Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia

<p>Abstract</p> <p>Background</p> <p>Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia <it>in vitro</it>. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E₂production in rat primary microglia.</p> <p>Results</p> <p>Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE₂production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by β-adrenoreceptors, since β-, but not α-adrenoreceptor agonists produced similar results. Furthermore, β-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and β-adrenoreceptor agonists.</p> <p>Conclusions</p> <p>Considering that PGE₂displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions.</p

A LigA Three-Domain Region Protects Hamsters from Lethal Infection by Leptospira interrogans

The leptospiral LigA protein consists of 13 bacterial immunoglobulin-like (Big) domains and is the only purified recombinant subunit vaccine that has been demonstrated to protect against lethal challenge by a clinical isolate of Leptospira interrogans in the hamster model of leptospirosis. We determined the minimum number and location of LigA domains required for immunoprotection. Immunization with domains 11 and 12 was found to be required but insufficient for protection. Inclusion of a third domain, either 10 or 13, was required for 100% survival after intraperitoneal challenge with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130. As in previous studies, survivors had renal colonization; here, we quantitated the leptospiral burden by qPCR to be 1.2×103 to 8×105 copies of leptospiral DNA per microgram of kidney DNA. Although renal histopathology in survivors revealed tubulointerstitial changes indicating an inflammatory response to the infection, blood chemistry analysis indicated that renal function was normal. These studies define the Big domains of LigA that account for its vaccine efficacy and highlight the need for additional strategies to achieve sterilizing immunity to protect the mammalian host from leptospiral infection and its consequences

Spectral densities and partition functions of modular quantum systems as derived from a central limit theorem

Using a central limit theorem for arrays of interacting quantum systems, we give analytical expressions for the density of states and the partition function at finite temperature of such a system, which are valid in the limit of infinite number of subsystems. Even for only small numbers of subsystems we find good accordance with some known, exact results.Comment: 6 pages, 4 figures, some steps added to derivation, accepted for publication in J. Stat. Phy

Application of high throughput in vitro metabolomics for hepatotoxicity mode of action characterization and mechanistic-anchored point of departure derivation: a case study with nitrofurantoin

Omics techniques have been increasingly recognized as promising tools for Next Generation Risk Assessment. Targeted metabolomics offer the advantage of providing readily interpretable mechanistic information about perturbed biological pathways. In this study, a high-throughput LC–MS/MS-based broad targeted metabolomics system was applied to study nitrofurantoin metabolic dynamics over time and concentration and to provide a mechanistic-anchored approach for point of departure (PoD) derivation. Upon nitrofurantoin exposure at five concentrations (7.5 µM, 15 µM, 20 µM, 30 µM and 120 µM) and four time points (3, 6, 24 and 48 h), the intracellular metabolome of HepG2 cells was evaluated. In total, 256 uniquely identified metabolites were measured, annotated, and allocated in 13 different metabolite classes. Principal component analysis (PCA) and univariate statistical analysis showed clear metabolome-based time and concentration effects. Mechanistic information evidenced the differential activation of cellular pathways indicative of early adaptive and hepatotoxic response. At low concentrations, effects were seen mainly in the energy and lipid metabolism, in the mid concentration range, the activation of the antioxidant cellular response was evidenced by increased levels of glutathione (GSH) and metabolites from the de novo GSH synthesis pathway. At the highest concentrations, the depletion of GSH, together with alternations reflective of mitochondrial impairments, were indicative of a hepatotoxic response. Finally, a metabolomics-based PoD was derived by multivariate PCA using the whole set of measured metabolites. This approach allows using the entire dataset and derive PoD that can be mechanistically anchored to established key events. Our results show the suitability of high throughput targeted metabolomics to investigate mechanisms of hepatoxicity and derive point of departures that can be linked to existing adverse outcome pathways and contribute to the development of new ones

Person-centred experiential therapy (PCET) training within a UK NHS IAPT service: experiences of selected counsellors in the PRaCTICED trial

We investigated the experiences of 10 counsellors undergoing training in a form of person-centred experiential therapy (PCET), known in the UK as Counselling for Depression (CfD). Training was delivered at a service level as part of the PRaCTICED trial. Counsellors who took part in the study either completed (N=5), failed to complete (N=3) or were ongoing (N = 2) in their PCET training. Framework analysis was selected to extract rich data and an in-depth account of counsellors’ experiences. Inconsistencies were reported between counsellors’ previous theoretical backgrounds and PCET. Difficulties were also reported in resolving person-centred and emotion-focused elements of PCET. Key facilitators and barriers to completing PCET training were identified, including counsellors’ intrapersonal factors

Relativistic Wavepackets in Classically Chaotic Quantum Cosmological Billiards

Close to a spacelike singularity, pure gravity and supergravity in four to eleven spacetime dimensions admit a cosmological billiard description based on hyperbolic Kac-Moody groups. We investigate the quantum cosmological billiards of relativistic wavepackets towards the singularity, employing flat and hyperbolic space descriptions for the quantum billiards. We find that the strongly chaotic classical billiard motion of four-dimensional pure gravity corresponds to a spreading wavepacket subject to successive redshifts and tending to zero as the singularity is approached. We discuss the possible implications of these results in the context of singularity resolution and compare them with those of known semiclassical approaches. As an aside, we obtain exact solutions for the one-dimensional relativistic quantum billiards with moving walls.Comment: 18 pages, 10 figure

