RESUMEN
RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replacement through transplantation of adult whole kidney marrow-derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue-restoring rnaset2 mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy.
Asunto(s)
Encéfalo , Macrófagos , Microglía , Animales , Encéfalo/patología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Leucoencefalopatías/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Microglía/patología , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/deficiencia , Proteínas de Pez Cebra/metabolismoRESUMEN
It is broadly acknowledged that contact center employees are subject to high levels of stress. In this profession, there is a distinction between back-office and front-office employees. In addition, employees may perform duties in various companies with different characteristics (i.e., human resources practices, job characteristics, social support, work-personal life relationship, among others). Thus, this study focuses on the analysis of the contact centers' (CC) psychosocial work environment and employees' levels of stress and well-being, seeking to understand whether they change due to the specific nature of the duties they perform and the characteristics of the company. This study involved 1440 participants from 15 companies. The results indicate that front-office and back-office duties influence the perception of some job characteristics and their environment and, consequently, the stress and well-being of these employees. Furthermore, the exhaustion and general well-being of employees are seemingly independent of the duties performed and common to all companies. However, the job characteristics, psychosocial environment and employees' levels of cynicism, work engagement and general stress were found to change according to the company in which they worked, thus highlighting the need for action in the psychosocial environment of these work duties.