The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist

Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs. © 2013 Erickson et al

Selective Detection of NADPH Oxidase in Polymorphonuclear Cells by Means of NAD(P)H-Based Fluorescence Lifetime Imaging

NADPH oxidase (NOX2) is a multisubunit membrane-bound enzyme complex that, upon assembly in activated cells, catalyses the reduction of free oxygen to its superoxide anion, which further leads to reactive oxygen species (ROS) that are toxic to invading pathogens, for example, the fungus Aspergillus fumigatus. Polymorphonuclear cells (PMNs) employ both nonoxidative and oxidative mechanisms to clear this fungus from the lung. The oxidative mechanisms mainly depend on the proper assembly and function of NOX2. We identified for the first time the NAD(P)H-dependent enzymes involved in such oxidative mechanisms by means of biexponential NAD(P)H-fluorescence lifetime imaging (FLIM). A specific fluorescence lifetime of 3670±140 picoseconds as compared to 1870 picoseconds for NAD(P)H bound to mitochondrial enzymes could be associated with NADPH bound to oxidative enzymes in activated PMNs. Due to its predominance in PMNs and due to the use of selective activators and inhibitors, we strongly believe that this specific lifetime mainly originates from NOX2. Our experiments also revealed the high site specificity of the NOX2 assembly and, thus, of the ROS production as well as the dynamic nature of these phenomena. On the example of NADPH oxidase, we demonstrate the potential of NAD(P)H-based FLIM in selectively investigating enzymes during their cellular function

Childhood school segregation and later life sense of control and physical performance in the African American Health cohort

BACKGROUND: The association between childhood school desegregation and later life sense of control and physical performance among African Americans is not clear. We hypothesized that childhood school desegregation adversely affected the sense of control of in later life, and that this reduced sense of control accounts in part for reduced physical performance. METHODS: In-home follow-up assessments were completed in 2010 with 582 of the 58–74 year old men and women participating in the on-going African American Health cohort. We used these data to examine the relationship between (a) retrospective self-reports of attending segregated schools during one’s 1(st)-to-12(th) grade education and one’s current sense of control, as well as (b) the association between current sense of control and physical performance. Multiple linear regression analysis with propensity score re-weighting was used. RESULTS: Attending segregated schools for at least half of one’s 1(st)-to-12(th) grade education was significantly associated with higher scores on the sense of control. Adjusting for all covariates and potential confounders, those receiving half or more of their 1(st)-to-12(th) grade education in segregated schools had sense of control scores that were .886 points higher (p ≤ .01; standardized effect size = .22). Sense of control scores were independently (all p < .01) associated with better systolic blood pressure, grip strength, peak expiratory flow, chair stands, balance tests, and the Short Portable Physical Battery even after adjusting for all covariates and potential confounders. Moreover, sense of control scores either partially or fully mediated the statistically significant beneficial associations between childhood school segregation and physical performance. CONCLUSIONS: Childhood school desegregation was adversely associated with the sense of control of African Americans in later life, and this reduced sense of control appears, in part, to account for their poorer physical performance. The etiologic mechanism through which childhood school segregation at the time that this cohort experienced it improved the sense of control in later life, which subsequently led to better physical performance, has not been identified. We suspect, however, that the pathway involves greater exposure to racial solidarity, same-race students as peer role models and same-race teachers and principals as authority role models, the reduced likelihood of exposure to race-based discrimination or antagonism during their formative early lives, and greater exposure to encouragement and support for academic and life success

Antihydrogen formation dynamics in a multipolar neutral anti-atom trap

Antihydrogen production in a neutral atom trap formed by an octupole-based magnetic field minimum is demonstrated using field-ionization of weakly bound anti-atoms. Using our unique annihilation imaging detector, we correlate antihydrogen detection by imaging and by field-ionization for the first time. We further establish how field-ionization causes radial redistribution of the antiprotons during antihydrogen formation and use this effect for the first simultaneous measurements of strongly and weakly bound antihydrogen atoms. Distinguishing between these provides critical information needed in the process of optimizing for trappable antihydrogen. These observations are of crucial importance to the ultimate goal of performing CPT tests involving antihydrogen, which likely depends upon trapping the anti-atom

