Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3.

Potassium leak conductances were recently revealed to exist as independent molecular entities. Here, the genomic structure, cardiac localization, and biophysical properties of a murine example are considered. Kcnk3 subunits have two pore-forming P domains and unique functional attributes. At steady state, Kcnk3 channels behave like open, potassium-selective, transmembrane holes that are inhibited by physiological levels of proton. With voltage steps, Kcnk3 channels open and close in two phases, one appears to be immediate and one is time-dependent (tau = approximately 5 ms). Both proton block and gating are potassium-sensitive; this produces an anomalous increase in outward flux as external potassium levels rise because of decreased proton block. Single Kcnk3 channels open across the physiological voltage range; hence they are "leak" conductances; however, they open only briefly and rarely even after exposure to agents that activate other potassium channels

The mechanics of decompressive craniectomy: Personalized simulations

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordDecompressive craniectomy is a traditional but controversial surgical procedure that removes part of the skull to allow an injured and swollen brain to expand outward. Recent studies suggest that mechanical strain is associated with its undesired, high failure rates. However, the precise strain fields induced by the craniectomy are unknown. Here we create a personalized craniectomy model from magnetic resonance images to quantify the strains during a decompressive craniectomy using finite element analysis. We swell selected regions of the brain and remove part of the skull to allow the brain to bulge outward and release the intracranical swelling pressure. Our simulations reveal three potential failure mechanisms associated with the procedure: axonal stretch in the center of the bulge, axonal compression at the edge of the craniectomy, and axonal shear around the opening. Strikingly, for a swelling of only 10%, axonal strain, compression, and shear reach local maxima of up to 30%, and exceed the reported functional and morphological damage thresholds of 18% and 21%. Our simulations suggest that a collateral craniectomy with the skull opening at the side of swelling is less invasive than a contralateral craniectomy with the skull opening at the opposite side: It induces less deformation, less rotation, smaller strains, and a markedly smaller midline shift. Our computational craniectomy model can help quantify brain deformation, tissue strain, axonal stretch, and shear with the goal to identify high-risk regions for brain damage on a personalized basis. While computational modeling is beyond clinical practice in neurosurgery today, simulations of neurosurgical procedures have the potential to rationalize surgical process parameters including timing, location, and size, and provide standardized guidelines for clinical decision making and neurosurgical planning.This work was supported by the Wolfson/Royal Society Merit Award to Alain Goriely and by the National Institutes of Health grant U01 HL119578 to Ellen Kuhl

Bulging brains

This is the author accepted manuscript. The final version is available from Springer Verlag via the DOI in this record.Brain swelling is a serious condition associated with an accumulation of fluid inside the brain that can be caused by trauma, stroke, infection, or tumors. It increases the pressure inside the skull and reduces blood and oxygen supply. To relieve the intracranial pressure, neurosurgeons remove part of the skull and allow the swollen brain to bulge outward, a procedure known as decompressive craniectomy. Decompressive craniectomy has been preformed for more than a century; yet, its effects on the swollen brain remain poorly understood. Here we characterize the deformation, strain, and stretch in bulging brains using the nonlinear field theories of mechanics. Our study shows that even small swelling volumes of 28 to 56 ml induce maximum principal strains in excess of 30 %. For radially outward-pointing axons, we observe maximal normal stretches of 1.3 deep inside the bulge and maximal tangential stretches of 1.3 around the craniectomy edge. While the stretch magnitude varies with opening site and swelling region, our study suggests that the locations of maximum stretch are universally shared amongst all bulging brains. Our model has the potential to inform neurosurgeons and rationalize the shape and position of the skull opening, with the ultimate goal to reduce brain damage and improve the structural and functional outcomes of decompressive craniectomy in trauma patients.We thank Allan L. Reiss and his group for providing the MRI scans. This work was supported by the Timoshenko Scholar Award to Alain Goriely and by the Humboldt Research Award and the National Institutes of Health grant U01 HL119578 to Ellen Kuhl

Reconstructing North Atlantic marine climate variability using an absolutely-dated sclerochronological network

