Rapid evolution and ecological host-parasite dynamics

Traditionally, the termination of parasite epidemics has been attributed to ecological causes: namely, the depletion of susceptible hosts as a result of mortality or acquired immunity. Here, we suggest that epidemics can also end because of rapid host evolution. Focusing on a particular host–parasite system, Daphnia dentifera and its parasite Metschnikowia bicuspidata , we show that Daphnia from lakes with recent epidemics were more resistant to infection and had less variance in susceptibility than Daphnia from lakes without recent epidemics. However, our studies revealed little evidence for genetic variation in infectivity or virulence in Metschnikowia . Incorporating the observed genetic variation in host susceptibility into an epidemiological model parameterized for this system reveals that rapid evolution can explain the termination of epidemics on time scales matching what occurs in lake populations. Thus, not only does our study provide rare evidence for parasite-mediated selection in natural populations, it also suggests that rapid evolution has important effects on short-term host–parasite dynamics.     

Greenhouse gas emissions from a constructed wetland in southern Sweden

This paper investigates the greenhouse gas emissions from a Swedish wetland, constructed to decrease nutrient content in sewage treatment water. To evaluate the effect of the construction in terms of greenhouse gas emissions we carried out ecosystem-atmosphere flux measurements of CO₂, CH₄ and N₂O using a closed chamber technique. To evaluate the importance of vascular plant species composition to gas emissions we distributed the measurement plots over the three dominating plant species at the field site, i.e., Typha latifolia, Phragmites australis and Juncus effusus. The fluxes of CO₂ (total respiration), CH₄ and N₂O from vegetated plots ranged from 1.39 to 77.5 (g m⁻² day⁻¹), −377 to 1387 and −13.9 to 31.5 (mg m⁻² day⁻¹) for CO₂, CH₄ and N₂O, respectively. Presence of vascular plants lead as expected to significantly higher total respiration rates compared with un-vegetated control plots. Furthermore, we found that the emission rates of N₂O and CH₄ was affected by presence of vascular plants and tended to be species-specific. We assessed the integrated greenhouse warming effect of the emissions using a Global Warming Potential over a 100-year horizon (GWP₁₀₀) and it corresponded to 431 kg CO₂ equivalents m⁻² day⁻¹. Assuming a 7-month season with conditions similar to the study period this is equal to 90 tonnes of CO₂ equivalents annually. N₂O emissions were responsible for one third of the estimated total greenhouse forcing. Furthermore, we estimated that the emission from the forested bog that was the precursor land to Magle constructed wetland amounted to 18.6 tonnes of CO₂ equivalents annually. Hence, the constructed wetland has increased annual greenhouse gas emissions by 71.4 tonnes of CO₂ equivalents for the whole area. Our findings indicate that management processes in relation to wetland construction projects must consider the primary function of the wetland in decreasing eutrophication, in relation to other positive aspects on for instance plant and animal life and recreation as well as possible negative climatic aspects of increased emissions of CH₄ and N₂O.     

Design,synthesis, and binding of homologated truncated 4′-thioadenosine derivatives at the human A3 adenosine receptors

We synthesized homologated truncated 4′-thioadenosine analogues 3 in which a methylene (CH₂) group was inserted in place of the glycosidic bond of a potent and selective A₃ adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A₃ adenosine receptor. However, all homologated nucleosides were devoid of binding affinity at all subtypes of adenosine receptors, indicating that free rotation through the single bond allowed the compound to adopt an indefinite number of conformations, disrupting the favorable binding interaction essential for receptor recognition.     

