18 research outputs found
Protein Scaffolds Can Enhance the Bistability of Multisite Phosphorylation Systems
The phosphorylation of a substrate at multiple sites is a common protein modification that can give rise to important structural and electrostatic changes. Scaffold proteins can enhance protein phosphorylation by facilitating an interaction between a protein kinase enzyme and its target substrate. In this work we consider a simple mathematical model of a scaffold protein and show that under specific conditions, the presence of the scaffold can substantially raise the likelihood that the resulting system will exhibit bistable behavior. This phenomenon is especially pronounced when the enzymatic reactions have sufficiently large KM, compared to the concentration of the target substrate. We also find for a closely related model that bistable systems tend to have a specific kinetic conformation. Using deficiency theory and other methods, we provide a number of necessary conditions for bistability, such as the presence of multiple phosphorylation sites and the dependence of the scaffold binding/unbinding rates on the number of phosphorylated sites
Bone refilling in cortical bone multicellular units: Insights into tetracycline double labelling from a computational model
Bone remodelling is carried out by `bone multicellular units' (BMUs) in which
active osteoclasts and active osteoblasts are spatially and temporally coupled.
The refilling of new bone by osteoblasts towards the back of the BMU occurs at
a rate that depends both on the number of osteoblasts and on their secretory
activity. In cortical bone, a linear phenomenological relationship between
matrix apposition rate (MAR) and BMU cavity radius is found experimentally. How
this relationship emerges from the combination of complex, nonlinear
regulations of osteoblast number and secretory activity is unknown.
Here, we extend our previous mathematical model of cell development within a
single BMU to investigate how osteoblast number and osteoblast secretory
activity vary along the BMU's closing cone. MARs predicted by the model are
compared with data from tetracycline double labelling experiments. We find that
the linear phenomenological relationship observed in these experiments between
MAR and BMU cavity radius holds for most of the refilling phase simulated by
our model, but not near the start and end of refilling. This suggests that at a
particular bone site undergoing remodelling, bone formation starts and ends
rapidly. Our model also suggests that part of the observed cross-sectional
variability in tetracycline data may be due to different bone sites being
refilled by BMUs at different stages of their lifetime. The different stages of
a BMU's lifetime depend on whether the cell populations within the BMU are
still developing or have reached a quasi-steady state while travelling through
bone. We find that due to their longer lifespan, active osteoblasts reach a
quasi-steady distribution more slowly than active osteoclasts. We suggest that
this fact may locally enlarge the Haversian canal diameter (due to a local lack
of osteoblasts compared to osteoclasts) near the BMU's point of origin.Comment: 16 pages, 6 figures, 3 tables. V3: minor changes: added 2 paragraphs
(BMU cavity in Section 2 and Model Robustness in Section 4), references
[52,54
Quercetin and hyperthermia modulate cisplatin-induced DNA damage in tumor and normal tissues in vivo
Tissue, cell and stage specificity of (epi)mutations in cancers.
Most (epi)mutations in cancers are specific to particular tumours or occur at specific stages of development, cell differentiation or tumorigenesis. Simple molecular mechanisms, such as tissue-restricted gene expression, seem to explain these associations only in rare cases. Instead, the specificity of (epi)mutations is probably due to the selection of a restricted spectrum of genetic changes by the cellular environment. In some cases, the resulting functional defects might be constrained to be neither too strong nor too weak for tumour growth to occur; that is, they lie within a 'window' that is permissive for tumorigenesis