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1
Dahlenborg, Katarina. "Celluar and molecular aspects of the germinal center reaction". Lund : Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/68945013.html.
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Alexander, Carla-Maria Alana. "T regulatory cells and the germinal center". Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/1117.
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Germinal center (GC) reactions are central features of T cell-driven B cell responses, and the site where antibody (Ab) producing cells and memory B cells are generated. Within GCs, a range of complex cellular and molecular events occur which are critical for the generation of high affinity Abs. These processes require exquisite regulation not only to ensure the production of desired Abs, but to minimize unwanted autoreactive or low affinity Abs.
To assess whether T regulatory cells (Treg) participate in the control of GC responses, immunized mice were treated with either an anti-glucocorticoid-induced TNFR-related protein (GITR) mAb or an anti-CD25 mAb to disrupt Treg activity. In both groups of treated mice, the GC B cell pool was significantly larger compared with control treated animals, with switched GC B cells composing an abnormally high proportion of the response. With these results indicating Tregs influence on GC dynamics, experiments were conducted to determine if Tregs were located in the GC, which subset of Treg was involved and by which mechanisms were their functions being effected. Within the spleens of immunized mice, CXCR5+ and CCR7- Tregs were documented by flow cytometry and Foxp3+ cells were found within GCs using immunohistology. Studies demonstrated administration of either anti-TGF-β or anti-IL-10R blocking mAb to likewise result in dysregulated GCs, suggesting that generation of inducible Tregs is important in controlling the GC response. Blockade of two Treg methods of suppression, PD-1/PD-L1 pathway and CTLA-4, also resulted in disrupted GCs, indicating the possible use of them for suppression by Treg. Collectively, these findings indicate that Tregs contribute to the overall size and quality of the humoral response by controlling homeostasis within GCs.
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Le, Thuc-vy L. "B cell clonal abundance and madcam-1 mediate affinity maturation and fate of germinal center B cells". Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/le.pdf.
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Blink, Elizabeth J. "B cell selection in the germinal centre /". Connect to thesis, 2002. http://eprints.unimelb.edu.au/archive/00001459.
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Alexander, Lou-Ella M. m. "Characterization of the Transcriptional Elongation Factor ELL3 in B cells and Its Role in B-cell Lymphoma Proliferation and Survival". Scholar Commons, 2018. http://scholarcommons.usf.edu/etd/7119.
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The studies presented in this dissertation establish the dynamics of Eleven nineteen Lysine-rich leukemia (ELL) family of elongation factors during B cell differentiation and provide a description of ELL3 function in B cells.
The transition from a mature naïve B cells into an activated B cell is dependent on a large increase in transcriptional output, which is followed by focused expression on secreted immunoglobulin upon terminal differentiation into plasma cell. While ELL family members have previously been implicated in alternative splicing at the immunoglobulin heavy chain locus in plasma cells, their presence and function prior to differentiation is currently not known. However, the use of elongation factors has been implied by the finding of mostly paused RNA polymerase II in the genome of naïve B cells.
In the first study, the expression of transcriptional elongation factor ELL3 is shown to be restricted to activated B cells and B cell lymphomas. All three family members were characterized in B cell lymphoma cell lines, genome wide expression, microarray analysis and primary B cell stimulus. The expression of ELL3 was induced upon activation of B cells concurrently with family member ELL. In addition, the abundant expression of ELL3 was restricted to GC derived B cell lymphoma cell lines. While the expression of ELL is maintained, the expression of ELL3 is diminished and ELL2 is up-regulated in terminally differentiated plasma cells.
The expression of master regulator of terminal plasma cell differentiation PRDM1 was inverse correlated with that of ELL3. To further establish PRDM1s role in regulating the ELL family member dynamics, global binding was assessed in plasma cell lines. Chromatin immunoprecipitation followed by quantitative PCR was utilized to identify direct association of PRDM1 at exclusively the ELL3 loci. Ectopic expression of PRDM1 in B cells down regulated the expression of ELL3. Furthermore, two consensus PRDM1 binding sites were defined at the ELL3 loci, which mediate significant repression of the promoter activity. Collectively, these experiments indicate that PRDM1 mediates the switch from ELL3 in B cells to ELL2 in plasma cells.
The data presented in the final chapter aimed at defining a function for ELL3 in the cells that express it most abundantly, which are B cell lymphoma cell lines. Transient depletion of ELL3 in a Burkitt’s lymphoma cell line resulted in a diminished proliferation rate due to a severe disruption of DNA replication and its regulators minichromosome maintenance proteins. Additionally, compromised cell division and mitotic regulators were observed along with increased DNA damage and cell death.
The data presented here demonstrate a key role for ELL3 in the proliferation and survival of B cell lymphomas and positions ELL3 as an attractive therapeutic target against B cell lymphoma’s with a germinal center origin.
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Yaghoubi, Houman. "Bio-Photoelectrochemical Solar Cells Incorporating Reaction Center and Reaction Center Plus Light Harvesting Complexes". Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5803.
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Harvesting solar energy can potentially be a promising solution to the energy crisis now and in the future. However, material and processing costs continue to be the most important limitations for the commercial devices. A key solution to these problems might lie within the development of bio-hybrid solar cells that seeks to mimic photosynthesis to harvest solar energy and to take advantage of the low material costs, negative carbon footprint, and material abundance. The bio-photoelectrochemical cell technologies exploit biomimetic means of energy conversion by utilizing plant-derived photosystems which can be inexpensive and ultimately the most sustainable alternative. Plants and photosynthetic bacteria harvest light, through special proteins called reaction centers (RCs), with high efficiency and convert it into electrochemical energy. In theory, photosynthetic RCs can be used in a device to harvest solar energy and generate 1.1 V open circuit voltage and ~1 mA cm-2 short circuit photocurrent. Considering the nearly perfect quantum yield of photo-induced charge separation, efficiency of a protein-based solar cell might exceed 20%. In practice, the efficiency of fabricated devices has been limited mainly due to the challenges in the electron transfer between the protein complex and the device electrodes as well as limited light absorption. The overarching goal of this work is to increase the power conversion efficiency in protein-based solar cells by addressing those issues (i.e. electron transfer and light absorption). This work presents several approaches to increase the charge transfer rate between the photosynthetic RC and underlying electrode as well as increasing the light absorption to eventually enhance the external quantum efficiency (EQE) of bio-hybrid solar cells. The first approach is to decrease the electron transfer distance between one of the redox active sites in the RC and the underlying electrode by direct attachment of the of protein complex onto Au electrodes via surface exposed cysteine residues. This resulted in photocurrent densities as large as ~600 nA cm-2 while still the incident photon to generated electron quantum efficiency was as low as %3 × 10-4. 2- The second approach is to immobilize wild type RCs of Rhodobacter sphaeroides on the surface of a Au underlying electrode using self-assembled monolayers of carboxylic acid terminated oligomers and cytochrome c charge mediating layers, with a preferential orientation from the primary electron donor site. This approach resulted in EQE of up to 0.06%, which showed 200 times efficiency improvement comparing to the first approach. In the third approach, instead of isolated protein complexes, RCs plus light harvesting (LH) complexes were employed for a better photon absorption. Direct attachment of RC-LH1 complexes on Au working electrodes, resulted in 0.21% EQE which showed 3.5 times efficiency improvement over the second approach (700 times higher than the first approach). The main impact of this work is the harnessing of biological RCs for efficient energy harvesting in man-made structures. Specifically, the results in this work will advance the application of RCs in devices for energy harvesting and will enable a better understanding of bio and nanomaterial interfaces, thereby advancing the application of biological materials in electronic devices. At the end, this work offers general guidelines that can serve to improve the performance of bio-hybrid solar cells.
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Hung, Hui-Fang. "Roles of the Mother Centriole Appendage Protein Cenexin in Microtubule Organization during Cell Migration and Cell Division: A Dissertation". eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/842.
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Epithelial cells are necessary building blocks of the organs they line. Their apicalbasolateral polarity, characterized by an asymmetric distribution of cell components along their apical-basal axis, is a requirement for normal organ function. Although the centrosome, also known as the microtubule organizing center, is important in establishing cell polarity the mechanisms through which it achieves this remain unclear. It has been suggested that the centrosome influences cell polarity through microtubule cytoskeleton organization and endosome trafficking. In the first chapter of this thesis, I summarize the current understanding of the mechanisms regulating cell polarity and review evidence for the role of centrosomes in this process.
In the second chapter, I examine the roles of the mother centriole appendages in cell polarity during cell migration and cell division. Interestingly, the subdistal appendages, but not the distal appendages, are essential in both processes, a role they achieve through organizing centrosomal microtubules. Depletion of subdistal appendages disrupts microtubule organization at the centrosome and hence, affects microtubule stability. These microtubule defects affect centrosome reorientation and spindle orientation during cell migration and division, respectively. In addition, depletion of subdistal appendages affects the localization and dynamics of apical polarity proteins in relation to microtubule stability and endosome recycling. Taken together, our results suggest the mother centriole subdistal appendages play an essential role in regulating cell polarity. A discussion of the significance of these results is included in chapter three.
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Hung, Hui-Fang. "Roles of the Mother Centriole Appendage Protein Cenexin in Microtubule Organization during Cell Migration and Cell Division: A Dissertation". eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/842.
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Epithelial cells are necessary building blocks of the organs they line. Their apicalbasolateral polarity, characterized by an asymmetric distribution of cell components along their apical-basal axis, is a requirement for normal organ function. Although the centrosome, also known as the microtubule organizing center, is important in establishing cell polarity the mechanisms through which it achieves this remain unclear. It has been suggested that the centrosome influences cell polarity through microtubule cytoskeleton organization and endosome trafficking. In the first chapter of this thesis, I summarize the current understanding of the mechanisms regulating cell polarity and review evidence for the role of centrosomes in this process.
In the second chapter, I examine the roles of the mother centriole appendages in cell polarity during cell migration and cell division. Interestingly, the subdistal appendages, but not the distal appendages, are essential in both processes, a role they achieve through organizing centrosomal microtubules. Depletion of subdistal appendages disrupts microtubule organization at the centrosome and hence, affects microtubule stability. These microtubule defects affect centrosome reorientation and spindle orientation during cell migration and division, respectively. In addition, depletion of subdistal appendages affects the localization and dynamics of apical polarity proteins in relation to microtubule stability and endosome recycling. Taken together, our results suggest the mother centriole subdistal appendages play an essential role in regulating cell polarity. A discussion of the significance of these results is included in chapter three.
