Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor:implications for adrenomedullin and calcitonin gene-related peptide pharmacology

Background and Purpose Receptor activity-modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor-like receptor (CLR). The interactions of the different RAMPs with this class B GPCR yield high-affinity calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear. Experimental Approach Guided by receptor models, we mutated residues in the N-terminal helix of CLR, RAMP2 and RAMP3 hypothesized to be involved in peptide interactions. These were assayed for cAMP production with AM, AM2 and CGRP together with their cell surface expression. Binding studies were also conducted for selected mutants. Key Results An important domain for peptide interactions on CLR from I32 to I52 was defined. Although I41 was universally important for binding and receptor function, the role of other residues depended on both ligand and RAMP. Peptide binding to CLR/RAMP3 involved a more restricted range of residues than that to CLR/RAMP1 or CLR/RAMP2. E101 of RAMP2 had a major role in AM interactions, and F111/W84 of RAMP2/3 was important with each peptide. Conclusions and Implications RAMP-dependent effects of CLR mutations suggest that the different RAMPs control accessibility of peptides to binding residues situated on the CLR N-terminus. RAMP3 appears to alter the role of specific residues at the CLR-RAMP interface compared with RAMP1 and RAMP2

The Ising-Kondo lattice with transverse field: an f-moment Hamiltonian for URu2Si2?

We study the phase diagram of the Ising-Kondo lattice with transverse magnetic field as a possible model for the weak-moment heavy-fermion compound URu2Si2, in terms of two low-lying f singlets in which the uranium moment is coupled by on-site exchange to the conduction electron spins. In the mean-field approximation for an extended range of parameters, we show that the conduction electron magnetization responds logarithmically to f-moment formation, that the ordered moment in the antiferromagnetic state is anomalously small, and that the Neel temperature is of the order observed. The model gives a qualitatively correct temperature-dependence, but not magnitude, of the specific heat. The majority of the specific heat jump at the Neel temperature arises from the formation of a spin gap in the conduction electron spectrum. We also discuss the single-impurity version of the model and speculate on ways to increase the specific heat coefficient. In the limits of small bandwidth and of small Ising-Kondo coupling, we find that the model corresponds to anisotropic Heisenberg and Hubbard models respectively.Comment: 20 pages RevTeX including 5 figures (1 in LaTeX, 4 in uuencoded EPS), Received by Phys. Rev. B 19 April 199

Disks, Tori, and Cocoons: Emission and Absorption Diagnostics of AGN Environments

One of the most important problems in the study of active galaxies is understanding the detailed geometry, physics, and evolution of the central engines and their environments. The leading models involve an accretion disk and torus structure around a central dense object, thought to be a supermassive black hole. Gas found in the environment of AGN is associated with different structures: molecular accretion disks, larger scale atomic tori, ionized and neutral "cocoons" in which the nuclear regions can be embedded. All of them can be studied at radio wavelengths by various means. Here, we summarize the work that has been done to date in the radio band to characterize these structures. Much has been learned about the central few parsecs of AGN in the last few decades with contemporary instruments but the picture remains incomplete. In order to be able to define a more accurate model of this region, significant advances in sensitivity, spectral and angular resolution, and bandpass stability are required. The necessary advances will only be provided by the Square Kilometer Array and we discuss the possibilities that these dramatic improvements will open for the study of the gas in the central region of AGN.Comment: To appear in "Science with the Square Kilometer Array," eds. C. Carilli and S. Rawlings, New Astronomy Reviews (Elsevier: Amsterdam); 17 pages, 7 figures (four of them in separate gif/tif files) The full paper with high resolution images can be downloaded from http://www.astron.nl/~morganti/Papers/AGNenvironment.ps.g

