GenoChemetic strategy for derivatization of the violacein natural product scaffold

H.E.L. was supported by an Imperial College President’s Ph.D. Scholarship. We thank UKRI EPSRC (EP/K038648/1, EP/L011573/1 to P.S.F.) and the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC grant agreement no. 614779 GenoChemetics to R.J.M.G.) for funding. A.M.C.O. receives funding from EPSRC CRITICAT, EP/L016419/1.Natural products and their analogues are often challenging to synthesize due to their complex scaffolds and embedded functional groups. Solely relying on engineering the biosynthesis of natural products may lead to limited compound diversity. Integrating synthetic biology with synthetic chemistry allows rapid access to much more diverse portfolios of xenobiotic compounds, which may accelerate the discovery of new therapeutics. As a proof-of-concept, by supplementing an Escherichia coli strain expressing the violacein biosynthesis pathway with 5-bromo-tryptophan in vitro or tryptophan 7-halogenase RebH in vivo, six halogenated analogues of violacein or deoxyviolacein were generated, demonstrating the promiscuity of the violacein biosynthesis pathway. Furthermore, 20 new derivatives were generated from 5-brominated violacein analogues via the Suzuki–Miyaura cross-coupling reaction directly using the crude extract without prior purification. Herein we demonstrate a flexible and rapid approach to access a diverse chemical space that can be applied to a wide range of natural product scaffolds.Publisher PDFPeer reviewe

The Nuclear Security Science and Policy Institute at Texas A&M University

The Nuclear Security Science and Policy Institute (NSSPI) is a multidisciplinary organization at Texas A&M University and was the first U.S. academic institution focused on technical graduate education, research, and service related to the safeguarding of nuclear materials and the reduction of nuclear threats. NSSPI employs science, engineering, and policy expertise to: (1) conduct research and development to help detect, prevent, and reverse nuclear and radiological proliferation and guard against nuclear terrorism; (2) educate the next generation of nuclear security and nuclear nonproliferation leaders; (3) analyze the interrelationships between policy and technology in the field of nuclear security; and (4) serve as a public resource for knowledge and skills to reduce nuclear threats. Since 2006, over 31 Doctoral and 73 Master degrees were awarded through NSSPI-sponsored research. Forty-one of those degrees are Master of Science in Nuclear Engineering with a specialization in Nuclear Nonproliferation and 16 were Doctorate of Philosophy degrees with a specific focus on nuclear nonproliferation. Over 200 students from both technical and policy backgrounds have taken classes provided by NSSPI at Texas A&M. The model for creating safeguards and security experts, which has in large part been replicated worldwide, was established at Texas A&M by NSSPI faculty and staff. In addition to conventional classroom lectures, NSSPI faculty have provided practical experiences; advised students on valuable research projects that have contributed substantially to the overall nuclear nonproliferation, safeguards and security arenas; and engaged several similar academic and research institutes around the world in activities and research for the benefit of Texas A&M students. NSSPI has had an enormous impact on the nuclear nonproliferation workforce (across the international community) in the past 8 years, and this paper is an attempt to summarize the activities accomplished by NSSPI during this time and the future direction of the program

Half-BPS quotients in M-theory: ADE with a twist

We classify Freund-Rubin backgrounds of eleven-dimensional supergravity of the form AdS_4 x X^7 which are at least half BPS; equivalently, smooth quotients of the round 7-sphere by finite subgroups of SO(8) which admit an (N>3)-dimensional subspace of Killing spinors. The classification is given in terms of pairs consisting of an ADE subgroup of SU(2) and an automorphism defining its embedding in SO(8). In particular we find novel half-BPS quotients associated with the subgroups of type D_n (for n>5), E_7 and E_8 and their outer automorphisms.Comment: 16 pages; V2: notational inconsistencies addressed, final version to be published in JHE

Observing Extended Sources with the \Herschel SPIRE Fourier Transform Spectrometer