Non-equilibrium relaxation and interface energy of the Ising model

{}From the non-equilibrium critical relaxation study of the two-dimensional Ising model, the dynamical critical exponent $z$ is estimated to be $2.165 \pm 0.010$ for this model. The relaxation in the ordered phase of this model is consistent with $\exp (-\sqrt{t/\tau })$ behavior. The interface energy of the three-dimensional Ising model is studied and the critical exponent of the correlation length $\nu$ and the critical amplitude of the surface tension $\sigma_0$ are estimated to be $0.6250\pm 0.025$ and $1.42\pm 0.04$, respectively. A dynamic Monte Carlo renormalization group method is applied to the equilibrium properties of the three-dimensional Ising model successfully.Comment: 32pages( 15 figures are not included. Their Postscript file is available. Request the author directly. ), LaTe

Multiplex ligation-dependent probe amplification analysis of the NR0B1(DAX1) locus enables explanation of phenotypic differences in patients with X-linked congenital adrenal hypoplasia

BACKGROUND/AIM:X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadic hypogonadism. It is caused by deletions or point mutations of the NR0B1 gene, on Xp21. AHC can be associated with glycerol kinase deficiency, Duchenne muscular dystrophy and mental retardation (MR), as part of a contiguous gene deletion syndrome. A synthetic probe set for multiplex ligation-dependent probe amplification analysis was developed to confirm and characterize NR0B1 deletions in patients with AHC and to correlate their genotypes with their divergent phenotypes. RESULTS:In 2 patients, isolated AHC was confirmed, while a patient at risk for metabolic crisis was revealed as the deletion extends to the GK gene. A deletion extending to IL1RAPL1 was confirmed in both patients showing MR. Thus, a good genotype-phenotype correlation was confirmed. CONCLUSIONS:Multiplex ligation-dependent probe amplification analysis is a valuable tool to detect NR0B1 and contiguous gene deletions in patients with AHC. It is especially helpful for IL1RAPL1 deletion detection as no clinical markers for MR are available. Furthermore, multiplex ligation-dependent probe amplification has the advantage to identify female carriers that, depending on the deletion extension, have a high risk of giving birth to children with MR, AHC, glycerol kinase deficiency and Duchenne muscular dystrophy

How can UK public health initiatives support each other to improve the maintenance of physical activity? Evidence from a cross-sectional survey of runners who move from Couch-to-5k to parkrun

Physical activity improves physical and mental well-being and reduces mortality risk. However, only a quarter of adults globally meet recommended physical activity levels for health. Two common initiatives in the UK are Couch-to-5k (an app-assisted 9-week walk/run programme) and parkrun (a free, weekly, timed 5-km walk/run). It is not known how these initiatives are linked, how Couch-to-5k parkrunners compare to parkrunners, and the extent to which this influences their parkrun performance. The aims were to compare the characteristics and motives and to compare physical activity levels, parkrun performance and the impact of parkrun between Couch-to-5k parkrunners and parkrunners. Three thousand two hundred and ninety six Couch-to-5k parkrunners were compared to 55,923 parkrunners to explore age, sex, ethnicity, employment status, neighbourhood deprivation, motives, physical activity levels, parkrun performance and the impact of parkrun. Couch-to-5k parkrunners were slightly older, more likely to be female and work part-time, but similar in ethnicity, and neighbourhood deprivation compared with other parkrunners. Couch-to-5k parkrunners had different motives for participation and reported high levels of physical activity at registration, which remained to the point of survey completion. This group had slower parkrun times but, when registered for a year, completed a similar number of runs (11) per year. Larger proportions of Couch-to-5k parkrunners perceived positive impacts compared with other parkrunners and 65% of Couch-to-5k parkrunners reported improvements to their lifestyle. parkrun appears to be an effective pathway for those on the Couch-to-5k programme, and the promising positive association between the two initiatives may be effective in assisting previously inactive participants to take part in weekly physical activity

The Hydrogen Atom in Combined Electric and Magnetic Fields with Arbitrary Mutual Orientations

For the hydrogen atom in combined magnetic and electric fields we investigate the dependence of the quantum spectra, classical dynamics, and statistical distributions of energy levels on the mutual orientation of the two external fields. Resonance energies and oscillator strengths are obtained by exact diagonalization of the Hamiltonian in a complete basis set, even far above the ionization threshold. At high excitation energies around the Stark saddle point the eigenenergies exhibit strong level repulsions when the angle between the fields is varied. The large avoided crossings occur between states with the same approximately conserved principal quantum number, n, and this intramanifold mixing of states cannot be explained, not even qualitatively, by conventional perturbation theory. However, it is well reproduced by an extended perturbation theory which takes into account all couplings between the angular momentum and Runge-Lenz vector. The large avoided crossings are interpreted as a quantum manifestation of classical intramanifold chaos. This interpretation is supported by both classical Poincar\'e surfaces of section, which reveal a mixed regular-chaotic intramanifold dynamics, and the statistical analysis of nearest-neighbor-spacingComment: two-column version, 10 pages, REVTeX, 10 figures, uuencoded, submitted to Rhys. Rev.