Benzimidazoles as new potent and selective DP antagonists for the treatment of allergic rhinitis

A series of 2-substituted N-benzyl benzimidazole containing molecules has been synthesized and its structure-activity relationship for the human DP receptor has been evaluated. Selective DP antagonists with nanomolar potency for the DP receptor were identified in this novel series of benzimidazoles.     

Modeling egg distribution of Tinocallis kahawaluokalani (Kirkaldy) (Hemiptera: Aphididae) on Lagerstroemia indica L. (Lythraceae)

This is the first record of winter eggs of the holocyclic monoeceous crapemyrtle aphid Tinocallis kahawaluokalani (Kirkaldy) on Lagerstroemia indica L., in Brazil. The shiny black eggs were observed since early autumn, laid on small folds and crevices of the branches. In order to evaluate and model the egg abundance and distribution, four branches from the cardinal points of 10 plants of two age groups, 5-10 and 20-30 years-old, were collected randomly and cut in eight segments of 10 cm and the number of eggs was registered, in the winter 2001. The eggs were laid mainly on the middle portion of the branch, from 40 cm to 60 cm from the apex on the older trees (54%) and on 30 cm to 60 cm on younger ones (58%). The data fit in a longitudinal regression model that expresses the tendency of the egg distribution on the branches. The number of eggs was greater on the 20-30 year-old plants (61%) than on younger ones (39%). The average number (+/- CI 95%) of eggs was 70.5 +/- 9.3 and 47.4 +/- 12.5, respectively, for the older and younger tree groups. There was no correlation between egg distribution and the cardinal positions of the branches.     

l7Rn6 encodes a novel protein required for clara cell function in mouse lung development

The highly secretory Clara cells play a pivotal role in protecting the lung against inflammation and oxidative stress. This study reports the positional cloning of a novel protein required for Clara cell physiology in mouse lung development. The perinatal lethal N-ethyl-N-nitrosourea-induced l7Rn6(4234SB) allele contained a nonsense mutation in the previously hypothetical gene NM_026304 on chromosome 7. Whereas l7Rn6 mRNA levels were indistinguishable from wild type, l7Rn6(4234SB) homozygotes exhibited decreased expression of the truncated protein, suggesting protein instability. During late gestation, l7Rn6 was widely expressed in the cytoplasm of lung epithelial cells, whereas perinatal expression was restricted to the bronchiolar epithelium. Homozygosity for the l7Rn6(4234SB) allele did not affect early steps in lung patterning, growth, or cellular differentiation. Rather, mutant lungs demonstrated severe emphysematous enlargement of the distal respiratory sacs at birth. Clara cell pathophysiology was evident from decreased cytoplasmic CCSP and SP-B protein levels, enlargement and disorganization of the Golgi complex, and formation of aberrant vesicular structures. Additional support for a role in the secretory pathway derived from l7Rn6 localization to the endoplasmic reticulum. Thus, l7Rn6 represents a novel protein required for organization and/or function of the secretory apparatus in Clara cells in mouse lung.     

Effect of conjugation methodology on the immunogenicity and protective efficacy of meningococcal group C polysaccharide-P64k protein conjugates

Neisseria meningitidis serogroup C polysaccharide (CCPS) was conjugated to the carrier protein P64k using two different conjugation procedures, condensation mediated by carbodiimide with adipic acid dihydrazide as spacer and the reductive amination method. BALB/c mice were immunized with the resultant polysaccharide-protein conjugates and the immune response was evaluated. All conjugates assayed generated at least 10-fold higher antibody titers than the free polysaccharide. The reductive amination method rendered the best conjugate (CCPS-P64kR) that was able to elicit antibody titers statistically higher than the titer elicited by the plain CCPS (P<0.001). The sera of the group immunized with CCPS-P64kR showed a three-fold higher bactericidal response than the sera of the group immunized with the plain CCPS and they were able to protect against challenge with meningococci in the infant rat protection model. In addition, three different conjugates were obtained from polysaccharides with molecular relative sizes of 2000-4000 Da, 4000-10,000 Da or 10,000-50,000 Da, but no differences were detected in the immune response obtained against the three conjugates. Our experiments demonstrate that it is possible to generate a protective, T-cell-dependent response against CCPS using the P64k protein as carrier.     

Drug resistance in parasites: can we stay ahead of the evolutionary curve?

The articles in this special issue of Trends in Parasitology document the current status of drug discovery in various helminth and protozoan parasitic infections. Parasitic diseases present a unique challenge to those who try to prevent or treat them. In most cases, the parasite has evolved to evade the human immune system, so the human host can control, but not eliminate, the parasite. Design of effective vaccines against these diseases presents daunting difficulties; therefore, drugs are currently the only way to prevent or treat parasitic diseases. Under these circumstances, selection of resistance to any effective, well-tolerated drug is inevitable; the question is not if, but when. The goal of this review is to try to draw general conclusions about the measurement and selection of resistance to drugs directed against a variety of very different parasites.     

The role of developmental plasticity in evolutionary innovation

Explaining the origins of novel traits is central to evolutionary biology. Longstanding theory suggests that developmental plasticity, the ability of an individual to modify its development in response to environmental conditions, might facilitate the evolution of novel traits. Yet whether and how such developmental flexibility promotes innovations that persist over evolutionary time remains unclear. Here, we examine three distinct ways by which developmental plasticity can promote evolutionary innovation. First, we show how the process of genetic accommodation provides a feasible and possibly common avenue by which environmentally induced phenotypes can become subject to heritable modification. Second, we posit that the developmental underpinnings of plasticity increase the degrees of freedom by which environmental and genetic factors influence ontogeny, thereby diversifying targets for evolutionary processes to act on and increasing opportunities for the construction of novel, functional and potentially adaptive phenotypes. Finally, we examine the developmental genetic architectures of environment-dependent trait expression, and highlight their specific implications for the evolutionary origin of novel traits. We critically review the empirical evidence supporting each of these processes, and propose future experiments and tests that would further illuminate the interplay between environmental factors, condition-dependent development, and the initiation and elaboration of novel phenotypes.