Infection with a Virulent Strain of Wolbachia Disrupts Genome Wide-Patterns of Cytosine Methylation in the Mosquito Aedes aegypti

BACKGROUND Cytosine methylation is one of several reversible epigenetic modifications of DNA that allow a greater flexibility in the relationship between genotype and phenotype. Methylation in the simplest models dampens gene expression by modifying regions of DNA critical for transcription factor binding. The capacity to methylate DNA is variable in the insects due to diverse histories of gene loss and duplication of DNA methylases. Mosquitoes like Drosophila melanogaster possess only a single methylase, DNMT2. DESCRIPTION Here we characterise the methylome of the mosquito Aedes aegypti and examine its relationship to transcription and test the effects of infection with a virulent strain of the endosymbiont Wolbachia on the stability of methylation patterns. CONCLUSION We see that methylation in the A. aegypti genome is associated with reduced transcription and is most common in the promoters of genes relating to regulation of transcription and metabolism. Similar gene classes are also methylated in aphids and honeybees, suggesting either conservation or convergence of methylation patterns. In addition to this evidence of evolutionary stability, we also show that infection with the virulent wMelPop Wolbachia strain induces additional methylation and demethylation events in the genome. While most of these changes seem random with respect to gene function and have no detected effect on transcription, there does appear to be enrichment of genes associated with membrane function. Given that Wolbachia lives within a membrane-bound vacuole of host origin and retains a large number of genes for transporting host amino acids, inorganic ions and ATP despite a severely reduced genome, these changes might represent an evolved strategy for manipulating the host environments for its own gain. Testing for a direct link between these methylation changes and expression, however, will require study across a broader range of developmental stages and tissues with methods that detect splice variants.This research was supported by The National Health and Medical Research Council of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Mixtures of Boosted Classifiers for Frontal Face Detection

This paper describes a new approach to automatic frontal face detection which employs Gaussian filters as local image descriptors. We then show how the paradigm of classifier combination can be used for building a face detector that outperforms the current state--of--the--art systems, while remaining fast enough for being used in real--time systems. It is based on the combination of several parallel classifiers trained on subsets of the complete training set. We report a number of results on some reference datasets and we use an unbiased method for comparing the detectors

Extraction of audio features specific to speech production for multimodal speaker detection

A method that exploits an information theoretic framework to extract optimized audio features using video information is presented. A simple measure of mutual information (MI) between the resulting audio and video features allows the detection of the active speaker among different candidates. This method involves the optimization of an MI-based objective function. No approximation is needed to solve this optimization problem, neither for the estimation of the probability density functions (pdf) of the features, nor for the cost function itself. The pdf are estimated from the samples using a non-parametric approach. The challenging optimization problem is solved using a global method: the Differential Evolution algorithm. Two information theoretic optimization criteria are compared and their ability to extract audio features specific to speech is discussed. Using these specific speech audio features, candidates video features are then classified as membership of the "speaker" or "non-speaker" class, resulting in a speaker detection scheme. As a result, our method achieves a speaker detection rate of 100% on home- grown test sequences, and of 85% on most commonly used sequences

On Performance Evaluation of Face Detection and Localization Algorithms

When comparing different methods for face detection or localization, one realizes that just simply comparing the reported results is misleading as, even if the results are reported on the same dataset, different authors have different views of what a correct detection/localization means. This paper addresses exactly this problem, proposing an objective measure for the goodness of a detection/localization for the case of frontal faces. The usage of the proposed technique insures a fair and unbiased way of reporting the results, making the experiment repeatable, measurable, and comparable by anybody else

Human monoclonal antibodies inhibit invasion of transgenic Plasmodium knowlesi expressing Plasmodium vivax Duffy binding protein

