Spatially structured oscillations in a two-dimensional excitatory neuronal network with synaptic depression

We study the spatiotemporal dynamics of a two-dimensional excitatory neuronal network with synaptic depression. Coupling between populations of neurons is taken to be nonlocal, while depression is taken to be local and presynaptic. We show that the network supports a wide range of spatially structured oscillations, which are suggestive of phenomena seen in cortical slice experiments and in vivo. The particular form of the oscillations depends on initial conditions and the level of background noise. Given an initial, spatially localized stimulus, activity evolves to a spatially localized oscillating core that periodically emits target waves. Low levels of noise can spontaneously generate several pockets of oscillatory activity that interact via their target patterns. Periodic activity in space can also organize into spiral waves, provided that there is some source of rotational symmetry breaking due to external stimuli or noise. In the high gain limit, no oscillatory behavior exists, but a transient stimulus can lead to a single, outward propagating target wave

Stationary bumps in a piecewise smooth neural field model with synaptic depression

We analyze the existence and stability of stationary pulses or bumps in a one–dimensional piecewise smooth neural field model with synaptic depression. The continuum dynamics is described in terms of a nonlocal integrodifferential equation, in which the integral kernel represents the spatial distribution of synaptic weights between populations of neurons whose mean firing rate is taken to be a Heaviside function of local activity. Synaptic depression dynamically reduces the strength of synaptic weights in response to increases in activity. We show that in the case of a Mexican hat weight distribution, there exists a stable bump for sufficiently weak synaptic depression. However, as synaptic depression becomes stronger, the bump became unstable with respect to perturbations that shift the boundary of the bump, leading to the formation of a traveling pulse. The local stability of a bump is determined by the spectrum of a piecewise linear operator that keeps track of the sign of perturbations of the bump boundary. This results in a number of differences from previous studies of neural field models with Heaviside firing rate functions, where any discontinuities appear inside convolutions so that the resulting dynamical system is smooth. We also extend our results to the case of radially symmetric bumps in two–dimensional neural field models

Vandetanib-eluting Radiopaque Beads: <i>In vivo</i> Pharmacokinetics, Safety and Toxicity Evaluation following Swine Liver Embolization.

To evaluate the plasma and tissue pharmacokinetics, safety and toxicity following intra-arterial hepatic artery administration of Vandetanib (VTB)-eluting Radiopaque Beads (VERB) in healthy swine. In a first phase, healthy swine were treated with hepatic intra-arterial administration of VERB at target dose loading strengths of 36 mg/mL (VERB36), 72 mg/mL (VERB72) and 120 mg/mL (VERB120). Blood and tissue samples were taken and analysed for VTB and metabolites to determine pharmacokinetic parameters for the different dose forms over 30 days. In a second phase, animals were treated with unloaded radiopaque beads or high dose VTB loaded beads (VERB100, 100 mg/mL). Tissue samples from embolized and non-embolized areas of the liver were evaluated at necropsy (30 and 90 days) for determination of VTB and metabolite levels and tissue pathology. Imaging was performed prior to sacrifice using multi-detector computed tomography (MDCT) and imaging findings correlated with pathological changes in the tissue and location of the radiopaque beads. The peak plasma levels of VTB (C &lt;sub&gt;max&lt;/sub&gt; ) released from the various doses of VERB ranged between 6.19-17.3 ng/mL indicating a low systemic burst release. The plasma profile of VTB was consistent with a distribution phase up to 6 h after administration followed by elimination with a half-life of 20-23 h. The AUC of VTB and its major metabolite N-desmethyl vandetanib (NDM VTB) was approximately linear with the dose strength of VERB. VTB plasma levels were at or below limits of detection two weeks after administration. In liver samples, VTB and NDM VTB were present in treated sections at 30 days after administration at levels above the &lt;i&gt;in vitro&lt;/i&gt; IC &lt;sub&gt;50&lt;/sub&gt; for biological effectiveness. At 90 days both analytes were still present in treated liver but were near or below the limit of quantification in untreated liver sections, demonstrating sustained release from the VERB. Comparison of the reduction of the liver lobe size and associated tissue changes suggested a more effective embolization with VERB compared to the beads without drug. Hepatic intra-arterial administration of VERB results in a low systemic exposure and enables sustained delivery of VTB to target tissues following embolization. Changes in the liver tissue are consistent with an effective embolization and this study has demonstrated that VERB100 is well tolerated with no obvious systemic toxicity

Gas6 Increases Myelination by Oligodendrocytes and Its Deficiency Delays Recovery following Cuprizone-Induced Demyelination

