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1
Jabre, Saline. "Impact of mechanical stress on nucleus morphology and transcription on skeletal muscle". Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS561.
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La réponse du noyau aux contraintes mécaniques impliquent les lamines de type A mais aussi la chromatine et les modifications post-traductionnelles des histones. Cette réponse est essentielle à l’adaptation des cellules aux contraintes mécaniques, notamment dans les tissus soumis à des contraintes mécaniques importantes comme le muscle squelettique. Cependant les mécanismes impliqués restent mal connus. Le premier objectif de ma thèse était de déterminer l'impact de la différenciation musculaire sur les caractéristiques nucléaires de cellules musculaires. Les objectifs suivants étaient d’analyser l’effet de l’expression des protéines de l'enveloppe nucléaire (lamines A/C, SUN1 et SUN2) et de la compaction de la chromatine sur la réponse nucléaire aux contraintes mécaniques. J’ai caractérisé la forme nucléaire et des marqueurs d’histone dans des cellules précurseurs musculaires (MuSC) immortalisées obtenus chez des patients sains et dans des myotubes (72h de différenciation). Les marqueurs d’histones suivants ont été analysés : 1-La tri-méthylation de la lysine4 de l'histone H3 (H3K4me3) et l'acétylation de H3K4 (H3K4ac), associés aux gènes activement transcrits 2- H3K27me3, un marqueur de l'hétérochromatine facultative, régulé par le développement 3- et H3K9me3, un marqueur de l'hétérochromatine constitutive. La différenciation en myotubes est associée à une élongation et à une réduction significative du volume nucléaire. De plus, l'intensité du marquage nucléaire H3K27me3 est significativement plus faible dans les myotubes par rapport aux MuSC alors que les intensités nucléaires H3K9me3 et H3K4me3 sont plus élevées. Ces résultats sont compatibles avec les modifications attendues de l'accessibilité de la machinerie transcriptionnelle avec la différenciation myogénique. Dans les myotubes, la déficience en lamines A/C entraîne une déformation nucléaire qui est majorée par le stretch mécanique (étirement cyclique de 10%, 4h) Le stretch est associé à une augmentation significative du volume nucléaire dans les myotubes témoins, qui est abolie dans les myotubes déficients en lamines A/C. Dans les myotubes témoins, le stretch augmente l'intensité du marquage H3K27me3 et réduit l'intensité du marquage H3K4me3 et H3K4ac. Dans les myotubes déficients en lamines A/C, l’intensité des marqueurs actifs de la chromatine est plus élevée en conditions statiques et stretch s’accompagne d’une augmentation paradoxale de H3K4me3 après. L’inhibition spécifique des histones désacétylases de classe I et II par la trichostatine A induit également une augmentation de H3K4ac en conditions statique et après stretch par rapport au myotubes témoins. A l’inverse, dans les myotubes déficients en SUN2 ou SUN1, l'étirement réduit l'intensité de H3K4me3, alors que l'augmentation de l'intensité nucléaire de H3K27me3 est abolie dans les myotubes déficients en SUN2 étirés. Par ailleurs, la déficience en lamines A/C s’accompagne d’une dérégulation majeure des gènes régulant les marqueurs d’histone. Dans l'ensemble, notre étude met en évidence des modifications importantes des marqueurs post-traductionnels des histones au cours de la différenciation musculaire et lors d'un stress mécanique. Les lamines de type A semblent cruciales pour prévenir l'activation anormale des marqueurs actifs de la chromatine dans les myotubes soumis à un défi mécanique. Nos résultats suggèrent que la mécano-réponse chromatinienne est étroitement régulée par les protéines de l'enveloppe nucléaire dans le muscle squelettiqueThe lamina, and specifically A-type lamins, are major contributors to nuclear stiffness and deformations. However, chromatin and its histone modification states also contribute to nuclear mechanics independently of A-type lamins. How A-type lamins and chromatin-mediated mechanoresponse contribute to mechanical load-mediated adaptation in normal and pathological skeletal muscle remains unknown. We sought to determine how muscle differentiation impacts nuclear characteristics in muscle cell precursors (MuSCs) and myotubes. Then, we investigated the respective roles of nuclear envelope proteins (lamin A/C, SUN1 and SUN2) and drug-modulated chromatin compaction on the mechanical load-mediated nuclear response in myonuclei. We used immortalized MuSCs obtained from healthy patients and analyzed nuclear shape and chromatin characteristics in MuSCs and myotubes obtained after 72h of differentiation. Histone modifications were analyzed: a) histone H3 lysine4 tri-methylation (H3K4me3) and H3K4 acetylation (H3K4ac), associated with transcriptionally active genes, b) H3K27 tri-methylation (H3K27me3), a chromatin repression marker, associated with facultative heterochromatin and c) H3K9 tri-methylation (H3K9me3), a chromatin repression marker associated with constitutive heterochromatin and mainly located at the nuclear periphery. Myotube differentiation was associated with nuclear elongation and significant reduction in nuclear volume. In addition, the relative intensity of nuclear H3K27me3 (chromatin repression marker) labelling was significantly lower in myotubes compared to MuSCs, whereas nuclear H3K9me3 and H3K4me3 (chromatin active marker) intensities were higher in myotubes compared to MuSCs, thereby showing that myogenic differentiation is modulating the accessibility of the transcriptional machinery. Myotubes were silenced for LMNA expression with silencing mRNA strategies and submitted to a cyclic stretch (10%,4hours) to investigate A-type lamin’ roles in nuclear shape and chromatin organization during mechanical stress. A-type lamin deficient myotubes had abnormal nuclear shape in static conditions and nuclear deformations further increased after cyclic stretch. Cyclic stretch was associated with a significant increase in nuclear volume in control myotubes that was abolished in A-type lamin deficient myotubes. In addition, stretching increased the intensity of the H3K27me3 and reduced H3K4me3 and H3K4ac intensities of labelling in nuclei from control myotubes. Importantly, A-type lamin deficiency was associated with higher intensity in chromatin active markers at baseline and a paradoxical increased in H3K4me3 after stretch. Consistent modifications in histone modifications were obtained by western-blots in control and A-type deficient myotubes. Interesting, stretch reduced H3K4me3 intensity both in SUN2 or SUN1-deficient myotubes while the increase in the nuclear intensity of the H3K27me3 was abolished in stretched SUN2-deficient myotubes. Transcriptomic changes associated with A-type lamin deficiency support these results. Trichostatin A (TSA) is a powerful and specific Class I and II histone deacetylase inhibitor (HDACi), widely used to increase the expression of genes silenced by chromatin condensation, thereby favoring chromatin decompaction. TSA increased nuclear volume without affecting nuclear shape both in static and stretched conditions. In addition, TSA decreased H3K27me3 and H3K9me3 intensities in static myotubes but did not prevent the stretch-induced increase in H3K27me3 intensity. Overall, our study highlights crucial changes of histone post-translational markers during muscle differentiation and upon mechanical challenge. A-type lamins appear crucial to prevent abnormal activation of chromatin active markers in mechanically challenged myotubes. Moreover, our results suggest that the nuclear mechano-response is tightly regulated by nuclear envelope proteins in skeletal muscle
2
DeLoyht, Jacqueline M. "The Role Of A Type Lamins In Regulating Myelination". VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5388.
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Multiple sclerosis (MS), a demyelinating disorder of the central nervous system (CNS), affects approximately 400,000 individuals in the United States, and 2.5 million people worldwide. It is a leading cause of disability in young adults. Current treatments for MS target the inflammatory aspects of the disease, but do not aid in remyelination. To address remyelination as a therapeutic strategy, it is imperative to identify mechanisms that regulate myelin formation, including epigenetic targets. In this study, we investigate the role of the LMNA, a gene encoding Lamins A and C, intermediate filaments of the nuclear lamina, in regulating oligodendrocyte development and myelination in the CNS. Using electron microscopic analyses, I examined levels of heterochromatin and its distribution in the oligodendrocyte nucleus as an indicator of gene expression, oligodendrocyte maturity, and myelin formation in the absence of A type lamins.. While overall levels of heterochromatin in oligodendrocytes were not altered in the absence of A type lamins, peripherally located heterochromatin was reduced and thinner myelin was observed in the spinal cord. My observations present novel findings for the role of LMNA in oligodendrocytes and myelination.
3
Poitelon, Yannick. "Explorations de modèles animaux et cellulaires de la maladie de Charcot-Marie-Tooth de type AR-CMT2A". Aix-Marseille 2, 2009. http://www.theses.fr/2009AIX20710.
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Woerner, Stéphanie. "Interaction entre les lamines de type A sauvages ou mutées et le facteur de transcription SREBP1 : caractérisation et impact sur la liaison de SREBP1 à l'ADN". Paris 7, 2011. http://www.theses.fr/2011PA077016.
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Les lamines de type A (prélamine A, lamines A et C) sont des protéines nucléaires codées par le gène LMNA. Elles jouent un rôle dans la structure du noyau et dans la régulation de l'expression de gènes grâce à leur capacité à interagir avec divers partenaires. Nous avons caractérisé l'interaction des lamines A/C avec le facteur de transcription SREBP1 (Sterol Regulatory Elément Binding Protein 1) impliqué dans la différenciation adipocytaire, afin d'élucider le mécanisme par lequel SREBP1 serait inactivé dans les lipodystrophies causées par des mutations du gène LMNA. Les tests de pull-down réalisés avec des domaines protéiques purifiés ont montré qu'/w vitro i) le domaine 227-487 de SREBP1, qui inclut les régions de liaison à l'ADN et de dimérisation (bHLH-zip), interagit avec un domaine de la région carboxyl-terminale des lamines qui est commun à la prélamine A et aux lamines A/C; et ii) les lamines mutées R482W et R453 W, responsables de lipodystrophie (FPLD) et de dystrophie musculaire (AD-EDMD), présentent un gain d'interaction pour SREBP1. De plus, les tests de retard sur gel et de pull-down réalisés en présence d'ADN SRE (Sterol Response Elément) suggèrent i) un chevauchement des sites d'interaction pour les lamines et l'ADN au sein du domaine 227-487 de SREBP1, et ii) une interaction préférentielle de SREBP1 avec l'ADN plutôt qu'avec les lamines, en raison de constantes d'affinités différentes. Nos résultats suggèrent que dans les cellules de tissu adipeux dystrophique, SREBP1 serait séquestré par les lamines de type A avant d'avoir lié ses séquences d'ADN cibles, inhibant ainsi sa fonction de facteur de transcriptionA-type lamins (prelamin A, lamins A and C) are nuclear proteins encoded by the LMNA gene. They play a role in the nuclear structure and in the regulation of gene expression due to their capacity to interact with many partners. We have characterized the interaction of A-type lamins with the transcription factor SREBP1 (Sterol Regulatory Element Binding Protein 1) involved in adipocyte differentiation, in order to elucidate the mechanisms by which SREBP1 would be inactivated in lipodystrophies caused by LMNA gene mutations. Pull-down assays performed with purified protein domains have shown that in vitro i) the domain 227-487 of SREBP1 that includes the DNA binding and the dimerization regions (bHLH-zip), interacts with a domain of the carboxyl-terminal region of lamins that is commun to prelamin A and lamins A/C; and ii) the R482W and R453W variants of lamins identified in lipodystrophy (FPLD) and muscular dystrophy (AD-EDMD) bound to SREBP1 227-487 with increased avidity. In addition, electrophoretic mobility shift assays and pull- down assays performed in the presence of SRE DNA(Sterol Response Element DNA) suggest i) an overlap of the interaction sites for lamins and DNA within the domain 227-487 of SREBP1 and ii) a preferential interaction of SREBP1 with DNA than with lamins, due to different affinity constants. Our results suggest that in cells of dystrophic adipose tissue, SREBP1 would be inactivated due to its sequestration by A-type lamins before reaching its target DNA sequences
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Parman-Ryans, Jaime L. "A-type Lamins in Cell Cycle Regulation". Digital Commons @ East Tennessee State University, 2017. https://dc.etsu.edu/etd/3240.
