Linear models of activation cascades: analytical solutions and coarse-graining of delayed signal transduction

Cellular signal transduction usually involves activation cascades, the sequential activation of a series of proteins following the reception of an input signal. Here we study the classic model of weakly activated cascades and obtain analytical solutions for a variety of inputs. We show that in the special but important case of optimal-gain cascades (i.e., when the deactivation rates are identical) the downstream output of the cascade can be represented exactly as a lumped nonlinear module containing an incomplete gamma function with real parameters that depend on the rates and length of the cascade, as well as parameters of the input signal. The expressions obtained can be applied to the non-identical case when the deactivation rates are random to capture the variability in the cascade outputs. We also show that cascades can be rearranged so that blocks with similar rates can be lumped and represented through our nonlinear modules. Our results can be used both to represent cascades in computational models of differential equations and to fit data efficiently, by reducing the number of equations and parameters involved. In particular, the length of the cascade appears as a real-valued parameter and can thus be fitted in the same manner as Hill coefficients. Finally, we show how the obtained nonlinear modules can be used instead of delay differential equations to model delays in signal transduction.Comment: 18 pages, 7 figure

Squeeze-and-Breathe Evolutionary Monte Carlo Optimisation with Local Search Acceleration and its application to parameter fitting

Motivation: Estimating parameters from data is a key stage of the modelling process, particularly in biological systems where many parameters need to be estimated from sparse and noisy data sets. Over the years, a variety of heuristics have been proposed to solve this complex optimisation problem, with good results in some cases yet with limitations in the biological setting. Results: In this work, we develop an algorithm for model parameter fitting that combines ideas from evolutionary algorithms, sequential Monte Carlo and direct search optimisation. Our method performs well even when the order of magnitude and/or the range of the parameters is unknown. The method refines iteratively a sequence of parameter distributions through local optimisation combined with partial resampling from a historical prior defined over the support of all previous iterations. We exemplify our method with biological models using both simulated and real experimental data and estimate the parameters efficiently even in the absence of a priori knowledge about the parameters.Comment: 15 Pages, 3 Figures, 6 Tables; Availability: Matlab code available from the authors upon reques

Health-related quality of life and health care resource utilization in COPD patients: A comparison of three instruments

This study involved comparison of the generic SF-36 questionnaire with two COPD-specific questionnaires, St. George\u27s Respiratory Questionnaire (SGRQ), and the Chronic Respiratory Disease Questionnaire (CRDQ), using health care resource data, and considering a managed care perspective. The major research questions addressed were: (1) How do the results from three commonly used generic and disease-specific health-related quality of life (HRQOL) instruments vary when administered to a sample of COPD patients? (2) Which of the three scales (generic/disease-specific) correlates most closely and best predicts overall health care resource utilization for the sample? (3) What is the effect of demographic factors on health care resource utilization after the effects of health status are controlled for? COPD patients from a local managed care organization were contacted and the three health-related quality of life questionnaires were administered via telephone at two time points with a three-month interval between the two. Health care utilization data for the three-month periods prior to each interview were obtained at both times from the HMO medical records database. The net response rate was 24.3 percent. The sample, in general, consisted of middle-income patients in the age range of 41 to 71 years, many having COPD for more than five years, and having a number of comorbidities. All three instruments provided similar results with respect to health status of the patient sample with negligible improvements in the second time interval. In general, the sample had poor physical health and somewhat better mental health status. All health care resource utilization costs had large standard deviations with mean total utilization costs decreasing in the second time interval as compared to the first. Among all three instruments, the SF-36 was the instrument that best predicted the highest proportion of variation in many of the health care utilization measures. The aggregate scores such as the summary scores of the SF-36, and the total score of the SGRQ did not perform as well as the complete instruments with respect to predicting health care utilization. Demographic factors, in general, did not have much of an impact on utilization after the effects of health status were controlled for

Function of hybrid histidine kinases in Arabidopsis flagellin-mediated defence responses

