Paths to a malaria vaccine illuminated by parasite genomics.

More human death and disease is caused by malaria parasites than by all other eukaryotic pathogens combined. As early as the sequencing of the first human genome, malaria parasite genomics was prioritized to fuel the discovery of vaccine candidate antigens. This stimulated increased research on malaria, generating new understanding of the cellular and molecular mechanisms of infection and immunity. This review of recent developments illustrates how new approaches in parasite genomics, and increasingly large amounts of data from population studies, are helping to identify antigens that are promising lead targets. Although these results have been encouraging, effective discovery and characterization need to be coupled with more innovation and funding to translate findings into newly designed vaccine products for clinical trials

Case-control approach to identify Plasmodium falciparum polymorphisms associated with severe malaria.

BACKGROUND: Studies to identify phenotypically-associated polymorphisms in the Plasmodium falciparum 23 Mb genome will require a dense array of marker loci. It was considered promising to undertake initial allelic association studies to prospect for virulence polymorphisms in Thailand, as the low endemicity would allow higher levels of linkage disequilibrium (LD) than would exist in more highly endemic areas. METHODOLOGY/PRINCIPAL FINDINGS: Assessment of LD was first made with 11 microsatellite loci widely dispersed in the parasite genome, and 16 microsatellite loci covering a approximately 140 kb region of chromosome 2 (an arbitrarily representative non-telomeric part of the genome), in a sample of 100 P. falciparum isolates. The dispersed loci showed minimal LD (Index of Association, I(S) (A) = 0.013, P = 0.10), while those on chromosome 2 showed significant LD values mostly between loci <5 kb apart. A disease association study was then performed comparing parasites in 113 severe malaria cases and 245 mild malaria controls. Genotyping was performed on almost all polymorphisms in the binding domains of three erythrocyte binding antigens (eba175, eba140 and eba181), and repeat sequence polymorphisms approximately 2 kb apart in each of three reticulocyte binding homologues (Rh1, Rh2a/b, and Rh4). Differences between cases and controls were seen for (i) codons 388-90 in eba175, and (ii) a repeat sequence centred on Rh1 codon 667. CONCLUSIONS/SIGNIFICANCE: Allelic association studies on P. falciparum require dense genotypic markers, even in a population of only moderate endemicity that has more extensive LD than highly endemic populations. Disease-associated polymorphisms in the eba175 and Rh1 genes encode differences in the middle of previously characterised erythrocyte binding domains, marking these for further investigation

Constructional Volcanic Edifices on Mercury: Candidates and Hypotheses of Formation

Mercury, a planet with a predominantly volcanic crust, has perplexingly few, if any, constructional volcanic edifices, despite their common occurrence on other solar system bodies with volcanic histories. Using image and topographical data from the MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) spacecraft, we describe two small (< 15 km‐diameter) prominences with shallow summit depressions associated with volcanically flooded impact features. We offer both volcanic and impact‐related interpretations for their formation, and then compare these landforms with volcanic features on Earth and the Moon. Though we cannot definitively conclude that these landforms are volcanic, the paucity of constructional volcanic edifices on Mercury is intriguing in itself. We suggest that this lack is because volcanic eruptions with sufficiently low eruption volumes, rates, and flow lengths, suitable for edifice construction, were highly spatiotemporally restricted during Mercury's geological history. We suggest that volcanic edifices may preferentially occur in association with late‐stage, post‐impact effusive volcanic deposits. The ESA/JAXA BepiColombo mission to Mercury will be able to investigate further our candidate volcanic edifices, search for other, as‐yet unrecognized edifices beneath the detection limits of MESSENGER data, and test our hypothesis that edifice construction is favored by late‐stage, low‐volume effusive eruptions

Electrostatic interactions mediated by polarizable counterions: weak and strong coupling limits

We investigate the statistical mechanics of an inhomogeneous Coulomb fluid composed of charged particles with static polarizability. We derive the weak- and the strong-coupling approximations and evaluate the partition function in a planar dielectric slab geometry with charged boundaries. We investigate the density profiles and the disjoining pressure for both approximations. Comparison to the case of non-polarizable counterions shows that polarizability brings important differences in the counterion density distribution as well as the counterion mediated electrostatic interactions between charged dielectric interfaces.Comment: 25 pages, 7 figure

