1,720,957 research outputs found
Stochastic models of stem cell dynamics
No full textThere is a growing body of evidence to suggest that stem cell populations from both the embryo and the adult are heterogeneous in their gene expression patterns. However, the underlying mechanisms are not well understood. This thesis explores cell-to-cell variability in both multipotent and pluripotent stem cell populations using mathematical models to provide a theoretical framework to understand the collective dynamics of stem cell populations.In the first part of the thesis we investigate the possibility that fluctuations in the transcription factor Nanog { which is central to the embryonic stem cell transcriptional regulatory network (ESCTRN) { regulate population variability by controlling important feedback mechanisms. Our analyses reveal the ESC TRN is rich in feedback, with global feedback structure critically dependent on Nanog, Oct4 and Sox2, which collectively participate in over two thirds of all feedback loops. Using a general measure of feedback centrality we show that removal of Nanog severely compromises the global feedback structure of the ESC TRN. These analyses indicate that Nanog fluctuations regulate population heterogeneity by transiently activating different regulatory subnetworks, driving transitions between a Nanog-expressing, feedback-rich, robust and self-perpetuating pluripotent state and a Nanog-diminished, feedback-sparse and differentiation-sensitive state.The majority of studies characterising heterogeneity in Nanog expression have used live-cell fluorescent reporter strategies. However, recent evidence suggests that these reporters may not give a faithful reflection of endogenous Nanog expression because the introduction of the reporter construct can perturb the kinetics of the underlying regulatory network. To investigate the role of Nanog further we therefore sought to model in detail the dynamics of Nanog expression in heterozygous fluorescent knock-in reporter cell lines. We develop chemical master equation, chemical Langevin equation and reaction rate equation models of the reporter system to determine how this might disturb normal Nanog transcriptional control. Our analyses indicate that the reporter construct can weaken the strength of autoactivatory feedback loops that are central to Nanog regulation, and thereby qualitatively perturbs endogenous Nanog dynamics. These results question the efficacy of commonly used reporter strategies and therefore have important implications for the design and use of synthetic reporters in general, not just for Nanog.In the second part of this thesis we consider the dynamics of populations of multipotent adult hematopoietic stem cells (HSCs). It is known that fluctuations within individual HSCs allow them to transit stochastically between functionally distinct metastable states, while the overall population distribution of expression remains stable. To investigate the relationship between single cell and population-level dynamics we propose a theoretical framework that views cellular multipotency as an instance of maximum entropy statistical inference, in which an underlying ergodic stochastic process gives rise to robust variability within the cell population. We illustrate this view by analysing expression fluctuations of the stem cell surface marker Sca1 in mouse HSCs and find that the observed dynamics naturally lie close to a critical state, thereby producing a diverse population that is able to respond rapidly to environmental changes. Although we focus on Sca1 dynamics, comparable expression fluctuations are known to generate functional diversity in other mammalian stem cell systems, including in pluripotent stem cells. Thus, the generation of ergodic expression fluctuations may be a generic way in which cell populations maintain robust multilineage differentiation potential under environmental uncertainty.<br/
Entropy, ergodicity, and stem cell multipotency
No full textPopulations of mammalian stem cells commonly exhibit considerable cell-cell variability. However, the functional role of this diversity is unclear. Here, we analyze expression fluctuations of the stem cell surface marker Sca1 in mouse hematopoietic progenitor cells using a simple stochastic model and find that the observed dynamics naturally lie close to a critical state, thereby producing a diverse population that is able to respond rapidly to environmental changes. We propose an information- theoretic interpretation of these results that views cellular multipotency as an instance of maximum entropy statistical inferenc
Cell fate regulatory networks
No full textCell fate decisions are controlled by intrinsically complex molecular regulatory networks, involving a wide variety of protein–protein and protein-DNA interactions. Due to this complexity, it is difficult to understand molecular regulation of cell fate at the ‘systems’ level. In this chapter we discuss mathematical modeling of cell fate regulatory networks, and explain some ways in which mathematical techniques may be used to elucidate the essential molecular mechanisms that underly cell fate determination. We consider both Boolean networks and ordinary differential equation (ODE) models. We give an illustrative worked example of an ODE model of a simple irreversible molecular switch due to an self-enhancing positive feedback loop and discuss how various commonly-occurring network ‘motifs’ can give rise to certain well-defined dynamics, including switches and oscillators. We conclude with some words on the role of stochasticity in cell fate regulatory networks
Nanog fluctuations in embryonic stem cells highlight the problem of measurement in cell biology
Full text linkA number of important pluripotency regulators, including the transcription factor Nanog, are observed to fluctuate stochastically in individual embryonic stem (ES) cells. By transiently priming cells for commitment to different lineages, these fluctuations are thought to be important to the maintenance of, and exit from, pluripotency. However, since temporal changes in intracellular protein abundances cannot be measured directly in live cells, fluctuations are typically assessed using genetically engineered reporter cell lines that produce a fluorescent signal as a proxy for protein expression. Here, using a combination of mathematical modeling and experiment, we show that there are unforeseen ways in which widely used reporter strategies can systematically disturb the dynamics they are intended to monitor, sometimes giving profoundly misleading results. In the case of Nanog we show how genetic reporters can compromise the behavior of important pluripotency-sustaining positive feedback loops, and induce a bifurcation in the underlying dynamics that gives rise to heterogeneous Nanog expression patterns in reporter cell lines that are not representative of the wild-type. These findings help explain the range of published observations of Nanog variability and highlight the problem of measurement in live cells
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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