Evolutionary History and Attenuation of Myxoma Virus on Two Continents

The attenuation of myxoma virus (MYXV) following its introduction as a biological control into the European rabbit populations of Australia and Europe is the canonical study of the evolution of virulence. However, the evolutionary genetics of this profound change in host-pathogen relationship is unknown. We describe the genome-scale evolution of MYXV covering a range of virulence grades sampled over 49 years from the parallel Australian and European epidemics, including the high-virulence progenitor strains released in the early 1950s. MYXV evolved rapidly over the sampling period, exhibiting one of the highest nucleotide substitution rates ever reported for a double-stranded DNA virus, and indicative of a relatively high mutation rate and/or a continually changing selective environment. Our comparative sequence data reveal that changes in virulence involved multiple genes, likely losses of gene function due to insertion-deletion events, and no mutations common to specific virulence grades. Hence, despite the similarity in selection pressures there are multiple genetic routes to attain either highly virulent or attenuated phenotypes in MYXV, resulting in convergence for phenotype but not genotype.     

Progressive island colonization and ancient origin of Hawaiian Metrosideros (Myrtaceae)

Knowledge of the evolutionary history of plants that are ecologically dominant in modern ecosystems is critical to understanding the historical development of those ecosystems. Metrosideros is a plant genus found in many ecological and altitudinal zones throughout the Pacific. In the Hawaiian Islands, Metrosideros polymorpha is an ecologically dominant species and is also highly polymorphic in both growth form and ecology. Using 10 non-coding chloroplast regions, we investigated haplotype diversity in the five currently recognized Hawaiian Metrosideros species and an established out-group, Metrosideros collina, from French Polynesia. Multiple haplotype groups were found, but these did not match morphological delimitations. Alternative morphologies sharing the same haplotype, as well as similar morphologies occurring within several distinct island clades, could be the result of developmental plasticity, parallel evolution or chloroplast capture. The geographical structure of the data is consistent with a pattern of age progressive island colonizations and suggests de novo intra-island diversification. If single colonization events resulted in a similar array of morphologies on each island, this would represent parallel radiations within a single, highly polymorphic species. However, we were unable to resolve whether the pattern is instead explained by ancient introgression and incomplete lineage sorting resulting in repeated chloroplast capture. Using several calibration methods, we estimate the colonization of the Hawaiian Islands to be potentially as old as 3.9 (-6.3) Myr with an ancestral position for Kaua'i in the colonization and evolution of Metrosideros in the Hawaiian Islands. This would represent a more ancient arrival of Metrosideros to this region than previous studies have suggested.     

No evidence that polyandry benefits females in Drosophila melanogaster

Understanding the evolution of polyandry (mating with multiple males) is a major issue in the study of animal breeding systems. We examined the adaptive significance of polyandry in Drosophila melanogaster, a species with well-documented costs of mating in which males generally cannot force copulations. We found no direct fitness advantages of polyandry. Females that mated with multiple males had no greater mean fitness and no different variance in fitness than females that mated repeatedly with the same male. Subcomponents of reproductive success, including fecundity, egg hatch rate, larval viability, and larval development time, also did not differ between polyandrous and monogamous females. Polyandry had no affect on progeny sex ratios, suggesting that polyandry does not function against costly sex-ratio distorters. We also found no evidence that polyandry functions to favor the paternity of males successful in precopulatory sexual selection. Experimentally controlled opportunities for precopulatory sexual selection had no effect on postcopulatory sperm precedence. Although these results were generally negative, they are supported with substantial statistical power and they help narrow the list of evolutionary explanations for polyandry in an important model species.     

Kinetic analysis of IgG antibodies to beta-amyloid oligomers with surface plasmon resonance

Surface plasmon resonance was used to investigate the kinetics, affinity, and specificity of binding between anti-Aβ (beta-amyloid) IgG antibodies and oligomeric Aβ. Two factors were needed to accurately characterize the IgG binding kinetics. First, a bivalent model was necessary to properly fit the kinetic association and dissociation sensograms. Second, a high concentration of IgG was necessary to overcome a significant mass transport limitation that existed regardless of oligomer density on the sensor surface. Using high IgG concentrations and bivalent fits, consistent kinetic parameters were found at varying sensor surface ligand densities. A comparison of binding specificity, affinity, and kinetic flux between monoclonal and natural human anti-Aβ IgG antibodies revealed the following findings. First, monoclonal antibodies 6E10 and 4G8 single-site binding affinity is similar between Aβ oligomers and monomers. Second, natural human anti-Aβ IgG binding readily binds Aβ oligomers but does not bind monomers. Third, natural human anti-Aβ IgG binds Aβ oligomers with a higher affinity and kinetic flux than 6E10 and 4G8. Both the current analytical methodology and antibody binding profiles are important for advances in antibody drug development and kinetic biomarker applications for Alzheimer’s disease.     

