Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cellautonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial highWnt environment.

ObjectivesThe objective of this study was to review software errors known as single event upsets (SEUs) or bit flips due to cosmic rays in epilepsy neurostimulators.Materials and methodsA case report of a single event upset or bit flip is discussed; device manufacturers and publicly available data were queried for both incidence and types of error as well as strategies of software error mitigation.ResultsNeurostimulators, like other implanted devices such as pacemakers, are prone to single event upsets. Strategies for SEU mitigation are reviewed.ConclusionsCosmic radiation can threaten RAM and settings of neurostimulators; neuromodulation teams and device designers need to take this threat into account when designing multifunctional neuromodulation systems.