Made-to-measure malaria vector control strategies: rational design based on insecticide properties and coverage of blood resources for mosquitoes.

Eliminating malaria from highly endemic settings will require unprecedented levels of vector control. To suppress mosquito populations, vector control products targeting their blood hosts must attain high biological coverage of all available sources, rather than merely high demographic coverage of a targeted resource subset, such as humans while asleep indoors. Beyond defining biological coverage in a measurable way, the proportion of blood meals obtained from humans and the proportion of bites upon unprotected humans occurring indoors also suggest optimal target product profiles for delivering insecticides to humans or livestock. For vectors that feed only occasionally upon humans, preferred animal hosts may be optimal targets for mosquito-toxic insecticides, and vapour-phase insecticides optimized to maximize repellency, rather than toxicity, may be ideal for directly protecting people against indoor and outdoor exposure. However, for vectors that primarily feed upon people, repellent vapour-phase insecticides may be inferior to toxic ones and may undermine the impact of contact insecticides applied to human sleeping spaces, houses or clothing if combined in the same time and place. These concepts are also applicable to other mosquito-borne anthroponoses so that diverse target species could be simultaneously controlled with integrated vector management programmes. Measurements of these two crucial mosquito behavioural parameters should now be integrated into programmatically funded, longitudinal, national-scale entomological monitoring systems to inform selection of available technologies and investment in developing new ones

Neural correlates of visuospatial working memory in the ‘at-risk mental state’

Background. Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. Method. fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 agematched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object–location paired-associate memory task, with experimental manipulation of mnemonic load. Results. In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. Conclusions. Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis

Preclinical assessment of the receptor-binding domain of Plasmodium vivax duffy-binding protein as a vaccine candidate in rhesus macaques

The receptor-binding domain of Plasmodium vivax Duffy-binding protein, region II (PvRII), is an attractive candidate for a vaccine against P. vivax malaria. Here, we have studied the safety and immunogenicity of recombinant PvRII in Macaca mulatta (rhesus monkeys). Recombinant PvRII with a C-terminal 6-histidine tag was expressed in E. coli, recovered from inclusion bodies, refolded into its functional conformation, purified to homogeneity and formulated with three adjuvants, namely, Alhydrogel, Montanide ISA 720 and the GSK proprietary Adjuvant System AS02A for use in immunogenicity studies. All the PvRII vaccine formulations tested were safe and highly immunogenic. The overall magnitude of the antibody response was significantly higher for both Montanide ISA 720 and AS02A formulations in comparison with Alhydrogel. Furthermore, there was a significant correlation between antibody recognition titers by ELISA and binding inhibition titers in in vitro binding assays. The PvRII vaccine formulations also induced IFN-γ recall responses that were identified using ex vivo ELISPOT assays. These results provide support for further clinical development of a vaccine for P. vivax malaria based on recombinant PvRII

The Burst and Transient Source Experiment (BATSE) Earth Occultation Catalog of Low-Energy Gamma-Ray Sources

The Burst and Transient Source Experiment (BATSE), aboard the Compton Gamma Ray Observatory (CGRO), provided a record of the low-energy gamma-ray sky (20-1000 keV) between 1991 April and 2000 May (9.1y). Using the Earth Occultation Technique to extract flux information, a catalog of sources using data from the BATSE large area detectors has been prepared. The first part of the catalog consists of results from the monitoring of 58 sources, mostly Galactic. For these sources, we have included tables of flux and spectral data, and outburst times for transients. Light curves (or flux histories) have been placed on the world wide web. We then performed a deep-sampling of 179 objects (including the aforementioned 58 objects) combining data from the entire 9.1y BATSE dataset. Source types considered were primarily accreting binaries, but a small number of representative active galaxies, X-ray-emitting stars, and supernova remnants were also included. The deep sample results include definite detections of 83 objects and possible detections of 36 additional objects. The definite detections spanned three classes of sources: accreting black hole and neutron star binaries, active galaxies and supernova remnants. Flux data for the deep sample are presented in four energy bands: 20-40, 40-70, 70-160, and 160-430 keV. The limiting average flux level (9.1 y) for the sample varies from 3.5 to 20 mCrab (5 sigma) between 20 and 430 keV, depending on systematic error, which in turn is primarily dependent on the sky location. To strengthen the credibility of detection of weaker sources (5-25 mCrab), we generated Earth occultation images, searched for periodic behavior using FFT and epoch folding methods, and critically evaluated the energy-dependent emission in the four flux bands.Comment: 64 pages, 17 figures, abstract abridged, Accepted by ApJ

