Carbon monoxide inhibits L-type Ca2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species

Conditions of stress, such as myocardial infarction, stimulate up-regulation of heme oxygenase (HO-1) to provide cardioprotection. Here, we show that CO, a product of heme catabolism by HO-1, directly inhibits native rat cardiomyocyte L-type Ca2+ currents and the recombinant alpha1C subunit of the human cardiac L-type Ca2+ channel. CO (applied via a recognized CO donor molecule or as the dissolved gas) caused reversible, voltage-independent channel inhibition, which was dependent on the presence of a spliced insert in the cytoplasmic C-terminal region of the channel. Sequential molecular dissection and point mutagenesis identified three key cysteine residues within the proximal 31 amino acids of the splice insert required for CO sensitivity. CO-mediated inhibition was independent of nitric oxide and protein kinase G but was prevented by antioxidants and the reducing agent, dithiothreitol. Inhibition of NADPH oxidase and xanthine oxidase did not affect the inhibitory actions of CO. Instead, inhibitors of complex III (but not complex I) of the mitochondrial electron transport chain and a mitochondrially targeted antioxidant (Mito Q) fully prevented the effects of CO. Our data indicate that the cardioprotective effects of HO-1 activity may be attributable to an inhibitory action of CO on cardiac L-type Ca2+ channels. Inhibition arises from the ability of CO to promote generation of reactive oxygen species from complex III of mitochondria. This in turn leads to redox modulation of any or all of three critical cysteine residues in the channel's cytoplasmic C-terminal tail, resulting in channel inhibition.

Enhancing fieldwork learning with technology: practitioner's perspectives

This research paper reports the findings from an international survey of fieldwork practitioners on their use of technology to enhance fieldwork teaching and learning. It was found that there was high information technology usage before and after time in the field, but some were also using portable devices such as smartphones and global positioning system whilst out in the field. The main pedagogic reasons cited for the use of technology were the need for efficient data processing and to develop students' technological skills. The influencing factors and barriers to the use of technology as well as the importance of emerging technologies are discussed.

Ensemble flood forecasting: a review.

Operational medium range flood forecasting systems are increasingly moving towards the adoption of ensembles of numerical weather predictions (NWP), known as ensemble prediction systems (EPS), to drive their predictions. We review the scientific drivers of this shift towards such ‘ensemble flood forecasting’ and discuss several of the questions surrounding best practice in using EPS in flood forecasting systems. We also review the literature evidence of the ‘added value’ of flood forecasts based on EPS and point to remaining key challenges in using EPS successfully.

Glaciodynamics of the central sector of the last British–Irish ice sheet in Northern England

The central sector of the last British–Irish Ice Sheet (BIIS) was characterised by considerable complexity, both in terms of its glacial stratigraphy and geomorphological signature. This complexity is reflected by the large number and long history of papers that have attempted to decipher the glaciodynamic history of the region. Despite significant advances in our understanding, reconstructions remain hotly debated and relatively local, thereby hindering attempts to piece together BIIS dynamics. This paper seeks to address these issues by reviewing geomorphological mapping evidence of palimpsest flow signatures and providing an up-to-date stratigraphy of the region. Reconciling geomorphological and sedimentological evidence with relative and absolute dating constraints has allowed us to develop a new six-stage glacial model of ice-flow history and behaviour in the central sector of the last BIIS, with three major phases of glacial advance. This includes: I. Eastwards ice flow through prominent topographic corridors of the north Pennines; II. Cessation of the Stainmore ice flow pathway and northwards migration of the North Irish Sea Basin ice divide; III. Stagnation and retreat of the Tyne Gap Ice Stream; IV. Blackhall Wood–Gosforth Oscillation; V. Deglaciation of the Solway Lowlands; and VI. Scottish Re-advance and subsequent final retreat of ice out of the central sector of the last BIIS. The ice sheet was characterised by considerable dynamism, with flow switches, initiation (and termination) of ice streams, draw-down of ice into marine ice streams, repeated ice-marginal fluctuations and the production of large volumes of meltwater, locally impounded to form ice-dammed glacial lakes. Significantly, we tie this reconstruction to work carried out and models developed for the entire ice sheet. This therefore situates research in the central sector within contemporary understanding of how the last BIIS evolved over time.