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Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach
We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation
Controle de plantas daninhas na cultura do algodoeiro (Gossypium hirsutum L.) em solo anteriormente ocupado por vegetação de Cerrado
Central Bank Intervention, Sterilization and Monetary Independence: The Case of Pakistan
Nutritional therapies for mental disorders
According to the Diagnostic and Statistical Manual of Mental Disorders, 4 out of the 10 leading causes of disability in the US and other developed countries are mental disorders. Major depression, bipolar disorder, schizophrenia, and obsessive compulsive disorder (OCD) are among the most common mental disorders that currently plague numerous countries and have varying incidence rates from 26 percent in America to 4 percent in China. Though some of this difference may be attributable to the manner in which individual healthcare providers diagnose mental disorders, this noticeable distribution can be also explained by studies which show that a lack of certain dietary nutrients contribute to the development of mental disorders. Notably, essential vitamins, minerals, and omega-3 fatty acids are often deficient in the general population in America and other developed countries; and are exceptionally deficient in patients suffering from mental disorders. Studies have shown that daily supplements of vital nutrients often effectively reduce patients' symptoms. Supplements that contain amino acids also reduce symptoms, because they are converted to neurotransmitters that alleviate depression and other mental disorders. Based on emerging scientific evidence, this form of nutritional supplement treatment may be appropriate for controlling major depression, bipolar disorder, schizophrenia and anxiety disorders, eating disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), addiction, and autism. The aim of this manuscript is to emphasize which dietary supplements can aid the treatment of the four most common mental disorders currently affecting America and other developed countries: major depression, bipolar disorder, schizophrenia, and obsessive compulsive disorder (OCD)
Statistical Evaluation of Diluents and Automatic Diluting and Pipetting Machines in Influenza Serology
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