Fast neurotransmitter release regulated by the endocytic scaffold intersectin.

Sustained fast neurotransmission requires the rapid replenishment of release-ready synaptic vesicles (SVs) at presynaptic active zones. Although the machineries for exocytic fusion and for subsequent endocytic membrane retrieval have been well characterized, little is known about the mechanisms underlying the rapid recruitment of SVs to release sites. Here we show that the Down syndrome-associated endocytic scaffold protein intersectin 1 is a crucial factor for the recruitment of release-ready SVs. Genetic deletion of intersectin 1 expression or acute interference with intersectin function inhibited the replenishment of release-ready vesicles, resulting in short-term depression, without significantly affecting the rate of endocytic membrane retrieval. Acute perturbation experiments suggest that intersectin-mediated vesicle replenishment involves the association of intersectin with the fissioning enzyme dynamin and with the actin regulatory GTPase CDC42. Our data indicate a role for the endocytic scaffold intersectin in fast neurotransmitter release, which may be of prime importance for information processing in the brain

Abstract robust coarse spaces for systems of PDEs via generalized eigenproblems in the overlaps

Coarse spaces are instrumental in obtaining scalability for domain decomposition methods for partial differential equations (PDEs). However, it is known that most popular choices of coarse spaces perform rather weakly in the presence of heterogeneities in the PDE coefficients, especially for systems of PDEs. Here, we introduce in a variational setting a new coarse space that is robust even when there are such heterogeneities. We achieve this by solving local generalized eigenvalue problems in the overlaps of subdomains that isolate the terms responsible for slow convergence. We prove a general theoretical result that rigorously establishes the robustness of the new coarse space and give some numerical examples on two and three dimensional heterogeneous PDEs and systems of PDEs that confirm this property

Synaptic vesicle recycling is unaffected in the Ts65Dn mouse model of Down syndrome

Down syndrome (DS) is the most common genetic cause of intellectual disability, and arises from trisomy of human chromosome 21. Accumulating evidence from studies of both DS patient tissue and mouse models has suggested that synaptic dysfunction is a key factor in the disorder. The presence of several genes within the DS trisomy that are either directly or indirectly linked to synaptic vesicle (SV) endocytosis suggested that presynaptic dysfunction could underlie some of these synaptic defects. Therefore we determined whether SV recycling was altered in neurons from the Ts65Dn mouse, the best characterised model of DS to date. We found that SV exocytosis, the size of the SV recycling pool, clathrin-mediated endocytosis, activity-dependent bulk endocytosis and SV generation from bulk endosomes were all unaffected by the presence of the Ts65Dn trisomy. These results were obtained using battery of complementary assays employing genetically-encoded fluorescent reporters of SV cargo trafficking, and fluorescent and morphological assays of fluid-phase uptake in primary neuronal culture. The absence of presynaptic dysfunction in central nerve terminals of the Ts65Dn mouse suggests that future research should focus on the established alterations in excitatory / inhibitory balance as a potential route for future pharmacotherapy

Experimental confirmation of efficient island divertor operation and successful neoclassical transport optimization in Wendelstein 7-X

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases.EC/H2020/633053/EU/Implementation of activities described in the Roadmap to Fusion during Horizon 2020 through a Joint programme of the members of the EUROfusion consortium/ EUROfusio

A High-Performance Implementation of a Robust Preconditioner for Heterogeneous Problems

We present an efficient implementation of the highly robust and scalable GenEO preconditioner in the high-performance PDE framework DUNE. The GenEO coarse space is constructed by combining low energy solutions of a local generalised eigenproblem using a partition of unity. In this paper we demonstrate both weak and strong scaling for the GenEO solver on over 15,000 cores by solving an industrially motivated problem with over 200 million degrees of freedom. Further, we show that for highly complex parameter distributions arising in certain real-world applications, established methods become intractable while GenEO remains fully effective. The purpose of this paper is two-fold: to demonstrate the robustness and high parallel efficiency of the solver and to document the technical details that are crucial to the efficiency of the code.Comment: Fixed error in definition of partition of unit