A Role for SKN-1/Nrf in Pathogen Resistance and Immunosenescence in Caenorhabditis elegans

A proper immune response ensures survival in a hostile environment and promotes longevity. Recent evidence indicates that innate immunity, beyond antimicrobial effectors, also relies on host-defensive mechanisms. The Caenorhabditis elegans transcription factor SKN-1 regulates xenobiotic and oxidative stress responses and contributes to longevity, however, its role in immune defense is unknown. Here we show that SKN-1 is required for C. elegans pathogen resistance against both Gram-negative Pseudomonas aeruginosa and Gram-positive Enterococcus faecalis bacteria. Exposure to P. aeruginosa leads to SKN-1 accumulation in intestinal nuclei and transcriptional activation of two SKN-1 target genes, gcs-1 and gst-4. Both the Toll/IL-1 Receptor domain protein TIR-1 and the p38 MAPK PMK-1 are required for SKN-1 activation by PA14 exposure. We demonstrate an early onset of immunosenescence with a concomitant age-dependent decline in SKN-1-dependent target gene activation, and a requirement of SKN-1 to enhance pathogen resistance in response to longevity-promoting interventions, such as reduced insulin/IGF-like signaling and preconditioning H2O2 treatment. Finally, we find that wdr-23(RNAi)-mediated constitutive SKN-1 activation results in excessive transcription of target genes, confers oxidative stress tolerance, but impairs pathogen resistance. Our findings identify SKN-1 as a novel regulator of innate immunity, suggests its involvement in immunosenescence and provide an important crosstalk between pathogenic stress signaling and the xenobiotic/oxidative stress response

Conclusion: an aggregate comparison of party leaders in Eastern Europe

This concluding chapter brings together all the country-specific observations and assessments made in the previous chapters in order to deliver a comparative, and slightly broader, perspective of party leadership in Eastern Europe. It reflects on the importance of the six character traits investigated in this book and on the impact they produce for the electoral fortune and internal organization of political parties. This is done with the aim of highlighting the implications of this book for the future study of party leadership

Machine learning methods to support personalized neuromusculoskeletal modelling.

Many biomedical, orthopaedic, and industrial applications are emerging that will benefit from personalized neuromusculoskeletal models. Applications include refined diagnostics, prediction of treatment trajectories for neuromusculoskeletal diseases, in silico design, development, and testing of medical implants, and human-machine interfaces to support assistive technologies. This review proposes how physics-based simulation, combined with machine learning approaches from big data, can be used to develop high-fidelity personalized representations of the human neuromusculoskeletal system. The core neuromusculoskeletal model features requiring personalization are identified, and big data/machine learning approaches for implementation are presented together with recommendations for further research.status: Published onlin