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Eijk, Martinus Cornelis van. "Regulation of germinal center B cell apoptosis". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/83857.
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Gimpel, Petra. "Mechanisms of non-centrosomal MTOC formation at the nucleus in muscle cells". Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066442/document.
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Le juste positionnement du noyau durant la formation musculaire semble important pour la fonction musculaire et des défauts ont été associés à plusieurs maladies musculaires. Le positionnement nucléaire dépend des microtubules (MTs), qui sont réorganisés depuis le centrosome, dans les myoblastes proliférants, vers l’enveloppe nucléaire (EN), dans les myotubes différenciés. Cette réorganisation s'accompagne de la redistribution des protéines centrosomales vers l’EN qui adopte le rôle de centre organisateur des microtubules (MTOC) lors de la différenciation myogénique. Néanmoins, les mécanismes sous-jacents restent inconnus. Ici, nous avons identifié les protéines Nesprin-1 et Sun1/2, localisées respectivement à la membrane nucléaire externe et interne, comme impliquées dans le recrutement de la fonction MTOC à l’EN. Les cellules déficientes en Nesprin-1 ou Sun1/2 ont montré une localisation altérée des protéines centrosomales dans le cytoplasme et l’absence des MTs depuis l’EN. De plus, Nesprin-1alpha, une myo-isoforme de Nesprin-1, s’associait aux protéines centrosomales Akap450, Pericentrin et Pcm1 dans les myotubes C2C12 et était suffisante pour corriger les défauts observés dans des cellules déplétées en Nesprin-1. Parmi les protéines centrosomales recrutées par Nesprin-1alpha, seule Akap450 semble nécessaire à la nucléation des MTs à l’EN. Ce processus, médié par Akap450 et Nesprin-1alpha, s’est avéré important pour le positionnement nucléaire lors du développement des myotubes. Ces résultats renforcent notre compréhension sur le lien causal entre des défauts lors de la formation du MTOC à l’EN et des défauts de positionnement nucléaire dans les dystrophies musculairesThe accurate position of the nucleus during skeletal muscle formation seems to be important for muscle function, and defects have been associated with numerous muscle diseases. Nuclear positioning requires microtubules (MTs) which are reorganized from the centrosome in proliferating myoblasts to the nuclear envelope (NE) in differentiated myotubes. This dramatic MT reorganization is accompanied by a redistribution of proteins from the centrosome to the NE which thus takes over the function as a microtubule-organizing center (MTOC) during myogenic differentiation. However, the underlying mechanisms are still unknown. Here, we identified Nesprin-1 and Sun1/2, outer and inner nuclear membrane proteins, respectively, to be involved in the recruitment of MTOC function to the NE. Nesprin-1 or Sun1/2 deficient cells displayed mislocalization of centrosomal proteins to the cytoplasm and failed to regrow MTs from the NE. Moreover, the muscle-specific isoform of Nesprin-1, namely Nesprin-1alpha, was shown to be highly associated with the centrosomal proteins Akap450, Pericentrin and Pcm1 in C2C12 myotubes and to be sufficient to rescue the observed defects in Nesprin-1 depleted cells. Among the centrosomal proteins localizing at the NE during myogenic differentiation, solely Akap450 seemed to be required for MT nucleation. Akap450-Nesprin-1alpha-mediated MT nucleation from the NE was demonstrated to play an important role in nuclear positioning during myotube formation. These findings strengthen our understanding on how defects in MTOC formation at the NE can link to nuclear positioning defects in muscular dystrophies
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Sakai, Tomomi. "Distinctive cell properties of B cells carrying the BCL2 translocation and their potential roles in the development of lymphoma of germinal center type". Kyoto University, 2010. http://hdl.handle.net/2433/120565.
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Atkinson, Jeffrey Ross. "Peripheral Germinal Centers Regulate Virus-Specific B Cell Accumulation in the CNS". Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1524683244217474.
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Le, Coz Carole. "Quelle contribution du centre germinatif et de ses composants moléculaires et cellulaires dans la physiopathologie du lupus ?" Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ077.
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Le lupus érythémateux disséminé est une maladie auto-immune systémique très invalidante dont les atteintes sont multiples, les plus fréquentes étant cutanées, articulaires et rénales. Dans ce type de maladie, le système immunitaire, hyperactif, ne se limite pas à lutter contre des agents extérieurs mais s'attaque à ses propres cellules, entre autres par le biais d'auto-anticorps. Ces anticorps délétères sont produits par des plasmocytes, cellules issus de la différenciation des lymphocytes B. Ce processus se déroule principalement au sein des centres germinatifs (GC) dans les organes lymphoïdes secondaires, et fait intervenir de nombreux acteurs moléculaires et cellulaires. Mon projet de thèse a porté sur l'étude de la contribution du GC et de ses constituants, tels que les cellules auxiliaires folliculaires (Tfh) et l'IL-21, au cours du lupus. Au cours de ce travail, nous avons mis en évidence une altération à la fois quantitative et qualitative des cellules Tfh chez des patients lupiques et dans un modèle murin, altération entre autres responsable de taux anormalement élevés d'IL-21. Nous avons également observé une sensibilité accrue des cellules B de souris lupiques à cette cytokine, dont la cause est une surexpression de molécules clés telles que STAT3, et dont la conséquence est un surcroit de différenciation plasmocytaire. Tous les éléments sont donc présents pour favoriser l'interaction "Tfh-B" et la réaction du GC, et amplifier la réponse autoimmune. Enfin, la découverte de l'existence de GC ectopiques fonctionnels dans les reins de souris lupiques permet d'envisager l'existence de réponses locales au sein même des organes cibles. Les données obtenues, fondamentales, sont prometteuses et laissent entrevoir de nouvelles perspectives de biothérapies, plus ciblées, pour le traitement de la maladie lupiqueSystemic lupus erythematosus is a disabling chronic autoimmune disease characterized by B cell hyperactivity leading to the production of autoantibodies, some of which exerting pathogenic effects. Autoantibodies are produced by plasma cells, which originate from the differentiation of B cells through a process that mainly takes place in germinal centers (GC) in secondary lymphoïd organs and involves many molecular and cellular parameters. The aim of my PhD project was to analyze the individual contribution of GC components, such as follicular helper T cells (Tfh) and IL-21, to lupus development. During this work, we have shown both a quantitative and qualitative impairment of Tfh cells in lupus patients and in a mouse model, leading, among other things, to high IL-21 levels. We also observed that B cells from lupus mice display a specific intrinsic sensitivity to this cytokine, due to over-expression of key molecules such as STAT3, which results in increased plasma cell differentiation. Thus, all elements are gathered that favor "Tfh-B" cell interactions and the GC reaction, and therefore the autoimmune response. Finally, the discovery of functional ectopic GC in the kidneys of lupus mice allows envisaging that local responses occur within the target organs and likely participate to kidney injury. The fundamental data we obtained are promising and anticipate new and better targeted biotherapies for lupus treatment
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Hussein, Mourad. "Caractérisation des mécanismes cellulaires, génétiques et épigénétiques de la différenciation terminale des lymphocytes B chez l’homme". Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1S198.
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Ces dernières années ont été marquées par une progression importante dans la connaissance de la physiologie des cellules B in vivo et de leur différenciation en plasmocytes, grâce aux modèles murins et à l'imagerie intravitale. La transposition à l'Homme des connaissances acquises chez la souris soulève cependant des difficultés, telles que le manque d'outils pour visualiser les évènements qui se déroulent dans les organes lymphoïdes humains. Dans l'optique d'apporter une réponse à cette problématique, nous avons développé au sein du laboratoire un modèle in vitro en deux étapes, permettant la différenciation des lymphocytes B naïfs humains en plasmocytes. Ce modèle est particulièrement adapté pour étudier l'induction, au cours de la différenciation terminale B, des voies de signalisation, des facteurs de transcription et des grands processus cellulaires tels que la prolifération ou la mort programmée. A l'aide de ce modèle, nous avons mené deux études relatives à la différenciation B dans le centre germinatif: (i) La caractérisation sur le plan phénotypique et fonctionnel des populations cellulaires générées in vitro. Par une approche transcriptomique, nous avons comparé le profil d'expression et identifié les gènes et fonctions biologiques spécifiques à chacune de ces populations différenciées. Nous nous sommes concentrés sur l'étude de l'expression et de l'activité de l'enzyme AID, notamment au travers de la mesure des fréquences des hypermutations somatiques à chaque stade de la différenciation. (ii) L'étude des mécanismes cellulaires (cycle cellulaire, apoptose), génétiques et épigénétiques menant à la transition des cellules du centre germinatif vers le stade de plasmablastes. Cette étude a permis de caractériser au plus près une population cellulaire fondatrice à l'origine des cellules différenciées. En outre, nous avons mis en évidence l'importance de la méthylation de l'ADN, en particulier la 5-hydroxyméthylation, dans le contrôle de la différenciation terminale BWithin the past few years there has been a significant increase in the knowledge of B cell physiology in vivo and their differentiation into plasma cells through the implementation of murine models and intravital imaging. However, the transposition of this knowledge from mouse to man raises difficulties such as the lack of tools available to visualize the ongoing events in human lymphoid organs. In order to overcome this issue, we have developed in our laboratory, a two-step in vitro model allowing naive B cell differentiation into plasma cells. This model is particularly suitable for studying the induction of signaling pathways, transcription factors and major cellular processes such as proliferation or programmed cell death. Using this model, we conducted two studies on B cell differentiation in the germinal center: (i) phenotypic and functional characterization of cell populations generated in vitro. This study involved a transcriptomic approach which identified and compared the expression profile of specific genes and their biological functions within each of these differentiated populations. Specifically, we focused on the expression and activity of the AID enzyme through the measurement of somatic hypermutation frequency at each stage of differentiation. (ii) The study of cellular (cell cycle, apoptosis), genetic and epigenetic mechanisms leading to the transition of the germinal center B cells into plasmablasts. This study allowed us to characterize a founder cell population of the in vitro generated plasmablasts. In addition, we have highlighted the importance of DNA methylation, in particular 5- hydroxymethylation in controlling terminal B cell differentiation
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Carlson, Amy L. "Applying fuel cells to data centers for power and cogeneration". Manhattan, Kan. : Kansas State University, 2009. http://hdl.handle.net/2097/1366.
