Three classes of ligands each bind to distinct sites on the orphan G protein-coupled receptor GPR84

Medium chain fatty acids can activate the pro-inflammatory receptor GPR84 but so also can molecules related to 3,3′-diindolylmethane. 3,3′-Diindolylmethane and decanoic acid acted as strong positive allosteric modulators of the function of each other and analysis showed the affinity of 3,3′-diindolylmethane to be at least 100 fold higher. Methyl decanoate was not an agonist at GPR84. This implies a key role in binding for the carboxylic acid of the fatty acid. Via homology modelling we predicted and confirmed an integral role of arginine172, located in the 2nd extracellular loop, in the action of decanoic acid but not of 3,3′-diindolylmethane. Exemplars from a patented series of GPR84 antagonists were able to block agonist actions of both decanoic acid and 3,3′-diindolylmethane at GPR84. However, although a radiolabelled form of a related antagonist, [3H]G9543, was able to bind with high affinity to GPR84, this was not competed for by increasing concentrations of either decanoic acid or 3,3′-diindolylmethane and was not affected adversely by mutation of arginine172. These studies identify three separable ligand binding sites within GPR84 and suggest that if medium chain fatty acids are true endogenous regulators then co-binding with a positive allosteric modulator would greatly enhance their function in physiological settings

Electrophysiological Assessment of Primary Cortical Neurons Genetically Engineered using Iron Oxide Nanoparticles

The development of safe technologies to genetically modify neurons is of great interest in regenerative neurology, for both translational and basic science applications. Such approaches have conventionally been heavily reliant on viral transduction methods, which have safety and production limitations. Magnetofection (magnet-assisted gene transfer using iron oxide nanoparticles as vectors) has emerged as a highly promising non-viral alternative for safe and reproducible genetic modification of neurons. Despite the high potential of this technology, there is an important gap in our knowledge of the safety of this approach, namely, whether it alters neuronal function in adverse ways, such as by altering neuronal excitability and signaling. We have investigated the effects of magnetofection in primary cortical neurons by examining neuronal excitability using the whole cell patch clamp technique. We found no evidence that magnetofection alters the voltage-dependent sodium and potassium ionic currents that underpin excitability. Our study provides important new data supporting magnetofection as a safe technology for bioengineering of neuronal cell populations

A disciplinary commons for database teaching

This paper discusses the experience of taking part in a disciplinary commons devoted to the teaching of database systems. It will discuss the structure of a disciplinary commons and our experience of the database version

Form factors for B−−>πlνB-->\pi l\nu decay in a model constrained by chiral symmetry and quark model

The form factors for the $B-->\pi$ transition are evaluated in the entire momentum transfer range by using the constraints obtained in the framework combining the heavy quark expansion and chiral symmetry for light quarks and the quark model. In particular, we calculate the valence quark contributions and show that it together with the equal time commutator contribution simulate a B-meson pole q^2-dependence of form factors in addition to the usual vector meson B^{*}-pole diagram for $B --> \pi l\nu$ in the above framework. We discuss the predictions in our model, which provide an estimate of |V_{ub}|^2.Comment: 7 pages, Revtex, 5 figure, fig 3 is replaced and some text is adde

Decays of ℓ=1\ell=1 Baryons --- Quark Model versus Large-NcN_c

We study nonleptonic decays of the orbitally excited, \su6 \rep{70}-plet baryons in order to test the hypothesis that the successes of the nonrelativistic quark model have a natural explanation in the large-$N_c$ limit of QCD. By working in a Hartree approximation, we isolate a specific set of operators that contribute to the observed s- and d-wave decays in leading order in $1/N_c$. We fit our results to the current experimental decay data, and make predictions for a number of allowed but unobserved modes. Our tentative conclusion is that there is more to the nonrelativistic quark model of baryons than large-$N_c$.Comment: LaTeX 49pp. (38 pp. landscape), PicTex, PrePicTex, PostPicTex required for 3 figures, Harvard Preprint HUTP-94/A008. (Two additional operators are included, but conclusions are unchanged.

