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‣ Fission Yeast Germinal Center (GC) Kinase Ppk11 Interacts with Pmo25 and Plays an Auxiliary Role in Concert with the Morphogenesis Orb6 Network (MOR) in Cell Morphogenesis*

Goshima, Tetsuya; Kume, Kazunori; Koyano, Takayuki; Ohya, Yoshikazu; Toda, Takashi; Hirata, Dai
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
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How cell morphology and the cell cycle are coordinately regulated is a fundamental subject in cell biology. In fission yeast, 2 germinal center kinases (GCKs), Sid1 and Nak1, play an essential role in septation/cytokinesis and cell separation/cell polarity control, respectively, as components of the septation initiation network (SIN) and the morphogenesis Orb6 network (MOR). Here we show that a third GCK, Ppk11, is also required for efficient cell separation particularly, at a high temperature. Although Ppk11 is not essential for cell division, this kinase plays an auxiliary role in concert with MOR in cell morphogenesis. Ppk11 physically interacts with the MOR component Pmo25 and is localized to the septum, by which Ppk11 is crucial for Pmo25 targeting/accumulation to the septum. The conserved C-terminal WDF motif of Ppk11 is essential for both septum accumulation of Pmo25 and efficient cell separation. In contrast its kinase activity is required only for cell separation. Thus, both interaction of Ppk11 with Pmo25 and Ppk11 kinase activity are critical for efficient cell separation.

‣ Cell Encapsulation in Sub-mm Sized Gel Modules Using Replica Molding

McGuigan, Alison P.; Butte, Manish; Whitesides, George; Bruzewicz, Derek A.; Glavan, Ana
Fonte: Public Library of Science Publicador: Public Library of Science
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For many types of cells, behavior in two-dimensional (2D) culture differs from that in three-dimensional (3D) culture. Among biologists, 2D culture on treated plastic surfaces is currently the most popular method for cell culture. In 3D, no analogous standard method—one that is similarly convenient, flexible, and reproducible—exists. This paper describes a soft-lithographic method to encapsulate cells in 3D gel objects (modules) in a variety of simple shapes (cylinders, crosses, rectangular prisms) with lateral dimensions between 40 and 1000 ?m, cell densities of 105 – 108 cells/cm3, and total volumes between 1×10?7 and 8×10?4 cm3. By varying (i) the initial density of cells at seeding, and (ii) the dimensions of the modules, the number of cells per module ranged from 1 to 2500 cells. Modules were formed from a range of standard biopolymers, including collagen, Matrigel™, and agarose, without the complex equipment often used in encapsulation. The small dimensions of the modules allowed rapid transport of nutrients by diffusion to cells at any location in the module, and therefore allowed generation of modules with cell densities near to those of dense tissues (108 – 109 cells/cm3). This modular method is based on soft lithography and requires little special equipment; the method is therefore accessible...

‣ IQGAP1-Dependent Signaling Pathway Regulates Endothelial Cell Proliferation and Angiogenesis

Meyer, Rosana D.; Rahimi, Nader; Sacks, David Barry
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Background: Vascular endothelial growth factor receptor-2 (VEGFR-2) signaling is an obligate requirement for normal development and pathological angiogenesis such as cancer and age-related macular degeneration. Although autophosphorylation of tyrosine 1173 (Y1173) of VEGFR-2 is considered a focal point for its angiogenic signal relay, however, the mechanism of phosphorylation of Y1173, signaling proteins that are recruited to this residue and their role in angiogenesis is not fully understood. Methodology/Principal Findings: In this study we demonstrate that c-Src kinase directly through its Src homology 2 (SH2) domain and indirectly via c-Cbl binds to phospho-Y1057 of VEGFR-2. Activation of c-Src kinase by a positive feedback mechanism phosphorylates VEGFR-2 at multi-docking site, Y1173. c-Src also catalyzes tyrosine phosphorylation of IQGAP1 and acts as an adaptor to bridge IQGAP1 to VEGFR-2. In turn, IQGAP1 activates b-Raf and mediates proliferation of endothelial cells. Silencing expression of IQGAP1 and b-Raf revealed that their activity is essential for VEGF to stimulate angiogenesis in an in vivo angiogenesis model of chicken chorioallantoic membrane (CAM). Conclusions/Significance: Angiogenesis contributes to the pathology of numerous human diseases ranging from cancer to age-related macular degeneration. Determining molecular mechanism of tyrosine phosphorylation of VEGFR-2 and identification of molecules that are relaying its angiogenic signaling may identify novel targets for therapeutic intervention against angiogenesis-associated diseases. Our study shows that recruitment and activation of c-Src by VEGFR-2 plays a pivotal role in relaying angiogenic signaling of VEGFR-2; it phosphorylates VEGFR-2 at Y1173...