Antioxidant responses of hyper-accumulator and sensitive fern species to arsenic

Plant species capable of hyper-accumulating heavy metals are of considerable interest for phytoremediation, and differ in their ability to accumulate metals from the environment. This work aims to examine (i) arsenic accumulation in three fern species [Chinese brake fern (Pteris vittata L.), slender brake fern (Pteris ensiformis Burm. f.), and Boston fern (Nephrolepis exaltata L.)], which were exposed to 0, 150, or 300 muM of arsenic (Na(2)HAsO(4).7H(2)O), and (ii) the role of anti-oxidative metabolism in arsenic tolerance in these fern species. Arsenic accumulation increased with an increase in arsenic concentration in the growth medium, the most being found in P. vittata fronds showing no toxicity symptoms. In addition, accumulation was highest in the fronds, followed by the rhizome, and finally the roots, in all three fern species. Thiobarbituric acid-reacting substances, indicators of stress in plants, were found to be lowest in P. vittata, which corresponds with its observed tolerance to arsenic. All three ferns responded differentially to arsenic exposure in terms of anti-oxidative defence. Higher levels of superoxide dismutase, catalase, and ascorbate peroxidase were observed in P. vittata than in P. ensiformis and N. exaltata, showing their active involvement in the arsenic detoxification mechanism. However, no significant increase was observed in either guaiacol peroxides or glutathione reductase in arsenic-treated P. vittata. Higher activity of anti-oxidative enzymes and lower thiobarbituric acid-reacting substances in arsenic-treated P. vittata correspond with its arsenic hyper-accumulation and no symptoms of toxicity.     

First Administration of the Fc-Attenuated Anti-β Amyloid Antibody GSK933776 to Patients with Mild Alzheimer’s Disease: A Randomized,Placebo-Controlled Study

Objective

To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-β amyloid (Aβ) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer’s disease (AD) or mild cognitive impairment (MCI).

Methods

This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001–6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1–6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436).

Results

There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or –hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t_1/2) was 10–15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased dose dependently; no changes were observed for placebo. For total Aβ42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aβ the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aβ showed increases from baseline to week 12 for Aβ X–38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aβ X–42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses.

Conclusion

In this FTIH study the Fc-inactivated anti-Aβ mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.

Trial Registration

ClinicalTrials.gov NCT00459550     

Purification and protective efficacy of monomeric and modified Yersinia pestis capsular F1-V antigen fusion proteins for vaccination against plague

The F1-V vaccine antigen, protective against Yersinia pestis, exhibits a strong tendency to multimerize that affects larger-scale manufacture and characterization. In this work, the sole F1-V cysteine was replaced with serine by site-directed mutagenesis for characterization of F1-V non-covalent multimer interactions and protective potency without participation by disulfide-linkages. F1-V and F1-V(C424S) proteins were overexpressed in Escherichia coli, recovered using mechanical lysis/pH-modulation and purified from urea-solubilized soft inclusion bodies, using successive ion-exchange, ceramic hydroxyapatite, and size-exclusion chromatography. This purification method resulted in up to 2mg/g of cell paste of 95% pure, mono-disperse protein having < or =0.5 endotoxin units per mg by a kinetic chromogenic limulus amoebocyte lysate reactivity assay. Both F1-V and F1-V(C424S) were monomeric at pH 10.0 and progressively self-associated as pH conditions decreased to pH 6.0. Solution additives were screened for their ability to inhibit F1-V self-association at pH 6.5. An L-arginine buffer provided the greatest stabilizing effect. Conversion to >500-kDa multimers occurred between pH 6.0 and 5.0. Conditions for efficient F1-V adsorption to the cGMP-compatible alhydrogel adjuvant were optimized. Side-by-side evaluation for protective potency against subcutaneous plague infection in mice was conducted for F1-V(C424S) monomer; cysteine-capped F1-V monomer; cysteine-capped F1-V multimer; and a F1-V standard reported previously. After a two-dose vaccination with 2 x 20 microg of F1-V, respectively, 100%, 80%, 80%, and 70% of injected mice survived a subcutaneous lethal plague challenge with 10(8) LD(50)Y. pestis CO92. Thus, vaccination with F1-V monomer and multimeric forms resulted in significant, and essentially equivalent, protection.     

High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10⁻². By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.     