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Belmonte, Mateos Carla 1992. "Unveiling the molecular and behavioral properties of hindbrain rhombomere centers". Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2022. http://hdl.handle.net/10803/673433.
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Precise regulation of neurogenesis is achieved by differentially allocating the neurogenic competence along the tissue. In the hindbrain proneural gene expression is stereotypically confined in segment boundary-adjacent regions, hence, being absent in segment centers. This segregation of proneural gene expression therefore hints rhombomere centers as a putative non-neurogenic population.
In this work, we unveil their spatiotemporal molecular profile as well as one of the mechanisms involved in their maintenance as non-committed progenitors. By 4D imaging we shed light for the first time into the in vivo cell behavior this population displays. We propose this population in rhombomere centers is indeed heterogeneous as it harbors cells with different proliferative capacity.La regulació precisa de la neurogènesi s’aconsegueix localitzant la competència neurogènica de manera diferencial al llarg del territori. Al cervell posterior, l’expressió de gens proneurals es restringeix a les zones adjacents a les cèl·lules de les fronteres, i per tant és absent als centres així doncs assenyalant els centres dels rombòmers com una població no neurogènica. En aquest treball, hem revelat el seu perfil molecular espai-temporal així com un dels mecanismes que manté aquestes cèl·lules com a no neurogèniques. Mitjançant imatges 4D hem aportat llum per primera vegada a l’enteniment del seu comportament cel·lular en viu, i proposem que aquesta població dels centres dels rombòmers és de fet heterogènia ja que conté cèl·lules amb diferent capacitat proliferativa.
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Jeffreys, Christopher G. (Christopher Grey) 1979. "Support vector machine and parametric wavelet-based texture classification of stem cell images". Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/16651.
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Thesis (S.M.)--Massachusetts Institute of Technology, Sloan School of Management, Operations Research Center, 2004.Includes bibliographical references (p. 117-121).
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Stem (cell research is one of the most promising and cutting-edge fields i the miedical sciences. It is believed that this innovative research will lead to life-saving treatments in the coming years. As part of their work, stem cell researchers must first determine which of their stem cell colonies are of sufficiently high quality to be suitable for experimental studies and therapeutic treatments. Since colony texture is a major discriminating feature in determining quality. we introduce a non-invasive, semi-automated texture-based stem cell colony classification methodology to aid researchers in colony quality control. We first consider the general problem of textural image segmentation. In a new approach to this problem. we characterize image texture by the subband energies of the image's wavelet decomposition, and we employ a non-parametric support vector machine to perform the classification that yields the segmentation. We also adapt a parametric wavelet-based classifier that utilizes the Kullback-Leibler distance. We apply both methods to a set of benchmark textural images, report low segmentation error rates and comment on the applicability of and tradeoffs between the non-parametric and parametric segmentation methods.
(cont.) We then apply the two classifiers to the segmentation of stem cell colony images into regions of varying quality. This provides stem cell researchers with a rich set of descriptive graphical representations of their colonies to aid in quality control. From these graphical representatiolns, we extract colony-wise textural features to which we add colony-wise border features. Taken together, these features characterize overall colony quality. Using these features as inputs to a multiclass support vector machine, we successfully categorize full stem cell colonies into several quality categories. This methodology provides stem cell researchers with a novel, non-invasive quantitative quality control tool.
by Christopher G. Jeffreys.
S.M.
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Vonderheide, Robert H. "Formation of germinal centres in the rat". Thesis, University of Oxford, 1988. http://ora.ox.ac.uk/objects/uuid:2a533d75-468a-44b0-a07c-60c6d8f6b17a.
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Xia, Lijin. "Regulators of G-protein Signaling, RGS13 and RGS16, are Associated with CXCL12-mediated CD4+ T Cell Migration". Diss., CLICK HERE for online access, 2008. http://contentdm.lib.byu.edu/ETD/image/etd2588.pdf.
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Schendler, Phillip J. "Costs and benefits of using fuel cells for stationary power generation at Marine Corps Logistics Base Barstow Maintenance Center". Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2002. http://library.nps.navy.mil/uhtbin/hyperion-image/02Dec%5FSchendler.pdf.
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Thesis (M.S. in Management)--Naval Postgraduate School, December 2002.Thesis advisor(s): William R. Gates, David R. Henderson. Includes bibliographical references (p. 73-76). Also available online.
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Wallin, Elizabeth. "The germinal centre reaction and follicular T cells in alloantibody formation". Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:e4ecdd13-7c1e-4d4e-8491-8a22857cdb86.
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Kidney transplantation is the optimal treatment for end-stage renal failure, however graft lifespan remains limited, and a major cause of graft loss is chronic, low-grade antibody-mediated damage. Understanding more about how these antibodies are produced, and how immunosuppression affects cells producing them, may allow both prediction of those at risk, and a mechanism for preventing or minimising antibody production, therefore improving graft lifespan. In particular, interest has grown in CD4 T cells known as circulating T follicular helper (cTfh) and T follicular regulatory (cTfr) cells, which appear to correlate with antibody production in vaccination, autoimmunity and potentially transplantation, however little is known about how immunosuppression alters these cells and their function. This study aimed to establish whether cTfh and cTfr cells could be used to predict the risk of de novo donor-specific antibody (DSA) formation in 61 kidney and simultaneous pancreas kidney (SPK) transplant recipients. Results suggested that high cTfh cells and low cTfr associated with de novo DSA formation, and the ratio of the two cells may be useful for identifying at-risk patients. Different immunosuppression regimens were associated with different levels of risk for de novo DSA formation, with basiliximab induction combined with azathioprine maintenance therapy having the lowest risk, despite being considered a less intensive regimen. In vitro experiments suggest this may be due to a differential effect of azathioprine on cTfh and B cells compared to mycophenolate mofetil, an alternative maintenance agent. Combining the in vitro and clinical data suggests that azathioprine may reduce the risk of de novo DSA formation after transplantation compared to other agents because of its effects on B cells, cTfh and cTfr. This is an exciting development that warrants further investigation.
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Goodlad, J. R. "Germinal centre cell proliferation in murine spleens". Thesis, University of Aberdeen, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241447.
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Germinal centres are dynamic structures in which a number of kinetic processes take place. This thesis was designed to investigate mechanisms whereby one of these kinetic events, germinal centre cell proliferation, is regulated in vivo. In order to achieve this, the proliferative rate of germinal centre cells was measured in C3H/HeN mice under a variety of experimental conditions. In particular, the effect on germinal centre cell proliferation of different classes of antigen and of variously timed doses of the immunosuppressant drug cyclosporin A, was examined. In some experiments, an immunohistochemical technique was employed to demonstrate the distribution of antigen within murine spleens and to correlate the presence of antigen within germinal centres with the germinal centre cell birth rate. The results showed that the type of antigen to which an animal is exposed does determine the subsequent rate of germinal centre cell proliferation. In addition it became apparent that specific regulatory mechanisms were at work within murine germinal centres which either stimulated or inhibited germinal centre cell proliferation depending on the stage of the germinal centre reaction. The proliferative response to antigen was also significantly affected by treatment of the animals with cyclosporin A. The effect of the drug varied depending on the timing of its administration in relation to antigen. These results indicated that T cell derived cytokines play a central role in regulating both stimulation and inhibition of germinal centre cell proliferation. It is proposed that interleukin-4 and interleukin-5 are involved in driving the former, while interferon-γ is a candidate for mediating the latter.
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Tan, Swee Ching. "Photosynthetic proteins photovoltaic devices". Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609050.
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Miles, Brodie, Shannon M. Miller i Elizabeth Connick. "CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection". FRONTIERS MEDIA SA, 2016. http://hdl.handle.net/10150/622733.
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T follicular helper cells (T-FH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in T-FH. Paradoxically, T-FH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased T-FH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in T-FH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in T-FH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of T-FH, other mechanisms that have been linked to T-FH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance T-FH function in HIV infection include lack of an established phenotype for memory T-FH as well as limited understanding of the relationship between peripheral T-FH and lymphoid tissue T-FH. Interventions to augment T-FH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.
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Rouers, Angéline. "Impact de l’infection par le virus de l’immunodéficience humaine sur les populations de lymphocytes T folliculaires helper et les réponses B mémoires". Thesis, Paris 6, 2016. http://www.theses.fr/2016PA066497/document.
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La réponse humorale est altérée lors de l’infection par le virus de l’immunodéficience humaine (VIH). Les lymphocytes T CD4+ folliculaires helper (Tfh) sont impliqués dans la maturation des lymphocytes B (LB) dans les organes lymphoïdes secondaires. Mon travail de thèse s’est articulé autour de deux axes complémentaires visant à étudier les Tfh et les réponses B mémoires lors de l’infection par le VIH. J’ai d’abord étudié les Tfh spléniques lors de la phase chronique de l’infection par le VIH. J’ai mis en évidence une augmentation des populations de Tfh dans les rates de patients VIH+. D’autre part l’infection par le VIH a un impact sur le profil transcriptionnel des Tfh de la rate et la production de cytokines impliquées dans la différenciation des LB, suggérant un défaut fonctionnel des Tfh. Parallèlement, la maturation des LB est altérée dans les rates VIH+. Dans le second axe de ma thèse, j’ai étudié les réponses B mémoires anti-VIH dans différentes cohortes de patients VIH+ : Elite controller (EC) contrôlant l’infection sans traitements et des patients VIH+ traités. J’ai mis en évidence que les EC préservent naturellement leurs compartiments B mémoires et que les réponses B mémoires spécifiques du VIH sont maintenues dans le sang de ces patients. Les réponses B mémoires IgG1+ anti-VIH sont majoritaires chez les EC, tandis que les réponses IgG2+ et IgG3+ sont plus rares. Ces travaux permettent une meilleure compréhension de la physiopathologie de l’infection par le VIH en apportant de nouveaux éléments sur la fonctionnalité des Tfh et les réponses B mémoires anti-VIHHIV infection is associated with a defect of humoral response. T follicular helper cells (Tfh) support multiple steps of B cell maturation and antibody production. My work was divided in two complementary axes aiming to characterize Tfh and memory B cell responses in HIV-infected patients.I identified several Tfh populations in HIV+ and HIV- spleens by FACS. These three populations were increased in HIV+ spleen. I also evidenced an impact of HIV infection on transcriptional profile and a compromised production of B cell differentiation-related cytokines by splenocytes from HIV+ donors. These results suggest Tfh functions impairment during HIV-infection. In parallel, we noticed an altered maturation of B cells in HIV+ spleens. In a cohort study, we compared memory B cell responses in the blood of Elite controllers (EC) who naturally control HIV and treated HIV+ patients. I evidenced that EC naturally preserve their memory B cell compartments. In contrast to anti-HIV IgG2 and IgG3 secreting B cells, most EC exhibit a high frequency of anti-HIV IgG1 secreting B cells. My work highlights a defective Tfh differentiation, which might explain why B cell maturation is severely affected in HIV-progressors. The status of HIV-controller seems associated with the presence of an IgG1 B cell memory response. Further work will highlight whether Tfh functions are preserved in EC
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Toraille, Loïc. "Utilisation de centres NV comme capteurs de champs magnétiques à haute pression dans des cellules à enclumes de diamant". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLN056/document.
