Isoform-Specific Biased Agonism of Histamine H 3 Receptor Agonists s

ABSTRACT The human histamine H 3 receptor (hH 3 R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H 3 R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH 3 R splice variants (hH 3 R 445 and hH 3 R 365 ) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3b (GSK3b) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH 3 R 365 is more permissive in its signaling than hH 3 R 445 : 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH 3 R 365 was completely unable to stimulate GSK3b phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G proteincoupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants

Magnetic Field Generation in Stars

Enormous progress has been made on observing stellar magnetism in stars from the main sequence through to compact objects. Recent data have thrown into sharper relief the vexed question of the origin of stellar magnetic fields, which remains one of the main unanswered questions in astrophysics. In this chapter we review recent work in this area of research. In particular, we look at the fossil field hypothesis which links magnetism in compact stars to magnetism in main sequence and pre-main sequence stars and we consider why its feasibility has now been questioned particularly in the context of highly magnetic white dwarfs. We also review the fossil versus dynamo debate in the context of neutron stars and the roles played by key physical processes such as buoyancy, helicity, and superfluid turbulence,in the generation and stability of neutron star fields. Independent information on the internal magnetic field of neutron stars will come from future gravitational wave detections. Thus we maybe at the dawn of a new era of exciting discoveries in compact star magnetism driven by the opening of a new, non-electromagnetic observational window. We also review recent advances in the theory and computation of magnetohydrodynamic turbulence as it applies to stellar magnetism and dynamo theory. These advances offer insight into the action of stellar dynamos as well as processes whichcontrol the diffusive magnetic flux transport in stars.Comment: 41 pages, 7 figures. Invited review chapter on on magnetic field generation in stars to appear in Space Science Reviews, Springe

Tides in colliding galaxies

Long tails and streams of stars are the most noticeable upshots of galaxy collisions. Their origin as gravitational, tidal, disturbances has however been recognized only less than fifty years ago and more than ten years after their first observations. This Review describes how the idea of galactic tides emerged, in particular thanks to the advances in numerical simulations, from the first ones that included tens of particles to the most sophisticated ones with tens of millions of them and state-of-the-art hydrodynamical prescriptions. Theoretical aspects pertaining to the formation of tidal tails are then presented. The third part of the review turns to observations and underlines the need for collecting deep multi-wavelength data to tackle the variety of physical processes exhibited by collisional debris. Tidal tails are not just stellar structures, but turn out to contain all the components usually found in galactic disks, in particular atomic / molecular gas and dust. They host star-forming complexes and are able to form star-clusters or even second-generation dwarf galaxies. The final part of the review discusses what tidal tails can tell us (or not) about the structure and content of present-day galaxies, including their dark components, and explains how tidal tails may be used to probe the past evolution of galaxies and their mass assembly history. On-going deep wide-field surveys disclose many new low-surface brightness structures in the nearby Universe, offering great opportunities for attempting galactic archeology with tidal tails.Comment: 46 pages, 13 figures, Review to be published in "Tidal effects in Astronomy and Astrophysics", Lecture Notes in Physics. Comments are most welcom

The spectral energy distribution of fermi bright blazars

We have conducted a detailed investigation of the broadband spectral properties of the γ-ray selected blazars of the Fermi LAT Bright AGN Sample (LBAS). By combining our accurately estimated Fermi γ-ray spectra with Swift, radio, infra-red, optical, and other hard X-ray/γ-ray data, collected within 3 months of the LBAS data taking period, we were able to assemble high-quality and quasi-simultaneous spectral energy distributions (SED) for 48 LBAS blazars. The SED of these γ-ray sources is similar to that of blazars discovered at other wavelengths, clearly showing, in the usual log ν-log ν Fν representation, the typical broadband spectral signatures normally attributed to a combination of low-energy synchrotron radiation followed by inverse Compton emission of one or more components. We have used these SED to characterize the peak intensity of both the low- and the high-energy components. The results have been used to derive empirical relationships that estimate the position of the two peaks from the broadband colors (i.e., the radio to optical, αro, and optical to X-ray, αox, spectral slopes) and from the γ-ray spectral index. Our data show that the synchrotron peak frequency (νSpeak) is positioned between 1012.5 and 1014.5 Hz in broad-lined flat spectrum radio quasars (FSRQs) and between 10 13 and 1017 Hz in featureless BL Lacertae objects. We find that the γ-ray spectral slope is strongly correlated with the synchrotron peak energy and with the X-ray spectral index, as expected at first order in synchrotron-inverse Compton scenarios. However, simple homogeneous, one-zone, synchrotron self-Compton (SSC) models cannot explain most of our SED, especially in the case of FSRQs and low energy peaked (LBL) BL Lacs. More complex models involving external Compton radiation or multiple SSC components are required to reproduce the overall SED and the observed spectral variability. While more than 50% of known radio bright high energy peaked (HBL) BL Lacs are detected in the LBAS sample, only less than 13% of known bright FSRQs and LBL BL Lacs are included. This suggests that the latter sources, as a class, may be much fainter γ-ray emitters than LBAS blazars, and could in fact radiate close to the expectations of simple SSC models. We categorized all our sources according to a new physical classification scheme based on the generally accepted paradigm for Active Galactic Nuclei and on the results of this SED study. Since the LAT detector is more sensitive to flat spectrum γ-ray sources, the correlation between νSpeak and γ-ray spectral index strongly favors the detection of high energy peaked blazars, thus explaining the Fermi overabundance of this type of sources compared to radio and EGRET samples. This selection effect is similar to that experienced in the soft X-ray band where HBL BL Lacs are the dominant type of blazars. © 2010 The American Astronomical Society

The 'hard' problem of consciousness is continually reproduced and made harder by all attempts to solve it

I argue that the so-called 'hard' problem of consciousness ' the problem of how consciousness is possible at all, and how it 'connects' with matter ' is only an artefact of the ways in which human scientists approach consciousness and (more generally) mind. Putting the point paradoxically but also quite precisely: the efforts to solve the mind'body problem, and this its latest variant form, are the very disease of which they take themselves to be the cure. I give examples drawn from sociology and from philosophy to support this claim, and then try to mitigate this vicious consequence of Cognitivism in both disciplines by offering a Wittgensteinian dissolution of the (pseudo-)problem as an alternative to (hopeless) cognitivist efforts to solve it

Southern ocean carbon and heat impact on climate

The Southern Ocean greatly contributes to the regulation of the global climate by controlling important heat and carbon exchanges between the atmosphere and the ocean. Rates of climate change on decadal timescales are therefore impacted by oceanic processes taking place in the Southern Ocean, yet too little is known about these processes. Limitations come both from the lack of observations in this extreme environment and its inherent sensitivity to intermittent processes at scales that are not well captured in current Earth system models. The Southern Ocean Carbon and Heat Impact on Climate programme was launched to address this knowledge gap, with the overall objective to understand and quantify variability of heat and carbon budgets in the Southern Ocean through an investigation of the key physical processes controlling exchanges between the atmosphere, ocean and sea ice using a combination of observational and modelling approaches. Here, we provide a brief overview of the programme, as well as a summary of some of the scientific progress achieved during its first half. Advances range from new evidence of the importance of specific processes in Southern Ocean ventilation rate (e.g. storm-induced turbulence, sea–ice meltwater fronts, wind-induced gyre circulation, dense shelf water formation and abyssal mixing) to refined descriptions of the physical changes currently ongoing in the Southern Ocean and of their link with global climate. This article is part of a discussion meeting issue ‘Heat and carbon uptake in the Southern Ocean: the state of the art and future priorities’.</jats:p&gt