Biochemical and Functional Analysis of Two Plasmodium falciparum Blood-Stage 6-Cys Proteins: P12 and P41

The genomes of Plasmodium parasites that cause malaria in humans, other primates, birds, and rodents all encode multiple 6-cys proteins. Distinct 6-cys protein family members reside on the surface at each extracellular life cycle stage and those on the surface of liver infective and sexual stages have been shown to play important roles in hepatocyte growth and fertilization respectively. However, 6-cys proteins associated with the blood-stage forms of the parasite have no known function. Here we investigate the biochemical nature and function of two blood-stage 6-cys proteins in Plasmodium falciparum, the most pathogenic species to afflict humans. We show that native P12 and P41 form a stable heterodimer on the infective merozoite surface and are secreted following invasion, but could find no evidence that this complex mediates erythrocyte-receptor binding. That P12 and P41 do not appear to have a major role as adhesins to erythrocyte receptors was supported by the observation that antisera to these proteins did not substantially inhibit erythrocyte invasion. To investigate other functional roles for these proteins their genes were successfully disrupted in P. falciparum, however P12 and P41 knockout parasites grew at normal rates in vitro and displayed no other obvious phenotypic changes. It now appears likely that these blood-stage 6-cys proteins operate as a pair and play redundant roles either in erythrocyte invasion or in host-immune interactions.     

Consistent abundance distributions of marine fishes in an old,climatically buffered,infertile seascape

Aim Macroecological theory predicts that along direct physiological gradients there will be unimodal abundance distributions of species and consistent rates of assemblage turnover. However, the majority of marine studies that have investigated the realized distribution of species along latitudinal or temperature gradients have generally found unimodal distributions to be rare. We assess fish distributions along a temperature gradient in a stable oligotrophic seascape and suggest that unimodal distributions will be more common. Location Nearshore demersal fish habitat extending 1500 km along the coast of south‐western Australia. Methods The relative abundances of demersal fish species were sampled off the coast of south‐western Australia along a temperature gradient. The confounding influence of other environmental variables was tested, and the assemblage was found to be highly correlated with temperature. For the 20 most abundant species, quantile regression spline models were used to construct a model within which 95% of their abundance was expected to fall. We compared the results from this study with the proportion of unimodal species abundance distributions observed in other studies. Results Of the 20 most abundant species, 19 displayed patterns that indicated temperature was an important factor influencing their range and relative abundance; with 15 species exhibiting unimodal abundance distributions, four having ramped distribution to one end of the sampled range and one showing no consistent pattern. Main conclusions The high diversity and percentage of endemic species in terrestrial and marine habitats of south‐western Australia is likely to be due to the stable geological and oceanographic history of the region. In comparison, studies of abundance distribution in other marine systems have been conducted in relatively heterogeneous and productive environments. The old, climatically buffered, oligotrophic seascape of south‐western Australia has provided a simple system in which the consistent influence of physiological gradients on the abundance distribution of fish species can be observed.     

Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations

Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10⁻²⁰⁴) and 10 loci for sphingolipids (smallest P-value = 3.10×10⁻⁵⁷). After a correction for multiple comparisons (P-value<2.2×10⁻⁹), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.     

Multi-parameter automodels and their applications

Motivated by the modelling of non-Gaussian data or positivelycorrelated data on a lattice, extensions of Besag's automodelsto exponential families with multi-dimensional parameters havebeen proposed recently. We provide a multiple-parameter analogueof Besag's one-dimensional result that gives the necessary formof the exponential families for the Markov random field's conditionaldistributions. We propose estimation of parameters by maximumpseudolikelihood and give a proof of the consistency of theestimators for the multi-parameter automodel. The methodologyis illustrated with examples, in particular the building ofa cooperative system with beta conditional distributions. Wealso indicate future applications of these models to the analysisof mixed-state spatial data.     