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Proteins of the nuclear lamina provide structural support to the nuclear envelope and participate in a variety of cellular functions, such as chromatin organization and transcriptional regulation. One of these proteins, Lamin A (72kDa), is synthesized as a 74 kDa precursor protein, Prelamin A, which undergoes an unusual maturation pathway that requires two farnesylation-dependent endoproteolytic cleavages. The second cleavage is unique to lamin A in higher vertebrates and is specifically carried out by the endoprotease zmpste24. Although most previous studies have focused mainly on the function of mature Lamin A, recent evidence from our laboratory shows important biological functions for Prelamin A as well. Prelamin A concentration in proliferating cells is very low or undetectable. Conversely, during quiescence induced by mitogen withdrawal or contact inhibition, Prelamin A levels increase dramatically. These variations are directly regulated by changes in expression and enzymatic activity of zmpste24. The central hypothesis of this dissertation is that full-length farnesylated and carboxymethylated prelamin A (FC-PreA) antagonizes both proliferation and apoptosis, therefore playing a role in cellular quiescence/senescence. To accomplish this goal, we studied the transcriptional regulation of zmpste24 and the interaction of FC-preA with proteins that participate in cell cycle control. 1) We identified and characterized a functional site for the E2F1 transcription factor (involved in the control of cell cycle) in the proximal 5’ UTR region of zmpste24. 2) By using proximity-labeling and co-immunoprecipitation-mass spectrometry techniques, we identified a set of proteins that interact preferentially with L467R-Prelamin A (uncleavable mutant) but not with mature Lamin A. Many of these proteins function to regulate progression through cell cycle.
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Perrin, Sophie. "Vieillissement, infection par le VIH-1 & traitements antirétroviraux". Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM5058.
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L'utilisation des antirétroviraux (ART) a permis une augmentation de la durée des patients infectés par le VIH. Par ailleurs, les comorbidités, retrouvées au cours du vieillissement physiologique, semblent être plus fréquentes et d'apparition plus précoce ce qui pourrait suggérer une modification du programme de vieillissement chez ces patients. L'étude ANRS EP45 « Aging » (clinicalTrials.gov, NCT01038999) a pour objectif d'analyser chez des patients infectés par le VIH traités ou non les mécanismes cellulaires connus pour être impliqués dans le vieillissement. Les PBMC d'une cohorte de 130 patients infectés par le VIH 1 appariés en âge et en sexe avec 49 sujets séronégatifs ont été analysés. Trois centres spécialisés (Marseille, Montpellier, Nice) ont recruté des patients infectés naïfs ou sous première ligne de traitement. Les résultats présentés dans ce manuscrit rapportent l'analyse des mitochondries et des lamines nucléaires. La maturation de la lamine A ne semble pas modifiée dans les PBMC de patients sous traitement contenant un inhibiteur de protéase. Cependant, ces cellules pourraient ne pas être le modèle le plus adapté pour explorer ce volet. D'autre part, l'infection est responsable d'anomalies mitochondriales dans les lymphocytes, partiellement corrigées par les traitements antirétroviraux qui modifient les mitochondries des monocytes moins sensibles à l'infection. Bien que les secondes générations de ART soient moins toxiques que les premières, leurs effets secondaires pourraient néanmoins, sur « le long terme » et/ou généralisés à l'ensemble de l'organisme, être l'un des facteurs modifiant le programme de vieillissement de ces patientsAntiretroviral therapy (ART) has increased life expectancy in HIV-infected patients. Moreover, some age-related disorders were found to be more frequent in HIV infected and treated patients than in an age-matched general population, suggesting a modified time course of aging in HIV infected patients. The ANRS EP45 « Aging » study (clinicalTrials.gov, NCT01038999) investigated in PBMC from HIV-1 infected patients under treatment or not the cellular mechanisms known to be involved in aging. The study was performed on a cohort of 130 patients HIV-1 infected age- and sex-matched with 49 seronegative control subjects. Patients never treated with ART (naïve) or under first line were recruited by 3 AIDS centres (Marseille, Montpellier, Nice). Results presented here describe explorations of mitochondria and nuclear lamin. No alteration of lamin A maturation was detected in PBMC from HIV-1 infected patients under treatment with protease inhibitor. However, these cells could not be the most appropriate models to investigate lamin A-related aging pathway. On another hand, mitochondrial modifications were observed in lymphocytes from HIV infected naive patients. These alterations were only partly rescued by ART whereas its induced slight changes in monocytes that appeared to be less sensitive to infection. While second generation of ART are less toxic than the first one, their secondary effects, due to long term exposure and/or generalised to different tissues, could lead to a modified time course of aging in HIV infected patients
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Lau, Chong Chuan. "A fracture mechanics approach to the adhesion of packaging laminates". Thesis, Imperial College London, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296356.
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Ylikärppä, R. (Ritva). "Type XVIII and XV collagens: primary structure of human alpha1(XVIII) chain, phenotypic studies of type XVIII collagen single null and type XVIII and XV collagen double null mice". Doctoral thesis, University of Oulu, 2003. http://urn.fi/urn:isbn:9514271416.
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Abstract
In this thesis study, the primary structure of the human α1(XVIII) polypeptide was elucidated, its tissue distribution was studied, and the phenotypic changes in the mouse eye due to lack of type XVIII collagen in a knock-out mouse model were studied further. In addition, the consequences of simultaneous lack of both type XVIII and XV collagen were studied in a mouse model lacking both of these proteins.
Two variant forms of human α1(XVIII) polypeptide were identified in this study, although, to date, a third form has also been characterized. The analysis of tissue distribution of the two polypeptide forms revealed differences in their tissue distribution, since the longest variant occurs prominently in the liver, while the short form is the major transcript in other tissues studied, e.g. in the kidney. The study of the type XVIII single null mouse eyes revealed abnormalities in the anterior eye segment in addition to the previously reported defects in the posterior eye part. In the type XVIII single null mice the iris was fragmented, pigment deposits could be seen in the pupil, and the pupillary ruff in the edge of a normal mouse iris was missing in these mice. The ciliary body was also abnormal, since the ciliary processes start to show regression in adult animals and eventually the basal infoldings of the non-pigmented ciliary body epithelia become flattened in the null mice. The intraocular pressure stabilizes to a lower level in adult mutant mice compared to controls, most likely reflecting the atrophied ciliary epithelia. The BM zones were also defective in the type XVIII null mouse eyes. The absence of an immunosignal with one of the antibodies detecting laminin γ2 chain in the type XVIII null mouse eyes may implicate conformational changes in the laminin γ2 chain due to lack of type XVIII collagen, and subsequently interaction between type XVIII collagen and laminin γ2 chain in normal mouse eye BMs. The study of the type XVIII and XV double null mice revealed that these mice were viable and fertile and had no major additional abnormalities compared to both single null mice. However, the regression of hyaloid capillaries (vasa hyaloidea propria, VHP) was studied in these mice, and a slight delay in the detachment of these vessels from the retina was noticed. Thus, the two collagens do not function entirely independently from each other.
The studies with type XVIII collagen single null mice indicate that in addition to the posterior eye phenotype, this collagen is needed for the normal structural integrity of the anterior eye segment and basement membranes of the eye. The mouse model lacking both type XVIII and type XV collagen indicates that the roles of the two collagens are essentially diverse, although a slight compensatory effect was observed in the detachment of the hyaloid capillaries from the retina.
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Nitta, Ryan Takeo. "A-type lamins are necessary for the stabilization of the retinoblastoma protein /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/9209.
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Harryman, William L., Erika Pond, Parminder Singh, Andrew S. Little, Jennifer M. Eschbacher, Raymond B. Nagle i Anne E. Cress. "Laminin-binding integrin gene copy number alterations in distinct epithelial-type cancers". E-CENTURY PUBLISHING CORP, 2016. http://hdl.handle.net/10150/615112.
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The laminin-binding integrin (LBI) family are cell adhesion molecules that are essential for invasion and metastasis of human epithelial cancers and cell adhesion mediated drug resistance. We investigated whether copy number alteration (CNA) or mutations of a five-gene signature (ITGB4, ITGA3, LAMB3, PLEC, and SYNE3), representing essential genes for LBI adhesion, would correlate with patient outcomes within human epithelial-type tumor data sets currently available in an open access format.
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Geiger, Stephanie. "Influence of the expression of mutated B-type lamins on nuclear architecture and function". [S.l. : s.n.], 2007. http://nbn-resolving.de/urn:nbn:de:bsz:16-opus-83247.
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Meier, Roger. "Phosphorylation and expression of human B-type lamins in normal and leukemic lymphoid cells /". [S.l.] : [s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Lin, Y. (Yanfeng). "Molecular control of organogenesis:role of laminin γ2 and γ2*, type XVIII collagen and Wnt2b". Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514265661.
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Abstract
How cell and tissue interactions lead to complex structures and differentiated
cell types during organogenesis is still one of the most fundermental questions
in modern molecular biology. Laminin appears to have a role in branching
morphogenesis during organ development. Laminin5 (α3β3γ2) is an
epithelium-specific isoform of laminin and previous report has shown that two
alternative transcripts for the γ2 chain, the longer γ2 and the shorter
γ2*, result from alternative use of the last exon in the human
LAMC2 gene. But the transcription of murine laminin γ2
and γ2* and their biological significance have remained unclear. Type XVIII
collagen is a newly identified member of the collagen family. It may be involved
in the Wnt signaling pathway, since its longest N-terminal variant contains a
frizzled domain, which is part of the Wnt receptor and could antagonize Wnt
signaling when secreted. Wnt2b is a new member of the Wnt family. Also its
function in organogenesis is unknown. In this study, we have investigated the
expressions of laminin γ2 and
γ2*, type XVIII collagen and
Wnt2b during mouse organogenesis. The function of type XVIII
collagen in developing lung, kidney and a recombination of ureteric bud and lung
mesenchyme tissue and the function of the Wnt-2b gene during
kidney organogenesis were studied by using the combined methods of traditional
experimental embryology and modern molecular biology.
Two alternative laminin γ2 transcripts were demonstrated in mouse. In the
developing kidney, the shorter γ2* form was localized in the mesenchyme,
whereas the longer γ2 form was only present in the epithelium of the
Wolffian duct and in the ureteric bud, indicating different functions for the
γ2 variants. Type XVIII collagen was expressed throughout the respective
epithelial bud at the initiation of lung and kidney organogenesis. It becomed
localized to the epithelial tips in the early-stage lung, while it was confined
to the epithelial stalk region and was absent from the nearly formed ureteric
tips in the kidney. In recombinants of ureteric bud and lung mesenchyme, the type
XVIII collagen expression pattern in the ureteric bud shifted from the kidney to
the lung type, accompanied by a shift in epithelial Sonic
Hedgehog expression. The lung mesenchyme was also sufficient to induce
ectopic lung Surfactant Protein C expression in the ureteric
bud. A blocking antibody for the type XVIII collagen reduced the number of
epithelial tips in the lung and completely blocked ureteric development with lung
mesenchyme, which was associated with a notable reduction in the expression of
Wnt2. The shift in type XVIII collagen expression in
ureteric bud and lung mesenchyme tissue recombinant was also accompanied by the
significant morphological changes in the branching pattern in ureteric bud
development. Wnt2b was expressed in numerous developing
organs in the mouse embryo, but it was typically localized in the perinephric
mesenchymal cells in the region that partly overlaps the presumptive renal stroma
at E11.5. Functional studies of the kidney demonstrated that 3T3 cells expressing
Wnt2b were not capable of inducing tubule formation but rather stimulated
ureteric development. Recombination of ureteric bud treated with cells expressing
Wnt2b and isolated kidney mesenchyme resulted in recovery of the expression of
epithelial marker genes and better reconstituted organogenesis. Lithium, a known
activator of Wnt signaling, was also sufficient to promote ureteric branching in
reconstituted kidney in a manner comparable to Wnt2b signaling.
