Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection.

Signal transduction networks can be perturbed biochemically, genetically, and pharmacologically to unravel their functions. But at the systems level, it is not clear how such perturbations are best implemented to extract molecular mechanisms that underlie network function. Here, we combined pairwise perturbations with multiparameter phosphorylation measurements to reveal causal mechanisms within the signaling network response of cardiomyocytes to coxsackievirus B3 (CVB3) infection. Using all possible pairs of six kinase inhibitors, we assembled a dynamic nine-protein phosphorylation signature of perturbed CVB3 infectivity. Cluster analysis of the resulting dataset showed repeatedly that paired inhibitor data were required for accurate data-driven predictions of kinase substrate links in the host network. With pairwise data, we also derived a high-confidence network based on partial correlations, which identified phospho-IκBα as a central "hub" in the measured phosphorylation signature. The reconstructed network helped to connect phospho-IκBα with an autocrine feedback circuit in host cells involving the proinflammatory cytokines, TNF and IL-1. Autocrine blockade substantially inhibited CVB3 progeny release and improved host cell viability, implicating TNF and IL-1 as cell autonomous components of CVB3-induced myocardial damage. We conclude that pairwise perturbations, when combined with network-level intracellular measurements, enrich for mechanisms that would be overlooked by single perturbants.

Reducing barriers to ethics in neuroscience.

Ethics is a growing interest for neuroscientists, but rather than signifying a commitment to the protection of human subjects, care of animals, and public understanding to which the professional community is engaged in a fundamental way, interest has been consumed by administrative overhead and the mission creep of institutional ethics reviews. Faculty, trainees, and staff (n = 605) in North America whose work involves brain imaging and brain stimulation completed an online survey about ethics in their research. Using factor analysis and linear regression, we found significant effects for invasiveness of imaging technique, professional position, gender, and local presence of bioethics centers. We propose strategies for improving communication between the neuroscience community and ethics review boards, collaborations between neuroscientists and biomedical ethicists, and ethics training in graduate neuroscience programs to revitalize mutual goals and interests.