deng, Huai. "Remodeling of higher order chromatin structure by the JIL-1 histone H3 kinase in Drosophila." [Ames, Iowa : Iowa State University], 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3320128.
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Farnung, Lucas [Verfasser], and Patrick [Akademischer Betreuer] Cramer. "Nucleosome-Chd1 structure and implications for chromatin remodelling / Lucas Farnung ; Betreuer: Patrick Cramer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1148276181/34.
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Pope, Adèle Joanna. "Characterising myocardial remodelling in hypertensive heart disease. Structural and functional changes in the spontaneously hypertensive rat." Thesis, University of Auckland, 2011. http://hdl.handle.net/2292/8517.
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Myocytes of varying orientation across the ventricular wall are grouped into layers, separated by cleavage planes. The role of extracellular matrix, in particular collagen, in this laminar organisation has not been fully delineated due to an inability to truly appreciate its 3D relationships. This thesis utilised an unique laser confocal scanning microscopy system to produce high resolution 3D images of normal adult rat myocardium to elucidate the arrangement of collagen with respect to myocytes. Perimysium was shown to have an ordered arrangement that played a direct role in laminar organisation. There were three distinct forms of perimysial structures seen in the midwall: an extensive meshwork on laminar surfaces, convoluted fibres connecting adjacent layers, and longitudinal cords. The subepicardium had a different structure that lacks distinct layers and the only perimysial collagen present was as longitudinal cords. Changes in perimysial collagen organisation were then studied using a rat model of hypertensive heart disease. Spontaneously Hypertensive Rats were studied at 3 months (hypertensive), 12 months (associated hypertrophy), 18 months (compensated failure) and 24 months or when determined to be in decompensated heart failure. Age-matched Wistar Kyoto rats were used as controls. Clinically used assessments, namely blood pressure measurements, echocardiography measurement of active left ventricular (LV) function and neurohormone BNP measurements were carried out on each rat to demonstrate disease progression. Hearts were then removed and passive LV function was determined using pressure-volume loop measurements on a Langendorff apparatus. Finally, hearts were then imaged as above. High resolution imaging of the diseased hearts showed the expected increased fibrosis. Moreover, there were distinct changes in perimysial and endomysial collagen that disrupted and in some places eradicated the myocardial laminar organisation. These changes persisted into LV decompensation along with LV hypertrophy and passive compliance, which is contrary to the current understanding of HHD. The mechanical and electrical consequences of this remodelling are likely to contribute to the transition from compensated to decompensated heart failure.Whole document restricted until Nov. 2012, but available by request, use the feedback form to request access.
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Grytz, Rafael [Verfasser]. "Computational Modeling and Remodeling of Human Eye Tissues as Biomechanical Structures at Multiple Scales / Rafael Grytz." Aachen : Shaker, 2009. http://d-nb.info/1161311599/34.
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Reinhardt, James W. "The Role of Cell-Substrate Interactions in ECM Remodeling, Migration, and the Formation of Multicellular Structures." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1417701676.
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Gokhan, Ezgi. "The Repo-Man/PP1 complex role in chromatin remodelling, nuclear structure and cancer progression." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/14731.
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Repo-Man is a chromatin-associated PP1 targeting subunit that coordinates chromosome re-organisation and nuclear envelope reassembly during mitotic exit. At the onset of mitosis, Repo-Man association with the chromosomes is very dynamic; at anaphase, Repo-Man targets to the chromatin in a stable manner and recruits PP1 to de-phosphorylate histone H3 at Thr3, Ser10 and Ser28. Previous studies have suggested that CDK1 and AuroraB are the kinases responsible for the inactivation of the complex and for its dispersal at the onset of mitosis respectively. We have previously shown that the binding of Repo-Man to PP1 is decreased in mitosis and we have identified a region adjacent to the RVTF motif that contains multiple mitotic phosphosites (RepoSLIM). This region is conserved only in another PP1 targeting subunit: Ki-67. In order to understand the importance of this region for the complex formation and stability, we have conducted mutational analyses on several residues, and addressed their contribution towards Repo-Man chromosome targeting and PP1 binding in vivo. We have identified new sites in Repo-Man that, when phosphorylated, contribute to the weakening of the binding between Repo-Man and PP1. Interestingly, our results also indicate that several kinases are involved in the mitotic regulation of the complex. We have also identified Lamin A/C as a Repo-Man substrate and introduced a new model for Lamin A/C regulation at interphase. Furthermore, we identified Repo-Man as a marker of malignancy in tripe egative breast cancer, which controls cell movement and levels of important oncogenic markers Aurora A and C-Myc, and propose Repo-Man/PP1 complex as a therapeutic target for the treatment of triple negative breast cancer through the newly identified RepoSLIM.