The Keap1/Nrf2 pathway in health and disease:from the bench to the clinic

The transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, with gene called NFE2L2) is a master regulator of the antioxidant response. In the last decade, interest has intensified in this research area as its importance in several physiological and pathological processes has become widely recognized; these include redox signalling and redox homoeostasis, drug metabolism and disposition, intermediary metabolism, cellular adaptation to stress, chemoprevention and chemoresistance, toxicity, inflammation, neurodegeneration, lipogenesis and aging. Regulation of Nrf2 is complex and although much attention has focussed on its repression by Kelch-like ECH-associated protein-1 (Keap1), recently it has become increasingly apparent that it is also controlled by cross-talk with other signalling pathways including the glycogen synthase kinase-3 (GSK-3) - β-transducin repeat-containing protein (β-TrCP) axis, ERAD (endoplasmic reticulum-associated degradation)-associated E3 ubiquitin-protein ligase (Hrd1, also called synoviolin), nuclear factor-kappa B (NF-κB), Notch and AMP kinase. Due to its beneficial role in several diseases, Nrf2 has become a major therapeutic target, with novel natural, synthetic and targeted small molecules currently under investigation to modulate the pathway and in clinical trials.</p

Exploring International Differences in Rates of Return to Education: Evidence from EU SILC. ESRI WP311, September 2009

This paper uses EU-SILC data from 2005 and 2006 to explore the hypothesis that international differences in rates of return to education reflect variations in the level of risk associated with educational investments. While there was some evidence to support this hypothesis with regards to returns to ISCED level 5 qualifications among males, the majority of the variation in international returns was related to distributional impacts. The results suggest that higher rates of return to more advanced qualifications relate to more dispersed distributions among poorly qualified workers which, in turn, raise the returns to credentials further up the educational spectrum

Explaining International Differences in Rates of Overeducation in Europe. ESRI WP365, December 2010

This paper examines the factors determining variations in international rates of overeducation. We find significant effects for a range of factors including labour market structural imbalances, risk, trade-union density and the structure of academic funding. The results suggest that international levels of overeducation are particularly sensitive to variations in higher education funding arrangements

Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl- bridging group to constrain the peptides, coupled with glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity

Outdoor terraces in Barcelona and Milan: configuration of new spaces for social interaction

This work approaches the phenomenon of the outdoor terraces of bars and restaurants, analysing the role of these privately owned collective elements whose layout has shaped the urban landscape at the pavement level for more than a century, and whose presence has become essential in the streets of many cities after a pandemic. The research highlights the interest of terraces as dynamic elements of urbanity: private domains in the public space where people eat collectively; they are apparently simple units that synthesise complex conflicts between individual behaviours and property boundary conditions. The investigation shows the increasing expansion that outdoor terraces have experienced since 2020, using the cities of Barcelona and Milan as case studies. A series of GIS maps show the image of both cities before and after the pandemic, allowing us to evaluate the amount of public space allocated to terraces, measure their increase in number and surface, establish the proportions of occupation of the street and find the patterns of concentration in the public space. Finally, the article offers some policy and planning recommendations based on the research findings.Peer ReviewedPostprint (published version

3D vanadium oxide inverse opal growth by electrodeposition

Three-dimensional vanadium pentoxide (V2O5) material architectures in the form of inverse opals (IOs) were fabricated using a simple electrodeposition process into artificial opal templates on stainless steel foil using an aqueous solution of VOSO4.χH2O with added ethanol. The direct deposition of V2O5 IOs was compared with V2O5 planar electrodeposition and confirms a similar progressive nucleation and growth mechanism. An in-depth examination of the chemical and morphological nature of the IO material was performed using X-ray crystallography, X-ray photoelectron spectroscopy, Raman scattering and scanning/transmission electron microscopy. Electrodeposition is demonstrated to be a function of the interstitial void fraction of the artificial opal and ionic diffusivity that leads to high quality, phase pure V2O5 inverse opals is not adversely affected by diffusion pathway tortuosity. Methods to alleviate electrodeposited overlayer formation on the artificial opal templates for the fabrication of the porous 3D structures are also demonstrated. Such a 3D material is ideally suited as a cathode for lithium ion batteries, electrochromic devices, sensors and for applications requiring high surface area electrochemically active metal oxides

