Attenuation of IgE affinity for FcepsilonRI radically reduces the allergic response in vitro and in vivo

The high affinity of IgE for its receptor, FcepsilonRI (K(a) approximately 10(10) M(-1)), is responsible for the persistence of mast cell sensitization. Cross-linking of FcepsilonRI-bound IgE by multivalent allergen leads to cellular activation and release of pro-inflammatory mediators responsible for the symptoms of allergic disease. We previously demonstrated that limiting the IgE-FcepsilonRI interaction to just one of the two Cepsilon3 domains in IgE-Fc, which together constitute the high affinity binding site, results in 1000-fold reduced affinity. Such attenuation, effected by a small molecule binding to part of the IgE:FcepsilonRI interface or a distant allosteric site, rather than complete blocking of the interaction, may represent a viable approach to the treatment of allergic disease. However, the degree to which the interaction would need to be disrupted is unclear, because the importance of high affinity for immediate hypersensitivity has never been investigated. We have incorporated into human IgE a mutation, R334S, previously characterized in IgE-Fc, which reduces its affinity for FcepsilonRI approximately 50-fold. We have compared the ability of wild type and R334S IgE to stimulate allergen-induced mast cell activation in vitro and in vivo. We confirmed the expected difference in affinity between wild type and mutant IgE for FcepsilonRI (approximately 50-fold) and found that, in vitro, mast cell degranulation was reduced proportionately. The effect in vivo was also marked, with a 75% reduction in the passive cutaneous anaphylaxis response. We have therefore demonstrated that the high affinity of IgE for FcepsilonRI is critical to the allergic response, and that even moderate attenuation of this affinity has a substantial effect in vivo.     

Robustness of central carbohydrate metabolism in developing maize kernels

The central carbohydrate metabolism provides the precursors for the syntheses of various storage products in seeds. While the underlying biochemical map is well established, little is known about the organization and flexibility of carbohydrate metabolic fluxes in the face of changing biosynthetic demands or other perturbations. This question was addressed in developing kernels of maize (Zea mays L.), a model system for the study of starch and sugar metabolism. ¹³C-labeling experiments were carried out with inbred lines, heterotic hybrids, and starch-deficient mutants that were selected to cover a wide range of performances and kernel phenotypes. In total, 46 labeling experiments were carried out using either [U-¹³C₆]glucose or [U-¹³C₁₂]sucrose and up to three stages of kernel development. Carbohydrate flux distributions were estimated based on glucose isotopologue abundances, which were determined in hydrolysates of starch by using quantitative ¹³C-NMR and GC-MS. Similar labeling patterns in all samples indicated robustness of carbohydrate fluxes in maize endosperm, and fluxes were rather stable in response to glucose or sucrose feeding and during development. A lack of ADP-glucose pyrophosphorylase in the bt2 and sh2 mutants triggered significantly increased hexose cycling. In contrast, other mutations with similar kernel phenotypes had no effect. Thus, the distribution of carbohydrate fluxes is stable and not determined by sink strength in maize kernels.     

Poleward bound: adapting to climate-driven species redistribution

Reviews in Fish Biology and Fisheries - One of the most pronounced effects of climate change on the world’s oceans is the (generally) poleward movement of species and fishery stocks in...     

Select plant tannins induce IL-2Ralpha up-regulation and augment cell division in gammadelta T cells

Gammadelta T cells are innate immune cells that participate in host responses against many pathogens and cancers. Recently, phosphoantigen-based drugs, capable of expanding gammadelta T cells in vivo, entered clinical trials with the goal of enhancing innate immune system functions. Potential shortcomings of these drugs include the induction of nonresponsiveness upon repeated use and the expansion of only the Vdelta2 subset of human gammadelta T cells. Vdelta1 T cells, the major tissue subset, are unaffected by phosphoantigen agonists. Using FACS-based assays, we screened primary bovine cells for novel gammadelta T cell agonists with activities not encompassed by the current treatments in an effort to realize the full therapeutic potential of gammadelta T cells. We identified gammadelta T cell agonists derived from the condensed tannin fractions of Uncaria tomentosa (Cat's Claw) and Malus domestica (apple). Based on superior potency, the apple extract was selected for detailed analyses on human cells. The apple extract was a potent agonist for both human Vdelta1 and Vdelta2 T cells and NK cells. Additionally, the extract greatly enhanced phosphoantigen-induced gammadelta T cell expansion. Our analyses suggest that a tannin-based drug may complement the phosphoantigen-based drugs, thereby enhancing the therapeutic potential of gammadelta T cells.     

