A novel series of positive modulators of the AMPA receptor: Structure-based lead optimization

Starting from lead compound 1, we demonstrate how X-ray structural data can be used to understand SAR and expediently optimize bioavailability in a novel series of AMPA receptor modulators, furnishing 5 with improved bioavailability and robust in vivo activity.     

Gender differences in leucine, but not lysine, kinetics.

There is a controversy in the literature as to the effects of gender on leucine kinetics. Two research groups found that men oxidize more leucine during exercise, whereas another group showed no gender effects. The purpose of our study was to examine the effects of gender on leucine and, for comparison purposes, lysine kinetics. Our subjects (n = 14) were seven matched pairs of men and women selected for their exercise habits and age. After 1 wk of a standardized diet, they exercised at 50% of maximal O(2) uptake for 1 h. There was an effect of exercise in both genders: an increased leucine oxidation and an attenuation in nonoxidative leucine disposal compared with rest (P < 0.05). Furthermore, our study confirms that there are gender differences in leucine, but not lysine, kinetics. Men had a higher rate of leucine oxidation and a lower rate of nonoxidative leucine disposal during exercise (P < 0.05). For women, a larger proportion of their exercise energy needs came from fat; for men, a greater fraction came from carbohydrate (P < 0.05). We conclude that female exercisers rely to a greater extent on fat as an energy source, thereby using less carbohydrate, amino acid, and protein as a fuel source.     

Neutrophil transmigration under shear flow conditions in vitro is junctional adhesion molecule-C independent

Endothelial cell junctional adhesion molecule (JAM)-C has been proposed to regulate neutrophil migration. In the current study, we used function-blocking mAbs against human JAM-C to determine its role in human leukocyte adhesion and transendothelial cell migration under flow conditions. JAM-C surface expression in HUVEC was uniformly low, and treatment with inflammatory cytokines TNF-alpha, IL-1beta, or LPS did not increase its surface expression as assessed by FACS analysis. By immunofluorescence microscopy, JAM-C staining showed sparse localization to cell-cell junctions on resting or cytokine-activated HUVEC. Surprisingly, staining of detergent-permeabilized HUVEC revealed a large intracellular pool of JAM-C that showed little colocalization with von Willebrand factor. Adhesion studies in an in vitro flow model showed that functional blocking JAM-C mAb alone had no inhibitory effect on polymorphonuclear leukocyte (PMN) adhesion or transmigration, whereas mAb to ICAM-1 significantly reduced transmigration. Interestingly, JAM-C-blocking mAbs synergized with a combination of PECAM-1, ICAM-1, and CD99-blocking mAbs to inhibit PMN transmigration. Overexpression of JAM-C by infection with a lentivirus JAM-C GFP fusion protein did not increase adhesion or extent of transmigration of PMN or evoke a role for JAM-C in transendothelial migration. These data suggest that JAM-C has a minimal role, if any, in PMN transmigration in this model and that ICAM-1 is the preferred endothelial-expressed ligand for PMN beta(2) integrins during transendothelial migration.     

Pyoverdine siderophores: from biogenesis to biosignificance

Pyoverdines are a group of structurally related siderophores produced by fluorescent Pseudomonas species. Recent genomic and biochemical data have shed new light on the complex molecular steps of pyoverdine biogenesis and explained the chemical diversity of these compounds. In the opportunistic pathogen Pseudomonas aeruginosa, pyoverdine is necessary for infection in several different disease models. The occurrence of pyoverdine-defective strains in chronic infections of patients with cystic fibrosis and the extremely high sequence diversity of genes involved in pyoverdine synthesis and uptake indicate that pyoverdine production is subject to high evolutionary pressure. Pyoverdine-dependent iron transport is also crucial for biofilm development, further expanding the importance of these siderophores in Pseudomonas biology.     

Mate preference for multiple cues: interplay between male and nest size in the sand goby, Pomatoschistus minutus

Female mating preferences are often based on more than one cue.In empirical studies, however, different mate choice cues aretypically treated separately ignoring their possible interactions.In the current work, we studied how male body size and sizeof the male's nest jointly affect mate preferences of femalesand gobies, Pomatoschistus minutus. The females were givena binary choice between males that differed either in body sizeor size of their nest or both. We found that neither body sizenor size of the nest alone affected male attractiveness, buttogether these 2 cues had a significant effect. Specifically,large males were more popular among females when they had alarge nest than when they occupied a small nest. The resultssuggest that if interaction effects between multiple mate choicecues are not considered, there is a danger of ignoring or underestimatingthe importance of these cues in sexual selection by female choice.     

Disentangling Competition, Herbivory, and Seasonal Effects on Young Plants in Newly Restored Communities

Optimizing techniques of impact and consequence assessment are critical when faced with the challenges of reclamation within a damaged or altered ecosystem. Much debate has arisen over an appropriate index to evaluate herbivore and competition effects on restored communities. We assessed concurrent environmental pressures by means of repeated measurements using three common indices of plant performance (biomass, shoot extension, and survival) in conjunction with monitoring for number and timing of plants eaten. Our design incorporated 24 species, representing a range of taxonomic groups and growth forms, planted at low and high densities, inside and outside large‐scale mammal exclosures. We demonstrate that biomass and height measurements are correlated (at both the individual and the combined species levels), whereas the survival index often showed independent information. Using the most conservative measure (survival), we delineate between plant deaths attributed to seasonal effects, competition (some facilitation was apparent), and herbivory (both compensation and loss of fitness were demonstrated). Plant spacing effects depended on the index (response variable) and whether we measured individual or combined species. The survival index rarely showed competition effects. Due to counter facilitation effects, competition was not demonstrated for any index at the combined species level. The comparison of the relative order and magnitude of plants being eaten against impact identified vulnerable and compensating species. Once identified, compensating species may be used sacrificially to buffer damage in new reclamation systems, whereas deterrents may be used around known vulnerable species.     

A molecular assessment of northeast Pacific Alaria species (Laminariales, Phaeophyceae) with reference to the utility of DNA barcoding

Despite their relatively complex morphologies, species in the genus Alaria Greville are notoriously difficult to identify with certainty. Morphological characters, often influenced by environmental factors, make individuals in similar habitats artificially appear related. Species identification would, therefore, benefit greatly from the application of molecular tools. We applied DNA barcoding, using the 5' end of the cytochrome c oxidase I (coxI-5') gene from the mitochondrial genome, to define species limits and relationships in northeast Pacific populations of Alaria. This emerging technique is being employed to catalogue species diversity worldwide, particularly among animals, and it has been shown to be sensitive enough to discriminate between closely related species. However, the utility of this marker for identifying or categorizing the majority of life remains unclear. We compared the resolution obtained with this marker to two other molecular systems commonly used in algal research: the nuclear internal transcribed spacer (ITS) of the ribosomal cistron, and the plastid Rubisco operon spacer (rbcSp). In agreement with previous results, Alaria fistulosa Postels & Ruprecht, with its distinct morphological, ecological and molecular features, stands apart from the other species in the genus and we establish Druehlia gen. nov. to accommodate it. For the remaining isolates, distinct mitochondrial haplotypes resolved with the barcode data indicate a period of genetic isolation for at least three incipient species in the northeast Pacific, whereas unexpected levels and patterns of ITS variation, as well as the extreme morphological plasticity found among these isolates, have most probably resulted from a recent collapse in species barriers. The cloning of ITS amplicons revealed multiple ITS copies in several individuals, further supporting this hypothesis.     

Influence of type of muscle contraction, gender, and lifting experience on postactivation potentiation performance

Postactivation potentiation (PAP) or enhanced contractile capabilities may be influenced by a number of factors. This study examined the influence of type of muscle contraction (isometric vs. dynamic), gender, and previous weightlifting experience on PAP as demonstrated by changes in jump height and power output. Thirty young men (n = 15) and women (n = 15), classified as either having previous weightlifting experience (n = 20) or not (n = 10), performed 3 different sets of countermovement jumps, with the first set used to determine baseline measures of jump height and power. The second set was performed after a maximal isometric squat protocol (maximal voluntary contraction [MVC]-PAP) to induce PAP, and the third set of jumps was performed after a maximal dynamic squat (DS) protocol (DS-PAP). A 3-way repeated measures analysis of variance determined that jump height after the MVC-PAP protocol was significantly higher than both the pretest and DS-PAP values, that men performed significantly better than women, and that the experienced lifters responded more favorably than the inexperienced lifters. Jump power was also significantly greater for the MVC-PAP condition compared with the other 2 conditions, and DS-PAP power also improved when compared with the pretest values, with men performing significantly better than women. All results remained consistent after accounting for height and weight differences (body mass index) between the groups. In conclusion, the isometric condition (MVC-PAP) evoked a greater muscle postactivation potentiation than the dynamic condition (DS-PAP), and postactivation was enhanced by previous weightlifting experience. The practical manipulation of MVC by pushing, squatting, or both against fixed objects, such as walls and low ceilings, could be a very simple and cost-effective way to arouse a state of PAP before sports performance that requires high force and power outputs.     

Record error and range contraction, real and imagined, in the restricted shrub Banksia hookeriana in south-western Australia

Banksia hookeriana Meissn. (Proteaceae) is a fire‐killed shrub endemic to the northern sandplains of south‐western Australia that could be described as endangered based on its small geographical range (< 5000 km²) and area of occupancy (～500 km²). Impacts on the species’ geographical range by land clearance for farming and mining, and by altered fire regime, were investigated using three lines of evidence: records of herbarium collections, a comprehensive field survey of extant populations, and air photo and satellite images revealing the recent history of land clearance and fires. These show that the species’ range has contracted by up to 40% in area and 26% latitudinally through the loss of outlier and range limit populations since 1960. In addition, 22% of remaining native shrubland on the Eneabba sandplain has been lost over this period through clearing for farming and mining, representing further habitat loss for B. hookeriana. Detailed investigation of B. hookeriana herbarium collections (n = 46) revealed important errors that artificially affected the geographical range of the species and emphasized the importance of close examination of all data captured from collection records. Recorded locations occurred hundreds of kilometres outside the current geographical range of the species in areas with different climate and substrate. Incorrect species identification of herbarium specimens further extended the apparent geographical range of the species. On the other hand, credible records indicated the loss of the species from localities at the limits of its range. Overall, a disconcertingly high proportion of records contained errors that may be difficult to identify without close examination of the original collections and detailed ground‐truthing. Were these records to be used to model climate envelopes, identify potential habitat where the species might occur, or might migrate to either as pests or under climate change scenarios, or to analyse evolutionary or ecological theory (for example) — as is now becoming commonplace — large errors may ensue.