Turning Defense into Offense: Defensin Mimetics as Novel Antibiotics Targeting Lipid II

We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections.     

MMP-9 and CXCL8/IL-8 Are Potential Therapeutic Targets in Epidermolysis Bullosa Simplex

Epidermolysis bullosa refers to a group of genodermatoses that affects the integrity of epithelial layers, phenotypically resulting in severe skin blistering. Dowling-Meara, the major subtype of epidermolysis bullosa simplex, is inherited in an autosomal dominant manner and can be caused by mutations in either the keratin-5 (K5) or the keratin-14 (K14) gene. Currently, no therapeutic approach is known, and the main objective of this study was to identify novel therapeutic targets. We used microarray analysis, semi-quantitative real-time PCR, western blot and ELISA to identify differentially regulated genes in two K14 mutant cell lines carrying the mutations K14 R125P and K14 R125H, respectively. We found kallikrein-related peptidases and matrix metalloproteinases to be upregulated. We also found elevated expression of chemokines, and we observed deregulation of the Cdc42 pathway as well as aberrant expression of cytokeratins and junction proteins. We further demonstrated, that expression of these genes is dependent on interleukin-1 β signaling. To evaluate these data in vivo we analysed the blister fluids of epidermolysis bullosa simplex patients vs. healthy controls and identified matrix metalloproteinase-9 and the chemokine CXCL8/IL-8 as potential therapeutic targets.     

Key Features of Intertidal Food Webs That Support Migratory Shorebirds

The migratory shorebirds of the East Atlantic flyway land in huge numbers during a migratory stopover or wintering on the French Atlantic coast. The Brouage bare mudflat (Marennes-Oléron Bay, NE Atlantic) is one of the major stopover sites in France. The particular structure and function of a food web affects the efficiency of carbon transfer. The structure and functioning of the Brouage food web is crucial for the conservation of species landing within this area because it provides sufficient food, which allows shorebirds to reach the north of Europe where they nest. The aim of this study was to describe and understand which food web characteristics support nutritional needs of birds. Two food-web models were constructed, based on in situ measurements that were made in February 2008 (the presence of birds) and July 2008 (absence of birds). To complete the models, allometric relationships and additional data from the literature were used. The missing flow values of the food web models were estimated by Monte Carlo Markov Chain – Linear Inverse Modelling. The flow solutions obtained were used to calculate the ecological network analysis indices, which estimate the emergent properties of the functioning of a food-web.The total activities of the Brouage ecosystem in February and July are significantly different. The specialisation of the trophic links within the ecosystem does not appear to differ between the two models. In spite of a large export of carbon from the primary producer and detritus in winter, the higher recycling leads to a similar retention of carbon for the two seasons. It can be concluded that in February, the higher activity of the ecosystem coupled with a higher cycling and a mean internal organization, ensure the sufficient feeding of the migratory shorebirds.     

Home range of newborn blacktip reef sharks (Carcharhinus melanopterus), as estimated using mark-recapture and acoustic telemetry

Coral Reefs - Sharks play important functional roles in coral reef ecosystems. Studying reef shark populations’ spatial ecology also contributes important data for effective conservation...     

On the Application of Widom's Test Particle Method to Homogeneous and Inhomogeneous Fluids

Abstract

Chemical potentials of a homogeneous and an inhomogeneous Lennard-Jones fluid have been determined by molecular dynamics simulations on the vector computer CYBER 205 by applying essentially the fictitious test particle method of Widom. For the homogeneous fluid we find, contrary to the previous result of Guillot and Guissani, that the simulated chemical potential is independent of the particle number. The crucial point, however, is a sufficiently large cut-off radius in the evaluation of the Boltzmann factor. Comparing with our WCA-type perturbation theory, we get agreement in the chemical potentials within 0.1 kT up to the density n[sgrave]³ = 0.80 and a difference of 0.2 kT at n[sgrave]³ = 0.85. For the inhomogeneous case we consider a fluid in a cylindrical pore and integrate Widom's equation over a certain probe volume as suggested earlier by us. Chemical potentials are then calculated independently in five different probe volumes, which are cylindrical shells. The results agree well from the second to the fourth shell. Inaccuracies in the innermost cylinder can be easily explained by bad statistics. In the shell close to the wall the extremely high local density is responsible for the inaccuracies. Extending the probe volume over all cylindrical shells besides the one closest to the wall is thought to yield rather reliable results for the chemical potential. As a by-product of the simulations we also obtained diffusion coefficients, which are given in an appendix.     

Distribution of duck broods relative to habitat characteristics in the Prairie Pothole Region

Conservation programs for breeding ducks in the Prairie Pothole Region (PPR) of the United States and Canada require effective means of evaluating and characterizing breeding habitat across large landscapes. Extensive surveys of the distribution of duck broods in late-summer could help identify wetland basins with greater probabilities of occupancy. Broods are difficult to detect, however, rendering presence–absence data from single-visit surveys difficult to interpret, particularly when probability of detection is related to habitat features. Multiple-visit occupancy surveys offer a potential solution. From 20 July to 5 August 2007–2009, we conducted a 3-visit survey of wetland basins located on 167 10.4-km² study plots in the PPR. Our survey focused on broods of the 5 most common breeding duck species (Anas spp.). Our main objectives were to investigate ecological relationships between occupancy of wetland basins by broods and habitat characteristics and to examine if habitat-specific detection was of enough concern to warrant multi-survey approaches in the future. We surveyed 3,226 wetland basins during the study. Probability of occupancy of a wetland basin by a brood was positively related to the log of wet area for all 5 study species and was greater on wetlands located on plots with a greater proportion of herbaceous perennial cover for 4 of 5 species. For example, the median probability of occupancy for gadwall (Anas strepera) increased from 0.08 (90% Credible Interval [CrI]: 0.07, 0.10) to 0.28 (90% CrI: 0.23, 0.33) as wet area increased from 0.19 ha to 2.12 ha, and increased from 0.12 (90% CrI: 0.09, 0.16) to 0.20 (90% CrI: 0.16, 0.25) as proportion of perennial grass cover on the study plot increased from 0.03 to 0.99. Because occupancy and detection were both related to attributes of wetland basins, we concluded that the multiple-visit survey was a useful approach for identifying habitat relationships of duck broods. Our results indicated that most broods of the study species were found in 10.4-km² landscapes with greater densities of small- to mid-sized wetland basins and a greater proportion of herbaceous perennial vegetation. Our study provided new empirical support that could be used to help target conservation actions to the most productive landscapes for breeding ducks. © 2012 The Wildlife Society.