Inhibiting transthyretin conformational changes that lead to amyloid fibril formation

Insoluble protein fibrils resulting from the self-assembly of a conformational intermediate are implicated as the causative agent in several severe human amyloid diseases, including Alzheimer's disease, familial amyloid polyneuropathy, and senile systemic amyloidosis. The latter two diseases are associated with transthyretin (TTR) amyloid fibrils, which appear to form in the acidic partial denaturing environment of the lysosome. Here we demonstrate that flufenamic acid (Flu) inhibits the conformational changes of TTR associated with amyloid fibril formation. The crystal structure of TTR complexed with Flu demonstrates that Flu mediates intersubunit hydrophobic interactions and intersubunit hydrogen bonds that stabilize the normal tetrameric fold of TTR. A small-molecule inhibitor that stabilizes the normal conformation of a protein is desirable as a possible approach to treat amyloid diseases. Molecules such as Flu also provide the means to rigorously test the amyloid hypothesis, i.e., the apparent causative role of amyloid fibrils in amyloid disease

Surface warming hiatus caused by increased heat uptake across multiple ocean basins

The first decade of the twenty-first century was characterised by a hiatus in global surface warming. Using ocean model hindcasts and reanalyses we show that heat uptake between the 1990s and 2000s increased by 0.7 ± 0.3Wm−2. Approximately 30% of the increase is associated with colder sea surface temperatures in the eastern Pacific. Other basins contribute via reduced heat loss to the atmosphere, in particular the Southern and subtropical Indian Oceans (30%), and the subpolar North Atlantic (40%). A different mechanism is important at longer timescales (1960s-present) over which the Southern Annular Mode trended upwards. In this period, increased ocean heat uptake has largely arisen from reduced heat loss associated with reduced winds over the Agulhas Return Current and southward displacement of Southern Ocean westerlies

Steric sea level variability (1993-2010) in an ensemble of ocean reanalyses and objective analyses

Quantifying the effect of the seawater density changes on sea level variability is of crucial importance for climate change studies, as the sea level cumulative rise can be regarded as both an important climate change indicator and a possible danger for human activities in coastal areas. In this work, as part of the Ocean Reanalysis Intercomparison Project, the global and regional steric sea level changes are estimated and compared from an ensemble of 16 ocean reanalyses and 4 objective analyses. These estimates are initially compared with a satellite-derived (altimetry minus gravimetry) dataset for a short period (2003–2010). The ensemble mean exhibits a significant high correlation at both global and regional scale, and the ensemble of ocean reanalyses outperforms that of objective analyses, in particular in the Southern Ocean. The reanalysis ensemble mean thus represents a valuable tool for further analyses, although large uncertainties remain for the inter-annual trends. Within the extended intercomparison period that spans the altimetry era (1993–2010), we find that the ensemble of reanalyses and objective analyses are in good agreement, and both detect a trend of the global steric sea level of 1.0 and 1.1 ± 0.05 mm/year, respectively. However, the spread among the products of the halosteric component trend exceeds the mean trend itself, questioning the reliability of its estimate. This is related to the scarcity of salinity observations before the Argo era. Furthermore, the impact of deep ocean layers is non-negligible on the steric sea level variability (22 and 12 % for the layers below 700 and 1500 m of depth, respectively), although the small deep ocean trends are not significant with respect to the products spread

VKORC1 Pharmacogenetics and Pharmacoproteomics in Patients on Warfarin Anticoagulant Therapy: Transthyretin Precursor as a Potential Biomarker

Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine. Such changes can be identified by pharmacoproteomics approach based on proteomic technologies. It can also be helpful in matching a particular target-based therapy to a particular marker in a subgroup of patients, in addition to the profile of genetic polymorphism. Warfarin is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease, venous thromboembolism and stroke.We used a combined pharmacogenetics and iTRAQ-coupled LC-MS/MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients, and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin. In addition, real-time RT-PCR, western blotting, human IL-6 ELISA assay were done for the results validation.This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target-based therapies, in matching a particular marker in a subgroup of patients, in addition to the profile of genetic polymorphism