Background: Plasmodium vivax has been more resistant to various control measures than Plasmodium falciparum malaria because of its greater transmissibility and ability to produce latent parasite forms. Therefore, developing P. vivax vaccines and therapeutic monoclonal antibodies (humAbs) remains a high priority. The Duffy antigen receptor for chemokines (DARC) expressed on erythrocytes is central to P. vivax invasion of reticulocytes. P. vivax expresses a Duffy binding protein (PvDBP) on merozoites, a DARC ligand, and the DARC: PvDBP interaction is critical for P. vivax blood stage malaria. Therefore, PvDBP is a leading vaccine candidate for P. vivax and a target for therapeutic human monoclonal antibodies (humAbs). Methods: Here, the functional activity of humAbs derived from naturally exposed and vaccinated individuals are compared for the first time using easily cultured Plasmodium knowlesi (P. knowlesi) that had been genetically modified to replace its endogenous PkDBP orthologue with PvDBP to create a transgenic parasite, PkPvDBPOR. This transgenic parasite requires DARC to invade human erythrocytes but is not reticulocyte restricted. This model was used to evaluate the invasion inhibition potential of 12 humAbs (9 naturally acquired; 3 vaccine-induced) targeting PvDBP individually and in combinations using growth inhibition assays (GIAs). Results: The PvDBP-specific humAbs demonstrated 70–100% inhibition of PkPvDBPOR invasion with the IC50 values ranging from 51 to 338 µg/mL for the 9 naturally acquired (NA) humAbs and 33 to 99 µg/ml for the 3 vaccine-induced (VI) humAbs. To evaluate antagonistic, additive, or synergistic effects, six pairwise combinations were performed using select humAbs. Of these combinations tested, one NA/NA (099100/094083) combination demonstrated relatively strong additive inhibition between 10 and 100 µg/mL; all combinations of NA and VI humAbs showed additive inhibition at concentrations below 25 µg/mL and antagonism at higher concentrations. None of the humAb combinations showed synergy. Invasion inhibition efficacy by some mAbs shown with PkPvDBPOR was closely replicated using P. vivax clinical isolates. Conclusion: The PkPvDBPOR transgenic model is a robust surrogate of P. vivax to assess invasion and growth inhibition of human monoclonal Abs recognizing PvDBP individually and in combination. There was no synergistic interaction for growth inhibition with the humAbs tested here that target different epitopes or subdomains of PvDBP, suggesting little benefit in clinical trials using combinations of these humAbs

PvDBPII elicits multiple antibody-mediated mechanisms that reduce growth in a Plasmodium vivax challenge trial

The receptor-binding domain, region II, of the Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on the reticulocyte surface to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI variant formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) in immunized volunteers challenged with the Thai P. vivax isolate PvW1. Here, we describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that significantly contribute to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant of the PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are likely to be associated with protection and the immune correlates identified could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates

Intervention Packages to Reduce the Impact of HIV and HCV Infections Among People Who Inject Drugs in Eastern Europe and Central Asia: A Modeling and Cost-effectiveness Study

Abstract Background: We evaluated the effectiveness and cost-effectiveness of interventions targeting hepatitis C virus (HCV) and HIV infections among people who inject drugs (PWID) in Eastern Europe/Central Asia. We specifically considered the needle-syringe program (NSP), opioid substitution therapy (OST), HCV and HIV diagnosis, antiretroviral therapy (ART), and/or new HCV treatment (direct acting antiviral [DAA]) in Belarus, Georgia, Kazakhstan, Republic of Moldova, and Tajikistan. Methods: We developed a deterministic dynamic compartmental model and evaluated the number of infections averted, costs, and incremental cost-effectiveness ratios (ICERs) of interventions. OST decreased frequencies of injecting by 85% and NSP needle sharing rates by 57%; ART was introduced at CD4 <350 and DAA at fibrosis stage ≥F2 at a $2370 to$23 280 cost. Results: Increasing NSP+OST had a high impact on transmissions (infections averted in PWID: 42% in Tajikistan to 55% in Republic of Moldova for HCV; 30% in Belarus to 61% in Kazakhstan for HIV over 20 years). Increasing NSP+OST+ART was very cost-effective in Georgia (ICER = $910/year of life saved [YLS]), and was cost-saving in Kazakhstan and Republic of Moldova. NSP+OST+ART and HIV diagnosis was very cost-effective in Tajikistan (ICER =$210/YLS). Increasing the coverage of all interventions was always the most effective strategy and was cost-effective in Belarus and Kazakhstan (ICER = $12 960 and$21 850/YLS); it became cost-effective/cost-saving in all countries when we decreased DAA costs. Conclusion: Increasing NSP+OST coverage, in addition to ART and HIV diagnosis, had a high impact on both epidemics and was very cost-effective and even cost-saving. When HCV diagnosis was improved, increased DAA averted a high number of new infections if associated with NSP+OST

The BANCA Database and Evaluation Protocol

In this paper we describe the acquisition and content of a new large, realistic and challenging multi-modal database intended for training and testing multi-modal verification systems. The BANCA database was captured in four European languages in two modalities (face and voice). For recording, both high and low quality microphones and cameras were used. The subjects were recorded in three different scenarios, controlled, degraded and adverse over a period of three months. In total 208 people were captured, half men and half women. In this paper we also describe a protocol for evaluating verification algorithms on the database. The database will be made available to the research community through http://www.ee.surrey.ac.uk/Research/VSSP/banca