Ecological impacts of non-native Pacific oysters (Crassostrea gigas) and management measures for protected areas in Europe

Pacific oysters are now one of the most ‘globalised’ marine invertebrates. They dominate bivalve aquaculture production in many regions and wild populations are increasingly becoming established, with potential to displace native species and modify habitats and ecosystems. While some fishing communities may benefit from wild populations, there is now a tension between the continued production of Pacific oysters and risk to biodiversity, which is of particular concern within protected sites. The issue of the Pacific oyster therefore locates at the intersection between two policy areas: one concerning the conservation of protected habitats, the other relating to livelihoods and the socio-economics of coastal aquaculture and fishing communities. To help provide an informed basis for management decisions, we first summarise evidence for ecological impacts of wild Pacific oysters in representative coastal habitats. At local scales, it is clear that establishment of Pacific oysters can significantly alter diversity, community structure and ecosystem processes, with effects varying among habitats and locations and with the density of oysters. Less evidence is available to evaluate regional-scale impacts. A range of management measures have been applied to mitigate negative impacts of wild Pacific oysters and we develop recommendations which are consistent with the scientific evidence and believe compatible with multiple interests. We conclude that all stakeholders must engage in regional decision making to help minimise negative environmental impacts, and promote sustainable industry development

Embryonic Diapause Is Conserved across Mammals

Embryonic diapause (ED) is a temporary arrest of embryo development and is characterized by delayed implantation in the uterus. ED occurs in blastocysts of less than 2% of mammalian species, including the mouse (Mus musculus). If ED were an evolutionarily conserved phenomenon, then it should be inducible in blastocysts of normally non-diapausing mammals, such as domestic species. To prove this hypothesis, we examined whether blastocysts from domestic sheep (Ovis aries) could enter into diapause following their transfer into mouse uteri in which diapause conditions were induced. Sheep blastocysts entered into diapause, as demonstrated by growth arrest, viability maintenance and their ED-specific pattern of gene expression. Seven days after transfer, diapausing ovine blastocysts were able to resume growth in vitro and, after transfer to surrogate ewe recipients, to develop into normal lambs. The finding that non-diapausing ovine embryos can enter into diapause implies that this phenomenon is phylogenetically conserved and not secondarily acquired by embryos of diapausing species. Our study questions the current model of independent evolution of ED in different mammalian orders

Structure-activity relationships of bioactive marine natural products leading to the identification of more potent non-natural analogues – the meroterpenoids, thiaplidiaquinones A and B

International audienceIn an effort to define the mechanism of cell death and to establish structure-activity relationship requirements for the marine meroterpenoid alkaloids thiaplidiaquinones A (1) and B (2) [1], we have developed a bioinspired synthetic route to these complex natural products [2] and used it to prepare a library of natural and non-natural product analogues. Included in this library are novel prenyl and farnesylated analogues. Biological evaluation of this library has found that, in contrast to previous reports, the mechanism of Jurkat cell death (necrosis vs. apoptosis) was dependent upon the positioning of one of the terpenoid sidechains in the compounds with one natural product, thiaplidiaquinone A, and its dioxothiazine regioisomer causing death dominantly by necrosis, while the second natural product, thiaplidiaquinone B and its dioxothiazine isomer caused cell death via apoptosis. The dioxothiazine regioisomer of thiaplidiaquinone A exhibited more potent in vitro antiproliferative activity against human tumour cells, with NCI sub-panel selectivity towards melanoma cell lines. The non-natural dioxothiazine regioisomers were also more active inhibitors of parasitic and human farnesyltransferase (IC50 0.054 – 0.14µM) and were also growth inhibitors of Plasmodium falciparum (IC50 4.4 – 4.6µM).This talk will present details of our biomimetic synthetic route to these natural products and the biological results, as summarised above [3]. These results will highlight the important role that natural product total synthesis can play in not only helping understand the structural basis of biological activity of natural products, but also the discovery of new bioactive scaffolds

Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi

The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 μM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) > 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 μM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p < 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long-term treatments in experimental Chagas disease

Efficacy of a series of alpha-pyrone derivatives against Leishmania (L.) infantum and Trypanosoma cruzi

The neglected tropical diseases Chagas disease and leishmaniasis affect together more than 20 million people living mainly in developing countries. The mainstay of treatment is chemotherapy, however the drugs of choice, which include benznidazole and miltefosine, are toxic and have numerous side effects. Safe and effective therapies are urgently needed. Marine alpha-pyrones have been previously identified as scaffolds with potential antiprotozoan activities. In this work, using a phenotypic screen, twenty-seven examples of 3-substituted 4-hydroxy-6-methyl alpha-pyrones were synthesized and their antiparasitic efficacy evaluated against Leishmania (L.) infantum and Trypanosoma cruzi in order to evaluate structure-activity relationships within the series. The mechanism of action and the in vivo efficacy of the most selective compound against T. cruzi were evaluated using different techniques. In vitro data indicated that compounds 8, 15, 25, 26 and 28 presented IC50 values in the range between 13 and 54 μM against L. infantum intracellular amastigotes. Among them, hexanoyl substituted pyrone 8 was the most selective and potent, with a Selectivity Index (SI) &gt; 14. Fifteen of the alpha-pyrones were effective against T. cruzi trypomastigotes, with 3-undecanoyl (11) and 3-tetradecanoyl (12) substituted pyrones being the most potent against trypomastigotes, with IC50 values of 1 and 2 μM, respectively, and SI higher than 70. Using flow cytometry and fluorescent-based assays, pyrone 12 was found to induce hyperpolarization of the mitochondrial membrane potential of T. cruzi, without affecting plasma membrane permeability. An experimental acute phase-murine model, demonstrated that in vivo dosing of 12 (30 mg/kg/day; 5 days), had no efficacy at the first parasitemia onset of T. cruzi, but reduced the second onset by 55% (p &lt; 0.05), suggesting a delayed action in BALB/c mice. Additionally, a histopathology study demonstrated no toxic effects to the treated mice. The finding that several 3-substituted alpha-pyrones have in vitro efficacy against both L. infantum and T. cruzi, and that one analogue exhibited moderate and non-toxic in vivo efficacy against T. cruzi is encouraging, and suggests that this compound class should be explored as long-term treatments in experimental Chagas disease