Multiple sclerosis (MS) is a complex demyelinating disease of the central nervous system. Current research has shown that at least in some cases, the primary insult in MS could be directed at the oligodendrocyte, and that the earliest immune responses are primarily via innate immune cells. We have identified a family of receptor protein tyrosine kinases, known as the TAM receptors (Tyro3, Axl and Mertk), as potentially important in regulating both the oligodendrocyte and immune responses. We have previously shown that Gas6, a ligand for the TAM receptors, can affect the severity of demyelination in mice, with a loss of signalling via Gas6 leading to decreased oligodendrocyte survival and increased microglial activation during cuprizone-induced demyelination. We hypothesised TAM receptor signalling would also influence the extent of recovery in mice following demyelination. A significant effect of the absence of Gas6 was detected upon remyelination, with a lower level of myelination after 4 weeks of recovery in comparison with wild-type mice. The delay in remyelination was accompanied by a reduction in oligodendrocyte numbers. To understand the molecular mechanisms that drive the observed effects, we also examined the effect of exogenous Gas6 in in vitro myelination assays. We found that Gas6 significantly increased myelination in a dose-dependent manner, suggesting that TAM receptor signalling could be directly involved in myelination by oligodendrocytes. The reduced rate of remyelination in the absence of Gas6 could thus result from a lack of Gas6 at a critical time during myelin production after injury. These findings establish Gas6 as an important regulator of both CNS demyelination and remyelination

Hormonal responses to cholinergic input are different in humans with and without type 2 diabetes mellitus

<div><p>Peripheral muscarinic acetylcholine receptors regulate insulin and glucagon release in rodents but their importance for similar roles in humans is unclear. Bethanechol, an acetylcholine analogue that does not cross the blood-brain barrier, was used to examine the role of peripheral muscarinic signaling on glucose homeostasis in humans with normal glucose tolerance (NGT; n = 10), impaired glucose tolerance (IGT; n = 11), and type 2 diabetes mellitus (T2DM; n = 9). Subjects received four liquid meal tolerance tests, each with a different dose of oral bethanechol (0, 50, 100, or 150 mg) given 60 min before a meal containing acetaminophen. Plasma pancreatic polypeptide (PP), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucose, glucagon, C-peptide, and acetaminophen concentrations were measured. Insulin secretion rates (ISRs) were calculated from C-peptide levels. Acetaminophen and PP concentrations were surrogate markers for gastric emptying and cholinergic input to islets. The 150 mg dose of bethanechol increased the PP response 2-fold only in the IGT group, amplified GLP-1 release in the IGT and T2DM groups, and augmented the GIP response only in the NGT group. However, bethanechol did not alter ISRs or plasma glucose, glucagon, or acetaminophen concentrations in any group. Prior studies showed infusion of xenin-25, an intestinal peptide, delays gastric emptying and reduces GLP-1 release but not ISRs when normalized to plasma glucose levels. Analysis of archived plasma samples from this study showed xenin-25 amplified postprandial PP responses ~4-fold in subjects with NGT, IGT, and T2DM. Thus, increasing postprandial cholinergic input to islets augments insulin secretion in mice but not humans.</p><p><b><i>Trial Registration</i>:</b> ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01434901?term=NCT01434901&rank=1" target="_blank">NCT01434901</a></p></div

Does R&D spur productivity growth in Australia’s broadacre agriculture? A semi-parametric smooth coefficient approach

© 2018 Informa UK Limited, trading as Taylor & Francis Group This article analyses the role of research and development (R & D) in Australia’s broadacre farming by using the semi-parametric smooth coefficient model. While the conventional production function approach only captures the direct effects of R & D, this methodology captures both the direct impact of a change in R & D on output and the indirect impact through changes in efficiency of use of factor inputs in the production process. Moreover, technical inefficiency is introduced in the model allowing it as a function of R & D. Using a unique state-level dataset covering the period 1995–2007, this empirical study finds that once both the direct and indirect effects are taken into consideration, R & D investments significantly increase outputs. The results also show that there are substantial variations in the effects of R & D on output across the state-level average farm through technology parameters as well as through technical inefficiency. Such variations need to be taken into account when designing policies for investing public R & D in agriculture

A proposed difficulty grading system for laparoscopic bile duct exploration: benefits to clinical practice, training and research

