Synthesis of oligodeoxyribonucleotides containing a tricyclic thio analogue of O6-methylguanine and their recognition by MGMT and Atl1

Promutagenic O6-alkylguanine adducts in DNA are repaired in humans by O6-methylguanine-DNA-methyltransferase (MGMT) in an irreversible reaction. Here we describe the synthesis of a phosphoramidite that allows the preparation of oligodeoxyribonucleotides (ODNs) containing a novel tricyclic thio analogue of O6-methylguanine in which the third ring bridges the 6-thio group and C7 of a 7-deazapurine. These ODNs are very poor substrates for MGMT and poorly recognised by the alkyltransferase-like protein, Atl1. Examination of the active sites of both MGMT and Atl1 suggest large steric clashes hindering binding of the analogue. Such analogues, if mutagenic, are likely to be highly toxic

Un outil pratique pour optimiser la rétention des eaux pluviales dans les toitures végétalisées

Colloque avec actes et comité de lecture. Internationale.International audienc

Carbon Nanotubes as Nanoelectromechanical Systems

We theoretically study the interplay between electrical and mechanical properties of suspended, doubly clamped carbon nanotubes in which charging effects dominate. In this geometry, the capacitance between the nanotube and the gate(s) depends on the distance between them. This dependence modifies the usual Coulomb models and we show that it needs to be incorporated to capture the physics of the problem correctly. We find that the tube position changes in discrete steps every time an electron tunnels onto it. Edges of Coulomb diamonds acquire a (small) curvature. We also show that bistability in the tube position occurs and that tunneling of an electron onto the tube drastically modifies the quantized eigenmodes of the tube. Experimental verification of these predictions is possible in suspended tubes of sub-micron length.Comment: 8 pages, 5 eps figures included. Major changes; new material adde

Evaluating Lifeworld as an emancipatory methodology

Disability research is conducted within a highly politicised ‘hotbed’ of competing paradigms and principles. New researchers, who want to work within the social model, are soon faced with complex and challenging methodological and philosophical dilemmas. The social model advocates research agendas that are focused on the emancipation and empowerment of disabled people but, in reality, these are rarely achieved. To be successful researchers need to engage with innovative and creative methodologies and to share their experiences of these within environments that welcome challenge and debate. This paper focuses on Lifeworld and assesses its value as a tool for emancipatory research. Using examples from a study with parents, whose children were in the process of being labelled as having autism, the paper illustrates how the principles that ‘underpin’ the methodology offered a supportive framework for a novice researcher

Diving efficiency at depth and pre-breeding foraging effort increase with haemoglobin levels in gentoo penguins

Individual differences in oxygen storage and carrying capacity have been associated with fitness-related traits and, for air-breathing aquatic animals, to diving ability and foraging success. In winter, many seabirds must replenish the energy reserves they have depleted during the breeding period. Thus, winter foraging efficiency can influence their upcoming breeding behaviour. Using gentoo penguins Pygoscelis papua as a study species, we investigated (1) if inter-individual variation in diving efficiency (proportion of time spent at the bottom) is associated with indices of oxygen storage and carrying capacity (haemoglobin, haematocrit, body mass), and (2) if measures of pre-breeding foraging effort (mean trip duration, total time at sea, and vertical distance travelled) are associated with these oxygen indices and breeding status. Haemoglobin was positively correlated with diving efficiency, particularly for deeper dives, and only penguins with high haemoglobin levels frequently dove to depths ≥140 m. Such differences could affect resource access. However, because reaching deep offshore waters likely requires travelling more than foraging nearshore, vertical distance travelled during pre-breeding increased with haemoglobin levels. The relationship with haematocrit was non-linear, suggesting that commonly used analyses may be inappropriate for this index. We found that early-laying penguins spent less time at sea prior to nesting than non-breeding penguins, suggesting that more efficient foragers lay earlier. Given that diving efficiency at depth is linked to aerobic capacity, anthropogenic activities taking place in either nearshore or offshore waters (e.g. shallow-water fisheries, offshore oil rigs) may have differing impacts on individuals. Further understanding these links could help the conservation of diving species

Do Seasonal Glucocorticoid Changes Depend on Reproductive Investment? A Comparative Approach in Birds

Animals go through different life history stages such as reproduction, moult, or migration, of which some are more energy-demanding than others. Baseline concentrations of glucocorticoid hormones increase during moderate, predictable challenges and thus are expected to be higher when seasonal energy demands increase, such as during reproduction. By contrast, stress-induced glucocorticoids prioritize a survival mode that includes reproductive inhibition. Thus, many species down-regulate stress-induced glucocorticoid concentrations during the breeding season. Interspecific variation in glucocorticoid levels during reproduction has been successfully mapped onto reproductive investment, with species investing strongly in current reproduction (fast pace of life) showing higher baseline and lower stress-induced glucocorticoid concentrations than species that prioritize future reproduction over current attempts (slow pace of life). Here we test the >glucocorticoid seasonal plasticity hypothesis>, in which we propose that interspecific variation in seasonal changes in glucocorticoid concentrations from the non-breeding to the breeding season will be related to the degree of reproductive investment (and thus pace of life). We extracted population means for baseline (for 54 species) and stress-induced glucocorticoids (for 32 species) for the breeding and the non-breeding seasons from the database >HormoneBase>, also calculating seasonal glucocorticoid changes. We focused on birds because this group offered the largest sample size. Using phylogenetic comparative methods, we first showed that species differed consistently in both average glucocorticoid concentrations and their changes between the two seasons, while controlling for sex, latitude, and hemisphere. Second, as predicted seasonal changes in baseline glucocorticoids were explained by clutch size (our proxy for reproductive investment), with species laying larger clutches showing a greater increase during the breeding season-especially in passerine species. In contrast, changes in seasonal stress-induced levels were not explained by clutch size, but sample sizes were more limited. Our findings highlight that seasonal changes in baseline glucocorticoids are associated with a species' reproductive investment, representing an overlooked physiological trait that may underlie the pace of life

Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern)

AbstractThreshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual ‘dose’ applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: The Treat-OA consortium

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genomewide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10-5). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA