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The emergence of pesticide-resistant mosquitoes and drug-resistant parasites in the last twenty years has made control of malaria more difficult. One novel strategy to better control malaria is the development and release of transgenic mosquitoes whose enhanced immunity prevents transmission of the parasite to the mammalian host. One candidate effector gene is Anopheles stephensi nitric oxide synthase (AsNOS), whose inducible expression and subsequent synthesis of nitric oxide (NO) limits Plasmodium development in A. stephensi. In mammals, one of the most potent physiological regulators of NOS gene expression and catalytic activity is transforming growth factor-β (TGF-β). Moreover, human TGF-β can activate Drosophila melanogaster Smads, the proteins responsible for TGF-β signal transduction. We have determined that following a bloodmeal, active human TGF-β1 (hTGF-β1) persists in the midgut of A. stephensi for up to 48 hours. My data demonstrate that the midgut epithelium recognizes hTGF-β1 as an immunomodulatory cytokine. Specifically, induction of AsNOS by hTGF-β1 occurs in the midgut within minutes of bloodfeeding. Moreover, hTGF-β1 limits development of the human malaria parasite Plasmodium falciparum in the midgut. In other experiments, provision of the AsNOS catalytic inhibitor L-NAME partially reverses the effect of hTGF-β1 on Plasmodium development. These results suggest that AsNOS is a target of hTGF-β1 signaling and additional effectors that impact parasite development may be regulated by hTGF-β1 as well. The fact that hTGF-β1 signals mosquito cells to limit malaria parasite development suggests that there is an endogenous TGF-β signaling network in place. An analysis of the A. gambiae genome database revealed the presence of six TGF-β ligands, including gene duplication in the 60A gene, the first evidence of ligand gene duplication outside of chordates. In addition to five receptors, three Smads were identified in the A. gambiae genome predicted to support TGF-β/Activin- and BMP-like signaling. Midgut epithelial cells and an immunocompetent A. stephensi cell line express all three Smads, confirming that a signaling pathway is in place to support signaling by divergent exogenous and endogenous TGF-β superfamily proteins. The results presented here provide the first evidence of immunological crosstalk between divergent free living hosts of a single parasite. Further, these results imply that the interface between mammals and the mosquitoes that feed on them provide a unique opportunity for circulating molecules in the blood, including TGF-β and other cytokines, to alter the mosquito immune response. / Master of Science

Nitric oxide (NO), despite being a minor species, influences the chemistry, composition and energy balance of the earth's atmosphere above 90 kilometers. Variations in its density have been shown to strongly correlate with solar x-ray irradiance at lower latitudes and precipitating energetic particles at higher latitudes. Though the broad variations in NO densities with altitude and latitude are well known, there are still uncertainties associated with its chemistry. It is important to accurately model NO and its associated chemistry in an atmospheric model in order to obtain an accurate representation of the thermosphere. The NCAR Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIEGCM) is a three dimensional first principles based model which includes a self consistent aeronomic scheme that solves for winds, temperatures and densities of various neutral and charged species in the earth's upper atmosphere. Using a combination of the solar irradiance spectrum and solar indices as inputs, the model computes these outputs at every time step. The ability of the TIEGCM to predict NO densities in the thermosphere is examined by comparing results from the model with data obtained from the Student Nitric Oxide Explorer (SNOE). The comparisons are made for the year 1999 at 110 km and 150 km at the equator. Changes are made to the NO chemistry present in the model to reflect recent results obtained from laboratory data. Paricularly, the reaction of atomic oxygen with the first excited electronic state of nitrogen, N ₂(A) has been shown to play an important role in the production of NO. These changes are introduced to the model and their effect on NO densities is studied. Overall, it is seen that the updated chemistry scheme reduces the model agreement with the SNOE data at 110 km while slightly improving the agreement at a 150 km. The loss of agreement at 110 km is attributed to the fact that the neutral temperatures and atomic oxygen densities calculated by the TIEGCM are in sharp disagreement to the temperatures predicted by the NRL-MSIS at a 110 km, on which the new chemistry scheme is based. While the chemistry scheme used in this thesis is a step in the right direction for modelling NO using the TIEGCM, the parameters used were determined from the best fit obtained from the 1-D NO model. In the light of the differences between the NRL-MSIS and TIEGCM, it is necessary to return to the laboratory data and modify the parameters used here to achieve a better agreement with the data. / Master of Science

