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Função do fator de crescimento progranulina na diferenciação e proliferação de células de linhagem hepática, durante o desenvolvimento embrionário de ratos Fischer 344; Function of the progranuline growth factor in the hepatic lineage cell differentiation and proliferation during the embryo development of fisher 344 rats

Passos, Cristiane Carlin
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 10/12/2010 PT
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Doenças envolvendo órgãos endodermicamente derivados afetam milhares de pessoas no mundo. O sucesso da terapia celular para o tratamento de doenças de órgãos oriundos da mesoderme e ectoderme gera ótimas perspectivas para o uso do mesmo em tratamento de doenças de órgãos de origem endodérmica (tireóide, pulmões, fígado, vesícula biliar e pâncreas). Particularmente, no fígado, ainda que sejam atribuídas propriedades regenerativas em muitas lesões o mecanismo de reparação é insuficiente, tornando o transplante hepático à única opção definitiva. Dentre as células-tronco embrionárias, as células de linhagens hepáticas fetais podem estabelecer-se como fonte importante para a terapia celular em indivíduos com doenças hepáticas, pois possuem um alto índice de diferenciação de hepatócitos e células do ducto biliar in vitro. Evidências apontam a progranulina como um fator de crescimento de grande habilidade para a indução de proliferação celular, uma vez que está envolvida no desenvolvimento embrionário e neonatal. Sendo assim, neste trabalho foram utilizados embriões de ratos Fischer 344 com idades gestacionais 12,5; 13,5; 14,5; 15,5; 16;5 para caracterizar o papel do novo fator de crescimento progranulina na hepatogênese. Foram realizadas análises histológicas...

Um Modelo para Estudos de Modulação da Pluripotência e Diferenciação Celular em Células-Tronco Pluripotentes; A Model for Studying the Modulation of Pluripotency and Cell Differentiation in Pluripotent Stem Cells

Lima, Ildercílio Mota de Souza
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 07/06/2013 PT
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Células pluripotentes são aquelas que possuem a capacidade de dar origem às células dos três folhetos embrionários (ectoderma, mesoderma e endoderma), bem como também às células germinativas. As células-tronco embrionárias (CTE) são as células pluripotentes mais conhecidas, as quais apresentam uma elevada capacidade de diferenciação celular e autorenovação. Estas propriedades tornam as CTE potenciais ferramentas para a medicina regenerativa, porém seu uso na prática clínica enfrenta várias barreiras. Neste sentido, o acúmulo de conhecimento a respeito dos mecanismos envolvidos na manutenção da pluripotência, levou ao desenvolvimento de técnicas capazes de induzir a pluripotência em células somáticas adultas. Na maioria das abordagens, isto se dá pela expressão ectópica de fatores de transcrição envolvidos na pluripotência (como Oct4 e Nanog). Com isto em vista, torna-se evidente que estudos que levem a um melhor entendimento destas propriedades biológicas, podem levar ao desenvolvimento desta importante área. Apesar destas inovações, os mecanismos responsáveis pela manutenção ou indução da pluripotência e da autorenovação, continuam largamente inexplorados. Neste sentido, o conjunto de técnicas referidas como High Content Screening (HCS) apresenta características fundamentais que permitiriam a interrogação sistemática e em larga-escala de fatores que possam estar influenciando nestes processos. A técnica de HCS se baseia no uso de microscopia de fluorescência em placas de 96 ou mais poços...

Association between human Papillomavirus and colorectal adenocarcinoma and its influence on tumor staging and degree of cell differentiation

