LIAD-fs: A novel method for studies of ultrafast processes in gas phase neutral biomolecules

A new experimental technique for femtosecond (fs) pulse studies of gas phase biomolecules is reported. Using Laser-Induced Acoustic Desorption (LIAD) to produce a plume of neutral molecules, a time-delayed fs pulse is employed for ionisation/fragmentation, with subsequent products extracted and mass analysed electrostatically. By varying critical laser pulse parameters, this technique can be used to implement control over molecular fragmentation for a range of small biomolecules, with specific studies of amino acids demonstrated.

An R-matrix approach for plasma modelling and the interpretation of astrophysical observation

Over the last decade an Auburn-Rollins-Strathclyde consortium has developed several suites of parallel R-matrix codes [1, 2, 3] that can meet the fundamental data needs required for the interpretation of astrophysical observation and/or plasma experiments. Traditionally our collisional work on light fusion-related atoms has been focused towards spectroscopy and impurity transport for magnetically confined fusion devices. Our approach has been to provide a comprehensive data set for the excitation/ionization for every ion stage of a particular element. As we progress towards a burning fusion plasma, there is a demand for the collisional processes involving tungsten, which has required a revitalization of the relativistic R-matrix approach. The implementation of these codes on massively parallel supercomputers has facilitated the progression to models involving thousands of levels in the close-coupling expansion required by the open d and f sub-shell systems of mid Z tungsten. This work also complements the electron-impact excitation of Fe-Peak elements required by astrophysics, in particular the near neutral species, which offer similar atomic structure challenges. Although electron-impact excitation work is our primary focus in terms of fusion application, the single photon photoionisation codes are also being developed in tandem, and benefit greatly from this ongoing work.

PS1-10afx at z = 1.388: Pan-STARRS1 Discovery of a New Type of Superluminous Supernova

We present the Pan-STARRS1 discovery of PS1-10afx, a unique hydrogen-deficient superluminous supernova (SLSN) at redshift z = 1.388. The light curve peaked at z P1 = 21.7 mag, making PS1-10afx comparable to the most luminous known SNe, with Mu = -22.3 mag. Our extensive optical and near-infrared observations indicate that the bolometric light curve of PS1-10afx rose on the unusually fast timescale of ~12 days to the extraordinary peak luminosity of 4.1 × 1044 erg s-1 (M bol = -22.8 mag) and subsequently faded rapidly. Equally important, the spectral energy distribution is unusually red for an SLSN, with a color temperature of ~6800 K near maximum light, in contrast to previous hydrogen-poor SLSNe, which are bright in the ultraviolet (UV). The spectra more closely resemble those of a normal SN Ic than any known SLSN, with a photospheric velocity of ~11, 000 km s-1 and evidence for line blanketing in the rest-frame UV. Despite the fast rise, these parameters imply a very large emitting radius (gsim 5 × 1015 cm). We demonstrate that no existing theoretical model can satisfactorily explain this combination of properties: (1) a nickel-powered light curve cannot match the combination of high peak luminosity with the fast timescale; (2) models powered by the spindown energy of a rapidly rotating magnetar predict significantly hotter and faster ejecta; and (3) models invoking shock breakout through a dense circumstellar medium cannot explain the observed spectra or color evolution. The host galaxy is well detected in pre-explosion imaging with a luminosity near L*, a star formation rate of ~15 M ⊙ yr-1, and is fairly massive (~2 × 1010 M ⊙), with a stellar population age of ~108 yr, also in contrast to the young dwarf hosts of known hydrogen-poor SLSNe. PS1-10afx is distinct from known examples of SLSNe in its spectra, colors, light-curve shape, and host galaxy properties, suggesting that it resulted from a different channel than other hydrogen-poor SLSNe.

N-terminal His(7)-modification of glucagon-like peptide-1(7-36) amide generates dipeptidyl peptidase IV-stable analogues with potent antihyperglycaemic activity

Glucagon-like peptide-1(7-36)amide (GLP-1) possesses several unique and beneficial effects for the potential treatment of type 2 diabetes. However, the rapid in-activation of GLP-1 by dipeptidyl peptidase IV (DPP IV) results in a short half-life in vivo (less than 2 min) hindering therapeutic development. In the present study, a novel His(7)-modified analogue of GLP-1, N-pyroglutamyl-GLP-1, as well as N-acetyl-GLP-1 were synthesised and tested for DPP IV stability and biological activity. Incubation of GLP-1 with either DPP IV or human plasma resulted in rapid degradation of native GLP-1 to GLP-1 (9-36),amide, while N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 were completely resistant to degradation. N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 bound to the GLP-1 receptor but had reduced affinities (IC50 values 32(.)9 and 6(.)7 nM, respectively) compared with native GLP-1 (IC50 0(.)37 nM). Similarly, both analogues stimulated cAMP production with EC50 values of 16(.)3 and 27 nM respectively compared with GLP-1 (EC50 4(.)7 nM). However, N-acetyl-GLP-1 and N-pyroglutamyl-GLP-1 exhibited potent insulinotropic activity in vitro at 5(.)6 mM glucose (P

GPCR structure, function, drug discovery and crystallography: report from Academia-Industry International Conference (UK Royal Society) Chicheley Hall, 1-2 September 2014

G-protein coupled receptors (GPCRs) are the targets of over half of all prescribed drugs today. The UniProt database has records for about 800 proteins classified as GPCRs, but drugs have only been developed against 50 of these. Thus, there is huge potential in terms of the number of targets for new therapies to be designed. Several breakthroughs in GPCRs biased pharmacology, structural biology, modelling and scoring have resulted in a resurgence of interest in GPCRs as drug targets. Therefore, an international conference, sponsored by the Royal Society, with world-renowned researchers from industry and academia was recently held to discuss recent progress and highlight key areas of future research needed to accelerate GPCR drug discovery. Several key points emerged. Firstly, structures for all three major classes of GPCRs have now been solved and there is increasing coverage across the GPCR phylogenetic tree. This is likely to be substantially enhanced with data from x-ray free electron sources as they move beyond proof of concept. Secondly, the concept of biased signalling or functional selectivity is likely to be prevalent in many GPCRs, and this presents exciting new opportunities for selectivity and the control of side effects, especially when combined with increasing data regarding allosteric modulation. Thirdly, there will almost certainly be some GPCRs that will remain difficult targets because they exhibit complex ligand dependencies and have many metastable states rendering them difficult to resolve by crystallographic methods. Subtle effects within the packing of the transmembrane helices are likely to mask and contribute to this aspect, which may play a role in species dependent behaviour. This is particularly important because it has ramifications for how we interpret pre-clinical data. In summary, collaborative efforts between industry and academia have delivered significant progress in terms of structure and understanding of GPCRs and will be essential for resolving problems associated with the more difficult targets in the future.