Modeling and Analysis of the Molecular Basis of Pain in Sensory Neurons

Intracellular calcium dynamics are critical to cellular functions like pain transmission. Extracellular ATP plays an important role in modulating intracellular calcium levels by interacting with the P2 family of surface receptors. In this study, we developed a mechanistic mathematical model of ATP-induced P2 mediated calcium signaling in archetype sensory neurons. The model architecture, which described 90 species connected by 162 interactions, was formulated by aggregating disparate molecular modules from literature. Unlike previous models, only mass action kinetics were used to describe the rate of molecular interactions. Thus, the majority of the 252 unknown model parameters were either association, dissociation or catalytic rate constants. Model parameters were estimated from nine independent data sets taken from multiple laboratories. The training data consisted of both dynamic and steady-state measurements. However, because of the complexity of the calcium network, we were unable to estimate unique model parameters. Instead, we estimated a family or ensemble of probable parameter sets using a multi-objective thermal ensemble method. Each member of the ensemble met an error criterion and was located along or near the optimal trade-off surface between the individual training data sets. The model quantitatively reproduced experimental measurements from dorsal root ganglion neurons as a function of extracellular ATP forcing. Hypothesized architecture linking phosphoinositide regulation with P2X receptor activity explained the inhibition of P2X-mediated current flow by activated metabotropic P2Y receptors. Sensitivity analysis using individual and the whole system outputs suggested which molecular subsystems were most important following P2 activation. Taken together, modeling and analysis of ATP-induced P2 mediated calcium signaling generated qualitative insight into the critical interactions controlling ATP induced calcium dynamics. Understanding these critical interactions may prove useful for the design of the next generation of molecular pain management strategies

Qualidade de kiwis minimamente processados e submetidos a tratamento com ácido ascórbico, ácido cítrico e cloreto de cálcio Quality of kiwis minimally processed and treated with ascorbic acid, citric acid and calcium chloride

Frutos e hortaliças minimamente processados devem apresentar atributos de conveniência e qualidade do produto fresco. O objetivo deste trabalho foi estudar o efeito do processamento mínimo de frutos tratados com soluções a 1% de ácido ascórbico, ácido cítrico e cloreto de cálcio, durante armazenamento refrigerado, na qualidade do kiwi (Actinidia deliciosa cv. Hayward). A perda de massa foi mínima durante o período de armazenamento. O ácido ascórbico fornecido pelo tratamento foi eficientemente absorvido pelos tecidos, mantendo os níveis de vitamina C cerca de 25% mais elevados nesses frutos do que nos demais tratamentos. A análise microbiológica detectou presença de bolores e leveduras e psicrotróficos, somente no tratamento com ácido cítrico, aos 8 e 10 dias, respectivamente. Não se detectaram coliformes totais e fecais e mesófilos, o que indica que o processamento foi realizado em boas condições higiênicas. Os kiwis minimamente processados e tratados com cloreto de cálcio apresentaram uma vida útil de dez dias. Nos demais tratamentos e no controle, esse tempo foi de seis dias.<br>Minimally processed fruits and vegetables might present the same convenience and quality of fresh products. In this work, the influence of minimal processing of fruits treated with 1% solutions of ascorbic acid, citric acid and calcium chloride on the quality of kiwi (Actinidia deliciosa cv. Hayward), during refrigerated storage were investigated. Mass loss was minimal over the storage period. Ascorbic acid furnished by the treatment was effectively absorbed by tissues, keeping the vitamin C levels 25% higher in those fruits, than in other treatments. Microbiological analysis detected the presence of the group molds and yeasts and psychrotrophic in citric acid treatment, at 8 and 10 days, respectively. Total and faecal coliforms and mesophyles were not found, indicating that processing was performed under good hygienic conditions. Minimally processed and calcium chloride treated kiwis presented a tenday shelflife. For other treatments and for control, shelflife was six days