Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcepsilon receptor (FcepsilonRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world. However, this increase has not been mirrored in developing countries, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcepsilonRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D-coupled, sphingosine kinase-mediated calcium mobilization and nuclear factor-kappaB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-alpha (PKC-alpha). This causes caveolae/lipid raft-mediated, proteasome-independent degradation of PKC-alpha, a molecule important for the coupling of FcepsilonRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell-dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.     

Maternal diabetes induces congenital heart defects in mice by altering the expression of genes involved in cardiovascular development

Background

Congenital heart defects are frequently observed in infants of diabetic mothers, but the molecular basis of the defects remains obscure. Thus, the present study was performed to gain some insights into the molecular pathogenesis of maternal diabetes-induced congenital heart defects in mice.

Methods and results

We analyzed the morphological changes, the expression pattern of some genes, the proliferation index and apoptosis in developing heart of embryos at E13.5 from streptozotocin-induced diabetic mice. Morphological analysis has shown the persistent truncus arteriosus combined with a ventricular septal defect in embryos of diabetic mice. Several other defects including defective endocardial cushion (EC) and aberrant myofibrillogenesis have also been found. Cardiac neural crest defects in experimental embryos were analyzed and validated by the protein expression of NCAM and PGP 9.5. In addition, the protein expression of Bmp4, Msx1 and Pax3 involved in the development of cardiac neural crest was found to be reduced in the defective hearts. The mRNA expression of Bmp4, Msx1 and Pax3 was significantly down-regulated (p < 0.001) in the hearts of experimental embryos. Further, the proliferation index was significantly decreased (p < 0.05), whereas the apoptotic cells were significantly increased (p < 0.001) in the EC and the ventricular myocardium of the experimental embryos.

Conclusion

It is suggested that the down-regulation of genes involved in development of cardiac neural crest could contribute to the pathogenesis of maternal diabetes-induced congenital heart defects.     

Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized,open-label,parallel group study in healthy subjects

The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes.     

Mitochondrial DNA analysis of field populations of <Emphasis Type="Italic">Helicoverpa armigera</Emphasis> (Lepidoptera: Noctuidae) and of its relationship to <Emphasis Type="Italic">H. zea</Emphasis>

Background  

Helicoverpa armigera and H. zea are amongst the most significant polyphagous pest lepidopteran species in the Old and New Worlds respectively. Separation of H. armigera and H. zea is difficult and is usually only achieved through morphological differences in the genitalia. They are capable of interbreeding to produce fertile offspring. The single species status of H. armigera has been doubted, due to its wide distribution and plant host range across the Old World. This study explores the global genetic diversity of H. armigera and its evolutionary relationship to H zea.     

Multiple host shifts by the emerging honeybee parasite,Varroa jacobsoni

Host shifts are a key mechanism of parasite evolution and responsible for the emergence of many economically important pathogens. Varroa destructor has been a major factor in global honeybee (Apis mellifera) declines since shifting hosts from the Asian honeybee (Apis cerana) > 50 years ago. Until recently, only two haplotypes of V. destructor (Korea and Japan) had successfully host shifted to A. mellifera. In 2008, the sister species V. jacobsoni was found for the first time parasitizing A. mellifera in Papua New Guinea (PNG). This recent host shift presents a serious threat to world apiculture but also provides the opportunity to examine host shifting in this system. We used 12 microsatellites to compare genetic variation of V. jacobsoni on A. mellifera in PNG with mites on A. cerana in both PNG and surrounding regions. We identified two distinct lineages of V. jacobsoni reproducing on A. mellifera in PNG. Our analysis indicated independent host shift events have occurred through small numbers of mites shifting from local A. cerana populations. Additional lineages were found in the neighbouring Papua and Solomon Islands that had partially host shifted to A. mellifera, that is producing immature offspring on drone brood only. These mites were likely in transition to full colonization of A. mellifera. Significant population structure between mites on the different hosts suggested host shifted V. jacobsoni populations may not still reproduce on A. cerana, although limited gene flow may exist. Our studies provide further insight into parasite host shift evolution and help characterize this new Varroa mite threat to A. mellifera worldwide.     

Dissecting the telomere region of barley chromosome 5HL using rice genomic sequences as references: new markers for tracking a complex region in breeding

The terminal region of barley chromosome 5HL controls malt extract, diastatic power, free amino acid nitrogen, alpha-amylase activity, seed dormancy and pre-harvest sprouting. Comparative analysis of the barley and rice maps has established that the terminal region of barley chromosome 5HL is syntenic to rice chromosome 3L near the telomere end. The rice BAC (Bacterial Artificial Chromosome) sequences covering the region of chromosome 3L were used to search barley expressed sequenced tags database. Thirty-three genes were amplified by PCR (polymerase chain reaction) with the primers designed from barley ESTs (expressed sequence tag). Comparison of the sequences of the PCR generated DNA fragments revealed polymorphisms including single nucleotide polymorphism (SNP), insertions or deletions between the barley varieties. Seven new PCR based molecular markers were developed and mapped within 10 cM in three doubled haploid barley populations (Stirling × Harrington, Baudin × AC Metcalfe and Chebec × Harrington). The mapped genes maintain the micro-syntenic relationship between barley and rice. These gene specific markers provide simple and efficient tools for germplasm characterization and marker-assisted selection for barley malting quality, and ultimately lead to isolation and identification of the major gene(s) controlling multiple quality traits on barley chromosome 5HL.