Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient.

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organisation of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine (4-AP) application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 μm.s-1), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAAreceptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than dorsal, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC. This article is protected by copyright. All rights reserved.This work was supported by a University of Exeter and Eli Lilly studentship (T.R). P.M 513 was supported by an MRC Proximity to Discovery award in partnership with 514 AstraZeneca. K.G.P was an employee of Eli Lilly. A.D.R was part funded by a Royal 515 Society Industrial Fellowship. J.T.B was an Alzheimer’s Research UK Senior Research 516 Fellow (ARUK-SRF2012-6)

Opioids, microglia, and temporal lobe epilepsy

This is the final version. Available from Frontiers Media via the DOI in this record. A lack of treatment options for temporal lobe epilepsy (TLE) demands an urgent quest for new therapies to recover neuronal damage and reduce seizures, potentially interrupting the neurotoxic cascades that fuel hyper-excitability. Endogenous opioids, along with their respective receptors, particularly dynorphin and kappa-opioid-receptor, present as attractive candidates for controlling neuronal excitability and therapeutics in epilepsy. We perform a critical review of the literature to evaluate the role of opioids in modulating microglial function and morphology in epilepsy. We find that, in accordance with anticonvulsant effects, acute opioid receptor activation has unique abilities to modulate microglial activation through toll-like 4 receptors, regulating downstream secretion of cytokines. Abnormal activation of microglia is a dominant feature of neuroinflammation, and inflammatory cytokines are found to aggravate TLE, inspiring the challenge to alter microglial activation by opioids to suppress seizures. We further evaluate how opioids can modulate microglial activation in epilepsy to enhance neuroprotection and reduce seizures. With controlled application, opioids may interrupt inflammatory cycles in epilepsy, to protect neuronal function and reduce seizures. Research on opioid-microglia interactions has important implications for epilepsy and healthcare approaches. However, preclinical research on opioid modulation of microglia supports a new therapeutic pathway for TLE

An interlaboratory study of the reproducibility of on-wafer S-parameter measurements from 140 GHz to 220 GHz

The development, modelling and characterization of millimeter-wave semiconductor devices calls for accurate and reproducible on-wafer measurements. We report on an interlaboratory study involving on-wafer S-parameter measurements in the 140 GHz to 220 GHz band, conducted by three well-established measurement laboratories. The measurements can be used to form typical reproducibility limits for these measurements when conducted in different laboratories using different equipment and calibration methods

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration

3-D printed rectangular waveguide 123-129 GHz packaging for commercial CMOS RFICs

This work demonstrates the hybrid integration of a complementary metal–oxide–semiconductor (CMOS) radio frequency integrated circuit (RFIC) into a host 3-D printed metal-pipe rectangular waveguide (MPRWG). On-chip Vivaldi antennas are used for TE 10 -to-thin-film microstrip (TFMS) mode conversion. Our packaging solution has a combined measured insertion loss of only 1 dB/transition at 126 GHz. This unique packaging and interconnect solution opens up new opportunities for implementing low-cost subterahertz (THz) multichip modules

Impaired speed encoding and grid cell periodicity in a mouse model of tauopathy

This is the final version. Available on open access from eLife Sciences Publications via the DOI in this record. Dementia is associated with severe spatial memory deficits which arise from dysfunction in hippocampal and parahippocampal circuits. For spatially sensitive neurons, such as grid cells, to faithfully represent the environment these circuits require precise encoding of direction and velocity information. Here, we have probed the firing rate coding properties of neurons in medial entorhinal cortex (MEC) in a mouse model of tauopathy. We find that grid cell firing patterns are largely absent in rTg4510 mice, while head-direction tuning remains largely intact. Conversely, neural representation of running speed information was significantly disturbed, with smaller proportions of MEC cells having firing rates correlated with locomotion in rTg4510 mice. Additionally, the power of local field potential oscillations in the theta and gamma frequency bands, which in wild-type mice are tightly linked to running speed, was invariant in rTg4510 mice during locomotion. These deficits in locomotor speed encoding likely severely impact path integration systems in dementia.Alzheimer’s Research U

C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci.