Simultaneous multi-wavelength observations of the TeV Blazar Mrk 421 during February - March 2003: X-ray and NIR correlated variability

In the present paper, we have reported the result of simultaneous multi-wavelength observations of the TeV blazar Mrk 421 during February $-$ March 2003. In this period, we have observed Mrk 421 using Pachmarhi Array of \v{C}erenkov Telescopes (PACT) of Tata Institute of Fundamental Research at Pachmarhi, India. Other simultaneous data were taken from the published literature and public data archives. We have analyzed the high quality X-ray (2-20 keV) observations from the NASA Rossi X-Ray Timing Explorer (RXTE). We have seen a possible correlated variability between X-ray and J band (1.25 $\mu$) near infrared (NIR) wavelength. This is the first case of X-ray and NIR correlated variability in Mrk 421 or any high energy peaked (HBL) blazar. The correlated variability reported here is indicating a similar origin for NIR and X-ray emission. The emission is not affected much by the environment of the surrounding medium around the central engine of the Mrk 421. The observations are consistent with the shock-in-jet model for the emission of radiations.Comment: 11 pages, 5 figures, Accepted for Publication in ChJA

White matter microstructure in 22q11 deletion syndrome: a pilot diffusion tensor imaging and voxel-based morphometry study of children and adolescents

Young people with 22q11 Deletion Syndrome (22q11DS) are at substantial risk for developing psychosis and have significant differences in white matter (WM) volume. However, there are few in vivo studies of both WM microstructural integrity (as measured using Diffusion Tensor (DT)-MRI) and WM volume in the same individual. We used DT-MRI and structural MRI (sMRI) with voxel based morphometry (VBM) to compare, respectively, the fractional anisotropy (FA) and WM volume of 11 children and adolescents with 22q11DS and 12 controls. Also, within 22q11DS we related differences in WM to severity of schizotypy, and polymorphism of the catechol-O-methyltransferase (COMT) gene. People with 22q11DS had significantly lower FA in inter-hemispheric and brainstem and frontal, parietal and temporal lobe regions after covarying for IQ. Significant WM volumetric increases were found in the internal capsule, anterior brainstem and frontal and occipital lobes. There was a significant negative correlation between increased schizotypy scores and reduced WM FA in the right posterior limb of internal capsule and the right body and left splenium of corpus callosum. Finally, the Val allele of COMT was associated with a significant reduction in both FA and volume of WM in the frontal lobes, cingulum and corpus callosum. Young people with 22q11DS have significant differences in both WM microstructure and volume. Also, there is preliminary evidence that within 22q11DS, some regional differences in FA are associated with allelic variation in COMT and may perhaps also be associated with schizotypy

Magnetic Fields of Accreting X-Ray Pulsars with the Rossi X-Ray Timing Explorer

Using a consistent set of models, we parameterized the X-ray spectra of all accreting pulsars in the Rossi X-ray Timing Explorer database which exhibit Cyclotron Resonance Scattering Features (CRSFs, or cyclotron lines). These sources in our sample are Her X-1, 4U 0115+63, Cen X-3, 4U 1626-67, XTE J1946-274, Vela X-1, 4U 1907+09, 4U 1538-52, GX 301-2, and 4U 0352+309 (X Per). We searched for correlations among the spectral parameters, concentrating on how the cyclotron line energy relates to the continuum and therefore how the neutron star B-field influences the X-Ray emission. As expected, we found a correlation between the CRSF energy and the spectral cutoff energy. However, with our consistent set of fits we found that the relationship is more complex than what has been reported previously. Also, we found that not only does the width of the cyclotron line correlate with the energy (as suggested by theory), but that the width scaled by the energy correlates with the depth of the feature. We discuss the implications of these results, including the possibility that accretion directly affects the relative alignment of the neutron star spin and dipole axes. Lastly, we comment on the current state of fitting phenomenological models to spectra in the RXTE/BeppoSAX era and the need for better theoretical models of the X-Ray continua of accreting pulsars.Comment: 36 Pages, 9 Figures, 9 Tables, ApJ in pres

Preclinical assessment of viral vectored and protein vaccines targeting the Duffy-binding protein region II of Plasmodium vivax

Malaria vaccine development has largely focused on Plasmodium falciparum; however, a reawakening to the importance of Plasmodium vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII – including human adenovirus serotype 5 (HAdV5), chimpanzee adenovirus serotype 63 (ChAd63), and modified vaccinia virus Ankara (MVA) vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in “mixed-modality” adenovirus prime – protein-in-­adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide®ISA720 or Abisco®100 adjuvants). Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII, and have recently entered clinical trials, which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans