Protein Kinase A (PKA) is the major receptor for the cyclic adenosine monophosphate (cAMP) secondary messenger in eukaryotes. cAMP binds to two tandem cAMP-binding domains (CBD-A and -B) within the regulatory subunit of PKA (R), unleashing the activity of the catalytic subunit (C). While CBD-A in RIα is required for PKA inhibition and activation, CBD-B functions as a “gatekeeper” domain that modulates the control exerted by CBD-A. Preliminary evidence suggests that CBD-B dynamics are critical for its gatekeeper function. To test this hypothesis, here we investigate by Nuclear Magnetic Resonance (NMR) the two-domain construct RIα (91–379) in its apo, cAMP2, and C-bound forms. Our comparative NMR analyses lead to a double conformational selection model in which each apo CBD dynamically samples both active and inactive states independently of the adjacent CBD within a nearly degenerate free energy landscape. Such degeneracy is critical to explain the sensitivity of CBD-B to weak interactions with C and its high affinity for cAMP. Binding of cAMP eliminates this degeneracy, as it selectively stabilizes the active conformation within each CBD and inter-CBD contacts, which require both cAMP and W260. The latter is contributed by CBD-B and mediates capping of the cAMP bound to CBD-A. The inter-CBD interface is dispensable for intra-CBD conformational selection, but is indispensable for full activation of PKA as it occludes C-subunit recognition sites within CBD-A. In addition, the two structurally homologous cAMP-bound CBDs exhibit marked differences in their residual dynamics profiles, supporting the notion that conservation of structure does not necessarily imply conservation of dynamics.

ObjectivesTo validate the factor structure of the Copenhagen Psychosocial Questionnaire (COPSOQ) in a North American population and dissect the associations between psychosocial factors and workplace psychological health and safety.MethodsConfirmatory factor analysis and multivariate linear regression were used to determine the associations between COPSOQ dimensions and a global rating of workplace psychological health and safety. Models were stratified by sex, gender roles, and age.ResultsThe COPSOQ factor structure was verified among Canadian workers. Three factors were found to significantly contribute to the global rating of the psychological health and safety for all workers. Few differences were observed across sex, gender roles, and age.ConclusionsThis study identified dimensions of the psychosocial work environment that are strongly associated with the global rating of workplace psychological health and safety. Using a standardized questionnaire like the COPSOQ allows for comparisons over time, between different industries, and worker populations.

Although radon is a well-established contributor to lung cancer mortality among uranium miners, the effects of radon decay products on different histopathologies of lung carcinoma are not well established. Using a retrospective cohort design, this study aims to examine the risks of lung cancer by histological subtypes associated with exposure to radon decay products among the Ontario Uranium Miners cohort. Cases were stratified by histological groups, and associated risks were estimated for cumulative radon exposure after adjustment for attained age and calendar period. Between 1969 and 2005, 1274 incident cases of primary lung cancer were identified. Of these, 1256 diagnoses (99%) contained information on histology. Squamous cell carcinoma was most common (31%), followed by adenocarcinoma (20%), large cells (18%), small cell lung carcinoma (14%), and other or unspecified cell types (17%). Of the histological sub-groups, small cell lung carcinoma had the strongest association with cumulative radon exposure; compared to the reference group (<1 cumulative working level months (WLM)), the highest exposure category (>60 cumulative WLM) had a relative risk (RR) of 2.76 (95% CI: 1.67–4.57). Adenocarcinoma had the lowest risk and was not significantly associated with exposure to radon decay products (RR = 1.49, 95% CI: 0.96–2.31). An increasing, linear trend in relative risk was noted with increasing cumulative WLM across small cell, squamous cell, and large cell lung carcinomas (Ptrend < 0.05). Similarly, the excess relative risk (ERR) per WLM was highest for small cell lung carcinoma (ERR/WLM = 0.15, p < 0.01), followed by squamous cell carcinoma (ERR/WLM = 0.12, p < 0.01). Non-statistically significant excess risk was observed for adenocarcinoma (ERR/WLM = 0.004, p = 0.07). Our analysis of the Ontario Uranium Miners cohort data shows differences in the magnitude of the risks across four histological subtypes of lung carcinoma; the strongest association was noted for small cell lung carcinoma, followed by squamous cell, large cell, and lastly adenocarcinoma, which showed no significant associations with exposure to radon decay products.

Background and objectivesIncreases in leukemia risk after exposure to gamma radiation have been well-demonstrated among nuclear energy workers and atomic bomb survivors. Although uranium miners are also exposed to gamma radiation, its health effects are not well characterized, and assumed to be insignificant relative to the effects of radon decay products. The objective of this study is to quantify the effects of whole-body gamma radiation exposure on the incident risk of leukemia among Ontario Uranium Miners.MethodsBased on a retrospective cohort of 28 546 uranium miners, leukemia cases were identified through record linkages with the Canadian Cancer Registry and Canadian Mortality Database. Gamma doses were estimated through dose prediction models and badge dosimeter readings collated by the National Dose Registry, blinded from case status. Person-years at risk of leukemia were stratified by exposure category, calendar period of employment, and attained age at risk. Poisson regression was used to model the risk (RR) of incident leukemia at increasing levels of cumulative gamma radiation exposure, adjusting for calendar period and attained age.ResultsBetween 1969 and 2005, 116 incident cases of leukemia were identified. On average, these miners were employed for 4.4 years with a mean cumulative dose of 5.25 millisieverts (mSv). With exposure lagged by 2 years, preliminary analyses showed that when compared to the referent group (0 mSv), those with >30 mSv of cumulative gamma dose had a non-statistically significant increase in the risk of leukemia diagnosis (RR=2.04, 95% CI: 0.93, 4.51) with increasing, linear trend (p=0.08).ConclusionsAlthough our results did not show a statistically significant relationship between gamma radiation and leukemia incidence, it is likely due to low statistically power. Future work may include pooling the Ontario Uranium Miners cohort with other similar cohorts to better quantify the potential associated risks.