Exploring the C^N^C theme: Synthesis and biological properties of tridentate cyclometalated gold(III) complexes

A family of cyclometalated Au(III) complexes featuring a tridentate CNC scaffold has been synthesized and characterized. Microwave assisted synthesis of the ligands has also been exploited and optimized. The biological properties of the thus formed compounds have been studied in cancer cells and demonstrate generally moderate antiproliferative effects. Initial mechanistic insights have also been gained on the gold complex [Au(CNC)(GluS)] (3), and support the idea that the thioredoxin system may be a target for this family of compounds together with other relevant intracellular thiol-containing molecules. (C) 2017 Elsevier Ltd. All rights reserved

Inconsistency of association between coffee consumption and cognitive function in adults and elderly in a cross-sectional study (ELSA-Brasil)

Abstract: Background: Coffee is one of the most consumed beverages worldwide and the effect on cognition appears to be task specific and vary by age. Method: In cohort of 14,563 public service workers (35–74 years old) we assessed coffee consumption habits and examined cognitive function using standardized neuropsychological test battery. By linear regression and generalize linear regression with logarithmic link and gamma distribution we investigated the relation of coffee consumption (never/almost never, ¤1 cup/day, 2–3 cups/day, ¥3 cups/day) in the last 12 months to performance on specific domains of cognition for adults and elderly separately. Results: Among elderly, after adjustments, coffee consumption was associated only with an increase in the mean words remembered on learning, recall, and word recognition tests when comparing the 2–3 cups/day to never/almost never category (arithmetic mean ratio (AMR): 1.03; 95% Confidence Interval (CI): 1.00 to 1.07), and to an increase in the mean words pronounced in semantic verbal fluency test when comparing the ¥3 cups/day to never/almost never category (difference of the mean: 1.23; 95% CI: 0.16 to 2.29). However, coffee consumption was not associated with any cognitive function tests in adults and also was not associated with the phonemic verbal fluency test and trail-making test B in elderly. Conclusions: Results suggest that coffee consumption might be slightly beneficial to memory in elderly but lacks a dose response relationship. Longitudinal analyses are needed to investigate possible, even if subtle, positive effects of coffee drinking on specific cognitive domains in elderly

Neck circumference is associated with carotid intimal-media thickness but not with coronary artery calcium : results from the ELSA-Brasil

Abstract Background and aims: It is uncertain whether neck circumference can be a risk indicator for subclinical atherosclerosis. We aimed to investigate their relationships measured by coronary artery calcium (CAC) and common carotid intima-media thickness (cc-IMT) with neck circumference in ELSA-Brasil. Methods and results: In cross-sectional and sex-specific analyses of 2266 women (50.6 8.4 yrs) and 1886 men (50.7 9.0 yrs) with both cc-IMT and CAC, free from previous cardiovascular disease at baseline, we built logistic models using diverse cut-off points for CAC score (0 vs >0, 0.05 for all). Conclusion: Neck circumference was significantly and independently associated with cc-IMT but not with CAC in women and men, indicating a possible effect of perivascular fat tissue on atherosclerosis

Modifying bacterial flagellin to evade Nod-like Receptor CARD 4 recognition enhances protective immunity against Salmonella.

Pattern recognition receptors (PRRs) expressed in antigen-presenting cells are thought to shape pathogen-specific immunity by inducing secretion of costimulatory cytokines during T-cell activation, yet data to support this notion in vivo are scarce. Here, we show that the cytosolic PRR Nod-like Receptor CARD 4 (NLRC4) suppresses, rather than facilitates, effector and memory CD4+ T-cell responses against Salmonella in mice. NLRC4 negatively regulates immunological memory by preventing delayed activation of the cytosolic PRR NLR pyrin domain 3 (NLRP3) that would otherwise amplify the production of cytokines important for the generation of Th1 immunity such as intereukin-18. Consistent with a role for NLRC4 in memory immunity, primary challenge with Salmonella expressing flagellin modified to largely evade NLRC4 recognition notably increases protection against lethal rechallenge. This finding suggests flagellin modification to reduce NLRC4 activation enhances protective immunity, which could have important implications for vaccine development against flagellated microbial pathogens.Wellcome Trus

A next generation vaccine against human rabies based on a single dose of a chimpanzee adenovirus vector serotype C

