Acylglucuronide in alkaline conditions: migration vs. hydrolysis

This work rationalizes the glucuronidation process (one of the reactions of the phase II metabolism) for drugs having a carboxylic acid moiety. At this stage, acylglucuronides (AG) metabolites are produced, that have largely been reported in the literature for various drugs (e.g., mycophenolic acid (MPA), diclofenac, ibuprofen, phenylacetic acids). The competition between migration and hydrolysis is rationalized by adequate quantum calculations, combing MP2 and density functional theory (DFT) methods. At the molecular scale, the former process is a real rotation of the drug around the glucuconic acid. This chemical-engine provides four different metabolites with various toxicities. Migration definitely appears feasible under alkaline conditions, making proton release from the OH groups. The latter reaction (hydrolysis) releases the free drug, so the competition is of crucial importance to tackle drug action and elimination. From the theoretical data, both migration and hydrolysis appear kinetically and thermodynamically favored, respectively.     

Synthesis and biological evaluation of enantiomerically pure cyclopropyl analogues of combretastatin A4

To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (?)-1b, (?)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.     

Temperature and host diet jointly influence the outcome of infection in a Daphnia-fungal parasite system

1. Climate change has the potential to shape the future of infectious diseases, both directly and indirectly. In aquatic systems, for example, elevated temperatures can modulate the infectivity of waterborne parasites and affect the immune response of zooplanktonic hosts. Moreover, lake warming causes shifts in the communities of primary producers towards cyanobacterial dominance, thus lowering the quality of zooplankton diet. This may further affect host fitness, resulting in suboptimal resources available for parasite growth.
2. Previous experimental studies have demonstrated the respective effects of temperature and host diet on infection outcomes, using the zooplankter Daphnia and its microparasites as model systems. Although cyanobacteria blooms and heat waves are concurrent events in nature, few attempts have been made to combine both stressors in experimental settings.
3. Here, we raised the zooplankter Daphnia (two genotypes) under a full factorial design with varying levels of temperature (the standard 19°C and elevated 23°C), food quality (Scenedesmus obliquus as high-quality green algae, Microcystis aeruginosa and Planktothrix agardhii as low-quality cyanobacteria) and exposed them to the parasitic yeast Metschnikowia bicuspidata. We recorded life history parameters of the host as well as parasite traits related to transmission.
4. The combination of low-quality cyanobacterial diets and elevated temperature resulted in additive detrimental effects on host fecundity. Low-quality diets reduced parasite output, while temperature effects were context dependent. Overall, we argue that the combined effects of elevated water temperature and poor-quality diets may decrease epidemics of a common fungal parasite under a climate change scenario.

     

Morphological complexity affects the diversity of marine microbiomes

Large eukaryotes support diverse communities of microbes on their surface—epibiota—that profoundly influence their biology. Alternate factors known to structure complex patterns of microbial diversity—host evolutionary history and ecology, environmental conditions and stochasticity—do not act independently and it is challenging to disentangle their relative effects. Here, we surveyed the epibiota from 38 sympatric seaweed species that span diverse clades and have convergent morphology, which strongly influences seaweed ecology. Host identity explains most of the variation in epibiont communities and deeper host phylogenetic relationships (e.g., genus level) explain a small but significant portion of epibiont community variation. Strikingly, epibiota community composition is significantly influenced by host morphology and epibiota richness increases with morphological complexity of the seaweed host. This effect is robust after controlling for phylogenetic non-independence and is strongest for crustose seaweeds. We experimentally validated the effect of host morphology by quantifying bacterial community assembly on latex sheets cut to resemble three seaweed morphologies. The patterns match those observed in our field survey. Thus, biodiversity increases with habitat complexity in host-associated microbial communities, mirroring patterns observed in animal communities. We suggest that host morphology and structural complexity are underexplored mechanisms structuring microbial communities.Subject terms: Microbial ecology, Biodiversity     

Morphological and agronomical characteristics of coconut (Cocos nucifera L.) palms produced from in vitro cultured zygotic embryos

In this study, we compared the evolution of morphological and agronomical characteristics of coconut (Cocos nucifera L.) palms produced from in vitro cultured embryos and from seeds over an 8-yr period. At the end of the second year after planting, the height and root collar diameter of plants originating from in vitro cultured embryos were significantly lower than those originating from seeds. However, palms from both categories had the same number of leaves. When palms originating from in vitro plantlets and from seeds were observed later in their development, they were similar for most morphological characteristics measured, except for minor differences in inflorescence morphology, which were still present 8 yr after planting. The flowering pattern, bunch, and fruit production were similar between the two categories of palms. These results indicate that in vitro culture of zygotic embryos does not adversely affect further development of palms in natural conditions.     

Estimating the Occupancy Rate of Spatially Rare or Hard to Detect Species: A Conditional Approach

Summary We consider the problem of estimating the occupancy rate of a target species in a region divided in spatial units (called quadrats); this quantity being defined as the proportion of quadrats occupied by this species. We mainly focus on spatially rare or hard to detect species that are typically detected in very few quadrats, and for which estimating the occupancy rate (with an acceptable precision) is problematic. We develop a conditional approach for estimating the quantity of interest; we condition on the presence of the target species in the region of study. We show that conditioning makes identifiable the occurrence and detectability parameters, regardless of the number of visits made in the sampled quadrats. Compared with an unconditional approach, it proves to be complementary, in that this allows us to deal with biological questions that cannot be addressed by the former. Two Bayesian analyses of the data are performed: one is noninformative, and the other takes advantage of the fact that some prior information on detectability is available. It emerges that taking such a prior into account significantly improves the precision of the estimate when the target species has been detected in few quadrats and is known to be easily detectable.     

Quaternary Structure of Pathological Prion Protein as a Determining Factor of Strain-Specific Prion Replication Dynamics

Prions are proteinaceous infectious agents responsible for fatal neurodegenerative diseases in animals and humans. They are essentially composed of PrP^Sc, an aggregated, misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrP^C). Stable variations in PrP^Sc conformation are assumed to encode the phenotypically tangible prion strains diversity. However the direct contribution of PrP^Sc quaternary structure to the strain biological information remains mostly unknown. Applying a sedimentation velocity fractionation technique to a panel of ovine prion strains, classified as fast and slow according to their incubation time in ovine PrP transgenic mice, has previously led to the observation that the relationship between prion infectivity and PrP^Sc quaternary structure was not univocal. For the fast strains specifically, infectivity sedimented slowly and segregated from the bulk of proteinase-K resistant PrP^Sc. To carefully separate the respective contributions of size and density to this hydrodynamic behavior, we performed sedimentation at the equilibrium and varied the solubilization conditions. The density profile of prion infectivity and proteinase-K resistant PrP^Sc tended to overlap whatever the strain, fast or slow, leaving only size as the main responsible factor for the specific velocity properties of the fast strain most infectious component. We further show that this velocity-isolable population of discrete assemblies perfectly resists limited proteolysis and that its templating activity, as assessed by protein misfolding cyclic amplification outcompetes by several orders of magnitude that of the bulk of larger size PrP^Sc aggregates. Together, the tight correlation between small size, conversion efficiency and duration of disease establishes PrP^Sc quaternary structure as a determining factor of prion replication dynamics. For certain strains, a subset of PrP assemblies appears to be the best template for prion replication. This has important implications for fundamental studies on prions.     

Circulating Cell-Free DNA from Colorectal Cancer Patients May Reveal High KRAS or BRAF Mutation Load

Our data might suggest a very high variation in the proportion of malignant cells in colorectal tumors and/or low tumor cell clonogenicity. However, the direct relationship between these data and the proportion of malignant cells is currently uncertain as the mechanism of ccfDNA release determines the yield (necrosis, apoptosis, or active release). Therefore, interindividual comparison of the proportion of mutant allele determined from circulating DNA could appear somewhat more difficult to interpret; however, this parameter could be an efficient biomarker for monitoring or following up CRC patients and could be combined with size fraction analysis, as demonstrated in this study, to provide a deeper examination toward this goal.