PICANÇO-JUNIOR,Olavo Magalhães; OLIVEIRA,Andre Luiz Torres; FREIRE,Lucia Thereza Mascarenhas; BRITO,Rosangela Baia; VILLA,Luisa Lina; MATOS,Délcio
Fonte: Colégio Brasileiro de Cirurgia Digestiva Publicador: Colégio Brasileiro de Cirurgia Digestiva
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/09/2014 EN
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BACKGROUND: Colorectal cancer is one of the most common types of neoplasia among the worldwide adult population. Among neoplasms of the gastrointestinal tract, it is ranked second in relation to prevalence and mortality, but its etiology is only known in around 5% of the cases. It is believed that 15% of malignant diseases are related to viral oncogenesis. AIM: To correlate the presence of HPV with the staging and degree of cell differentiation among patients with colorectal adenocarcinoma. METHODS: A retrospective case-control study was conducted on 144 patients divided between a test group of 79 cases of colorectal cancer and a control group to analyze 144 patients aged 25 to 85 years (mean, 57.85 years; standard deviation, 15.27 years and median, 58 years). Eighty-six patients (59.7%) were male. For both groups, tissue samples from paraffin blocks were subjected to DNA extraction followed by the polymerase chain reaction using generic and specific primers for HPV 16 and 18. Dot blot hybridization was also performed with the aim of identifying HPV DNA. RESULTS: The groups were shown to be homogenous regarding sex, age and site of HPV findings in the samples analyzed. Out of the 41 patients with HPV, 36 (45.6%) were in the cases and five (7.7%) were in the control group (p<0.001). All the HPV cases observed comprised HPV 16...

E2F4 Actively Promotes the Initiation and Maintenance of Nerve Growth Factor-Induced Cell Differentiation

Persengiev, Stephan P.; Kondova, Ivanela I.; Kilpatrick, Daniel L.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /09/1999 EN
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E2F transcription factors play a critical role in cell cycle progression through the regulation of genes required for G1/S transition. They are also thought to be important for growth arrest; however, their potential role in the cell differentiation process has not been previously examined. Here, we demonstrate that E2F4 is highly upregulated following the neuronal differentiation of PC12 cells with nerve growth factor (NGF), while E2F1, E2F3, and E2F5 are downregulated. Immunoprecipitation and subcellular fractionation studies demonstrated that both the nuclear localization of E2F4 and its association with the Rb family member p130 increased following neuronal differentiation. The forced expression of E2F4 markedly enhanced the rate of PC12 cell differentiation induced by NGF and also greatly lowered the rate at which cells lost their neuronal phenotype following NGF removal. Importantly, this effect occurred in the absence of any significant change in the growth regulation of PC12 cells by NGF. Further, the downregulation of E2F4 expression with antisense oligodeoxynucleotides inhibited NGF-induced neurite outgrowth, indicating an important role for this factor during PC12 cell differentiation. Finally, E2F4 expression was found to increase dramatically in the developing rat cerebral cortex and cerebellum...

A Guanidine-rich Regulatory Oligodeoxynucleotide Improves Type-2 Diabetes in Obese Mice by Blocking T-cell Differentiation

Cheng, Xiang; Wang, Jing; Xia, Ni; Yan, Xin-Xin; Tang, Ting-Ting; Chen, Han; Zhang, Hong-Jian; Liu, Juan; Kong, Wen; Sjöberg, Sara; Folco, Eduardo; Libby, Peter; Liao, Yu-Hua; Shi, Guo-Ping
Fonte: WILEY-VCH Verlag Publicador: WILEY-VCH Verlag
Tipo: Artigo de Revista Científica
EN_US
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T lymphocytes exhibit pro-inflammatory or anti-inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine-rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2-cell counterbalance. This study reveals a non-toxic regulatory ODN (ODNR01) that inhibits Th1- and Th17-cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet-induced obese (DIO) and genetically generated obese (ob/ob) mice. Mechanistic studies show that ODNR01 suppresses Th1- and Th17-cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte-free Rag1-deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4(^+) T-cell-reconstituted Rag1-deficient DIO mice, suggesting its beneficial effect on insulin resistance is T-cell-dependent. Therefore, regulatory ODNR01 reduces obesity-associated insulin resistance through modulation of T-cell differentiation.

miRNA-720 Controls Stem Cell Phenotype, Proliferation and Differentiation of Human Dental Pulp Cells