Rabies, caused by RNA viruses in the Genus Lyssavirus, is the most fatal of all infectious diseases. This neglected zoonosis remains a major public health problem in developing countries, causing the death of an estimated 25,000-159,000 people each year, with more than half of them in children. The high incidence of human rabies in spite of effective vaccines is mainly linked to the lack of compliance with the complicated administration schedule, inadequacies of the community public health system for local administration by the parenteral route and the overall costs of the vaccine. The goal of our work was the development of a simple, affordable and effective vaccine strategy to prevent human rabies virus infection. This next generation vaccine is based on a replication-defective chimpanzee adenovirus vector belonging to group C, ChAd155-RG, which encodes the rabies glycoprotein (G). We demonstrate here that a single dose of this vaccine induces protective efficacy in a murine model of rabies challenge and elicits strong and durable neutralizing antibody responses in vaccinated non-human primates. Importantly, we demonstrate that one dose of a commercial rabies vaccine effectively boosts the neutralizing antibody responses induced by ChAd155-RG in vaccinated monkeys, showing the compatibility of the novel vectored vaccine with the current post-exposure prophylaxis in the event of rabies virus exposure. Finally, we demonstrate that antibodies induced by ChAd155-RG can also neutralize European bat lyssaviruses 1 and 2 (EBLV-1 and EBLV-2) found in bat reservoirs

The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin

Tetherin (CD317/BST2) is an interferon-induced membrane protein that inhibits the release of diverse enveloped viral particles. Several mammalian viruses have evolved countermeasures that inactivate tetherin, with the prototype being the HIV-1 Vpu protein. Here we show that the human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is sensitive to tetherin restriction and its activity is counteracted by the KSHV encoded RING-CH E3 ubiquitin ligase K5. Tetherin expression in KSHV-infected cells inhibits viral particle release, as does depletion of K5 protein using RNA interference. K5 induces a species-specific downregulation of human tetherin from the cell surface followed by its endosomal degradation. We show that K5 targets a single lysine (K18) in the cytoplasmic tail of tetherin for ubiquitination, leading to relocalization of tetherin to CD63-positive endosomal compartments. Tetherin degradation is dependent on ESCRT-mediated endosomal sorting, but does not require a tyrosine-based sorting signal in the tetherin cytoplasmic tail. Importantly, we also show that the ability of K5 to substitute for Vpu in HIV-1 release is entirely dependent on K18 and the RING-CH domain of K5. By contrast, while Vpu induces ubiquitination of tetherin cytoplasmic tail lysine residues, mutation of these positions has no effect on its antagonism of tetherin function, and residual tetherin is associated with the trans-Golgi network (TGN) in Vpu-expressing cells. Taken together our results demonstrate that K5 is a mechanistically distinct viral countermeasure to tetherin-mediated restriction, and that herpesvirus particle release is sensitive to this mode of antiviral inhibition

Cone-Rod Dystrophy Due to Mutations in a Novel Photoreceptor-Specific Homeobox Gene (CRX) Essential for Maintenance of the Photoreceptor

Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form of cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members of a CORD2-linked family, the highly conserved glutamic acid at the first position of the recognition helix is replaced by alanine (E80A). In another CRD family, a 1 bp deletion (E168 [delta1 bp]) within a novel sequence, the WSP motif, predicts truncation of the C-terminal 132 residues of CRX. Mutations in the CRX gene cause adCRD either by haploinsufficiency or by a dominant negative effect and demonstrate that CRX is essential for the maintenance of mammalian photoreceptorsThis work was supported by the RP Foundation of Canada (R. R. M.), the Foundation Fighting Blindness (R. R. M. and S. G. J.), the Canadian Genetic Disease Network (R. R. M. and A. D.), the Medical Research Council of Canada (R. R. M.), The Wellcome Trust (043825/Z/95) and the Human Genome Mapping Resource Centre (C. Y. G.-E. and S. S. B.), the Howard Hughes Medical Institute and NIH R01 EY0 8064 (C. L. C.), the Canadian Genome Analysis and Technology Genome Resource Facility (S. W. S. and L.-C. T.), the NIH/NEI (EY05627) (S. G. J.), and the Greek National Scholarship Foundation (M. P.). R. R. M. and L.-C. T. are International Research Scholars of the Howard Hughes Medical Institute