Avirulent Strains of Toxoplasma Gondii Infect Macrophages by Active Invasion from the Phagosome

Unlike most intracellular pathogens that gain access into host cells through endocytic pathways, Toxoplasma gondii initiates infection at the cell surface by active penetration through a moving junction and subsequent formation of a parasitophorous vacuole. Here, we describe a noncanonical pathway for T. gondii infection of macrophages, in which parasites are initially internalized through phagocytosis, and then actively invade from within a phagosomal compartment to form a parasitophorous vacuole. This phagosome to vacuole invasion (PTVI) pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. The PTVI pathway is preferentially used by avirulent strains of T. gondii and confers an infectious advantage over virulent strains for macrophage tropism

Osteoblasts contribute to a protective niche that supports melanoma cell proliferation and survival

Melanoma is the deadliest form of skin cancer; a primary driver of this high level of morbidity is the propensity of melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions the new local tissue niche is known to impact on the biology of the cancer cells. However, little is known about how different metastatic tissue sites impact on frontline targeted therapies. Intriguingly, melanoma bone lesions have significantly lower response to BRAF or MEK inhibitor therapies. Here, we have investigated how the cellular niche of the bone can support melanoma cells by stimulating growth and survival via paracrine signalling between osteoblasts and cancer cells. Melanoma cells can enhance the differentiation of osteoblasts leading to increased production of secreted ligands, including RANKL. Differentiated osteoblasts in turn can support melanoma cell proliferation and survival via the secretion of RANKL that elevates the levels of the transcription factor MITF, even in the presence of BRAF inhibitor. By blocking RANKL signalling, either via neutralizing antibodies, genetic alterations or the RANKL receptor inhibitor SPD304, the survival advantage provided by osteoblasts could be overcome

The Fitness Landscape of HIV-1 Gag: Advanced Modeling Approaches and Validation of Model Predictions by In Vitro Testing

Viral immune evasion by sequence variation is a major hindrance to HIV-1 vaccine design. To address this challenge, our group has developed a computational model, rooted in physics, that aims to predict the fitness landscape of HIV-1 proteins in order to design vaccine immunogens that lead to impaired viral fitness, thus blocking viable escape routes. Here, we advance the computational models to address previous limitations, and directly test model predictions against in vitro fitness measurements of HIV-1 strains containing multiple Gag mutations. We incorporated regularization into the model fitting procedure to address finite sampling. Further, we developed a model that accounts for the specific identity of mutant amino acids (Potts model), generalizing our previous approach (Ising model) that is unable to distinguish between different mutant amino acids. Gag mutation combinations (17 pairs, 1 triple and 25 single mutations within these) predicted to be either harmful to HIV-1 viability or fitness-neutral were introduced into HIV-1 NL4-3 by site-directed mutagenesis and replication capacities of these mutants were assayed in vitro. The predicted and measured fitness of the corresponding mutants for the original Ising model (r = −0.74, p = 3.6×10−6) are strongly correlated, and this was further strengthened in the regularized Ising model (r = −0.83, p = 3.7×10−12). Performance of the Potts model (r = −0.73, p = 9.7×10−9) was similar to that of the Ising model, indicating that the binary approximation is sufficient for capturing fitness effects of common mutants at sites of low amino acid diversity. However, we show that the Potts model is expected to improve predictive power for more variable proteins. Overall, our results support the ability of the computational models to robustly predict the relative fitness of mutant viral strains, and indicate the potential value of this approach for understanding viral immune evasion, and harnessing this knowledge for immunogen design

A hybrid double-dot in silicon

We report electrical measurements of a single arsenic dopant atom in the tunnel-barrier of a silicon SET. As well as performing electrical characterization of the individual dopant, we study series electrical transport through the dopant and SET. We measure the triple points of this hybrid double dot, using simulations to support our results, and show that we can tune the electrostatic coupling between the two sub-systems.Comment: 11 pages, 6 figure

High Redshift Supernova Rates

We use a sample of 42 supernovae detected with the Advanced Camera for Surveys on-board the Hubble Space Telescope as part of the Great Observatories Origins Deep Survey to measure the rate of core collapse supernovae to z~0.7 and type Ia supernovae to z~1.6. This significantly increases the redshift range where supernova rates have been estimated from observations. The rate of core collapse supernovae can be used as an independent probe of the cosmic star formation rate. Based on the observations of 17 core collapse supernovae, we measure an increase in the core collapse supernova rate by a factor of 1.6 in the range 0.3<z<0.7, and an overall increase by a factor of 7 to z~0.7 in comparison to the local core collapse supernova rate. The increase in the rate in this redshift range in consistent with recent measurements of the star formation rate derived from UV-luminosity densities and IR datasets. Based on 25 type Ia supernovae, we find a SN Ia rate that is a factor 3-5 higher at z~1 compared to earlier estimates at lower redshifts (z<0.5), implying that the type Ia supernova rate traces a higher star formation rate at redshifts z>1 compared to low redshift. At higher redshift (z>1), we find a suggested decrease in the type Ia rate with redshift. This evolution of the Ia rate with redshift is consistent with a type Ia progenitor model where there is a substantial delay between the formation of the progenitor star and the explosion of the supernova. Assuming that the type Ia progenitor stars have initial main sequence masses 3-8 M_Sun, we find that 5-7% of the available progenitors explode as type Ia supernovae.Comment: 16 pages, 3 figures, accepted for publication in the Astrophysical Journa

