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Basal synaptic transmission involves the release of neurotransmitters at individual synapses in response to a single action potential. Recent discoveries show that astrocytes modulate the activity of neuronal networks upon sustained and intense synaptic activity. However, their ability to regulate basal synaptic transmission remains ill defined and controversial. Here, we show that astrocytes in the hippocampal CA1 region detect synaptic activity induced by single-synaptic stimulation. Astrocyte activation occurs at functional compartments found along astrocytic processes and involves metabotropic glutamate subtype 5 receptors. In response, astrocytes increase basal synaptic transmission, as revealed by the blockade of their activity with a Ca(2+) chelator. Astrocytic modulation of basal synaptic transmission is mediated by the release of purines and the activation of presynaptic A(2A) receptors by adenosine. Our work uncovers an essential role for astrocytes in the regulation of elementary synaptic communication and provides insight into fundamental aspects of brain function.

Accumulating evidence is redefining the importance of neuron-glial interactions at synapses in the CNS. Astrocytes form "tripartite" complexes with presynaptic and postsynaptic structures and regulate synaptic transmission and plasticity. Despite our understanding of the importance of neuron-glial relationships in physiological contexts, little is known about the structural interplay between astrocytes and synapses. In the past, this has been difficult to explore because studies have been hampered by the lack of a system that preserves complex neuron-glial relationships observed in the brain. Here we present a system that can be used to characterize the intricate relationship between astrocytic processes and synaptic structures in situ using organotypic hippocampal slices, a preparation that retains the three-dimensional architecture of astrocyte-synapse interactions. Using time-lapse confocal imaging, we demonstrate that astrocytes can rapidly extend and retract fine processes to engage and disengage from motile postsynaptic dendritic spines. Surprisingly, astrocytic motility is, on average, higher than its dendritic spine counterparts and likely relies on actin-based cytoskeletal reorganization. Changes in astrocytic processes are typically coordinated with changes in spines, and astrocyte-spine interactions are stabilized at larger spines. Our results suggest that dynamic structural changes in astrocytes help control the degree of neuron-glial communication at hippocampal synapses.

Mutations in the parkin gene are responsible for a common familial form of Parkinson's disease. As parkin encodes an E3 ubiquitin ligase, defects in proteasome-mediated protein degradation are believed to have a central role in the pathogenesis of Parkinson's disease. Here, we report a novel role for parkin in a proteasome-independent ubiquitination pathway. We have identified a regulated interaction between parkin and Eps15, an adaptor protein that is involved in epidermal growth factor (EGF) receptor (EGFR) endocytosis and trafficking. Treatment of cells with EGF stimulates parkin binding to both Eps15 and the EGFR and promotes parkin-mediated ubiquitination of Eps15. Binding of the parkin ubiquitin-like (Ubl) domain to the Eps15 ubiquitin-interacting motifs (UIMs) is required for parkin-mediated Eps15 ubiquitination. Furthermore, EGFR endocytosis and degradation are accelerated in parkin-deficient cells, and EGFR signalling via the phosphoinositide 3-kinase (PI(3)K)-Akt pathway is reduced in parkin knockout mouse brain. We propose that by ubiquitinating Eps15, parkin interferes with the ability of the Eps15 UIMs to bind ubiquitinated EGFR, thereby delaying EGFR internalization and degradation, and promoting PI(3)K-Akt signalling. Considering the role of Akt in neuronal survival, our results have broad new implications for understanding the pathogenesis of Parkinson's disease.

Reliable and accurate measurements serve as the basis for evaluation in many scientific disciplines. Issues related to reliable and accurate measurement have evolved over many decades, dating back to the nineteenth century and the pioneering work of Galton (1886), Pearson (1896, 1899, 1901), and Fisher (1925). Requiring a new measurement to be identical to the truth is often impractical, either because (1) we are willing to accept a measurement up to some tolerable (or acceptable) error, or (2) the truth is simply not available to us, either because it is not measurable or is only measurable with some degree of error. To deal with issues related to both (1) and (2), a number of concepts, methods, and theories have been developed in various disciplines. Some of these concepts have been used across disciplines, while others have been limited to a particular field but may have potential uses in other disciplines. In this paper, we elucidate and contrast fundamental concepts employed in different disciplines and unite these concepts into one common theme: assessing closeness (agreement) of observations. We focus on assessing agreement with continuous measurements and classify different statistical approaches as (1) descriptive tools; (2) unscaled summary indices based on absolute differences of measurements; and (3) scaled summary indices attaining values between -1 and 1 for various data structures, and for cases with and without a reference. We also identify gaps that require further research and discuss future directions in assessing agreement.

In this population, there was no detectable additional benefit of hand sanitizer or face masks over targeted education on overall rates of URIs, but mask wearing was associated with reduced secondary transmission and should be encouraged during outbreak situations. During the study period, community concern about methicillin-resistant Staphylococcus aureus was occurring, perhaps contributing to the use of hand sanitizer in the Education control group, and diluting the intervention's measurable impact.

Demonstration of a high influenza VE using tests with imperfect sensitivity and specificity should provide reassurance that the program has been effective in reducing influenza illnesses, assuming adequate control of confounding factors.

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