ABSTRACT We report the results of the statistical analysis of planetary signals discovered in MOA-II microlensing survey alert system events from 2007 to 2012. We determine the survey sensitivity as ...a function of planet-star mass ratio, q, and projected planet-star separation, s, in Einstein radius units. We find that the mass-ratio function is not a single power law, but has a change in slope at q ∼ 10−4, corresponding to ∼20 M⊕ for the median host-star mass of ∼0.6 . We find significant planetary signals in 23 of the 1474 alert events that are well-characterized by the MOA-II survey data alone. Data from other groups are used only to characterize planetary signals that have been identified in the MOA data alone. The distribution of mass ratios and separations of the planets found in our sample are well fit by a broken power-law model of the form for q > qbr and for q < qbr, where qbr is the mass ratio of the break. We also combine this analysis with the previous analyses of Gould et al. and Cassan et al., bringing the total sample to 30 planets. This combined analysis yields , n = −0.93 0.13, , and for qbr 1.7 × 10−4. The unbroken power-law model is disfavored with a p-value of 0.0022, which corresponds to a Bayes factor of 27 favoring the broken power-law model. These results imply that cold Neptunes are likely to be the most common type of planets beyond the snow line.
Amphotericin B is an increasingly important tool in efforts to reduce the global disease burden posed by Leishmania parasites. With few other chemotherapeutic options available for the treatment of ...leishmaniasis, the potential for emergent resistance to this drug is a considerable threat. Here we characterised four novel amphotericin B-resistant Leishmania mexicana lines. All lines exhibited altered sterol biosynthesis, and hypersensitivity to pentamidine. Whole genome sequencing demonstrated resistance-associated mutation of the sterol biosynthesis gene sterol C5-desaturase in one line. However, in three out of four lines, RNA-seq revealed loss of expression of sterol C24-methyltransferase (SMT) responsible for drug resistance and altered sterol biosynthesis. Additional loss of the miltefosine transporter was associated with one of those lines. SMT is encoded by two tandem gene copies, which we found to have very different expression levels. In all cases, reduced overall expression was associated with loss of the 3' untranslated region of the dominant gene copy, resulting from structural variations at this locus. Local regions of sequence homology, between the gene copies themselves, and also due to the presence of SIDER1 retrotransposon elements that promote multi-gene amplification, correlate to these structural variations. Moreover, in at least one case loss of SMT expression was not associated with loss of virulence in primary macrophages or in vivo. Whilst such repeat sequence-mediated instability is known in Leishmania genomes, its presence associated with resistance to a major antileishmanial drug, with no evidence of associated fitness costs, is a significant concern.
Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin ...B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of the miltefosine transporter gene was found. Differences in sensitivity to amphotericin B were apparent, depending on whether cells were grown in HOMEM, supplemented with foetal bovine serum, or a serum free defined medium (DM). Metabolomic analysis after exposure to AmB showed that a large increase in glucose flux via the pentose phosphate pathway preceded cell death in cells sustained in HOMEM but not DM, indicating the oxidative stress was more significantly induced under HOMEM conditions. Several of the lines were tested for their ability to infect macrophages and replicate as amastigote forms, alongside their ability to establish infections in mice. While several AmB resistant lines showed reduced virulence, at least two lines displayed heightened virulence in mice whilst retaining their resistance phenotype, emphasising the risks of resistance emerging to this critical drug.
MOA-2006-BLG-074 was selected as one of the most promising planetary candidates in a retrospective analysis of the MOA collaboration: its asymmetric high-magnification peak can be perfectly explained ...by a source passing across a central caustic deformed by a small planet. However, after a detailed analysis of the residuals, we have realized that a single lens and a source orbiting with a faint companion provides a more satisfactory explanation for all the observed deviations from a Paczynski curve and the only physically acceptable interpretation. Indeed the orbital motion of the source is constrained enough to allow a very good characterization of the binary source from the microlensing light curve. The case of MOA-2006-BLG-074 suggests that the so-called xallarap effect must be taken seriously in any attempts to obtain accurate planetary demographics from microlensing surveys.
