Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs

From E_8 to F via T

We argue that T-duality and F-theory appear automatically in the E_8 gauge bundle perspective of M-theory. The 11-dimensional supergravity four-form determines an E_8 bundle. If we compactify on a two-torus, this data specifies an LLE_8 bundle where LG is a centrally-extended loopgroup of G. If one of the circles of the torus is smaller than sqrt(alpha') then it is also smaller than a nontrivial circle S in the LLE_8 fiber and so a dimensional reduction on the total space of the bundle is not valid. We conjecture that S is the circle on which the T-dual type IIB theory is compactified, with the aforementioned torus playing the role of the F-theory torus. As tests we reproduce the T-dualities between NS5-branes and KK-monopoles, as well as D6 and D7-branes where we find the desired F-theory monodromy. Using Hull's proposal for massive IIA, this realization of T-duality allows us to confirm that the Romans mass is the central extension of our LE_8. In addition this construction immediately reproduces the conjectured formula for global topology change from T-duality with H-flux.Comment: 25 pages, 4 eps figure

Closed string tachyons, flips and conifolds

Following the analysis of tachyons and orbifold flips described in hep-th/0412337, we study nonsupersymmetric analogs of the supersymmetric conifold singularity and show using their toric geometry description that they are nonsupersymmetric orbifolds of the latter. Using linear sigma models, we see that these are unstable to localized closed string tachyon condensation and exhibit flip transitions between their two small resolutions (involving 2-cycles), in the process mediating mild dynamical topology change. Our analysis shows that the structure of these nonsupersymmetric conifolds as quotients of the supersymmetric conifold obstructs the 3-cycle deformation of such singularities, suggesting that these nonsupersymmetric conifolds decay by evolving towards their stable small resolutions.Comment: Latex, 22 pgs, 2 figs. v4: matches JHEP version, 29 pgs, 3 figures, more elaborate Introduction, various clarifications adde

Perturbative Gauge Theory and Closed String Tachyons

We find an interesting connection between perturbative large N gauge theory and closed superstrings. The gauge theory in question is found on N D3-branes placed at the tip of the cone R^6/Gamma. In our previous work we showed that, when the orbifold group Gamma breaks all supersymmetry, then typically the gauge theory is not conformal because of double-trace couplings whose one-loop beta functions do not possess real zeros. In this paper we observe a precise correspondence between the instabilities caused by the flow of these double-trace couplings and the presence of tachyons in the twisted sectors of type IIB theory on orbifolds R^{3,1}x R^6/Gamma. For each twisted sectors that does not contain tachyons, we show that the corresponding double-trace coupling flows to a fixed point and does not cause an instability. However, whenever a twisted sector is tachyonic, we find that the corresponding one-loop beta function does not have a real zero, hence an instability is likely to exist in the gauge theory. We demonstrate explicitly the one-to-one correspondence between the regions of stability/instability in the space of charges under Gamma that arise in the perturbative gauge theory and in the free string theory. Possible implications of this remarkably simple gauge/string correspondence are discussed.Comment: 25 pages, Latex; V2: Clarifications and references adde

Toda systems in closed string tachyon condensation

We consider $tt^*$ equations appearing in the study of localized tachyon condensations. They are described by various Toda system when we consider the condensation by the lowest tachyon corresponding to the monomial $xy$. The tachyon potential is calculated as a solution to these equations. The Toda system appearing in the deformation of \C^2/\Z_n by $xy$ is identical to that of $D_n$ singularity deformed by $x$. For \C^3/\Z_n with $xyz$ deformation, we find only generic non-simple form, similar to the case appearing in \C/\Z_5\to \C/\Z_3 and we discuss the difficulties in these cases.Comment: 20 pages, no figur

Identification of host odour attractants for tsetse flies. Final report 1986-1990