A protocol for a systematic review of clinical guidelines and published systematic reviews on the early detection of oral cancer

Background: The predicted increase in incidence of oral cavity cancer (OCC) coupled with high mortality and poor prognosis – particularly when diagnosed at a late/advanced stage – highlights the need for prevention and early detection/screening to reverse these trends. Dental healthcare professionals in primary care settings have a pivotal role in this effort. Aim: The aim of this protocol is to detail the process for assessing the evidence for the best practice and methods of early detection/screening for OCC in primary care dental settings by undertaking a systematic review of global clinical guidelines and published systematic reviews. Method: Searches for clinical guidelines and systematic reviews will be conducted in the following databases: Cochrane library, Medical Literature Analysis and Retrieval System Online (Ovid), Excerpta Medical dataBASE, PubMed, Turning Research into Practice, SCOPUS and Web of Science Core Collection. Our search will extend to include Google Scholar and international professional organizations/associations websites. In addition, we will handsearch the bibliographies and undertake citation searches of the selected papers. Quality appraisal will be undertaken using the Appraisal of Guidelines for Research and Evaluation version II instrument for the clinical guidelines and both A MeaSurement Tool to Assess Systematic Reviews and Risk of Bias in Systematic Reviews tools for the systematic reviews. A narrative synthesis approach will be used to assess the evidence of extracted data, primarily taking account of quality appraisal and recency of publication. Discussion: The synthesis of evidence will determine best practice for OCC early detection/screening by primary care dental healthcare professionals and will evaluate the relationship between clinical guidelines and the evidence base available from systematic reviews in this area

Mechanisms of explosive volcanism on Mercury: implications from its global distribution and morphology

The identification of widespread pyroclastic vents and deposits on Mercury has important implications for the planet's bulk volatile content and thermal evolution. However, the significance of pyroclastic volcanism for Mercury depends on the mechanisms by which the eruptions occurred. Using images acquired by the MErcury Surface, Space ENvironment, GEochemistry, and Ranging spacecraft, we have identified 150 sites where endogenic pits are surrounded by a relatively bright and red diffuse-edged spectral anomaly, a configuration previously used to identify sites of explosive volcanism. We find that these sites cluster at the margins of impact basins and along regional tectonic structural trends. Locally, pits and deposits are usually associated with zones of weakness within impact craters and/or with the surface expressions of individual thrust faults. Additionally, we use images and stereo-derived topographic data to show that pyroclastic deposits are dispersed up to 130 km from their source vent and commonly have either no relief or low circumpit relief within a wider, thinner deposit. These eruptions were therefore likely driven by a relatively high concentration of volatiles, consistent with volatile concentration in a shallow magma chamber prior to eruption. The colocation of sites of explosive volcanism with near-surface faults and crater-related fractures is likely a result of such structures acting as conduits for volatile and/or magma release from shallow reservoirs, with volatile overpressure in these reservoirs a key trigger for eruption in at least some cases. Our findings suggest that widespread, long-lived explosive volcanism on Mercury has been facilitated by the interplay between impact cratering, tectonic structures, and magmatic fractionation

Hollows on Mercury: materials and mechanisms involved in their formation

Recent images of the surface of Mercury have revealed an unusual and intriguing landform: sub-kilometre scale, shallow, flat-floored, steep-sided rimless depressions typically surrounded by bright deposits and generally occurring in impact craters. These ‘hollows’ appear to form by the loss of a moderately-volatile substance from the planet’s surface and their fresh morphology and lack of superposed craters suggest that this process has continued until relatively recently (and may be on-going). Hypotheses to explain the volatile-loss have included sublimation and space weathering, and it has been suggested that hollow-forming volatiles are endogenic and are exposed at the surface during impact cratering. However, detailed verification of these hypotheses has hitherto been lacking. In this study, we have conducted a comprehensive survey of all MESSENGER images obtained up to the end of its fourth solar day in orbit in order to identify hollowed areas. We have studied how their location relates to both exogenic processes (insolation, impact cratering, and solar wind) and endogenic processes (explosive volcanism and flood lavas) on local and regional scales. We find that there is a weak correlation between hollow formation and insolation intensity, suggesting formation may occur by an insolation-related process such as sublimation. The vast majority of hollow formation is in localised or regional low-reflectance material within impact craters, suggesting that this low-reflectance material is a volatile-bearing unit present below the surface that becomes exposed as a result of impacts. In many cases hollow occurrence is consistent with formation in volatile-bearing material exhumed and exposed during crater formation, while in other cases volatiles may have accessed the surface later through re-exposure and possibly in association with explosive volcanism. Hollows occur at the surface of thick flood lavas only where a lower-reflectance substrate has been exhumed from beneath them, indicating that this form of flood volcanism on Mercury lacks significant concentrations of hollow-forming volatiles

