Functional characterization of GABAA receptor-mediated modulation of cortical neuron network activity in microelectrode array recordings

The numerous γ-aminobutyric acid type A receptor (GABAAR) subtypes are differentially expressed and mediate distinct functions at neuronal level. In this study we have investigated GABAAR-mediated modulation of the spontaneous activity patterns of primary neuronal networks from murine frontal cortex by characterizing the effects induced by a wide selection of pharmacological tools at a plethora of activity parameters in microelectrode array (MEA) recordings. The basic characteristics of the primary cortical neurons used in the recordings were studied in some detail, and the expression levels of various GABAAR subunits were investigated by western blotting and RT-qPCR. In the MEA recordings, the pan-GABAAR agonist muscimol and the GABABR agonist baclofen were observed to mediate phenotypically distinct changes in cortical network activity. Selective augmentation of αβγ GABAAR signaling by diazepam and of δ-containing GABAAR (δ-GABAAR) signaling by DS1 produced pronounced changes in the majority of the activity parameters, both drugs mediating similar patterns of activity changes as muscimol. The apparent importance of δ-GABAAR signaling for network activity was largely corroborated by the effects induced by the functionally selective δ-GABAAR agonists THIP and Thio-THIP, whereas the δ-GABAAR selective potentiator DS2 only mediated modest effects on network activity, even when co-applied with low THIP concentrations. Interestingly, diazepam exhibited dramatically right-shifted concentration-response relationships at many of the activity parameters when co-applied with a trace concentration of DS1 compared to when applied alone. In contrast, the potencies and efficacies displayed by DS1 at the networks were not substantially altered by the concomitant presence of diazepam. In conclusion, the holistic nature of the information extractable from the MEA recordings offers interesting insights into the contributions of various GABAAR subtypes/subgroups to cortical network activity and the putative functional interplay between these receptors in these neurons

The Effect of Columnar Disorder on the Superconducting Transition of a Type-II Superconductor in Zero Applied Magnetic Field

We investigate the effect of random columnar disorder on the superconducting phase transition of a type-II superconductor in zero applied magnetic field using numerical simulations of three dimensional XY and vortex loop models. We consider both an unscreened model, in which the bare magnetic penetration length is approximated as infinite, and a strongly screened model, in which the magnetic penetration length is of order the vortex core radius. We consider both equilibrium and dynamic critical exponents. We show that, as in the disorder free case, the equilibrium transitions of the unscreened and strongly screened models lie in the same universality class, however scaling is now anisotropic. We find for the correlation length exponent $\nu=1.2\pm 0.1$, and for the anisotropy exponent $\zeta=1.3\pm 0.1$. We find different dynamic critical exponents for the unscreened and strongly screened models.Comment: 30 pages 12 ps figure

Cost-effectiveness of rosuvastatin in comparison with generic atorvastatin and simvastatin in a Swedish population at high risk of cardiovascular events

Background: To assess the long-term cost-effectiveness of rosuvastatin therapy compared with generic simvastatin and generic atorvastatin in reducing the incidence of cardiovascular events and mortality in a Swedish population with Framingham risk ≥20%. Methods: A probabilistic Monte Carlo simulation model based on data from JUPITER (the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was used to estimate the long-term cost-effectiveness of rosuvastatin 20 mg daily versus simvastatin or atorvastatin 40 mg for the prevention of cardiovascular death and morbidity. The three-stage model included cardiovascular event prevention simulating the 4 years of JUPITER, initial prevention beyond the trial, and subsequent cardiovascular event prevention. A Swedish health care payer perspective (direct costs only) was modeled for a lifetime horizon, with 2008/2009 as the costing period. Univariate and probabilistic sensitivity analyses were performed. Results: The incremental cost per quality-adjusted life-year (QALY) gained with rosuvastatin 20 mg over simvastatin or atorvastatin 40 mg ranged from SEK88,113 (rosuvastatin 20 mg versus simvastatin 40 mg; Framingham risk ≥30%; net avoidance of 34 events/1000 patients) to SEK497,542 (versus atorvastatin 40 mg: Framingham risk ≥20%; net avoidance of 11 events/1000 patients) over a lifetime horizon. Probabilistic sensitivity analyses indicated that at a willingness-to-pay threshold of SEK500,000/QALY, rosuvastatin 20 mg would be cost-effective for approximately 75%–85% of simulations relative to atorvastatin or simvastatin 40 mg. Sensitivity analyses indicated the findings to be robust. Conclusion: Rosuvastatin 20 mg is cost-effective over a lifetime horizon compared with generic simvastatin or atorvastatin 40 mg in patients at high cardiovascular risk in Sweden

Hyperparasitism in caves:bats, bat flies and ectoparasitic fungus

Bat flies (Nycteribiidae) of the order Diptera are highly specialized bloodsucking ectoparasites living on bats. The life-cycle of the bat flies emphasizes their obligate relationship with their hosts as they spend almost their entire life on bats. Upon mating, the female bat fly carries the larvae internally until the 3rd-instar when it deposits the larvae on the ceiling of the roost occupied by bats. The larvae then form a puparium. After 3-4 weeks the adult bat fly emerges from the puparium and starts searching for a host bat to colonize. Some of these ectoparasitic bat flies themselves are infected with an ectoparasitic fungus of the genus Arthrorhynchus (Laboulbeniales). Ascospores of the fungi attach themselves to the cuticle of the bat fly and develop a very conspicuous haustorium that penetrates into the soft tissues from where it presumably extract nutrition from the hemolymph of the bat flies. This interaction converts the fungus into a hyperparasite. Both the parasite and hyperparasite are obligates and cannot live separate from their hosts. This peculiar case of hyperparasitism remains highly unknown. The bat flies were collected in caves of Portugal, in maternity and hibernation bat seasons, and in the autumn migration period. The most common species of cave-dwelling bat species in Portugal is Miniopterus schreibersii, frequently parasitized with Nycteribia schmidlii and Penicillidia conspicua bat flies. We have studied the prevalence of the Laboulbeniales of the genus Arthrorhynchus in natural populations of bat flies. The site and position of the fungus on male and female bat flies unveils the mechanism of fungal transmission among bat flies, indicating that it occurs during mating behavior. This study is the starting point towards the understanding of this unique case of fungus-insect-vertebrate hyperparasitism interaction. See Suppl. material 1