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11.
Background
Most mathematical models of biochemical pathways consider either signalling events that take place within a single cell in isolation, or an 'average' cell which is considered to be representative of a cell population. Likewise, experimental measurements are often averaged over populations consisting of hundreds of thousands of cells. This approach ignores the fact that even within a genetically-homogeneous population, local conditions may influence cell signalling and result in phenotypic heterogeneity. We have developed a multi-scale computational model that accounts for emergent heterogeneity arising from the influences of intercellular signalling on individual cells within a population. Our approach was to develop an ODE model of juxtacrine EGFR-ligand activation of the MAPK intracellular pathway and to couple this to an agent-based representation of individual cells in an expanding epithelial cell culture population. This multi-scale, multi-paradigm approach has enabled us to simulate Extracellular signal-regulated kinase (Erk) activation in a population of cells and to examine the consequences of interpretation at a single cell or population-based level using virtual assays.Results
A model consisting of a single pair of interacting agents predicted very different Erk activation (phosphorylation) profiles, depending on the formation rate and stability of intercellular contacts, with the slow formation of stable contacts resulting in low but sustained activation of Erk, and transient contacts resulting in a transient Erk signal. Extension of this model to a population consisting of hundreds to thousands of interacting virtual cells revealed that the activated Erk profile measured across the entire cell population was very different and may appear to contradict individual cell findings, reflecting heterogeneity in population density across the culture. This prediction was supported by immunolabelling of an epithelial cell population grown in vitro, which confirmed heterogeneity of Erk activation.Conclusion
These results illustrate that mean experimental data obtained from analysing entire cell populations is an oversimplification, and should not be extrapolated to deduce the signal:response paradigm of individual cells. This multi-scale, multi-paradigm approach to biological simulation provides an important conceptual tool in addressing how information may be integrated over multiple scales to predict the behaviour of a biological system. 相似文献12.
Vanheusden V Van Rompaey P Munier-Lehmann H Pochet S Herdewijn P Van Calenbergh S 《Bioorganic & medicinal chemistry letters》2003,13(18):3045-3048
The affinity of a series of 2', 3'- and 5-modified thymidine analogues for Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) was evaluated. The affinities of several non-phosphorylated analogues are in the same order of magnitude as those of their phosphorylated congeners. In view of drug delivery problems associated with phosphorylated compounds, these 'free' nucleosides seem more promising leads in the search of TMPKmt inhibitors as novel anti-tuberculosis agents. 相似文献
13.
Juliano Timm Ingrid Van Rompaey Catherine Tricot Marc Massaer Françoise Haeseleer Alan Fauconnier Victor Stalon Alex Bollen Paul Jacobs 《Molecular & general genetics : MGG》1992,234(3):475-480
Summary A genomic library of Mycobacterium bovis BCG has been constructed by cloning DNA partially digested with Sau3A into the Escherichia coli expression vector pAS1. The gene coding for ornithine carbamoyltransferase (EC.2.1.3.3 ; OTCase), hereafter referred to as argF, was isolated from the library by complementation of a double argF-argI mutant of E. coli and its sequence was determined. The translation initiation codon used, GTG, was identified by comparing the amino acid sequence deduced from the gene with the N-terminal sequence of the corresponding purified protein. On this basis, the M. bovis BCG OTCase monomer consists of 307 amino acid residues and displays about 44% identity with other OTCases, the most closely related homologue being the anabolic enzyme of Pseudomonas aeruginosa. The native enzyme has an estimated molecular mass of 110 kDa, suggesting a trimeric structure as is the case for most of the anabolic OTCases known from various organisms. 相似文献
14.
Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. 总被引:22,自引:0,他引:22
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J Schwaller J Frantsve J Aster I R Williams M H Tomasson T S Ross P Peeters L Van Rompaey R A Van Etten R Ilaria Jr P Marynen D G Gilliland 《The EMBO journal》1998,17(18):5321-5333
Recent reports have demonstrated fusion of the TEL gene on 12p13 to the JAK2 gene on 9p24 in human leukemias. Three variants have been identified that fuse the TEL pointed (PNT) domain to (i) the JAK2 JH1-kinase domain, (ii) part of and (iii) all of the JH2 pseudokinase domain. We report that all of the human TEL/JAK2 variants, and a human/mouse chimeric hTEL/mJAK2(JH1) fusion gene, transform the interleukin-3 (IL-3)-dependent murine hematopoietic cell line Ba/F3 to IL-3-independent growth. Transformation requires both the TEL PNT domain and JAK2 kinase activity. Furthermore, all TEL/JAK2 variants strongly activated STAT 5 by phosphotyrosine Western blots and by electrophoretic mobility shift assays (EMSA). Mice (n = 40) transplanted with bone marrow infected with the MSCV retrovirus containing either the hTEL/mJAK2(JH1) fusion or its human counterpart developed a fatal mixed myeloproliferative and T-cell lymphoproliferative disorder with a latency of 2-10 weeks. In contrast, mice transplanted with a TEL/JAK2 mutant lacking the TEL PNT domain (n = 10) or a kinase-inactive TEL/JAK2(JH1) mutant (n = 10) did not develop the disease. We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo- and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia. 相似文献
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16.
Jeroen Caremans Evert Hamans Ludo Muylle Paul Van de Heyning Vincent Van Rompaey 《Cell and tissue banking》2016,17(2):199-204
Allograft tympano-ossicular systems (ATOS) have proven their use over many decades in tympanoplasty and reconstruction after resection of cholesteatoma. The transcranial bone plug technique has been used in the past 50 years to procure en bloc ATOS (tympanic membrane with malleus, incus and stapes attached). Recently, our group reported the feasibility of the endoscopic procurement technique. The aim of this study was to assess whether clinical outcome is equivalent in ATOS acquired by using the endoscopic procurement technique compared to ATOS acquired by using the transcranial technique. A double-blind randomized controlled audit was performed in a tertiary referral center in patients that underwent allograft tympanoplasty because of chronic otitis media with and without cholesteatoma. Allograft epithelialisation was evaluated at the short-term postoperative visit by microscopic examination. Failures were reported if reperforation was observed. Fifty patients underwent allograft tympanoplasty: 34 received endoscopically procured ATOS and 16 received transcranially procured ATOS. One failed case was observed, in the endoscopic procurement group. We did not observe a statistically significant difference between the two groups in failure rate. This study demonstrates equivalence of the clinical outcome of allograft tympanoplasty using either endoscopic or transcranial procured ATOS and therefore indicates that the endoscopic technique can be considered the new standard procurement technique. Especially because the endoscopic procurement technique has several advantages compared to the former transcranial procurement technique: it avoids risk of prion transmission and it is faster while lacking any noticeable incision. 相似文献
17.
Cosyn L Gao ZG Van Rompaey P Lu C Jacobson KA Van Calenbergh S 《Bioorganic & medicinal chemistry》2006,14(5):1403-1412
We investigated the A(3)AR affinity and selectivity of a series of 2-substituted 3'-azido and 3'-amino adenosine derivatives as well as some 5'-uronamide derivatives thereof. All compounds showed high A(3)AR selectivity. While the 3'-azides appeared to be A(3)AR antagonists with moderate A(3)AR affinity, their 3'-amino congeners exhibit significantly improved A(3)AR affinity and behave as partial agonists. For both the 3'-azides and the 3'-amines, the 5'-methylcarbamoyl modification improved the overall affinity. Introduction of a 2-phenylethynyl substituent provided high affinity for the A(3)AR. 相似文献
18.
Nandakumar KV Karthickeyan Duraisamy Shibu Balakrishnan Sunilkumar M Jaya Sankar S Karuna D. Sagili Srinath Satyanarayana Ajay Kumar MV Donald A. Enarson 《PloS one》2013,8(10)
Settings
Kerala State, India has reported the greatest dual burden of Tuberculosis (TB) and Diabetes Mellitus (DM). Malappuram district in Kerala has monitored and recorded DM status and its control from 2010 under Revised National Tuberculosis Control Program (RNTCP).Objectives
To assess, under programme conditions, comprehensiveness of recording DM status among TB cases and the TB treatment outcomes among DM patients (disaggregated by glycemic control) and compare with-non DM patients.Design
This retrospective record review included 3,116TB patients from April 2010 to September 2011.DM was defined as per international guidelines and TB treatment outcomes were categorized as favourable(cured and treatment completed) and unfavourable(death, default, failure and transfer out). Relative Risk (RR) and 95% confidence intervals(CI) were calculated to assess the risk of unfavourable outcomes.Results
DM status was recorded in 90% of TB cases and 667 (24%) had DM. 17% of DM patients and 23% of patients with unknown DM status had unfavourable outcomes but this difference was not statistically significant. Unadjusted RR for poor glycemic control or unknown control status for unfavourable outcome were (2.00; 95% CI 0.97–4.13) and (2.14; 95% CI 1.11–4.13).Conclusion
This study could not confirm an adverse association between DM or its control during treatment and the course of response to TB treatment.DM screening in TB cases and recording of DM care needs to be improved to enable more conclusive evidence. 相似文献19.
Van Rompaey P Jacobson KA Gross AS Gao ZG Van Calenbergh S 《Bioorganic & medicinal chemistry》2005,13(4):973-983
In this paper we investigated the influence on affinity, selectivity and intrinsic activity upon modification of the adenosine agonist scaffold at the 3'- and 5'-positions of the ribofuranosyl moiety and the 2- and N6-positions of the purine base. This resulted in the synthesis of various analogues, that is, 3-12 and 24-33, with good hA3AR selectivity and moderate-to-high affinities (as in 32, Ki=27 nM). Interesting was the ability to tune the intrinsic activity depending on the substituent introduced at the 3'-position. 相似文献
20.