In plants, the first line of microbial recognition relies on the perception of pathogen-associated molecular patterns (PAMPs) allowing plants to detect microorganisms and respond with a set of basal defence responses. The best studied PAMP is flagellin, the main protein component of bacterial flagella. The sensor histidine kinase AHK5 has been shown to play a novel role in mediating flagellin-induced stomatal closure. AHK5 belongs to a family of 9 Arabidopsis hybrid-histidine kinases (HKs). To further investigate the role of such HKs in flagellin-induced signal transduction, physiological responses to the flagellin derived peptide flg22 were examined in available hybrid HK mutant lines. Seedlings of the ethylene insensitive HK ETR1 mutant (etr1-1) showed dramatically reduced flg22 sensitivity as assayed by flg22-mediated seedling growth inhibition. A novel role for the hormone ethylene in flg22-mediated growth inhibition was thus identified. Conversely enhanced sensitivity to low concentrations of flg22 was observed in the AHK2 cytokinin receptor mutant (ahk2-2). However, the absence of flg22-associated growth phenotype in other cytokinin receptor mutants would suggest the role of AHK2 in flg22-mediated seedling growth inhibition may be independent of its role in cytokinin perception. Despite a wild-type sensitivity in aerial plant tissues, distinct flg22-mediated root growth arrest phenotypes were observed in plants defective in the HKs ETR1 and AHK5. Dissection of the mechanisms underlying flg22-mediated root growth inhibition led to the identification of nitric oxide and the ethylene precursor ACC as key secondary messengers. Further characterisation of etr1 mutants showed that, in addition to seedling growth inhibition, ethylene perception is also required for flg22-mediated callose deposition however surprisingly, does not appear to be a requirement for flg22-mediated bacterial immunity. Despite the known requirement for AHK5 in flg22-mediated stomatal closure, flg22-mediated post-invasive bacterial defences were found to be intact in ahk5-1 mutant plants. In summary this study has shown that ethylene perception via the ethylene receptor HK family plays an integral part in flg22-mediated signalling. In addition, organ/tissue specific functions for three of the nine hybrid kinases, AHK2, AHK5 and ETR1 in flg22-mediated signal transduction have been identified.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Function of hybrid histidine kinases in Arabidopsis flagellin-mediated defence responses

In plants, the first line of microbial recognition relies on the perception of pathogen-associated molecular patterns (PAMPs) allowing plants to detect microorganisms and respond with a set of basal defence responses. The best studied PAMP is flagellin, the main protein component of bacterial flagella. The sensor histidine kinase AHK5 has been shown to play a novel role in mediating flagellin-induced stomatal closure. AHK5 belongs to a family of 9 Arabidopsis hybrid-histidine kinases (HKs). To further investigate the role of such HKs in flagellin-induced signal transduction, physiological responses to the flagellin derived peptide flg22 were examined in available hybrid HK mutant lines. Seedlings of the ethylene insensitive HK ETR1 mutant (etr1-1) showed dramatically reduced flg22 sensitivity as assayed by flg22-mediated seedling growth inhibition. A novel role for the hormone ethylene in flg22-mediated growth inhibition was thus identified. Conversely enhanced sensitivity to low concentrations of flg22 was observed in the AHK2 cytokinin receptor mutant (ahk2-2). However, the absence of flg22-associated growth phenotype in other cytokinin receptor mutants would suggest the role of AHK2 in flg22-mediated seedling growth inhibition may be independent of its role in cytokinin perception. Despite a wild-type sensitivity in aerial plant tissues, distinct flg22-mediated root growth arrest phenotypes were observed in plants defective in the HKs ETR1 and AHK5. Dissection of the mechanisms underlying flg22-mediated root growth inhibition led to the identification of nitric oxide and the ethylene precursor ACC as key secondary messengers. Further characterisation of etr1 mutants showed that, in addition to seedling growth inhibition, ethylene perception is also required for flg22-mediated callose deposition however surprisingly, does not appear to be a requirement for flg22-mediated bacterial immunity. Despite the known requirement for AHK5 in flg22-mediated stomatal closure, flg22-mediated post-invasive bacterial defences were found to be intact in ahk5-1 mutant plants. In summary this study has shown that ethylene perception via the ethylene receptor HK family plays an integral part in flg22-mediated signalling. In addition, organ/tissue specific functions for three of the nine hybrid kinases, AHK2, AHK5 and ETR1 in flg22-mediated signal transduction have been identified.EThOS - Electronic Theses Online ServiceGBUnited Kingdo