HIV-1 Envelope Proteins and V1/V2 Domain Scaffolds with Mannose-5 to Improve the Magnitude and Quality of Protective Antibody Responses to HIV-1

Two lines of investigation have highlighted the importance of antibodies to the V1/V2 domain of gp120 in providing protection from HIV-1 infection. First, the recent RV144 HIV-1 vaccine trial documented a correlation between non-neutralizing antibodies to the V2 domain and protection. Second, multiple broadly neutralizing monoclonal antibodies to the V1/V2 domain (e.g. PG9) have been isolated from rare infected individuals, termed elite neutralizers. Interestingly, the binding of both types of antibodies appears to depend on the same cluster of amino acids (positions 167–171) adjacent to the junction of the B and C strands of the four-stranded V1/V2 domain β-sheet structure. However, the broadly neutralizing mAb, PG9, additionally depends on mannose-5 glycans at positions 156 and 160 for binding. Because the gp120 vaccine immunogens used in previous HIV-1 vaccine trials were enriched for complex sialic acid-containing glycans, and lacked the high mannose structures required for the binding of PG9-like mAbs, we wondered if these immunogens could be improved by limiting glycosylation to mannose-5 glycans. Here, we describe the PG9 binding activity of monomeric gp120s from multiple strains of HIV-1 produced with mannose-5 glycans. We also describe the properties of glycopeptide scaffolds from the V1/V2 domain also expressed with mannose-5 glycans. The V1/V2 scaffold from the A244 isolate was able to bind the PG9, CH01, and CH03 mAbs with high affinity provided that the proper glycans were present. We further show that immunization with A244 V1/V2 fragments alone, or in a prime/boost regimen with gp120, enhanced the antibody response to sequences in the V1/V2 domain associated with protection in the RV144 trial.     

The distribution and reproduction of Pterosiphonia complanata

The geographical distribution of the red alga Pterosiphonia complanata (Clem.) Falkenb. is described. New records confirm that it is restricted to the warmer waters of the North Atlantic and extend its known distribution in the British Isles where it is at the northern limits of its range. The apparent scarcity and restricted distribution of the species in the British Isles and the absence of sexual plants throughout its range are discussed in relation to the habitat and possible life history of the species.     

Phytoplankton phenology in the global ocean

In recent years, phytoplankton phenology has been proposed as an indicator to monitor systematically the state of the pelagic ecosystem and to detect changes triggered by perturbation of the environmental conditions. Here we describe the phenology of phytoplankton growth for the world ocean using remote-sensing ocean colour data, and analyse its variability between 1998 and 2007. Generally, the tropics and subtropics present long growing period (≈15-20 weeks) of low amplitude (<0.5 mg Chl m⁻³), whereas the high-latitudes show short growing period (<10 weeks) of high amplitude (up to 7 mg Chl m⁻³). Statistical analyses suggest a close coupling between the development of the growing period and the seasonal increase in insolation in the North Atlantic and Southern Ocean. In the tropics and subtropics, variability in light is low, and the growing period is controlled by nutrient supply occurring when mixing increases. Large interannual variability in the duration of the growing period is observed over the decade 1998-2007, with positive anomalies following the major 1997-1998 El Niño-La Niña events, and generally negative anomalies from 2003 to 2007. Warmer Sea-Surface Temperature (SST) over the duration of the growing period is associated with longer duration at high-latitudes indicating an extension of the growing period over summer months. The opposite is observed in the tropics and subtropics, where the duration is shorter when the SST is warmer, indicating increased stratification. Positive phases of North Atlantic Oscillation and Southern Annular Mode and negative phases of Multivariate El Niño-Southern Oscillation index (El Niño conditions), associated with enhanced water mixing and nutrients supply, generally sustain longer growth. On the basis of the results, perspectives are drawn on the utility of phenology as an organising principle for the analysis of pelagic ecosystem.     

Kinetic analysis of calcium activation of brain acetylcholinesterase forms.

Calcium activation of acetylcholine hydrolysis by bovine brain acetylcholinesterase (Acetylcholine hydrolase, EC 3.1.1.7) forms has been analyzed in terms of changes in kinetic constants and thermodynamic activation parameters. De-acetylation was determined to be the major rate-influencing step in acetylcholine hydrolysis by both 60 000- and 240 000-dalton forms of the brain enzyme and 10 mM Ca2+ increased the rate constant for this step (k+3) by approximately 30% for both forms. For the smaller acetylcholinesterase form the effects of Ca2+ on de-acetylation was equivalent to its effect on the overall rate constant (k) and occurred without an effect on pK. In the case of the 240 000-dalton species, the overall rate constant was increased by Ca2+ by 33% at pH 8.0 and 81% at pH 7.25 and involved a pK shift of -0.2 pH units. For both enzyme forms the rate constants for acetylation (k+2) were increased by Ca2+. Thermodynamic analysis suggested that Ca2+ activation of the acetylation step was entropically driven. Differences between the two enzymes forms in terms of Ca2+ appear to result from association of low molecular weight species.     

Spatial Heterogeneity,Host Movement and Mosquito-Borne Disease Transmission

Mosquito-borne diseases are a global health priority disproportionately affecting low-income populations in tropical and sub-tropical countries. These pathogens live in mosquitoes and hosts that interact in spatially heterogeneous environments where hosts move between regions of varying transmission intensity. Although there is increasing interest in the implications of spatial processes for mosquito-borne disease dynamics, most of our understanding derives from models that assume spatially homogeneous transmission. Spatial variation in contact rates can influence transmission and the risk of epidemics, yet the interaction between spatial heterogeneity and movement of hosts remains relatively unexplored. Here we explore, analytically and through numerical simulations, how human mobility connects spatially heterogeneous mosquito populations, thereby influencing disease persistence (determined by the basic reproduction number R ₀), prevalence and their relationship. We show that, when local transmission rates are highly heterogeneous, R ₀ declines asymptotically as human mobility increases, but infection prevalence peaks at low to intermediate rates of movement and decreases asymptotically after this peak. Movement can reduce heterogeneity in exposure to mosquito biting. As a result, if biting intensity is high but uneven, infection prevalence increases with mobility despite reductions in R ₀. This increase in prevalence decreases with further increase in mobility because individuals do not spend enough time in high transmission patches, hence decreasing the number of new infections and overall prevalence. These results provide a better basis for understanding the interplay between spatial transmission heterogeneity and human mobility, and their combined influence on prevalence and R ₀.