On-board the International Space Station (ISS), the Remote Atmospheric and Ionospheric Detection System (RAIDS) is a suite of limb-scanning monitors taking measurements from the extreme ultraviolet (EUV) to the near infrared (NIR). A single-scattering Rayleigh model is developed to eliminate the scattered brightness below 90 km and an inversion technique is applied on limb-scanned radiance profiles at 236.5 nm, NO (0,1) gamma band. The ISS orbit allows observations from 7:00 to 16:00 local hours over a one-month period from mid-June to mid-July of 2010 and observation of the local-time variation of NO abundance in the lower thermosphere is derived. The uniquely stable solar activity during 2010 allows the local time variation of NO to be observed with limited influence of solar variability. The comparison with a 1D model shows good agreement at altitude above 120 km, suggesting that most of the local time variation of NO is due to solar illumination, radiation, chemistry, and vertical diffusion. Solar soft X-ray is the major driver of the variability observed in the ionospheric and thermospheric constituents at the equatorial region. Over the years measurements in these wavelengths are scarce and discrepancies lie among the existing data. The Solar Aspect Monitor (SAM) is a pinhole camera on the Extreme-ultraviolet Variability Experiment (EVE) flying on the Solar Dynamics Observatory (SDO). Every 10 seconds SAM projects the solar disk onto the CCD through a metallic filter designed to allow only solar photons shortward of 7 nm to pass. Contamination from energetic particles and out-of-band irradiance is, however, present. The broadband (BB) technique is developed for isolating the 0.1 to 7 nm integrated irradiance to produce broadband irradiance. The results agree with the zeroth-order product from the EUV SpectroPhotometer (ESP) with 25% regardless of solar activity level. Active regions in the solar atmosphere are tracked by the Apertural Progression Procedure for Light Estimate (APPLE). The photon event detection (PED) algorithm takes both BB and APPLE results as prior information to extract in-band photons. Applications of the PED products, including solar feature studies and spectral resolved irradiance, are demonstrated. / Ph. D.

Yes / Quercetin is reported to reduce blood pressure in hypertensive but not normotensive humans, but the role of endothelial redox signaling in this phenomenon has not been assessed. This study investigated the effects of physiologically obtainable quercetin concentrations in a human primary cell model of endothelial dysfunction in order to elucidate the mechanism of action of its antihypertensive effects. Angiotensin II (100 nM, 8 h) induced dysfunction, characterized by suppressed nitric oxide availability (85 ± 4% p<0.05) and increased superoxide production (136 ± 5 %, p<0.001). These effects were ablated by an NADPH oxidase inhibitor. Quercetin (3 μM, 8 h) prevented angiotensin II induced changes in nitric oxide and superoxide levels, but no effect upon nitric oxide or superoxide in control cells. The NADPH oxidase subunit p47(phox) was increased at the mRNA and protein levels in angiotensin II-treated cells (130 ± 14% of control, p<0.05), which was ablated by quercetin co-treatment. Protein kinase C activity was increased after angiotensin II treatment (136 ± 51%), however this was unaffected by quercetin co-treatment. Physiologically obtainable quercetin concentrations are capable of ameliorating angiotensin II-induced endothelial nitric oxide and superoxide imbalance via protein kinase C-independent restoration of p47(phox) gene and protein expression. / Innovate UK and Boots Pharmaceuticals

Yes / This study describes the screening of 13 commercially-available plant extracts for pharmacological activity modulating vascular function using an endothelial cell model. A French maritime pine bark extract (FMPBE) was found to have the greatest effect upon nitric oxide availability in control (181% ± 36% of untreated cells) and dysfunctional cells (132% ± 8% of untreated control cells). In healthy volunteers, the FMPBE increased plasma nitrite concentrations 8 h post-consumption compared to baseline (baseline corrected median 1.71 ± 0.38 (25% IQR) and 4.76 (75% IQR) µM, p < 0.05). This was followed by a placebo-controlled, healthy volunteer study, which showed no effects on plasma nitrite. It was confirmed that different batches of extract had been used in the healthy volunteer studies, and this second batch lacked bioactivity, assessed using the in vitro model. No difference in plasma catechin levels was seen at 8 h following supplementation between the studies (252 ± 194 nM versus 50 ± 64 nM, p > 0.05), however HPLC-UV fingerprinting showed that the new batch had a 5-15% in major constituents (including procyanidins A2, B1 and B2) compared to the original batch. This research describes a robust mechanism for screening bioactive extracts for vascular effects. It also highlights batch variability as a significant limitation when using complex extracts for pharmacological activity, and suggests the use of in vitro systems as a tool to identify this problem in future studies.

No / We examined the influence of S-nitrosoglutathione (GSNO) on alpha(IIb)beta(3) integrin-mediated platelet adhesion to immobilised fibrinogen. GSNO induced a time- and concentration-dependent inhibition of platelet adhesion. Inhibition was cGMP-independent and associated with both reduced platelet spreading and protein tyrosine phosphorylation. To investigate the cGMP-independent effects of NO we evaluated integrin beta(3) phosphorylation. Adhesion to fibrinogen induced rapid phosphorylation of beta(3) on tyrosines 773 and 785, which was reduced by GSNO in a cGMP independent manner. Similar results were observed in suspended platelets indicating that NO-induced effects were independent of spreading-induced signalling. This is the first demonstration that NO directly regulates integrin beta(3) phosphorylation.

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