Hara, Emilio Satoshi; Ono, Mitsuaki; Eguchi, Takanori; Kubota, Satoshi; Pham, Hai Thanh; Sonoyama, Wataru; Tajima, Shoji; Takigawa, Masaharu; Calderwood, Stuart K.; Kuboki, Takuo
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
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Dental pulp cells (DPCs) are known to be enriched in stem/progenitor cells but not well characterized yet. Small non-coding microRNAs (miRNAs) have been identified to control protein translation, mRNA stability and transcription, and have been reported to play important roles in stem cell biology, related to cell reprogramming, maintenance of stemness and regulation of cell differentiation. In order to characterize dental pulp stem/progenitor cells and its mechanism of differentiation, we herein sorted stem-cell-enriched side population (SP) cells from human DPCs and periodontal ligament cells (PDLCs), and performed a locked nucleic acid (LNA)-based miRNA array. As a result, miR-720 was highly expressed in the differentiated main population (MP) cells compared to that in SP cells. In silico analysis and a reporter assay showed that miR-720 targets the stem cell marker NANOG, indicating that miR-720 could promote differentiation of dental pulp stem/progenitor cells by repressing NANOG. Indeed, gain-and loss-of-function analyses showed that miR-720 controls NANOG transcript and protein levels. Moreover, transfection of miR-720 significantly decreased the number of cells positive for the early stem cell marker SSEA-4. Concomitantly, mRNA levels of DNA methyltransferases (DNMTs)...

Mechanisms of Stem Cell Maintenance and Cell Differentiation in the Intestinal Epithelium

San Roman, Adrianna Katrina
Fonte: Harvard University Publicador: Harvard University
Tipo: Thesis or Dissertation; text Formato: application/pdf
EN
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Constant regeneration of the intestinal epithelium, a dynamic tissue with vital digestive and barrier functions, depends on proliferation of resident stem cells and their differentiation into mature cell types. This epithelium thus provides an ideal model to study stem cells and mechanisms of cell differentiation in an adult tissue. The identification of a proliferative population of intestinal stem cells (ISCs) at the base of intestinal crypts presents the prospect of understanding their regulation by extrinsic and intrinsic factors. Although activation of Wnt signaling in ISCs is thought to be one crucial function of the ISC niche, the cellular source of Wnt ligands is uncertain. Chapter 2 addresses this question through genetic elimination of Wnt ligand secretion in candidate niche cell populations. The data reveal that Wnts originating in any of the sources considered in the literature – the epithelium (including Paneth cells) and sub-epithelial myofibroblasts – are not required for ISC function. These data support models of highly complex cell redundancy or alternative, non-Wnt ligands. Chapter 3 investigates the cell-intrinsic contributions of an intestine-restricted transcription factor (TF), CDX2, to important ISC behaviors. Cdx2 loss in vivo perturbs ISC proliferation and differentiation...

Glutathione homeostasis during terminal human leukemia-60 (HL-60) cell differentiation

Krance, Suzanne M. ; Ballatori, Nazzareno
Fonte: Universidade de Rochester Publicador: Universidade de Rochester
Tipo: Tese de Doutorado Formato: Number of Pages:xvi, 145 leaves
ENG
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Thesis (Ph. D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Environmental Medicine, 2008. ; The tripeptide glutathione (L-γ-glutamyl-L-cysteinylglycine; GSH), is the most abundant intracellular thiol and functions as a major regulator of the intracellular redox state. Imbalances in GSH homeostasis are associated with a wide array of disease states, and are implicated in the aging process. For years, research on GSH has focused on its role in detoxification, however a renewed interest in the molecule has focused on its role in major cell processes, including cell differentiation. A number of studies have described GSH status in differentiated cells, however limited information is available concerning GSH status during the process. In addition, many seemingly contradictory reports have been made concerning the effects of altering GSH levels on differentiation outcomes. Studies in this thesis were designed to elucidate GSH status during terminal differentiation, and to determine how altering GSH during the process affects differentiation. It was hypothesized that GSH status is dynamic during terminal differentiation, and that depleting levels of this tripeptide modulates differentiation outcomes. In order to test this hypothesis...

