RESUMO
Maintaining the optimal performance of cell processes and organelles is the task of auto-regulatory systems. Here we describe an auto-regulatory device that helps to maintain homeostasis of the endoplasmic reticulum (ER) by adjusting the secretory flux to the cargo load. The cargo-recruiting subunit of the coatomer protein II (COPII) coat, Sec24, doubles as a sensor of folded cargo and, upon cargo binding, acts as a guanine nucleotide exchange factor to activate the signaling protein Gα12 at the ER exit sites (ERESs). This step, in turn, activates a complex signaling network that activates and coordinates the ER export machinery and attenuates proteins synthesis, thus preventing large fluctuations of folded and potentially active cargo that could be harmful to the cell or the organism. We call this mechanism AREX (autoregulation of ER export) and expect that its identification will aid our understanding of human physiology and diseases that develop from secretory dysfunction.
Assuntos
Retículo Endoplasmático/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Transporte Biológico , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/fisiologia , Linhagem Celular , Proteína Coatomer/metabolismo , Retículo Endoplasmático/fisiologia , Estresse do Retículo Endoplasmático/fisiologia , Feminino , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Complexo de Golgi/metabolismo , Fatores de Troca do Nucleotídeo Guanina/fisiologia , Células HeLa , Humanos , Masculino , Dobramento de Proteína , Transporte Proteico , Proteostase/fisiologia , Transdução de SinaisRESUMO
To describe the epidemiology of X-linked recessive diseases we developed a discrete time, structured, non linear mathematical model. The model allows for de novo mutations (i.e. affected sibling born to unaffected parents) and selection (i.e., distinct fitness rates depending on individual's health conditions). Applying Lyapunov direct method we found the domain of attraction of model's equilibrium point and studied the convergence properties of the degenerate equilibrium where only affected individuals survive.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Modelos Genéticos , Modelos Teóricos , Alelos , Cromossomos Humanos X , Feminino , Humanos , Masculino , Polimorfismo GenéticoRESUMO
We adopt the second Liapunov method to derive stability property of the equilibrium point in a non linear, discrete time, positive system, modeling the inheritance pattern of X-chromosome linked recessive diseases in the human population. By constructing a Liapunov function we derive globally asymptotically stable properties of the non trivial equilibrium point.
Assuntos
Genes Recessivos/genética , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genética Populacional , Modelos Genéticos , Simulação por Computador , Feminino , Humanos , Incidência , Masculino , Modelos de Riscos Proporcionais , Medição de RiscoRESUMO
BACKGROUND: Ribavirin administration for chronic hepatitis C is associated with the development of haemolytic anaemia, which affects treatment efficacy and tolerability. In a pilot study, the exogenous administration of erythropoietin has been shown to be beneficial, reducing the rate of ribavirin dose reduction. How ribavirin administration affects normal erythropoietin production has not been determined. AIM: To investigate the endogenous erythropoietin response in hepatitis C patients with ribavirin-induced anaemia. METHODS: Serum erythropoietin was measured before and during interferon-ribavirin treatment in 18 HCV-positive subjects. Mathematical analysis and modelling were applied to compare the degree of erythropoietin increase in HCV-positive and in otherwise healthy anaemic patients, and estimate the endogenous excess erythropoietin production in response to ribavirin-induced anaemia. RESULTS: Erythropoietin concentration increased significantly in response to anaemia caused by ribavirin. The physiological erythropoietin response to the ribavirin-induced anaemia was as adequate in HCV-positive subjects as it is in anaemic subjects without liver disease. The recommended exogenous erythropoietin dose appears three-times greater than the endogenous erythropoietin boost. CONCLUSION: Chronic liver damage by HCV does not affect the physiological erythropoietin response to ribavirin-induced anaemia. While the rationale for erythropoietin treatment of ribavirin-induced anaemia is not straightforward, the currently recommended dosing regimen should be reassessed.