WFPC2 Observations of the Hubble Deep Field-South

The Hubble Deep Field-South observations targeted a high-galactic-latitude field near QSO J2233-606. We present WFPC2 observations of the field in four wide bandpasses centered at roughly 300, 450, 606, and 814 nm. Observations, data reduction procedures, and noise properties of the final images are discussed in detail. A catalog of sources is presented, and the number counts and color distributions of the galaxies are compared to a new catalog of the HDF-N that has been constructed in an identical manner. The two fields are qualitatively similar, with the galaxy number counts for the two fields agreeing to within 20%. The HDF-S has more candidate Lyman-break galaxies at z > 2 than the HDF-N. The star-formation rate per unit volume computed from the HDF-S, based on the UV luminosity of high-redshift candidates, is a factor of 1.9 higher than from the HDF-N at z ~ 2.7, and a factor of 1.3 higher at z ~ 4.Comment: 93 pages, 25 figures; contains very long table

The Unusual Infrared Object HDF-N J123656.3+621322

We describe an object in the Hubble Deep Field North with very unusual near-infrared properties. It is readily visible in Hubble Space Telescope NICMOS images at 1.6um and from the ground at 2.2um, but is undetected (with signal-to-noise <~ 2) in very deep WFPC2 and NICMOS data from 0.3 to 1.1um. The f_nu flux density drops by a factor >~ 8.3 (97.7% confidence) from 1.6 to 1.1um. The object is compact but may be slightly resolved in the NICMOS 1.6um image. In a low-resolution, near-infrared spectrogram, we find a possible emission line at 1.643um, but a reobservation at higher spectral resolution failed to confirm the line, leaving its reality in doubt. We consider various hypotheses for the nature of this object. Its colors are unlike those of known galactic stars, except perhaps the most extreme carbon stars or Mira variables with thick circumstellar dust shells. It does not appear to be possible to explain its spectral energy distribution as that of a normal galaxy at any redshift without additional opacity from either dust or intergalactic neutral hydrogen. The colors can be matched by those of a dusty galaxy at z >~ 2, by a maximally old elliptical galaxy at z >~ 3 (perhaps with some additional reddening), or by an object at z >~ 10 whose optical and 1.1um light have been suppressed by the intergalactic medium. Under the latter hypothesis, if the luminosity results from stars and not an AGN, the object would resemble a classical, unobscured protogalaxy, with a star formation rate >~ 100 M_sun/yr. Such UV-bright objects are evidently rare at 2 < z < 12.5, however, with a space density several hundred times lower than that of present-day L* galaxies.Comment: Accepted for publication in the Astrophysical Journal. 27 pages, LaTeX, with 7 figures (8 files); citations & references updated + minor format change

Anti-DLL4 VNAR targeted nanoparticles for targeting of both tumour and tumour associated vasculature

Acknowledgements The authors acknowledge the Engineering and Physical Sciences Research Council (EPSRC) (S3802ASA) and the generous support of the Martin Family Foundation for funding the Ph.D. studentships of P. S. and A. L., respectively. This work was also partially funded through a US-Ireland R&D Partnership grant awarded by HSCNI (STL/5010/14), Medical Research Council UK (MC_PC_15013), and the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/R009112/1).Peer reviewedPublisher PD

The Hubble Deep Field South Flanking Fields

As part of the Hubble Deep Field South program, a set of shorter 2-orbit observations were obtained of the area adjacent to the deep fields. The WFPC2 flanking fields cover a contiguous solid angle of 48 square arcminutes. Parallel observations with the STIS and NICMOS instruments produce a patchwork of additional fields with optical and near-infrared (1.6 micron) response. Deeper parallel exposures with WFPC2 and NICMOS were obtained when STIS observed the NICMOS deep field. These deeper fields are offset from the rest, and an extended low surface brightness object is visible in the deeper WFPC2 flanking field. In this data paper, which serves as an archival record of the project, we discuss the observations and data reduction, and present SExtractor source catalogs and number counts derived from the data. Number counts are broadly consistent with previous surveys from both ground and space. Among other things, these flanking field observations are useful for defining slit masks for spectroscopic follow-up over a wider area around the deep fields, for studying large-scale structure that extends beyond the deep fields, for future supernova searches, and for number counts and morphological studies, but their ultimate utility will be defined by the astronomical community.Comment: 46 pages, 15 figures. Images and full catalogs available via the HDF-S at http://www.stsci.edu/ftp/science/hdfsouth/hdfs.html at present. The paper is accepted for the February 2003 Astronomical Journal. Full versions of the catalogs will also be available on-line from AJ after publicatio