The evolution of Pd/Sn catalytic surfaces in electroless copper deposition

This paper describes the different catalytic surfaces of Pd/Sn formed before electroless copper deposition onto a glass substrate. In this study, silanization of the glass surfaces with (3-aminopropyl) trimethoxysilane was used to provide a surface-coupled layer of functional molecules to assist in the adsorption of Pd/Sn catalyst and the subsequent copper deposition. The composition and microstructure of the modified glass surfaces were characterized by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry. These showed that catalytic Pd/Sn structures on the surface changed with increasing immersion time in the catalyst bath. The core-level XPS spectrum of Pd indicated that metallic Pd(0) became more significant in the catalyst layer than Pd(II) with the increasing immersion time. A model of the adsorption process is proposed to explain these changes. It was observed that too high a quantity of Pd(0) does not always improve the adhesion of the Cu deposits in the electroless process

Analyzing Dynamics of Cooperating Spacecraft

A software library has been developed to enable high-fidelity computational simulation of the dynamics of multiple spacecraft distributed over a region of outer space and acting with a common purpose. All of the modeling capabilities afforded by this software are available independently in other, separate software systems, but have not previously been brought together in a single system. A user can choose among several dynamical models, many high-fidelity environment models, and several numerical-integration schemes. The user can select whether to use models that assume weak coupling between spacecraft, or strong coupling in the case of feedback control or tethering of spacecraft to each other. For weak coupling, spacecraft orbits are propagated independently, and are synchronized in time by controlling the step size of the integration. For strong coupling, the orbits are integrated simultaneously. Among the integration schemes that the user can choose are Runge-Kutta Verner, Prince-Dormand, Adams-Bashforth-Moulton, and Bulirsh- Stoer. Comparisons of performance are included for both the weak- and strongcoupling dynamical models for all of the numerical integrators

Cardiovascular disease biomarkers are associated with declining renal function in type 2 diabetes

Aims/hypothesis: We investigated whether biochemical cardiovascular risk factors and/or markers of subclinical cardiovascular disease were associated with the development of reduced renal function in people with type 2 diabetes. Methods: A cohort of 1066 Scottish men and women aged 60–74 years with type 2 diabetes from the Edinburgh Type 2 Diabetes Study were followed up for a median of 6.7 years. New-onset reduced renal function was defined as two eGFRs &#60;60 ml−1 min−1 (1.73 m)−2 at least 3 months apart with a &#62; 25% decline from baseline eGFR. Ankle brachial pressure index (ABI), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) were measured at baseline. Pulse wave velocity (PWV) and carotid intima media thickness were measured 1 year into follow-up. Data were analysed using Cox proportional hazards models. Results: A total of 119 participants developed reduced renal function during follow-up. ABI, PWV, NT-proBNP and hsTnT were all associated with onset of decline in renal function following adjustment for age and sex. These associations were attenuated after adjustment for additional diabetes renal disease risk factors (systolic BP, baseline eGFR, albumin:creatinine ratio and smoking pack-years), with the exception of hsTnT which remained independently associated (HR 1.51 [95% CI 1.22, 1.87]). Inclusion of hsTnT in a predictive model improved the continuous net reclassification index by 0.165 (0.008, 0.286). Conclusions/interpretation: Our findings demonstrate an association between hsTnT, a marker of subclinical cardiac ischaemia, and subsequent renal function decline. Further research is required to establish the predictive value of hsTnT and response to intervention