Our data suggest that different organ morphogenesis is regulated by an intraorgan
patterning process that involves coordination between inductive signals and
matrix molecules, such as type XVIII collagen. In the mouse kidney,
Wnt2b may act as an early mesenchymal signal controlling
morphogenesis of epithelial tissue, and the Wnt pathway may regulate ureteric
branching directly.
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PekovicÌ, Vanja. "The role of A-type lamins and LAP2α in cellular ageing of human fibroblasts in vitro". Thesis, Durham University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426434.
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Pekovic, Vanja. "The role of A-Type lamins and LAP2a in cellular ageing of human fibroblasts in vitro". Thesis, Durham University, 2005. http://etheses.dur.ac.uk/2746/.
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Mutations in LMNA gene have been linked to a number of age-related tissue-specific diseases and premature ageing syndromes termed laminopathies. The finding that A- type lamins affect longevity and maintenance of a number of somatic tissues makes them potential candidates in ageing of normal tissues. At the cellular level, ageing is manifested by an accumulation of irreversibly arrested senescent cells. Premature senescence is also hallmark of premature ageing syndromes. A-type lamins and lamina- associated polypeptide 2 α (LAP2a) bind to and tether retinoblastoma protein (Rb) in the nucleus, a main regulator of senescence pathway. In order to explore the role of A- type lamins and LAP2a in normal ageing and disease, I studied these proteins during ageing of wild type human fibroblasts in vitro. My results show that protein expression level of lamins and LAP2s does not change during ageing of wild-type fibroblasts in vitro. Nonetheless, fibroblasts aged in vitro acquire a range of nuclear morphological changes characteristic of laimnopathy fibroblasts. These nuclear 'laminopathy' phenotypes are accompanied by changes in peripheral heterochromatin, accumulation of lamins А/С in the nucleoplasm, aggregation of LAP2a and decreased Rb phosphorylation. Interestingly, acquisition of such abnormal nuclear changes correlates with premature senescent arrest in five laminopathy cell lines studied. In contrast, although a down-regulation of LAP2a expression and Rb dephosphorylation accompany a reversible quiescent arrest, quiescent fibroblasts do not acquire alterations in nuclear morphology and instead show increased association of lamins at the NE. A-type and B- type lamms become more insoluble in quiescent cells, which may be a cause of a loss of nuclear anchorage of LAP2a and Rb as well as an increased solubility of LAP2ß. On the contrary, during biochemical fractionation of aged fibroblasts, lamin A, but not lamin B2， becomes altered in a manner which makes it more unstable (i.e. prone to degradation) which leads to accumulation of a soluble lamin A proteolytic fragment whilst lamin с and LAP2a become lost from detergent/salt-resistant nucleoskdeton. Protein sequence analysis revealed that both lamm A and LAP2a contain number of cysteine residues in their C-terminal specific tails. Glutathione blot assay and immunoprecipitation under non-reducing conditions showed that A-type lamins and LAP2a become s-glutathiolated in senescent cells, which may cause their decreased binding seen on immunoprecipitation. Both lamin A and LAP2a show an age-dependent accumulation of monomeric protein under non-reducing conditions, which տ early passage cells leads to formation of non-native disulphide cross-links in these proteins. Interestingly, neither of the four laminopathy cell lines studied show an increased accumulation of monomeric lamin A as compared to their age-matched controls. Aged and lamin A/C-deficient laminopathy fibroblasts display a targeted loss of nucleoplasmic but not speckle-associated forms of Rb. These Rb speckles associate with sites of DNA damage in both senescent and laminopathy cells and may be involved in DNA damage signalling or post-transcriptional regulation of gene expression. sRNAi knockdown of LAP2a also leads to decreased phosphorylation and a loss of nucleoplasmic forms of Rb, which correlates with cell cycle arrest. I propose a model for ageing of human fibroblasts in vitro whereby oxidative modification of A-type lamin filaments induces changes in their structural conformation leading to destabilisation and a less efficient assembly at the nuclear envelope. In addition, aberrant telomere targeting of oxidatively modified LAP2a in senescent cells or aggregated LAP2a m laminopathy cells would lead to destabilised telomere structures, telomere uncapping and/or chromosome fusions which would trigger Rb-mediated DNA damage-induced senescent arrest.
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Roos, René. "Model for interlaminar normal stresses in doubly curved laminates /". Zürich : ETH, 2008. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17725.
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Shelley, Deeke. "Identifying the Isoforms of a Novel Muscle-enriched A-type Lamin-Interacting Protein". Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19906.
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A novel gene entitled Muscle-enriched A-type Lamin-Interacting Protein, or MLIP was identified through a yeast-two hybrid screen using Lamin A as bait, in an attempt to shed light on the intricate nature of laminopathies. The objective of this study was to identify MLIP’s isoforms. Immunoblotting experiments revealed that MLIP is expressed differentially in both mouse and human tissues. A cloning strategy was performed which demonstrated extensive tissue-dependant alternative splicing, however not all protein bands observed by immunoblotting could be accounted for by the splice variants identified. Hence 5’ and 3’ Rapid Amplification of Complementary DNA Ends was performed, however only a single 5’ and 3’ untranslated region was uncovered. MLIP contains five highly conserved regions of homology, one of which contains a consensus SUMOylation site. MLIP was investigated as a substrate for SUMO through in vitro and in vivo assays, however it was not modified by SUMO. It remains to be determined whether MLIP undergoes other post-translational modification. MLIP’s function has yet to be defined; however preliminary experiments in our laboratory and MLIP’s association with lamin suggest that it may play a role in tissue differentiation.
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Gibbs-Seymour, Ian David. "The multiple roles of A-type lamins in cellular aging, cell cycle progression and the DNA damage response". Thesis, Durham University, 2011. http://etheses.dur.ac.uk/3491/.
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A-type lamins are a group of type V intermediate filaments whose main members are lamin A and C. Lamins A/C are components of the nuclear lamina and are encoded by the LMNA gene. Lamins A/C have a variety of cellular functions, including maintaining the structural integrity of the nucleus and the regulation of signal transduction pathways, transcription factors and DNA replication. Mutations in LMNA give rise to a diverse spectrum of diseases, termed laminopathies, which include premature aging syndromes. In Chapter 3, I sought to understand the role of wild type lamin A in normal cellular aging. Lamin A C-terminal cysteine residues were irreversibly oxidized during the in vitro aging of human dermal fibroblasts (HDFs), which impaired the ability of lamin A to form disulfide bonds, causing loss of function. Furthermore, loss of these cysteine residues induced premature senescence, suggesting that these cysteine residues are important for lamin A function during cellular aging. In Chapter 4, I extended previous findings implicating A-type lamins in the control of cell cycle progression. Loss of A-type lamins or its nucleoplasmic binding partner, LAP2α, caused delayed G1/S-phase progression, reduced cellular proliferation and cell cycle exit. Proliferative defects could not be rescued via treatment with anti-oxidants. In Chapters 5 and 6, I addressed the role of wild type mature lamin A/C in the DNA damage response (DDR). A-type lamins interact with the DDR mediator protein 53BP1 via its Tudor domain. Loss of LMNA caused endogenous DNA damage and loss of 53BP1 protein levels. Furthermore, loss of LMNA resulted in defective DNA repair that ultimately led to increased sensitivity to DNA damage. Together, the data presented here extends previous findings implicating A-type lamins in cell cycle progression and provides novel insights into the cellular roles of A-type lamins in cellular aging and the DNA damage response.
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Fuentes, Andres. "Interactions between the reaction zone and soot field in a laminar boundary layer type diffusion flame". Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/1765.
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The concurrent spreading of a boundary layer type diffusion flame is studied. The impossibility of obtaining a low velocity laminar flow without any perturbation induced by buoyancy has lead to the development of an experimental apparatus for use in micro-gravity facilities. Based on previous experimental observations, an original numerical approach has been developed showing, first the dominating role of the radiative heat transfer on the structure of the flame and second the major role of the soot on the extinction phenomenon at the flame trailing edge. The influence of the forced flow velocity, the fuel injection velocity and oxygen concentration on the geometry of the flame has been examined by imaging of CH* and OH* radicals spontaneous emission. Laser-Induced Incandescence (LII) is used to determine the soot field concentration in the flame. The soot formation has been studied by Laser Induced Fluorescence (LIF) of Polycyclic Aromatic Hydrocarbons (PAHs). The interaction between the reaction zone and the field of soot formation/oxidation is taken into account to analyze the flame length. These results can be used as the experimental input data for a future complete validation of numerical model simulating the soot formation and oxidation in this kind of flame.
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Rabaa, Seham. "Elucidating the Functional Role of MLIP, a Novel Muscle A-type Lamin Interacting Protein". Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20027.
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A-type lamin mutations are associated with degenerative disorders causing dilated cardiomyopathy, Charcot-Marie-Tooth neuropathy and Limb-Girdle Muscular Dystrophy. Our lab has identified MLIP; a novel protein that interacts with lamin A/C. Knocked down MLIP expression in C2C12 myoblasts down regulates myogenic regulatory factors, MyoD and Myogenin, which delays myogenic differentiation. We hypothesize that MLIP is essential for myogenic differentiation. Our goal is to define the MLIP associated pathways involved in myogenic programming. Gene expression profiling of MLIP stably knocked down C2C12 cells, identified 30 genes implicated in human disease. Mutations in five of those genes (DMPK, HSPB8, LMNB2, NEFL and SGCD) cause muscular dystrophy, neuropathies, and lipodystrophies that have phenotypic overlap with laminopathies. Further studies involving the MLIP knocked down cell lines demonstrated that in the absence of puromycin, MLIP protein expression returns to normal. This in turn affects the interpretation of the gene expression data and attempted MLIP recovery experiments.
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Ahmady, Elmira. "The functional role of A-type lamin interacting transcription factor (LITF) during skeletal myogenesis". Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28529.
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Lamin A/C (LMNA) is ubiquitously expressed in tissues, however specific missense mutations in LMNA result in discrete tissue specific phenotypes such as muscular dystrophy. Using a yeast-two-hybrid assay against a human heart cDNA library, a previously uncharacterized cDNA clone, A-type lamin interacting transcription factor (LITF), was identified. In this thesis the major objective was to determine the function of LITF using C2C12 mouse myoblast cell line. It is hypothesized that LITF is a myogenic factor that is required for myogenesis. Initiation of C2C12 differentiation led to an increase in LITF protein expression by 6 hours and peaking at 18 hours. LITF mediated chromatin immunoprecipitation from C2C12 nuclei with array analysis revealed a significant enrichment (p<0.00001) of promoter regions of developmentally important muscle transcription factors (Six1, Six4, Mef2c, Myogenin) and several other genes implicated in cell cycle and differentiation. Electrophoretic mobility shift assays and co-transactivation experiments revealed that LITF is capable of binding specific DNA sequences and activating transcription. Specific knockdown of LITF in C2C 12 led to a reduction in the expression of Myogenin, MyoD and myosin heavy chain with a significant reduction in myotube formation. Collectively this data suggests that LITF may be a myogenic transcription factor/regulator.
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Piffaretti, Stefano Giuseppe. "Flame age model : a transient laminar flamelet approach for turbulent diffusion flames /". Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=16961.
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Vu, Amber Marie. "Mechanisms of nuclear lamina disruption and regulation of nuclear budding of herpes simplex virus type-1". Diss., University of Iowa, 2018. https://ir.uiowa.edu/etd/6659.