Persistent Expression of Notch2 Delays Gonadotrope Differentiation

Raetzman, L.; Wheeler, B.; Ross, S.; Thomas, P.; Camper, S.
Fonte: Endocrine Soc Publicador: Endocrine Soc
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
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Normal pituitary gland development requires coordination between maintenance of progenitor cell pools and selection of progenitors for differentiation. The spatial and temporal expression of Notch2 during pituitary development suggested that it could control progenitor cell differentiation in the pituitary. Consistent with this idea, Notch2 is not expressed in Prop1 mutants, and anterior pituitary progenitors in Prop1 mutants appear to be unable to transition from proliferation to differentiation properly, resulting in anterior lobe failed cell specification and evolving hypoplasia. To test the function of Notch2 directly, we used the GSU subunit promoter to express activated NOTCH2 persistently in pre-gonadotropes and pre-thyrotropes of transgenic mice. At birth, there is a small reduction in the population of fully differentiated thyrotropes and almost no fully differentiated gonadotropes. The temporal and spatial expression of Hey1 suggests that it could be a mediator of this effect. Gonadotropes complete their differentiation program eventually, although expression of LH and FSH is mutually exclusive with NOTCH2 transgene expression. This demonstrates that activated Notch2 is sufficient to delay gonadotrope differentiation, and it supports the hypothesis that Notch2 regulates progenitor cell differentiation in the pituitary gland.; Lori T. Raetzman...

CD molecules 2006 - Human cell differentiation molecules

Zola, H.; Swart, B.; Banham, A.; Barry, S.; Beare, A.; Bensussan, A.; Boumsell, L.; Buckley, C.; Buhring, H.J.; Clark, G.; Engel, P.; Fox, D.; Jin, B.Q.; Macardle, P.; Malavasi, F.; Mason, D.; Stockinger, H.; Yang, X.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2007 EN
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The Human Leucocyte Differentiation Antigens Workshops (HLDA) have since 1984 provided a forum for the characterization and study of leucocyte surface molecules and antibodies against them. HLDA devised the CD nomenclature, which is sanctioned by IUIS. The HLDA Council reviewed and modified the objectives of HLDA in 2004, and changed the name of the organization to Human Cell Differentiation Molecules (HCDM) to reflect the broader objectives. Workshop studies under the HCDM banner proceeded during 2005 and early 2006, culminating in a meeting in May 2006. At that meeting the Council, acting as Nomenclature Committee, approved a number of new CD designations and changes to some pre-existing CD designations, which are summarized in this report.; http://www.elsevier.com/wps/find/journaldescription.cws_home/506022/description#description; Heddy Zola, Bernadette Swart, Alison Banham, Simon Barry, Alice Beare, Armand Bensussan, Laurence Boumsell, Chris D. Buckley, Hans-Jörg Bühring, Georgina Clark, Pablo Engel, David Fox, Bo-Quan Jin, Peter J. Macardle, Fabio Malavasi, David Mason, Hannes Stockinger and Xifeng Yang; Copyright © 2006 Elsevier B.V. All rights reserved.

Manipulation of cell: Cell contacts and mesoderm suppressing activity direct lineage choice from pluripotent primitive ectoderm-like cells in culture

Hughes, J.; Washington, J.; Zheng, Z.; Lau, X.; Yap, C.; Rathjen, P.; Rathjen, J.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2009 EN
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In the mammal, the pluripotent cells of embryo differentiate and commit to either the mesoderm/endoderm lineages or the ectoderm lineage during gastrulation. In culture, the ability to direct lineage choice from pluripotent cells into the mesoderm/endoderm or ectoderm lineages will enable the development of technologies for the formation of highly enriched or homogenous populations of cells. Here we show that manipulation of cell:cell contact and a mesoderm suppressing activity in culture affects the outcome of pluripotent cell differentiation and when both variables are manipulated appropriately they can direct differentiation to either the mesoderm or ectoderm lineage. The disruption of cell:cell contacts and removal of a mesoderm suppressor activity results in the differentiation of pluripotent, primitive ectoderm-like cells to the mesoderm lineage, while maintenance of cell:cell contacts and inclusion, within the culture medium, of a mesoderm suppressing activity results in the formation of near homogenous populations of ectoderm. Understanding the contribution of these variables in lineage choice provides a framework for the development of directed differentiation protocols that result in the formation of specific cell populations from pluripotent cells in culture.; James N. Hughes...

Mechanisms of embryonic stem cell division and differentiation.

