Negative Ions in Outer Solar System Plasmas: TItan, Europa & Rhea

Negative ions exist in many astrophysical environments. They are the major source of opacity in stars such as our sun and played a role in forming the first stars in the early-universe. In recent years, significant populations of negatively charged ions have been discovered in plasma environments within the outer solar system, discoveries which in many cases were serendipitously made by instruments not designed for this purpose. This thesis uses a combination of spacecraft data analysis and numerical simulations to study negatively charged ions observed by Cassini at the Saturnian moons, Titan and Rhea, and by Galileo at the Jovian moon Europa. The first study focuses on detections by Cassini's Electron Spectrometer of negatively charged ions and aerosols in Titan's ionosphere. An advanced model of the instrument response function is developed and used to statistically identify the presence of carbon chain anions, the first such detections within a planetary atmosphere. Observations of slightly larger anions are interpreted as a hitherto unknown chemical regime involving chemical structures incompatible with previously observed, or even known, anion species. Moreover, a multi-flyby analysis shows the smaller species to deplete with decreasing altitude at a rate proportional to the growth of the larger aerosols, a correlation which suggest these anions are coupled to this growth process. These results demonstrate the importance of tracing a route from small to large species to understand how complex organics can be produced within a planetary atmosphere. The second study derives from Galileo magnetometer observations near Europa which, surprisingly, showed both left-hand and right-hand wave power at the Chlorine ion gyrofrequency. These waves are generated by the outflow of newly ionised material and, in this case, the mix of polarisations was inferred to result from the presence of both positive and negative Chlorine ions. To test this hypothesis, a hybrid particle-in-cell simulation technique is used to carry out the first study focussing on negative ions generating the Alfv\'en-cyclotron instability in order to constrain the non-linear relation between sources densities, wave amplitudes and polarisation, for Chlorine pickup ions in conditions representative of the Europa plasma environment. Through relating simulated and observed wave properties, Chlorine pickup ion densities are constrained to within 0.1-1.5 cm$^{-3}$ in localised regions in Europa's plasma wake, with not less than 5\% resulting from a negatively charged component. These results suggest the moon is a net source of these species with implications for the salinity of the global sub-surface ocean. The third study focuses on both positive and negative pickup ions detected by Cassini's Plasma Spectrometer at Rhea. Using velocity space analysis and expressions derived for partially filled velocity-ring distributions, the positive pickup ions observed during two Rhea flybys are identified as compatible with CO$_2^+$. The negative pickup ions, observed during the first targeted Rhea flyby, are identified as incompatible with the previous identification of O$^-$ and instead are shown as compatible with heavier species in the range of 26$\pm$3 u. These are consequently attributed to carbon-based compounds, such as CN$^-$, C$_2$H$^-$, C$_2^-$, or HCO$^-$, and are suggested to derive from carbonaceous material on the moon's, likely negatively charged, surface. Unidentified, dark, possibly carbon-bearing material, is apparent in near-infrared observations of the surfaces of Rhea, Dione, Pheobe, Iapetus, Hyperion, Epimetheus and throughout Saturn's F-ring. These identifications thus provide context for understanding what minority species could be present within the surfaces of the icy moons of the giant planets

Hybrid simulations of positively and negatively charged pickup ions and cyclotron wave generation at Europa

In the vicinity of Europa, Galileo observed bursty Alfvén-cyclotron wave power at thegyrofrequencies of a number of species including K+,O+2,Na+, and Cl+, indicating the localized pickupof these species. Additional evidence for the presence of chlorine was the occurrence of both left-hand(LH) and right-hand (RH) polarized transverse wave power near the Cl+gyrofrequency, thought to bedue to the pickup of both Cl+and the easily formed chlorine anion, Cl−. To test this hypothesis, we useone-dimensional hybrid (kinetic ion, massless fluid electron) simulations for both positive and negativepickup ions and self-consistently reproduce the growth of both LH and RH Alfvén-cyclotron waves inagreement with linear theory. We show how the simultaneous generation of LH and RH waves can result innongyrotropic ion distributions and increased wave amplitudes, and how even trace quantities of negativepickup ions are able to generate an observable RH signal. Through comparing simulated and observed waveamplitudes, we are able to place the first constraints on the densities of Chlorine pickup ions in localizedregions at Europa