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During herpes simplex virus 1 (HSV-1) replication, newly constructed capsids escape the nucleus to undergo maturation in the cytoplasm via a process termed nuclear egress. Capsids perform nuclear egress through localized disruption of the nuclear lamina, envelopment of the inner nuclear membrane to create a perinuclear enveloped virion, and de-envelopment of the outer nuclear membrane for capsid release into the cytoplasm. Critical virial factors for this process are viral proteins pUL31 and pUL34 that interact to form heterodimers. These heterodimers form larger hexameric arrays to drive membrane budding. Through the
characterization of phenotypes of UL34 point mutants, we are able to further study the underlying mechanisms of nuclear lamina disruption and nuclear budding. One such mutant, UL34(Q163A), results in impaired virus production, cell-cell spread, and an inability to disrupt lamin A/C networks. Selection for extragenic suppression of UL34(Q163A) yielded the UL31(R229L) mutation, that partially rescued the growth and spread defects of UL34(Q163A), but was unable to regain the ability to disrupt lamin A/C networks. Through this study we concluded that disruption of lamin A/C networks was not required for efficient HSV-1 replication. In order to understand the underlying mechanisms of membrane budding, the previously characterized UL34(CL13) double mutant, which results in a 100-fold reduction in virus production, a severe impairment in cell-cell spread, and an accumulation of capsid-less perinuclear vesicles was further studied. Characterization of the single mutations of UL34(CL13), UL34(R158A) and UL34(R161A) revealed that neither single mutation was responsible for spread or growth defect, but that either single mutation resulted in a promiscuous budding phenotype. Through this study, we concluded that although individual steps of the nuclear egress pathway are tightly regulated, alteration of the regulation at a single step does not grossly impact HSV-1 replication.
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Ozcelikkale, Altug. "Development Of An Incompressible, Laminar Flowsolver Based On Least Squares Spectral Element Methodwith P-type Adaptive Refinement Capabilities". Master's thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/3/12612096/index.pdf.
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The aim of this thesis is to develop a flow solver that has the ability to obtain an accurate numerical solution fast and efficiently with minimum user intervention. In this study, a two-dimensional viscous, laminar, incompressible flow solver based on Least-Squares Spectral Element Method (LSSEM) is developed. The LSSEM flow solver can work on hp-type nonconforming grids and can perform p-type adaptive refinement. Several benchmark problems are solved in order to validate the solver and successful results are obtained. In particular, it is demonstrated that p-type adaptive refinement on hp-type non-conforming grids can be used to improve the quality of the solution. Moreover, it is found that mass conservation performance of LSSEM can be enhanced by using p-type adaptive refinement strategies while keeping computational costs reasonable.
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Schofield, Samuel Phillip. "Dynamics of Laminar Jets in Stratified Fluids". Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1474%5F1%5Fm.pdf&type=application/pdf.
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Afonso, Pauline. "Complications cardiovasculaires liées aux défauts de maturation de la lamine A : Rôle des traitements antirétroviraux et des mutations LMNA". Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066375/document.
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Les patients lipodystrophiques porteurs de mutations du gène LMNA codant pour les lamines de type A, et les patients infectés par le VIH (Virus de l’Immunodéficience Humaine) traités par des antirétroviraux (ARV) sont à risque de développer une athérosclérose précoce avec calcifications et des comorbidités liées au vieillissement. Pour mieux comprendre la physiopathologie des atteintes vasculaires, j’ai étudié l’impact d’ARV ou de mutations LMNA sur des cellules musculaires lisses (CML) ou endothéliales d’artères coronaires humaines in vitro. Ce travail a révélé que certains ARV (les inhibiteurs de protéase lopinavir ou atazanavir associés au ritonavir) induisent une sénescence prématurée et des dysfonctions des cellules endothéliales, alors que d’autres ont peu ou pas de conséquences (maraviroc, dolutégravir, maraviroc/dolutégravir et darunavir/ritonavir). De plus, le lopinavir/ritonavir ou l’atazanavir/ritonavir, ou l’expression des mutations LMNA p.R482W, p.D47Y ou p.R133L induisent une sénescence prématurée, une transdifférenciation ostéogénique avec calcification, et un stress oxydant dans les CML. L’accumulation de prélamine A farnésylée (une lamine A immature) et la diminution de l’expression de ZMPSTE24, son enzyme de maturation, sont, au moins en partie, responsables de ces effets.Ainsi, les ARV étudiés ont des impacts différents et agissent par des mécanismes physiopathologiques pro-athérogéniques en partie communs avec certaines mutations LMNA associées aux lipodystrophies. Le rôle majeur de l’accumulation de prélamine A farnésylée liée à une diminution d’expression de ZMPSTE24 ouvrent de nouvelles perspectives thérapeutiquesPatients with lipodystrophies dues to mutation in the LMNA gene encoding A-type lamins, or HIV-infected patients (Human Immunodeficiency Virus) receiving antiretroviral therapy (ARV) are prone to develop early atherosclerosis and vascular calcifications associated with comorbidities linked to premature aging. Our study focused on the impact of LMNA mutations or antiretroviral treatment in vitro on vascular smooth muscle cells (VSMC) or endothelial cells from human coronary arteries. The results obtained during my thesis showed that some ARV (the protease inhibitors lopinavir or atazanavir associated with ritonavir) induce a cellular premature senescence with associated dysfunctions in endothelial cells, whereas others have little or no consequences (maraviroc, dolutegravir, maraviroc/dolutegravir and darunavir/ritonavir). In addition, some ARV (lopinavir or atazanavir with ritonavir) or the expression of LMNA mutations p.R482W, p.D47Y or p.R133L induce premature senescence, osteogenic transdifferentiation with calcification and oxidative stress of VSMC. Our results reveal that the accumulation of farnesylated prelamin A (an immature lamin A) and the decreased expression of its processing enzyme ZMPSTE24 are, at least partly, responsible for these effects.This work shows the different effects of ARVs and highlights the existence of common pro-atherogenic pathophysiological mechanisms in HIV-infected patients receiving some protease inhibitors and in lipodystrophic patients with LMNA mutations, initiated by an accumulation of farnesylated prelamin A related to a decrease expression of ZMPSTE24. These abnormalities could give rise to new therapeutic perspectives
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Sundblom, Jimmy. "Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease : Translational Studies of Two Neurogenetic Diseases". Doctoral thesis, Uppsala universitet, Neurologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-162048.
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There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases: 1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood. 2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.
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Linnola, R. (Reijo). "The sandwich theory:a bioactivity based explanation for posterior capsule opacification after cataract surgery with intraocular lens implantation". Doctoral thesis, University of Oulu, 2001. http://urn.fi/urn:isbn:9514259793.
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Abstract
This study was undertaken to identify mechanisms of adhesion of intraocular lenses (IOLs) to the
capsular bag after cataract surgery and IOL implantation. It was also done to challenge the sandwich
theory presented for posterior capsular opacification (PCO): If the IOL is made of a bioactive material
it would allow a single lens epithelial cell layer to bond both to the IOL and the posterior capsule at
the same time. This would produce a sandwich pattern including the IOL, the cell monolayer and the
posterior capsule. The sealed sandwich structure would prevent further epithelial ingrowth. The degree
of bioactivity of the IOL could explain the basic difference in the incidence of PCO and capsulotomy
rates with different IOL materials.
The sandwich theory was put forward on the basis of a search for a keratoprosthesis material,
which would allow maximal adhesion of the prosthesis to corneal tissue. Titanium and glass-ceramic
coated titanium were found to develop better adhesion than poly (methyl methacrylate) (PMMA). The
adhesion of PMMA to the corneal stromal tissue was loose, and down growth of corneal epithelial cells
was seen around the prosthesis.
The differences between various IOL materials were first tested with rabbit corneal tissue
cultures. There was better adhesion of corneal tissue to soft, hydrophobic acrylate than to PMMA,
heparin surface modified (HSM)-PMMA, silicone or hydrogel IOLs.
To assess differences in protein adhesion to IOL surfaces, different IOLs were incubated for 24
hours with radioactive iodine labeled fibronectin. Soft hydrophobic acrylate (AcrySof®) showed the
highest binding of fibronectin, and the differences relative to all the other materials were significant
(p < 0.01-0.001), except to PMMA (p = 0.31).
The sandwich theory and the results with rabbit corneal tissue cultures and the protein adhesion
study in vitro were evaluated against the results found in pseudophakic autopsy eyes. Altogether, 70
autopsy eyes were analyzed. From 38 autopsy eyes containing PMMA, silicone, soft hydrophobic acrylate or
hydrogel IOLs histological sections were prepared from the capsular bag and immunohistochemical analyses
were performed for fibronectin, vitronectin, laminin and collagen type IV. A total of 152 specimens were
analyzed. From 32 autopsy eyes containing IOLs made of PMMA, silicone, acrylate or hydrogel, IOLs were
explanted from the capsular bag and immunohistochemical analysis was done on both sides of the IOLs for
fibronectin, vitronectin, laminin or collagen type IV. Soft hydrophobic acrylate IOLs had significantly
more adhesion of fibronectin to their surfaces than PMMA or silicone IOLs. Also, more vitronectin was
attached to acrylate IOLs than to the other IOL materials. Silicone IOLs had more collagen type IV
adhesion in comparison to the other IOL materials studied. In histologic sections a sandwich-like
structure (anterior or posterior capsule-fibronectin-one cell layer-fibronectin-IOL surface) was seen
significantly more often in eyes with acrylate IOLs than in PMMA, silicone or hydrogel IOL eyes.
These studies support the sandwich theory for posterior capsule opacification after
cataract surgery with IOLs. The results suggest that fibronectin may be the major extracellular protein
responsible for the attachment of acrylate IOLs to the capsular bag. This may represent a true bioactive
bond between the IOL and the lens epithelial cells, and between the IOL and the capsular bag. This may
explain the reason for clinical observations of less posterior capsular opacification and lower
capsulotomy rates with the soft hydrophobic acrylate material of AcrySof® IOLs compared to the
other IOL materials studied.
29
Postl, Dieter. "Numerical Investigation of Laminar Separation Control Using Vortex Generator Jets". Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1237%5F1%5Fm.pdf&type=application/pdf.
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Koalaga, Zacharie. "Contribution a l'etude experimentale et theorique des plasmas d'arcs electriques lamines". Clermont-Ferrand 2, 1991. http://www.theses.fr/1991CLF21343.
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La telemecanique electrique a mis au point une nouvelle technique de coupure basee sur le laminage de l'arc entre deux pieces isolantes. Ce mode de coupure entraine de fortes interactions arc-parois, et conduit a des plasmas constitues essentiellement de vapeurs d'isolant. De ce fait, la nature du materiau des parois et la largeur de la fente constituent les parametres les plus importants de cette methode de coupure. L'etude experimentale presentee est un prolongement de travaux effectues anterieurement au laboratoire. Les grandeurs physiques mesurees sont le courant, la tension, le champ electrique et la pression. Le choix du materiau des parois est fait en considerant les valeurs maximales du courant et surtout du champ electrique. Pour une meilleure efficacite de la coupure, il convient d'atteindre des valeurs de champ electrique tres elevees. Les polymeres se revelent etre les plus prometteurs. Une grande partie de ce memoire est consacree a l'etude theorique des plasmas issus des isolants de type c#xh#yo#zn#t. Cette etude permet la determination de la composition d'equilibre, des coefficients de transport et des fonctions thermodynamiques de ces plasmas. Le calcul des differentes proprietes des plasmas du type c#xh#yo#zn#t est effectuee grace a un logiciel de calcul elabore au laboratoire. Il est possible d'effectuer un choix du materiau des parois a partir des valeurs des conductivites thermique () et electrique (), de la densite d'energie (. H) et du flux de puissance (. H. A. )
31
Hall, Heike. "Identification and characterization of the L2/HNK-1 carbohydrate binding site on laminin responsible for the L2/HNK-1 carbohydrate mediated neural cell adhesion /". [S.l.] : [s.n.], 1993. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10368.