White, Josephine
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2004
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The regulatory mechanisms governing dramatic proliferative changes during early mouse development are not well understood. This thesis aims to address this question using in vitro model systems of mouse embryogenesis. In particular, this thesis aimed to assess the function of the elevated, constitutive levels of cyclin dependent kinase 2 (CDK2) activity in embryonic stern (ES) and early primitive ectoderm-like (EPL) cells and the changes associated with differentiation into EPL embryoid bodies, in vitro equivalent of differentiation primarily to a mesodermal fate. It was determined that active CDK2 complexes associate with an increased proportion of substrates in pluripotent ES and EPL cells compared to EPL embryoid bodies. In addition, this thesis assessed the presence of other G1 CDK activity, determining that ES cells have high levels of constitutive CDK6 activity, which is refractory to inhibition by p16. Lineage specific decreases in CDK6 activity highlighted the complexities regulating cell proliferation during differentiation. Due to the reported constitutive E2F target gene expression in ES cells, this thesis also aimed to further analyse the regulation and activity of E2F transcription factors and pocket proteins in ES cells. It was demonstrated that constitutive phosphorylation of p107 and increased E2F-4 stability in ES cells contributes to increased levels of free E2F-4...

Funktionelle Charakterisierung der Zellwandproteine AmiC2 und SepJN und ihre Bedeutung für die Vielzelligkeit des filamentösen Cyanobakteriums Nostoc punctiforme ATCC 29133; Functional characterization of the cell wall proteins AmiC2 and SepJN and their interests in the multicellular filamentous cyanobacterium Nostoc punctiforme ATCC 29133

Lehner, Josef
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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Nostoc punctiforme ATCC 29133 ist ein multizelluläres Cyanobakterium, welches photoautotroph in Filamenten aus mehreren hundert Zellen wächst, die über eine kontinuierliche äußere Membran und einen Mureinsacculus miteinander verbunden sind. Nach der Zellteilung werden die Zellen nicht wie bei einzelligen Bakterien voneinander getrennt, sondern bleiben als kommunizierende Einheit miteinander verbunden. Der Informationsaustausch unter den Zellen ermöglicht dem Filament schnell auf Änderungen der Umwelt zu reagieren und sich durch Zelldifferenzierung diesen anzupassen. Um eine schnelle und koordinierte Zelldifferenzierung zu gewährleisten, muss ein komplexes Kommunikationssystem existieren, welches die Zelldifferenzierung von einzelnen stickstofffixierenden Heterozysten, von kurzen beweglichen Filamenten, den Hormogonien, und von klimastabilen Akineten ermöglicht. Mit der Charakterisierung der Septum-lokalisierten Zellwand-Amidase AmiC2 in N. punctiforme ist es gelungen, einen Baustein zu identifizieren, welcher essentiell für die Ausbildung eines solchen Kommunikationssystems ist. Die Inaktivierung des amiC2 Gens in N. punctiforme führte zum Verlust der Zell-Zell-Kommunikation. Des Weiteren war die Mutante nicht zur Zelldifferenzierung befähigt. Stattdessen verharrten die Zellen in einem primordialen Stadium...

Modulation of marrow stromal cell differentiation in bone tissue engineering constructs

Holtorf, Heidi Lynn
Fonte: Universidade Rice Publicador: Universidade Rice
ENG
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Better understanding of the factors that affect marrow stromal cell differentiation will allow researchers to optimize the design of bone tissue engineering constructs toward healing large bone defects in human patients. This research characterizes the effects of scaffold properties and culture supplements on the osteoblastic differentiation of marrow stromal cells (MSCs) seeded on solid, porous scaffolds and cultured in a flow perfusion bioreactor. This bioreactor creates a culture environment similar to that experienced by osteoblasts in vivo by minimizing diffusional constraints and providing mechanical stimulation to the cells through fluid shear. For these studies, MSCs were seeded on scaffolds, cultured under static or flow perfusion conditions, and assayed for DNA, alkaline phosphatase activity, osteopontin, and calcium to assess osteoblastic differentiation. Light and electron microscopy were used to visualize cell morphology and matrix deposition. The results show that brief exposure of MSCs to dexamethasone, a chemical stimulus typically required for osteoblast differentiation, was required prior to seeding on a titanium fiber mesh scaffold for ectopic bone formation to occur in a subcutaneous implantation site. However, in the absence of dexamethasone...

