A target repurposing approach identifies N-myristoyltransferase as a new candidate drug target in filarial nematodes

Myristoylation is a lipid modification involving the addition of a 14-carbon unsaturated fatty acid, myristic acid, to the N-terminal glycine of a subset of proteins, a modification that promotes their binding to cell membranes for varied biological functions. The process is catalyzed by myristoyl-CoA:protein N-myristoyltransferase (NMT), an enzyme which has been validated as a drug target in human cancers, and for infectious diseases caused by fungi, viruses and protozoan parasites. We purified Caenorhabditis elegans and Brugia malayi NMTs as active recombinant proteins and carried out kinetic analyses with their essential fatty acid donor, myristoyl-CoA and peptide substrates. Biochemical and structural analyses both revealed that the nematode enzymes are canonical NMTs, sharing a high degree of conservation with protozoan NMT enzymes. Inhibitory compounds that target NMT in protozoan species inhibited the nematode NMTs with IC50 values of 2.5-10 nM, and were active against B. malayi microfilariae and adult worms at 12.5 µM and 50 µM respectively, and C. elegans (25 µM) in culture. RNA interference and gene deletion in C. elegans further showed that NMT is essential for nematode viability. The effects observed are likely due to disruption of the function of several downstream target proteins. Potential substrates of NMT in B. malayi are predicted using bioinformatic analysis. Our genetic and chemical studies highlight the importance of myristoylation in the synthesis of functional proteins in nematodes and have shown for the first time that NMT is required for viability in parasitic nematodes. These results suggest that targeting NMT could be a valid approach for the development of chemotherapeutic agents against nematode diseases including filariasis

Debris Disks: Probing Planet Formation

Debris disks are the dust disks found around ~20% of nearby main sequence stars in far-IR surveys. They can be considered as descendants of protoplanetary disks or components of planetary systems, providing valuable information on circumstellar disk evolution and the outcome of planet formation. The debris disk population can be explained by the steady collisional erosion of planetesimal belts; population models constrain where (10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size) typically form in protoplanetary disks. Gas is now seen long into the debris disk phase. Some of this is secondary implying planetesimals have a Solar System comet-like composition, but some systems may retain primordial gas. Ongoing planet formation processes are invoked for some debris disks, such as the continued growth of dwarf planets in an unstirred disk, or the growth of terrestrial planets through giant impacts. Planets imprint structure on debris disks in many ways; images of gaps, clumps, warps, eccentricities and other disk asymmetries, are readily explained by planets at >>5au. Hot dust in the region planets are commonly found (<5au) is seen for a growing number of stars. This dust usually originates in an outer belt (e.g., from exocomets), although an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018

Evolution from protoplanetary to debris discs: The transition disc around HD 166191

HD 166191 has been identified by several studies as hosting a rare and extremely bright warm debris disc with an additional outer cool disc component. However, an alternative interpretation is that the star hosts a disc that is currently in transition between a full gas disc and a largely gas-free debris disc. With the help of new optical to mid-IR spectra and Herschel imaging, we argue that the latter interpretation is supported in several ways: i) we show that HD 166191 is co-moving with the ~4 Myr-old Herbig Ae star HD 163296, suggesting that the two have the same age, ii) the disc spectrum of HD 166191 is well matched by a standard radiative transfer model of a gaseous protoplanetary disc with an inner hole, and iii) the HD 166191 mid-IR silicate feature is more consistent with similarly primordial objects. We note some potential issues with the debris disc interpretation that should be considered for such extreme objects, whose lifetime at the current brightness is mush shorter than the stellar age, or in the case of the outer component requires a mass comparable to the solid component of the Solar nebula. These aspects individually and collectively argue that HD 166191 is a 4-5 Myr old star that hosts a gaseous transition disc. Though it does not argue in favour of either scenario, we find strong evidence for 3-5 um disc variability. We place HD 166191 in context with discs at different evolutionary stages, showing that it is a potentially important object for understanding the protoplanetary to debris disc transition.Comment: accepted to MNRAS, fixed typos in abstract and axis labe

