Effects of the CB1 cannabinoid receptor antagonist AM281 on kissorphin protection against amyloid-β neurotoxicity

Introduction: Previous in vitro and in vivo studies demonstrate protective properties of kissorphin (KSO) peptides against amyloid-β (Aβ) neurotoxicity1,2. Overexpression of the KiSS-1 gene, that encodes the KSO peptides, is also neuroprotective1,3. Endocannabinoids and KSO peptides are neuroprotective against Aβ 25-35, but not Aβ 31-35 peptides1,4. The KiSS-1 gene expression is regulated by endocannabinoids5. The aim of this study was to determine whether endocannabinoids contribute to KSO protection against Aβ toxicity using a CB1 cannabinoid receptor antagonist. Method: This study employed MTT cell viability assays to investigate the effects of the CB1 antagonist AM281 on KSO 1-6 protection against Aβ 25-35 neurotoxicity in human neuroblastoma SH-SY5Y cells. The effects of AM281 on Aβ 25-35 induced neurotoxicity in KiSS-1 gene overexpressing SH-SY5Y cells (PKiSS)1,3 was also investigated1,3. Data was analyzed by one-way analysis of variance (ANOVA). Results: The CB1 antagonist AM281 (0.01-10μM) promoted a concentration dependent increase in 10μM Aβ 25-35 induced neurotoxicity in SH-SY5Y cells in the presence of 10μM KSO 1-6 (Figure 1A). The PKiSS protection against 10μM Aβ 25-35 was reversed by the CB1 antagonist AM281 (10μM) and anti-KSO antibody (1μg/ml). In the presence of anti-KSO antibody 10μM 2-AG was protective against 10μM Aβ 25-35. Figure 1. (A) Dose-response curves for AM281 in the presence of 10μM Aβ 25-35 with or without 10μM KSO 1-6, on MTT reduction in SH-SY5Y cells. (B) PKiSS SH-SY5Y cells were exposed to 10μM Aβ 25-35 alone; 10μM Aβ 25-35 plus 10μM AM281; 10μM Aβ 25-35 plus 1μg/ml anti-KSO antibody; 10μM Aβ 25-35 plus 1μg/ml control antibody; 10μM Aβ 25-35 plus 1μg/ml anti-KSO antibody with 10μM 2-AG; 10μM Aβ 25-35 plus 1μg/ml control antibody with 10μM 2-AG; and cell viability determined by MTT reduction. Results are mean ± SEM (n=8 for each data point); * = P< 0.05 vs Aβ 25-35 alone (one-way ANOVA). Conclusion: In conclusion, protection against Aβ 25-35 induced neurotoxicity by KSO and KiSS-1 overexpression in SH-SY5Y cells is reversed by the AM281 CB1 antagonist. Anti-KSO antibodies prevent neuroprotection by KiSS-1 overexpression and 2-AG restores neuroprotection. This suggests KSO neuroprotection against Aβ involves activation of endocannabinoids. References: (1) Milton NGN et al. (2012). ACS Chem Neurosci 3: 706-719. (2) Jiang JH et al. (2015). Neurobiol Learn Mem. 123: 187-95. (3) Chilumuri A & Milton NGN (2013). ISRN Neuroscience 2013: 253210. (4) Milton NGN (2002). Neurosci Letts 332: 127-130. (5) Karamikheirabad M et al. (2013). Clin Exp Reprod Med 40: 155-162

A metamaterial frequency-selective super-absorber that has absorbing cross section significantly bigger than the geometric cross section

Using the idea of transformation optics, we propose a metamaterial device that serves as a frequency-selective super-absorber, which consists of an absorbing core material coated with a shell of isotropic double negative metamaterial. For a fixed volume, the absorption cross section of the super-absorber can be made arbitrarily large at one frequency. The double negative shell serves to amplify the evanescent tail of the high order incident cylindrical waves, which induces strong scattering and absorption. Our conclusion is supported by both analytical Mie theory and numerical finite element simulation. Interesting applications of such a device are discussed.Comment: 16 pages, 5 figure

Maxwell-Chern-Simons Casimir effect. II. Circular boundary conditions

The topology of (2+1)-dimensional space permits the construction of quantum electrodynamics with the usual Maxwell action augmented by a gauge-invariant, but {ital P}- and {ital T}-violating, Chern-Simons mass term. We discuss the Casimir effect between parallel lines in such a theory. The effect of finite temperature is also considered. In principle, our results provide a way to measure the topological mass of the photon

Casimir Energy for a Spherical Cavity in a Dielectric: Applications to Sonoluminescence

In the final few years of his life, Julian Schwinger proposed that the ``dynamical Casimir effect'' might provide the driving force behind the puzzling phenomenon of sonoluminescence. Motivated by that exciting suggestion, we have computed the static Casimir energy of a spherical cavity in an otherwise uniform material. As expected the result is divergent; yet a plausible finite answer is extracted, in the leading uniform asymptotic approximation. This result agrees with that found using zeta-function regularization. Numerically, we find far too small an energy to account for the large burst of photons seen in sonoluminescence. If the divergent result is retained, it is of the wrong sign to drive the effect. Dispersion does not resolve this contradiction. In the static approximation, the Fresnel drag term is zero; on the mother hand, electrostriction could be comparable to the Casimir term. It is argued that this adiabatic approximation to the dynamical Casimir effect should be quite accurate.Comment: 23 pages, no figures, REVTe

Observability of the Bulk Casimir Effect: Can the Dynamical Casimir Effect be Relevant to Sonoluminescence?

