Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5MBq labelled antibody conjugate (1.11GBq/mg) 2 days after an intravenous graft of 5·106 Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300µg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with 149Tb is worthy of consideration as a new-generation radio-immunotherapeutic approac

In silico assessment of potential druggable pockets on the surface of α1-Antitrypsin conformers

The search for druggable pockets on the surface of a protein is often performed on a single conformer, treated as a rigid body. Transient druggable pockets may be missed in this approach. Here, we describe a methodology for systematic in silico analysis of surface clefts across multiple conformers of the metastable protein α1-antitrypsin (A1AT). Pathological mutations disturb the conformational landscape of A1AT, triggering polymerisation that leads to emphysema and hepatic cirrhosis. Computational screens for small molecule inhibitors of polymerisation have generally focused on one major druggable site visible in all crystal structures of native A1AT. In an alternative approach, we scan all surface clefts observed in crystal structures of A1AT and in 100 computationally produced conformers, mimicking the native solution ensemble. We assess the persistence, variability and druggability of these pockets. Finally, we employ molecular docking using publicly available libraries of small molecules to explore scaffold preferences for each site. Our approach identifies a number of novel target sites for drug design. In particular one transient site shows favourable characteristics for druggability due to high enclosure and hydrophobicity. Hits against this and other druggable sites achieve docking scores corresponding to a Kd in the µM–nM range, comparing favourably with a recently identified promising lead. Preliminary ThermoFluor studies support the docking predictions. In conclusion, our strategy shows considerable promise compared with the conventional single pocket/single conformer approach to in silico screening. Our best-scoring ligands warrant further experimental investigation

Composite modelling of the interactions between beaches and structures

An overview of Composite Modelling (CM) is presented, as elaborated in the EU/HYDRALAB joint research project Composite Modelling of the Interactions Between Beaches and Structures. An ntroduction and are view of the main literature on CM in the hydraulic community are given. In Section 3, the case studies of CM of the seven partners participating in this project are discussed. The focus is on the methodologies used and their impact on the modeling approach, rather than the results of the experiment sperse. A further section presents reflections on key elements in CM, as they emerged in the various case studies. The related subject of Good Modelling Practice is summarized in Section5. Then guidelines are given on how to decide if CM may be beneficial, and how to set up a CM experiment. It is concluded that CM in the hydraulic community is still in its infancy but involves challenging research with significant potential

Taming the Invisible Monster: System Parameter Constraints for Epsilon Aurigae from the Far-Ultraviolet to the Mid-Infrared

We have assembled new Spitzer Space Telescope Infrared Array Camera observations of the mysterious binary star Epsilon Aurigae, along with archival far-ultraviolet to mid-infrared data, to form an unprecedented spectral energy distribution spanning three orders of magnitude in wavelength from 0.1 microns to 100 microns. The observed spectral energy distribution can be reproduced using a three component model consisting of a 2.2+0.9/-0.8 Msun F type post-asymptotic giant branch star, and a 5.9+/-0.8 Msun B5+/-1 type main sequence star that is surrounded by a geometrically thick, but partially transparent, disk of gas and dust. At the nominal HIPPARCOS parallax distance of 625 pc, the model normalization yields a radius of 135+/-5 Rsun for the F star, consistent with published interferometric observations. The dusty disk is constrained to be viewed at an inclination of i > 87 deg, and has effective temperature of 550+/-50 K with an outer radius of 3.8 AU and a thickness of 0.95 AU. The dust content of the disk must be largely confined to grains larger than ~10 microns in order to produce the observed gray optical-infrared eclipses and the lack of broad dust emission features in the archival Spitzer mid-infrared spectra. The total mass of the disk, even considering a potential gaseous contribution in addition to the dust that produces the observed infrared excess, is << 1 Msun. We discuss evolutionary scenarios for this system that could lead to the current status of the stellar components and suggests possibilities for its future evolution, as well as potential observational tests of our model.Comment: 13 pages, 3 figures. Accepted for publication in The Astrophysical Journal

The Orbital Solution and Spectral Classification of the High-Mass X-Ray Binary IGR J01054-7253 in the Small Magellanic Cloud

We present X-ray and optical data on the Be/X-ray binary (BeXRB) pulsar IGR J01054-7253 = SXP11.5 in the Small Magellanic Cloud (SMC). Rossi X-ray Timing Explorer (RXTE) observations of this source in a large X-ray outburst reveal an 11.483 +/- 0.002s pulse period and show both the accretion driven spin-up of the neutron star and the motion of the neutron star around the companion through Doppler shifting of the spin period. Model fits to these data suggest an orbital period of 36.3 +/- 0.4d and Pdot of (4.7 +/- 0.3) x 10^{-10} ss^{-1}. We present an orbital solution for this system, making it one of the best described BeXRB systems in the SMC. The observed pulse period, spin-up and X-ray luminosity of SXP11.5 in this outburst are found to agree with the predictions of neutron star accretion theory. Timing analysis of the long-term optical light curve reveals a periodicity of 36.70 +/- 0.03d, in agreement with the orbital period found from the model fit to the X-ray data. Using blue-end spectroscopic observations we determine the spectral type of the counterpart to be O9.5-B0 IV-V. This luminosity class is supported by the observed V-band magnitude. Using optical and near-infrared photometry and spectroscopy, we study the circumstellar environment of the counterpart in the months after the X-ray outburst.Comment: 12 pages, 13 figures and 3 tables. This paper has been accepted for publication in MNRA

