The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils

The 17-residue N-terminus (httNT) directly flanking the polyQ sequence in huntingtin (htt) N-terminal fragments plays a crucial role in initiating and accelerating the aggregation process that is associated with Huntington's disease pathogenesis. Here we report on magic-angle-spinning solid-state NMR studies of the amyloid-like aggregates of an htt N-terminal fragment. We find that the polyQ portion of this peptide exists in a rigid, dehydrated amyloid core that is structurally similar to simpler polyQ fibrils and may contain antiparallel β-sheets. In contrast, the httNT sequence in the aggregates is composed in part of a well-defined helix, which likely also exists in early oligomeric aggregates. Further NMR experiments demonstrate that the N-terminal helical segment displays increased dynamics and water exposure. Given its specific contribution to the initiation, rate, and mechanism of fibril formation, the helical nature of httNT and its apparent lack of effect on the polyQ fibril core structure seem surprising. The results provide new details about these disease-associated aggregates and also provide a clear example of an amino acid sequence that greatly enhances the rate of amyloid formation while itself not taking part in the amyloid structure. There is an interesting mechanistic analogy to recent reports pointing out the early-stage contributions of transient intermolecular helix-helix interactions in the aggregation behavior of various other amyloid fibrils. © 2011 American Chemical Society

Amyloid-like fibrils from a domain-swapping protein feature a parallel, in-register conformation without native-like interactions

The formation of amyloid-like fibrils is characteristic of various diseases, but the underlying mechanism and the factors that determine whether, when, and how proteins form amyloid, remain uncertain. Certain mechanisms have been proposed based on the three-dimensional or runaway domain swapping, inspired by the fact that some proteins show an apparent correlation between the ability to form domain-swapped dimers and a tendency to form fibrillar aggregates. Intramolecular β-sheet contacts present in the monomeric state could constitute intermolecular β-sheets in the dimeric and fibrillar states. One example is an amyloid-forming mutant of the immunoglobulin binding domain B1 of streptococcal protein G, which in its native conformation consists of a four-stranded β-sheet and one α-helix. Under native conditions this mutant adopts a domainswapped dimer, and it also forms amyloid-like fibrils, seemingly in correlation to its domain-swapping ability. We employ magic angle spinning solid-state NMR and other methods to examine key structural features of these fibrils. Our results reveal a highly rigid fibril structure that lacks mobile domains and indicate a parallel in-register β-sheet structure and a general loss of native conformation within the mature fibrils. This observation contrasts with predictions that native structure, and in particular intermolecular β-strand interactions seen in the dimeric state, may be preserved in "domain-swapping" fibrils. We discuss these observations in light of recent work on related amyloidforming proteins that have been argued to follow similar mechanisms and how this may have implications for the role of domain-swapping propensities for amyloid formation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc

A Novel Application of Time Reversed Acoustics: Salt Dome Flank Imaging Using Walk Away VSP Surveys

In the past few years, there has been considerable research and interest in a topic known by various names, such as Time Reverse Acoustics (TRA), Time Reverse Mirrors (TRM), and Time Reverse Cavities (TRC), which exploits reciprocity and the time symmetric property of the wave equation. Very little of this work has been directed at the seismic exploration imaging problem. In fact, most of the work has had application in sonar, medical and non-destructive testing applications. Here we present some initial results of applying this technology to the seismic imaging of a salt dome flank. We create a set of synthetic traces representing a multi-level, walk away VSP for a model composed of a simplified Gulf of Mexico vertical velocity gradient and an embedded overhanging salt dome. To process these data, we first apply the concepts of TRA to the synthetic traces. This creates a set of stacked traces without having to perform any velocity analysis or complicated processing. Each of these stacked traces is equivalent to the output of a spatially coincident, or zero offset, down hole source and receiver pair. Thus we have the equivalent of a zero offset seismic section as if it were collected from down hole sources and receivers. After having applied the TRA concepts, we then apply conventional post stack depth migration to this zero offset section to produce the final image of the salt dome flank. Our results show a very good image of the salt. In fact, the image created is nearly identical to an image actually using data from down hole, zero offset source and receiver pairs. The simplicity of the TRA implementation provides a virtually automated method to create a stacked section as if it had been collected from the reference frame of the borehole containing the VSP survey.Massachusetts Institute of Technology. Earth Resources Laborator