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La pression est un paramètre physique qui modifie les interactions structurales, électroniques et magnétiques dans les matériaux. Créer une très haute pression permet donc la synthèse de nouveaux matériaux, comme par exemple des supraconducteurs ayant des valeurs de température critique record. Ces pressions peuvent être générées au moyen d’une cellule à enclume de diamant (DAC) qui peut comprimer un matériau jusqu’à des pressions de plusieurs centaines de GPa. Il est cependant difficile de caractériser les propriétés magnétiques de matériaux à l’intérieur d’une DAC à cause du très faible volume occupé par l’échantillon et des contraintes techniques. Dans cette thèse, nous proposons d’utiliser une technique de magnétométrie optique fondée sur la résonance de spin électronique de centres colorés NV du diamant. Ces centres NV sont fabriqués à la surface d’une des deux enclumes de la DAC et sont ainsi au contact de l’échantillon magnétique à caractériser.Dans un premier chapitre, nous rappelons le fonctionnement de la DAC et décrivons les techniques de mesures magnétiques développées pour la physique des hautes pressions. Nous présentons ensuite le principe de la magnétométrie à centres NV et l’appliquons à la mesure de l’aimantation d’un micro-aimant à pression ambiante. La sensibilité de cette mesure atteint celle des magnétomètres à SQUID. Le troisième chapitre discute de la façon dont les contraintes mécaniques modifient la résonance de spin du centre NV, et détaille la manière dont cet effet se combine avec celui dû à un champ magnétique externe. La possibilité de découpler les deux effets nous permet d’observer la transition de phase magnétique du fer autour de 15 à 30 GPa dans le quatrième chapitre. Enfin, le dernier chapitre décrit le contexte et les enjeux liés à la synthèse d’hydrures supraconducteurs à haute température critique. Nous montrons ensuite qu’il est possible de détecter optiquement une phase supraconductrice à l’intérieur d’une DAC en utilisant les centres NV pour observer l’effet Meissner de MgB2 à une pression de 7 GPa et avec une température critique de 30 KPressure is a physical variable that alters structural, electronic and magnetic interactions in all materials. Reaching high pressure is thus a way to create new materials such as superconductors with record critical temperatures. High pressures can be enabled through the use of diamond anvil cells (DAC), which can attain pressures of several hundred of GPa. It is however quite a challenge to measure magnetic properties of materials inside a DAC because of the very small sample volume available and of technical constraints. In this PhD thesis, we demonstrate the use of a magnetometry method based on the electronic spin resonance of NV centers in diamond. These NV centers are fabricated directly on top of one of the DAC anvils, which places them in contact with the magnetic sample.In the first chapter, we describe how the DAC works and we present the different ways of probing magnetic properties that have been developed for high pressure conditions. We then explain the operating principle of NV magnetometry and use this method to measure the magnetization of a micro-magnet at ambient pressure. The sensitivity of this measure is comparable to that of SQUID magnetometry. In the third chapter, we discuss how mechanical constraints modify the spin resonance of the NV center, and describe how this effect combines with the influence of an external magnetic field. By decoupling these two effects, we can observe the magnetic phase transition of iron around 15 to 30 GPa, which is displayed in the fourth chapter. Finally, the last chapter briefly presents the context and stakes associated with the synthesis of superconducting superhydrides with high critical temperature. We perform an optical detection of a superconducting phase inside a DAC with NV centers through the observation of the Meissner effect in MgB2 at a pressure of 7 GPa and with a critical temperature of 30 K
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Palacios, Arnold Raul. "Role of GSK-3 alpha beta in B cell proliferation during germinal center information". Thesis, Boston University, 2013. https://hdl.handle.net/2144/21229.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.Glycogen Synthase Kinase-3αß is an enzyme that is involved in cell cycle regulation by promoting the degradation of cyclin D1 and cycling D3 in cells. Special emphasis is placed in its regulatory role in B cells, as there it is evidence that suggests that this protein is inhibited during germinal center formation, where B cells undergo proliferation, somatic hypermutation and class switch recombination. By inducing DNA recombination via the Cre/lLxP recombination system and utilizing tamoxifen as a Cre activity inducer, B cells were culture in 40LB cells to form induced germinal center in vitro. Flow cytometry analysis suggests that in the absence of GSK-3 αß B cells proliferate extensively in germinal centers and being the process of class switch recombination. Although the results of this study are in accord with current theory, more experiments and research need to be made to validate the conclusions set forth in this study.
2031-01-01
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Yang, Liqun. "Characterization of the Physiologic Function of NF-κB2 p100". University of Toledo Health Science Campus / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1263334529.
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Boyden, Alexander Wiser. "Influenza A virus induces regulated T cell-driven B cell responses". Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3432.
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Protection from influenza A virus (IAV) challenge requires switched, high affinity Abs derived from long-lived memory B cells and plasma cells. These subsets are generated in germinal centers (GCs), hallmark structures of T helper cell-driven B cell immunity. A full understanding of the acute and persistent GC B cell reaction following respiratory IAV infection is lacking, as is the characterization of IAV-induced T follicular helper (TFH) cells that support GCs. Additionally, it remains unclear as to whether IAV-induced GC B cells are subject to control by regulatory T cells (Tregs). To address this, GC B cell and TFH cell responses were analyzed in mice following pulmonary challenge with IAV. Studies demonstrated that marked GC reactions were induced in lung-draining lymph nodes (dLNs), lung, spleen and nasal-associated lymphoid tissue (NALT), although the magnitude, kinetics, and isotype switching patterns of the response was site-specific, and largely depended on the magnitude of IAV-induced TFH cell populations. TFH cell magnitude peaked prior to that of GC B cells in all tissues, and TFH cells purified from dLNs generated IL-21 and IFN-gamma upon activation, although CD4+CXCR5- T effector cells produced higher levels of all cytokines. IgA+ GC B cells were infrequent in most sites, but composed a significant subset of the switched GC population in NALT. Further, splenectomized mice withstood a lethal recall challenge, suggesting the spleen to be unnecessary for long-term protection. Additionally, GC B cell populations were analyzed at distal time points to assess the understudied, persistent GC B cell response after IAV infection. Our analysis demonstrated that persistent GC B cell populations in mouse lungs directly correlated with infectious dose, pathogenicity of the virus, as well as the presence of long-term CD4+ T cell help. Finally, experiments showed that Tregs contribute to the control of GCs induced in the spleen by IAV challenge. This was demonstrated by a marked increase in the number of total and switched GC B cell numbers when Tregs were either depleted or disrupted in vivo proximal to IAV exposure.
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Vanderleyden, Ine. "Follicular regulatory T cell migration and differentiation". Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/288422.
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The germinal centre (GC) response is critical for generating highly effective humoral immune responses and immunological memory that forms the basis of successful immunisation. Control of the output of the GC response requires Follicular regulatory T (Tfr) cells, a subset of Foxp3+ Treg cells located within germinal centres. Tfr cells were first characterised in detail in 2011 and because of this relatively little is known about the exact role of Tfr cells within the GC, and the mechanism/s through which they exert their suppressive function. At the outset of this work, the major barrier to understanding Tfr cell biology was the lack of appropriate tools to study Tfr cells specifically, without affecting Tfh cells or other Treg cell subsets. This thesis set out to develop a strain of mice that specifically lacks Tfr cells. A unique feature of Tfr cells is their CXCR5-dependent localisation within the GC. Therefore, genetic strategies that exclude Treg cells from entering the GC are a rational approach to generating a mouse model that lacks Tfr cells. To this end, I generated a strain of mice that lacks CXCR5 on Foxp3+ Treg cells. These animals show a ~50% reduction in GC localised Tfr cells, and a GC response that is comparable to control animals. These data indicated that redundant mechanisms are involved in Treg cell homing to the GC. I identified CXCR4 as a chemokine receptor that is also highly expressed on Tfr cells, and hypothesised that it may also be involved in Tfr cell localisation to the GC. Surprisingly, simultaneous deletion of both CXCR4 and CXCR5 in Treg cells resulted in a less marked reduction in Tfr cells compared to deletion of CXCR5 alone, suggesting that CXCR4 might be involved in negative regulation of Treg homing to the GC. These data identify both CXCR4 and CXCR5 as key regulators of Tfr cell biology. Bcl6 drives Tfr cell differentiation, but how this transcriptional repressor facilitates commitment to the Tfr cell subset is unknown. I hypothesised that Bcl6 drives Tfr cell differentiation by repressing Tbx21, the transcriptional regulator involved in the differentiation of Th1-like Treg cells. I tested this hypothesis in Bcl6fl/fl CD4cre/+ animals and unexpectedly found that loss of Bcl6 regulates Treg cell differentiation in the absence of immunisation or infection. I have demonstrated that thymic loss of Bcl6 results in an increase in activated effector Treg cells, which occurs very early in life. These data point to a novel role for Bcl6 in preventing early thymic Treg activation, indicating that Bcl6 has a global role in Treg development and differentiation that is not simply limited to Tfr cells.
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Chaimowitz, Natalia. "The role of Fyn and B-cell expressed ADAM10 in early B cell development, germinal center formation and terminal B cell differentiation". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/374.