Vocal divergence is concordant with genomic evidence for strong reproductive isolation in grasshopper mice (Onychomys)

Behavioral barriers to gene flow often evolve faster than intrinsic incompatibilities and can eliminate the opportunity for hybridization between interfertile species. While acoustic signal divergence is a common driver of premating isolation in birds and insects, its contribution to speciation in mammals is less studied. Here we characterize the incidence of, and potential barriers to, hybridization among three closely related species of grasshopper mice (genus Onychomys). All three species use long‐distance acoustic signals to attract and localize mates; Onychomys arenicola and Onychomys torridus are acoustically similar and morphologically cryptic whereas Onychomys leucogaster is larger and acoustically distinct. We used genotyping‐by‐sequencing (GBS) to test for evidence of introgression in 227 mice from allopatric and sympatric localities in the western United States and northern Mexico. We conducted laboratory mating trials for all species pairs to assess reproductive compatibility, and recorded vocalizations from O. arenicola and O. torridus in sympatry and allopatry to test for evidence of acoustic character displacement. Hybridization was rare in nature and, contrary to prior evidence for O. torridus/O. arenicola hybrids, only involved O. leucogaster and O. arenicola. In contrast, laboratory crosses between O. torridus and O. arenicola produced litters whereas O. leucogaster and O. arenicola crosses did not. Call fundamental frequency in O. torridus and O. arenicola was indistinguishable in allopatry but significantly differentiated in sympatry, a pattern consistent with reproductive character displacement. These results suggest that assortative mating based on a long‐distance signal is an important isolating mechanism between O. torridus and O. arenicola and highlight the importance of behavioral barriers in determining the permeability of species boundaries.     

Effects of planted tree fallows on soil nitrogen dynamics,above-ground and root biomass,N2-fixation and subsequent maize crop productivity in Kenya

The effects of planted fallows of Sesbania sesban (L.) Merr. and Calliandra calothyrsus (Meissner) on soil inorganic nitrogen dynamics and two subsequent maize crops were evaluated under field conditions in the highlands of eastern Kenya. Continuous unfertilised maize, maize/bean rotation and natural regrowth of vegetation (weed fallow) were used as control treatments. The proportion of symbiotic N₂-fixation was estimated by measuring both leaf ¹⁵N enrichment and whole-plant ¹⁵N enrichment by the ¹⁵N dilution technique for Sesbania and Calliandra, using Eucalyptus saligna (Sm.) and Grevillea robusta (A. Cunn) as reference species. Above- and below-ground biomass and N contents were examined in Sesbania, Calliandra, Eucalyptus and Grevillea 22 months after planting. Both the content of inorganic N in the topsoil and the quantity of N mineralised during rainy seasons were higher after the Sesbania fallows than after the other treatments. Compared to the continuous unfertilised maize treatment, both residual crop yields were significantly higher when mineral N (one application of 60 kg N ha^–1) was added. Furthermore, the second crop following the Sesbania fallow was significantly higher than the continuous maize crop. The above-ground biomass of the trees at final harvest were 31.5, 24.5, 32.5 and 43.5 Mg ha^–1 for the Sesbania, Calliandra, Grevillea and Eucalyptus, respectively. For the total below-ground biomass the values for these same tree species were 11.1, 15.5, 17.7, and 19.1 Mg ha^–1, respectively, of which coarse roots (>2 mm), including tap roots, amounted to 70–90%. About 70–90% of the N in Sesbania, and 50–70% in Calliandra, was derived from N₂-fixation. Estimates based on leaf ¹⁵N enrichment and whole-plant ¹⁵N enrichment were strongly correlated. The N added by N₂-fixation amounted to 280–360 kg N ha^–1 for Sesbania and 120–170 kg N ha^–1 for Calliandra, resulting in a positive N balance after two maize cropping seasons of 170–250 kg N ha^–1 and 90–140 kg N ha^–1, for Sesbania and Calliandra, respectively. All the other treatments gave negative N balances after two cropping seasons. We conclude that Sesbania sesban is a tree species well suited for short duration fallows due to its fast growth, high nutrient content, high litter quality and its ability to fix large amounts of N₂ from the atmosphere.