Tsetse flies, Glossina spp., are blood-feeding insects and vectors of trypanosomes, microorganisms which cause sleeping sickness in man and a similar disease, "nagana" in domestic animals. The economic importance of trypanosomiasis is the constraint it imposes on orderly rural development in Africa, leading to under-exploitation of infested land and over-exploitation and degradation of trypanosomiasis-free areas. Traps and targets which attract tsetse flies and kill them could provide environmentally-acceptable, appropriate technology for monitoring and control of tsetse in Africa. Unbaited devices providing only visual attraction have proved effective in monitoring and control of riverine species of tsetse, but not the savannah species found in the fly belt of Malawi, Mozambique, Zambia and Zimbabwe covered by the EDF Regional Tsetse and Trypanosomiasis Control Project (RTTCP). Previously, collaborative was begun between glossinologists of the Zimbabwe Department of Veterinary Services (DVS) and UK Tsetse Research Laboratory (TRL) and chemists at NRI. This brought together the experience of the DVS in the field, the experience of TRL in laboratory bioassay work, and the experience of NRI in using gas chromatography linked to electroantennography (GC-EAG) and chemical techniques to detect and identify insect behaviour-modifying chemicals. Tsetse attractants produced by host animals were identified and synthesised, and dispensing systems for these compounds devised. Traps and targets impregnated with insecticide, baited with these lures were shown to provide effective control of the savannah tsetse species, G. pallidipes and G. m. morsitans

Asymptotic behaviour of a semilinear elliptic system with a large exponent

Consider the problem \begin{eqnarray*} -\Delta u &=& v^{\frac 2{N-2}},\quad v>0\quad {in}\quad \Omega, -\Delta v &=& u^{p},\:\:\:\quad u>0\quad {in}\quad \Omega, u&=&v\:\:=\:\:0 \quad {on}\quad \partial \Omega, \end{eqnarray*} where $\Omega$ is a bounded convex domain in $\R^N,$ $N>2,$ with smooth boundary $\partial \Omega.$ We study the asymptotic behaviour of the least energy solutions of this system as $p\to \infty.$ We show that the solution remain bounded for $p$ large and have one or two peaks away form the boundary. When one peak occurs we characterize its location.Comment: 16 pages, submmited for publicatio

Search for Exotic Mesons in pi- P Interactions at 18 GeV/c

The recent search for non $q \bar{q}$ mesons in $\pi^{-}p$ interactions at Brookhaven National Laboratory is summarized. Many final states such as $\eta \pi$, $\eta' \pi^{-}$, $a_{0} \pi$, $f_{1} \pi$, $a_{2} \pi$, $b_{1} \pi$, which are favored decay modes of exotics, are under investigation.Comment: 9 pages, PostScript, Presented at the International School of Nuclear Physics, Erice, Sicily, Italy, September 199

Leading strategies in competitive on-line prediction

We start from a simple asymptotic result for the problem of on-line regression with the quadratic loss function: the class of continuous limited-memory prediction strategies admits a "leading prediction strategy", which not only asymptotically performs at least as well as any continuous limited-memory strategy but also satisfies the property that the excess loss of any continuous limited-memory strategy is determined by how closely it imitates the leading strategy. More specifically, for any class of prediction strategies constituting a reproducing kernel Hilbert space we construct a leading strategy, in the sense that the loss of any prediction strategy whose norm is not too large is determined by how closely it imitates the leading strategy. This result is extended to the loss functions given by Bregman divergences and by strictly proper scoring rules.Comment: 20 pages; a conference version is to appear in the ALT'2006 proceeding

Ricci-flat deformation of orbifolds and localized tachyonic modes

We study Ricci-flat deformations of orbifolds in type II theory. We obtain a simple formula for mass corrections to the twisted modes due to the deformations, and apply it to originally tachyonic and massless states in several examples. In the case of supersymmetric orbifolds, we find that tachyonic states appear when the deformation breaks all the supersymmetries. We also study nonsupersymmetric orbifolds C^2/Z_{2N(2N+1)}, which is T-dual to N type 0 NS5-branes. For N>=2, we compute mass corrections for states, which have string scale tachyonic masses. We find that the corrected masses coincide to ones obtained by solving the wave equation for the tachyon field in the smeared type 0 NS5-brane background geometry. For N=1, we show that the unstable mode representing the bubble creation is the unique tachyonic mode.Comment: 20 pages, minor collection