‣ 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
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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)...

‣ Disrupting the Interaction between Retinoblastoma Protein and Raf-1 Leads to Defects in Progenitor Cell Proliferation and Survival during Early Inner Ear Development

Li, Wenyan; Sun, Shan; Chen, Yan; Yu, Huiqian; Chen, Zheng-Yi; Li, Huawei
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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The retinoblastoma protein (pRb) is required for cell-cycle exit of embryonic mammalian hair cells but is not required for hair cell fate determination and early differentiation, and this provides a strategy for hair cell regeneration by manipulating the pRb pathway. To reveal the mechanism of pRb functional modification in the inner ear, we compared the effects of attenuated pRb phosphorylation by an inhibitor of the Mitogen-Activated Protein (MAP) kinase pathway and an inhibitor of the Rb–Raf-1 interaction on cultured chicken otocysts. We demonstrated that the activity of pRb is correlated with its phosphorylation state, which is regulated by a newly established cell cycle-independent pathway mediated by the physical interaction between Raf-1 and pRb. The phosphorylation of pRb plays an important role during the early stage of inner ear development, and attenuated phosphorylation in progenitor cells leads to cell cycle arrest and increased apoptosis along with a global down-regulation of the genes involved in cell cycle progression. Our study provides novel routes to modulate pRb function for hair cell regeneration.

‣ FAS-Based Cell Depletion Facilitates the Selective Isolation of Mouse Induced Pluripotent Stem Cells

Warlich, Eva; Schambach, Axel; Lock, Dominik; Wedekind, Dirk; Glage, Silke; Eckardt, Dominik; Bosio, Andreas; Knöbel, Sebastian
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Cellular reprogramming of somatic cells into induced pluripotent stem cells (iPSC) opens up new avenues for basic research and regenerative medicine. However, the low efficiency of the procedure remains a major limitation. To identify iPSC, many studies to date relied on the activation of pluripotency-associated transcription factors. Such strategies are either retrospective or depend on genetically modified reporter cells. We aimed at identifying naturally occurring surface proteins in a systematic approach, focusing on antibody-targeted markers to enable live-cell identification and selective isolation. We tested 170 antibodies for differential expression between mouse embryonic fibroblasts (MEF) and mouse pluripotent stem cells (PSC). Differentially expressed markers were evaluated for their ability to identify and isolate iPSC in reprogramming cultures. Epithelial cell adhesion molecule (EPCAM) and stage-specific embryonic antigen 1 (SSEA1) were upregulated early during reprogramming and enabled enrichment of OCT4 expressing cells by magnetic cell sorting. Downregulation of somatic marker FAS was equally suitable to enrich OCT4 expressing cells, which has not been described so far. Furthermore, FAS downregulation correlated with viral transgene silencing. Finally...