The experimental observation of intense light emission by acoustically driven, periodically collapsing bubbles of air in water (sonoluminescence) has yet to receive an adequate explanation. One of the most intriguing ideas is that the conversion of acoustic energy into photons occurs quantum mechanically, through a dynamical version of the Casimir effect. We have argued elsewhere that in the adiabatic approximation, which should be reliable here, Casimir or zero-point energies cannot possibly be large enough to be relevant. (About 10 MeV of energy is released per collapse.) However, there are sufficient subtleties involved that others have come to opposite conclusions. In particular, it has been suggested that bulk energy, that is, simply the naive sum of ${1\over2}\hbar\omega$, which is proportional to the volume, could be relevant. We show that this cannot be the case, based on general principles as well as specific calculations. In the process we further illuminate some of the divergence difficulties that plague Casimir calculations, with an example relevant to the bag model of hadrons.Comment: 13 pages, REVTe

Access to Drinking-water and Arsenicosis in Bangladesh

The discovery of arsenic contamination in groundwater has challenged efforts to provide safe drinking-water to households in rural Bangladesh. Two nationally-representative surveys in 2000 and 2002 investigated water-usage patterns, water-testing, knowledge of arsenic poisoning, and behavioural responses to arsenic contamination. Knowledge of arsenicosis rose between the two surveys among women from 42% to 64% but awareness of consequences of arsenic remained limited; only 13% knew that it could lead to death. Behavioural responses to arsenic have been limited, probably in part because of the lack of concern but also because households are uncertain of how best to respond and have a strong preference for tubewell water even when wells are known to be contaminated. Further work conducted by the survey team highlighted the difficulties in providing alternative sources of water, with many households switching back to their original sources of water

Long-term correction of ornithine transcarbamylase deficiency by WPRE-mediated overexpression using a helper-dependent adenovirus

The urea cycle disorders (UCDs) are important models for developing gene replacement therapy for liver diseases. Long-term correction of the most common UCD, ornithine transcarbamylase (OTC) deficiency, has yet to be achieved in clinical or preclinical settings. The single human clinical trial using early-generation adenovirus (Ad) failed to show any biochemical correction. In adult OTC-deficient mice, an E1/E2-deleted Ad vector expressing the mouse OTC gene, but not the human, was only transiently therapeutic. By using post-transcriptional overexpression in the context of the less immunogenic helper-dependent adenoviral vector, we achieved metabolic correction of adult OTC-deficient mice for \u3e6 months. Demonstrating this result were normalized orotic aciduria, normal hepatic enzyme activity, and elevated OTC RNA and protein levels in the absence of chronic hepatotoxicity. Overexpressing the human protein may have overcome two potential mechanisms accounting for poor cross-species complementation: a kinetic block at the level of mitochondrial import or a dominant negative effect by the mutant polypeptide. These data represent an important approach for treating human inborn errors of hepatocyte metabolism like the UCDs that require high-level transduction and gene expression for clinical correction

The Casimir Effect in the Presence of a Minimal Length

Large extra dimensions lower the Planck scale to values soon accessible. Not only is the Planck scale the energy scale at which effects of modified gravity become important. The Planck length also acts as a minimal length in nature, providing a natural ultraviolet cutoff and a limit to the possible resolution of spacetime. In this paper we examine the influence of the minimal length on the Casimir energy between two plates.Comment: references and comment on the figure in section III adde

Maintenance of behaviour change following a community-wide gamification based physical activity intervention

Gamification refers to the use of game mechanics (e.g. competition, point scoring, progress visualisation and task setting) to engage and motivate people to achieve an end goal. Public health programs that incorporate gamification-based approaches which aim to improve the public's health have grown in popularity, however most commonplace are individualistic, smartphone-based applications and few studies have been conducted on community-wide interventions. Furthermore, the few studies which have been conducted have relied on small sample sizes with short-term follow-up. In view of this gap in current understanding, this study explored the impact of a community-wide gamified intervention, called ‘Beat the Street’ (in Reading UK) on levels of physical activity at 1 and 2-years post-intervention (between 2014 and 2016). Data were available for N = 1567 participants at one-year post-intervention and N = 723 participants at 2-years post-intervention. A Pretest-Posttest analysis revealed a 11% and 13% decrease in levels of inactivity at 1 and 2-years post-intervention respectively. Furthermore, participants who were inactive at baseline reported undertaking 3.4 and 3.8 days of activity at 1 and 2-years post-intervention, respectively. These findings provide promising preliminary evidence that gamification may be effective for decreasing physical inactivity and game-design mechanisms which may support behaviour change are discussed