This is the final version of the article. Available from Elsevier via the DOI in this record.Reconstructing regional to hemispheric-scale climate variability requires the application of spatially representative and climatically sensitive proxy archives. Large spatial networks of dendrochronologies have facilitated the reconstruction of atmospheric variability and inferred variability in the Atlantic Ocean system. However, the marine environment has hitherto lacked the direct application of the spatial network approach because of the small number of individual absolutely-dated marine archives. In this study we present the first analyses of a network of absolutely-dated annually-resolved growth increment width chronologies from the marine bivalves Glycymeris glycymeris and Arctica islandica. The network contains eight chronologies spanning > 500 km along the western British continental shelf from the southern Irish Sea to North West Scotland. Correlation analysis of the individual chronologies and a suite of climate indices, including the Atlantic Multidecadal Oscillation (AMO), Central England surface air temperature (CET), northeast Atlantic sea surface temperatures (SST's) and the winter North Atlantic Oscillation (wNAO), demonstrates that, despite the large geographical distances been sites and the heterogeneous nature of the marine environment, the increment width variability in these series contains an element of coherence likely driven by a common response to changing environmental forcing. A nested Principal component analysis (PCA) was used to construct five composite series which explain between 31% and 74% of the variance across the individual chronologies. Linear regression analyses indicate that the composite series explain up to 41% of the variance in Northeast Atlantic SSTs over the calibration period (1975–2000). Calibration verification (reduction of error [RE] and coefficient of efficiency [CE]) statistics indicate that the composite series contains significant skill at reconstructing multi-decadal northeast Atlantic SST variability over the past two centuries (1805–2010). These data suggest that composite series derived from sclerochronology networks can facilitate the robust reconstruction of marine climate over past centuries to millennia providing invaluable baseline records of natural oceanographic variability.This work was supported financially by the NERC funded project Climate of the Last Millennium Project (CLAM; project No. NE/N001176/1) and the Marie Curie Frame work Partnership Annually Resolved Archives of Marine Climate Change (ARAMACC; Project No. FP7 604802). The authors would like to thank the three anonymous reviewer‘s for their constructive comments during the peer review process

Editorial: The Marine Carbon Cycle: From Ancient Storage to Future Challenges

Understanding the oceanic carbon cycle, its dynamics, and its historical and future trajectories is key to our ability to model future climate change. With this in mind, the second Shackleton conference, held in September 2019 at the Geological Society of London (GSL), and organized by the Marine Studies Group of the GSL, focused on oceanic carbon storage, specifically the dynamic processes by which carbon is permanently removed from the atmosphere and/or the terrestrial lithosphere and biosphere and stored in coastal and marine sediments

Archaeology and sclerochronology of marine bivalves

This is the final version. Available on open access from Springer via the DOI in this record. In a rapidly changing world, maintenance of the good health of the marine environment requires a detailed understanding of its mechanisms of change, and the ability to detect early signals of a shift away from the equilibrium state that we assume characterized it before there was any significant human impact. Given that instrumental measurements of the oceans go back no further than a few decades, the only way in which we can assess the long-term baseline variability that characterizes the pre-perturbation equilibrium state of the marine environment is by the use of proxy records contained in stratified or layered natural archives such as corals, fish otoliths and bivalve mollusc shells. In this chapter we will look at the ways in which the environmental signals recorded in the shells of bivalve molluscs can be used to shed light on marine variability both in the present and over past centuries and millennia, and specifically how they can be used to study marine climate, the marine environment and the economic and cultural history of the relationship between humans and the oceans. The chapter is divided into two parts: section one describes the morphological, geochemical and crystallographic techniques that are used to obtain information from the shells, while section two covers the use of bivalve shells in a wide range of applications, including ecosystem services, environmental monitoring, archaeology, climate reconstruction, and climate modeling

Metabolism of ticagrelor in patients with acute coronary syndromes.

© The Author(s) 2018Ticagrelor is a state-of-the-art antiplatelet agent used for the treatment of patients with acute coronary syndromes (ACS). Unlike remaining oral P2Y12 receptor inhibitors ticagrelor does not require metabolic activation to exert its antiplatelet action. Still, ticagrelor is extensively metabolized by hepatic CYP3A enzymes, and AR-C124910XX is its only active metabolite. A post hoc analysis of patient-level (n = 117) pharmacokinetic data pooled from two prospective studies was performed to identify clinical characteristics affecting the degree of AR-C124910XX formation during the first six hours after 180 mg ticagrelor loading dose in the setting of ACS. Both linear and multiple regression analyses indicated that ACS patients presenting with ST-elevation myocardial infarction or suffering from diabetes mellitus are more likely to have decreased rate of ticagrelor metabolism during the acute phase of ACS. Administration of morphine during ACS was found to negatively influence transformation of ticagrelor into AR-C124910XX when assessed with linear regression analysis, but not with multiple regression analysis. On the other hand, smoking appears to increase the degree of ticagrelor transformation in ACS patients. Mechanisms underlying our findings and their clinical significance warrant further research.Peer reviewedFinal Published versio

