Activating transcription factor-4 promotes neuronal death induced by Parkinson's disease neurotoxins and α-synuclein aggregates.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra resulting in severe and progressive motor impairments. However, the mechanisms underlying this neuronal loss remain largely unknown. Oxidative stress and ER stress have been implicated in PD and these factors are known to activate the integrated stress response (ISR). Activating transcription factor 4 (ATF4), a key mediator of the ISR, and has been reported to induce the expression of genes involved in cellular homeostasis. However, during prolonged activation ATF4 can also induce the expression of pro-death target genes. Therefore, in the present study, we investigated the role of ATF4 in neuronal cell death in models of PD. We demonstrate that PD neurotoxins (MPP+ and 6-OHDA) and α-synuclein aggregation induced by pre-formed human alpha-synuclein fibrils (PFFs) cause sustained upregulation of ATF4 expression in mouse cortical and mesencephalic dopaminergic neurons. Furthermore, we demonstrate that PD neurotoxins induce the expression of the pro-apoptotic factors Chop, Trb3, and Puma in dopaminergic neurons in an ATF4-dependent manner. Importantly, we have determined that PD neurotoxin and α-synuclein PFF induced neuronal death is attenuated in ATF4-deficient dopaminergic neurons. Furthermore, ectopic expression of ATF4 but not transcriptionally defective ATF4ΔRK restores sensitivity of ATF4-deficient neurons to PD neurotoxins. Finally, we demonstrate that the eIF2α kinase inhibitor C16 suppresses MPP+ and 6-OHDA induced ATF4 activation and protects against PD neurotoxin induced dopaminergic neuronal death. Taken together these results indicate that ATF4 promotes dopaminergic cell death induced by PD neurotoxins and pathogenic α-synuclein aggregates and highlight the ISR factor ATF4 as a potential therapeutic target in PD.

Evaluation of ActiGraph's low-frequency filter in laboratory and free-living environments.

UNLABELLED: The ActiGraph (AG) is the most commonly used research-grade physical activity monitor. Although several investigators have examined the effects of the "low-frequency extension" (LFE) on step counts in the free-living environment, a direct comparison with a valid criterion method is lacking. We sought to determine the accuracy of the AG's LFE to measure step counts during laboratory and free-living activities in two versions of the device (GT1M and GT3X). METHODS: Twenty-four participants wore the StepWatch 3 and two versions of the AG, with the LFE turned on (GT1M-LFE and GT3X-LFE) and the LFE turned off (GT1M-N and GT3X-N), on different days. Direct observation of steps and the ankle-worn StepWatch 3 served as the criterion methods for the treadmill and free-living condition, respectively. All statistical analyses were performed on the percent difference between the devices as [(measured - actual)/actual]. RESULTS: During treadmill walking, the GT1M-N and GT3X-N underestimated steps by approximately 60% at 40 m·min (P < 0.001) and by 31% at 54 m·min (P < 0.001). With the LFE turned on, this underestimation was reduced to 7% and 4% for the GT1M and GT3X, respectively. Under free-living conditions, both the GT1M-LFE and GT3X-LFE overestimated steps by approximately 32% (P < 0.001) whereas the GT1M-N and GT3X-N steps were underestimated by 30% and 25%, respectively (P < 0.001). CONCLUSIONS: Turning the LFE on lessens the underestimation of steps recorded at walking speeds ≤54 m·min for both the GT3X and GT1M. However, the increased sensitivity provided by the AG's LFE results in overestimation of steps taken throughout the day, when compared with the criterion device. Meanwhile, failure to turn the LFE on results in an underestimation of steps taken throughout the day.

The evolution of cold tolerance in Drosophila larvae.

Temperature is a primary determinant of insect and other ectotherm distribution and activity. Physiological and behavioral adaptations allow many insects to survive at subzero temperatures, yet the evolutionary influences on insect cold tolerance are unclear. Supercooling points, basal cold tolerance, cold-tolerance strategy, and inducible cold tolerance from rapid cold-hardening or acclimation were measured in a phylogenetically independent context in larvae of 27 phylogenetically diverse Drosophila species acquired from stock collections. Supercooling capacity is attributed primarily to physical factors, such as dry mass and water mass. Species of the obscura group were more resistant to acute cold tolerance than species of other groups within the genus, and plasticity in cold tolerance is constrained by phylogeny rather than by basal cold tolerance. The more cold-tolerant freeze-avoiding species appear to have arisen multiple times in Drosophila and are distinct from chill-susceptible species, which likely indicate the ancestral state. A phylogenetic influence is apparent on several measures of cold tolerance, which show considerable interspecific variation and indicate varying physiological mechanisms among Drosophila species when temperature limits are met.

An integrative research review: effective school-based childhood overweight interventions.

PURPOSE: To describe theoretical and methodological characteristics of effective school-based interventions that used healthy lifestyle education, dietary habits, and/or physical activity in children ages 4 to 14. DESIGN: Integrative research review. METHODS: Stetler's model of research utilization. RESULTS: Social Cognitive Theory was the stated or implied theory in eight of the 10 studies. Healthy lifestyle education was initiated in nine studies, dietary habits in four, and physical activity in eight. Four of the 10 studies used a combination of all three interventions; three used a combination of two interventions; and three used only one intervention. PRACTICE IMPLICATIONS: Social Cognitive Theory and the role of social learning are useful when designing interventions for preventing and treating childhood overweight.