Detection of negative pickup ions at Saturn's moon Dione

We investigate a possible negative ion feature observed by the Cassini Plasma Spectrometer (CAPS) during a flyby of Saturn's moon Dione that occurred on April 7, 2010. By examining possible particle trajectories, we find that the observed particles are consistent with negative pick‐up ions originating near the moon's surface. We find that the mass of the negative pick‐up ions is in the range of 15 – 25 u and tentatively identify this species as O‐, likely resulting from ionization and subsequent pick‐up from Dione's O2‐CO2 exosphere. Our estimates show that the negative ion density is ~3 x 10‐3 cm‐3. This is comparable to, but slightly smaller than, that previously reported for the density of O2+ pick‐up ions for the same flyby, indicating that negative pick‐up ions may represent a major loss channel for Dione's exosphere

Dipole tilt effect on magnetopause reconnection and the steady‐state magnetosphere‐ionosphere system: global MHD simulation

The Earth’s dipole tilt angle changes both diurnally and seasonally and introduces numerous variabilities in the coupled magnetosphere‐ionosphere system. By altering the location and intensity of magnetic reconnection, the dipole tilt influences convection on a global scale. However, due to the nonlinear nature of the system, various other effects like dipole rotation, varying IMF orientation and non‐uniform ionospheric conductance can smear tilt effects arising purely from changes in coupling with the solar wind. To elucidate the underlying tilt angle‐dependence, we perform MHD simulations of the steady‐state magnetosphere‐ionosphere system under purely southward IMF conditions for tilt angles from 0°‐90°. We identify the location of the magnetic separator in each case, and find that an increasing tilt angle shifts the 3‐D X‐line southward on the magnetopause due to changes in magnetic shear angle. The separator is highly unsteady above 50° tilt angle, characteristic of regular FTE generation on the magnetopause. The reconnection rate drops as the tilt angle becomes large, but remains continuous across the dayside such that the magnetosphere is open even for 90°. These trends map down to the ionosphere, with the polar cap contracting as the tilt angle increases, and region‐I field‐aligned current (FAC) migrating to higher latitudes with changing morphology. The tilt introduces a north‐south asymmetry in magnetospheric convection, thus driving more FAC in the northern (sunward‐facing) hemisphere for large tilt angles than in the south independent of conductance. These results highlight the strong sensitivity to onset time in the potential impact of a severe space weather event

Lactate signalling regulates fungal β-glucan masking and immune evasion

AJPB: This work was supported by the European Research Council (STRIFE, ERC- 2009-AdG-249793), The UK Medical Research Council (MR/M026663/1), the UK Biotechnology and Biological Research Council (BB/K017365/1), the Wellcome Trust (080088; 097377). ERB: This work was supported by the UK Biotechnology and Biological Research Council (BB/M014525/1). GMA: Supported by the CNPq-Brazil (Science without Borders fellowship 202976/2014-9). GDB: Wellcome Trust (102705). CAM: This work was supported by the UK Medical Research Council (G0400284). DMM: This work was supported by UK National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/K000306/1). NARG/JW: Wellcome Trust (086827, 075470,101873) and Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377). ALL: This work was supported by the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).Peer reviewedPostprin

Sphingolipid metabolism: roles in signal transduction and disruption by fumonisins.

