Setting Parameters for Biological Models With ANIMO

ANIMO (Analysis of Networks with Interactive MOdeling) is a software for modeling biological networks, such as e.g. signaling, metabolic or gene networks. An ANIMO model is essentially the sum of a network topology and a number of interaction parameters. The topology describes the interactions between biological entities in form of a graph, while the parameters determine the speed of occurrence of such interactions. When a mismatch is observed between the behavior of an ANIMO model and experimental data, we want to update the model so that it explains the new data. In general, the topology of a model can be expanded with new (known or hypothetical) nodes, and enables it to match experimental data. However, the unrestrained addition of new parts to a model causes two problems: models can become too complex too fast, to the point of being intractable, and too many parts marked as "hypothetical" or "not known" make a model unrealistic. Even if changing the topology is normally the easier task, these problems push us to try a better parameter fit as a first step, and resort to modifying the model topology only as a last resource. In this paper we show the support added in ANIMO to ease the task of expanding the knowledge on biological networks, concentrating in particular on the parameter settings

A narrative review on spinal deformities in people with cerebral palsy: Measurement, norm values, incidence, risk factors and treatment

Spinal deformities are common in people with cerebral palsy (CP), and there is a concern of an increase during the adult ageing period. There is especially a worry about the increase of scoliosis, thoracic hyperkyphosis, lumbar hyperlordosis, spondylolysis and spondylolisthesis incidence, though supporting literature is lacking. Therefore, the aim of this narrative review is to provide a scientific overview of how spinal curvatures should be measured, what the norm values are and the incidence in people with CP, as well as a description of the risk factors and the treatment regimens for these spinal abnormalities. This review can be used as a guideline relevant for a range of clinicians, including orthopaedic and neurosurgeons, radiologists, physiotherapists, and biokineticists, as well as academics

Resolved lower limb muscle tone abnormalities in children with HIV encephalopathy receiving standard antiretroviral therapy

BackgroundThis short report arose from a follow-up study of children previously diagnosed with human immunodeficiency virus (HIV) encephalopathy and spastic diplegia and is among the first to describe that increased lower limb muscle tone in children with a confirmed HIV encephalopathy diagnosis may resolve over time in some cases.ResultsOf 19 children previously diagnosed with HIV encephalopathy and increased lower limb muscle tone, some were found to have resolved muscle tone abnormalities during a follow-up physical examination [resolved group, n=13, median age 9years 7months (interquartile range 7years 3months–10years 9months)] whereas others continued to show increased lower limb muscle tone at follow-up [unresolved group, n=6 median age 8years 6months (interquartile range 7years 9months–9years 7months)]. A review of clinical records showed no significant differences in age or follow-up time between the resolved and unresolved groups. However, the unresolved group appeared to have severe disease at an earlier age than the resolved group, based on the age at antiretroviral treatment initiation [median age at start of treatment 2years 3months (interquartile range 7months–5years 3months) vs. 8months (interquartile range 6–12months), p=0.08] and had more severe neurological signs at the initial assessment.ConclusionsIt is anticipated that this information may be of immediate value to those involved in the treatment of children with HIV encephalopathy and increased lower limb muscle tone whilst awaiting the outcome of future controlled clinical trials

Expression of the Wilms' tumor gene WT1 in human malignant mesothelioma cell lines and relationship to platelet-derived growth factor A and insulin- like growth factor 2 expression

