For this reason, missense variants are assigned a value for their likelihood of

Therefore, to determine if these dif ferences in expression profiles are important, the change in the mean number of tokens per node at the 20th time point, compared to the baseline, was considered for CRKL up buy JNJ-7706621 or down regulated. This enables one to further understand the affect that perturbing CRKL has on its neighbours. These differences are summarised in columns 5 and 6 of Table 1, which shows the most statistically signifi cantly changed nodes. Knowing that down regulation of CRKL is of interest, as the gene appears to be up regulated in RA, few words are necessary to discuss the case of ABL1, which was shown to be statistically significant only when CRKL was up regulated: ABL1 is a well known part of the network of interactions of CRKL, with its activity contributing to the phosphorylation and therefore activation of CRKL.<br><br> The computational result indicating that ABL1 appears to be significantly affected by the enhanced activity of CRKL, but not by the reverse, is clearly interpretable in purchase LDN193189 biological terms as ABL1 is, in a physiological condition, a trigger of CRKL activity. Therefore, CRKL activation is necessarily due to phosphorylation, requiring ABL1 to display significant levels of activity, Conversely in our scenario, inhibition of CRKL is forced from outside the network with the token depletion that mimics the possible inhibitory activity of a novel drug.<br><br> If this were to be done directly on CRKL, indeed inhibition of ABL1 would not be relevant, However, despite the smooth interpret ation of this LY2228820 particular result, we wish to warn potential users of our approach in that such situations can, in some cases, be ambiguous and possibly interpretable as unreliable, As always, computational results, obtained by more or less simplified modelling of the bio logical reality, require manually curated biological interpretation. For CRKL down regulated, we investigate the following further: RAP1B, RAPGEF1, PXN and RHOQ. The known inter actions among these four molecules indicate that PXN phosphorylation activates CRKL, which triggers the RAS and JUN pathways involved in cytoskeleton remodelling and cell adhesion, Considering first the central mol ecule in this sub network, we observed that no compound was listed in as being able to target the gene of interest.<br><br> Since RHOQ and RAP1B are dir ectly connected to RAPGEF1 in the activation of GTPases we concentrated our efforts around PXN and CRKL to identify overlapping compounds for discussion. CRKL is associated with a number of pathways, for in stance the MAPK signalling pathway, chronic myeloid leukaemia and regulation of the actin cytoskeleton path way. Most of these pathways are related to immune and inflammation reactions. However, as far as searching Pharmacogenomics Knowledge Base website we found no evidence to suggest that CRKL is being used as a drug target. In the following we therefore discuss the implication of CRKL down regulation only, as this is relevant to our original goal of identifying CRKL as pos sible drug target in RA. CRKL is activated by phosphorylation and PXN binds to CRKL once phosphorylated.