‣ Genetic Deletion of SEPT7 Reveals a Cell Type-Specific Role of Septins in Microtubule Destabilization for the Completion of Cytokinesis

Menon, Manoj B.; Sawada, Akihiro; Chaturvedi, Anuhar; Mishra, Pooja; Schuster-Gossler, Karin; Galla, Melanie; Schambach, Axel; Gossler, Achim; Förster, Reinhold; Heuser, Michael; Kotlyarov, Alexey; Kinoshita, Makoto; Gaestel, Matthias
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Cytokinesis terminates mitosis, resulting in separation of the two sister cells. Septins, a conserved family of GTP-binding cytoskeletal proteins, are an absolute requirement for cytokinesis in budding yeast. We demonstrate that septin-dependence of mammalian cytokinesis differs greatly between cell types: genetic loss of the pivotal septin subunit SEPT7 in vivo reveals that septins are indispensable for cytokinesis in fibroblasts, but expendable in cells of the hematopoietic system. SEPT7-deficient mouse embryos fail to gastrulate, and septin-deficient fibroblasts exhibit pleiotropic defects in the major cytokinetic machinery, including hyperacetylation/stabilization of microtubules and stalled midbody abscission, leading to constitutive multinucleation. We identified the microtubule depolymerizing protein stathmin as a key molecule aiding in septin-independent cytokinesis, demonstrated that stathmin supplementation is sufficient to override cytokinesis failure in SEPT7-null fibroblasts, and that knockdown of stathmin makes proliferation of a hematopoietic cell line sensitive to the septin inhibitor forchlorfenuron. Identification of septin-independent cytokinesis in the hematopoietic system could serve as a key to identify solid tumor-specific molecular targets for inhibition of cell proliferation.

‣ 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
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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...

‣ Crosstalk between E2F3 and p19ARF/p53 in the regulation of cell cycle progression and tumorigenesis

Aslanian, Aaron Spencer
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 238 leaves; 12067415 bytes; 12077479 bytes; application/pdf; application/pdf
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E2F activity was originally identified as a critical component of the cellular machinery responsible for promoting cell cycle progression that is co-opted during transformation and tumorigenesis. Classic E2F target genes have functions required for S-phase entry and progression. However, the role of E2F has expanded in recent years through the identification of novel E2F target genes. Now E2F is linked to many different cellular processes beyond basic cell cycle control. One such example is p19ARF, a positive upstream regulator of the p53 tumor suppressor protein. This dissertation examines the relationship between one member of the E2F family of transcription factors, E2F3, and the p19ARF/p53 pathway. E2F3 has previously been shown to be critical for cell cycle re-entry, cellular proliferation, and tumor development. The contribution of p19ARF/p53 to E2F3 function was assessed through the generation of compound mutant cells and mice. The nature of the relationship between E2F3, p19ARF, and p53 was highly context dependent. E2F3 is required to repress pl9Arf expression in quiescent cells. This places E2F3 upstream of p19ARF and p53 during cell cycle re-entry.; (cont.) The loss of either p9Arf or p53 completely suppresses the cell cycle re-entry defects in E2f3-deficient cells. In contrast...

‣ Quantitative analysis of the T cell receptor signaling network in response to altered peptide ligands

Wille, Lucia
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 107 p.; 13560659 bytes; 13560167 bytes; application/pdf; application/pdf
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Understanding the adaptive immune system poses a great conceptual challenge. It has evolved to respond to foreign invaders with exquisite sensitivity and selectivity. In particular, the T cell branch of the immune system is trained to distinguish between self and non-self. This requires that a single receptor, the T cell receptor, bind to multiple ligands resulting in different cell fates, based in part on the avidity of the ligand. To address the question of ligand affinity discrimination in T cells, several T cell lines, both mouse and human, were screened for their ability to exhibit multiple cell fates in response to stimulation through the T cell receptor. A hybridoma system was identified that exhibits different levels of both apoptosis and cytokine production in response to three altered peptide ligands. We investigated how the consequent downstream signaling networks integrate to ultimately govern avidity-appropriate T cell responses in this hybridoma system. Here, we hypothesized that a quantitative combination of key downstream network signals can effectively represent the information processing generated by TCR ligation, providing a model capable of interpreting and predicting T cell functional responses.; (cont.) We generated a multivariate regression model from over 1100 signaling measurements that could predict IL-2 production in response...