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In these studies we sought to determine the role of Fyn kinase and ADAM10 in B cell biology. A disintegrin and metalloproteinase 10 (ADAM10) is a zinc dependent proteinase related to matrix metalloproteinases. ADAM10 has emerged as a key regulator of cellular processes by cleaving and shedding extracellular domains of multiple transmembrane receptors and ligands. In particular, ADAM10 has been identified as a key regulator of lymphocyte development. Here we report that ADAM10 is dispensable for early B cell development within the bone marrow. However, deletion of ADAM10 from all peripheral B cells or in post-switch cells leads to severe impairments in humoral responses. When ADAM10 was deleted from all peripheral B cells a decrease in antigen specific IgG production was seen both with respect to serum levels and IgG ASCs, indicating that plasma cell (PC) differentiation is influenced. Cells producing high affinity antigen specific antibodies were particularly affected, consistent with defects in germinal center (GC) reactions. Moreover, changes in lymphoid architecture were also observed. Consistent with these findings, follicular dendritic cell (FDC)-reticula was undetectable following immunization. On the other hand, when ADAM10 was deleted in post-switch B cells, GC formation and lymphoid architecture were not impaired. Despite normal architecture, however, antibody production was still affected, likely due to abnormal gene expression in ADAM10-deficient PCs. Consistent with this hypothesis, PCs isolated from ADAM10Δ/ΔIgG1-cre+/- showed decreased expression of genes that facilitate plasma cell differentiation and function and increased expression of Bcl6, an inhibitor of PC differentiation. Fyn kinase is a member of the Src protein tyrosine kinase. Fyn is widely expressed in many cell types, including lymphocytes. Fyn has been shown to interact with both the B cell and T cell receptor (BCR and TCR, respectively). While Fyn-deletion did not impair the development of immature T cells and B cells, TCR signaling was altered in mature T cells. Our results demonstrate that Fyn-KO mice have significantly low basal levels of IgG1 and IgG2a. Additionally, these mice displayed delayed kinetics in the production of NP-specific IgG1 and IgG2b, and significantly low NP-specific IgG2a after a T-dependent immunization protocol. Defects in antibody production correlated with significantly reduced numbers of GC B cells, TFH cells and splenic PCs. Moreover, Fyn-KO B cells showed decreased production antibody following in vitro activation. Our results thus demonstrate that Fyn-mediated signaling and B cell ADAM10 expression are necessary for optimal humoral responses.
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Garzon-Coral, Carlos. "The forces that center the mitotic spindle in the C. elegans embryo". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-163529.
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The precise positioning of the mitotic spindle to the cell center during mitosis is a fundamental process for chromosome segregation and the division plane definition. Despite its importance, the mechanism for spindle centering remains elusive. To study this mechanism, the dynamic of the microtubules was characterized at the bulk and at the cortex in the C. elegans embryo. Then, this dynamic was correlated to the centering forces of the spindle that were studied by applying calibrated magnetic forces via super-paramagnetic beads inserted into the cytoplasm of one- and two-cell C. elegans embryos. Finally, these results were confronted with the different centering models: cortical pushing model, cortical pulling model and the cytoplasmic pulling model.
This thesis shows that: (i) The microtubules dynamic of the spindle aster is controlled spatially in the C. elegans embryo, with not rescues and catastrophes in the cytoplasm but in the centrosome and the cortex, respectively. (ii) The centering mechanism of the spindle behaved roughly as a damped spring with a spring constant of 18 12 pN/ m and a drag coefficient of 127 65 pN s/ m (mean SD). This viscoelastic behavior is evidence of a centering force that recovers and/or maintains the position of the spindle in the cell center. (iii) It seems to be two mechanisms that recover/maintain the spindle position. A fast one that may work for transient displacements of the spindle and a slow one that work over large and long perturbations. (iv) The centering forces scale with the cell size. The centering forces are higher in the two-cell embryo. This result argues against a centering mechanism mediated by cytoplasmic factors. It seems to be a limit for the relation of centering force to size, as the forces found in the four-cell embryo are comparable to the single-cell ones. (v) The centering forces scale with the amount of microtubules in the cell. This strengthens the belief that the microtubules are the force transmission entities of the centering mechanism. (vi) The boundary conditions are important to maintain the centering forces. A transient residency time of microtubules at the cortex, which is controlled by cortical catastrophe factors, is indispensable for a proper force transmission by the microtubules. (vii) The elimination of cortical catastrophe factors provides evidence for microtubules buckling, which is taken as a proof of polymerization forces. (viii) The cortical pulling forces mediated by the gpr-1/2 pathway do not seem to be involved in centering and it is proposed they are present in the cell for off-center positioning purposes. (ix) The forces generated by vesicle transport are enough to displace the spindle and they are suggested to be auxiliary forces to centering. (x) The forces associated with the spindle change dramatically during cell division. From metaphase to anaphase the forces associated with the spindle scale up to five times. This behavior was consistent during the development of the embryo as the same pattern was observed in the one-, two- and four-cell embryo. (xi) The higher forces found during anaphase are not cortical pulling (via pgr-1/2 pathway) depended, and it is proposed the spindle is `immobilised' by tethering or by an unknown cortical pulling pathway.
To this date, this thesis presents the most complete in-vivo measurements of the centering forces in association with the microtubules dynamics. Taken together the results constrain molecular models of centering. This thesis concludes that most probably the predominant forces of the spindle centering mechanism during mitosis are generated by astral microtubules pushing against the cortex.
Additionally, this thesis presents the most complete map of forces during cell division during development, which will prove to be indispensable to understand the changes the spindle undergoes when it changes its function.
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Miles, Brodie, Shannon M. Miller, Joy M. Folkvord, David N. Levy, Eva G. Rakasz, Pamela J. Skinner i Elizabeth Connick. "Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection". PUBLIC LIBRARY SCIENCE, 2016. http://hdl.handle.net/10150/622413.
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During chronic HIV infection, viral replication is concentrated in secondary lymphoid follicles. Cytotoxic CD8 T cells control HIV replication in extrafollicular regions, but not in the follicle. Here, we show CXCR5(hi)CD44(hi)CD8 T cells are a regulatory subset differing from conventional CD8 T cells, and constitute the majority of CD8 T cells in the follicle. This subset, CD8 follicular regulatory T cells (CD8 T-FR), expand in chronic SIV infection, exhibit enhanced expression of Tim-3 and IL-10, and express less perforin compared to conventional CD8 T cells. CD8 T-FR modestly limit HIV replication in follicular helper T cells (T-FH), impair T-FH IL-21 production via Tim-3, and inhibit IgG production by B cells during ex vivo HIV infection. CD8 T-FR induce T-FH apoptosis through HLA-E, but induce less apoptosis than conventional CD8 T cells. These data demonstrate that a unique regulatory CD8 population exists in follicles that impairs GC function in HIV infection.
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Caganova, M. "THE ROLE OF EZH2 IN B CELL DEVELOPMENT AND ADAPTIVE IMMUNITY". Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/214665.
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Polycomb group (PcG) proteins are epigenetic modifiers that act as transcriptional repressors modulating chromatin accessibility of target genes. Methylation on lysine-27 of histone H3 (H3K27me3) catalyzed by the PcG protein Ezh2 is a bona fide epigenetic mark linked to lineage specification and identity.
Analyses on PcG mutant mice have revealed an essential role of PcG proteins in haematopoiesis. In the B cell compartment, Ezh2 is expressed in progenitor B cells and is strongly induced upon recruitment of naïve B cells into the germinal center (GC) reaction, during a T cell dependent immune response. Using a conditional gene targeting approach in vivo, we addressed the effects of Ezh2 inactivation on GC B cell responses, terminal differentiation, memory B cell generation and function.
Conditional inactivation of Ezh2 in GC B cells caused a significant reduction in numbers and frequency of GC B cells. Loss of Ezh2 promoted a significant increase in the fraction of GC B cells undergoing apoptosis.
As a result of the impaired GC reaction, serum titers of antigen-specific, class-switched antibodies were significantly decreased and formation of memory B cells significantly impaired in mutant mice. Instead, mutant GC B cells showed premature onset of terminal differentiation, as assessed by the induction of genes coding for the master regulators of plasma cell differentiation Prdm1, Irf4 and Xbp1.
In this work we provide evidence that sets the ground for a model where Ezh2 together with GC master regulator Bcl6 supports GC B cell identity and function.
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Rydyznski, Carolyn E. "Natural Killer Cell Regulation of Humoral Immunity". University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535377157934852.
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Panjwani, Deep R. "Metal blacks as scattering centers to increase the efficiency of thin film solar cells". Master's thesis, University of Central Florida, 2011. http://digital.library.ucf.edu/cdm/ref/collection/ETD/id/5004.
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Metal nano particles are investigated as scattering centers on front surface of thin-film solar cells to improve efficiency. The principle is that scattering, which is enhanced near the plasmon resonance frequency of the particle and depends on particle size, increases the effective optical path length of incident light, leading to more light absorption in active layer of thin film solar cell. The particular types of particles investigated here are known as "metal-black", well known as an IR absorber for bolometric infrared detectors. Gold-black was deposited on commercial thin-film solar cells using a thermal evaporator in a nitrogen ambient at pressures of ~1 Torr. We suggest that the broad range of length scales for gold black particles, as quantified by scanning electron microscopy, gives rise to efficient scattering over a broad range of wavelengths across the solar spectrum. The solar cell efficiency was determined both as a function of wavelength and for a solar spectrum produced by a Xe lamp and appropriate filters. Up to 20% increase in short-circuit photocurrent, and a 7% increase in efficiency at the maximum power point, were observed.ID: 030423114; System requirements: World Wide Web browser and PDF reader.; Mode of access: World Wide Web.; Thesis (M.S.)--University of Central Florida, 2011.; Includes bibliographical references (p. 53-56).
M.S.
Masters
Physics
Sciences
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Chirimuuta, Fungai Natalie Winnie. "The exploitation of neuronal survival factors in Burkitt’s lymphoma and germinal centre B cells". Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/930/.