An expanded GGGGCC repeat in a non-coding region of the C9orf72 gene is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Non-coding repeat expansions may cause disease by reducing the expression level of the gene they reside in, by producing toxic aggregates of repeat RNA termed RNA foci, or by producing toxic proteins generated by repeat-associated non-ATG translation. We present the first definitive report of C9orf72 repeat sense and antisense RNA foci using a series of C9FTLD cases, and neurodegenerative disease and normal controls. A sensitive and specific fluorescence in situ hybridisation protocol was combined with protein immunostaining to show that both sense and antisense foci were frequent, specific to C9FTLD, and present in neurons of the frontal cortex, hippocampus and cerebellum. High-resolution imaging also allowed accurate analyses of foci number and subcellular localisation. RNA foci were most abundant in the frontal cortex, where 51 % of neurons contained foci. RNA foci also occurred in astrocytes, microglia and oligodendrocytes but to a lesser degree than in neurons. RNA foci were observed in both TDP-43- and p62-inclusion bearing neurons, but not at a greater frequency than expected by chance. RNA foci abundance in the frontal cortex showed a significant inverse correlation with age at onset of disease. These data establish that sense and antisense C9orf72 repeat RNA foci are a consistent and specific feature of C9FTLD, providing new insight into the pathogenesis of C9FTLD

Graphene-based waveguide resonators for submillimeter-wave applications

Utilization of graphene covered waveguide inserts to form tunable waveguide resonators is theoretically explained and rigorously investigated by means of full-wave numerical electromagnetic simulations. Instead of using graphene-based switching elements, the concept we propose incorporates graphene sheets as parts of a resonator. Electrostatic tuning of the graphene surface conductivity leads to changes in the electromagnetic field boundary conditions at the resonator edges and surfaces, thus producing an effect similar to varying the electrical length of a resonator. The presented outline of the theoretical background serves to give phenomenological insight into the resonator behavior, but it can also be used to develop customized software tools for design and optimization of graphene-based resonators and filters. Due to the linear dependence of the imaginary part of the graphene surface impedance on frequency, the proposed concept was expected to become effective for frequencies above 100 GHz, which is confirmed by the numerical simulations. A frequency range from 100 GHz up to 1100 GHz, where the rectangular waveguides are used, is considered. Simple, all-graphene-based resonators are analyzed first, to assess the achievable tunability and to check the performance throughout the considered frequency range. Graphene–metal combined waveguide resonators are proposed in order to preserve the excellent quality factors typical for the type of waveguide discontinuities used. Dependence of resonator properties on key design parameters is studied in detail. Dependence of resonator properties throughout the frequency range of interest is studied using eight different waveguide sections appropriate for different frequency intervals. Proposed resonators are aimed at applications in the submillimeter-wave spectral region, serving as the compact tunable components for the design of bandpass filters and other devices

Beta bursting in the retrosplenial cortex is a neurophysiological correlate of environmental novelty which is disrupted in a mouse model of Alzheimer's disease

This is the author accepted manuscript. The final version is available from the Society for Neuroscience via the DOI in this recordThe retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer's disease. In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of Alzheimer's disease-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of beta (20-30 Hz) oscillations (beta bursts) which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of beta bursts. Additionally, theta-alpha/beta cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during beta bursts. Finally, excessive beta bursting was seen in J20 mice, including increased beta bursting during novelty and familiarity, yet a loss of coupling between beta bursts and spiking activity. These findings support the concept that beta bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.SIGNIFICANCE STATEMENTThe retrosplenial cortex is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of beta oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive beta bursting in the retrosplenial cortex of J20 mice, a mouse model of Alzheimer's disease, alongside the disassociation of beta bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of Alzheimer's disease related cortical dysfunction.University of ExeterJanssen PharmaceuticaAlzheimer’s Research U

Ethane steam reforming over a platinum/alumina catalyst: effect of sulphur poisoning

In this study we have examined the adsorption of hydrogen sulfide and methanethiol over platinum catalysts and examined the effect of these poisons on the steam reforming of ethane. Adsorption of hydrogen sulfide was measured at 293 and 873 K. At 873 K the adsorbed state of hydrogen sulfide in the presence of hydrogen was SH rather than S, even though the Pt:S ratio was unity. The effect of 11.2 ppm hydrogen sulfide or methanethiol on the steam reforming of ethane was studied at 873 K and 20 barg. Both poisons deactivated the catalyst over a number of hours, but methanethiol was found to be more deleterious, reducing the conversion by almost an order of magnitude, possibly due to the co-deposition of sulfur and carbon. Changes in the selectivity revealed that the effect of sulfur was not uniform on the reactions occurring, with the production of methane reduced proportionally more than the other products, due to the surface sensitivity of the hydrogenolysis and methanation reactions. The water-gas shift reaction was affected to a lesser extent. No regeneration was observed when hydrogen sulfide was removed from the feedstream in agreement with adsorption studies. A slight regeneration was observed when methanethiol was removed from the feed, but this was believed to be due to the removal of carbon rather than sulfur. The overall effect of sulfur poisoning was to reduce activity and enhance hydrogen selectivity