Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases

Valuation and estimation from experience

The processing of sequentially presented numerical information is a prerequisite for decisions from experience, where people learn about potential outcomes and their associated probabilities and then make choices between gambles. Little is known, however, about how people's preference for choosing a gamble is affected by how they perceive and process numerical information. To address this, we conducted a series of experiments wherein participants repeatedly sampled numbers from continuous outcome distributions. They were incentivized either to estimate the means of the numbers or to state their minimum selling prices to forgo a consequential draw from the distributions (i.e., the certainty equivalents or valuations). We found that participants valued distributions below their means, valued high-variance sequences lower than low-variance sequences, and valued left-skewed sequences lower than right-skewed sequences. Though less pronounced, similar patterns occurred in the mean estimation task where preferences should not play a role. These results are not consistent with prior findings in decision from experience such as the overweighting of high numbers and the underweighting of rare events. Rather, the qualitative effects, as well as the similarity of effects in valuation and estimation, are consistent with the assumption that people process numbers on a compressed mental number line in valuations from experience

The average laboratory samples a population of 7,300 Amazon Mechanical Turk workers

Using capture-recapture analysis we estimate the effective size of the active Amazon Mechanical Turk (MTurk) population that a typical laboratory can access to be about 7,300 workers. We also estimate that the time taken for half of the workers to leave the MTurk pool and be replaced is about 7 months. Each laboratory has its own population pool which overlaps, often extensively, with the hundreds of other laboratories using MTurk. Our estimate is based on a sample of 114,460 completed sessions from 33,408 unique participants and 689 sessions across seven laboratories in the US, Europe, and Australia from January 2012 to March 2015

Pleistocene Relative Sea Levels in the Chesapeake Bay Region and Their Implications for the Next Century

Today, relative sea-level rise (3.4 mm/yr) is faster in the Chesapeake Bay region than any other location on the Atlantic coast of North America, and twice the global average eustatic rate (1.7 mm/yr). Dated interglacial deposits suggest that relative sea levels in the Chesapeake Bay region deviate from global trends over a range of timescales. Glacio-isostatic adjustment of the land surface from loading and unloading of continental ice is likely responsible for these deviations, but our understanding of the scale and timeframe over which isostatic response operates in this region remains incomplete because dated sea-level proxies are mostly limited to the Holocene and to deposits 80 ka or older. To better understand glacio-isostatic control over past and present relative sea level, we applied a suite of dating methods to the stratigraphy of the Blackwater National Wildlife Refuge, one of the most rapidly subsiding and lowest-elevation surfaces bordering Chesapeake Bay. Data indicate that the region was submerged at least for portions of marine isotope stage (MIS) 3 (ca. 60–30 ka), although multiple proxies suggest that global sea level was 40–80 m lower than present. Today MIS 3 deposits are above sea level because they were raised by the Last Glacial Maximum forebulge, but decay of that same forebulge is causing ongoing subsidence. These results suggest that glacio-isostasy controlled relative sea level in the mid-Atlantic region for tens of thousands of years following retreat of the Laurentide Ice Sheet and continues to influence relative sea level in the region. Thus, isostatically driven subsidence of the Chesapeake Bay region will continue for millennia, exacerbating the effects of global sea-level rise and impacting the region’s large population centers and valuable coastal natural resources

Amplitude equations and pattern selection in Faraday waves

We present a systematic nonlinear theory of pattern selection for parametric surface waves (Faraday waves), not restricted to fluids of low viscosity. A standing wave amplitude equation is derived from the Navier-Stokes equations that is of gradient form. The associated Lyapunov function is calculated for different regular patterns to determine the selected pattern near threshold. For fluids of large viscosity, the selected wave pattern consists of parallel stripes. At lower viscosity, patterns of square symmetry are obtained in the capillary regime (large frequencies). At lower frequencies (the mixed gravity-capillary regime), a sequence of six-fold (hexagonal), eight-fold, ... patterns are predicted. The regions of stability of the various patterns are in quantitative agreement with recent experiments conducted in large aspect ratio systems.Comment: 12 pages, 1 figure, Revte

Wound-up phase turbulence in the Complex Ginzburg-Landau equation

We consider phase turbulent regimes with nonzero winding number in the one-dimensional Complex Ginzburg-Landau equation. We find that phase turbulent states with winding number larger than a critical one are only transients and decay to states within a range of allowed winding numbers. The analogy with the Eckhaus instability for non-turbulent waves is stressed. The transition from phase to defect turbulence is interpreted as an ergodicity breaking transition which occurs when the range of allowed winding numbers vanishes. We explain the states reached at long times in terms of three basic states, namely quasiperiodic states, frozen turbulence states, and riding turbulence states. Justification and some insight into them is obtained from an analysis of a phase equation for nonzero winding number: rigidly moving solutions of this equation, which correspond to quasiperiodic and frozen turbulence states, are understood in terms of periodic and chaotic solutions of an associated system of ordinary differential equations. A short report of some of our results has been published in [Montagne et al., Phys. Rev. Lett. 77, 267 (1996)].Comment: 22 pages, 15 figures included. Uses subfigure.sty (included) and epsf.tex (not included). Related research in http://www.imedea.uib.es/Nonlinea

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice

An accumulating body of evidence demonstrates that radiation therapy can generate adaptive immune responses that contribute to tumor control. However, in the absence of additional immune therapy, the adaptive immune response is insufficient to prevent tumor recurrence or affect distant disease. It has been shown in multiple models that tumor-infiltrating myeloid cells exhibit alternative activation phenotypes and are able to suppress adaptive immune responses, and recent data suggests that the myeloid response in tumors treated with cytotoxic therapy limits tumor control. We hypothesized that tumor myeloid cells inhibit the adaptive immune response after radiation therapy through expression of the enzyme arginase I. Using a myeloid cell-specific deletion of arginase I in mice, we demonstrate an improved tumor control after radiation therapy. However, tumors still recurred despite the conditional knockdown of arginase I. Since multiple alternative factors may combine to inhibit adaptive immunity, we propose that targeting macrophage differentiation may be a more effective strategy than targeting individual suppressive pathways