Detecting signatures of balancing selection to identify targets of anti-parasite immunity.

Parasite antigen genes might evolve under frequency-dependent immune selection. The distinctive patterns of polymorphism that result can be detected using population genetic methods that test for signatures of balancing selection, allowing genes encoding important targets of immunity to be identified. Analyses can be complicated by population structures, histories and features of a parasite's genome. However, new sequencing technologies facilitate scans of polymorphism throughout parasite genomes to identify the most exceptional gene specific signatures. We focus on malaria parasites to illustrate challenges and opportunities for detecting targets of frequency-dependent immune selection to discover new potential vaccine candidates

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

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

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

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

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

Discovery of circularly polarised radio emission from SS 433

We report the discovery of circularly polarised radio emission from the radio-jet X-ray binary SS 433 with the Australia Telescope Compact Array. The flux density spectrum of the circular polarization, clearly detected at four frequencies between 1 - 9 GHz, has a spectral index of (-0.9 +/- 0.1). Multiple components in the source and a lack of very high spatial resolution do not allow a unique determination of the origin of the circular polarization, nor of the spectrum of fractional polarization. However, we argue that the emission is likely to arise in the inner regions of the binary, possibly via propagation-induced conversion of linear to circular polarization, and the fractional circular polarization of these regions may be as high as 10%. Observations such as these have the potential to investigate the composition, whether pairs or baryonic, of the ejecta from X-ray binaries.Comment: Accepted for publication in ApJ Letter

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

Isometric hip and knee torque measurements as an outcome measure in robot assisted gait training

Strength changes in lower limb muscles following robot assisted gait training (RAGT) in subjects with incomplete spinal cord injury (ISCI) has not been quantified using objective outcome measures. To record changes in the force generating capacity of lower limb muscles (recorded as peak voluntary isometric torque at the knee and hip), before, during and after RAGT in both acute and subacute/chronic ISCI subjects using a repeated measures study design. Eighteen subjects with ISCI participated in this study (Age range: 26–63 years mean age = 49.3 ± 11 years). Each subject participated in the study for a total period of eight weeks, including 6 weeks of RAGT using the Lokomat system (Hocoma AG, Switzerland). Peak torques were recorded in hip flexors, extensors, knee flexors and extensors using torque sensors that are incorporated within the Lokomat. All the tested lower limb muscle groups showed statistically significant (p < 0.001) increases in peak torques in the acute subjects. Comparison between the change in peak torque generated by a muscle and its motor score over time showed a non-linear relationship. The peak torque recorded during isometric contractions provided an objective outcome measure to record changes in muscle strength following RAGT

Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm

Retinal ganglion cell (RGC) axons from each eye execute a series of maneuvers as they converge on the ventral surface of the brain at the optic chiasm for sorting into the optic tracts. Heparan sulfate proteoglycans (HSPGs) are extracellular glycoproteins involved in cell-surface interactions. HSPGs exhibit massive structural diversity, conferred partly by extensive post-translational modification including differential sulfation. Here we examine the roles of HSPG sulfation in RGC axon guidance at the chiasm. We identified different axon navigation phenotypes in two heparan sulfate sulfotransferase (Hst) mutant embryos, Hs2st-/- and Hs6st1-/-, each lacking an enzyme that catalyzes a particular HSPG modification. Hs2st-/- embryos display axon disorganization at the chiasm. Hs6st1-/- embryos exhibit prolific inter-retinal innervation. We show that RGCs express Hs2st and Hs6st1 and that navigation errors made by their axons coincide with regions of high Hs2st and/or Hs6st1 expression at the chiasm. Slit proteins are expressed at particular locations in the retina and around the chiasm and are normally deployed to prevent axons entering inappropriate territories. We show that Hs2st and/or Hs6st1 expression coincides with Slit expression domains at locations where RGC axons make navigation errors in Hs2st-/- and Hs6st1-/- mutants and that Hs6st1-/- RGC axons are less sensitive to Slit2 repulsion than their wild-type counterparts in vitro. We suggest that (1) Hs2st and Hs6st1 are each deployed to generate distinct patterns of heparan sulfation on RGCs and at the optic chiasm and (2) this differential sulfation directs retinal axons through the chiasm, at least in part by modulating the response of the navigating growth cone to Slit proteins