Antibody Maturation and Viral Diversification in HIV-Infected Women

Introduction

The Post-exposure Prophylaxis in Infants (PEPI)-Malawi trial evaluated infant antiretroviral regimens for prevention of post-natal HIV transmission. A multi-assay algorithm (MAA) that includes the BED capture immunoassay, an avidity assay, CD4 cell count, and viral load was used to identify women who were vs. were not recently infected at the time of enrollment (MAA recent, N = 73; MAA non-recent, N = 2,488); a subset of the women in the MAA non-recent group known to have been HIV infected for at least 2 years before enrollment (known non-recent, N = 54). Antibody maturation and viral diversification were examined in these women.

Methods

Samples collected at enrollment (N = 2,561) and 12–24 months later (N = 1,306) were available for serologic analysis using the BED and avidity assays. A subset of those samples was used for analysis of viral diversity, which was performed using a high resolution melting (HRM) diversity assay. Viral diversity analysis was performed using all available samples from women in the MAA recent group (61 enrollment samples, 38 follow-up samples) and the known non-recent group (43 enrollment samples, 22 follow-up samples). Diversity data from PEPI-Malawi were also compared to similar data from 169 adults in the United States (US) with known recent infection (N = 102) and known non-recent infection (N = 67).

Results

In PEPI-Malawi, results from the BED and avidity assays increased over time in the MAA recent group, but did not change significantly in the MAA non-recent group. At enrollment, HIV diversity was lower in the MAA recent group than in the known non-recent group. HRM diversity assay results from women in PEPI-Malawi were similar to those from adults in the US with known duration of HIV infection.

Conclusions

Antibody maturation and HIV diversification patterns in African women provide additional support for use of the MAA to identify populations with recent HIV infection.     

Wavelength dependence of biological damage induced by UV radiation on bacteria

The biological effects of UV radiation of different wavelengths (UVA, UVB and UVC) were assessed in nine bacterial isolates displaying different UV sensitivities. Biological effects (survival and activity) and molecular markers of oxidative stress [DNA strand breakage (DSB), generation of reactive oxygen species (ROS), oxidative damage to proteins and lipids, and the activity of antioxidant enzymes catalase and superoxide dismutase] were quantified and statistically analyzed in order to identify the major determinants of cell inactivation under the different spectral regions. Survival and activity followed a clear wavelength dependence, being highest under UVA and lowest under UVC. The generation of ROS, as well as protein and lipid oxidation, followed the same pattern. DNA damage (DSB) showed the inverse trend. Multiple stepwise regression analysis revealed that survival under UVA, UVB and UVC wavelengths was best explained by DSB, oxidative damage to lipids, and intracellular ROS levels, respectively.     

An estimation of Canadian population exposure to cosmic rays from air travel

Based on air travel statistics in 1984, it was estimated that less than 4 % of the population dose from cosmic ray exposure would result from air travel. In the present study, cosmic ray doses were calculated for more than 3,000 flights departing from more than 200 Canadian airports using actual flight profiles. Based on currently available air travel statistics, the annual per capita effective dose from air transportation is estimated to be 32 μSv for Canadians, about 10 % of the average cosmic ray dose received at ground level (310 μSv per year).     

AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca²⁺/calmodulin-dependent kinase β-independent and liver kinase β 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease.     

Assessment of wind‐farm and other bird casualties from carcasses found on a Northumbrian beach over an 11‐year period

Capsule For 3748 bird carcasses found on 4.7 km of shoreline, the main cause of death was starvation. Three percent of deaths were attributed to wind turbines.

Aims To assess the main mortality causes from bird bodies washed ashore near wind turbines built in 1993.

Methods Weekly searches were made for bird carcasses to ascertain causes of death. Experiments tested the efficiency of searches, longevity of carcasses, and effects of wind direction on deposition rates.

Results In total, 3748 bird carcasses were found, an average of 341 per year. Guillemots formed 24.3% of the total, Kittiwakes 9.7%, Herring Gulls 9.0%, Black‐headed Gulls 7.4%, Great Black‐backed Gulls 6.4% and Feral Pigeons 11.3%. Each year more carcasses were found in winter than in summer, with a nine‐fold variation between winters. About 28.1% of carcasses were classed as starved, and 23.3% as eaten at sea (predation or scavenging). Of human‐related causes, 3.3% were birds affected by fishing gear, 3.0% were oiled, 6.4% had died from collisions (including 3% with wind‐turbines), the rest from minor or unidentified causes. Small passerines were probably under‐represented.

Conclusion Allowing for bodies not found, the local wind‐farm probably killed 148.5–193.5 birds per year, or 16.5–21.5 birds per turbine per year (mainly large gulls).     

Tracking niche variation over millennial timescales in sympatric killer whale lineages

Niche variation owing to individual differences in ecology has been hypothesized to be an early stage of sympatric speciation. Yet to date, no study has tracked niche width over more than a few generations. In this study, we show the presence of isotopic niche variation over millennial timescales and investigate the evolutionary outcomes. Isotopic ratios were measured from tissue samples of sympatric killer whale Orcinus orca lineages from the North Sea, spanning over 10 000 years. Isotopic ratios spanned a range similar to the difference in isotopic values of two known prey items, herring Clupea harengus and harbour seal Phoca vitulina. Two proxies of the stage of speciation, lineage sorting of mitogenomes and genotypic clustering, were both weak to intermediate indicating that speciation has made little progress. Thus, our study confirms that even with the necessary ecological conditions, i.e. among-individual variation in ecology, it is difficult for sympatric speciation to progress in the face of gene flow. In contrast to some theoretical models, our empirical results suggest that sympatric speciation driven by among-individual differences in ecological niche is a slow process and may not reach completion. We argue that sympatric speciation is constrained in this system owing to the plastic nature of the behavioural traits under selection when hunting either mammals or fish.     

Carbon pools recover more quickly than plant biodiversity in tropical secondary forests

Although increasing efforts are being made to restore tropical forests, little information is available regarding the time scales required for carbon and plant biodiversity to recover to the values associated with undisturbed forests. To address this knowledge gap, we carried out a meta-analysis comparing data from more than 600 secondary tropical forest sites with nearby undisturbed reference forests. Above-ground biomass approached equivalence to reference values within 80 years since last disturbance, whereas below-ground biomass took longer to recover. Soil carbon content showed little relationship with time since disturbance. Tree species richness recovered after about 50 years. By contrast, epiphyte richness did not reach equivalence to undisturbed forests. The proportion of undisturbed forest trees and epiphyte species found in secondary forests was low and changed little over time. Our results indicate that carbon pools and biodiversity show different recovery rates under passive, secondary succession and that colonization by undisturbed forest plant species is slow. Initiatives such as the Convention on Biological Diversity and REDD+ should therefore encourage active management to help to achieve their aims of restoring both carbon and biodiversity in tropical forests.     

Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists–serotonin reuptake transporter inhibitors for the treatment of depression

This report describes the synthesis, structure–activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK₁ receptor (NK₁R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK₁R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK₁R antagonists-SERT inhibitors may be useful in treating depression disorders.     

Nucleic acid changes during photodynamic inactivation of bacteria by cationic porphyrins

Light activation of photosensitizing dyes in presence of molecular oxygen generates highly cytotoxic reactive oxygen species leading to cell inactivation. Nucleic acids are molecular targets of this photodynamic action but not considered the main cause of cell death. The in vivo effect of the photodynamic process on the intracellular nucleic acid content of Escherichia coli and Staphylococcus warneri was evaluated herein.Two cationic porphyrins (Tetra-Py⁺-Me and Tri-Py⁺-Me-PF) were used to photoinactivate E. coli (5.0 μM; 10⁸ cells mL^?1) and S. warneri (0.5 μM; 10⁸ cells mL^?1) upon white light irradiation at 4.0 mW cm^?2 for 270 min and 40 min, respectively. Total nucleic acids were extracted from photosensitized bacteria after different times of irradiation and analyzed by agarose gel electrophoresis. The double-stranded DNA was quantified by fluorimetry and the porphyrin binding to bacteria was determined by spectrofluorimetry.E. coli was completely photoinactivated with both porphyrins (5.0 μM), whereas S. warneri was only completely inactivated by Tri-Py⁺-Me-PF (0.5 μM). The hierarchy of nucleic acid changes in E. coli was in the order: 23S rRNA > 16S rRNA > genomic DNA. The nucleic acids of S. warneri were extensively reduced after 5 min with Tri-Py⁺-Me-PF but almost unchanged with Tetra-Py⁺-Me after 40 min of irradiation. The amount of Tri-Py⁺-Me-PF bound to E. coli after washing the cells is higher than Tetra-Py⁺-Me and the opposite was observed for S. warneri. The binding capacity of the photosensitizers is not directly related to the PDI efficiency or nucleic acid reduction and this reduction occurs in parallel with the decrease of surviving cells.