Cryo-EM structure of the mature dengue virus at 3.5-Å resolution.

Regulated by pH, membrane-anchored proteins E and M function during dengue virus maturation and membrane fusion. Our atomic model of the whole virion from cryo-electron microscopy at 3.5-Å resolution reveals that in the mature virus at neutral extracellular pH, the N-terminal 20-amino-acid segment of M (involving three pH-sensing histidines) latches and thereby prevents spring-loaded E fusion protein from prematurely exposing its fusion peptide. This M latch is fastened at an earlier stage, during maturation at acidic pH in the trans-Golgi network. At a later stage, to initiate infection in response to acidic pH in the late endosome, M releases the latch and exposes the fusion peptide. Thus, M serves as a multistep chaperone of E to control the conformational changes accompanying maturation and infection. These pH-sensitive interactions could serve as targets for drug discovery

First results of the Kourovka Planet Search: discovery of transiting exoplanet candidates in the first three target fields

We present the first results of our search for transiting exoplanet candidates as part of the Kourovka Planet Search (KPS) project. The primary objective of the project is to search for new hot Jupiters which transit their host stars, mainly in the Galactic plane, in the $R_c$ magnitude range of 11 to 14 mag. Our observations were performed with the telescope of the MASTER robotic network, installed at the Kourovka astronomical observatory of the Ural Federal University (Russia), and the Rowe-Ackermann Schmidt Astrograph, installed at the private Acton Sky Portal Observatory (USA). As test observations, we observed three celestial fields of size $2\times2$ deg$^2$ during the period from 2012 to 2015. As a result, we discovered four transiting exoplanet candidates among the 39000 stars of the input catalogue. In this paper, we provide the description of the project and analyse additional photometric, spectral, and speckle interferometric observations of the discovered transiting exoplanet candidates. Three of the four transiting exoplanet candidates are most likely astrophysical false positives, while the nature of the fourth (most promising) candidate remains to be ascertained. Also, we propose an alternative observing strategy that could increase the project's exoplanet haul.Comment: 11 pages, 16 figures; Accepted for publication in Monthly Notices of the Royal Astronomical Society 201

Mechanical, structural and dissolution properties of heat treated thin-film phosphate based glasses

Here we show the deposition of 2.7 μm thick phosphate based glass films produced by magnetron sputtering, followed by post heat treatments at 500 °C. Variations in degradation properties pre and post heat treatment were attributed to the formation of Hematite crystals within a glass matrix, iron oxidation and the depletion of hydrophilic P-O-P bonds within the surface layer. As deposited and heat treated coatings showed interfacial tensile adhesion in excess of 73.6 MPa; which surpassed ISO and FDA requirements for HA coatings. Scratch testing of coatings on polished substrates revealed brittle failure mechanisms, amplified due to heat treatment and interfacial failure occurring from 2.3 to 5.0 N. Coatings that were deposited onto sandblasted substrates to mimic commercial implant surfaces, did not suffer from tensile cracking or trackside delamination showing substantial interfacial improvements to between 8.6 and 11.3 N. An exponential dissolution rate was observed from 0 to 2 h for as deposited coatings, which was eliminated via heat treatment. From 2 to 24 h ion release rates ordered P > Na > Mg > Ca > Fe whilst all coatings exhibited linear degradation rates, which reduced by factors of 2.4–3.0 following heat treatments

Vibrations of a chain of Xe atoms in a groove of carbon nanotube bundle

We present a lattice dynamics study of the vibrations of a linear chain of Xe adsorbates in groove positions of a bundle of carbon nanotubes. The characteristic phonon frequencies are calculated and the adsorbate polarization vectors discussed. Comparison of the present results with the ones previously published shows that the adsorbate vibrations cannot be treated as completely decoupled from the vibrations of carbon nanotubes and that a significant hybridization between the adsorbate and the tube modes occurs for phonons of large wavelengths.Comment: 3 PS figure

Dissecting Accountability and Effectiveness of International Nongovernmental Organization (INGO) Work: Converging and Diverging Perspectives between Academia and the Field

International Non-governmental Organizations (INGOs) have undergone a dramatic growth and evolution in recent history. Along with the growth in numbers, INGOs have also experienced an increase in their scope of responsibilities, and the freedom and autonomy to implement their policies into practice (Charnovitz, 1997; Iriye, 1999, 2002). However, the twenty-first century has also witnessed a growing body of criticism against INGOs suggesting the increasing demand for INGOs to demonstrate accountability and effectiveness (Charnovitz, 2006; Lister, 2003; Steffek & Hahn, 2010). This thesis explored the perspectives of two INGOs, and their staff members and volunteers on how they view, understand and experience issues of accountability and effectiveness as it relates to their work. Using content analysis of publicly obtainable organizational documents and conducting qualitative interviews with staff members and volunteers, this thesis found that key themes identified are: multi-faceted donor accountability where different donors exert their own pressures on INGOs; the ability to sustainably support Partners working in the Global South as the primary focus of INGO work; the summative and descriptive reporting of impact; and the continuing challenge of conducting impact assessment. This study concludes that despite sampling INGOs using two different models to further the goal of international development, there were more similarities in the issues of accountability and effectiveness faced than differences. By considering the perspectives of INGOs and those working on the field, we can move towards developing constructive approaches that can meaningfully assist INGOs in documenting and assessing their own accountability and effectiveness

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

Benchmarking the power of amateur observatories for TTV exoplanets detection

This document is the Accepted Manuscript version of the following article: Roman v. Baluev, et al, ‘Benchmarking the power of amateur observatories for TTV exoplanets detection’, Monthly Notices of the Royal Astronomical Society, Vol. 450(3): 3101-3113, first published online 9 May 2015. The version of record is available at doi: https://doi.org/10.1093/mnras/stv788 © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.We perform an analysis of ~80000 photometric measurements for the following 10 stars hosting transiting planets: WASP-2, -4, -5, -52, Kelt-1, CoRoT-2, XO-2, TrES-1, HD 189733, GJ 436. Our analysis includes mainly transit lightcurves from the Exoplanet Transit Database, public photometry from the literature, and some proprietary photometry privately supplied by other authors. Half of these lightcurves were obtained by amateurs. From this photometry we derive 306 transit timing measurements, as well as improved planetary transit parameters. Additionally, for 6 of these 10 stars we present a set of radial velocity measurements obtained from the spectra stored in the HARPS, HARPS-N, and SOPHIE archives using the HARPS-TERRA pipeline. Our analysis of these TTV and RV data did not reveal significant hints of additional orbiting bodies in almost all of the cases. In the WASP-4 case, we found hints of marginally significant TTV signals having amplitude 10-20 sec, although their parameters are model-dependent and uncertain, while radial velocities did not reveal statistically significant Doppler signals.Peer reviewe