Transcriptome correlation analysis identifies two unique craniosynostosis subtypes associated with IRS1 activation.

The discovery of causal mechanisms associated with nonsyndromic craniosynostosis has proven to be a difficult task due to the complex nature of the disease. In this study, differential transcriptome correlation analysis was used to identify two molecularly distinct subtypes of nonsyndromic craniosynostosis, termed subtype A and subtype B. In addition to unique correlation structure, subtype A was also associated with high IGF pathway expression, whereas subtype B was associated with high integrin expression. To identify a pathologic link between altered gene correlation/expression and the disease state, phosphorylation assays were performed on primary osteoblast cell lines derived from cases within subtype A or subtype B, as well as on primary osteoblast cell lines with novel IGF1R variants previously reported by our lab (Cunningham ML, Horst JA, Rieder MJ, Hing AV, Stanaway IB, Park SS, Samudrala R, Speltz ML. Am J Med Genet A 155A: 91-97, 2011). Elevated IRS1 (pan-tyr) and GSK3ß (ser-9) phosphorylation were observed in two novel IGF1R variants with receptor L domain mutations. In subtype A, a hypomineralization phenotype coupled with decreased phosphorylation of IRS1 (ser-312), p38 (thr-180/tyr-182), and p70S6K (thr-412) was observed. In subtype B, decreased phosphorylation of IRS1 (ser-312) as well as increased phosphorylation of Akt (ser-473), GSK3ß (ser-9), IGF1R (tyr-1135/tyr-1136), JNK (thr-183/tyr-187), p70S6K (thr-412), and pRPS6 (ser-235/ser-236) was observed, thus implicating the activation of IRS1-mediated Akt signaling in potentiating craniosynostosis in this subtype. Taken together, these results suggest that despite the stimulation of different pathways, activating phosphorylation patterns for IRS1 were consistent in cell lines from both subtypes and the IGF1R variants, thus implicating a key role for IRS1 in the pathogenesis of nonsyndromic craniosynostosis.

Work and rest variables in the acquisition of psychomotor tracking skill.

College students (75 men, 75 women) matched in preliminary performance of 100 sec on the rotary pursuit apparatus were randomly assigned to five experimental groups. Their work/rest ratios, measured in seconds, were: 20/20, 30/30, 60/60, 90/90,120/120. All subjects received 30 min of total practice time after the matching trial. There was a significant practice effect and a significant practice x conditions interaction, but no main effect due to the cycles' length or number. The decay rate of reactive inhibition (lr) is probably independent of its prior growth level; hence postrest residual lr is proportional to prerest accumulation. Partly because they generated lr in hypothetically greater amounts, women were significantly less proficient on the average than men, and sex interacted with practice. Although males had higher initial and final levels of ability than females, the two sexes' acquisition curves showed the same rate parameters in our mathematical model.

Pursuit tracking skill as a joint function of work and rest variables.

Early studies suggested that the effects of varying length of work period (TW) and duration of rest period (TR) are additive when TW and TR alternate and are constant within experimental conditions. Recent investigations indicate that the joint effect of these variables on performance depends on the ratio TW:TR. this ratio effect is not predicted by functions traditionally used to describe theoretical massing and distribution effects. Parabolic functions were suggested and were shown to describe reminiscence data adequately. College students were given 30 min, of rotary pursuit practice with 10- or 30-sec work periods alternating with 5-, 10-, or 30-sec rest intervals (n = 30 per group). Predictions that work and rest variables would have orthogonal effects while final performance levels could be described as a parabolic function of the ratio TW:TR were confirmed.

Interleukin 6 modulates c-sis gene expression in cultured human endothelial cells.

Human vascular endothelial cells secrete platelet-derived growth factor (PDGF)-like polypeptides which may mediate some of the vascular effects in the inflammatory process. We have demonstrated that IL-6 caused a significant increase in the mRNA level of the c-sis gene (PDGF B chain) in cultured human endothelial cells. IL-1 alpha and IL-1 beta also increased c-sis mRNA transcripts after an extended incubation period and both cytokines acted synergistically with IL-6 in increasing c-sis expression. Tumor necrosis factor enhanced the accumulation of c-sis mRNA and interferon-gamma decreased its level. In the inflammatory process specific cytokines can modulate c-sis expression in human endothelial cells. Their subsequent production of PDGF-like polypeptides could stimulate cell migration and proliferation, and cause the release of vascular inflammatory mediators.