The role of phosphodiesterase 12 (PDE12) as a negative regulator of the innate immune response and the discovery of antiviral inhibitors

2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity

Mitigation and development pathways in the near- to mid-term (Chapter 4)

This chapter focuses on accelerating mitigation and on shifting development pathways to increased sustainability, based on literature particularly at national scale. While previous WGIII assessments have discussed mitigation pathways, focus on development pathways is more recent. The timeframe is the near term (now up to 2030) to mid-term (2030 to 2050), complementing Chapter 3 on the long term (from 2050 onward)

A feeding inhibition based prediction of the toxic effect of dissolved metal mixtures upon Echinogammarus marinus (Crustacea: Amphipoda) at field relevant concentrations across a latitudinal gradient

Risk assessment of metals in the environment is performed mainly with toxicity evaluations on single metals, which is largely inadequate since these substances occur in mixtures. The development of models predicting combined toxic effects on the basis of the concentration-response relationships of individual compounds has emerged as an answer. In the present study, metal effects on post-exposure anorexia (the concept of FdC(50)-concentration causing 50% of feeding inhibition-is implemented) in Echinogammarus marinus, a widely distributed gammarid amphipod, were assessed and compared with modelled ones obtained through the application of the concentration addition (CA) model, which represents a reasonable worst-case scenario for the risk assessment of metal mixtures. Data were validated using in situ experiments performed along a latitudinal gradient (Iceland, Scotland and Portugal) aiming at establishing a geographic profile of autochthonous population susceptibilities to metals. For all of the metals studied concentrations in the water column at exposure sites were in good agreement with feeding inhibition levels. Models gave low to relatively high percentage agreement between predictions and experimental data. Boreal populations demonstrated higher susceptibility to single metals, but not to mixture exposures. Meridional populations denoted lower susceptibilities with higher FdC(50).FCTSFRH/BPD/26689/2006SMC - IHP/ARIEC - Marie Curie Actions -EC-IH

EAVY METALS PRESENCE IN MUFULIRA RIVER ON THE COPPER BELT PROVINCE OF ZAMBIA, A CASE STUDY

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Tolerance to heavy metals in Littorina saxatilis from a metal contaminated estuary in the Isle of Man

Population differences were measured in the tolerance of Littorina saxatilis from sites around the Isle of Man, to acute exposure to zinc, lead, copper and cadmium. Animals from a site influenced by disused mine run-off in Laxey estuary (high zinc) were compared with animals from less contaminated estuaries (Peel-high lead, but lower zinc), and the relatively uncontaminated Castletown and Ramsey estuaries, plus the open coast near Derbyhaven. Median lethal times (LT50) were estimated for each test concentration (5, 10, 20 mg l?1 Zn; 5, 10 mg l?1 Pb; 0·5, 1·0, 2·0 mg l?1 Cu and Cd) except for those that did not produce sufficient mortalities. Individuals from Laxey estuary showed significantly higher tolerances to zinc (10 mg l?1) and lead (5 mg l?1) than animals from the unpolluted sites. No co-tolerance to copper or cadmium was apparent. Population tolerance to zinc was correlated with reduced accumulation rates. Lead tolerance may result from the ability of the tolerant individuals to sequester the metal and detoxify it in their tissues; the littorinids from Laxey had significantly higher rates of lead accumulation

Reproductive effects of heavy metals on the rough periwinkle <i style="">Littorina saxatilis </i>(Mollusca: Prosobranchia)

218-224The effects of chronic mine-related heavy metal contamination on reproduction of Littorina saxatilis from sites around the Isle of Man were assessed. Size at birth of young, reproductive output (i.e. number of embryos in brood pouch) and frequencies of abnormal embryos in the brood pouch were examined in animals from five sites. Laxey estuary was the most contaminated compared to other sites with less contamination (Peel) and relatively uncontaminated control sites (Castletown, Ramsey estuaries and the open coast near Derbyhaven). The size at birth of young ranged from 0.365-0.876 mm and the lowest mean size at birth (0.517 + 0.048 mm) was found in the animals from Laxey estuary. Those from Derbyhaven had the highest mean size at birth (0.632 + 0.063 mm). ANOVA showed a significant difference in mean size at birth of young, between individuals from the five sites (p<0.0001). However, the individuals from Laxey also had the highest absolute mean count of embryos in their brood pouch implying that there might be some trade-off between reproductive output and size of young as a result of metal contamination. No heavy metal related differences in embryo abnormality were apparent. Rather, a high proportion of abnormal embryos in animals from Derbyhaven suggested that disease conditions, genetic factors or unidentified toxins might account for the differences observed