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Neurotrophins are neuromodulatory proteins utilised within neuronal networks for development and survival. Based on previous evidence revealing the expression of neurotrophin components in immune cells, the present study investigates neurotrophin component expression within Burkitt’s Lymphoma B cells. Different latency stages within Burkitt’s Lymphoma B cells are observed due to the expression of resident EBV latency genes. These B cells are said to display germinal centre B cell markers and interact with other cells within a germinal centre environment, such as Follicular Dendritic Cells (FDCs) and T cells. EBV latency phenotypes were characterised for the lines used here; these lines were then screened for the expression of neurotrophin ligands and their receptors: the selective high affinity Tropomyosin receptor kinases TrkA, TrkB and TrkC and the (common) low affinity, tumour necrosis factor receptor member, p75NTR. FDC-like cell lines were also analysed for neurotrophin component expression. This was to question FDCs as potential providers of paracrine neurotrophin signalling to Burkitt’s lymphoma B cells. Neurotrophin and neurotrophin receptor expression was detected by flow cytometry, confocal microscopy, reverse transcription polymerase chain reaction (PCR) and real time PCR methods. Cell lines with the full complement of EBV latency genes expressed were positive for the neurotrophin, Brain Derived Neurotrophic Factor (BDNF) and all neurotrophin receptors in question. Burkitt’s lymphoma cells expressing limited EBV latency genes revealed more restricted expression of neurotrophin components. FDC-like lines also express neurotrophin and neurotrophin receptors, thus paracrine signalling between Burkitt’s lymphoma cells and FDCs may occur via this axis, perhaps to enhance B cell survival.
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Yu, Wenjie. "A Pitx2-Irx1 regulatory network controls dental epithelial stem cell differentiation during tooth development". Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/6020.
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Tooth development is precisely controlled by epithelium-mesenchyme interactions, coordinated signaling pathways and associated transcription factors. Although the processes involved in tooth development are well established, details of the cellular and molecular mechanisms that control tooth development are not fully understood. One of the primary unknown mechanisms is the regulation of dental epithelial stem cells (DESCs), including DESC specification, proliferation and differentiation. In this dissertation, I have addressed this gap in knowledge by studying the role of Pituitary homeobox 2 (Pitx2) and Iroquois 1 (Irx1) in teeth at the cellular and molecular level in mice. PITX2 contains mutations of which are associated for Axenfeld-Rieger syndrome (ARS) in humans and is also required for early tooth development. All the background knowledge is included in Chapter I. In Chapter II, I describe the conditional ablation of Pitx2 in the dental epithelium using a Krt14Cre driver line (Pitx2cKO mice). Knocking out Pitx2 in teeth led to delayed epithelial invagination at bud stage and disruption of tooth morphogenesis at cap stage. At the cellular level, Pitx2 mediates DESC differentiation, daughter cell proliferation in bud stage tooth and regulates enamel knot formation in cap stage tooth. At the molecular level, Pitx2 acts as an upstream regulator of the sonic hedgehog (Shh) signaling pathway by regulating the expression of Shh in the dental epithelial signaling center during early tooth development. In addition, I demonstrated that Pitx2 directly controls the transcription of Irx1. In Chapter III, I determined the cellular and molecular mechanisms of Irx1 in mice. Irx1 general knockout mice were generated by replacing the entire Irx1 gene body with a LacZ reporter gene. Irx1 null mice are neonatal lethal and this lethality is due to pulmonary immaturity with defective surfactant protein secretion. In teeth, Irx1 is expressed in the outer enamel epithelium (OEE) and stratum reticulum (SR) and mediates DESC to OEE and SR differentiation through regulation of Forkhead box protein J1 (Foxj1) and Sex determining region Y-box9 (Sox9).
In summary, I identified a Pitx2-Irx1 regulatory network that controls DESC differentiation in teeth, which provided the field with a better understanding of tooth development and tooth regeneration.
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GRECO, FEDERICA. "THE ROLE OF THE M6A METHYLTRANSFERASE METTL3 IN AN IN VITRO MODEL OF ANTIGEN-SELECTED GERMINAL CENTER B CELLS". Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/824035.
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N6-methyladenosine (m6A) represents the most abundant modification introduced into messenger RNA. In mammals, m6A regulates gene expression by controlling different facets of mRNA metabolism including splicing, translation and stability. Emerging evidences have assigned to m6A a critical role in the regulation of cellular and humoral immunity.
To date, the function of m6A in mature B cells, especially those recruited into T-cell dependent immune responses, remains unexplored. Here, we show that the Mettl3 gene, encoding for the catalytic subunit of the m6A methyltransferase complex, is expressed at relatively stable levels throughout B-cell development and increases in mature B cells activated in response to the engagement of the CD40 receptor. Given the crucial role played during a T-cell dependent immune response by CD40 signaling in sustaining the transient expansion of antigen-selected B cells in the light zone of the germinal center (GC) and, together with Interleukin-21 (IL-21), their terminal differentiation into antibody-secreting plasma cells (PCs), we asked to which extent these processes are under m6A methylation control. To answer these questions, we disrupted by CRISPR/Cas9 technology the Mettl3 gene in primary in vitro-induced germinal center-like B (iGB) cells, which were stimulated for 8-to-13 days with membrane-bound CD40-ligand (mCD40L). Efficient targeting of the Mettl3 gene in iGB cells exerted distinct phenotypes on CD40-activated B cells starting from the fourth day of the culture, when IL-4 was replaced with IL-21 in the culture medium. Using two independent sgRNAs to disrupt the Mettl3 gene, we observed a consistent significant growth delay of Mettl3-mutant iGB cells, which was restricted to the first 48 hours of mCD40L + IL-21 stimulation. The proliferation defect of Mettl3-mutant iGB cells caused their rapid counter selection when placed in competition with Mettl3-proficient counterparts.
The growth impairment of CD40-activated Mettl3-mutant iGB cells was associated with limited upregulation of c-MYC expression, a defect in cell-cycle progression at the G1-to-S transition, due to reduced expression of E2F family members, and defective activation of the nutrient-sensitive mTORC1 signaling pathway. During the first 48 hours of mCD40L + IL-21 stimulation, Mettl3-mutant cultures suffered also from a significant defect in the transcriptional activation of genes encoding for master regulators of PC differentiation, including Irf4, Blimp1, Pou2af1 and Xbp1. The growth and developmental defects of Mettl3-mutant iGB cultures were normalized in the following 48 hours, due to the exhaustion of the proliferative burst of control B cells, while mutant ones completed the missing cell divisions, prior to undergoing terminal differentiation and/or senescence.
Sequencing of the Mettl3 gene, retrieved from day-8 Mettl3-mutant iGB cultures, indicated a strong counter selection of iGB cells carrying loss-of-function alleles. This result was confirmed in terminally differentiated CD138+ plasmablasts isolated from day-13 in Mettl3-mutant iGB cultures, which displayed METTL3 protein levels comparable to those of wild-type cells. Altogether, these results establish for the first time a strict requirement for a full complement of METTL3 molecules, for optimal mitogenic B cell response to CD40 engagement, for initiating PC differentiation and for PCs persistence. In light of these results, our work assigns to METTL3 a crucial supportive function in B cells for the processes of clonal selection and antibody affinity maturation occurring in the GC during T-cell dependent immune responses.
To shed further light on the importance of METTL3 function in developmental decision-making processes, we employed an in vitro model of reversible immortalization of multipotent murine hematopoietic progenitor cells (HPCs), by expression of an estradiol-inducible form of the HoxB8 (H8) transcription factor. Application of CRISPR/Cas9 technology to H8-HPCs ensured efficient Mettl3 gene targeting in these cells. We could show that interference with Mettl3 expression led to the counter selection of highly proliferating Mettl3-mutant H8-HPCs. Moreover, Mettl3-targeted H8-HPCs expressed prematurely the myeloid-associated marker CD11b and displayed accelerated myeloid differentiation upon estradiol withdrawal from the culture medium. Altogether, these results support a view whereby METTL3 sustains self-renewal of multipotent HPCs and prevents inappropriate and premature differentiation of these cells into the myeloid lineage.
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Mongeon, Kevin. "The Study of Hereditary Spastic Paraplegia-Causing Gene DDHD2 Using Cell Models". Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/37474.
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Hereditary spastic paraplegia type 54 is a rare autosomal recessive neurological gait disorder characterized by paraplegia, muscle spasticity, and intellectual disability. This length-dependent distal axonopathy is caused by mutations in the DDHD2 gene, which encodes the intracellular phospholipase A1 DDHD2. Little is known about the molecular function of the DDHD2 protein, especially in the context of HSP54. Thus, there is a need to further investigate its molecular functions and investigate the impact of DDHD2 deficiency in disease-relevant cells. Here, lipidomic profiling of dermal fibroblasts derived from three unrelated patients has revealed 19 glycerophosphoethanolamine species at differential levels in patients relative to unaffected controls. However, patient cells appear to have an unaffected Golgi apparatus morphology and lipid droplet formation, despite DDHD2’s proposed roles in these processes. To study the gene function in neuronal cells, I transdifferentiated the fibroblasts into induced neuronal precursor cells and found all the patient cells arrested in the G0/G1 phase of upon conversion. Given that these cell lines are unsustainable, I generated a stable knockdown cell line in the highly proliferative HEK293A to study the molecular biology of DDHD2. The knockdown cells had a reduced growth, were delayed in the G2/M phase of the cell cycle, and became multinucleated. I then treated the cells with antineoplastic compounds paclitaxel and nocodazole and found more knockdown cells in G0/G1 than controls, suggesting the possible occurrence of mitotic slippage. Lastly, I report a novel subcellular localization for DDHD2 at the microtubule organization center.
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Goldman, Lea Nichole. "Kinetics and phenotype of the draining lymph node and pulmonary B cell response to an influenza A virus-like particle vaccine". Thesis, University of Iowa, 2013. https://ir.uiowa.edu/etd/4634.
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Influenza A virus (IAV) infection is a serious respiratory disease associated with significant morbidity and mortality worldwide. Annual vaccination is the most effective way to prevent infection and its potentially severe complications; however, the vaccines currently offered have several drawbacks that limit its availability and protective efficacy. Influenza virus-like particles (VLPs), which lack viral genetic material and are non-infectious, represent a promising vaccine candidate. Previous reports have shown VLPs are more immunogenic than subunit or recombinant proteins, and confer protection upon lethal challenge. A critical component of this protection is mediated by influenza HA-specific neutralizing Abs produced by memory B cells and plasma cells, the cellular products of the germinal center (GC) reaction. While preliminary studies have examined the humoral immune response to VLP vaccination, the current study is the first to characterize the GC response in secondary and tertiary lymphoid tissues. Mice were vaccinated with influenza VLPs using three immunization routes: subcutaneous (s.c.), intramuscular (i.m.), and intranasal (i.n.) and the GC response was assessed over time. Robust GC reactions were induced in the dLNs regardless of vaccination route, though the largest response was generated with VLPs s.c. The pattern of isotype expression was remarkably similar between routes, with IgM+ and IgG2+ B cells representing the majority of the GC B cell population. Mucosal immune responses in the upper (nasal) and lower (lung) airway were measured in mice vaccinated i.n. Marked GC reactions were induced in the nasal-associated lymphoid tissue (NALT), while the pulmonary response was relatively modest and short-lived compared to infection with IAV. Within the GC B cell population, IgM+ and IgG2+ B cells made up the majority, similar to the dLN response. Importantly, the pattern of isotype expression induced by VLPs mimicked the response induced by natural IAV infection, and suggests that VLPs contain the necessary innate immune agonists to induce a TH1 biased response.