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Elkhatib, Razan. "Caractérisation de la lamina nucléaire et de ses protéines partenaires au cours de la spermatogenèse humaine". Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0203.
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La morphogénèse des spermatozoïdes a lieu pendant la spermiogénèse, la dernière phase de la spermatogenèse.Cette différenciation est accompagnée de modifications drastiques de l’enveloppe nucléaire associées à un fort remodelage chromatinien. Notre travail été centré sur l'enveloppe nucléaire des spermatides pendant la spermiogénèse humaine. Nous avons notamment caractérisé la lamina nucléaire, réseau protéique composant de l’enveloppe nucléaire, et ses protéines partenaires potentiellement impliqués dans les liaisons lamine-chromatine: les protéines à domaine LEM, LBR, la protéine chromatinienne BAF et BAF-L.Nous avons révélé la présence exclusive des lamines de type B concentrées au pôle postérieur à la fin de la spermiogénèse dans les spermatozoïdes, et nous avons identifié et caractérisé l’isoforme testicule-spécifique lamine B3 humain.Nous avons découvert et caractérisé la lamine A2, un isoforme méiotique du gène LMNA, chez l'homme et la souris.Nous avons ensuite étudié ces protéines chez des patients atteints de globozoospermie, et nous avons pu identifier BAF comme un nouveau biomarqueur de l’immaturité des noyaux de spermatozoïdes. Par ailleurs, nous avons identifié la deuxième mutation perte de fonction dans le gène SUN5 chez 3 patients apparentés, et validé son implication dans la mise en place de la jonction tête-flagelle des spermatozoïdes.Notre caractérisation de la lamina nucléaire et ses protéines partenaires au cours de la spermiogénèse humaine apporte une meilleure compréhension de son rôle dans la différenciation des spermatides en spermatozoïdeset peut être la base de nouveaux champs d’investigation cas d’infertilité liés à des anomalies nucléairesThe morphogenesis of mature spermatozoa takes place during spermiogenesis, the last phase of spermatogenesis.This differentiation involves drastic changes in the nuclear envelope associated with profound chromatin remodelling.Our work was focused on the nuclear envelope of spermatids during human spermatogenesis.We have characterized, the nuclear lamina, a protein meshwork component of the nuclear envelope, and its protein partners potentially implicated in the linkage lamin-chromatin: LEM-domain proteins, LBR, chromatinien protein BAF and BAF-L.Our study revealed the exclusive presence of B-type lamins concentrated at the posterior pole of mature spermatozoaat the end of spermiogenisis and we have identified and characterised the testis-specific isoform lamin B3 in human.We have also discovered and characterized the lamin A2, a meiotic isoform expressed from the LMNA gene in human and mouse. By studying abnormal globozoospermic spermatozoa, we were able to identify BAF as a potential biomarker of spermatozoa nucleus immaturity.Moreover, we have identified the second loss-of-function mutation in the nuclear envelope protein SUN5 in three related patients, and thus demonstrated its involvement in the formation of the spermatozoa head-tail junction.Our characterization of the nuclear lamina and its protein partners during human spermiogenesis, provides a better understanding of its role in the differentiation of spermatids into spermatozoa, and provides a solid basis for future investigation of cases of male infertility related to nuclear anomalies
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Karliychuk, M. A. "Tomography peculiarities of retinal structural changes in patients with type II diabetic mellitus depending on the scleral lamina cribrosa thickness". Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18143.
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Guilly, Marie-Noëlle. "Les lamines : antigenicite en pathologie humaine, expression au cours de la differenciation". Paris 7, 1988. http://www.theses.fr/1988PA077070.
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Guilly, Marie-Noëlle. "Les Lamines antigénicité en pathologie humaine, expression au cours de la différenciation /". Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb37614123g.
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Gaudy-Marqueste, Caroline. "Etude génomique et fonctionnelle des lamines et de leurs partenaires dans la sclérodermie". Aix-Marseille 2, 2009. http://www.theses.fr/2009AIX20711.
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Etude génomique et fonctionnelle des Lamines et de leurs partenaires dans la sclérodermie. Les Laminopathies constituent un groupe hétérogène de pathologies secondaires à des mutations de protéines de l’enveloppe nucléaire, les Lamines. Certaines Laminopathies présentent des similitudes cliniques avec la Sclérodermie. Les régions promotrices, les régions codantes et les bornes introniques de LMNA, ZMPSTE24 et LBR ont été amplifiées par PCR puis séquencées au sein d’une cohorte de 28 patients sclérodermiques et de 100 témoins. Aucune variation de séquence potentiellement pathogène n’a été retrouvée au sein des gènes LMNA et ZMPSTE24. Une mutation hétérozygote faux-sens a été identifiée au sein de l’exon 9 de LBR (c. 1114C>T ; p. R372C) chez une patiente atteinte d’une sclérodermie cutanée limitée chez laquelle le séquençage de LMNB1, MAN1, SYNE1α et TMPO a également été réalisée. Cette mutation n’était pas retrouvée dans une population contrôle. Chez cette patiente, des polymorphismes homozygotes étaient retrouvés au sein de MAN1, SYNE1α et LBR tandis ques les séquences des autres gènes étaient de type sauvage. Le caractère pathogène de la mutation était prédit par différentes bases de données bioinformatiques. Les Western-Blots réalisés sur les fibroblastes de la patiente montraient une diminution importante de l’expression de LBR, des Lamines A/C et de LMNB2 ainsi qu’une abolition de l’expression de LMNB1 et HP1a. Les marquages de LBR, HP1α et de la Lamine A étaient réduits, et la distribution des Lamines B1 et B2 anormale. Au contraire, l’expression et la localisation de ces mêmes protéines étaient tout à fait conservées dans une lignée lymphoblastoïde réalisée pour la patiente. Nos travaux suggèrent que la mutation pourrait avoir un impact sur l’ensemble du réseau complexe formé par les Lamines et leurs partenaires nucléaires, en perturbant la stoechiométrie protéique spécifiquement au sein des fibroblastes. Un impact sur les patrons d’expression génique des protéines impliquées peut également être envisagé. Les mutations de LBR pourraient ainsi représenter une cause rare de Sclérodermie, agissant soit comme un élément pathogénétique nécessaire et suffisant, soit comme un facteur prédisposant au développement de la maladieLamins are proteins of the nuclear envelope which mutations lead to an heterogeneous group of diseases called Laminopathies. Some laminopathies share clinical similarities with Systemic Sclerosis. Promoters, coding regions and intron-exon boundaries of LMNA, ZMPSTE24 and LBR were PCR-amplified and sequenced in a series of 28 sclerodermic patients and 100 controls. No mutation was found within LMNA and ZMPSTE24. A heterozygous missense mutation was identified in exon 9 of LBR (c. 1114C>T; R372C) in one Caucasian patient affected with a limited form of disease for which the sequencing of LMNB1, MAN1, SYNE1α and TMPO was further performed. The variant was absent in 200 controls. In this patient, several sequence polymorphisms were found throughout the LBR gene as well as in MAN1 and SYNE1α while wild type sequences were observed for the other genes. Arginine 372 residue was highly conserved throughout evolution. The mutation was predicted to induce a change in LBR tertiary structure by bioinformatics tools. Functional explorations were performed on patient’s fibroblasts and lymphoblastoïd cell lines. While analysis performed on lymphoblastoïd cell lines were normal, western Blots showed an impressive reduction of LBR, Lamin A/C and LMNB2 expression, together with abolished expression of LMNB1 and HP1a. Immunocytochemical explorations displayed normal LBR localisation but reduced Lamin A specific staining with abnormal distribution of Lamin B1, Lamin B2 and HP1a. Our results suggest that the LBR mutation induces both LBR reduced expression levels and structural modifications of the residual protein. This mutation might have a downstream deleterious effect on several molecular partners through fibroblats specific modifications of the nuclear envelope stoichiometry. An impact on gene expression patterns of the proteins involved may also be hypothesized. LBR mutations might thus represent a rare cause of SSc, either by a direct pathogenicity of the mutation or by constituting a predisposing factor
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MourÃo, Renata Veras Carvalho. "Estudo da relaÃÃo do Infiltrado InflamatÃrio Mononuclear e ExpressÃo de Ki-67, ColÃgeno IV e Laminina em Cistos Radiculares". Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=9525.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorOs cistos dos ossos maxilares sÃo classificados como odontogÃnicos e nÃo odontogÃnicos. Dentre os odontogÃnicos inflamatÃrios, destaca-se o cisto radicular, e entre os de desenvolvimento, o dentÃgero. Estes cistos e suas variantes apresentam etiopatogÃnese e comportamento biolÃgico diferentes, mas sÃo igualmente lÃticos. A atividade proliferativa do epitÃlio de revestimento, dos componentes da membrana basal e da matriz extracelular, possivelmente, interferem nos mecanismos de crescimento, constituindo alvos de pesquisas. Este trabalho teve por objetivo avaliar a relaÃÃo do infiltrado inflamatÃrio mononuclear com a expressÃo de marcadores de proliferaÃÃo (Ki 67) e das proteÃnas da membrana basal e matriz extracelular nos cistos radiculares. Trata-se de um estudo retrospectivo e observacional tendo sido realizado um levantamento dos casos catalogados no ServiÃo de Biopsia do Departamento de Patologia e Medicina Legal (FAMED) e no LaboratÃrio de Patologia Bucal (FFOE) (UFC). ApÃs a revisÃo histolÃgica, os grupos foram divididos em cisto radicular intensamente inflamado (CRII) (n=17), cisto radicular levemente inflamado(CRLI)(n=.9) e cisto dentÃgero (CD) (n= 9). A presenÃa e intensidade do infiltrado inflamatÃrio histiolinfoplasmocitÃrio e preservaÃÃo do epitÃlio de revestimento foram os parÃmetros utilizados para seleÃÃo dos casos. Os espÃcimes foram submetidos à reaÃÃo de imuno-histoquÃmica por estreptoavidina biotina, utilizando-se os anticorpos Ki 67 (DakoÂ, 1:50), anti-colÃgeno IV (DBSÂ, 1:40) e anti-laminina (DBSÂ, 1:20). A expressÃo de Ki 67 foi mais intensa no grupo CRLI, quando comparada ao grupo CRII e CD. A expressÃo de colÃgeno tipo IV na membrana basal foi significante no grupo CRLI, quando comparada com o grupo CRII e CD. Jà a imunomarcaÃÃo de matriz extracelular variou de ausente a fraca nos grupos CRII e CRLI, enquanto no CD se exibiu de forma fraca a moderada, sendo esta diferenÃa significativa. A expressÃo de laminina em membrana basal nos grupos CRII e CD foi negativa e no grupo dos CRLI foi fraca e pontual. Concluiu-se que a presenÃa e a intensidade do conteÃdo inflamatÃrio na parede dos cistos radiculares parecem modificar a expressÃo dos fatores de proliferaÃÃo no epitÃlio de revestimento, e colÃgeno tipo IV e laminina na membrana basal, mas nÃo interferem no comportamento do colÃgeno IV da matriz extracelular nos cistos radiculares. A expressÃo de componentes da membrana basal (laminina e colÃgeno tipo IV) à maior nos cistos radiculares com leve infiltrado inflamatÃrio.