Dynamic association of RNA-editing enzymes with the nucleolus

© The Company of Biologists Limited 2003ADAR1 and ADAR2 are editing enzymes that deaminate adenosine to inosine in long double stranded RNA duplexes and specific pre-mRNA transcripts. Here, we show that full-length and N-terminally truncated forms of ADAR1 are simultaneously expressed in HeLa and COS7 cells owing to the usage of alternative starting methionines. Because the N-terminus of ADAR1 contains a nuclear export signal, the full-length protein localizes predominantly in the cytoplasm, whereas the N-terminally truncated forms are exclusively nuclear and accumulate in the nucleolus. ADAR2, which lacks a region homologous to the N-terminal domain of ADAR1, localizes exclusively to the nucleus and similarly accumulates in the nucleolus. Within the nucleolus, ADAR1 and ADAR2 co-localize in a novel compartment. Photobleaching experiments demonstrate that, in live cells, ADAR1 and ADAR2 are in constant flux in and out of the nucleolus. When cells express the editing-competent glutamate receptor GluR-B RNA, endogenous ADAR1 and ADAR2 de-localize from the nucleolus and accumulate at sites where the substrate transcripts accumulate. This suggests that ADAR1 and ADAR2 are constantly moving through the nucleolus and might be recruited onto specific editing substrates present elsewhere in the cell.This study was supported by grants from Fundação para a Ciência e Tecnologia,Portugal, and the European Commission (QLG2-CT-2001-01554). This work was also supported by the MRC, a grant from the British Heart Foundation (PG/98086),Ministerio de Ciencia y Tecnologia of Spain (BFI2002-00454) and Fundación Marqués de Valdecilla' of Santander, Spain (A05/02). J.M.P.D. was supported by a long-term fellowship of the European Molecular Biology Organization (EMBO-ALTF 239-2000).info:eu-repo/semantics/publishedVersio

Cardiovascular Mechanisms of Action of Anthocyanins May Be Associated with the Impact of Microbial Metabolites on Heme Oxygenase-1 in Vascular Smooth Muscle Cells

Anthocyanins are reported to have cardio-protective effects, although their mechanisms of action remain elusive. We aimed to explore the effects of microbial metabolites common to anthocyanins and other flavonoids on vascular smooth muscle heme oxygenase-1 (HO-1) expression. Thirteen phenolic metabolites identified by previous anthocyanin human feeding studies, as well as 28 unique mixtures of metabolites and their known precursor structures were explored for their activity on HO-1 protein expression in rat aortic smooth muscle cells (RASMCs). No phenolic metabolites were active when treated in isolation; however, five mixtures of phenolic metabolites significantly increased HO-1 protein expression (127.4-116.6%, p ≤ 0.03). The present study demonstrates that phenolic metabolites of anthocyanins differentially affect HO-1 activity, often having additive, synergistic or nullifying effects

Estimating cancer distant recurrence rates from administrative datasets: comparison of cancer registry and hospital records.

We thank the NSW Central Cancer Registry and the NSW Department of Health for providing data for this study and the Centre for Health Research Linkage for undertaking the record linkage. This study was supported through an Australian National Health and Medical Research Council Project Grant (No 633223) and the NSW Health BiostatisticalOfficer Training Program (for J Patterson)

Carbon and Nitrogen Isotopic Signatures of Hair, Nail, and Breath from tropical African Human Populations

RATIONALE: Stable isotopic analyses are increasingly used to study the diets of past and present human populations. Yet, the carbon and nitrogen isotopic data of modern human diets collected so far are biased towards Europe and North America. Here, we address this gap by reporting on the dietary isotopic signatures of six tropical African communities: El Molo, Turkana (Kerio), Luhya (Webuye), Luhya (Port Victoria), and Luo (Port Victoria) from Kenya, and Baka from Cameroon; representing four subsistence strategies: fishing, pastoralism, agriculturalism, and hunter-gatherer. METHODS: We used EA-CF-IRMS to measure the carbon and nitrogen isotopic ratios of hair (n = 134) and nail (n = 80), and the carbon isotopic ratios of breath (n = 184) from these communities, as well as the carbon and nitrogen isotopic ratios of some food samples from the Kenyan communities. RESULTS: We expand on the known range of δ13 C values in human hair through the hunter-gatherer Baka, with a diet based on C3 plants, and through the agriculturalist Luhya (Webuye), with a diet based on C4 plants. In addition, we found that the consumption of fish from East African lakes is difficult to detect isotopically due to the combined effects of high nitrogen isotopic ratios of plants and the low nitrogen isotopic ratios of fish. Finally, we found that some of the communities studied are markedly changing their diets through increasing sedentism and urbanization. CONCLUSION: Our findings contribute substantially to the understanding of the environmental, demographic and economic dynamics that affect the dietary landscape of different tropical populations of Africa. These results highlight the importance of studying a broader sample of human populations and their diet, with a focus on their precise context - both from an isotopic and more general anthropological perspectives.This study was funded by a European Research Council Advanced Award to MML (In-Africa Project, ERC 295907), and carried out with permission from the National Commission for Science, Technology and Innovation, Kenya, No. NACOSTI/P/15/2669/4758