Computational Oral Absorption Simulation for Low‐Solubility Compounds

Bile micelles play an important role in oral absorption of low‐solubility compounds. Bile micelles can affect solubility, dissolution rate, and permeability. For the pH–solubility profile in bile micelles, the Henderson–Hasselbalch equation should be modified to take bile‐micelle partition into account. For the dissolution rate, in the Nernst–Brunner equation, the effective diffusion coefficient in bile‐micelle media should be used instead of the monomer diffusion coefficient. The diffusion coefficient of bile micelles is 8‐ to 18‐fold smaller than that of monomer molecules. For permeability, the effective diffusion coefficient in the unstirred water layer adjacent to the epithelial membrane, and the free fraction at the epithelial membrane surface should be taken into account. The importance of these aspects is demonstrated here using several in vivo and clinical oral‐absorption data of low‐solubility model compounds. Using the theoretical equations, the food effect on oral absorption is further discussed.     

Measuring sexual selection on females in sex‐role‐reversed Mormon crickets (Anabrus simplex,Orthoptera: Tettigoniidae)

Although many studies examine the form of sexual selection in males, studies characterizing this selection in females remain sparse. Sexual selection on females is predicted for sex‐role‐reversed Mormon crickets, Anabrus simplex, where males are choosy of mates and nutrient‐deprived females compete for matings and nutritious nuptial gifts. We used selection analyses to describe the strength and form of sexual selection on female morphology. There was no positive linear sexual selection on the female body size traits predicted to be associated with male preferences and female competition. Instead, we detected selection for decreasing head width and mandible length, with stabilizing selection as the dominant form of nonlinear selection. Additionally, we tested the validity of a commonly used instantaneous measure of mating success by comparing selection results with those determined using cumulative mating rate. The two fitness measures yielded similar patterns of selection, supporting the common sampling method comparing mated and unmated fractions.     

Imprints of glacial history and current environment on correlations between endemic plant and invertebrate species richness

Aim We evaluate how closely diversity patterns of endemic species of vascular plants, beetles, butterflies, molluscs and spiders are correlated with each other, and to what extent similar environmental requirements or survival in common glacial refugia and comparable dispersal limitations account for their existing congruence. Location Austria. Methods We calculated pairwise correlations among species numbers of the five taxonomic groups in 1405 cells of a 3′ × 5′ raster (c. 35 km²) using the raw data as well as the residuals of regression models that accounted for: (1) environmental variables, (2) environmental variables and the occurrence of potential refugia during the Last Glacial Maximum, or (3) environmental variables, refugia and spatial filters. Results Pairwise cross‐taxonomic group Spearman’s rank correlations in the raw data were significantly positive in most cases, but only moderate (0.3 < ρ < 0.5) to weak (ρ < 0.3) throughout. Correlations were closest between plants and beetles, plants and butterflies, and plants and snails, respectively, whereas the distribution of endemic spiders was largely uncorrelated with those of the other groups. Environmental variables explained only a moderate proportion of the variance in endemic richness patterns, and the response of individual groups to environmental gradients was only partly consistent. The inclusion of refugium locations and the spatial filters increased the goodness of model fit for all five taxonomic groups. Moreover, removing the effects of environmental conditions reduced congruence in endemic richness patterns to a lesser extent than did filtering the influence of refugium locations and spatial autocorrelation, except for spiders, which are probably the least dispersal‐limited of the five groups. Main conclusions The moderate to weak congruence of endemic richness patterns clearly limits the usefulness of a surrogacy approach for designating areas for the protection of regional endemics. On the other hand, our results suggest that dispersal limitations still shape the distributions of many endemic plant, snail, beetle and butterfly species, even at the regional scale; that is, survival in shared refugia and subsequent restricted spread retain a detectable signal in existing correlations. Concentrating conservation efforts on well‐known Pleistocene refugia hence appears to be a reasonable first step towards a strategy for protecting regional endemics of at least the less mobile invertebrate groups.     

Short hairpin RNAs against eotaxin or interleukin‐5 decrease airway eosinophilia and hyper‐responsiveness in a murine model of asthma

Background

Eosinophilia plays the major role in the pathogenesis of asthma and correlates with the up‐regulation of eotaxin, which, together with interleukin (IL)‐5, is important for differentiation, chemo‐attraction, degranulation, and survival of eosinophils in local tissue. In a previous study, we found that administration of lentivirus‐delivered short hairpin RNA (shRNA) to suppress the expression of IL‐5 inhibited airway inflammation. The present study aimed to investigate the role of eotaxin shRNA and the synergistic effect of eotaxin and IL‐5 shRNAs on airway inflammation in an ovalbumin (OVA)‐induced murine model of asthma.

Methods

Lentivirus‐delivered shRNAs were used to suppress the expression of eotaxin and/or IL‐5 in local tissue in an OVA‐induced murine asthma model.

Results

Intra‐tracheal administration of lentivirus containing eotaxin shRNA expressing cassette (eoSEC3.3) efficiently moderated the characteristics of asthma, including airway hyper‐responsiveness, cellular infiltration of lung tissues, and eotaxin and IL‐5 levels in bronchio‐alveolar lavage fluid. Administration of lentiviruses expressing IL‐5 or eotaxin shRNAs (IL5SEC4 + eoSEC3.3) also moderated the symptoms of asthma in a mouse model.

Conclusions

Local delivery of lentiviruses expressing IL‐5 and eotaxin shRNAs provides a potential tool in moderating airway inflammation and also has the potential for developing clinical therapy based on the application of shRNAs of chemokines and cytokines involved in T helper 2 cell inflammation and eosinophilia. Copyright © 2008 John Wiley & Sons, Ltd.     

Accurate MS-based Rab10 Phosphorylation Stoichiometry Determination as Readout for LRRK2 Activity in Parkinson's Disease

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Highlights

• •MS-based clinical assay that accurately determines phospho Rab10 occupancy.
• •Stable isotope labeled phosphopeptide injected as a standard with endogenous tryptic phospho Rab peptide for accurate ratio determination.
• •Determination of pRab levels in neutrophils of Parkinson disease patients.
• •Relevance of pRab levels as marker of PD.