Interaction effects among multiple job demands: an examination of healthcare workers across different contexts.

BACKGROUND AND OBJECTIVES: Simultaneous exposure to time, cognitive, and emotional demands is a feature of the work environment for healthcare workers, yet effects of these common stressors in combination are not well established. DESIGN: Survey data were collected from 125 hospital employees (Sample 1, Study 1), 93 ambulance service employees (Sample 2, Study 1), and 380 aged care/disability workers (Study 2). METHODS: Hierarchical multiple regressions were conducted. RESULTS: In Sample 1, high cognitive demand exacerbated high emotional demand on psychological strain and job burnout, whereas the negative effect of high emotional demand was not present at low cognitive demand. In Sample 2, a similar pattern between emotional demand and time demand on stress-remedial intentions was observed. In Study 2, emotional demand × time demand and time demand × cognitive demand interactions again revealed that high levels of two demands were stress-exacerbating and low levels of one demand neutralized the other. A three-way interaction on job satisfaction showed the negative impact of emotional demand was exacerbated when both time and cognitive demands were high, creating a "triple disadvantage" of job demands. CONCLUSIONS: The results demonstrate that reducing some job demands helps attenuate the stressful effects of other job demands on different employee outcomes.

The NADH oxidase ENOX1, a critical mediator of endothelial cell radiosensitization, is crucial for vascular development.

ENOX1 is a highly conserved NADH oxidase that helps to regulate intracellular nicotinamide adenine dinucleotide levels in many cell types, including endothelial cells. Pharmacologic and RNA interference (RNAi)-mediated suppression of ENOX1 impairs surrogate markers of tumor angiogenesis/vasculogenesis, providing support for the concept that ENOX1 represents an antiangiogenic druggable target. However, direct genetic evidence that demonstrates a role for ENOX1 in vascular development is lacking. In this study, we exploited a zebrafish embryonic model of development to address this question. Whole-mount in situ hybridization coupled with immunofluorescence performed on zebrafish embryos demonstrate that enox1 message and translated protein are expressed in most tissues, and its expression is enriched in blood vessels and heart. Morpholino-mediated suppression of Enox1 in Tg(fli1-eGFP) and Tg(flk1-eGFP) zebrafish embryos significantly impairs the development of vasculature and blood circulation. Using in vivo multiphoton microscopy, we show that morpholino-mediated knockdown of enox1 increases NADH levels, consistent with loss of enzyme. VJ115 is a small-molecule inhibitor of Enox1's oxidase activity shown to increase intracellular NADH in endothelial cells; we used VJ115 to determine if the oxidase activity was crucial for vascular development. We found that VJ115 suppressed vasculogenesis in Tg(fli1-eGFP) embryos and impaired circulation. Previously, it was shown that suppression of ENOX1 radiosensitizes proliferating tumor vasculature, a consequence of enhanced endothelial cell apoptosis. Thus, our current findings, coupled with previous research, support the hypothesis that ENOX1 represents a potential cancer therapy target, one that combines molecular targeting with cytotoxic sensitization.

The novel antiangiogenic VJ115 inhibits the NADH oxidase ENOX1 and cytoskeleton-remodeling proteins.

Targeting tumor vasculature represents a rational strategy for controlling cancer. (Z)-(+/-)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (denoted VJ115) is a novel chemical entity that inhibits the enzyme ENOX1, a NADH oxidase. Genetic and small molecule inhibition of ENOX1 inhibits endothelial cell tubule formation and tumor-mediated neo-angiogenesis. Inhibition of ENOX1 radiosensitizes tumor vasculature, a consequence of enhanced apoptosis. However, the molecular mechanisms underlying these observations are not well understood. Herein, we mechanistically link ENOX1-mediated regulation of cellular NADH concentrations with proteomics profiling of endothelial cell protein expression following exposure to VJ115. Pathway Studios network analysis of potential effector molecules identified by the proteomics profiling indicated that a VJ115 exposure capable of altering intracellular NADH concentrations impacted proteins involved in cytoskeletal reorganization. The analysis was validated using RT-PCR and immunoblotting of selected proteins. RNAi knockdown of ENOX1 was shown to suppress expression of stathmin and lamin A/C, proteins identified by the proteomics analysis to be suppressed upon VJ115 exposure. These data support the hypothesis that VJ115 inhibition of ENOX1 can impact expression of proteins involved in cytoskeletal reorganization and support a hypothesis in which ENOX1 activity links elevated cellular NADH concentrations with cytoskeletal reorganization and angiogenesis.