Energy levels of light atoms in strong magnetic fields

In this review article we provide an overview of the field of atomic structure of light atoms in strong magnetic fields. There is a very rich history of this field which dates back to the very birth of quantum mechanics. At various points in the past significant discoveries in science and technology have repeatedly served to rejuvenate interest in atomic structure in strong fields, broadly speaking, resulting in three eras in the development of this field; the historical, the classical and the modern eras. The motivations for studying atomic structure have also changed significantly as time progressed. The review presents a chronological summary of the major advances that occurred during these eras and discusses new insights and impetus gained. The review is concluded with a description of the latest findings and the future prospects for one of the most remarkably cutting-edge fields of research in science today.Comment: 37 pages, 16 figures, 1 tabl

Precision Astrometry of a Sample of Speckle Binaries and Multiples with the Adaptive Optics Facilities at the Hale and Keck II Telescopes

Using the adaptive optics facilities at the 200-in Hale and 10-m Keck II, we observed in the near infrared a sample of 12 binary and multiple stars and one open cluster. We used the near diffraction limited images of these systems to measure the relative separations and position angles between their components. In this paper, we investigate and correct for the influence of the differential chromatic refraction and chip distortions on our relative astrometric measurements. Over one night, we achieve an astrometric precision typically well below 1 miliarcsecond and occasionally as small as 40 microarcseconds. Such a precision is in principle sufficient to astrometrically detect planetary mass objects around the components of nearby binary and multiple stars. Since we have not had sufficiently large data sets for the observed sample of stars to detect planets, we provide the limits to planetary mass objects based on the obtained astrometric precision.Comment: 18 pages, 8 figures, 9 tables, to appear in MNRA

Changes in duodenal tissue-associated microbiota following hookworm infection and consecutive gluten challenges in humans with coeliac disease

A reduced diversity of the gastrointestinal commensal microbiota is associated with the development of several inflammatory diseases. Recent reports in humans and animal models have demonstrated the beneficial therapeutic effects of infections by parasitic worms (helminths) in some inflammatory disorders, such as inflammatory bowel disease (IBD) and coeliac disease (CeD). Interestingly, these studies have described how helminths may alter the intestinal microbiota, potentially representing a mechanism by which they regulate inflammation. However, for practical reasons, these reports have primarily analysed the faecal microbiota. In the present investigation, we have assessed, for the first time, the changes in the microbiota at the site of infection by a parasitic helminth (hookworm) and gluten-dependent inflammation in humans with CeD using biopsy tissue from the duodenum. Hookworm infection and gluten exposure were associated with an increased abundance of species within the Bacteroides phylum, as well as increases in the richness and diversity of the tissue-resident microbiota within the intestine, results that are consistent with previous reports using other helminth species in humans and animal models. Hence, this may represent a mechanism by which parasitic helminths may restore intestinal immune homeostasis and exert a therapeutic benefit in CeD, and potentially other inflammatory disorders.This work was supported by grants 613718 to P.G., and 1037304 and 1020114 to A.L. from the National Health and Medical Research Council of Australia (NHMRC), and by the Royal Society and the Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grants Scheme to C.C. T.J. is supported by scholarships from the Biotechnology and Biological Sciences Research Council (BBSRC) Doctoral Training Partnerships program

The case for inclusive area profiling applied in geographic information systems

This paper introduces the history and role of consultation processes of contemporary planning and, after presenting the popularity and criticisms of different practices including communities in urban decision making, it explores how rational planning tools like the geographic information system (GIS) could be exploited to reshape consultation and formally include subjective data in traditional area profiling. Focusing on the popular consultation tool of community mapping, primary and secondary research methods (a literature review, seven interviews to planners and two observational studies) identified seven different problems with contemporary community mapping: spatial and temporal scale, generalisation, integration, representativeness, accessibility, relatedness and visualisation. The conceptualisation, physical modelling and testing of a new community mapping procedure ‘Submap’ is then used to address these problems and discuss (a) the strengths and limitations of formalising community mapping activities for area profiling in GIS and (b) the role of pragmatic research in promoting inclusive practices in contemporary planning

Initial conditions, Discreteness and non-linear structure formation in cosmology

In this lecture we address three different but related aspects of the initial continuous fluctuation field in standard cosmological models. Firstly we discuss the properties of the so-called Harrison-Zeldovich like spectra. This power spectrum is a fundamental feature of all current standard cosmological models. In a simple classification of all stationary stochastic processes into three categories, we highlight with the name ``super-homogeneous'' the properties of the class to which models like this, with $P(0)=0$, belong. In statistical physics language they are well described as glass-like. Secondly, the initial continuous density field with such small amplitude correlated Gaussian fluctuations must be discretised in order to set up the initial particle distribution used in gravitational N-body simulations. We discuss the main issues related to the effects of discretisation, particularly concerning the effect of particle induced fluctuations on the statistical properties of the initial conditions and on the dynamical evolution of gravitational clustering.Comment: 28 pages, 1 figure, to appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, eds N.G. Sanchez and Y.M. Pariiski, uses crckapb.st pages, 3 figure, ro appear in Proceedings of 9th Course on Astrofundamental Physics, International School D. Chalonge, Kluwer, Eds. N.G. Sanchez and Y.M. Pariiski, uses crckapb.st