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

Measuring global ocean heat content to estimate the earth energy imbalance

The energy radiated by the Earth toward space does not compensate the incoming radiation from the Sun leading to a small positive energy imbalance at the top of the atmosphere (0.4–1 Wm–2). This imbalance is coined Earth’s Energy Imbalance (EEI). It is mostly caused by anthropogenic greenhouse gas emissions and is driving the current warming of the planet. Precise monitoring of EEI is critical to assess the current status of climate change and the future evolution of climate. But the monitoring of EEI is challenging as EEI is two orders of magnitude smaller than the radiation fluxes in and out of the Earth system. Over 93% of the excess energy that is gained by the Earth in response to the positive EEI accumulates into the ocean in the form of heat. This accumulation of heat can be tracked with the ocean observing system such that today, the monitoring of Ocean Heat Content (OHC) and its long-term change provide the most efficient approach to estimate EEI. In this community paper we review the current four state-of-the-art methods to estimate global OHC changes and evaluate their relevance to derive EEI estimates on different time scales. These four methods make use of: (1) direct observations of in situ temperature; (2) satellite-based measurements of the ocean surface net heat fluxes; (3) satellite-based estimates of the thermal expansion of the ocean and (4) ocean reanalyses that assimilate observations from both satellite and in situ instruments. For each method we review the potential and the uncertainty of the method to estimate global OHC changes. We also analyze gaps in the current capability of each method and identify ways of progress for the future to fulfill the requirements of EEI monitoring. Achieving the observation of EEI with sufficient accuracy will depend on merging the remote sensing techniques with in situ measurements of key variables as an integral part of the Ocean Observing System

Expedition 381 Summary

The primary objective of International Ocean Discovery Program Expedition 381 was to retrieve a record of early continental rifting and basin evolution from the Corinth rift, central Greece. Continental rifting is fundamental for the formation of ocean basins, and active rift zones are dynamic regions of high geohazard potential. However, the detailed spatial and temporal evolution of a complete rift system needed to understand rift development from the fault to plate scale is poorly resolved. In the active Corinth rift, deformation rates are high, the recent synrift succession is preserved and complete offshore, and earlier rift phases are preserved onshore. Additionally, a dense seismic database provides high-resolution imaging of the fault network and seismic stratigraphy around the basin. As the basin has subsided, its depositional environment has been affected by fluctuating global sea level and its absolute position relative to sea level, and the basin sediments record this changing environment through time. In Corinth, we can therefore achieve an unprecedented precision of timing and spatial complexity of rift-fault system development, rift-controlled drainage system evolution, and basin fill in the first few million years of rift history. The following are the expedition themes: High-resolution fault slip and rift evolution history, Surface processes in active rifts, High-resolution late Quaternary Eastern Mediterranean paleoclimate and paleoenvironment of a developing rift basin, and Geohazard assessment in an active rift. These objectives were and will be accomplished as a result of successful drilling, coring, and logging at three sites in the Gulf of Corinth, which collectively yielded 1645 m of recovered core over a 1905 m cored interval. Together, these cores provide (1) a long rift history (Sites M0078 and M0080), (2) a high-resolution record of the most recent phase of rifting (Site M0079), and (3) the spatial variation of rift evolution (comparison of sites in the central and eastern rift). The sediments contain a rich and complex record of changing sedimentation, sediment and pore water geochemistry, and environmental conditions from micropaleontological assemblages. The preliminary chronology developed by shipboard analyses will be refined and improved during postexpedition research, providing a high-resolution chronostratigraphy down to the orbital timescale for a range of tectonic, sedimentological, and paleoenvironmental studies. This chronology will provide absolute timing of key rift events, rates of fault movement, rift extension and subsidence, and the spatial variations of these parameters. The core data will also allow us to investigate the relative roles of and feedbacks between tectonics, climate, and eustasy in sediment flux, basin evolution, and basin environment. Finally, the Corinth rift boreholes will provide the first long Quaternary record of Mediterranean-type climate in the region. The potential range of scientific applications for this unique data set is very large, encompassing tectonics, sedimentary processes, paleoenvironment, paleoclimate, paleoecology, geochemistry, and geohazards

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

Exploring deep microbial life in coal-bearing sediment down to ~2.5 km below the ocean floor

Peer reviewedPostprin