Mutations in the WT1 tumor suppressor gene are known to contribute to the development of Wilms' tumor (WT) and associated gonadal abnormalities. WT1 is expressed principally in the fetal kidney, developing gonads, and spleen and also in the mesothelium, which lines the coelomic cavities. These tissues develop from mesenchymal components that have subsequently become epithelialized, and it has therefore been proposed that WT1 may play a role in this transition of cell types. To test the possible involvement of this gene in malignant mesothelioma, we have first studied its expression in a panel of human normal and malignant mesothelial cell lines. WT1 mRNA expression levels varied greatly between the cell lines and no specific chromosomal aberration on 11p, which could be related to the variation in WT1 expression in these cell lines, was observed. Furthermore, no gross deletions, rearrangements, or functionally inactivating point mutations in the WT1 coding region were identified. All four WT1 splice variants were observed at similar levels in these cell lines. The WT1 gene encodes a zinc-finger transcription factor and the four protein isoforms are each believed to act as transcriptional repressors of certain growth factor genes. Lack of WT1 expression is thus predicted to result in growth stimulation of tumor cells. Binding of one particular WT1 isoform construct to the insulin-like growth factor 2 (IGF2) and platelet-derived growth factor A (PDGFA) gene promoters has been demonstrated to result in repression of these genes in transient transfection studies. Analysis of IGF2 and PDGFA mRNA expression levels compared with WT1 mRNA expression levels failed to demonstrate an inverse correlation in the mesothelial cell lines, which endogenously express these genes. Finally, the putative role of WT1 in the transition of cell types was investigated. No obvious correlation between WT1 expression levels and cell morphology of the malignant mesothelial cell lines was evident from this study. Moreover, no change in WT1 expression was observed in normal mesothelial cells which were, by alteration of culture conditions, manipulated to switch from the mesenchymal to epithelial morphology

MB 700 Anthropology for Christian Mission

Textbook: Cultural Anthropology: An Applied Perspective, fifth edition by Gary Ferraro Readings: Anthropology and Christian Mission: A Reader, Darrell Whiteman (ed.)Customs and Cultures by Eugene Nidahttps://place.asburyseminary.edu/syllabi/2521/thumbnail.jp

Modeling Biological Pathway Dynamics With Timed Automata

Living cells are constantly subjected to a plethora of environmental stimuli that require integration into an appropriate cellular response. This integration takes place through signal transduction events that form tightly interconnected networks. The understanding of these networks requires to capture their dynamics through computational support and models. ANIMO (Analysis of Networks with Interactive MOdelling) is a tool that enables construction and exploration of executable models of biological networks, helping to derive hypotheses and to plan wet-lab experiments. The tool is based on the formalism of Timed Automata, which can be analysed via the UPPAAL model checker. Thanks to Timed Automata, we can provide a formal semantics for the domain-specific language used to represent signalling networks. This enforces precision and uniformity in the definition of signalling pathways, contributing to the integration of isolated signalling events into complex network models. We propose an approach to discretization of reaction kinetics that allows us to efficiently use UPPAAL as the computational engine to explore the dynamic behaviour of the network of interest. A user-friendly interface hides the use of Timed Automata from the user, while keeping the expressive power intact. Abstraction to single-parameter kinetics speeds up construction of models that remain faithful enough to provide meaningful insight. The resulting dynamic behaviour of the network components is displayed graphically, allowing for an intuitive and interactive modelling experience

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality

Lack of common TCRA and TCRB clonotypes in CD8+/ TCRαβ+ T-cell large granular lymphocyte leukemia: A review on the role of antigenic selection in the immunopathogenesis of CD8+ T-LGL

Clonal CD8 +/T-cell receptor (TCR)αβ+ T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the pathogenesis of this disorder. In the present study, we explored the association between expanded TCR-Vβ and TCR-V clonotypes in a cohort of 26 CD8 +/TCRαβ + T-LGL leukemia patients, in conjunction with the HLA-ABC genotype, to find indications for common antigenic stimuli. In addition, we applied purpose-built sophisticated computational tools for an in-depth evaluation of clustering of TCRβ (TCRB) complementarity determining region 3 (CDR3) amino-acid LGL clonotypes. We observed a lack of clear TCRA and TCRB CDR3 homology in CD8 +/ TCRαβ + T-LGL, with only low level similarity between small numbers of cases. This is in strong contrast to the homology that is seen in CD4 +/TCRβ + T-LGL and TCRγδ + T-LGL and thus underlines the idea that the LGL types have different etiopathogenesis. The heterogeneity of clonal CD8 +/ TCRαβ + T-LGL proliferations might in fact suggest that multiple pathogens or autoantigens are involved