‣ 7.012 Introduction to Biology, Fall 2001; Introduction to Biology

Weinberg, Robert A. (Robert Allan), 1942-; Lander, Eric S.; Gardel, Claudette L.; Mischke, Michelle D.
Fonte: MIT - Massachusetts Institute of Technology Publicador: MIT - Massachusetts Institute of Technology
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Cell biology, immunology, neurobiology, and an exploration into current research in cancer, genomics, and molecular medicine.

‣ The regulation of programmed and pathological cell death in C. elegans

Galvin, Brendan D. (Brendan Daniel)
Fonte: Massachusetts Institute of Technology Publicador: Massachusetts Institute of Technology
Tipo: Tese de Doutorado Formato: 175 leaves
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Programmed cell death, or apoptosis, is important in the development and homeostasis of metazoans. In the nematode C. elegans, four genes, egl-1, ced-9, ced-4, and ced-3, constitute the core pathway acting in all somatic programmed cell deaths. This pathway is evolutionarily conserved in humans. The BH3-only protein EGL-1 is transcriptionally upregulated in cells fated to undergo programmed cell death, and EGL-1 blocks cell-death inhibition by the cell-death regulator CED-9, a Bcl-2 family member. The binding of EGL- 1 to CED-9 releases the Apaf- 1-like adaptor protein CED-4 from CED-9, so that CED-4 can activate the caspase CED-3, a protease that is the effector of programmed cell death. In this thesis, I describe three projects, each of which examines one aspect of C. elegans cell death. From. screens for mutations that increase cell death in a sensitized genetic background, I identified a gene that protects cells from programmed cell death.; (cont.) This gene, spk-1, encodes a homolog of SR protein kinases, which regulate alternative splicing. Previous work has shown that ced-4 pre-mRNA is alternatively spliced to generate two transcripts that function oppositely in cell death. I found that spk-1 regulates ced-4 transcript splicing...

‣ Evolutionary cell biology: two origins, one objective

Lynch, Michael; Field, Mark C; Goodson, Holly V; Malik, Harmit S; Pereira-Leal, José B; Roos, David S; Turkewitz, Aaron P; Sazer, Shelley
Fonte: National Academy of Sciences Publicador: National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 02/12/2014 Português
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All aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology...

‣ Multi-Scale Imaging and Informatics Pipeline for In Situ Pluripotent Stem Cell Analysis

Gorman, Bryan R.; Lu, Junjie; Baccei, Anna; Lowry, Nathan C.; Purvis, Jeremy E.; Mangoubi, Rami S.; Lerou, Paul H.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Human pluripotent stem (hPS) cells are a potential source of cells for medical therapy and an ideal system to study fate decisions in early development. However, hPS cells cultured in vitro exhibit a high degree of heterogeneity, presenting an obstacle to clinical translation. hPS cells grow in spatially patterned colony structures, necessitating quantitative single-cell image analysis. We offer a tool for analyzing the spatial population context of hPS cells that integrates automated fluorescent microscopy with an analysis pipeline. It enables high-throughput detection of colonies at low resolution, with single-cellular and sub-cellular analysis at high resolutions, generating seamless in situ maps of single-cellular data organized by colony. We demonstrate the tool's utility by analyzing inter- and intra-colony heterogeneity of hPS cell cycle regulation and pluripotency marker expression. We measured the heterogeneity within individual colonies by analyzing cell cycle as a function of distance. Cells loosely associated with the outside of the colony are more likely to be in G1, reflecting a less pluripotent state, while cells within the first pluripotent layer are more likely to be in G2, possibly reflecting a G2/M block. Our multi-scale analysis tool groups colony regions into density classes...

