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Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications Udgivelsesdato: 2008/6/15

Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications Udgivelsesdato: 2008/6/15

A model health and safety programme was designed at a coal mining company and a gold mining company. The model programme was implemented primarily by providing training on loss control, accident investigation, and operation of mobile equipment; and by providing technical assistance to help solve health and safety problems. Data was obtained from company records on occupational injuries, illnesses, accidents and "near misses"; and through direct observation of employees performing a large number of randomly selected jobs. At the coal mine, employees were observed five times over a 15-month period. At the gold mine, employees were observed six times over a 16-month. During the study, the percentage of sampled jobs containing one or more safety deficiences decreased from 74.3% to 36.6% at the coal mine and 86.4% to 19.1% at the gold mine., A model health and safety programme was designed at a coal mining company and a gold mining company. The model programme was implemented primarily by providing training on loss control, accident investigation, and operation of mobile equipment; and by providing technical assistance to help solve health and safety problems. Data was obtained from company records on occupational injuries, illnesses, accidents and "near misses"; and through direct observation of employees performing a large number of randomly selected jobs. At the coal mine, employees were observed five times over a 15-month period. At the gold mine, employees were observed six times over a 16-month. During the study, the percentage of sampled jobs containing one or more safety deficiences decreased from 74.3% to 36.6% at the coal mine and 86.4% to 19.1% at the gold mine.