Jawbone cysts are classified as odontogenic and non-odontogenic cysts. The radicular cyst is the most common odontogenic cyst of inflammatory origin, whereas the detigerous cyst is the most common type of developmental odontogenic cyst. These cysts and their variations have different etiopathogenesis and biological behavior, but are equally lytic. The proliferation activity of the epithelial lining and the components of the basement membrane and extracellular matrix constitute targets of research. The aim of this study was to evaluate the relation between mononuclear inflammatory infiltrate and the expression of proliferative immunomarkers (Ki 67), and proteins of basement membrane and extracellular matrix in radicular cysts. In this retrospective observational study, all cases of jawbone cysts that had been recorded in the files of the Department of Pathology and Legal Medicine (FAMED), and of the Laboratory of Oral Pathology (FFOE) of the Federal University of Cearà (UFC) and reviewed. After histological revision, the groups were divided into heavily inflamed radicular cysts (HIRC) (n=17), slightly inflamed radicular cysts (SIRC) (n=9) and dentigerous cysts (DC) (n=9). The presence and intensity of the lymphoplasmacytic inflammatory infiltrate and the preservation of the epithelial lining were the parameters used to select the cases. Immunohistochemical analyses were performed using the standard streptavidin-biotin-peroxidase method. The primary antibodies used in this study included Ki 67 (DakoÂ, 1:50), Anti-Collagen Type IV (DBSÂ, 1:40) and Anti- Laminin (DBSÂ, 1:20).The immunoexpression of Ki-67 was more intense in the SIRC group compared to the HIRC group and DC. Likewise, the immunoexpression of Anti-Collagem Type IV in the basement membrane of the SIRC group presented a statistically significant difference compared to the HIRC group and DC . The expression of laminin in the basement membrane and in group HIRC and DC was negative and the group of SIRC was weak and punctual. It was concluded that presence and severity of inflammatory content wall of radicular cysts appear to modify the expression of proliferation factors in the coating epithelium and collagen type IV and laminin in the basement membrane but not modific with the behavior of extracellular matrix in radicular cyst. The expression of basement membrane components (laminin and collage type IV) is higher in radicular cyst with mild inflammatory infiltrade.
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Delbarre, Erwan. "Etude comparative de l' assemblage en cellules vivantes des lamines sauvages et mutées". Paris 6, 2005. http://www.theses.fr/2005PA066398.
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Le, Dour Caroline. "Liposdystrophies partielles liées à des mutations de la périlipine et des lamines A/C". Paris 6, 2010. http://www.theses.fr/2010PA066467.
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Les lipodystrophies familiales partielles (FPLD) sont des maladies génétiques rares caractérisées par une perte de tissu adipeux, une insulino-résistance et une dyslipidémie. Nous avons identifié une nouvelle cause de FPLD, liée aux mutations inactivatrices de la périlipine, protéine de la gouttelette lipidique régulant la lipolyse adipocytaire. Ces mutations Co ségrégent avec le syndrome lipodystrophique dans les trois familles atteintes. Le tissu adipeux des patients est fibrotique, avec des adipocytes de taille diminuée et une infiltration macrophagique. Exprimés dans un modèle pré-adipocytaire, les deux variants de la périlipine perdent leur capacité à former des gouttelettes de triglycérides et à inhiber la lipolyse basale. Ces résultats soulignent l’importance des protéines de la gouttelette lipidique dans les régulations métaboliques à l’échelle de l’organisme. Les mutations des lamines A/C, protéines nucléaires, sont également responsables de FPLD. Les anomalies de maturation de la prélamine A, et en particulier l'accumulation de sa forme farnésylée, jouent un rôle dans sa physiopathologie. Nous avons étudié les conséquences d’une nouvelle mutation, retrouvée pour la première fois à l’état homozygote chez sept patients atteints de FPLD, empêchant la farnésylation de la prélamine A. Dans les fibroblastes des patients, la mutation induit des déformations nucléaires, un vieillissement cellulaire accéléré et une augmentation du stress oxydant. Ainsi, l’expression exclusive d’une prélamine A non farnésylée est pathogène, infirmant l'hypothèse du rôle central de la farnésylation persistante de la prélamine A dans les laminopathies avec lipodystrophie
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Issa, Johnny Samir. "Scaling of Convective Heat Transfer in Laminar and Turbulent Wall Jets With Effects of Freestream Flow and Forcing". Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1672%5F1%5Fm.pdf&type=application/pdf.
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Pasqualin, Livia Meirelles de Araujo. "Estudo clínico, histológico e molecular de crianças com distrofia muscular congênita por deficiência de lamina A/C". Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-14102013-123033/.
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Introdução: As Distrofias Musculares Congênitas (DMCs) são um grupo clínica e geneticamente heterogêneo de doenças musculares que se manifestam ao nascimento ou no primeiro ano de vida, sendo caracterizadas por hipotonia, fraqueza muscular, retardo do desenvolvimento motor e retrações fibrotendíneas. O músculo esquelético apresenta-se distrófico, mas sem alterações estruturais específicas. Em quase metade dos casos a doença é causada pela deficiência da laminina alfa;-2 (merosina). Outras deficiências proteicas descritas incluem: colágeno VI, selenoproteína N1, várias glicosiltransferases responsáveis pela glicosilação da alfa- distroglicana e lamina A/C. Vários genes já foram identificados. Objetivo: o objetivo deste estudo foi a caracterização clínica, histológica e molecular das crianças com DMC por deficiência de lamina A/C. Método: Foram incluídos 13 pacientes com diagnóstico clínico e histológico de DMC, com expressão muscular normal para distrofina, sarcoglicanas, merosina, colágeno 6 e disferlina. Os pacientes foram reavaliados segundo protocolo clínico e neurológico. As biópsias musculares realizadas previamente foram revisadas e o estudo das mutações no gene da lamina A/C foi realizado através de sequenciamento de toda região codificadora do gene. Resultados: Identificamos mutações em 30,7% dos pacientes (quatro casos) com fenótipo clínico de DMC por deficiência de lamina A/C. Todas as mutações encontradas (p.E358K, p.R249W, e p.N39S) ocorreram em heterozigose e de novo e já haviam sido descritas na literatura em pacientes com distrofias musculares. Em geral, estes pacientes apresentavam um grave comprometimento motor com o característico aspecto de cabeça caída, com início dos sintomas nos primeiros dois anos de vida. A CPK estava elevada entre 2 a 6 vezes o padrão superior da normalidade. O padrão histológico variou desde um músculo levemente até gravemente distrófico. Curiosamente, no estudo histológico do músculo, um dos pacientes apresentou agregados intracitoplasmáticos. Um outro paciente apresentava associadamente alterações neurogênicas ao estudo eletroneuromiográfico. Em todos os casos observamos complicações respiratórias, cardíacas e distúrbios de deglutição. Houve um caso de morte súbita, provavelmente em decorrência de arritmia cardíaca. Conclusões: A correlação genótipo-fenótipo permanece difícil, mas todos os casos apresentaram sinal da cabeça caída, comprometimento respiratório, cardíaco e biópsia muscular distrófica. A ampliação do conhecimento clínico e histológico pode orientar o diagnóstico e direcionar para o estudo molecular adequado, além de permitir o diagnóstico precoce das complicações, tão frequentes na DMC por deficiência de lamina A/C. Os exons 1, 4 e 6 são os mais frequentemente mutados e devem ser pesquisados inicialmente. Esta série de casos contribui também por demonstrar a distribuição universal da doençaBackground: The Congenital Muscular Dystrophies (CMD) are a clinically and genetically heterogeneous group of myopathies characterized by muscle hypotonia, delayed motor development and early onset of progressive muscle weakness with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. Almost half of the cases is caused by deficiency of laminin-alfa 2 (merosin). Other protein deficiencies described include: collagen VI, selenoprotein N1, several glycosyltransferases responsible for glycosylation of alfa-dystroglycan and lamin A/C. Several genes have been identified and the increased knowledge of new clinical and histological forms of CMD can guide diagnosis and direct appropriate molecular studies. LMNA-related CMD is often characterized by muscle weakness and a dropped head developed in the early years of life. Regarding lamin A/C deficiency, the immunohistochemical findings can be normal, probably because the protein change is functional only; this makes diagnosis using muscle samples more difficult. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in patients with CMD related to deficiency of lamin A/C. Methods: thirteen children with clinical and histological diagnosis of CMD with normal muscle expression for dystrophin, merosin, collagen 6, sarcoglycans and dysferlin were included in this study. The LMNA gene was sequenced after amplification of all coding exons. In addition, the muscle biopsies were revised. Results: In 30.7% (four cases) of our patients with typical clinical phenotype of lamin A/C deficiency were detected mutations on LMNA gene and all of them presented dropped-head syndrome, restrictive ventilator insufficiency, cardiac changes, increased serum CPK level and myopathic/dystrophic aspect on muscle biopsy. Two of the patients had normal motor development milestones in the first months of life and subsequently developed cervical and limb weakness. The other two patients presented a more severe motor involvement and failure to walk. One patient showed associated peripheral neuropathy. Curiously one case had myofibrillar aggregates on muscle biopsy. All mutations (p.E358K, p.R249W and p.N39S) were heterozygous and de novo and had been previously described in patients with muscular dystrophy. Conclusion: Genotype/phenotype correlation in CMD remains difficult. However patients with LMNA mutation and CMD seems to have a more homogeneous phenotype characterized by dropped head, severe motor disability, and cardiac and pulmonary involvement. Mutations on exons 1, 4 and 6 should be tested first. This case series also contributes for showing the universal distribution of the disease
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Leveugle, Benoît. "Simulation DNS de l’interaction flamme-paroi dans les moteurs à allumage commandé". Thesis, Rouen, INSA, 2012. http://www.theses.fr/2012ISAM0021/document.
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Dans le cadre du projet INTERMARC (INTERaction dans les Moteurs à Allumage Commandé), la tâche du CORIA a consisté à produire une base de données à l'échelle RANS (provenant de données DNS) afin de tester, valider et modifier le modèle d'interaction développée par IFPen. Ce modèle vise l'ajout d'une composante d'interaction, phénomène non pris en compte par les lois de paroi actuelles.Ce projet repose sur l'interaction forte entre les différents protagonistes présents. Le CORIA et le CETHIL ont travaillé ensemble à la réalisation d'une base de données pour tester les modèles initiaux proposés par IFPen, puis en fonction des résultats obtenus, à itérer avec IFPen pour modifier et améliorer les modèles. Ces tests ont inclus des simulations 2D laminaires, 2D turbulentes, et 3D turbulentesUnder the INTERMARC project (Flame wall interaction in spark ignition engines), CORIA's job was to produce a database to RANS scale (from DNS data) to test, validate and modify the interaction model developed by IFPEN. This model aims the addition of the interaction phenomena, non-captured by the current wall laws. This project is based on the strong interaction between the different actors. The CORIA and the CETHIL have worked together in the creation of the database, where the experimental data were also used to validate the resuslts of the DNS code.CORIA then used this database to test the original model proposed by IFPPEN, then according to the results obtained, CORIA iterated with IFPEN to modify and improve the models. These tests included laminar 2D simulations, 2D turbulent and 3D turbulent simulations
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GEY, NATHALIE Humbert M. "ETUDE DES CHANGEMENTS DE TEXTURES PAR TRANSFORMATION DE PHASE BETA-ALPHA DANS DES PRODUITS TA6V LAMINES A CHAUD /". [S.l.] : [s.n.], 1996. ftp://ftp.scd.univ-metz.fr/pub/Theses/1996/Gey.Nathalie.SMZ9634.pdf.
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NOAT, PIERRE. "Determination experimentale et prise en compte dans un code de calcul par elements finis de l'anisotropie mecanique d'alliages d'aluminium lamines". Paris, ENMP, 1996. http://www.theses.fr/1996ENMP0706.