‣ Multi-step loading of human minichromosome maintenance proteins in live human cells; Running title: Maximal loading of MCM2/4 in late G1

Symeonidou, Ioanna Eleni; Kotsantis, Panagiotis; Roukos, Vassilis; Rapsomaniki, Maria Anna; Grecco, Hernan Edgardo; Bastiaens, Philippe; Taraviras, Stavros; Lygerou, Zoi
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: info:eu-repo/semantics/article; info:ar-repo/semantics/artículo; info:eu-repo/semantics/publishedVersion Formato: application/pdf
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Once-per-cell cycle replication is regulated through the assembly onto chromatin of multisubunit protein complexes that license DNA for a further round of replication. Licensing consists of the loading of the hexameric MCM2-7 complex onto chromatin during G1 phase and is dependent on the licensing factor Cdt1. In vitro experiments have suggested a two-step binding mode for minichromosome maintenance (MCM) proteins, with transient initial interactions converted to stable chromatin loading. Here, we assess MCM loading in live human cells using an in vivo licensing assay on the basis of fluorescence recovery after photobleaching of GFP-tagged MCM protein subunits through the cell cycle. We show that, in telophase, MCM2 and MCM4 maintain transient interactions with chromatin, exhibiting kinetics similar to Cdt1. These are converted to stable interactions from early G1 phase. The immobile fraction of MCM2 and MCM4 increases during G1 phase, suggestive of reiterative licensing. In late G1 phase, a large fraction of MCM proteins are loaded onto chromatin, with maximal licensing observed just prior to S phase onset. Fluorescence loss in photobleaching experiments show subnuclear concentrations of MCM-chromatin interactions that differ as G1 phase progresses and do not colocalize with sites of DNA synthesis in S phase.; Fil: Symeonidou...

‣ Mapping Differentiation under Mixed Culture Conditions Reveals a Tunable Continuum of T Cell Fates

Antebi, Yaron E.; Reich-Zeliger, Shlomit; Hart, Yuval; Mayo, Avi; Eizenberg, Inbal; Rimer, Jacob; Putheti, Prabhakar; Pe'er, Dana; Friedman, Nir
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
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Cell differentiation is typically directed by external signals that drive opposing regulatory pathways. Studying differentiation under polarizing conditions, with only one input signal provided, is limited in its ability to resolve the logic of interactions between opposing pathways. Dissection of this logic can be facilitated by mapping the system's response to mixtures of input signals, which are expected to occur in vivo, where cells are simultaneously exposed to various signals with potentially opposing effects. Here, we systematically map the response of naïve T cells to mixtures of signals driving differentiation into the Th1 and Th2 lineages. We characterize cell state at the single cell level by measuring levels of the two lineage-specific transcription factors (T-bet and GATA3) and two lineage characteristic cytokines (IFN-γ and IL-4) that are driven by these transcription regulators. We find a continuum of mixed phenotypes in which individual cells co-express the two lineage-specific master regulators at levels that gradually depend on levels of the two input signals. Using mathematical modeling we show that such tunable mixed phenotype arises if autoregulatory positive feedback loops in the gene network regulating this process are gradual and dominant over cross-pathway inhibition. We also find that expression of the lineage-specific cytokines follows two independent stochastic processes that are biased by expression levels of the master regulators. Thus...

‣ Cancer Cell Motility: Optimizing Spatial Search Strategies

Chen, L. Leon; Zhang, Le; Yoon, Jeongah; Deisboeck, Thomas S.
Fonte: Universidade Cornell Publicador: Universidade Cornell
Tipo: Artigo de Revista Científica
Publicado em 25/06/2008 Português
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Aberrantly regulated cell motility is a hallmark of cancer cells. A hybrid agent-based model has been developed to investigate the synergistic and antagonistic cell motility-impacting effects of three microenvironment variables simultaneously: chemoattraction, haptotactic permission, and biomechanical constraint or resistance. Reflecting distinct cell-specific intracellular machinery, the cancer cells are modelled as processing a variety of spatial search strategies that respond to these three influencing factors with differential weights attached to each. While responding exclusively to chemoattraction optimizes cell displacement effectiveness, incorporating permission and resistance components becomes increasingly important with greater distance to the chemoattractant source and/or after reducing the ligand's effective diffusion coefficient. Extending this to a heterogeneous population of cells shows that displacement effectiveness increases with clonal diversity as characterized by the Shannon index. However, the resulting data can be fit best to an exponential function, suggesting that there is a level of population heterogeneity beyond which its added value to the cancer system becomes minimal as directionality ceases to increase. Possible experimental extensions and potential clinical implications are discussed.; Comment: 31 pages...