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Caeser, Rebecca. "Elucidating oncogenic mechanisms in human B cell malignancies". Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/285011.
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This study consists of two pieces of work investigating haematological malignancies; Acute Lymphoblastic Leukaemia (ALL) and Diffuse Large B Cell Lymphoma (DLBCL). Firstly, Pre-B ALL represents the most common paediatric malignancy and despite increasingly improved outcomes for patients, ~ 20% of all patients diagnosed with ALL relapse. Activating mutations in the RAS pathway are common (~50%) and result in hyperactivation of the MAPK pathway. I identified Erk negative feedback control via DUSP6 to be crucial for NRASG12D-mediated pre-B cell transformation and investigated its potential as a therapeutic target. I showed that a small molecule inhibitor of DUSP6 (BCI) selectively induced cell death in patient-derived pre-B ALL cells; with a higher sensitivity observed in relapse pre-B ALL. I also discovered that a high level of Erk activity is required for proliferation of normal pre-B cells, but dispensable in leukemic pre-B ALL cells. In addition, I found that human B cell malignancies can be grouped into three categories that fundamentally differ in their ability to control Erk signalling strength. Secondly, DLBCL is the most common haematological malignancy and although potentially curable with chemotherapy, 40% of patients still succumb from their disease. Recent exome sequencing studies have identified hundreds of genetic alterations but, for most, their contribution to disease, or their importance as therapeutic targets, remains uncertain. I optimised a novel approach to screen the functional importance of these mutations. This was achieved by reconstituting non-malignant, primary, human germinal centre B cells (GC B cells) with combinations of wildtype and mutant genes to recapitulate the genetic events of DLBCL. When injected into immunodeficient mice, these oncogene-transduced GC B cells gave rise to tumours that closely resemble human DLBCL, reinforcing the biological relevance of this system. To screen potential tumour suppressor mutations in this system in a high throughput fashion, I developed a lymphoma-focused CRISPR library of 692 genes recurrently altered in B cell lymphomas. These experiments identified GNA13 as an unexpectedly potent tumour suppressor in human GC B cells and provided new understanding to its mechanism of action. These findings provide novel understanding of the complexity of oncogenic mechanisms in human B cell malignancies.
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Alyafei, Saud Abdalla Mubarak Mohamed. "Study of the reactivity of a monoclonal antibody that recognises human marginal zone B cells and a subset of germinal centre cells in tissue sections". Thesis, King's College London (University of London), 2018. https://kclpure.kcl.ac.uk/portal/en/theses/study-of-the-reactivity-of-a-monoclonal-antibody-that-recognises-human-marginal-zone-b-cells-and-a-subset-of-germinal-centre-cells-in-tissue-sections(7fcf0edc-b729-4215-ae52-a9e2d2622493).html.
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Marginal Zone (MZ) cells are a subset of B cells. They reside the marginal zone outside the mantle zone of the spleen and circulate the blood in humans. They have also been identified in the crypt epithelium of tonsil, the sub-capsular sinus in lymph node and in the dome area of Peyer’s patches in gut-associated lymphoid tissue of human intestine. A monoclonal antibody (4D12) that recognises an antigen on MZ B cells and a subset of GC cells in tissue sections has been described previously but this has not been investigated in detail and features of the 4D12 antigen and the lymphocytes that express it are unknown. The re-establishment and culture of the 4D12 MoAb secreting clone after a long-term storage is described. A method to analyse the distribution of 4D12 antigen on subsets of B cells was devised. Subsets expressing 4D12 antigen included CD27+IgM+IgD+ cells, CD27+IgM+IgD- cells, transitional B cells and plasmablasts. Lower expression by mature naïve and class switched memory B cells was observed. 4D12 MoAb tended to recognise a greater proportion of CD27+IgM+IgD+ cells and CD27+IgM+IgD- cells in spleen compared to tonsil and blood. Intracellular staining showed that the 4D12 antigen is proportionally more presented in the cytoplasm than the cell surface and that cytoplasmic 4D12 antigen expression is not restricted to B cells. The identity of the antigen was sought by western blotting and mass spectrometry (by collaborators) and the output of the mass spectrometry was provided for this study. Mass spectrometry data was analysed here and a list of candidates for the identity of 4D12 antigen were selected and tested by flow cytometry.
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LINDER, CATHERINE. "Etude numerique de la methode des volumes-finis cell-center implicite pour les systemes conservatifs". Paris 11, 1998. http://www.theses.fr/1998PA112176.
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Ce travail porte sur l'approximation numerique de systemes conservatifs par la methode des volumes finis cell-center. On etudie plus particulierement la version implicite en temps de cette methode et on la met en uvre sur trois systemes : l'equation de convection-diffusion, les equations d'euler compressibles et les equations de la magnetohydrodynamique compressible. On commence par rappeler en detail le principe de l'approximation spatiale cell-center dans ses variantes d'ordre 1 et 2. Plusieurs formules de flux numerique sont presentees pour les trois systemes. Nous etudions ensuite la version implicite en temps de la methode dont le but est classiquement d'accelerer la convergence en augmentant le pas de temps. En contrepartie, la linearisation du schema implicite demande la resolution a chaque pas de temps d'un systeme lineaire dont la matrice est le jacobien du flux. Le systeme est preconditionne par une factorisation incomplete ilu(0) puis resolu par une methode de krylov iterative, bi-cgstab ou gmres. Le pas de temps est augmente progressivement au cours des iterations selon differentes strategies cfl. La methode ainsi mise en uvre est evaluee numeriquement sur plusieurs cas tests : l'equation de convection-diffusion, les equations d'euler sur plusieurs cas classiques en aerodynamique (reflexion de chocs de collela et ecoulements transsoniques autour du profil naca012). Ces cas mettent en evidence une superiorite en temps cpu de la version implicite du schema par rapport au schema explicite a pas de temps local, pour des strategies cfl bien choisies. Dans le cas des equations de la mhd, nous comparons deux formules de flux (flux cinetique et flux de type roe) sur des cas 1d de tube a chocs. Puis nous presentons un premier test implicite qui consiste en une adaptation a la mhd du cas aerodynamique de la double rampe. Le schema implicite est robuste et donne de bons resultats en temps cpu.
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Hollowood, Kevin. "A cell kinetic study of the normal and malignant germinal centre". Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243410.
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Ottensmeier, Christian H. H. "Immunogenetic analysis of human follicle centre lymphomas and diffuse large cell lymphomas". Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287053.
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Santamaria, Kathleen. "Etude de l’hétérogénéité des centrocytes humains à travers l’expression du CD23 : différenciation en plasmablastes et expression d’une signature minimale transcriptionnelle au niveau cellule-unique comportant DEC2". Thesis, Rennes 1, 2020. http://www.theses.fr/2020REN1B038.
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La différenciation terminale des lymphocytes B à travers le centre germinatif conduit à la production de cellules sécrétrices d’anticorps : les plasmocytes (PC) à longue durée de vie et de haute affinité pour l’antigène. Cette réaction implique la formation d’une microstructure anatomique qui comprend une zone sombre : lieu d’intenses proliférations des centroblastes et de maturation d’affinité de leur BCR, et une zone claire dans laquelle ont lieu les commutations de classes isotypiques du BCR et la sélection des centrocytes (CC). Ce processus est finement contrôlé par les lymphocytes T folliculaires auxiliaires (Tfh) notamment à travers la production de molécules comme l’IL-4, le CD40L et l’IL-21. Ce travail de thèse s'intéresse à l'expression du CD23 à la surface des CC lors de leur métamorphose en PC. J'ai d’abord montré que l'expression de ce récepteur de faible affinité aux IgE est régulée par les signaux Tfh : CD40L et IL-4. De plus j'ai mis en évidence que les CC humains exposés aux signaux Tfh mais négatifs pour le CD23 sont capables de se différencier en PC. Dans ce cadre, la signature transcriptionnelle de ces progéniteurs de PC a été étudiée à l'échelle de la cellule unique et a permis d’identifier un gène jusqu’alors jamais décrit dans les PC qui code pour le facteur de transcription DEC2 et dont la fonction reste à déterminer. J'ai par ailleurs étudié l'expression du CD23 dans le lymphome folliculaire et mis en évidence qu’il existe des différences entre les populations tumorales positives et négatives pour le CD23, suggérant que les cellules CD23neg ont un avantage de survie et une capacité de différenciation supérieure en culture que les cellules CD23posTerminal B cell differentiation through the germinal center leads to the production of antibody-secreting cells: plasma cells (PC) with a long lifespan and high affinity for the antigen. This reaction involves the formation of an anatomical microstructure that includes a dark zone: site of intense proliferation and affinity maturation of the BCR of the centroblasts, and a light zone in which the class switch recombination of the BCR and centrocyte (CC) selection take place. This differentiation is finely controlled by follicular helper T cells (Tfh) that produce molecules such as IL-4, CD40L and IL-21. This phD work focus on the CD23 expression on the surface of CC during their metamorphosis into PC. Firstly, I showed that the expression of the low affinity IgE receptor is regulated by Tfh derived IL-4 and CD40L. Moreover, I showed that CC exposed to Tfh signals and which do not express the CD23 were the ones that have the ability to differentiate into PC. In this context, I identified at the single cell level a transcriptional signature expressed specifically by these cells which contains a gene never described in PC, encoding the transcription factor DEC2 whose function remains to be determined. In addition, I studied CD23 expression in follicular lymphoma and showed the existence of differences between these two populations, suggesting a preferential survival and differentiation of CD23neg cells compared to CD23pos cells
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Ribeiro, Coutinho Rita. "Exploring biomarkers from the tumour and the microenvironment in Diffuse Large B-cell Lymphoma". Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/9108.
