Nuclear Export of the Oncoprotein v-ErbA Is Mediated by Acquisition of a Viral Nuclear Export Sequence

v-ErbA, an oncogenic derivative of the thyroid hormone receptor α (TRα) carried by the avian erythroblastosis virus, contains several alterations including fusion of a portion of avian erythroblastosis virus Gag to its N terminus, N- and C-terminal deletions, and 13 amino acid substitutions. Nuclear export of v-ErbA occurs through a CRM1-mediated pathway. In contrast, nuclear export of TRα and another isoform, TRβ, is CRM1-independent. To determine which amino acid changes in v-ErbA confer CRM1-dependent nuclear export, we expressed a panel of green and yellow fluorescent protein-tagged mutant and chimeric proteins in mammalian cells. The sensitivity of subcellular trafficking of these mutants to leptomycin B (LMB), a specific inhibitor of CRM1, was assessed by fluorescence microscopy. Our data showed that a nuclear export sequence resides within a 70-amino acid domain in the C-terminal portion of the p10 region of Gag, and in vitro binding assays demonstrated that Gag interacts directly with CRM1. However, a panel of ligand-binding domain mutants of v-ErbA lacking the Gag sequence exhibited greater nuclear localization in the presence of LMB, suggesting that the various amino acid substitutions/deletions may cause a conformation shift, unmasking an additional CRM1-dependent nuclear export sequence. In contrast, the altered DNA-binding domain of the oncoprotein did not contribute to CRM1-dependent nuclear export. Heterokaryon experiments revealed that v-ErbA did not undergo nucleocytoplasmic shuttling when the CRM1 export pathway was blocked by LMB treatment, suggesting that the ability to follow the export pathway used by TRα has been lost by the oncoprotein during its evolution. Our findings thus point to the intriguing possibility that acquisition of altered nuclear export capabilities contributes to the oncogenic properties of v-ErbA

Pedestrian Safety Among High School Runners: a Case Series

Background: Participation in high school cross-country and track has increased over the last few decades. At the same time, the rate of pedestrian-involved motor vehicle crashes (MVCs) has also increased. In the context of organized sport, pedestrian safety among runners is often not highlighted, despite the risk of catastrophic injury. Purpose: To describe incidents of pedestrian-involved MVCs involving student athletes captured by the National Center for Catastrophic Sport Injury Research (NCCSIR) at the University of North Carolina at Chapel Hill. Study Design: Case series. Level of Evidence: Level 5. Methods: This study utilized surveillance data from the NCCSIR from 2011 to 2020. It presents descriptive statistics, including frequencies and percentages, detailed summaries, and a Haddon Matrix. Results: There were 8 incidents involving 11 student athletes, resulting in 9 fatalities. Of these, 5 cases occurred in the afternoon or early evening, 4 occurred in the Fall, and 6 occurred in a rural area. Haddon Matrix analyses of case descriptions indicate schools should implement a runner safety program for all new runners and ensure that runner safety measures are included in emergency action plans. Conclusion: Runner-related MVCs are relatively rare, but tragic, incidents. Pedestrian safety measures should be incorporated into school-sponsored practices and training runs. Clinical Relevance: Pedestrian safety should be incorporated into runner safety and injury prevention efforts

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action

Optimizing linkage and retention to hypertension care in rural Kenya (LARK hypertension study): Study protocol for a randomized controlled trial

10.1186/1745-6215-15-143Trials15114

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action