Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major

Background The macrophage infectivity potentiator (Mip) protein, which belongs to the immunophilin superfamily, is a peptidyl-prolyl cis/trans isomerase (PPIase) enzyme. Mip has been shown to be important for virulence in a wide range of pathogenic microorganisms. It has previously been demonstrated that small-molecule compounds designed to target Mip from the Gram-negative bacterium Burkholderia pseudomallei bind at the site of enzymatic activity of the protein, inhibiting the in vitro activity of Mip. Objectives In this study, co-crystallography experiments with recombinant B. pseudomallei Mip (BpMip) protein and Mip inhibitors, biochemical analysis and computational modelling were used to predict the efficacy of lead compounds for broad-spectrum activity against other pathogens. Methods Binding activity of three lead compounds targeting BpMip was verified using surface plasmon resonance spectroscopy. The determination of crystal structures of BpMip in complex with these compounds, together with molecular modelling and in vitro assays, was used to determine whether the compounds have broad-spectrum antimicrobial activity against pathogens. Results Of the three lead small-molecule compounds, two were effective in inhibiting the PPIase activity of Mip proteins from Neisseria meningitidis, Klebsiella pneumoniae and Leishmania major. The compounds also reduced the intracellular burden of these pathogens using in vitro cell infection assays. Conclusions These results indicate that Mip is a novel antivirulence target that can be inhibited using small-molecule compounds that prove to be promising broad-spectrum drug candidates in vitro. Further optimization of compounds is required for in vivo evaluation and future clinical applications

Cross-Correlation of the Cosmic Microwave Background with the 2MASS Galaxy Survey: Signatures of Dark Energy, Hot Gas, and Point Sources

We cross-correlate the Cosmic Microwave Background (CMB) temperature anisotropies observed by the Wilkinson Microwave Anisotropy Probe (WMAP) with the projected distribution of extended sources in the Two Micron All Sky Survey (2MASS). By modelling the theoretical expectation for this signal, we extract the signatures of dark energy (Integrated Sachs-Wolfe effect;ISW), hot gas (thermal Sunyaev-Zeldovich effect;thermal SZ), and microwave point sources in the cross-correlation. Our strongest signal is the thermal SZ, at the 3.1-3.7 \sigma level, which is consistent with the theoretical prediction based on observations of X-ray clusters. We also see the ISW signal at the 2.5 \sigma level, which is consistent with the expected value for the concordance LCDM cosmology, and is an independent signature of the presence of dark energy in the universe. Finally, we see the signature of microwave point sources at the 2.7 \sigma level.Comment: 35 pages (preprint format), 8 figures. In addition to minor revisions based on referee's comments, after correcting for a bug in the code, the SZ detection is consistent with the X-ray observations. Accepeted for publication in Physical Review

The 2dF Galaxy Redshift Survey: the dependence of galaxy clustering on luminosity and spectral type

We investigate the dependence of galaxy clustering on luminosity and spectral type using the 2dF Galaxy Redshift Survey (2dFGRS). Spectral types are assigned using the principal-component analysis of Madgwick et al. We divide the sample into two broad spectral classes: galaxies with strong emission lines ('late types') and more quiescent galaxies ('early types'). We measure the clustering in real space, free from any distortion of the clustering pattern owing to peculiar velocities, for a series of volume-limited samples. The projected correlation functions of both spectral types are well described by a power law for transverse separations in the range 2<(σ/h-1 Mpc)<15, with a marginally steeper slope for early types than late types. Both early and late types have approximately the same dependence of clustering strength on luminosity, with the clustering amplitude increasing by a factor of 2.5 between L* and 4L*. At all luminosities, however, the correlation function amplitude for the early types is 50 per cent higher than that of the late types. These results support the view that luminosity, and not type, is the dominant factor in determining how the clustering strength of the whole galaxy population varies with luminosity

Galaxy And Mass Assembly (GAMA): data release 4 and the z < 0.1 total and z < 0.08 morphological galaxy stellar mass functions

Galaxie

An interfaith polemic of medieval anatolia:Qāḍī burhān al-dīn al-anawī on the armenians and their heresies

The sources for the study of the relationship between Muslims and non-Muslims in medieval Anatolia are overwhelmingly Christian. The Muslim world of course had a rich tradition of writing about non-Muslims, through both specialised works like heresiographies and polemics as well as more general literature such as history and poetry. Indeed, such specialised works were often composed in areas which probably did not have much of a Christian population at all. For instance, ʿAbd al-Jabbār’s Tathbīt Dalāʾil al-Nubuwwa, produced in Buyid Rayy in the late tenth century, shows a profound knowledge of Christian doctrine, and discusses the Bible, church rituals and Christian claims to miracles.1 Naturally, works dealing with Christianity were also regularly produced in areas with a significant Christian population, such as Spain, as has been meticulously documented by David Thomas and Alex Mallet in their Bibliographical History of Christian-Muslim relations.2.</p

Introduction:The Ottoman Empire and its Frontiers

Stretching across Europe, Asia and Africa for half a millennium bridging the end of the Middle Ages and the early twentieth century, the Ottoman Empire was one of the major forces that forged the modern world. The chapters in this book focus on four key themes: frontier fortifications, the administration of the frontier, frontier society and relations between rulers and ruled, and the economy of the frontier. Through snapshots of aspects of Ottoman frontier policies in such diverse times and places as fifteenth-century Anatolia, seventeenth-century Hungary, nineteenth-century Iraq or twentieth-century Jordan, the book provides a richer picture than hitherto available of how this complex empire coped with the challenge of administering and defending disparate territories in an age of comparatively primitive communications. By way of introduction, this chapter seeks to provide an overview of these four themes in the history of Ottoman frontiers.</p

Aḥmad of Niğde's al-Walad al-Shafῑq and the Seljuk past

The unpublished unique manuscript of the 14th century Persian work known as al-Walad al-Shafiq (‘The Compassionate Child’) held in the Süleymaniye Library in Istanbul has hitherto never been studied in detail, although it is of considerable importance as a source for medieval Anatolia. This article assesses al-Walad al-Shafiq in the context of the Persian historiography of Anatolia and the historical milieu in which it was composed, arguing that the work is characterised by a sense of loyalty to the vanished Seljuk dynasty that ruled much of Anatolia from the late 11th to the early 14th century. I also examine such information as has survived about the life and background of its author, Qāḍῑ, Aḥmad of Niğde, and consider why the work was written and for whom.</p

Mediaeval Islamic historiography and political legitimacy:Bal'ami's Tarikhnamah

The Tarikhnamah is a history of the world and the oldest surviving work of Persian prose. This book examines it as a political and cultural document and why it became such an influential work in the Islamic world.</p