Calcium-Permeable AMPA Receptors Mediate the Induction of the Protein Kinase A-Dependent Component of Long-Term Potentiation in the Hippocampus

Two forms of NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) at hippocampal CA1 synapses can be distinguished based on their sensitivity to inhibitors of protein kinase A (PKA). The PKA-dependent form requires multiple episodes of high-frequency stimulation (HFS) or theta burst stimuli (TBS) with a spacing between episodes in the order of minutes. To investigate the mechanism by which spaced episodes induce the PKA-dependent form of LTP, we have compared, in interleaved experiments, spaced (s) and compressed (c) TBS protocols in the rat CA1 synapses. We find that LTP induced by sTBS, but not that induced by cTBS, involves the insertion of calcium-permeable (CP) AMPARs, as assessed using pharmacological and electrophysiological criteria. Furthermore, a single TBS when paired with rolipram [4-(3-(cyclopentyloxy)-4-methoxyphenyl)pyrrolidin-2-one], to activate PKA, generates an LTP that also involves the insertion of CP-AMPARs. These data demonstrate that the involvement of CP-AMPARs in LTP is critically determined by the timing of the induction trigger and is associated specifically with the PKA-dependent form of LTP. SIGNIFICANCE STATEMENT Long-term potentiation is a family of synaptic mechanisms that are believed to be important for learning and memory. Two of the most extensively studied forms are triggered by the synaptic activation of NMDA receptors and expressed by changes in AMPA receptor function. They can be distinguished on the basis of their requirement for activation of a protein kinase, PKA. We show that the PKA-dependent form also involves the transient insertion of calcium-permeable AMPA receptors. These results have implications for relating synaptic plasticity to learning and memory and suggest a specific linkage between PKA activation and the rapid synaptic insertion of calcium-permeable AMPA receptors during long-term potentiation

Integration Framework of MES Toward Data Security Interoperation

© 2020, Springer Nature Switzerland AG. The core problem of the application of MES (Manufacturing Execution System) in intelligent manufacturing systems is integration, which solves the problem of the data interoperation between the distributed manufacturing systems. The previous researches on MES integration rarely considered the problem of system data security access. A three-level data security access mechanism based on the independence of the system administrators, security administrators, and security auditors is proposed which integrated into the MES integration framework to guarantee the business and engineering data security access for the related distributed clients. The principle is using the domain to make the logical isolation for different clients and data sources and applying the pre-defined data sharing rules for safe access. In the proposed MES integration framework model, the data interoperation between MES and the engineering software systems is discussed which includes ERP (Enterprise Resource Management), CAPP (Computer Aided Process Planning), DNC (Distribution Numerical Control), WMS (Warehouse Management System), and SCADA (Supervisory Control and Data Acquisition), etc., the implementation method of personalized data display GUI is discussed as well. The study is based on the KMMES developed by Wuhan KM-Software of China, and it has been deployed in over forty companies from the sections of aerospace, automotive, shipbuilding and other industries

Disrupted-in-schizophrenia 1 (DISC1) and Syntaphilin collaborate to modulate axonal mitochondrial anchoring

In neuronal axons, the ratio of motile-to-stationary mitochondria is tightly regulated by neuronal activation, thereby meeting the need for local calcium buffering and maintaining the ATP supply. However, the molecular players and detailed regulatory mechanisms behind neuronal mitochondrial movement are not completely understood. Here, we found that neuronal activation-induced mitochondrial anchoring is regulated by Disrupted-in-schizophrenia 1 (DISC1), which is accomplished by functional association with Syntaphilin (SNPH). DISC1 deficiency resulted in reduced axonal mitochondrial movement, which was partially reversed by concomitant SNPH depletion. In addition, a SNPH deletion mutant lacking the sequence for interaction with DISC1 exhibited an enhanced mitochondrial anchoring effect than wild-type SNPH. Moreover, upon neuronal activation, mitochondrial movement was preserved by DISC1 overexpression, not showing immobilized response of mitochondria. Taken together, we propose that DISC1 in association with SNPH is a component of a modulatory complex that determines mitochondrial anchoring in response to neuronal activation.117Ysciescopu