Significance of proneural basic helix-loop-helix transcription factors in neuroendocrine differentiation of fetal lung epithelial cells and lung carcinoma cells

Ito, T.; Udaka, N.; Ikeda, M.; Yazawa, T.; Kageyama, R.; Kitamura, H.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
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In this brief review article, we describe how cell fate determination by which the airway epithelial cells become neuroendocrine or non-neuroendocrine is regulated by a network of basic helix-loop-helix transcription (bHLH) factors in a similar manner to neurona1 differentiation, and how this system could work to determine cell differentiation of human lung carcinomas. Immunohistochemical studies reveal that mammalina achaete-scute complex homologue (Mash)l is expressed in pulmonary neuroendocrine cells (PNEC), while hairy and Enhancer of split (Hes)l is expressed in pulmonary non-neuroendocrine cells (non-PNEC). Studies using gene-deficient mice for the bHLH factors revealed that in Mashl homozygous null mice no PNEC are detected, while PNEC increase markedly in Hesl homozygous null mice. These obse~at ionss uggest that Mashl is an essential positive factor for neuroendocrine differentiation of lung epithelium, and that Hesl is one of the repressive factors for neuroendocrine differentiation. Moreover, immunohistochemical studies revealed that Notch receptors are detected in non-PNEC, and thus the Notch signalling pathway could play a role in the determination of airway epithelial cell differentiation. In human lung carcinomas...

Symmetry applied to nuclear microanatomy: a review of gene function and cell differentiation

Bell, C.D.
Fonte: Murcia : F. Hernández Publicador: Murcia : F. Hernández
Tipo: Artigo de Revista Científica Formato: application/pdf
ENG
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The purpose of this paper is to review current knowledge and understandings of gene control and cell differentiation, based upon an appreciation of a possible role that nuclear microanatomy and considerations of steric symmetry might play. Metaphase sister chromatids have identical base codes but show a mirror image symmetry of higher order coiling. Chromosomes in the interphase nucleus have spatially well defined domains and are anatomically distinct and ordered. Chromosomes are known to have interactions i.e. sex chromosome inactivation, PEV etc An hypothesis of gene activation is made based on steric interactions among chromosomes and between chromosomes and activating and repressor proteins. These interactions may be influenced by the handedness of higher order chromatid coiling, since homologues show mirror-image symmetrical coiling in metaphase, which might be retained to a certain degree in interphase. This may result in a binary switching of genes. All possible combinations of chromatids in the interphase nucleus, would be enabled by a differential segregation of homologous chromatids at mitosis. To conserve patterns of interchromatid interactions, there must be a programmed segregation of chromatids towards one of the two spindle pole attachments. This orientation might be effected by preferential attachment of microtubules to kinetochore attachment sites...

Transcriptional regulation of effector CD8+ T cell differentiation and molecular dysfunction during HIV-1 infection

Noto, Alessandra
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
EN
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Les cellules T CD8+ jouent un rôle primordial dans le contrôle des infections virales en limitant la dissémination des cellules infectées. Lors de l’infection chronique par le virus HIV, les cellules T CD8+ HIV-spécifiques ne se différencient pas en cellules effectrices fonctionnelles capables de tuer les cellules infectées par le virus ; ces cellules ne sont plus capables de proliférer ou de produire l’ IL-2. Ces cellules expriment PD-1 et l’engagement de PD-1, par son ligand, aboutit a plusieurs de ces déficits fonctionnels des cellules T . Le rôle de PD-1 dans la régulation d'évènements transcriptionnels contrôlant la différentiation et l'obtention des fonction effectrices des cellules T CD8+ reste à démontrer. Id2 joue un rôle central dans la différenciation des cellules T CD8+ effectrices. Nous avons émis l’hypothèse que le défaut de maturation observé chez les cellules T CD8+ PD-1 high HIV-spécifiques (CD8+PD-1hi) au cours de l’infection chronique par le virus HIV pouvait être lié à la diminution d’expression du régulateur Id2. Nous avons ainsi démontré que l'engagement de PD-1 contribuait à une diminution d'expression de Id2 et de ses cibles transcriptionnelles. La surexpression de Id2 de ces cellules a permis de restaurer l'expression de marqueurs tels que Granzyme B et Bcl-2 et diminuir l’expression du marqueur de maturation de CD27. La famille des cytokines à chaine gamma joue un rôle clef dans la survie et l’homéostasie des cellules T. Dans ce travail...