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L'objet de ce travail a ete l'etude de l'influence de l'anisotropie mecanique d'alliages d'aluminium au cours du laminage et de sa prise en compte dans un code par elements finis. L'analogie du developpement de la texture cristallographique au cours du laminage a chaud et du bipoinconnement a ete etudiee pour differents alliages d'aluminium. L'anisotropie mecanique a ete determinee par la mesure du coefficient de lankfod et de la contrainte d'ecoulement suivant sept angles dans la direction de laminage pour des toles presentant des textures de deformation et de recristallisation. A partir de ces essais, les coefficients d'un critere de hill quadratique ont ete determines pour chacune des toles. Trois modeles polycristallins, un modele cmtp, un modele de taylor et un modele auto-coherent ont ete utilises pour predire les developpements d'anisotropie mecanique et de texture cristallographique au cours de la deformation. Le modele auto-coherent a donne les resultats les plus en accord avec l'experience. Le critere de hill et une loi de comportement de sellars et teggart ont ete implementes dans un code tridimensionnel par elements finis. L'influence de l'anisotropie sur l'elargissement au cours du laminage et du bipoinconnement a ete mise en evidence. Une procedure qui prevoie la fraction recristallisee pendant l'inter passe et qui utilise cette valeur pour calculer la contrainte d'ecoulement a ete developpee et integree dans le code de calcul. Les previsions de fraction recristallisee apres la derniere passe du laminage reversible ont ete en accord avec les observations effectuees sur des toles industrielles. Le champ de vitesse calcule par le code de calcul a ete utilise par un modele de taylor pour predire l'evolution de texture au cours des quatre passes du laminage tandem, le modele de taylor a ete integre au code de calcul
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Frankel, Diane. "Lamines et microARNs : implication dans un modèle de laminopathie héréditaire, la Progeria de Hutchinson-Gilford et de laminopathie acquise, l'adénocarcinome bronchique". Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0761.
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Les laminopathies regroupent des pathologies liées aux lamines. La Progeria est due à une mutation du gène LMNA entrainant la synthèse d’une protéine anormale : la progérine. Elle s’accumule dans le noyau et entraîne des dommages cellulaires aboutissant à une sénescence prématurée, à l’origine d’un vieillissement prématuré et accéléré des patients dont le décès survient vers l’âge de 14 ans. Les microARNs (miRs) sont des petits ARNs non-codants régulant l’expression des gènes. Dans le projet principal de ma Thèse, nous avons identifié par un miRNome en RT-qPCR, 14 miRs différentiellement exprimés dans les fibroblastes HGPS. Certains d’entre eux appartenant à la région 14q32.2-14q32-3, sont surexprimés à cause de modifications chromatiniennes. Nous avons ensuite étudié l’impact de la surexpression des miR-376a-3p et miR-376b-3p sur la régulation de l’autophagie. L’inhibition de ces miRNAs entraine une augmentation du niveau d’autophagie, associée à une diminution de la progérine. Une 2ème étude miRNome réalisée en NGS, a permis d’identifier d’autres miRNAs potentiellement impliqués dans la Progeria. Dans un second projet, nous avons analysé l’expression des lamines de type A dans des cellules tumorales métastatiques issues d’épanchements pleuraux de patients atteints d’adénocarcinome bronchique. Nous avons démontré que la diminution d’expression de la lamine A chez un groupe de patient est corrélée à un mauvais pronostic. Cette diminution pourrait être due à miR-9 qui cible directement l’ARNm de la prélamine A. Ces travaux de Thèse illustrent le rôle fondamental des lamines et suggère une place importante des miRNAs dans la physiopathologie de ces 2 types de laminopathiesLaminopathies are diseases linked to lamins. Progeria (HGPS) is a genetic disease caused by a mutation in LMNA gene leading to an abnormal protein called progerin. It accumulates in nucleus and causes cell damages leading to a premature senescence. Patient die around 14 years old. miRNAs are small non coding RNA regulating gene expression. In my main project, I identified with a miRNome approach by RT-qPCR, 14 differentially expressed miRNAs in dermal HGPS fibroblasts. We demonstrated that the overexpression of the miRNAs that belong to the 14q32 region was caused by chromatin modulation. Next, we studied the role of miR-376-3p and miR-376b-3p on autophagy and demonstrated that the inhibition of their overexpression increases autophagy and decreases progerin. A second miRNome by NGS identified other miRNAs potentially linked to HGPS pathophysiology. In my second project, I studied lamins expression in metastatic cells from pleural effusion of lung adenocarcinoma patients. We showed that the decreased expression of lamin A in a group of patients was correlated with poor prognosis, which could be linked to miR-9 expression. This thesis illustrates the fundamental role of lamins and suggest the role of miRNAs in the pathophysiology of this to types of laminopathies
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De, Sandre-Giovannoli Annachiara. "Implication du gène LMNA, codant pour les Lamines A/C, dans les neuropathies périphériques héréditaires et la progeria de Hutchinson-Gilford". Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX20698.
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Hurskainen, M. (Merja). "The roles of collagens XV and XVIII in vessel formation, the function of recombinant human full-length type XV collagen and the roles of collagen XV and laminin α4 in peripheral nerve development and function". Doctoral thesis, Oulun yliopisto, 2010. http://urn.fi/urn:isbn:9789514263651.
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Abstract Transgenic mice were used to evaluate the roles of collagens XV and XVIII in retinal vessel development and to examine the roles of collagen XV and laminin α4 in peripheral nerve development and function. Also, in vitro methods were used to study the functions of recombinant, full-length human collagen XV produced in insect cells. The lack of collagen XVIII alone was found to result in overproliferation of astrocytes in the mouse retina and deficient vascularization of the retina, which was ultimately rescued by the persistent hyaloid vessels. VEGF mRNA expression was appropriately regulated in the retina of the collagen XVIII deficient mice, which also showed reduced susceptibility to oxygen-induced neovascularization. Lack of collagen XV alone had no obvious effect on the mouse eye, but an abnormal migration of astrocytes onto the persistent hyaloid vessels could be seen in mice lacking both collagens XVIII and XV. Recombinant full-length human collagen XV was seen in rotary shadowing EM as an extended protein with numerous kinks and a globular domain at its N-terminus. The mean length of the molecules was 241 nm and they had a tendency to form aggregates. Collagen XV attaches to the collagen binding region of fibronectin and to a lesser extent to vitronectin and laminin. It was rapidly bound to cultured cells with a staining pattern co-localizing with fibronectin. Collagen XV was also found to inhibit the adhesion and migration of cells in vitro. Lack of collagen XV in mice was found to result in ultrastructural abnormalities in the sciatic nerves, such as polyaxonal myelination and more loosely packed C-fibres, mild impairment of BM assembly and mild motor dysfunction with a lower sensory nerve conduction velocity. Polyaxonal myelination and a failure in the segregation of axons were evident in laminin α4 null mice, which also had diminished amounts of C-fibres, BM abnormalities, diminished myelin and a greater myelin period compared with wild-type mice. They performed poorly in the round beam test and showed diminished compound muscle action potentials. A simultaneous lack of collagen XV and laminin α4 resulted in a permanent defect in the segregation of axons and C-fibre development. The performance of the double null mice on the round beam was poor relative to the other genotypesTiivistelmä Tässä väitöskirjatyössä on tutkittu kollageenien XV ja XVIII merkitystä silmän verkkokalvon verisuonituksen kehittymiselle sekä kollageeni XV:n ja laminiini α4:n merkitystä ääreishermon kehittymiselle ja toiminnalle käyttäen hyväksi muuntogeenisiä hiiriä. Lisäksi tässä työssä on käytetty in vitro –menetelmiä hyönteissoluissa yhdistelmä-DNA-tekniikalla tuotetun kollageeni XV:n toiminnan tutkimiseksi. Kollageeni XVIII:n puutteen todettiin johtavan verkkokalvon astrosyyttien määrän lisääntymiseen sekä verkkokalvon suonituksen kehittymiseen epänormaalilla tavalla lasiaissuonista, jotka eivät olleetkaan hävinneet kehityksen aikana. VEGF:n lähetti-RNA:n ilmentyminen oli asianmukaisesti säädelty eri verkkokalvon alueilla kollageeni XVIII:n suhteen poistogeenisillä hiirillä, joilla kehittyi myös vähemmän uudissuonia matalalle hapen osapaineelle altistamisen jälkeen. Kollageeni XV:n puute ei johtanut havaittaviin muutoksiin silmässä, mutta molempien kollageenien XV ja XVIII puuttuessa havaittiin silmässä epänormaalia astrosyyttien soluvaellusta lasiaissuonten päälle. Tässä väitöskirjatyössä osoitetaan, että yhdistelmä-DNA-tekniikalla tuotettu kokopitkä ihmisen kollageeni XV näytti elektronimikroskopiassa pitkältä molekyyliltä, jonka pituus oli keskimäärin 241 nm ja joka sitoutui helposti toisiin kollageeni XV -molekyyleihin. Kollageeni XV sitoutuu fibronektiinin kollageenia sitovaan osaan sekä vitronektiiniin ja laminiiniin. Viljeltyihin soluihin kollageeni XV sitoutui siten, että vasta-ainevärjäyksellä todettiin sen paikallistuvan samoille alueille fibronektiinin kanssa. Kollageeni XV:n todettiin myös vähentävän solujen kiinnittymistä ja liikkumista. Hiirissä kollageeni XV:n puutoksen todettiin johtavan iskiahermoissa polyaksonaaliseen myelinisaatioon, C-säikeiden lievään kehityshäiriöön, tyvikalvon koostumuksen häiriöön, lieviin motorisiin vaikeuksiin ja matalampaan tuntohermojen johtonopeuteen. Laminiini α4 –puutteisilla hiirillä oli todettavissa myös polyaksonaalista myelinisaatiota ja lisäksi häiriö aksonien erottelussa. Niiden hermoista löytyi myös tyvikalvon epämuodostumia, vähemmän myeliiniä ja C-säikeitä sekä suuremmat myeliinijaksot verrattuna villityypin hiiriin. Ne selviytyivät huonosti kävelytestissä ja niiden lihasten aktiopotentiaalit olivat pienemmät kuin kontrollihiirillä. Samanaikainen kollageeni XV:n ja laminiini α4:n puutos johti pysyvään aksonien erottelun ja C-säikeiden kehittymisen häiriöön. Kävelytestissä tuplapoistogeeniset hiiret selviytyivät huonoiten muihin genotyyppeihin verrattuna
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Jebeniani, Imen. "Etude in vitro et in vivo d'une cardiomyopathie secondaire à une laminopathie". Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0025.
