Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.     

Conjugation of complex polyubiquitin chains to WRNIP1

Werner helicase interacting protein 1 (WRNIP1) is a ubiquitin-binding protein that undergoes extensive post-translational modification including ubiquitination, sumoylation, and phosphorylation. These post-translational modifications are expected to regulate the function of WRNIP1 in the DNA damage response. In this study, we use a denaturing tandem affinity purification technique along with mass spectrometry to show that, unlike most ubiquitin-binding proteins, WRNIP1 is polyubiquitinated. WRNIP1 polyubiquitination is reminiscent of the well-characterized phenomenon of the coupled monoubiquitination of ubiquitin-binding proteins in that this polyubiquitination is dependent on the presence of an intact ubiquitin-binding domain. The polyubiquitin chains conjugated to WRNIP1 are linked through lysines 11, 48, and 63. This study presents the first evidence for the conjugation of K11-K48-K63 polyubiquitin chains to a specific substrate in vivo. Polyubiquitination is likely to regulate WRNIP1's function in the DNA damage response, as UV radiation induces the hyperubiquitination of WRNIP1. Polyubiquitination with noncanonical intraubiquitin linkages may represent a unique mode of regulation of UBZ domain-containing proteins.     

What is the Fungal Diversity of Marine Ecosystems in Europe?

In 2001 the European Register of Marine Species 1.0 was published (Costello et al. 2001 and http://erms.biol.soton.ac.uk/, and latterly: http://www.marbef.org/data/stats.php) [Costello MJ, Emblow C, White R, 2001. European register of marine species: a check list of the marine species in Europe and a bibliography of guides to their identification. Collection Patrimoines Naturels50, 463p.]. The lists of species (from fungi to mammals) were published as part of a European Union Concerted action project (funded by the European Union Marine Science and Technology (MAST) research programme) and the updated version (ERMS 2) is EU-funded through the Marine Biodiversity and Ecosystem Functioning (MARBEF) Framework project 6 Network of Excellence. Among these lists, a list of the fungi isolated and identified from coastal and marine ecosystems in Europe was included (Clipson et al. 2001) [Clipson NJW, Landy ET, Otte ML, 2001. Fungi. In@ Costelloe MJ, Emblow C, White R (eds), European register of marine species: a check-list of the marine species in Europe and a bibliography of guides to their identification. Collection Patrimoines Naturels50: 15-19.]. This article deals with the results of compiling a new taxonomically correct and complete list of all fungi that have been reported occurring in European marine waters.     

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels. This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity. Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS. Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms. HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.     

Structure-activity relationships of N-substituted piperazine amine reuptake inhibitors

We report the structure-activity relationships of further analogues in a series of piperazine derivatives as dual inhibitors of serotonin and noradrenaline reuptake, that is, with additional substitution of the phenyl rings, or their replacement by heterocycles. The enantiomers of compounds 1 and 2 were also profiled, and possessed drug-like physicochemical properties. In particular, compound (-)-2 lacked potent inhibitory activity against any of the important cytochromes P(450) and high selectivity over a wide range of receptors, which is unusual for a compound that inhibits human amine transporters.