Background: A gap remains between the mounting evidence for single session management of bile duct stones and the adoption of this approach. Laparoscopic bile duct exploration (LBDE) is limited by the scarcity of training opportunities and adequate equipment and by the perception that the technique requires a high skill-set. The aim of this study was to create a new classification of difficulty based on operative characteristics and to stratify postoperative outcomes of easy vs. difficult LBDE irrespective of the surgeon’s experience. Methods: A cohort of 1335 LBDEs was classified according to the location, number and size of ductal stones, the retrieval technique, utilisation of choledochoscopy and specific biliary pathologies encountered. A combination of features indicated easy (Grades I and II A &amp; B) or difficult (Grades III A and B, IV and V) transcystic or transcholedochal explorations. Results: 78.3% of patients with acute cholecystitis or pancreatitis, 37% with jaundice and 46% with cholangitis had easy explorations. Difficult explorations were more likely to present as emergencies, with obstructive jaundice, previous sphincterotomy and dilated bile ducts on ultrasound scans. 77.7% of easy explorations were transcystic and 62.3% of difficult explorations transductal. Choledochoscopy was utilised in 23.4% of easy vs. 98% of difficult explorations. The use of biliary drains, open conversions, median operative time, biliary-related complications, hospital stay, readmissions, and retained stones increased with the difficulty grade. Grades I and II patients had 2 or more hospital episodes in 26.5% vs. 41.2% for grades III to V. There were 2 deaths in difficulty Grade V and one in Grade IIB. Conclusion: Difficulty grading of LBDE is useful in predicting outcomes and facilitating comparison between studies. It ensures fair structuring and assessment of training and progress of the learning curve. LBDEs were easy in 72% with 77% completed transcystically. This may encourage more units to adopt this approach

Early Spectra of the Gravitational Wave Source GW170817: Evolution of a Neutron Star Merger

On 2017 August 17, Swope Supernova Survey 2017a (SSS17a) was discovered as the optical counterpart of the binary neutron star gravitational wave event GW170817. We report time-series spectroscopy of SSS17a from 11.75 hours until 8.5 days after merger. Over the first hour of observations the ejecta rapidly expanded and cooled. Applying blackbody fits to the spectra, we measure the photosphere cooling from $11,000^{+3400}_{-900}$ K to $9300^{+300}_{-300}$ K, and determine a photospheric velocity of roughly 30% of the speed of light. The spectra of SSS17a begin displaying broad features after 1.46 days, and evolve qualitatively over each subsequent day, with distinct blue (early-time) and red (late-time) components. The late-time component is consistent with theoretical models of r-process-enriched neutron star ejecta, whereas the blue component requires high velocity, lanthanide-free material.Comment: 33 pages, 5 figures, 2 tables, Accepted to Scienc

A single residue substitution in the receptor-binding domain of H5N1 hemagglutinin is critical for packaging into pseudotyped lentiviral particles

© 2012 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Serological studies for influenza infection and vaccine response often involve microneutralization and hemagglutination inhibition assays to evaluate neutralizing antibodies against human and avian influenza viruses, including H5N1. We have previously characterized lentiviral particles pseudotyped with H5-HA (H5pp) and validated an H5pp-based assay as a safe alternative for high-throughput serological studies in BSL-2 facilities. Here we show that H5-HAs from different clades do not always give rise to efficient production of H5pp and the underlying mechanisms are addressed. Methodology/Findings: We have carried out mutational analysis to delineate the molecular determinants responsible for efficient packaging of HA from A/Cambodia/40808/2005 (H5Cam) and A/Anhui/1/2005 (H5Anh) into H5pp. Our results demonstrate that a single A134V mutation in the 130-loop of the receptor binding domain is sufficient to render H5Anh the ability to generate H5Anh-pp efficiently, whereas the reverse V134A mutation greatly hampers production of H5Cam-pp. Although protein expression in total cell lysates is similar for H5Anh and H5Cam, cell surface expression of H5Cam is detected at a significantly higher level than that of H5Anh. We further demonstrate by several independent lines of evidence that the behaviour of H5Anh can be explained by a stronger binding to sialic acid receptors implicating residue 134. Conclusions: We have identified a single A134V mutation as the molecular determinant in H5-HA for efficient incorporation into H5pp envelope and delineated the underlying mechanism. The reduced binding to sialic acid receptors as a result of the A134V mutation not only exerts a critical influence in pseudotyping efficiency of H5-HA, but has also an impact at the whole virus level. Because A134V substitution has been reported as a naturally occurring mutation in human host, our results may have implications for the understanding of human host adaptation of avian influenza H5N1 virusesThis work was supported by grants from the Research Fund for the Control of Infectious Diseases of Hong Kong (RFCID#08070972), the Area of Excellence Scheme of the University Grants Committee (grant AoE/M-12/-06 of the Hong Kong Special Administrative Region, China), the French Ministry of Health, and the RESPARI project of the Institut Pasteur International Network