A user's guide to radiation transport in ALEGRA-HEDP : version 4.6.

This manual describes the input syntax to the ALEGRA radiation transport package. All input and output variables are defined, as well as all algorithmic controls. This manual describes the radiation input syntax for ALEGRA-HEDP. The ALEGRA manual[2] describes how to run the code and general input syntax. The ALEGRA-HEDP manual[13] describes the input for other physics used in high energy density physics simulations, as well as the opacity models used by this radiation package. An emission model, which is the lowest order radiation transport approximation, is also described in the ALEGRA-HEDP manual. This document is meant to be used with these other manuals

Enantiopure Cyclopropane-Bearing Pyridyldiazabicyclo[3.3.0]Octanes As Selective α4β2-Nachr Ligands

We report the synthesis and characterization of a series of enantiopure 5-cyclopropane-bearing pyridyldiazabicyclo[3.3.0]octanes that display low nanomolar binding affinities and act as functional agonists at α4β2-nicotinic acetylcholine receptor (nAChR) subtype. Structure-activity relationship studies revealed that incorporation of a cyclopropane-containing side chain at the 5-position of the pyridine ring provides ligands with improved subtype selectivity for nAChR β2 subunit-containing nAChR subtypes (β2∗-nAChRs) over α4∗-nAChRs compared to the parent compound 4. Compound 15 exhibited subnanomolar binding affinity for α4β2-and α4β2∗-nAChRs with negligible interaction. Functional assays confirm selectivity for α4β2-nAChRs. Furthermore, using the SmartCube assay system, this ligand showed antidepressant, anxiolytic, and antipsychotic features, while mouse forced-swim assay further confirm the antidepressant-like property of 15

Discovery Of Highly Potent And Selective α4β2-Nicotinic Acetylcholine Receptor (Nachr) Partial Agonists Containing An Isoxazolylpyridine Ether Scaffold That Demonstrate Antidepressant-Like Activity. Part II

In our continued efforts to develop α4β2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [ 3 H]epibatidine binding studies together with functional assays based on 86 Rb + ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics. © 2012 American Chemical Society

Identification Of Novel α4β2-Nicotinic Acetylcholine Receptor (Nachr) Agonists Based On An Isoxazole Ether Scaffold That Demonstrate Antidepressant-Like Activity

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening toward other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested. © 2011 American Chemical Society

A Viewing Angle - Kinetic Luminosity Unification Scheme For BL Lacertae Objects

We propose a unified classification for BL Lac objects (BLs), focusing on the synchrotron peak frequency of the spectral energy distribution. The unification scheme is based on the angle Theta that describes the orientation of the relativistic jet and on the electron kinetic luminosity Lambda of the jet. We assume that Lambda scales with the size of the jet r in a self-similar fashion (Lambda propto r^2), as supported by observational data. The jets are self-similar in geometry and have the same pressure and median magnetic field at the inlet, independent of size. The self-similarity is broken for the highest energy electrons, which radiate mainly at high frequencies, since for large sources they suffer more severe radiative energy losses over a given fraction of the jet length. We calculate the optically thin synchrotron spectrum using an accelerating inner jet model based on simple relativistic gas dynamics and show that it can fit the observed infrared to X-ray spectrum of PKS 2155--304. We couple the accelerating jet model to the unification scheme and compare the results to complete samples of BLs. The negative apparent evolution of X-ray selected BLs is explained as a result of positive evolution of the jet electron kinetic luminosity $\Lambda_{kin}$. We review observational arguments in favor of the existence of scaled-down accretion disks and broad emission-line regions in BLs. The proposed unification scheme can explain the lack of observed broad emission lines in X-ray selected BLs, as well as the existence of those lines preferentially in luminous radio-selected BLs. Finally, we review observational arguments that suggest the extension of this unification scheme to all blazars.Comment: 32 pages, 8 figures, to be published in the ApJ (Oct 20, 1998

Chemistry Pharmacology And Behavioral Studies Identify Chiral Cyclopropanes As Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting An Antidepressant Profile. Part II

A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline. © 2013 American Chemical Society

Multiwaveband Observations of Quasars with Flat Radio Spectra and Strong Millimeter Emission