Elevated Soluble CD163 in Gestational Diabetes Mellitus: Secretion from Human Placenta and Adipose Tissue

Recently soluble CD163 (sCD163), a cleaved form of the macrophage receptor CD163, was identified as a macrophage-specific risk-predictor for developing Type 2 Diabetes. Here, we investigate circulating levels of sCD163 in gestational diabetes mellitus (GDM). Furthermore, given the role of the placenta in the pathogenesis of GDM, we assessed placental contribution to sCD163 secretion. Paired maternal (venous) and umbilical vein blood samples from GDM (n = 18) and Body Mass Index (BMI) matched control women (n = 20) delivered by caesarean section at 39–40 week gestation were assessed for circulating levels of sCD163, Tumour necrosis factor alpha (TNF-α) and Interleukin 6 (IL-6). Media from explant culture of maternal subcutaneous fat and corresponding placental tissues were assayed for these same molecules. CD163 positive cell numbers were determined in placental and adipose tissues of GDM and control women. We found significantly elevated circulating sCD163 levels in GDM mothers (688.4±46.9 ng/ml vs. 505.6±38.6 ng/ml) and their offspring (418.2±26.6 ng/ml vs. 336.3±24.4 ng/ml [p<0.05 for both]) as compared to controls, together with elevated circulating TNF-α and IL-6 levels. Moreover, both GDM placentae (268.1±10.8 ng/ml/mg vs. 187.6±20.6 ng/ml/mg) and adipose explants (41.1±2.7 ng/ml/mg vs. 26.6±2.4 ng/ml/mg) released significantly more sCD163 than controls. Lastly, significantly more CD163 positive cells were observed in GDM placentae (25.7±1.1 vs. 22.1±1.2) and adipose tissue (19.1±1.1 vs 12.7±0.9) compared to controls. We describe elevated sCD163 levels in GDM and identify human placenta as a novel source of sCD163 suggesting that placental tissues might contribute to the increased levels of circulating sCD163 in GDM pregnancies.     

The maximal exercise ECG in asymptomatic men

Lead MC5 bipolar exercise ECG was obtained in 510 asymptomatic males, aged 40 to 65, utilizing the bicycle ergometer, with maximal stress in 71% of the subjects. “Ischemic changes” occurred in 61 subjects, the frequency increasing from 4% at age 40 to 45, to 20% at age 50 to 55, to 37% at age 61 to 65. Subjects having an ischemic type ECG change on exercise had more frequent minor resting ECG changes, more resting hypertension, and a greater incidence of high cholesterol values than subjects with a normal ECG response to exercise, but there was no difference in the incidence of obesity, low fitness, or high systolic blood pressure after exercise. Current evidence suggests that asymptomatic male subjects with an abnormal exercise ECG develop clinical coronary heart disease from 2.5 to over 30 times more frequently than those with a normal exercise ECG.     

What controls variation in carbon use efficiency among Amazonian tropical forests?

Why do some forests produce biomass more efficiently than others? Variations in Carbon Use Efficiency (CUE: total Net Primary Production (NPP)/ Gross Primary Production (GPP)) may be due to changes in wood residence time (Biomass/NPP_wood), temperature, or soil nutrient status. We tested these hypotheses in 14, one ha plots across Amazonian and Andean forests where we measured most key components of net primary production (NPP: wood, fine roots, and leaves) and autotrophic respiration (R_a; wood, rhizosphere, and leaf respiration). We found that lower fertility sites were less efficient at producing biomass and had higher rhizosphere respiration, indicating increased carbon allocation to belowground components. We then compared wood respiration to wood growth and rhizosphere respiration to fine root growth and found that forests with residence times <40 yrs had significantly lower maintenance respiration for both wood and fine roots than forests with residence times >40 yrs. A comparison of rhizosphere respiration to fine root growth showed that rhizosphere growth respiration was significantly greater at low fertility sites. Overall, we found that Amazonian forests produce biomass less efficiently in stands with residence times >40 yrs and in stands with lower fertility, but changes to long‐term mean annual temperatures do not impact CUE.