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In the last decade unprecedented improvement in cure rates and overall survival was achieved in diffuse large B-cell Lymphoma (DLBCL) through the introduction of rituximab and anthracyclin-based chemotherapy (R-CHOP) as first line treatment. However, 40% of patients are refractory or relapse after R-CHOP and are hardly salvaged. To date, only age, International Prognostic Index (IPI) stratification and genetic aberrations defining gray-zone lymphomas have been used in clinical trials to select high-risk patients for more aggressive regimens. However, these prognostic features do not take into account the full biological heterogeneity of DLBCL. This reflects our limited knowledge on comprehensive prognostication in this group of disorders and supports our choice to investigate old and new prognostic factors for DLBCL in this thesis. Molecular characterization is generating opportunities for personalized therapy in poor-risk DLBCL. In order for targeted therapies to succeed in this disease, reliable and reproducible strategies that adequately segregate patients into distinct molecular groups are needed. While gene expression profiling (GEP) is the gold standard method, there is presently a lack of standardized methodology for array analysis, which can lead to variable results. The lack of a routine methodology for GEP has led investigators to develop immunohistochemistry (IHC) based approaches for the molecular classification in DLBCL. In fact, the Hans algorithm is being used to identify non-GCB DLBCLs in clinical trials offering NF-kB targeting agents to patients with this subtype. By performing a systematic comparison of nine IHC algorithms for molecular classification in a new large dataset of diagnostic DLBCL, we document an extremely low concordance across all classifiers (<21%) when classifying each individual patient, and a lack of outcome impact of all strategies, demonstrating that IHC is not a reliable alternative to molecular-based methods to be used for clinical decisions in DLBCL. GEP studies also suggested that the microenvironment could provide prognostic biomarkers in DLBCL in the R-CHOP era. Most authors have focused on the use of IHC to enumerate and functionally characterize the microenvironment in DLBCL. In our second study, by comparing two methods of semi-automated analysis for IHC staining Abstract 6 of the microenvironment, we demonstrate that the computerized results are highly reproducible, add the required robustness to IHC studies and should be used in the future instead of manual analysis. By applying comprehensive statistical analysis we propose that CD3 and FoxP3 should be validated as predictors of response to R-CHOP in clinical trials. Whereas a number of mechanisms by which cancer cells influence macrophage function have been described, currently there is very limited understanding of the macrophage polarisation status and effector function in human DLBCL. In our third study we analysed the GEP of macrophages sorted from human DLBCL samples. Unsupervised hierarchical clustering does not resolve DLBCL macrophage samples from reactive macrophage samples, indicating that macrophage heterogeneity in DLBCL should be considered. 202 genes are differentially expressed in DLBCL relative to controls. Functional annotation supports that these genes are macrophage-specific. We demonstrate that DLBCL macrophages have a bidirectional M1 and M2 functional activation, challenging the concept, widespread in the literature, that macrophages in tumours have a predominant M2 transcriptome. In our fifth study we used a two-cell co-culture model in an attempt to demonstrate that DLBCL cells influence macrophage transcriptome and proteome. The heterogeneity of the results, which precludes the confirmation of our hypothesis, is fully discussed. In our last study we tease out the DLBCL macrophage GEP heterogeneity and propose IFN- as a culprit B-cell derived molecule influencing macrophage activation status. Finally, using immunofluorescence we demonstrate that both M1 and M2 proteins are expressed in DLBCL macrophages.
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Weber, Tom. "Optimal timing of phase resolved cell cycle progression". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2015. http://dx.doi.org/10.18452/17253.
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Selbstreproduktion ist eines der Kennzeichen aller lebenden Organismen. Der Zellzyklus dient der Selbstreproduktion in einzelligen Organismen. In mehrzelligen Organismen ist der Zellzyklus darüber hinaus für andere lebenswichtige Prozesse, einschließlich Immunreaktionen, unerlässlich. In dieser Arbeit wird eine Methode entwickelt mit der die Dauer der Zellzyklus Phasen bestimmt werden kann. Kenntnis über die Zellzyklusphasendauer ermöglicht vorherzusagen, wie schnell eine Population von proliferierenden Zellen wachsen wird, oder wie viele neue Zellen pro Stunde in einem Gewebe geboren werden. Im Kapitel 1 dieser Arbeit wird ein Zellzyklusmodell aufgestellt und mit experimentellen Bromdesoxyuridin Daten verglichen. Die Analyse zeigt, dass das Modell gut die experimentelle Kinetik beschreibt, hebt jedoch auch hervor dass einige der Parameter nicht identifiziert werden können. Dieses Problem wird in Kapitel 2 bearbeitet, wo zwei Ansätze erforscht werden, um den Informationsgehalt der Experimente zu erhöhen. In einem ersten Ansatz wird die Theorie der Versuchsplanung angewendet, um optimale Versuchspläne zu bestimmen. In einem zweiten Ansatz wird das übliche Bromdesoxyuridin Protokoll durch ein zweites Nukleosid erweitert. Beide Methoden verbessern in silico erheblich die Genauigkeit und Präzision der Abschätzungen. Im dritten Kapitel wird die Methodik in der Analyse der Keimzentrumsreaktion angewendet. Ein erheblicher Zufluss von Zellen in die dunkle Zone von Keimzentren wird vorhergesagt, und die Ansicht einer extrem schellen Zellteilung im Keimzentrum erscheint in dem Modell als ein Artefakt der Zellmigration.Self-reproduction is one of the distinguishing marks of living organisms. The cell cycle is the underlying process by which self-reproduction is accomplished in single-celled organisms. In multi-cellular organisms, the cell cycle is in addition indispensable for other vital processes, including immune reactions. In this thesis a method is developed that allows to estimate the time it takes for a dividing cells to complete the CC phases. Knowledge of the CC phase durations allows to predict, for example, how fast a population of proliferating cells will grow in size, or how many new cells are born per hour in a given tissue. In Chapter 1 of this thesis, a cell cycle model with delays and variability in the completion times of each phase is developed. Analytical solutions are derived to describe a common experimental technique used for cell cycle analysis, namely pulse labeling with bromodeoxyuridine (BrdU). Comparison with data shows that the model reproduces closely measured cell cycle kinetics, however also reveals that some of the parameter values cannot be identified. This problem is addressed in Chapter 2. In a first approach, the framework of D-optimal experimental designs is employed, in order to choose optimal sampling schemes. In a second approach, the prevailing protocol with a single nucleoside is modified by adding a second nucleoside analog pulse. Both methods are tested and the results suggest that experimental design can significantly improve parameter estimation. In Chapter 3, the model is applied to the germinal center reaction. A substantial influx of cells into the dark zone of germinal centers is predicted. Moreover the wide-held view of rapid proliferation in germinal centers, appears, under this model, as an artifact of cell migration.
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Ramis, Zaldívar Juan Enrique. "Decoding the genetic landscape of pediatric and young adult germinal center-derived B-cell non-Hodgkin lymphoma". Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/672372.
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B-cell non-Hodgkin lymphoma (B-NHL) of pediatric and young adult population is a diverse group of neoplasms predominantly composed of aggressive B-cell lymphomas from the germinal center (GC). Molecular characterization of pediatric series has allowed the identification of several subtypes that predominantly occur in this subgroup of age. Despite of that, genomic features of these pediatric entities and their relationship to other B-NHL in this group of patients have not been extensively investigated. This thesis has aimed to address this gap of knowledge by performing a genetic and molecular characterization of large series of pediatric and young adult variants of GC-derived B-NHL including the Burkitt- like lymphoma with 11q aberration (BLL-11q) , pediatric type follicular lymphoma (PTFL) and large B-cell lymphomas (LBCL) such as diffuse large B-cell lymphomas (DLBCL) , high grade B- cell lymphomas, not otherwise specified (HGBCL, NOS) and large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) entities.
In the Study 1 we have molecularly characterized a series of 11 BLL-11q observing that BLL- 11q differed clinically, morphologically and immunophenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL. Genomic profile was also different from that of BL and DLBCL with a mutational landscape characterized by the lack of typical BL mutations in ID3, TCF3, or CCND3 genes and recurrent specific BTG2 and ETS1 mutations, not present in BL but in germinal center B-cell (GCB) DLBCL subtype. All these observations suggest that BLL-11q is a neoplasm closer to other GC-derived lymphomas rather than BL. In Study 2, we expanded our knowledge on the genetic alterations associated to PTFL by verifying the presence of MAP2K1 and IRF8 mutations in a previously well characterized series of 43 PTFL. We demonstrate the activating effect of MAP2K1 mutations by immunohistochemical analysis observing phosphorylation of the MAP2K1 downstream target extracellular signal-regulated kinase in those mutated cases. Besides, we demonstrate the specificity of MAP2K1 and IRF8-K66R mutations since they are absent in conventional FL or in t(14;18)-negative FL. Finally, in the Study 3 we characterized a large series of LBCL including DLBCL, HGBCL, NOS and LBCL-IRF4 through an integrative analysis including targeted next generation sequencing, copy number, and transcriptome data. Results showed that each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B) whereas DLBCL, NOS was predominantly of GCB-DLBCL subtype and carried gene mutations similar to the adult counterpart (e.g., SOCS1 and KMT2D). A subset of HGBCL, NOS displayed recurrent alterations of BL-related genes such as MYC, ID3, CCND3 and SMARCA4, whereas other cases were genetically closer to GCB-DLBCL. Interestingly, we could identify age-related differences in pediatric DLBCL since pediatric and young adult cases were mainly of GCB subtype, displayed low genetic complexity and virtually lacked primary aberrations (BCL2, MYC and BCL6 rearrangements). Finally, we identify clinical and molecular features related to unfavorable outcome such as age >18 years, high LDH levels, activated B-cell (ABC) DLBCL profile, high genetic complexity, homozygous deletions of 19p13.3/TNFSF7/TNFSF9, gains of 1q21-q44/MDM4/MCL1 and TP53 mutations.
Altogether, we conclude that GC-derived B-NHL of pediatric and young adult population is a heterogeneous group of tumors including different entities with specific molecular profiles and clinical behavior. This thesis has contributed to increase the knowledge of these lymphoma entities identifying biomarkers that might be helpful to improve their diagnosis and to design management strategies more adapted to their particular biological behavior.