Compact jets as probes for sub-parsec scale regions in AGN

Compact relativistic jets in active galactic nuclei offer an effective tool for investigating the physics of nuclear regions in galaxies. The emission properties, dynamics, and evolution of jets in AGN are closely connected to the characteristics of the central supermassive black hole, accretion disk and broad-line region in active galaxies. Recent results from studies of the nuclear regions in several active galaxies with prominent outflows are reviewed in this contribution.Comment: AASLaTeX, 5 pages, 4 figures. Accepted in Astrophysics and Space Scienc

Confined granular packings: structure, stress, and forces

The structure and stresses of static granular packs in cylindrical containers are studied using large-scale discrete element molecular dynamics simulations in three dimensions. We generate packings by both pouring and sedimentation and examine how the final state depends on the method of construction. The vertical stress becomes depth-independent for deep piles and we compare these stress depth-profiles to the classical Janssen theory. The majority of the tangential forces for particle-wall contacts are found to be close to the Coulomb failure criterion, in agreement with the theory of Janssen, while particle-particle contacts in the bulk are far from the Coulomb criterion. In addition, we show that a linear hydrostatic-like region at the top of the packings unexplained by the Janssen theory arises because most of the particle-wall tangential forces in this region are far from the Coulomb yield criterion. The distributions of particle-particle and particle-wall contact forces $P(f)$ exhibit exponential-like decay at large forces in agreement with previous studies.Comment: 11 pages, 11 figures, submitted to PRE (v2) added new references, fixed typo

Fermi liquid interactions and the superfluid density in d-wave superconductors

We construct a phenomenological superfluid Fermi liquid theory for a two-dimensional d-wave superconductor on a square lattice, and study the effect of quasiparticle interactions on the superfluid density. Using simple models for the dispersion and the Landau interaction function, we illustrate the deviation of these results from those for the isotropic superfluid. This allows us to reconcile the value and doping dependence of the superfluid density slope at low temperature obtained from penetration depth measurements, with photoemission data on nodal quasiparticles.Comment: 5 latex pages, 1 eps-figure. submitted to PR

Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality

OBJECTIVES: Height is inversely associated with cardiovascular disease mortality risk and has shown variable associations with cancer incidence and mortality. The interpretation of findings from previous studies has been constrained by data limitations. Associations between height and specific causes of death were investigated in a large general population cohort of men and women from the West of Scotland. DESIGN: Prospective observational study. SETTING: Renfrew and Paisley, in the West of Scotland. SUBJECTS: 7052 men and 8354 women aged 45-64 were recruited into a study in Renfrew and Paisley, in the West of Scotland, between 1972 and 1976. Detailed assessments of cardiovascular disease risk factors, morbidity and socioeconomic circumstances were made at baseline. MAIN OUTCOME MEASURES: Deaths during 20 years of follow up classified into specific causes. RESULTS: Over the follow up period 3347 men and 2638 women died. Height is inversely associated with all cause, coronary heart disease, stroke, and respiratory disease mortality among men and women. Adjustment for socioeconomic position and cardiovascular risk factors had little influence on these associations. Height is strongly associated with forced expiratory volume in one second (FEV1) and adjustment for FEV1 considerably attenuated the association between height and cardiorespiratory mortality. Smoking related cancer mortality is not associated with height. The risk of deaths from cancer unrelated to smoking tended to increase with height, particularly for haematopoietic, colorectal and prostate cancers. Stomach cancer mortality was inversely associated with height. Adjustment for socioeconomic position had little influence on these associations. CONCLUSION: Height serves partly as an indicator of socioeconomic circumstances and nutritional status in childhood and this may underlie the inverse associations between height and adulthood cardiorespiratory mortality. Much of the association between height and cardiorespiratory mortality was accounted for by lung function, which is also partly determined by exposures acting in childhood. The inverse association between height and stomach cancer mortality probably reflects Helicobacter pylori infection in childhood resulting inor being associated withshorter height. The positive associations between height and several cancers unrelated to smoking could reflect the influence of calorie intake during childhood on the risk of these cancers