1,721,198 research outputs found
Exploring Treatment Strategies for Type 1 Diabetes through Mathematical Modelling: Updating and Expanding an Existing Model
No full textIn this thesis we start out by dealing with a mathematical model of the onset of type 1 diabetes as proposed by Marée et al. (2006). It is a 5-dimensional model that uses ordinary differential equations (ODEs) to simulate the behavior of macrophages, activated macrophages, apoptotic beta-cells, necrotic beta-cells, and cytotoxic cytokines in neonate NOD- and Balb/c-mice. The purpose of Marée et al. (2006) is primarily to investigate the hypothesis that impaired macrophage phagocytosis can mean the difference between health and type 1 diabetes (in mice). Marée et al. (2006) base their hypothesis on previous work by Trudeau et al. (2003) and Marée et al. (2005). We start out by presenting an introduction to the biology behind the DuCa model and introduce some of the tentative treatment strategies as of today. With the groundwork in place we present, and discuss the foundations of, the model, which we have dubbed the DuCa model, and provide an analysis of a reduced version of the DuCa model, called the intermediate model (IM). The IM is based on the so-called Copenhagen model, made by Blasio et al. (1999). After this gentle interlude we proceed to do a codimension 1 bifurcation analysis of the DuCa model. The analysis serves to determine the overall soundness of the model. Where by “soundness” we mean the lack of nonphysiological behavior within a reasonable range of key parameters. The bifurcation analysis, and a thorough discussion of the adherent assumptions as well as simplifications, leads us to conclude that the DuCa model is sound. Based on these findings we expand the DuCa model, guided by recent data and guidelines that should apply to all mathematical models as well as some criteria that pertain to this model in particular. The expansion consists of a compartment of healthy beta-cells. By this expansion we add to the realism of the model and set up a model from which future researches can analyze how best to go about countering the chronic inflammation of the Islets of Langerhans that leads to T1D in 80 % of female NOD-mice. In our discussion of the expanded model we also provide some hints as to how one would go about implementing the effect of, in particular, one tentative drug, as well as point to additional features that need implementing (and how this could be done).In this thesis we start out by dealing with a mathematical model of the onset of type 1 diabetes as proposed by Marée et al. (2006). It is a 5-dimensional model that uses ordinary differential equations (ODEs) to simulate the behavior of macrophages, activated macrophages, apoptotic beta-cells, necrotic beta-cells, and cytotoxic cytokines in neonate NOD- and Balb/c-mice. The purpose of Marée et al. (2006) is primarily to investigate the hypothesis that impaired macrophage phagocytosis can mean the difference between health and type 1 diabetes (in mice). Marée et al. (2006) base their hypothesis on previous work by Trudeau et al. (2003) and Marée et al. (2005). We start out by presenting an introduction to the biology behind the DuCa model and introduce some of the tentative treatment strategies as of today. With the groundwork in place we present, and discuss the foundations of, the model, which we have dubbed the DuCa model, and provide an analysis of a reduced version of the DuCa model, called the intermediate model (IM). The IM is based on the so-called Copenhagen model, made by Blasio et al. (1999). After this gentle interlude we proceed to do a codimension 1 bifurcation analysis of the DuCa model. The analysis serves to determine the overall soundness of the model. Where by “soundness” we mean the lack of nonphysiological behavior within a reasonable range of key parameters. The bifurcation analysis, and a thorough discussion of the adherent assumptions as well as simplifications, leads us to conclude that the DuCa model is sound. Based on these findings we expand the DuCa model, guided by recent data and guidelines that should apply to all mathematical models as well as some criteria that pertain to this model in particular. The expansion consists of a compartment of healthy beta-cells. By this expansion we add to the realism of the model and set up a model from which future researches can analyze how best to go about countering the chronic inflammation of the Islets of Langerhans that leads to T1D in 80 % of female NOD-mice. In our discussion of the expanded model we also provide some hints as to how one would go about implementing the effect of, in particular, one tentative drug, as well as point to additional features that need implementing (and how this could be done)
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells
No full textPancreatic β-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon (IFN)-regulated pathways and tyrosine kinase 2 (TYK2). Polymorphisms in the TYK2 gene predicted to decrease function are associated with a decreased risk of developing type 1 diabetes. We presently evaluated whether TYK2 plays a role in human pancreatic β-cell apoptosis and production of proinflammatory mediators. TYK2-silenced human β-cells exposed to polyinosinic-polycitidilic acid (PIC) (a mimick of double-stranded RNA produced during viral infection) showed less type I IFN pathway activation and lower production of IFNα and CXCL10. These cells also had decreased expression of major histocompatibility complex (MHC) class I proteins, a hallmark of early β-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced β-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways in pancreatic β-cells via modulation of IFNα signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets
The relevance of international consortia in studies on the pathogenesis of type 1 diabetes: the role of ET1DGN
No full textThe Type 1 Diabetes Genetics Consortium (T1DGC), funded September 2002, is a collaborative effort to develop resources for the purpose of identifying risk genes for type 1 diabetes. One of the aims is to establish a renewable resource of DNA on 2500 affected sib-pair families. Regional networks have been established and in continental Europe, the European Type 1 Diabetes Genetics Network (ET1DGN) is responsible for identifying and collecting families. Most European countries have shown interest in this study and many have started recruiting families. The consortium is open to participation and there are several ways one can participate as a member of the consortium. ET1DGN suggests going beyond the tasks of T1DGC and establishing a well-organized network for additional and future studies in Europe. Copyright (c) 2005 John Wiley & Sons, Ltd
Variations on the Author
Get PDF“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
Capturing residual beta cell function in type 1 diabetes
No full textSince the 1970s, C-peptide has been used as a surrogate marker for monitoring the progression of type 1 and type 2 diabetes and to determine the effects of interventions designed to preserve or improve residual beta cell function. C-peptide measurement is a well-established surrogate of residual beta cell activity and of clinical significance as it is associated with HbA1c, risk for microvascular complications and the incidence of hyperglycaemia in longitudinal studies. Measurement of C-peptide after a mixed meal tolerance test is considered the gold standard of measuring beta cell function in type 1 diabetes, but the method is laborious and inconvenient. In this issue of Diabetologia, Wentworth et al ( https://doi.org/10.1007/s00125-018-4722-z ) report an algorithm for estimating C-peptide (CPEST) based on six routine clinical measures. These do not include stimulated C-peptide measurement and outperform other prevailing algorithms for estimating residual beta cell function. Going forward it is very likely that this new algorithm will serve as a simple measure of beta cell function in routine practice and as a more acceptable primary outcome measure in future trials of disease-modifying therapies.</p
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe 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
MicroRNA 21's effect on apoptosis and insulin secretion in insulin secreting beta-cell lines
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