Uncertainties in steric sea level change estimation during the satellite altimeter era: concepts and practices

This article presents a review of current practice in estimating steric sea level change, focussed on the treatment of uncertainty. Steric sea level change is the contribution to the change in sea level arising from the dependence of density on temperature and salinity. It is a significant component of sea level rise and a reflection of changing ocean heat content. However tracking these steric changes remains still a significant challenge for the scientific community. We review the importance of understanding the uncertainty in estimates of steric sea level change. Relevant concepts of uncertainty are discussed and illustrated with the example of observational uncertainty propagation from a single profile of temperature and salinity measurements to steric height. We summarise and discuss the recent literature on methodologies and techniques used to estimate steric sea level in the context of the treatment of uncertainty. Our conclusions are that progress in quantifying steric sea level uncertainty will benefit from: greater clarity and transparency in published discussions of uncertainty, including exploitation of international standards for quantifying and expressing uncertainty in measurement; and the development of community ‘recipes’ for quantifying the error covariances in observations and from sparse sampling, and for estimating and propagating uncertainty across spatio-temporal scales

Recent progress in understanding and projecting regional and global mean sea-level change

Considerable progress has been made in understanding the present and future regional and global sea level in the 2 years since the publication of the Fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. Here, we evaluate how the new results affect the AR5’s assessment of (i) historical sea level rise, including attribution of that rise and implications for the sea level budget, (ii) projections of the components and of total global mean sea level (GMSL), and (iii) projections of regional variability and emergence of the anthropogenic signal. In each of these cases, new work largely provides additional evidence in support of the AR5 assessment, providing greater confidence in those findings. Recent analyses confirm the twentieth century sea level rise, with some analyses showing a slightly smaller rate before 1990 and some a slightly larger value than reported in the AR5. There is now more evidence of an acceleration in the rate of rise. Ongoing ocean heat uptake and associated thermal expansion have continued since 2000, and are consistent with ocean thermal expansion reported in the AR5. A significant amount of heat is being stored deeper in the water column, with a larger rate of heat uptake since 2000 compared to the previous decades and with the largest storage in the Southern Ocean. The first formal detection studies for ocean thermal expansion and glacier mass loss since the AR5 have confirmed the AR5 finding of a significant anthropogenic contribution to sea level rise over the last 50 years. New projections of glacier loss from two regions suggest smaller contributions to GMSL rise from these regions than in studies assessed by the AR5; additional regional studies are required to further assess whether there are broader implications of these results. Mass loss from the Greenland Ice Sheet, primarily as a result of increased surface melting, and from the Antarctic Ice Sheet, primarily as a result of increased ice discharge, has accelerated. The largest estimates of acceleration in mass loss from the two ice sheets for 2003–2013 equal or exceed the acceleration of GMSL rise calculated from the satellite altimeter sea level record over the longer period of 1993–2014. However, when increased mass gain in land water storage and parts of East Antarctica, and decreased mass loss from glaciers in Alaska and some other regions are taken into account, the net acceleration in the ocean mass gain is consistent with the satellite altimeter record. New studies suggest that a marine ice sheet instability (MISI) may have been initiated in parts of the West Antarctic Ice Sheet (WAIS), but that it will affect only a limited number of ice streams in the twenty-first century. New projections of mass loss from the Greenland and Antarctic Ice Sheets by 2100, including a contribution from parts of WAIS undergoing unstable retreat, suggest a contribution that falls largely within the likely range (i.e., two thirds probability) of the AR5. These new results increase confidence in the AR5 likely range, indicating that there is a greater probability that sea level rise by 2100 will lie in this range with a corresponding decrease in the likelihood of an additional contribution of several tens of centimeters above the likely range. In view of the comparatively limited state of knowledge and understanding of rapid ice sheet dynamics, we continue to think that it is not yet possible to make reliable quantitative estimates of future GMSL rise outside the likely range. Projections of twenty-first century GMSL rise published since the AR5 depend on results from expert elicitation, but we have low confidence in conclusions based on these approaches. New work on regional projections and emergence of the anthropogenic signal suggests that the two commonly predicted features of future regional sea level change (the increasing tilt across the Antarctic Circumpolar Current and the dipole in the North Atlantic) are related to regional changes in wind stress and surface heat flux. Moreover, it is expected that sea level change in response to anthropogenic forcing, particularly in regions of relatively low unforced variability such as the low-latitude Atlantic, will be detectable over most of the ocean by 2040. The east-west contrast of sea level trends in the Pacific observed since the early 1990s cannot be satisfactorily accounted for by climate models, nor yet definitively attributed either to unforced variability or forced climate change