Late Holocene seasonal temperature variability of the western Scottish shelf (St Kilda) recorded in fossil shells of the bivalve Glycymeris glycymeris

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThe North Atlantic Ocean and adjacent shelf seas play a crucial role in global climate. To better constrain long-term natural variability and marine-terrestrial linkages in this region, a network of highly resolved marine archives from the open ocean and continental shelves is needed. In recent decades, bivalve sclerochronology has emerged as a field providing such records from the mid- to high latitudes. In May 2014, dead valves and young live specimens of the bivalve Glycymeris glycymeris were collected at St Kilda, Scotland. A floating chronology spanning 187 years was constructed with fossil shells and radiocarbon dated to 3910–3340 cal yr before present (BP), with a probability density cluster at ca. 3700–3500 cal yr BP. Sub-annual δ18O data were obtained from five fossil and three modern specimens and showed a strong seasonal signal in both time intervals. The growth season of G. glycymeris at this location today lasts from May to October, with most growth occurring before the temperature peak in August. Thus, the modern specimens and the fossil chronology represent late-spring and summer sea surface temperatures (SST). The annual temperature range was 4.4 °C in the fossil shells, which is similar to the range observed today (3.8 °C). Average SSTs reconstructed from the fossil shells were 1 °C cooler than in 2003–2013 CE and similar to the early 20th century CE. The radiocarbon age of the floating chronology coincides with a climatic shift to wetter conditions on the British Isles and with a cold interval observed in palaeoceanographic records from south of Iceland. However, our data do not provide evidence of a cold interval on the Scottish shelf. The similarity in growth season and temperature range between the fossil and modern specimens are attributed to similar boundary conditions in the fourth millennium BP compared to today

Annually resolved North Atlantic marine climate over the last millennium

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Owing to the lack of absolutely dated oceanographic information before the modern instrumental period, there is currently significant debate as to the role played by North Atlantic Ocean dynamics in previous climate transitions (for example, Medieval Climate Anomaly-Little Ice Age, MCA-LIA). Here we present analyses of a millennial-length, annually resolved and absolutely dated marine δ(18)O archive. We interpret our record of oxygen isotope ratios from the shells of the long-lived marine bivalve Arctica islandica (δ(18)O-shell), from the North Icelandic shelf, in relation to seawater density variability and demonstrate that solar and volcanic forcing coupled with ocean circulation dynamics are key drivers of climate variability over the last millennium. During the pre-industrial period (AD 1000-1800) variability in the sub-polar North Atlantic leads changes in Northern Hemisphere surface air temperatures at multi-decadal timescales, indicating that North Atlantic Ocean dynamics played an active role in modulating the response of the atmosphere to solar and volcanic forcing.We thank the members of the RV Bjarni Sæmundsson (Cruise No. B05-2006). This work was supported by the NERC-funded ULTRA project (Grant Number NE/H023356/1), NERC-funded CLAM project; (Project No. NE/N001176/1) and EU Millennium Project (Project number 017008). This study is a contribution to the Climate Change Consortium for Wales (C3W). We thank Brian Long (Bangor University) and Dr Julia Becker (Cardiff University) for their technical support, and Dr Manfred Mudelsee for his assistance with the trend analysis. We thank Dr Jessica Tierney and an anonymous reviewer for providing the constructive comments in the reviewing process

Dating of the oldest continental sediments from the Himalayan foreland basin

A detailed knowledge of Himalayan development is important for our wider understanding of several global processes, ranging from models of plateau uplift to changes in oceanic chemistry and climate(1-4). Continental sediments 55 Myr old found in a foreland basin in Pakistan(5) are, by more than 20 Myr, the oldest deposits thought to have been eroded from the Himalayan metamorphic mountain belt. This constraint on when erosion began has influenced models of the timing and diachrony of the India-Eurasia collision(6-8), timing and mechanisms of exhumation(9,10) and uplift(11), as well as our general understanding of foreland basin dynamics(12). But the depositional age of these basin sediments was based on biostratigraphy from four intercalated marl units(5). Here we present dates of 257 detrital grains of white mica from this succession, using the Ar-40-(39) Ar method, and find that the largest concentration of ages are at 36-40 Myr. These dates are incompatible with the biostratigraphy unless the mineral ages have been reset, a possibility that we reject on the basis of a number of lines of evidence. A more detailed mapping of this formation suggests that the marl units are structurally intercalated with the continental sediments and accordingly that biostratigraphy cannot be used to date the clastic succession. The oldest continental foreland basin sediments containing metamorphic detritus eroded from the Himalaya orogeny therefore seem to be at least 15-20 Myr younger than previously believed, and models based on the older age must be re-evaluated