Non-genetic heterogeneity criticality and cell differentiation

Pal, Mainak; Ghosh, Sayantari; Bose, Indrani
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
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The different cell types in a living organism acquire their identity through the process of cell differentiation in which the multipotent progenitor cells differentiate into distinct cell types. Experimental evidence and analysis of large-scale microarray data establish the key role played by a two-gene motif in cell differentiation in a number of cell systems. The two genes express transcription factors which repress each other's expression and autoactivate their own production. A number of theoretical models have recently been proposed based on the two-gene motif to provide a physical understanding of how cell differentiation occurs. In this paper, we study a simple model of cell differentiation which assumes no cooperativity in the regulation of gene expression by the transcription factors. The latter repress each other's activity directly through DNA binding and indirectly through the formation of heterodimers. We specifically investigate how deterministic processes combined with stochasticity contribute in bringing about cell differentiation. The deterministic dynamics of our model give rise to a supercritical pitchfork bifurcation from an undifferentiated stable steady state to two differentiated stable steady states. The stochastic dynamics of our model are studied using the approaches based on the Langevin equations and the linear noise approximation. The simulation results provide a new physical understanding of recent experimental observations. We further propose experimental measurements of quantities like the variance and the lag-1 autocorrelation function in protein fluctuations as the early signatures of an approaching bifurcation point in the cell differentiation process.; Comment: Cell Differentiation...

Minimal Model for Stem-Cell Differentiation

Goto, Yusuke; Kaneko, Kunihiko
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 29/03/2013
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565.81055%
To explain the differentiation of stem cells in terms of dynamical systems theory, models of interacting cells with intracellular protein expression dynamics are analyzed and simulated. Simulations were carried out for all possible protein expression networks consisting of two genes under cell--cell interactions mediated by the diffusion of a protein. Networks that show cell differentiation are extracted and two forms of symmetric differentiation based on Turing's mechanism and asymmetric differentiation are identified. In the latter network, the intracellular protein levels show oscillatory dynamics at a single-cell level, while cell-to-cell synchronicity of the oscillation is lost with an increase in the number of cells. Differentiation to a fixed-point type behavior follows with a further increase in the number of cells. The cell type with oscillatory dynamics corresponds to a stem cell that can both proliferate and differentiate, while the latter fixed-point type only proliferates. This differentiation is analyzed as a saddle-node bifurcation on an invariant circle, while the number ratio of each cell type is shown to be robust against perturbations due to self-consistent determination of the effective bifurcation parameter as a result of the cell--cell interaction. Complex cell differentiation is designed by combing these simple two-gene networks. The generality of the present differentiation mechanism...

ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation

Rui, Lixin; Healy, James; Blasioli, Julie; Goodnow, Christopher
Fonte: American Association of Immunologists Publicador: American Association of Immunologists
Tipo: Artigo de Revista Científica
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Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents mast be selected whereas self-reactive Abs are suppressed. Bacterial LPS is a uniquely potent bacterial immunogen that can bypass self-tolerance within the T cell repertoire. We show here that during LPS-induced plasma cell differentiation, the ERK intracellular signaling pathway serves as a pivotal switch integrating opposing inputs from Ag via BCR and from the two best characterized B cell differentiation factors made by T cells, IL-2 and IL-5. Continuous Ag receptor signaling through the RAS/MEK/ERK pathway, as occurs in self-reactive B cells, inhibits LPS induction of Blimp-1 and the plasma cell differentiation program. Differentiation resumes after a transient pulse of Ag-ERK signaling, or upon inactivation of ERK by IL-2 and IL-5 through induction of dual-specificity phosphatase 5 (Dusp5). The architecture of this molecular switch provides a framework for understanding the specificity of antibacterial Ab responses and resistance to bacterially induced autoimmune diseases such as Guillain-Barré syndrome.