Practical Spectrophotometric Assay for the \u3cem\u3edapE\u3c/em\u3e-Encoded \u3cem\u3eN\u3c/em\u3e-Succinyl-L,L-Diaminopimelic Acid Desuccinylase, a Potential Antibiotic Target

A new enzymatic assay for the bacterial enzyme succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) is described. This assay employs N6-methyl-N2-succinyl-L,L-diaminopimelic acid (N6-methyl-L,L-SDAP) as the substrate with ninhydrin used to detect cleavage of the amide bond of the modified substrate, wherein N6-methylation enables selective detection of the primary amine enzymatic product. Molecular modeling supported preparation of the mono-N6-methylated-L,L-SDAP as an alternate substrate for the assay, given binding in the active site of DapE predicted to be comparable to the endogenous substrate. The alternate substrate for the assay, N6-methyl-L,L-SDAP, was synthesized from the tert-butyl ester of Boc-L-glutamic acid employing a Horner-Wadsworth-Emmons olefination followed by an enantioselective reduction employing Rh(I)(COD)(S,S)-Et-DuPHOS as the chiral catalyst. Validation of the new ninhydrin assay was demonstrated with known inhibitors of DapE from Haemophilus influenza (HiDapE) including captopril (IC50 = 3.4 [± 0.2] μM, 3-mercaptobenzoic acid (IC50 = 21.8 [±2.2] μM, phenylboronic acid (IC50 = 316 [± 23.6] μM, and 2-thiopheneboronic acid (IC50 = 111 [± 16] μM. Based on these data, this assay is simple and robust, and should be amenable to high-throughput screening, which is an important step forward as it opens the door to medicinal chemistry efforts toward the discovery of DapE inhibitors that can function as a new class of antibiotics

Open Heterotic Strings

We classify potential cosmic strings according to the topological charge measurable outside the string core. We conjecture that in string theory it is this charge that governs the stability of long strings. This would imply that the SO(32) heterotic string can have endpoints, but not the E_8 x E_8 heterotic string. We give various arguments in support of this conclusion.Comment: 15 pages. v.2: typos, references correcte

The SuperMACHO Microlensing Survey

We present the first results from our next-generation microlensing survey, the SuperMACHO project. We are using the CTIO 4m Blanco telescope and the MOSAIC imager to carry out a search for microlensing toward the Large Magellanic Cloud (LMC). We plan to ascertain the nature of the population responsible for the excess microlensing rate seen by the MACHO project. Our observing strategy is optimized to measure the differential microlensing rate across the face of the LMC. We find this derivative to be relatively insensitive to the details of the LMC's internal structure but a strong discriminant between Galactic halo and LMC self lensing. In December 2003 we completed our third year of survey operations. 2003 also marked the first year of real-time microlensing alerts and photometric and spectroscopic followup. We have extracted several dozen microlensing candidates, and we present some preliminary light curves and related information. Similar to the MACHO project, we find SNe behind the LMC to be a significant contaminant - this background has not been completely removed from our current single-color candidate sample. Our follow-up strategy is optimized to discriminate between SNe and true microlensing.Comment: To appear in Proceedings of IAU Symposium 225: Impact of Gravitational Lensing on Cosmology, 6 page

Spectral Identification of an Ancient Supernova using Light Echoes in the LMC

We report the successful identification of the type of the supernova responsible for the supernova remnant SNR 0509-675 in the Large Magellanic Cloud (LMC) using Gemini spectra of surrounding light echoes. The ability to classify outbursts associated with centuries-old remnants provides a new window into several aspects of supernova research and is likely to be successful in providing new constraints on additional LMC supernovae as well as their historical counterparts in the Milky Way Galaxy (MWG). The combined spectrum of echo light from SNR 0509-675 shows broad emission and absorption lines consistent with a supernova (SN) spectrum. We create a spectral library consisting of 26 SNe Ia and 6 SN Ib/c that are time-integrated, dust-scattered by LMC dust, and reddened by the LMC and MWG. We fit these SN templates to the observed light echo spectrum using $\chi^2$ minimization as well as correlation techniques, and we find that overluminous 91T-like SNe Ia with \dm15<0.9 match the observed spectrum best.Comment: 12 pages, 18 Figures, to be published in Ap

Pushing the Boundaries of Conventional Core-Collapse Supernovae: The Extremely Energetic Supernova SN 2003ma