Sphingolipids have important roles in membrane and lipoprotein structure and in cell regulation as second messengers for growth factors, differentiation factors, cytokines, and a growing list of agonists. Bioactive sphingolipids are formed both by the turnover of complex sphingolipids and as intermediates of sphingolipid biosynthesis. Usually, the amounts are highly regulated; however, by inhibiting ceramide synthase, fumonisins block the biosynthesis of complex sphingolipids and cause sphinganine (and sometimes sphingosine) to accumulate. Where the mechanism has been studied most thoroughly, the accumulation of sphingoid bases is a primary cause of the toxicity of fumonisin B (FB). Nonetheless, the full effects of fumonisins probably involve many biochemical events. The elevations in sphingoid bases also affect the amounts of other lipids, including the 1-phosphates and N-acetyl derivatives of sphinganine. Furthermore, the aminopentol backbone of FB1 (AP1) is both an inhibitor and a substrate for ceramide synthase, and the resultant N-palmitoyl-AP1 (PAP1) is an even more potent inhibitor of ceramide synthase (presumably as a product analog). PAP1 is 10 times more toxic than FB1 or AP1 for HT-29 cells in culture, and hence may play a role in the toxicity of nixtamalized fumonisins. All these processes--the effects of fumonisins on sphingolipid metabolism, the pathways altered by perturbation of sphingolipid metabolism, and the complex cellular behaviors regulated by sphingolipids--must be borne in mind when evaluating the pathologic effects of fumonisins

The role of sexually transmitted infections in male circumcision effectiveness against HIV – insights from clinical trial simulation

BACKGROUND: A landmark randomised trial of male circumcision (MC) in Orange Farm, South Africa recently showed a large and significant reduction in risk of HIV infection, reporting MC effectiveness of 61% (95% CI: 34%–77%). Additionally, two further randomised trials of MC in Kisumu, Kenya and Rakai, Uganda were recently stopped early to report 53% and 48% effectiveness, respectively. Since MC may protect against both HIV and certain sexually transmitted infections (STI), which are themselves cofactors of HIV infection, an important question is the extent to which this estimated effectiveness against HIV is mediated by the protective effect of circumcision against STI. The answer lies in the trial data if the appropriate statistical analyses can be identified to estimate the separate efficacies against HIV and STI, which combine to determine overall effectiveness. OBJECTIVES AND METHODS: Focusing on the MC trial in Kisumu, we used a stochastic prevention trial simulator (1) to determine whether statistical analyses can validly estimate efficacy, (2) to determine whether MC efficacy against STI alone can produce large effectiveness against HIV and (3) to estimate the fraction of all HIV infections prevented that are attributable to efficacy against STI when both efficacies combine. RESULTS: Valid estimation of separate efficacies against HIV and STI as well as MC effectiveness is feasible with available STI and HIV trial data, under Kisumu trial conditions. Under our parameter assumptions, high overall effectiveness of MC against HIV was observed only with a high MC efficacy against HIV and was not possible on the basis of MC efficacy against STI alone. The fraction of all HIV infections prevented which were attributable to MC efficacy against STI was small, except when efficacy of MC specifically against HIV was very low. In the three MC trials which reported between 48% and 61% effectiveness (combining STI and HIV efficacies), the fraction of HIV infections prevented in circumcised males which were attributable to STI was unlikely to be more than 10% to 20%. CONCLUSION: Estimation of efficacy, attributable fraction and effectiveness leads to improved understanding of trial results, gives trial results greater external validity and is essential to determine the broader public health impact of circumcision to men and women

Factors Influencing the Emergence and Spread of HIV Drug Resistance Arising from Rollout of Antiretroviral Pre-Exposure Prophylaxis (PrEP)

Background: The potential for emergence and spread of HIV drug resistance from rollout of antiretroviral (ARV) pre-exposure prophylaxis (PrEP) is an important public health concern. We investigated determinants of HIV drug resistance prevalence after PrEP implementation through mathematical modeling. Methodology: A model incorporating heterogeneity in age, gender, sexual activity, HIV infection status, stage of disease, PrEP coverage/discontinuation, and HIV drug susceptibility, was designed to simulate the impact of PrEP on HIV prevention and drug resistance in a sub-Saharan epidemic. Principal Findings: Analyses suggest that the prevalence of HIV drug resistance is influenced most by the extent and duration of inadvertent PrEP use in individuals already infected with HIV. Other key factors affecting drug resistance prevalence include the persistence time of transmitted resistance and the duration of inadvertent PrEP use in individuals who become infected on PrEP. From uncertainty analysis, the median overall prevalence of drug resistance at 10 years was predicted to be 9.2% (interquartile range 6.9%-12.2%). An optimistic scenario of 75% PrEP efficacy, 60% coverage of the susceptible population, and 5% inadvertent PrEP use predicts a rise in HIV drug resistance prevalence to only 2.5% after 10 years. By contrast, in a pessimistic scenario of 25% PrEP efficacy, 15% population coverage, and 25% inadvertent PrEP use, resistance prevalence increased to over 40%. Conclusions: Inadvertent PrEP use in previously-infected individuals is the major determinant of HIV drug resistance prevalence arising from PrEP. Both the rate and duration of inadvertent PrEP use are key factors. PrEP rollout programs should include routine monitoring of HIV infection status to limit the spread of drug resistance. © 2011 Abbas et al

Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: Responses to high fat and high cholesterol diets

Increased catabolism of arginine by arginase is increasingly viewed as an important pathophysiological factor in cardiovascular disease, including atherosclerosis induced by high cholesterol diets. Whereas previous studies have focused primarily on effects of high cholesterol diets on arginase expression and arginine metabolism in specific blood vessels, there is no information regarding the impact of lipid diets on arginase activity or arginine bioavailability at a systemic level. We, therefore, evaluated the effects of high fat (HF) and high fat-high cholesterol (HC) diets on arginase activity in plasma and tissues and on global arginine bioavailability (defined as the ratio of plasma arginine to ornithine + citrulline) in apoE-/- and wild-type C57BL/6J mice. HC and HF diets led to reduced global arginine bioavailability in both strains. The HC diet resulted in significantly elevated plasma arginase in both strains, but the HF diet increased plasma arginase only in apoE-/- mice. Elevated plasma arginase activity correlated closely with increased alanine aminotransferase levels, indicating that liver damage was primarily responsible for elevated plasma arginase. The HC diet, which promotes atherogenesis, also resulted in increased arginase activity and expression of the type II isozyme of arginase in multiple tissues of apoE-/- mice only. These results raise the possibility that systemic changes in arginase activity and global arginine bioavailability may be contributing factors in the initiation and/or progression of cardiovascular disease

A promising method for identifying cross-cultural differences in patient perspective: the use of Internet-based focus groups for content validation of new Patient Reported Outcome assessments

OBJECTIVES: This proof of concept (POC) study was designed to evaluate the use of an Internet-based bulletin board technology to aid parallel cross-cultural development of thematic content for a new set of patient-reported outcome measures (PROs). METHODS: The POC study, conducted in Germany and the United States, utilized Internet Focus Groups (IFGs) to assure the validity of new PRO items across the two cultures – all items were designed to assess the impact of excess facial oil on individuals' lives. The on-line IFG activities were modeled after traditional face-to-face focus groups and organized by a common 'Topic' Guide designed with input from thought leaders in dermatology and health outcomes research. The two sets of IFGs were professionally moderated in the native language of each country. IFG moderators coded the thematic content of transcripts, and a frequency analysis of code endorsement was used to identify areas of content similarity and difference between the two countries. Based on this information, draft PRO items were designed and a majority (80%) of the original participants returned to rate the relative importance of the newly designed questions. FINDINGS: The use of parallel cross-cultural content analysis of IFG transcripts permitted identification of the major content themes in each country as well as exploration of the possible reasons for any observed differences between the countries. Results from coded frequency counts and transcript reviews informed the design and wording of the test questions for the future PRO instrument(s). Subsequent ratings of item importance also deepened our understanding of potential areas of cross-cultural difference, differences that would be explored over the course of future validation studies involving these PROs. CONCLUSION: The use of IFGs for cross-cultural content development received positive reviews from participants and was found to be both cost and time effective. The novel thematic coding methodology provided an empirical platform on which to develop culturally sensitive questionnaire content using the natural language of participants. Overall, the IFG responses and thematic analyses provided a thorough evaluation of similarities and differences in cross-cultural themes, which in turn acted as a sound base for the development of new PRO questionnaires