We demonstrate that uptake of oligomeric cognate antigen (OVA-hen egg lysozyme, OVA-HEL) alone or incorporated in immune-stimulating complexes (ISCOMS) facilitates presentation and simultaneous ...cross-presentation of OVA by HEL-specific B cells in vitro. HEL-specific B cells stimulated CD8⁺ T cell responses in vitro to the same extent as bone marrow-derived dendritic cells. Cross-presentation by specific B cells required endosomal acidification, proteasomal processing and classical MHC class I/peptide transport. Specific B cells also acquired both antigens rapidly in vivo and presented them to CD4⁺ T cells. However, only HEL-specific B cells from OVA-HEL ISCOMS-immunised mice could cross-present OVA to naive OVA-specific CD8⁺ T cells. Antigen-specific B cells were also activated selectively by OVA-HEL ISCOMS in vitro and importantly, the presence of HEL-specific B cells promoted the persistence of clonal expansion of OVA-specific CD8⁺ T cells after in vivo immunisation with OVA-HEL ISCOMS. These results demonstrate preferential MHC class I and class II processing of cognate antigen incorporated in ISCOMS by specific B cells in vitro and in vivo, highlighting the ability of ISCOMS to target B cells and offering novel insights into the role of B cells in cross-presentation to CD8⁺ T cells.
We present the MOA Collaboration light-curve data for the planetary microlensing event OGLE-2015-BLG-0954, which was previously announced in a paper by the KMTNet and OGLE Collaborations. The MOA ...data cover the caustic exit, which was not covered by the KMTNet or Optical Gravitational Lensing Experiment (OGLE) data, and they provide a more reliable measurement of the finite source effect. The MOA data also provide a new source color measurement that reveals a lens-source relative proper motion of rel = 11.8 0.8 mas yr−1, which compares to the value of rel = 18.4 1.7 mas yr−1 reported in the KMTNet-OGLE paper. This new MOA value for rel has an a priori probability that is a factor of 100 times larger than the previous value, and it does not require a lens system distance of DL < 1 kpc. Based on the corrected source color, we find that the lens system consists of a planet of mass orbiting a star at an orbital separation of and a distance of .
Guillain-Barré syndrome (GBS) is a post-infectious polyradiculoneuropathy, frequently associated with antecedent Campylobacter jejuni (C. jejuni) infection. The presence of sialic acid on C. jejuni ...lipo-oligosaccharide (LOS) is considered a risk factor for development of GBS as it crucially determines the structural homology between LOS and gangliosides, explaining the induction of cross-reactive neurotoxic antibodies. Sialylated C. jejuni are recognised by TLR4 and sialoadhesin; however, the functional implications of these interactions in vivo are unknown.
In this study we investigated the effects of bacterial sialylation on phagocytosis and cytokine secretion by mouse myeloid cells in vitro and in vivo. Using fluorescently labelled GM1a/GD1a ganglioside-mimicking C. jejuni strains and corresponding (Cst-II-mutant) control strains lacking sialic acid, we show that sialylated C. jejuni was more efficiently phagocytosed in vitro by BM-MΦ, but not by BM-DC. In addition, LOS sialylation increased the production of IL-10, IL-6 and IFN-β by both BM-MΦ and BM-DC. Subsequent in vivo experiments revealed that sialylation augmented the deposition of fluorescent bacteria in splenic DC, but not macrophages. In addition, sialylation significantly amplified the production of type I interferons, which was independent of pDC.
These results identify novel immune stimulatory effects of C. jejuni sialylation, which may be important in inducing cross-reactive humoral responses that cause GBS.
Radiation therapy plays an important role in the care of patients with head and neck cancer. When the oral cavity and the salivary glands are exposed to high doses of radiation, there can be dramatic ...effects on the patient's oral health. The clinical consequences of radiation can include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries and trismus. This paper looks at the available literature regarding the effects of radiotherapy on the oral environment and outlines practical clinical approaches to prevent or reduce the adverse side effects of treatment.
The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mucosal adjuvant that greatly potentiates humoral and cellular immune responses. It ...was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4(+) T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector.
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