Human contribution to the European heatwave of 2003

The summer of 2003 was probably the hottest in Europe since at latest ad 1500, and unusually large numbers of heat-related deaths were reported in France, Germany and Italy. It is an ill-posed question whether the 2003 heatwave was caused, in a simple deterministic sense, by a modification of the external influences on climate--for example, increasing concentrations of greenhouse gases in the atmosphere--because almost any such weather event might have occurred by chance in an unmodified climate. However, it is possible to estimate by how much human activities may have increased the risk of the occurrence of such a heatwave. Here we use this conceptual framework to estimate the contribution of human-induced increases in atmospheric concentrations of greenhouse gases and other pollutants to the risk of the occurrence of unusually high mean summer temperatures throughout a large region of continental Europe. Using a threshold for mean summer temperature that was exceeded in 2003, but in no other year since the start of the instrumental record in 1851, we estimate it is very likely (confidence level >90%) that human influence has at least doubled the risk of a heatwave exceeding this threshold magnitude.     

Neuronal responses to extracellularly applied cyclic AMP: Role of the adenosine receptor

Summary At low doses, theophylline blocks the neuronal depressant effects of 5-AMP, but not cyclic AMP. Higher doses (100 mg/kg) block cyclic AMP responses and reduce the effects of noradrenaline and GABA. It is concluded that cyclic AMP does not depress neurones via the adenosine receptor.We are grateful to the Wellcome Trust and Royal Society for travel grants.     

Late Pliocene Greenland glaciation controlled by a decline in atmospheric CO2 levels

It is thought that the Northern Hemisphere experienced only ephemeral glaciations from the Late Eocene to the Early Pliocene epochs (about 38 to 4 million years ago), and that the onset of extensive glaciations did not occur until about 3 million years ago. Several hypotheses have been proposed to explain this increase in Northern Hemisphere glaciation during the Late Pliocene. Here we use a fully coupled atmosphere-ocean general circulation model and an ice-sheet model to assess the impact of the proposed driving mechanisms for glaciation and the influence of orbital variations on the development of the Greenland ice sheet in particular. We find that Greenland glaciation is mainly controlled by a decrease in atmospheric carbon dioxide during the Late Pliocene. By contrast, our model results suggest that climatic shifts associated with the tectonically driven closure of the Panama seaway, with the termination of a permanent El Ni?o state or with tectonic uplift are not large enough to contribute significantly to the growth of the Greenland ice sheet; moreover, we find that none of these processes acted as a priming mechanism for glacial inception triggered by variations in the Earth's orbit.     

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.     

Common variants in ZNF365 are associated with both mammographic density and breast cancer risk

High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer.     

Variation in genome-wide mutation rates within and between human families

J.B.S. Haldane proposed in 1947 that the male germline may be more mutagenic than the female germline. Diverse studies have supported Haldane's contention of a higher average mutation rate in the male germline in a variety of mammals, including humans. Here we present, to our knowledge, the first direct comparative analysis of male and female germline mutation rates from the complete genome sequences of two parent-offspring trios. Through extensive validation, we identified 49 and 35 germline de novo mutations (DNMs) in two trio offspring, as well as 1,586 non-germline DNMs arising either somatically or in the cell lines from which the DNA was derived. Most strikingly, in one family, we observed that 92% of germline DNMs were from the paternal germline, whereas, in contrast, in the other family, 64% of DNMs were from the maternal germline. These observations suggest considerable variation in mutation rates within and between families.     

Evolutionary change in the insulin receptors of hystricomorph rodents

INSULIN receptors have been thought to have remained unaltered despite evolutionary changes in the hormone(1). Because insulins from hystricomorph rodents are known to be highly substituted compared with other mammalian insulins, we decided to investigate the insulin receptor of some hystricomorphs to determine whether evolutionary change had occurred within the receptor itself. Here we present the first evidence that hystricomorph rodent insulin receptors have undergone evolutionary change.     

Anthropogenic greenhouse gas contribution to flood risk in England and Wales in autumn 2000

Interest in attributing the risk of damaging weather-related events to anthropogenic climate change is increasing. Yet climate models used to study the attribution problem typically do not resolve the weather systems associated with damaging events such as the UK floods of October and November 2000. Occurring during the wettest autumn in England and Wales since records began in 1766, these floods damaged nearly 10,000 properties across that region, disrupted services severely, and caused insured losses estimated at ￡1.3 billion (refs 5, 6). Although the flooding was deemed a 'wake-up call' to the impacts of climate change at the time, such claims are typically supported only by general thermodynamic arguments that suggest increased extreme precipitation under global warming, but fail to account fully for the complex hydrometeorology associated with flooding. Here we present a multi-step, physically based 'probabilistic event attribution' framework showing that it is very likely that global anthropogenic greenhouse gas emissions substantially increased the risk of flood occurrence in England and Wales in autumn 2000. Using publicly volunteered distributed computing, we generate several thousand seasonal-forecast-resolution climate model simulations of autumn 2000 weather, both under realistic conditions, and under conditions as they might have been had these greenhouse gas emissions and the resulting large-scale warming never occurred. Results are fed into a precipitation-runoff model that is used to simulate severe daily river runoff events in England and Wales (proxy indicators of flood events). The precise magnitude of the anthropogenic contribution remains uncertain, but in nine out of ten cases our model results indicate that twentieth-century anthropogenic greenhouse gas emissions increased the risk of floods occurring in England and Wales in autumn 2000 by more than 20%, and in two out of three cases by more than 90%.