Design,synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus

We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication.     

Exploring nucleo-cytoplasmic large DNA viruses in Tara Oceans microbial metagenomes

Nucleo-cytoplasmic large DNA viruses (NCLDVs) constitute a group of eukaryotic viruses that can have crucial ecological roles in the sea by accelerating the turnover of their unicellular hosts or by causing diseases in animals. To better characterize the diversity, abundance and biogeography of marine NCLDVs, we analyzed 17 metagenomes derived from microbial samples (0.2–1.6 μm size range) collected during the Tara Oceans Expedition. The sample set includes ecosystems under-represented in previous studies, such as the Arabian Sea oxygen minimum zone (OMZ) and Indian Ocean lagoons. By combining computationally derived relative abundance and direct prokaryote cell counts, the abundance of NCLDVs was found to be in the order of 10⁴–10⁵ genomes ml⁻¹ for the samples from the photic zone and 10²–10³ genomes ml⁻¹ for the OMZ. The Megaviridae and Phycodnaviridae dominated the NCLDV populations in the metagenomes, although most of the reads classified in these families showed large divergence from known viral genomes. Our taxon co-occurrence analysis revealed a potential association between viruses of the Megaviridae family and eukaryotes related to oomycetes. In support of this predicted association, we identified six cases of lateral gene transfer between Megaviridae and oomycetes. Our results suggest that marine NCLDVs probably outnumber eukaryotic organisms in the photic layer (per given water mass) and that metagenomic sequence analyses promise to shed new light on the biodiversity of marine viruses and their interactions with potential hosts.     

Ultraphytoplankton abundances and chlorophyll a concentrations in ice-covered waters of northern seas

The abundances and chlorophyll aconcentrations (Chl a) of ultraphytoplankton (<5 m) were determined at four ice-covered sites in northern seas, i.e. southeastern Hudson Bay, Saroma-ko Lagoon, Resolute Passage and the Northeast Water Polynya. Numbers of total ultraphytoplankton were low, ranging from 3.6 x 10⁷ to 9.7 x 10⁹ cells m^-3, which confirms the overall paucity of ultra-phytoplankton in cold waters. Concentrations of <5 m Chl a varied between 0.002 and 10.8 mg m^-3, which accounted for 0.2-99.7% of total Chla. Chlorophyll a concentrations of ultraphytoplankton can thus reach high values and make up a substantial fraction of total Chl a. Ultraphytoplankton were ubiquitous, but they showed high among- and within-site variability in abundance, biomass and contribution to total Chla concentrations. The ultraphytoplankton comprised primarily eukaryotes and prokaryotic phycoerythrin-rich cyanobacteria, but also some cryptomonads and phycocyanin-rich cyanobacteria. Concentrations of ultraplanktonic eukaryotes reached 7.8 x 10⁹ cells m^-3, but were generally <5 x 10⁹ cells m^-3, whereas the maximum concentration of prokaryotes was 6.2 x 10⁹ cells m^-3. The concentrations of eukaryotes and prokaryotes were related, overall, to water mass characteristics, i.e. temperature, salinity, percent irradiance, and concentrations of nitrate and ammonium. Depending on sites, the abundances of eukaryotes were positively liked to salinity, percent irradiance, nitrate and ammonium, whereas the abundances of prokaryotes were positively correlated with ammonium and nitrate. Phycocyanin-rich cyanobacteria were generally confined to brackish waters (Hudson Bay). The highest cell numbers of ultraphytoplankton were found at temperatures of <0.5C and salinities of >30 p.s.u.      

Synthesis and biological evaluation of (-)-laulimalide analogues

Analogues of the marine natural product (-)-laulimalide were prepared by total synthesis and evaluated in vitro for anticancer activity.     

A holistic approach to marine eco-systems biology

The structure, robustness, and dynamics of ocean plankton ecosystems remain poorly understood due to sampling, analysis, and computational limitations. The Tara Oceans consortium organizes expeditions to help fill this gap at the global level.     

Pathways of carbon cycling in marine surface waters: the fate of small-sized phytoplankton in the Northeast Water Polynya

The fate of small-sized phytoplankton (<5 µm) and pathwaysof carbon cycling in surface waters, i.e. recycling within orexport out of the mixed layer, were investigated in the NortheastWater (NEW) Polynya (77–81°N) from 23 May to 22 July1993. The sampling covered a wide range of ice, hydrographicand nutrient conditions. Chlorophyll a concentrations, phytoplanktonproduction rates and zooplankton abundances were determinedin the field, and potential rates of grazing by protozoa, copepodsand appendicularians were calculated from abundances, usingassumptions from the literature. To our knowledge, this is thefirst published attempt to assess concurrently the grazing ofthese three plankton groups in the Arctic. The production rateof small-sized phytoplankton was significantly higher in ice-freecompared with ice-covered areas, but the biomasses of small-sizedphytoplankton and zooplankton were not. Potential recycling,downward export and horizontal advection of phytoplankton werecalculated by resolving carbon budgets for the mixed layer.A large fraction of the small-sized phytoplankton produced insidethe polynya was advected horizontally to the ice-covered partof the NEW, where these algae were necessary to sustain theheterotrophic community. We conclude that the fate of small-sizedphytoplankton production was mostly recycling (>70%). Downwardexport would have occurred infrequently, as a result of intensegrazing by appendicularians. Size-differential pathways of carboncycling in planktonic food webs are discussed.     

Cardiotoxicity of the cancer therapeutic agent imatinib mesylate

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.     

Pathways of carbon cycling in the euphotic zone: the fate of largesized phytoplankton in the Northeast Water Polynya

The fate of large-sized phytoplankton and pathways of carboncycling in surface waters, i.e. recycling within or export outof the euphotic zone, were investigated in the Northeast Water(NEW) Polynya (77–81N) from 23 May to 17 August 1993.Sampling represented a wide range of ice, hydrographic and nutrientconditions. Phytoplankton and zooplankton abundances, and phytoplanktonproduction rates were determined in the field, whereas potentialrates of grazing by copepods, dino flagellates and appendicularianswere calculated from abundances and temperature, using assumptionsfrom the literature. The potential downward and lateral exportof phytoplankton was also calculated by resolving a carbon budgetfor the euphotic zone. The present study suggests that, in theNEW, different pathways for the cycling of carbon existed inseasonally ice-free (in the polynya) and continuously ice-coveredareas (outside the polynya). Outside the polynya, the fate oflarge-sized phytoplankton could not be assessed because theheterotrophic community presumably grazed on a variety of fooditems, including ice algae, microzooplankton and large-sizedphytoplankton. In the polynya, the fate of large-sized phytoplanktonproduction was to be mostly recycled at the beginning of samplingand to be mostly exported downward or laterally as the bloomof large-sized phyto plankton developed. Generally, copepodsmostly contributed to recycling, but sometimes dinoflagellatesor appendicularians alone recycled most of the large-sized phytoplanktonproduction.