We report the discovery of a supernova (SN) with the highest apparent energy output to date and conclude that it represents an extreme example of the Type IIn subclass. The SN, which was discovered behind the Large Magellanic Cloud at z = 0.289 by the SuperMACHO microlensing survey, peaked at M_R = -21.5 mag and only declined by 2.9 mag over 4.7 years after the peak. Over this period, SN 2003ma had an integrated bolometric luminosity of 4 x 10^51 ergs, more than any other SN to date. The radiated energy is close to the limit allowed by conventional core-collapse explosions. Optical spectra reveal that SN 2003ma has persistent single-peaked intermediate-width hydrogen lines, a signature of interaction between the SN and a dense circumstellar medium. The light curves show further evidence for circumstellar interaction, including a long plateau with a shape very similar to the classic SN IIn 1988Z -- however, SN 2003ma is ten times more luminous at all epochs. The fast velocity measured for the intermediate-width H_alpha component (~6000 km/s) points towards an extremely energetic explosion (> 10^52 ergs), which imparts a faster blast-wave speed to the post-shock material and a higher luminosity from the interaction than is observed in typical SNe IIn. Mid-infrared observations of SN 2003ma suggest an infrared light echo is produced by normal interstellar dust at a distance ~0.5 pc from the SN.Comment: 21 pages, 15 figures, accepted for publication in Ap

The SuperMacho Project: Wide-field, Time-domain Survey of the Large Magellanic Cloud

The MACHO Project sought evidence for Massive Compact Halo Objects (MACHO) by surveying for the gravitational effort of the objects on light, microlensing

The impact of Cochrane Systematic Reviews : a mixed method evaluation of outputs from Cochrane Review Groups supported by the UK National Institute for Health Research

© 2014 Bunn et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: There has been a growing emphasis on evidence-informed decision making in health care. Systematic reviews, such as those produced by the Cochrane Collaboration, have been a key component of this movement. The UK National Institute for Health Research (NIHR) Systematic Review Programme currently supports 20 Cochrane Review Groups (CRGs). The aim of this study was to identify the impacts of Cochrane reviews published by NIHR funded CRGs during the years 2007-11. Methods: We sent questionnaires to CRGs and review authors, interviewed guideline developers and used bibliometrics and documentary review to get an overview of CRG impact and to evaluate the impact of a sample of 60 Cochrane reviews. We used a framework with four categories (knowledge production, research targeting, informing policy development, and impact on practice/services). Results: A total of 1502 new and updated reviews were produced by the 20 NIHR funded CRGs between 2007-11. The clearest impacts were on policy with a total of 483 systematic reviews cited in 247 sets of guidance; 62 were international, 175 national (87 from the UK) and 10 local. Review authors and CRGs provided some examples of impact on practice or services, for example safer use of medication, the identification of new effective drugs or treatments and potential economic benefits through the reduction in the use of unproven or unnecessary procedures. However, such impacts are difficult to objectively document and the majority of reviewers were unsure if their review had produced specific impacts. Qualitative data suggested that Cochrane reviews often play an instrumental role in informing guidance although a poor fit with guideline scope or methods, reviews being out of date and a lack of communication between CRGs and guideline developers were barriers to their use. Conclusions: Health and economic impacts of research are generally difficult to measure. We found that to be the case with this evaluation. Impacts on knowledge production and clinical guidance were easier to identify and substantiate than those on clinical practice. Questions remain about how we define and measure impact and more work is needed to develop suitable methods for impact analysis.Peer reviewe

Attracting volunteers in highly multicultural societies: a marketing challenge

Volunteer managers face a typical marketing problem: how to identify the right consumers (in this case, volunteers), attract them, and keep them loyal. In multicultural societies this challenge is amplified because of the different groups originating from countries that can vary significantly in terms of the extent of volunteering and reasons for being involved. The consequence of this heterogeneity is limited success of generic marketing campaigns. Using the theory of planned behavior, we investigate differences between Australian residents from different cultural backgrounds in their volunteering behavior. Groups differed in attitude, social norm, and perceived behavioral control, suggesting the need for customized marketing strategies. Theoretically, results provide evidence that volunteers in multicultural societies cannot be viewed as one homogeneous mass. Practically, results offer insight into the factors influencing the behavior of each cultural group, and can inform customized campaigns to tap into the large base of volunteers from different backgrounds

Quantum Gravity from Noncommutative Spacetime

We review a novel and authentic way to quantize gravity. This novel approach is based on the fact that Einstein gravity can be formulated in terms of a symplectic geometry rather than a Riemannian geometry in the context of emergent gravity. An essential step for emergent gravity is to realize the equivalence principle, the most important property in the theory of gravity (general relativity), from U(1) gauge theory on a symplectic or Poisson manifold. Through the realization of the equivalence principle, which is an intrinsic property in symplectic geometry known as the Darboux theorem or the Moser lemma, one can understand how diffeomorphism symmetry arises from noncommutative U(1) gauge theory; thus, gravity can emerge from the noncommutative electromagnetism, which is also an interacting theory. As a consequence, a background-independent quantum gravity in which the prior existence of any spacetime structure is not a priori assumed but is defined by using the fundamental ingredients in quantum gravity theory can be formulated. This scheme for quantum gravity can be used to resolve many notorious problems in theoretical physics, such as the cosmological constant problem, to understand the nature of dark energy, and to explain why gravity is so weak compared to other forces. In particular, it leads to a remarkable picture of what matter is. A matter field, such as leptons and quarks, simply arises as a stable localized geometry, which is a topological object in the defining algebra (noncommutative $\star$-algebra) of quantum gravity.Comment: 97 pages, to be published in J. Korean Phys. So