A PI3K-mediated negative feedback regulates Drosophila motor neuron excitability

Negative feedback can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. At the Drosophila neuromuscular junction, a mutation in the type II metabotropic glutamate receptor gene (mGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that mGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in an mGluRA-dependent manner. In humans, PI3K and type II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia and other neurological disorders; however, neither the link between type II mGluRs and PI3K, nor the role of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability

Patching vs Packaging: Complementary Effects, Goodness of Fit, Degrees of Freedom and Intentionality in Policy ...

10.2139/ssrn.22733421-2

Supply of Policy and Management Consultancies to Canadian Federal Departments: New Evidence on Contract Size, Type and Structure

10.2139/ssrn.22484021-3

The Achilles Heel of Governance: Critical Capacity Deficits and Their Role in Governance Failures

10.2139/ssrn.24231661-2

Dealing with the Likelihood of Failure over the Long-Term: Adaptive Policy Design under Uncertainty

10.2139/ssrn.23943481-2

Who Is a Stream? Epistemic Communities, Instrument Constituencies and Advocacy Coalitions in Public Policy-Making

John Kingdon’s Multiple Streams Framework (MSF) was articulated in order to better understand how issues entered onto policy agendas, using the concept of policy actors interacting over the course of sequences of events in what he referred to as the “problem”, “policy” and “politics” “streams”. However, it is not a priori certain who the agents are in this process and how they interact with each other. As was common at the time, in his study Kingdon used an undifferentiated concept of a “policy subsystem” to group together and capture the activities of various policy actors involved in this process. However, this article argues that the policy world Kingdon envisioned can be better visualized as one composed of distinct subsets of actors who engage in one specific type of interaction involved in the definition of policy problems: either the articulation of problems, the development of solutions, or their enactment. Rather than involve all subsystem actors, this article argues that three separate sets of actors are involved in these tasks: epistemic communities are engaged in discourses about policy problems; instrument constituencies define policy alternatives and instruments; and advocacy coalitions compete to have their choice of policy alternatives adopted. Using this lens, the article focuses on actor interactions involved both in the agenda-setting activities Kingdon examined as well as in the policy formulation activities following the agenda setting stage upon which Kingdon originally worked. This activity involves the definition of policy goals (both broad and specific), the creation of the means and mechanisms to realize these goals, and the set of bureaucratic, partisan, electoral and other political struggles involved in their acceptance and transformation into action. Like agenda-setting, these activities can best be modeled using a differentiated subsystem approach

The Politics of Policy Anomalies: Bricolage and the Hermeneutics of Paradigms

10.2139/ssrn.230045582183-20