We present multiwaveband observations of a well selected sample of 28 quasars and two radio galaxies with flat radio spectra and strong millimeter wave emission (referred to here as FSRQ's). The observations include multifrequency VLBI measurements, X-ray observations with ROSAT and submillimeter observations with the JCMT. Particularly interesting among many findings is a correlation between the X-ray to millimeter spectral index and fraction of flux density contained in the VLBI core. This tendency toward higher X-ray fluxes from sources with stronger jet emission implies that the knots in the jet are the prominent source of X-rays.Comment: 38 pages, 17 figures, 12 tables, accepted for publication in Ap J Suppl, May 199

Quantifying multivariate genotype-by-environment interactions, evolutionary potential and its context-dependence in natural populations of the water flea,<i>Daphnia magna</i>

ABSTRACT Genotype-by-environment interactions (G x E) underpin the evolution of plastic responses in natural populations. Theory assumes that G x E interactions exist but empirical evidence from natural populations is equivocal and difficult to interpret because G x E interactions are normally univariate plastic responses to a single environmental gradient. We compared multivariate plastic responses of 43 Daphnia magna clones from the same population in a factorial experiment that crossed temperature and food environments. Multivariate plastic responses explained more than 30% of the total phenotypic variation in each environment. G x E interactions were detected in most environment combinations irrespective of the methodology used. However, the nature of G x E interactions was context-dependent and led to environment-specific differences in additive genetic variation (G-matrices). Clones that deviated from the population average plastic response were not the same in each environmental context and there was no difference in whether clones varied in the nature (phenotypic integration) or magnitude of their plastic response in different environments. Plastic responses to food were aligned with additive genetic variation ( g max) at both temperatures, whereas plastic responses to temperature were not aligned with additive genetic variation ( g max) in either food environment. These results suggest that fundamental differences may exist in the potential for our population to evolve novel responses to food versus temperature changes, and challenges past interpretations of thermal adaptation based on univariate studies

Tests of the Accelerating Universe with Near-Infrared Observations of a High-Redshift Type Ia Supernova

We have measured the rest-frame B,V, and I-band light curves of a high-redshift type Ia supernova (SN Ia), SN 1999Q (z=0.46), using HST and ground-based near-infrared detectors. A goal of this study is the measurement of the color excess, E_{B-I}, which is a sensitive indicator of interstellar or intergalactic dust which could affect recent cosmological measurements from high-redshift SNe Ia. Our observations disfavor a 30% opacity of SN Ia visual light by dust as an alternative to an accelerating Universe. This statement applies to both Galactic-type dust (rejected at the 3.4 sigma confidence level) and greyer dust (grain size > 0.1 microns; rejected at the 2.3 to 2.6 sigma confidence level) as proposed by Aguirre (1999). The rest-frame $I$-band light cur ve shows the secondary maximum a month after B maximum typical of nearby SNe Ia of normal luminosi ty, providing no indication of evolution as a function of redshift out to z~0.5. A n expanded set of similar observations could improve the constraints on any contribution of extragalactic dust to the dimming of high-redshift SNe Ia.Comment: Accepted to the Astrophysical Journal, 12 pages, 2 figure

The importance of the local density in shaping the galaxy stellar mass functions

Exploiting the capabilities of four different surveys --- the Padova-Millennium Galaxy and Group Catalogue (PM2GC), the WIde-field Nearby Galaxy-cluster Survey (WINGS), the IMACS Cluster Building Survey (ICBS) and the ESO Distant Cluster Survey (EDisCS) --- we analyze the galaxy stellar mass distribution as a function of local density in mass-limited samples, in the field and in clusters from low (z>0.04) to high (z<0.8) redshift. We find that at all redshifts and in all environments, local density plays a role in shaping the mass distribution. In the field, it regulates the shape of the mass function at any mass above the mass limits. In clusters, it seems to be important only at low masses (log M_ast/M_sun <10.1 in WINGS and log M_ast/M_sun < 10.4 in EDisCS), otherwise it seems not to influence the mass distribution. Putting together our results with those of Calvi et al. and Vulcani et al. for the global environment, we argue that at least at $z\leq 0.8$ local density is more important than global environment in determining the galaxy stellar mass distribution, suggesting that galaxy properties are not much dependent of halo mass, but do depend on local scale processes.Comment: MNRAS accepted, in pres