Molecular basis of arrested liver stage development of the gamma irradiated Plasmodium yoelii sporozoite

Worldwide, about 270 million people are diagnosed with malaria annually and about a million deaths occur from this disease mostly in children and pregnant women in Africa. Despite enormous effort and resources directed towards malaria control and eradication, problems of resistance to chloroquine by the malaria parasite and resistance to insecticide by the mosquito vector have only contributed to worsening of the spread of the disease. These problems have led to the search for alternate and efficacious mode of treatments with one being vaccine. Previously, sporozoites isolated from mosquitoes exposed to 12,000 rads of radiation from a 137Cesium source and injected into mice in laboratory studies were determine to invade hepatocytes where their development became arrested at the trophozoite stage, causing them to confer protection against subsequent challenge with live sporozoites. However, attempts to expand these studies in field trials on susceptible human in malaria endemic areas has been complicated by the problem of a need for large colonies of mosquitoes that can deploy the whole parasite-based vaccine. To circumvent this obstacle, peptide vaccines were developed. Unfortunately, only a few of the antigenic determinant on the surface of sporozoites were developed as peptide vaccines leading to an efficacy that is inferior to that of the whole parasite-based vaccine. Hence, to improve on the efficacy of the peptide vaccine, in this study, axenically-derived cultures of P. yoelii EEFs that were incubated as irradiation-attenuated sporozoites and as nonirradiated sporozoites were subjected to two rounds of suppression subtractive hybridization (SSH) along with dot blot analyses and southern blot (RT-PCR) to generate differentially expressed cDNA library clones from which peptide antigens will be identified for use in a multi subunit vaccine

Targeting the Novel Cell Cycle Regulator, Spy1, for Treatment of Medulloblastoma

Targeting the Novel Cell Cycle Regulator, Spy1, for Treatment of Medulloblastoma Philip Habashy, Rosa M. Ferraiuolo, Dorota Lubanska, Lisa A. Porter Medulloblastoma (MB) is the most common malignant pediatric brain tumour. It occurs in 16-25% of cases, with higher incidence in children between the ages of 1 to 9 years. Current standard of care includes combination radiation, surgery and chemotherapy, this treatment relies on DNA damage to induce death of quickly growing cells. While effective for a small margin of patients the treatment is highly aggressive, is plagued with cytotoxicity and ultimately fails in many patients. One recent approach entering clinical development is the use of synthetic cyclin-dependent kinase inhibitors (CKIs). Finding new drugs and optimizing existing approaches for MB are of high importance. Our lab studies a cell cycle regulatory protein called Speedy (Spy1), which promotes cell proliferation, even during times of DNA damage produced by chemotherapeutic agents. Spy1 has been implicated in the maintenance and expansion of stem-like populations of tumour initiating cells known to be the most chemo-resistant among solid tumours. It is our hypothesis that Spy1 drives tumour initiating cells in MB and reducing the levels of Spy1 will increase sensitivity of aggressive MB to standard of care and CKI therapy. To address this hypothesis we have used patient-derived MB cells and have manipulated the levels of Spy1 using a lentiviral system. Using a high throughput platform these cells are injected into zebrafish prior to the establishment of the acquired immune system. We then determine the effect of CKI treatment on these in vivo tumours. To date our results show promise that this approach may sensitize, at least a subset of MB patients, to therapy. Our work may contribute toward optimizing the design of CKIs and the use in combination therapy. This project holds promise for improving survival and quality of life for MB patients

Constraints on cosmic-ray propagation models from a global Bayesian analysis

Research in many areas of modern physics such as, e.g., indirect searches for dark matter and particle acceleration in SNR shocks, rely heavily on studies of cosmic rays (CRs) and associated diffuse emissions (radio, microwave, X-rays, gamma rays). While very detailed numerical models of CR propagation exist, a quantitative statistical analysis of such models has been so far hampered by the large computational effort that those models require. Although statistical analyses have been carried out before using semi-analytical models (where the computation is much faster), the evaluation of the results obtained from such models is difficult, as they necessarily suffer from many simplifying assumptions, The main objective of this paper is to present a working method for a full Bayesian parameter estimation for a numerical CR propagation model. For this study, we use the GALPROP code, the most advanced of its kind, that uses astrophysical information, nuclear and particle data as input to self-consistently predict CRs, gamma rays, synchrotron and other observables. We demonstrate that a full Bayesian analysis is possible using nested sampling and Markov Chain Monte Carlo methods (implemented in the SuperBayeS code) despite the heavy computational demands of a numerical propagation code. The best-fit values of parameters found in this analysis are in agreement with previous, significantly simpler, studies also based on GALPROP.Comment: 19 figures, 3 tables, emulateapj.sty. A typo is fixed. To be published in the Astrophysical Journal v.728 (February 10, 2011 issue). Supplementary material can be found at http://www.g-vo.org/pub/GALPROP/GalpropBayesPaper

Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses

<p>Abstract</p> <p>Background</p> <p>Current literature suggests that dipeptidyl peptidase IV (DPP-IV; CD26) plays an essential role in T-dependent immune responses, a role that could have important clinical consequences. To rigorously define the role of DPP-IV in the immune system, we evaluated genetic and pharmacological inhibition of the enzyme on T-dependent immune responses <it>in vivo</it>.</p> <p>Results</p> <p>The DPP-IV null animals mounted robust primary and secondary antibody responses to the T dependent antigens, 4-hydroxy-3-nitrophenylacetyl-ovalbumin (NP-Ova) and 4-hydroxy-3-nitrophenylacetyl-chicken gamma globulin (NP-CGG), which were comparable to wild type mice. Serum levels of antigen specific IgM, IgG1, IgG2a, IgG2b and IgG3 were similar between the two groups of animals. DPP-IV null animals mounted an efficient germinal center reaction by day 10 after antigen stimulation that was comparable to wild type mice. Moreover, the antibodies produced by DPP-IV null animals after repeated antigenic challenge were affinity matured. Similar observations were made using wild type animals treated with a highly selective DPP-IV inhibitor during the entire course of the experiments. T cell recall responses to ovalbumin and MOG peptide, evaluated by measuring proliferation and IL-2 release from cells isolated from draining lymph nodes, were equivalent in DPP-IV null and wild type animals. Furthermore, mice treated with DPP-IV inhibitor had intact T-cell recall responses to MOG peptide. In addition, female DPP-IV null and wild type mice treated with DPP-IV inhibitor exhibited normal and robust <it>in vivo</it><it/> cytotoxic T cell responses after challenge with cells expressing the male H-Y minor histocompatibility antigen.</p> <p>Conclusion</p> <p>These data indicate Selective inhibition of DPP-IV does not impair T dependent immune responses to antigenic challenge.</p

Development of a Data Management Framework in Support of Southeastern Tidal Creek Research

2008 S.C. Water Resources Conference - Addressing Water Challenges Facing the State and Regio

CHANG-ES IV: Radio continuum emission of 35 edge-on galaxies observed with the Karl G. Jansky Very Large Array in D-configuration, Data Release 1

We present the first part of the observations made for the Continuum Halos in Nearby Galaxies, an EVLA Survey (CHANG-ES) project. The aim of the CHANG-ES project is to study and characterize the nature of radio halos, their prevalence as well as their magnetic fields, and the cosmic rays illuminating these fields. This paper reports observations with the compact D configuration of the Karl G. Jansky Very Large Array (VLA) for the sample of 35 nearby edge-on galaxies of CHANG-ES. With the new wide bandwidth capabilities of the VLA, an unprecedented sensitivity was achieved for all polarization products. The beam resolution is an average of 9.6" and 36" with noise levels reaching approximately 6 and 30 microJy per beam for C- and L-bands, respectively (robust weighting). We present intensity maps in these two frequency bands (C and L), with different weightings, as well as spectral index maps, polarization maps, and new measurements of star formation rates (SFRs). The data products described herein are available to the public in the CHANG-ES data release available at www.queensu.ca/changes. We also present evidence of a trend among galaxies with larger halos having higher SFR surface density, and we show, for the first time, a radio continuum image of the median galaxy, taking advantage of the collective signal-to-noise ratio of 30 of our galaxies. This image shows clearly that a typical spiral galaxy is surrounded by a halo of magnetic fields and cosmic rays.Comment: 70 pages, of which 35 pages present the data of each galax

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Continuum Halos in Nearby Galaxies -- an EVLA Survey (CHANG-ES) -- II: First Results on NGC 4631

We present the first results from the CHANG-ES survey, a new survey of 35 edge-on galaxies to search for both in-disk as well as extra-planar radio continuum emission. The motivation and science case for the survey are presented in a companion paper (Paper I). In this paper (Paper II), we outline the observations and data reduction steps required for wide-band calibration and mapping of EVLA data, including polarization, based on C-array test observations of NGC 4631. With modest on-source observing times (30 minutes at 1.5 GHz and 75 minutes at 6 GHz for the test data) we have achieved best rms noise levels of 22 and 3.5 $\mu$Jy beam$^{-1}$ at 1.5 GHz and 6 GHz, respectively. New disk-halo features have been detected, among them two at 1.5 GHz that appear as loops in projection. We present the first 1.5 GHz spectral index map of NGC 4631 to be formed from a single wide-band observation in a single array configuration. This map represents tangent slopes to the intensities within the band centered at 1.5 GHz, rather than fits across widely separated frequencies as has been done in the past and is also the highest spatial resolution spectral index map yet presented for this galaxy. The average spectral index in the disk is $\bar\alpha_{1.5 GHz}\,=\,-0.84\,\pm\,0.05$ indicating that the emission is largely non-thermal, but a small global thermal contribution is sufficient to explain a positive curvature term in the spectral index over the band. Two specific star forming regions have spectral indices that are consistent with thermal emission. Polarization results (uncorrected for internal Faraday rotation) are consistent with previous observations and also reveal some new features. On broad scales, we find strong support for the notion that magnetic fields constrain the X-ray emitting hot gas.Comment: Accepted to the Astronomical Journal, Version 2 changes: Added acknowledgement to NRA