Linear Stability of Triangular Equilibrium Points in the Generalized Photogravitational Restricted Three Body Problem with Poynting-Robertson Drag

In this paper we have examined the linear stability of triangular equilibrium points in the generalised photogravitational restricted three body problem with Poynting-Robertson drag. We have found the position of triangular equilibrium points of our problem. The problem is generalised in the sense that smaller primary is supposed to be an oblate spheroid. The bigger primary is considered as radiating. The equations of motion are affected by radiation pressure force, oblateness and P-R drag. All classical results involving photogravitational and oblateness in restricted three body problem may be verified from this result. With the help of characteristic equation, we discussed the stability. Finally we conclude that triangular equilibrium points are unstable.Comment: accepted for publication in Journal of Dynamical Systems & Geometric Theories Vol. 4, Number 1 (2006

The NStED Exoplanet Transit Survey Service

The NASA Star and Exoplanet Database (NStED) is a general purpose stellar archive with the aim of providing support for NASA's planet finding and characterization goals, stellar astrophysics, and the planning of NASA and other space missions. There are two principal components of NStED: a database of (currently) 140,000 nearby stars and exoplanet-hosting stars, and an archive dedicated to high-precision photometric surveys for transiting exoplanets. We present a summary of the latter component: the NStED Exoplanet Transit Survey Service (NStED-ETSS), along with its content, functionality, tools, and user interface. NStED-ETSS currently serves data from the TrES Survey of the Kepler Field as well as dedicated photometric surveys of four stellar clusters. NStED-ETSS aims to serve both the surveys and the broader astronomical community by archiving these data and making them available in a homogeneous format. Examples of usability of ETSS include investigation of any time-variable phenomena in data sets not studied by the original survey team, application of different techniques or algorithms for planet transit detections, combination of data from different surveys for given objects, statistical studies, etc. NStED-ETSS can be accessed at \tt{http://nsted.ipac.caltech.edu}Comment: To appear in the Proceedings of the 253rd IAU Symposium: "Transiting Planets", May 2008, Cambridge, MA. 4 pages, 2 figure

From vocational training to education: the development of a no-frontiers education policy for Europe?

This article focuses on developments towards an EU educational policy. Education was not included as one of the Community competencies in the Treaty of Rome. The first half of the article analyses the way that the European Court of Justice and the Commission of the European Communities between them managed to develop a series of substantial Community programmes out of Article 128 on vocational training. The second half of the article discusses educational developments in the community following the Treaty on European Union and the Treaty of Amsterdam. Whilst the legal competence of the community now includes education, the author's argument is that the inclusion of an educational competence will not result in further developments to mirror those in the years before the Treaty on Europe</p

Optimisation of variables for studying dilepton transverse momentum distributions at hadron colliders

In future measurements of the dilepton ($Z/\gamma^*$) transverse momentum, \Qt, at both the Tevatron and LHC, the achievable bin widths and the ultimate precision of the measurements will be limited by experimental resolution rather than by the available event statistics. In a recent paper the variable \at, which corresponds to the component of \Qt\ that is transverse to the dilepton thrust axis, has been studied in this regard. In the region, \Qt\ $<$ 30 GeV, \at\ has been shown to be less susceptible to experimental resolution and efficiency effects than the \Qt. Extending over all \Qt, we now demonstrate that dividing \at\ (or \Qt) by the measured dilepton invariant mass further improves the resolution. In addition, we propose a new variable, \phistarEta, that is determined exclusively from the measured lepton directions; this is even more precisely determined experimentally than the above variables and is similarly sensitive to the \Qt. The greater precision achievable using such variables will enable more stringent tests of QCD and tighter constraints on Monte Carlo event generator tunes.Comment: 8 pages, 5 figures, 2 table