Search For Trapped Antihydrogen

We present the results of an experiment to search for trapped antihydrogen atoms with the ALPHA antihydrogen trap at the CERN Antiproton Decelerator. Sensitive diagnostics of the temperatures, sizes, and densities of the trapped antiproton and positron plasmas have been developed, which in turn permitted development of techniques to precisely and reproducibly control the initial experimental parameters. The use of a position-sensitive annihilation vertex detector, together with the capability of controllably quenching the superconducting magnetic minimum trap, enabled us to carry out a high-sensitivity and low-background search for trapped synthesised antihydrogen atoms. We aim to identify the annihilations of antihydrogen atoms held for at least 130 ms in the trap before being released over ~30 ms. After a three-week experimental run in 2009 involving mixing of 10^7 antiprotons with 1.3 10^9 positrons to produce 6 10^5 antihydrogen atoms, we have identified six antiproton annihilation events that are consistent with the release of trapped antihydrogen. The cosmic ray background, estimated to contribute 0.14 counts, is incompatible with this observation at a significance of 5.6 sigma. Extensive simulations predict that an alternative source of annihilations, the escape of mirror-trapped antiprotons, is highly unlikely, though this possibility has not yet been ruled out experimentally.Comment: 12 pages, 7 figure

Highly sensitive and broadband carbon nanotube radio-frequency single-electron transistor

We have investigated radio-frequency single-electron transistor (RF-SET) operation of single-walled carbon nanotube quantum dots in the strong tunneling regime. At 4.2 K and carrier frequency 754.2 MHz, we reach a charge sensitivity of 2.3e-6 e/Hz^(1/2) over a bandwidth of 85 MHz. Our results indicate a gain-bandwidth product of 3.7e13 Hz^(3/2)/e, which is by one order of magnitude better than for typical RF-SETs.Comment: 4 pages, 3 figure

Production of antihydrogen at reduced magnetic field for anti-atom trapping

We have demonstrated production of antihydrogen in a 1$,$T solenoidal magnetic field. This field strength is significantly smaller than that used in the first generation experiments ATHENA (3$,$T) and ATRAP (5$,$T). The motivation for using a smaller magnetic field is to facilitate trapping of antihydrogen atoms in a neutral atom trap surrounding the production region. We report the results of measurements with the ALPHA (Antihydrogen Laser PHysics Apparatus) device, which can capture and cool antiprotons at 3$,$T, and then mix the antiprotons with positrons at 1$,$T. We infer antihydrogen production from the time structure of antiproton annihilations during mixing, using mixing with heated positrons as the null experiment, as demonstrated in ATHENA. Implications for antihydrogen trapping are discussed

A linear nonequilibrium thermodynamics approach to optimization of thermoelectric devices

Improvement of thermoelectric systems in terms of performance and range of applications relies on progress in materials science and optimization of device operation. In this chapter, we focuse on optimization by taking into account the interaction of the system with its environment. For this purpose, we consider the illustrative case of a thermoelectric generator coupled to two temperature baths via heat exchangers characterized by a thermal resistance, and we analyze its working conditions. Our main message is that both electrical and thermal impedance matching conditions must be met for optimal device performance. Our analysis is fundamentally based on linear nonequilibrium thermodynamics using the force-flux formalism. An outlook on mesoscopic systems is also given.Comment: Chapter 14 in "Thermoelectric Nanomaterials", Editors Kunihito Koumoto and Takao Mori, Springer Series in Materials Science Volume 182 (2013

Influence of the 6^1S_0-6^3P_1 Resonance on Continuous Lyman-alpha Generation in Mercury

Continuous coherent radiation in the vacuum-ultraviolet at 122 nm (Lyman-alpha) can be generated using sum-frequency mixing of three fundamental laser beams in mercury vapour. One of the fundamental beams is at 254 nm wavelength, which is close to the 6^1S_0-6^3P_1 resonance in mercury. Experiments have been performed to investigate the effect of this one-photon resonance on phasematching, absorption and the nonlinear yield. The efficiency of continuous Lyman-alpha generation has been improved by a factor of 4.5.Comment: 8 pages, 7 figure