Effects of dynamics on ecological networks

Ecological food webs define the feeding patterns of interacting species. The architecture of such networks may be affected by dynamical processes operating within them, ultimately influencing the capacity of the networks to persist. As yet relatively little is known about these effects. We compared the architecture of ecological networks with a fixed number of species, constructed in four contrasting ways: (I) topological networks, which required only that species had prey to eat; (II) persistent networks, in which species had also to persist under a simple model of population dynamics; (III) assembled networks, built up by sequential addition of species with dynamical persistence at each step in the sequence; (IV) evolved networks where, in addition to dynamical persistence, body size of species was determined by a simple mutation-selection process. Dynamics had fundamental effects on architecture, the networks of classes II, III and IV being restricted to a small number of trophic levels, in contrast to the non-dynamic, topological class I networks. Class III assembled networks tended to have fewer trophic levels and a more pyramidal biomass distribution than networks of classes II and IV. In evolved class IV networks, the smallest consumers converged to similar body sizes, whereas larger consumers evolved more slowly and did not show such convergence. The results indicate that dynamics affect the architecture of food webs, and that assumptions about simultaneous arrival, sequential arrival and evolution lead to different outcomes. Sequential assembly was shown to have a special property of finding rare sets of persistent species in a small number of steps, suggesting that the rarity of stable communities is not a serious problem in the development of complex communities.     

Molecules to remember

"Working memory" is used for the transient storage of information in the brain. In this issue of Cell, Wang et al. (2007) now reveal how a series of molecular events involving alpha2A-adrenoceptors and a class of ion channels gated by cAMP tune the responses of neural circuits that function in working memory in mammals.     

Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists

Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4 h.     

Long-term patterns of sleeping site use in wild saddleback (Saguinus fuscicollis) and mustached tamarins (S. mystax): effects of foraging, thermoregulation, predation, and resource defense constraints

Sleeping sites are an important aspect of an animal's ecology given the length of time that they spend in them. The sleep ecology of wild saddleback and mustached tamarins is examined using a long-term data set covering three mixed-species troops and 1,300+ tamarin nights. Seasonal changes in photoperiod accounted for a significant amount of variation in sleeping site entry and exit times. Time of exit was more closely correlated with sunrise than time of entry was with sunset. Both species entered their sleeping sites when light levels were significantly higher than when they left them in the morning. Troops of both species used >80 individual sites, the majority being used once. Mustached tamarins never used the same site for more than two consecutive nights, but saddlebacks reused the same site for up to four consecutive nights. Mustached tamarins slept at significantly greater heights than saddleback tamarins. There were consistent interspecific differences in the types of sites used. Neither the presence of infants, season, nor rainfall affected the types or heights of sites chosen. Sleeping sites were located in the central area of exclusive use more often than expected, and their position with respect to fruiting trees indicated a strategy closer to that of a multiple central place forager than a central place forager. These findings are discussed in light of species ecology, with particular reference to predation risk, which is indicated as the major factor influencing the pattern of sleeping site use in these species.     

Comparison of acoustic and traditional point count methods to assess bird diversity and composition in the Aberdare National Park,Kenya

Afromontane forests, like those in the Aberdare National Park (ANP) in Kenya, sustain unique avifaunal assemblages. There is a growing need for biodiversity inventories for Afromontane forests, especially through the utilisation of unskilled observers. Acoustic surveys are a potential aid to this, but more comparisons of this technique with that of traditional point counts are needed. We conducted a systematic survey of the ANP avifauna, assessing whether acoustic and traditional surveys resulted in different species richness scores, and whether this varied with habitat and species characteristics. We also investigated the role of habitat and elevation in driving variation in species richness. The ANP provides habitat types including scrub, moorland, montane, hagenia and bamboo forests. Overall, the surveys yielded 101 identified species. The acoustic method resulted in higher species richness scores compared to the traditional method across all habitats, and the relative performance of the two methods did not vary with habitat type or visibility. The methods detected different species, suggesting that they should be used together to maximise the range of species recorded. We found that habitat type was the primary driver of variation in species richness, with scrub and montane forest having higher species richness scores than other habitats.