Highly absorbed X-ray binaries in the Small Magellanic Cloud

Many of the high mass X-ray binaries (HMXRBs) discovered in recent years in our Galaxy are characterized by a high absorption, most likely intrinsic to the system, which hampers their detection at the softest X-ray energies. We have undertaken a search for highly-absorbed X-ray sources in the Small Magellanic Cloud (SMC) with a systematic analysis of 62 XMM-Newton SMC observations. We obtained a sample of 30 sources showing evidence for an equivalent hydrogen column density larger than 3x10^23 cm^-2. Five of these sources are clearly identified as HMXRBs: four were already known (including three X-ray pulsars) and one, XMM J005605.8-720012, reported here for the first time. For the latter, we present optical spectroscopy confirming the association with a Be star in the SMC. The other sources in our sample have optical counterparts fainter than magnitude ~16 in the V band, and many of them have possible NIR counterparts consistent with highly reddened early type stars in the SMC. While their number is broadly consistent with the expected population of background highly-absorbed active galactic nuclei, a few of them could be HMXRBs in which an early type companion is severely reddened by local material.Comment: 10 pages, 4 figures, 4 tables. Accepted for publication by Astronomy & Astrophysic

Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 rnRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19//GF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS

The Phyre2 web portal for protein modeling, prediction and analysis

Phyre2 is a suite of tools available on the web to predict and analyze protein structure, function and mutations. The focus of Phyre2 is to provide biologists with a simple and intuitive interface to state-of-the-art protein bioinformatics tools. Phyre2 replaces Phyre, the original version of the server for which we previously published a paper in Nature Protocols. In this updated protocol, we describe Phyre2, which uses advanced remote homology detection methods to build 3D models, predict ligand binding sites and analyze the effect of amino acid variants (e.g., nonsynonymous SNPs (nsSNPs)) for a user's protein sequence. Users are guided through results by a simple interface at a level of detail they determine. This protocol will guide users from submitting a protein sequence to interpreting the secondary and tertiary structure of their models, their domain composition and model quality. A range of additional available tools is described to find a protein structure in a genome, to submit large number of sequences at once and to automatically run weekly searches for proteins that are difficult to model. The server is available at http://www.sbg.bio.ic.ac.uk/phyre2. A typical structure prediction will be returned between 30 min and 2 h after submission

Stronger diversity effects with increased environmental stress : a study of multitrophic interactions between oak, powdery mildew and ladybirds

Recent research has suggested that increasing neighbourhood tree species diversity may mitigate the impact of pests or pathogens by supporting the activities of their natural enemies and/or reducing the density of available hosts. In this study, we attempted to assess these mechanisms in a multitrophic study system of young oak (Quercus), oak powdery mildew (PM, caused by Erysiphe spp.) and a mycophagous ladybird (Psyllobora vigintiduo-punctata). We assessed ladybird mycophagy on oak PM in function of different neighbourhood tree species compositions. We also evaluated whether these species interactions were modulated by environmental conditions as suggested by the Stress Gradient Hypothesis. We adopted a complementary approach of a field experiment where we monitored oak saplings subjected to a reduced rainfall gradient in a young planted forest consisting of different tree species mixtures, as well as a lab experiment where we independently evaluated the effect of different watering treatments on PM infections and ladybird mycophagy. In the field experiment, we found effects of neighbourhood tree species richness on ladybird mycophagy becoming more positive as the target trees received less water. This effect was only found as weather conditions grew drier. In the lab experiment, we found a preference of ladybirds to graze on infected leaves from trees that received less water. We discuss potential mechanisms that might explain this preference, such as emissions of volatile leaf chemicals. Our results are in line with the expectations of the Natural Enemies Hypothesis and support the hypothesis that biodiversity effects become stronger with increased environmental stress

DEM L241, a Supernova Remnant containing a High-Mass X-ray Binary

A Chandra observation of the Large Magellanic Cloud supernova remnant DEM L241 reveals an interior unresolved source which is probably an accretion-powered binary. The optical counterpart is an O5III(f) star making this a High-Mass X-ray Binary (HMXB) with orbital period likely to be of order tens of days. Emission from the remnant interior is thermal and spectral information is used to derive density and mass of the hot material. Elongation of the remnant is unusual and possible causes of this are discussed. The precursor star probably had mass > 25 solar masse