Vigorous lateral export of the meltwater outflow from beneath an Antarctic ice shelf

The instability and accelerated melting of the Antarctic Ice Sheet are among the foremost elements of contemporary global climate change1, 2. The increased freshwater output from Antarctica is important in determining sea level rise1, the fate of Antarctic sea ice and its effect on the Earth’s albedo4, 5, ongoing changes in global deep-ocean ventilation6, and the evolution of Southern Ocean ecosystems and carbon cycling7, 8. A key uncertainty in assessing and predicting the impacts of Antarctic Ice Sheet melting concerns the vertical distribution of the exported meltwater. This is usually represented by climate-scale models3–5, 9 as a near-surface freshwater input to the ocean, yet measurements around Antarctica reveal the meltwater to be concentrated at deeper levels10, 11, 12, 13, 14. Here we use observations of the turbulent properties of the meltwater outflows from beneath a rapidly melting Antarctic ice shelf to identify the mechanism responsible for the depth of the meltwater. We show that the initial ascent of the meltwater outflow from the ice shelf cavity triggers a centrifugal overturning instability that grows by extracting kinetic energy from the lateral shear of the background oceanic flow. The instability promotes vigorous lateral export, rapid dilution by turbulent mixing, and finally settling of meltwater at depth. We use an idealized ocean circulation model to show that this mechanism is relevant to a broad spectrum of Antarctic ice shelves. Our findings demonstrate that the mechanism producing meltwater at depth is a dynamically robust feature of Antarctic melting that should be incorporated into climate-scale models

Causes of the regional variability in observed sea level, sea surface temperature and ocean colour over the period 1993-2011

We analyse the regional variability in observed sea surface height (SSH), sea surface temperature (SST) and ocean colour (OC) from the ESA Climate Change Initiative (CCI) datasets over the period 1993-2011. The analysis focuses on the signature of the ocean large-scale climate fluctuations driven by the atmospheric forcing and do not address the mesoscale variability. We use the ECCO version 4 ocean reanalysis to unravel the role of ocean transport and surface buoyancy fluxes in the observed SSH, SST and OC variability. We show that the SSH regional variability is dominated by the steric effect (except at high latitude) and is mainly shaped by ocean heat transport divergences with some contributions from the surface heat fluxes forcing that can be significant regionally (confirming earlier results). This is in contrast with the SST regional variability, which is the result of the compensation of surface heat fluxes by ocean heat transport in the mixed layer and arises from small departures around this background balance. Bringing together the results of SSH and SST analyses, we show that SSH and SST bear some common variability. This is because both SSH and SST variability show significant contributions from the surface heat fluxes forcing. It is evidenced by the high correlation between SST and buoyancy forced SSH almost everywhere in the ocean except at high latitude. OC, which is determined by phytoplankton biomass, is governed by the availability of light and nutrients that essentially depend on climate fluctuations. For this reason OC show significant correlation with SST and SSH. We show that the correlation with SST display the same pattern as the correlation with SSH with a negative correlation in the tropics and subtropics and a positive correlation at high latitude. We discuss the reasons for this pattern