The Spectral and Photometric Imaging Receiver (SPIRE) on the European Space Agency's Herschel Space Observatory utilizes a pioneering design for its imaging spectrometer in the form of a Fourier Transform Spectrometer (FTS). The standard FTS data reduction and calibration schemes are aimed at objects with either a spatial extent much larger than the beam size or a source that can be approximated as a point source within the beam. However, when sources are of intermediate spatial extent, neither of these calibrations schemes is appropriate and both the spatial response of the instrument and the source's light profile must be taken into account and the coupling between them explicitly derived. To that end, we derive the necessary corrections using an observed spectrum of a fully extended source with the beam profile and the source's light profile taken into account. We apply the derived correction to several observations of planets and compare the corrected spectra with their spectral models to study the beam coupling efficiency of the instrument in the case of partially extended sources. We find that we can apply these correction factors for sources with angular sizes up to \theta_{D} ~ 17". We demonstrate how the angular size of an extended source can be estimated using the difference between the sub-spectra observed at the overlap bandwidth of the two frequency channels in the spectrometer, at 959<\nu<989 GHz. Using this technique on an observation of Saturn, we estimate a size of 17.2", which is 3% larger than its true size on the day of observation. Finally, we show the results of the correction applied on observations of a nearby galaxy, M82, and the compact core of a Galactic molecular cloud, Sgr B2.Comment: Accepted for publication by A&

Microclusters of inhibitory killer immunoglobulin–like receptor signaling at natural killer cell immunological synapses

We report the supramolecular organization of killer Ig–like receptor (KIR) phosphorylation using a technique applicable to imaging phosphorylation of any green fluorescent protein–tagged receptor at an intercellular contact or immune synapse. Specifically, we use fluorescence lifetime imaging (FLIM) to report Förster resonance energy transfer (FRET) between GFP-tagged KIR2DL1 and a Cy3-tagged generic anti-phosphotyrosine monoclonal antibody. Visualization of KIR phosphorylation in natural killer (NK) cells contacting target cells expressing cognate major histocompatibility complex class I proteins revealed that inhibitory signaling is spatially restricted to the immune synapse. This explains how NK cells respond appropriately when simultaneously surveying susceptible and resistant target cells. More surprising, phosphorylated KIR was confined to microclusters within the aggregate of KIR, contrary to an expected homogeneous distribution of KIR signaling across the immune synapse. Also, yellow fluorescent protein–tagged Lck, a kinase important for KIR phosphorylation, accumulated in a multifocal distribution at inhibitory synapses. Spatial confinement of receptor phosphorylation within the immune synapse may be critical to how activating and inhibitory signals are integrated in NK cells

Diagnosis of breast cancer using elastic-scattering spectroscopy: preliminary clinical results

We report on the first stages of a clinical study designed to test elastic-scattering spectroscopy, mediated by fiberoptic probes, for three specific clinical applications in breast-tissue diagnosis: (1) a transdermal-needle (interstitial) measurement for instant diagnosis with minimal invasiveness similar to fine-needle aspiration but with sensitivity to a larger tissue volume, (2) a hand-held diagnostic probe for use in assessing tumor/resection margins during open surgery, and (3) use of the same probe for real-time assessment of the `sentinel' node during surgery to determine the presence or absence of tumor (metastatic). Preliminary results from in vivo measurements on 31 women are encouraging. Optical spectra were measured on 72 histology sites in breast tissue, and 54 histology sites in sentinel nodes. Two different artificial intelligence methods of spectral classification were studied. Artificial neural networks yielded sensitivities of 69% and 58%, and specificities of 85% and 93%, for breast tissue and sentinel nodes, respectively. Hierarchical cluster analysis yielded sensitivities of 67% and 91%, and specificities of 79% and 77%, for breast tissue and sentinel nodes, respectively. These values are expected to improve as the data sets continue to grow and more sophisticated data preprocessing is employed. The study will enroll up to 400 patients over the next two years

Effect of ketoconazole-mediated CYP3A4 inhibition on clinical pharmacokinetics of panobinostat (LBH589), an orally active histone deacetylase inhibitor

Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmaxand AUC of panobinostat, respectively. No substantial change in Tmaxor half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary

Evidence-based national vaccine policy

India has over a century old tradition of development and production of vaccines. The Government rightly adopted self-sufficiency in vaccine production and self-reliance in vaccine technology as its policy objectives in 1986. However, in the absence of a full-fledged vaccine policy, there have been concerns related to demand and supply, manufacture vs. import, role of public and private sectors, choice of vaccines, new and combination vaccines, universal vs. selective vaccination, routine immunization vs. special drives, cost-benefit aspects, regulatory issues, logistics etc. The need for a comprehensive and evidence based vaccine policy that enables informed decisions on all these aspects from the public health point of view brought together doctors, scientists, policy analysts, lawyers and civil society representatives to formulate this policy paper for the consideration of the Government. This paper evolved out of the first ever ICMR-NISTADS national brainstorming workshop on vaccine policy held during 4-5 June, 2009 in New Delhi, and subsequent discussions over email for several weeks, before being adopted unanimously in the present form