Inhibitory effect of combinations of digoxin and endogenous cardiotonic steroids on Na+/K+-ATPase activity in human kidney membrane preparation

AimsCardiac glycosides have been extensively used in the treatment of congestive heart failure for more than 200 years. Recently, cardenolides and bufadienolides were isolated from mammalian tissue and are considered as a new class of steroidal hormones. The aim of the present work was to characterize the interaction between the most clinical used cardiac glycoside digoxin and the cardiac glycosides known to exist endogenously, i.e., ouabain, marinobufagin and telocinobufagin, on human kidney Na⁺/K⁺-ATPase.Main methodsInhibition of Na⁺/K⁺-ATPase activity from crude membrane preparations of human kidney was performed using increasing concentrations of the drugs alone or mixtures of ouabain:digoxin, telocinobufagin:digoxin and marinobufagin:digoxin in a fixed ratio 1:4, 2:3 and 3:2, respectively. The colorimetric method of Fiske and Subbarow was used to measure the inorganic phosphate released.Key findingsAnalyses of inhibition curves showed that the experimental curves for all combinations were superimposed on the theoretical additive curves indicating that an additive effect occurs among distinct cardenolides and bufadienolides combinations on the human α1β1 Na⁺/K⁺-ATPase protomer.SignificanceConsidering the extensive use of digoxin in the treatment of heart failure and the recent findings that endogenous cardiac glycosides may have altered levels in many diseases, including heart failure, the demonstration of additive effect between cardiac glycosides can help in the understanding of recent clinical observations, including that lower than usual doses of cardiac glycosides are necessary for decreasing mortality in these patients.     

Trisubstituted and tetrasubstituted pyrazolines as a novel class of cell-growth inhibitors in tumor cells with wild type p53

Derivatives with scaffolds of 1,3,5-tri-substituted pyrazoline and 1,3,4,5-tetra-substituted pyrazoline were synthesized and tested for their inhibitory effects versus the p53^+/+ HCT116 and p53^?/? H1299 human tumor cell lines. Several compounds were active against the two cell lines displaying IC₅₀ values in the low micromolar range with a clearly more pronounced effect on the p53^+/+ HCT116 cells. The compound class shows excellent developability due to the modular synthesis, allowing independent optimization of all three to four key substituents to improve the properties of the molecules.     

ICAMs Are Not Obligatory for Functional Immune Synapses between Naive CD4 T Cells and Lymph Node DCs

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Assessing the effectiveness of a community intervention for monkeypox prevention in the Congo basin

Background

In areas where health resources are limited, community participation in the recognition and reporting of disease hazards is critical for the identification of outbreaks. This is particularly true for zoonotic diseases such as monkeypox that principally affect people living in remote areas with few health services. Here we report the findings of an evaluation measuring the effectiveness of a film-based community outreach program designed to improve the understanding of monkeypox symptoms, transmission and prevention, by residents of the Republic of the Congo (ROC) who are at risk for disease acquisition.

Methodology/Principal Findings

During 90 days, monkeypox outreach was conducted for ∼23,860 people in northern ROC. Two hundred seventy-one attendees (selected via a structured sample) were interviewed before and after participating in a small-group outreach session. The proportion of interviewees demonstrating monkeypox-specific knowledge before and after was compared. Significant gains were measured in areas of disease recognition, transmission, and mitigation of risk. The ability to recognize at least one disease symptom and a willingness to take a family member with monkeypox to the hospital increased from 49 and 45% to 95 and 87%, respectively (p<0.001, both). Willingness to deter behaviors associated with zoonotic risk, such as eating the carcass of a primate found dead in the forest, remained fundamentally unchanged however, suggesting additional messaging may be needed.

Conclusions/Significance

These results suggest that our current program of film-based educational activities is effective in improving disease-specific knowledge and may encourage individuals to seek out the advice of health workers when monkeypox is suspected.     

Glycosylation reaction of unprotected sugars with hydroxyalkylthymine

Under mild conditions (Lewis acid/solvent/room temperature), the reaction of unprotected glucose, deoxyribose or xylose with hydroxylalkylthymine gives selectively nucleoside analogs with a spacer arm between sugar and base moiety. Experimental conditions (Lewis acid, solvent) for this new strategy leading to nucleoside analogs synthesis are discussed.