Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5 negative allosteric modulation

Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences

Shining light on an mGlu5 photoswitchable NAM: A theoretical perspective

Metabotropic glutamate receptors (mGluRs) are important drug targets because of their involvement in several neurological diseases. Among mGluRs, mGlu5 is a particularly high-profile target because its positive or negative allosteric modulation can potentially treat schizophrenia or anxiety and chronic pain, respectively. Here, we computationally and experimentally probe the functional binding of a novel photoswitchable mGlu5 NAM, termed alloswitch-1, which loses its NAM functionality under violet light. We show alloswitch-1 binds deep in the allosteric pocket in a similar fashion to mavoglurant, the co-crystallized NAM in the mGlu5 transmembrane domain crystal structure. Alloswitch-1, like NAM 2-Methyl-6-(phenylethynyl)pyridine (MPEP), is significantly affected by P655M mutation deep in the allosteric pocket, eradicating its functionality. In MD simulations, we show alloswitch-1 and MPEP stabilize the co-crystallized water molecule located at the bottom of the allosteric site that is seemingly characteristic of the inactive receptor state. Furthermore, both NAMs form H-bonds with S809 on helix 7, which may constitute an important stabilizing interaction for NAM-induced mGlu5 inactivation. Alloswitch-1, through isomerization of its amide group from trans to cis is able to form an additional interaction with N747 on helix 5. This may be an important interaction for amide-containing mGlu5 NAMs, helping to stabilize their binding in a potentially unusual cis-amide state. Simulated conformational switching of alloswitch-1 in silico suggests photoisomerization of its azo group from trans to cis may be possible within the allosteric pocket. However, photoexcited alloswitch-1 binds in an unstable fashion, breaking H-bonds with the protein and destabilizing the co-crystallized water molecule. This suggests photoswitching may have destabilizing effects on mGlu5 binding and functionality

Wavelet-based Image deconvolution for Wide Field CCD Imagery

We show how a wavelet-based image adaptive deconvolution algorithm can provide significant improvements in the analysis of wide-field CCD images. To illustrate it, we apply our deconvolution protocol to a set of images from a Baker-Nunn telescope. This f/1 instrument has an outstanding field of view of 4.4°x4.4° with high optical quality offering unique properties to study our deconvolution process and results. In particular, we obtain an estimated gain in limiting magnitude of ΔR∼0.6 mag and in limiting resolution of Δρ∼3.9 arcsec. These results increase the number of targets and the efficiency of the underlying scientific project

Evaluating the use of amber in palaeoatmospheric reconstructions: The carbon-isotope variability of modern and Cretaceous conifer resins.

Stable carbon-isotope geochemistry of fossilized tree resin (amber) potentially could be a very useful tool to infer the composition of past atmospheres. To test the reliability of amber as a proxy for the atmosphere, we studied the variability of modern resin d13C at both local and global scales. An amber d13C curve was then built for the Cretaceous, a period of abundant resin production, and interpreted in light of data from modern resins. Our data show that hardening changes the pristine d13C value by causing a 13C-depletion in solid resin when compared to fresh liquid-viscous resin, probably due to the loss of 13C-enriched volatiles. Modern resin d13C values vary as a function of physiological and environmental parameters in ways that are similar to those described for leaves and wood. Resin d13C varies between plant species and localities, within the same tree and between different plant tissues by up to 6¿, and in general increases with increasing altitudes of the plant-growing site. We show that, as is the case with modern resin, Cretaceous amber d13C has a high variability, generally higher than that of other fossil material. Despite the high natural variability, amber shows a negative 2.5-3¿ d13C trend from the middle Early Cretaceous to the Maastrichtian that parallels published terrestrial d13C records. This trend mirrors changes in the atmospheric d13C calculated from the d13C and d18O of benthic foraminiferal tests, although the magnitude of the shift is larger in plant material than in the atmosphere. Increasing mean annual precipitation and pO2 could have enhanced plant carbon-isotope fractionation during the Late Cretaceous, whereas changing pCO2 levels seem to have had no effect on plant carbon-isotope fractionation. The results of this study suggest that amber is a powerful fossil plant material for palaeoenvironmental and palaeoclimatic reconstructions. Improvement of the resolution of the existing data coupled with more detailed information about botanical source and environmental growing conditions of the fossil plant material will probably allow a more faithful interpretation of amber d13C records and a wider understanding of the composition of the past atmosphere

Unfolding Rates for the Diffusion-Collision Model

In the diffusion-collision model, the unfolding rates are given by the likelihood of secondary structural cluster dissociation. In this work, we introduce an unfolding rate calculation for proteins whose secondary structural elements are $\alpha$-helices, modeled from thermal escape over a barrier which arises from the free energy in buried hydrophobic residues. Our results are in good agreement with currently accepted values for the attempt rate.Comment: Shorter version of cond-mat/0011024 accepted for publication in PR

Study of the correlation between columnar aerosol burden, suspended matter at ground and chemical components in a background European environment

Although routinely monitored by ground based air quality networks, the particulate matter distribution could be eventually better described with remote sensing techniques. However, valid relationships between ground level and columnar ground based quantities should be known beforehand. In this study we have performed a comparison between particulate matter measurements at ground level at different cut sizes (10, 2.5 and 1.0 mm), and the aerosol optical depth obtained by means of a ground based sunphotometer during a multiinstrumental field campaign held in El Arenosillo (Huelva, Spain) from 28 June to 4 July 2006. All the PM fractions were very well correlated with AOD with correlation coefficients that ranged from 0.71 to 0.81 for PM10, PM2.5 and PM1. Furthermore, the influence of the mixing layer height in the correlations was explored. The improvement in the correlation when the vertical distribution is taken into account was significant for days with a homogeneous mixing layer. Moreover, the chemical analysis of the individual size fractions allowed us to study the origin of the particulate matter. Secondary components were the most abundant and also well correlated in the three size fractions; but for PM10 fraction, chemical species related to marine origin were best correlated. Finally, we obtained a relationship between MODIS L3 AOD from collection 5.1 and the three PM cut sizes. In spite of being a relatively clean environment, all the techniques were able to capture similar day to day variations during this field campaign.Peer ReviewedPostprint (published version

Scalar field "mini--MACHOs": a new explanation for galactic dark matter

We examine the possibility that galactic halos are collisionless ensembles of scalar field ``massive compact halo objects'' (MACHOs). Using mass constraints from MACHO microlensing and from theoretical arguments on halos made up of massive black holes, as well as demanding also that scalar MACHO ensambles of all scales do not exhibit gravothermal instability (as required by consistency with observations of LSB galaxies), we obtain the range: m\alt 10^{-7} M_\odot or 30 M_\odot\alt m\alt 100 M_\odot. The rather narrow mass range of large MACHOs seems to indicate that the ensambles we are suggesting should be probably made up of scalar MACHOs in the low mass range (``mini--MACHOs''). The proposed model allows one to consider a non--baryonic and non--thermal fundamental nature of dark matter, while at the same time keeping the same phenomenology of the CDM paradigm.Comment: 5 pages, 1 eps figure. RevTex 4 style. To appear in Physical Review