Quantifying the phosphorylation timescales of receptor-ligand complexes: a Markovian matrix-analytic approach.

Cells interact with the extracellular environment by means of receptor molecules on their surface. Receptors can bind different ligands, leading to the formation of receptor-ligand complexes. For a subset of receptors, called receptor tyrosine kinases, binding to ligand enables sequential phosphorylation of intra-cellular residues, which initiates a signalling cascade that regulates cellular function and fate. Most mathematical modelling approaches employed to analyse receptor signalling are deterministic, especially when studying scenarios of high ligand concentration or large receptor numbers. There exist, however, biological scenarios where low copy numbers of ligands and/or receptors need to be considered, or where signalling by a few bound receptor-ligand complexes is enough to initiate a cellular response. Under these conditions stochastic approaches are appropriate, and in fact, different attempts have been made in the literature to measure the timescales of receptor signalling initiation in receptor-ligand systems. However, these approaches have made use of numerical simulations or approximations, such as moment-closure techniques. In this paper, we study, from an analytical perspective, the stochastic times to reach a given signalling threshold for two receptor-ligand models. We identify this time as an extinction time for a conveniently defined auxiliary absorbing continuous time Markov process, since receptor-ligand association/dissociation events can be analysed in terms of quasi-birth-and-death processes. We implement algorithmic techniques to compute the different order moments of this time, as well as the steady-state probability distribution of the system. A novel feature of the approach introduced here is that it allows one to quantify the role played by each kinetic rate in the timescales of signal initiation, and in the steady-state probability distribution of the system. Finally, we illustrate our approach by carrying out numerical studies for the vascular endothelial growth factor and one of its receptors, the vascular endothelial growth factor receptor of human endothelial cells.

Pain assessment during outpatient hysteroscopy using room temperature versus warm normal saline solution as a distention medium - a prospective randomized study.

OBJECTIVE: To assess the efficacy of warm normal saline distention solution versus a standard, room-temperature normal saline as distention medium for pain relief during outpatient hysteroscopy. MATERIALS AND METHODS: A prospective randomized case-placebo controlled study was conducted in tertiary care centre - Central Clinical Hospital of Ministry of Interior and Administration. Study group consisted of 100 women referred for outpatient hysteroscopy between January 2015 and July 2015. Every patient, who was referred for an office hysteroscopy, was offered to participate in the study to receive a sterile, 0.9% normal saline warmed up to 36°C as distention medium. Control group were women receiving sterile, room temperature of 25°C, 0.9% normal saline solution as a distention medium. No pre-medication nor analgesia were used. A visual analogue scale (VAS) was used for one-dimensional pain assessment. Women were asked to mark a VAS score before, during, and five and 15 minutes following the procedure. RESULTS: Median VAS scores during and directly after the anaesthesia-free hysteroscopy were no different between two groups. (p = 0.554 and p = 0.121, respectively). There were also no differences in the procedure time between groups (p = 0.845). CONCLUSIONS: Warm normal saline distention solution does not reduce the pain during and at the end of the outpatient hysteroscopy. The effect does not depend on the age of women, menopausal status, parity or type of outpatient hysteroscopy (operative or diagnostic).