Simultaneous determination of natural and synthetic steroid estrogens and their conjugates in aqueous matrices by liquid chromatography / mass spectrometry

An analytical method for the simultaneous determination of nine free and conjugated steroid estrogens was developed with application to environmental aqueous matrices. Solid phase extraction (SPE) was employed for isolation and concentration, with detection by liquid chromatography/mass spectrometry (LC/MS) using electrospray ionisation (ESI) in the negative mode. Method recoveries for various aqueous matrices (wastewater, lake and drinking water) were determined, recoveries proving to be sample dependent. When spiked at 50 ng/l concentrations in sewage influent, recoveries ranged from 62-89 % with relative standard deviations (RSD) < 8.1 %. In comparison, drinking water spiked at the same concentrations had recoveries between 82-100 % with an RSD < 5%. Ion suppression is a known phenomenon when using ESI; hence its impact on method recovery was elucidated for raw sewage. Both ion suppression from matrix interferences and the extraction procedure has bearing on the overall method recovery. Analysis of municipal raw sewage identified several of the analytes of interest at ng/l concentrations, estriol (E3) being the most abundant. Only one conjugate, estrone 3-sulphate (E1-3S) was observe

Bigger, Better, Faster, More at the LHC

Multijet plus missing energy searches provide universal coverage for theories that have new colored particles that decay into a dark matter candidate and jets. These signals appear at the LHC further out on the missing energy tail than two-to-two scattering indicates. The simplicity of the searches at the LHC contrasts sharply with the Tevatron where more elaborate searches are necessary to separate signal from background. The searches presented in this article effectively distinguish signal from background for any theory where the LSP is a daughter or granddaughter of the pair-produced colored parent particle without ever having to consider missing energies less than 400 GeV.Comment: 26 pages, 8 Figures. Minor textual changes, typos fixed and references adde

Chronic excitotoxin-induced axon degeneration in a compartmented neuronal culture model

Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic axonal degeneration may also occur in white matter tracts. Recent identification of axonal glutamate receptor subunits within axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. Individual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

Seasonal and year-round intercropping systems for smallholder farmers : results from on-farm intercropping trials on terraces in Nepal on maize, millet, mustard, wheat and ginger

We would like to thank the Canadian International Food Security Research Fund (CIFSRF), jointly sponsored by the International Development Research Centre (IDRC, Ottawa) and Global Affairs Canada (GAC) for funding.Low yield and total land productivity are major challenges associated with smallholder terrace agriculture in developing countries. Crop intensification and diversification by introducing legumes as intercrop could help alleviate these challenges. We compared 10 intercrop combinations with sole cropping system for two rotation cycles (2015-17) to identify the most productive and economic intercrop combinations for smallholder terrace agriculture. In the spring-summer season (March/April-July/August), cowpea (var. Makaibodi and Suryabodi) and bean were intercropped with maize in rows of 1:1 whereas soybean, blackgram and horsegram were broadcasted with millet (30:70 ratios) during summer-rainy season (July/August-November/December). Pea and lentil were used as winter intercrop (November/December-March/April) in wheat (30:70 ratios) while mustard was planted with pea. Ginger was planted with maize in 1:1 rows during spring-summer season in which the maize rows were replaced by soybean and lentil during summer-rainy and winter season, respectively

SUSY parameter determination at the LHC using cross sections and kinematic edges

We study the determination of supersymmetric parameters at the LHC from a global fit including cross sections and edges of kinematic distributions. For illustration, we focus on a minimal supergravity scenario and discuss how well it can be constrained at the LHC operating at 7 and 14 TeV collision energy, respectively. We find that the inclusion of cross sections greatly improves the accuracy of the SUSY parameter determination, and allows to reliably extract model parameters even in the initial phase of LHC data taking with 7 TeV collision energy and 1/fb integrated luminosity. Moreover, cross section information may be essential to study more general scenarios, such as those with non-universal gaugino masses, and distinguish them from minimal, universal, models.Comment: 22 pages, 8 figure