Rescue of replication failure by Fanconi anaemia proteins

Chromosomal aberrations are often associated with incomplete genome duplication, for instance at common fragile sites, or as a consequence of chemical alterations in the DNA template that block replication forks. Studies of the cancer-prone disease Fanconi anaemia (FA) have provided important insights into the resolution of replication problems. The repair of interstrand DNA crosslinks induced by chemotherapy drugs is coupled with DNA replication and controlled by FA proteins. We discuss here the recent discovery of new FA-associated proteins and the development of new tractable repair systems that have dramatically improved our understanding of crosslink repair. We focus also on how FA proteins protect against replication failure in the context of fragile sites and on the identification of reactive metabolites that account for the development of Fanconi anaemia symptoms

Retrofitting social housing : reflections by tenants on adopting and living with retrofit technology

Retrofit has been described as one of the major engineering challenges of the twenty-first century (Kelly 2009). However, the industry needs to look beyond regarding the problem as restricted to the physical upgrade of properties. Asset managers, engineers and installers work on and in people’s homes and, in many cases, are subsequently changing the way householders use their homes to meet their comfort and wider energy needs. Here we consider how the twin issues of adopting and living with retrofit technologies have affected groups of residents in social housing. We discuss issues of trust, social norms, engagement and concern that have shaped the adoption process, as well as investigating the everyday experience of living with new configurations of energy consumption. The findings have relevance not only for the social housing sector but also raise questions as to how to effectively deliver programmes such as the Green Deal and the Energy Company Obligation within the UK

Evidence that endogenous formaldehyde produces immunogenic and atherogenic adduct epitopes

Abstract Endogenous formaldehyde is abundantly present in our bodies, at around 100 µM under normal conditions. While such high steady state levels of formaldehyde may be derived by enzymatic reactions including oxidative demethylation/deamination and myeloperoxidation, it is unclear whether endogenous formaldehyde can initiate and/or promote diseases in humans. Here, we show that fluorescent malondialdehyde-formaldehyde (M2FA)-lysine adducts are immunogenic without adjuvants in mice. Natural antibody titers against M2FA are elevated in atherosclerosis-prone mice. Staining with an antibody against M2FA demonstrated that M2FA is present in plaque found on the aortic valve of ApoE −/− mice. To mimic inflammation during atherogenesis, human myeloperoxidase was incubated with glycine, H2O2, malondialdehyde, and a lysine analog in PBS at a physiological temperature, which resulted in M2FA generation. These results strongly suggest that the 1,4-dihydropyridine-type of lysine adducts observed in atherosclerosis lesions are likely produced by endogenous formaldehyde and malondialdehyde with lysine. These highly fluorescent M2FA adducts may play important roles in human inflammatory and degenerative diseases