‣ Computational methods for multi-omic models of cell metabolism and their importance for theoretical computer science

Angione, Claudio
Fonte: University of Cambridge; Faculty of Computer Science and Technology; Computer Laboratory Publicador: University of Cambridge; Faculty of Computer Science and Technology; Computer Laboratory
Tipo: Thesis; doctoral; PhD
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To paraphrase Stan Ulam, a Polish mathematician who became a leading figure in the Manhattan Project, in this dissertation I focus not only on how computer science can help biologists, but also on how biology can inspire computer scientists. On one hand, computer science provides powerful abstraction tools for metabolic networks. Cell metabolism is the set of chemical reactions taking place in a cell, with the aim of maintaining the living state of the cell. Due to the intrinsic complexity of metabolic networks, predicting the phenotypic traits resulting from a given genotype and metabolic structure is a challenging task. To this end, mathematical models of metabolic networks, called genome-scale metabolic models, contain all known metabolic reactions in an organism and can be analyzed with computational methods. In this dissertation, I propose a set of methods to investigate models of metabolic networks. These include multi-objective optimization, sensitivity, robustness and identifiability analysis, and are applied to a set of genome-scale models. Then, I augment the framework to predict metabolic adaptation to a changing environment. The adaptation of a microorganism to new environmental conditions involves shifts in its biochemical network and in the gene expression level. However...

‣ Quantitative analysis of cellular networks: cell cycle entry

Lee, Tae J.
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 5766628 bytes; application/pdf
Publicado em //2010 Português
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Cellular dynamics arise from intricate interactions among diverse components, such as metabolites, RNAs, and proteins. An in-depth understanding of these interactions requires an integrated approach to the investigation of biological systems. This task can benefit from a combination of mathematical modeling and experimental validations, which is becoming increasingly indispensable for basic and applied biological research.

Utilizing a combination of modeling and experimentation, we investigate mammalian cell cycle entry. We begin our investigation by making predictions with a mathematical model, which is constructed based on the current knowledge of biology. To test these predictions, we develop experimental platforms for validations, which in turn can be used to further refine the model. Such iteration of model predictions and experimental validations has allowed us to gain an in-depth understanding of the cell cycle entry dynamics.

In this dissertation, we have focused on the Myc-Rb-E2F signaling pathway and its associated pathways, dysregulation of which is associated with virtually all cancers. Our analyses of these signaling pathways provide insights into three questions in biology: 1) regulation of the restriction point (R-point) in cell cycle entry...

‣ Defining Roles for Cyclin Dependent Kinases and a Transcriptional Oscillator in the Organization of Cell-Cycle Events

Simmons Kovacs, Laura Anne
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação Formato: 13836852 bytes; application/pdf
Publicado em //2009 Português
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The cell cycle is a series of ordered events that culminates in a single cell dividing into two daughter cells. These events must be properly coordinated to ensure the faithful passage of genetic material. How cell cycle events are carried out accurately remains a fundamental question in cell biology. In this dissertation, I investigate mechanisms orchestrating cell-cycle events in the yeast, Saccharomyces cerevisiae.

Cyclin dependent kinase (CDK) activity is thought to both form the fundamental cell-cycle oscillator and act as an effector of that oscillator, regulating cell-cycle events. By measuring transcript dynamics over time in cells lacking all CDK activity, I show that transcriptional oscillations are not dependent on CDK activity. This data indicates that CDKs do not form the underlying cell-cycle oscillator. I propose a model in which a transcription factor network rather than CDK activity forms the cell-cycle oscillator. In this model, CDKs are activated by the periodic transcription of cyclin genes and feedback on the network increasing the robustness of network oscillations in addition to regulating cell-cycle events.

I also investigate CDK-dependent and -independent mechanism regulating the duplication of the yeast centrosome...