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La mutation LMNA H222P est responsable de dystrophie musculaire d’Emery Dreifuss autosomale dominante (DMED-AD). Les patients atteints de DMED-AD souffrent d’une dystrophie musculaire et de cardiomyopathie dilatée. Les mécanismes moléculaires impliqués dans cette pathologie sont encore peu connus. Dans mes travaux de thèse, je me suis servie de cellules souches pluripotentes murines ainsi que de souris portant la mutation LMNA H222P afin d’étudier une approche thérapeutique potentielle. L'échocardiographie des souris LMNA H222P in utero révèle une dilatation des cœurs embryonnaires dès E13.5, ce qui indique une origine développementale de la maladie. La différenciation cardiaque des cellules souches pluripotentes murines est altérée dès le stade mésoderme. Aussi, les niveaux d’expression de Mesp1, snail1 et twist, gènes impliqués dans la transition épithélio-mésenchymateuse (TEM) sont diminués dans les cellules mutées en comparaison avec les cellules sauvages en cours de différenciation. L'immunoprécipitation de la chromatine dans les cellules différenciées révèle une diminution spécifique de la marque d'histone H3K4me1 sur des régions régulatrices de Mesp1 et Twist. L'inhibition de LSD1, une déméthylase spécifique de H3K4me1 rétablit le taux de la marque H3K4me1 sur les régions génomiques étudiées dans les cellules mutées. De plus, la baisse de LSD1 améliore la contraction des cardiomyocytes différenciés obtenus à partir des cellules souches embryonnaires portant la mutation LMNA H222P. L'inhibiteur de LSD1, utilisé dans les essais cliniques en cancérologie, pourrait être une molécule thérapeutique potentielle pour le traitement des laminopathies à phénotype cardiaqueThe LMNA H222P missense mutation in autosomal dominant Emery-Dreifuss muscular dystrophy patients is responsible for a muscular dystrophy and dilated cardiomyopathy. The molecular mechanisms underlying the origin and development of the pathology are still unknown. Herein, we used mouse pluripotent stem cells as well as a mutant mouse, all harboring the LMNA H222P mutation, to investigate potential therapeutic approaches. Echocardiography of LMNA H222P mice in utero revealed dilatation of heart as early as E13.5, pointing to a developmental origin of the disease. Cardiac differentiation of mouse pluripotent stem cells was impaired as early as the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene as well as snail1 and twist, involved in epithelial-mesenchymal transition (EMT) of epiblast cells, was decreased in mutated cells when compared to wild type in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. Chromatin immunoprecipitation assays of the H3K4me1 epigenetic mark in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of MesP1 and Twist. Downregulation or inhibition of LSD1, that specifically demethylates H3K4me1, rescued the epigenetic landscape in mutated cells. In turn downregulation of LSD1 rescued contraction in cardiomyocytes differentiated from LMNA H222P pluripotent stem cells. Our data point to LSD1 inhibitor, used in clinical trials in cancerology, as potential therapeutic molecule for laminopathies with a cardiac phenotype
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Hookana, E. (Eeva). "Characteristics of victims of non-ischemic sudden cardiac death". Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789526200224.
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Abstract A non-ischemic etiology of sudden cardiac death (SCD), mostly due to various cardiomyopathies (CMP), accounts for about 20% of all SCDs. Most of the major studies of risk factors for SCD have focused on coronary artery disease (CAD). The aim of the present study was to clarify the characteristics of non-ischemic SCD in Northern Finland. In this study, consecutive victims of SCD (n=2661) were prospectively collected, and among whom post-mortem examinations were performed between 1998 and 2007. Information about the SCD victims was obtained from a combination of available medical records, postmortem examination reports, medication used at the time of SCD, and standardized questionnaire filled out by the closest family members of the victims of SCD. We also screened the candidate genes from a Finnish family in which fatal arrhythmias was first manifestation of a cardiac disease. The collagen content of the myocardium from histological samples in victims of SCD due to idiopathic myocardial fibrosis (IMF) was also evaluated. CAD was the most common cause of death (2082 victims, 78.2%). The prevalence of non-ischemic SCDs was 21.8% of all the SCDs. After sub-grouping the non-ischemic SCDs into various categories, the most common cause of death was CMP related to obesity (23.7%), followed by alcoholic CMP (19.0%), hypertensive CMP (15.5%) and IMF (13.6%). The association of SCD with IMF is notably frequent among victims <40 years old (28.3%). The prevalence of family history of SCD was significantly higher in the victims of ischemic (34.2%) than non-ischemic SCD (13.4%, P<0.001) or controls (17.6%, P<0.001). Lamin A/C gene mutation R541C was found from Finnish SCD family, in which the IMF was predominant pathologic-anatomic finding. Myocardial type I collagen synthesis was increased in victims of SCD due to IMF. In conclusion, the characteristics of non-ischemic SCD in Finland differ from those reported previously. Higher prevalences of CMP-associated SCDs related to obesity, IMF and alcoholic CMP were observed as clinical and/or pathologic bases for non-ischemic SCD. The family history of SCD is not significantly increased in victims of non-ischemic SCD, suggesting a larger role of sporadic occurrence than inherited traits as the cause of non-ischemic SCD. Replacement of cardiac myocytes by fibrosis can be responsible for fatal cardiac arrhythmias in subjects with the lamin A/C gene mutation. The victims of SCD due to IMF have increased myocardial type I collagen synthesisTiivistelmä Ei-iskeeminen sydänperäinen äkkikuolema aiheuttaa noin 20 % kaikista sydänperäisistä äkkikuolemista. Suurin osa ei-iskeemisistä sydänperäisistä äkkikuolemista johtuu erilaisista sydänlihassairauksista, kardiomyopatioista. Useimmat sydänperäisen äkkikuoleman riskitekijöitä kartoittavista tutkimuksista ovat keskittyneet sepelvaltimotautiin. Tämän tutkimuksen tarkoituksena oli selvittää ei-iskeemisen sydänperäisen äkkikuoleman tunnuspiirteitä pohjoissuomalaisessa väestössä. Tutkimuksessa käytettiin potilasaineistona sydänperäiseen äkkikuolemaan menehtyneitä vainajia (n=2661), joille on tehty oikeuslääketieteellinen ruumiinavaus. Tiedot vainajista saatiin saatavilla olevista potilaskertomuksista, ruumiinavauspöytäkirjoista, äkkikuoleman aikaisesta lääkityksestä ja lähiomaisille lähetetystä standardisoidusta kyselylomakkeesta. Kandidaattigeenit tutkittiin pohjoissuomalaisesta perheestä, jossa ensimmäinen oire sydänsairaudesta oli hengenvaarallinen rytmihäiriö. Lisäksi sydänlihaksen kollageenikoostumus analysoitiin histologisista näytteistä potilailta, joiden sydänperäinen äkillinen kuolema johtui idiopaattisesta sydänlihaksen sidekudoskasvusta. Sepelvaltimotauti oli yleisin sydänperäisen äkkikuoleman aiheuttaja (n=2082, 78,2 %). Ei-iskeemisten sydänperäisten äkkikuolemien osuus oli 21,8 % (n=579) kaikista sydänperäisistä äkkikuolemista. Ei-iskeemiset sydänperäiset äkkikuolemat jaettiin alaryhmiin, joista yleisimmät olivat lihavuuteen assosioituva kardiomyopatia (23,7 %), alkoholikardiomyopatia (19,0 %), korkeaan verenpaineeseen assosioituva kardiomyopatia (15,5 %) sekä idiopaattinen sydänlihaksen sidekudoskasvu (13,6 %), joka myös oli yleisin ei-iskeemiseen sydänperäiseen äkkikuolemaan johtava syy alle 40-vuotiailla (28,3 %). Positiivinen sydänperäisen äkkikuoleman sukuhistoria oli tilastollisesti merkitsevästi yleisempää iskeemisillä (34,2 %) kuin ei-iskeemisillä (13,4 %) sydänperäisen äkkikuoleman uhreilla. Lamin A/C – geenin mutaatio löydettiin pohjoissuomalaisesta äkkikuolemaperheestä, jossa idiopaattinen sydänlihaksen sidekudoskasvu todettiin pääasialliseksi patologiseksi löydökseksi. Tyypin I kollageenin synteesi todettiin kohonneeksi idiopaattiseen sydänlihaksen sidekudoskasvuun menehtyneillä vainajilla. Yhteenvetona voidaan todeta, pohjoissuomalaisen väestön ei-iskeemisen sydänperäisen äkkikuoleman tunnuspiirteet eroavat aiemmin raportoiduista; lihavuuteen assosioituva kardiomyopatia, alkoholikardiomyopatia, sekä idiopaattinen sydänlihaksen sidekudoskasvu olivat aiempaa yleisempiä ei-iskeemisen äkkikuoleman aiheuttajia. Positiivinen sydänperäisen äkkikuoleman sukuhistoria ei ollut tilastollisesti merkitsevästi kohonnut ei-iskeemisen sydänperäiseen äkkikuolemaan menehtyneillä. Tämä tarkoittaa, että perinnöllinen syy ei-iskeemisen sydänperäisen äkkikuoleman aiheuttajana on luultua harvinaisempi. Lamin A/C – geenimutaation kantajilla sydänlihassolujen korvautuminen sidekudoksella todettiin hengenvaarallisen rytmihäiriön aiheuttajaksi. Lisäksi, tyypin I kollageenin synteesi todettiin kohonneeksi idiopaattiseen sydänlihaksen sidekudoskasvuun menehtyneillä vainajilla
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Janin, Alexandre. "Altérations de la voie de signalisation BMP4 responsables de la différenciation accélérée de myoblastes mutés sur le gène LMNA". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1237/document.
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Les lamines A et C sont deux composants majeurs de la lamina nucléaire, réseau de filaments intermédiaires situé sous la membrane nucléaire interne. Les mutations du gène LMNA, codant les lamines A/C, ont été associées à de nombreuses pathologies humaines, appelées laminopathies, et affectant un ou plusieurs tissus dont le muscle. Les mécanismes physiopathologiques sous-jacents ne sont encore que partiellement élucidés. Les lamines A/C jouant un rôle crucial dans l’architecture nucléaire et l’organisation de la chromatine, l’hypothèse d’une altération de l’expression de facteurs de transcription ou de gènes tissus-spécifiques a été formulée. De plus, au niveau musculaire, il a été décrit que les lamines A/C jouent un rôle majeur dans la mise en place d’une différenciation musculaire efficace.Afin d’identifier des altérations potentielles au sein des voies de signalisation régulant la différenciation musculaire, nous avons utilisés un modèle de myoblastes murins conditionnellement immortalisés et comparés le profil d’expression entre les myoblastes sauvages et inactivés pour le gène Lmna (Lmna-/-). Nous avons donc identifiés deux altérations majeures de la voie BMP (Bone Morphogenetic Pathway) : la diminution de l’expression du ligand Bmp4 et l’augmentation de celle de Smad6, un inhibiteur intracellulaire de la voie. Cette surexpression de Smad6 est responsable d’une séquestration cytoplasmique des Smads 1, 5 et 8 phosphorylées et d’une diminution de l’expression des gènes cibles, Id1 et Id2. Les myoblastes Lmna-/- montrent une différenciation myogénique prématurée, phénotype réversible par des expériences d’ARN interférent ciblant Smad6. Enfin, nous avons montré que ces défauts sont retrouvés dans des myoblastes humains porteurs hétérozygotes de la mutation LMNA R310X.Ces résultats apportent un nouveau mécanisme physiopathologique des laminopathies musculaires et identifient une nouvelle cible thérapeutique potentielleLMNA gene encodes lamins A and C, two major components of the nuclear lamina, a network of intermediate filaments underlying the inner nuclear membrane. LMNA mutations have been associated with a wide spectrum of human diseases collectively called “laminopathies” affecting one or several tissues, such as muscles. The physiopathological mechanisms underlying laminopathies remain unclear. Given the crucial role of lamins A/C in nuclear architecture and chromatin organization, the “gene regulation” hypothesis have been proposed. It suggests that LMNA mutations could alter in a tissue-specific manner transcription factors and/or genes expression. Moreover, lamins A/C have been described as important regulators in muscle differentiation regulation.To identify potential alterations in signaling pathways regulating muscle differentiation in LMNA-mutated myoblasts, we used a previously described model of conditionally immortalized murine myoblasts and compared gene expression profiles in wild-type and Lmna-/- H-2K myoblasts. We identified two major alterations of the Bone Morphogenetic Protein (BMP) pathway in Lmna-/- myoblasts: Bmp4 downregulation and Smad6 overexpression. We demonstrated that Smad6 overexpression lead to Smad1/5/8 sequestration in the cytoplasm and to the downregulation of their target genes, Id1 and Id2. As a consequence, Lmna-null myoblasts displayed a premature differentiation which could be rescued by downregulating Smad6 expression. Finally, we showed that these defects are relevant for human laminopathies as they are also present in myoblasts from a human patient carrying a LMNA+/Q310X mutation.Taken together, these results provide a potential mechanism for the muscle stem cell exhaustion and muscle atrophy observed in muscle laminopathies and identify a new therapeutical target likely to reverse pathological phenotypes