Factors affecting metal mobilisation during oxidation of sulphidic, sandy wetland substrates

Most metals accumulate as sulphides under anoxic conditions in wetland substrates, reducing their bioavailability due to the solubility of metal sulphides. However, upon oxidation of these sulphides when the substrate is occasionally oxidised, metals can be released from the solid phase to the pore water or overlaying surface water. This release can be affected by the presence of carbonates, organic matter and clay. We compared changes of Cd, Cu and Zn mobility (CaCl2 extraction) during oxidation of a carbonate-rich and a carbonate-poor sulphidic, sandy wetland substrate. In addition, we studied how clay with low and high cation sorption capacity (bentonite and kaolinite, respectively) and organic matter (peat) can counteract Cd, Cu and Zn release during oxidation of both carbonate-rich and carbonate-poor sulphidic sediments. CaCl2-extractability of Cu, a measure for its availability, is low in both carbonate-poor and carbonate-rich substrates, whereas its variability is high. The availability of Cd and Zn is much higher and increases when peat is supplied to carbonate-poor substrates. A strong reduction of Cd and Zn extractability is observed when clay is added to carbonate-poor substrates. This reduction depends on the clay type. Most observations could be explained taking into account pH differences between treatments, with kaolinite resulting in a lower pH in comparison to bentonite. These pH differences affect the presence and characteristics of dissolved organic carbon and the metal speciation, which in turns affects the interaction of metals with the solid soil phase. In carbonate-rich substrates, Cd and Zn availability is lower and the effects of peat and clay amendment are less clear. The latter can also be attributed to the high pH and lack of pH differences between treatments

Huntingtin exon 1 fibrils feature an interdigitated β-hairpin-based polyglutamine core

Polyglutamine expansion within the exon1 of huntingtin leads to protein misfolding, aggregation, and cytotoxicity in Huntington’s Disease. This incurable neurodegenerative disease is the most prevalent member of a family of CAG repeat expansion disorders. Although mature exon1 fibrils are viable candidates for the toxic species, their molecular structure and how they form have remained poorly understood. Using advanced magic angle spinning solid state NMR, we directly probe the structure of the rigid core that is at the heart of huntingtin exon1 fibrils and other polyglutamine aggregates, via measurements of long-range intra- and inter-molecular contacts, backbone and side chain torsion angles, relaxation measurements, and calculations of chemical shifts. These reveal the presence of β-hairpin-containing β-sheets that are connected through interdigitating extended side chains. Despite dramatic differences in aggregation behavior, huntingtin exon1 fibrils and other polyglutamine-based aggregates contain identical β-strand-based cores. Prior structural models, derived from X-ray fiber diffraction and computational analyses, are shown to be inconsistent with the solid-state NMR results. Internally, the polyglutamine amyloid fibrils are co-assembled from differently structured monomers, which we describe as a type of ‘intrinsic’ polymorphism. A stochastic polyglutamine-specific aggregation mechanism is introduced to explain this phenomenon. Weshow that the aggregation of mutant huntingtin exon1 proceeds via an intramolecular collapse of the expanded polyglutamine domain, and discuss the implications of this observation for our understanding of its misfolding and aggregation mechanisms

A global Carleman estimate in a transmission wave equation and application to a one-measurement inverse problem

We consider a transmission wave equation in two embedded domains in $R^2$, where the speed is $a1 > 0$ in the inner domain and $a2 > 0$ in the outer domain. We prove a global Carleman inequality for this problem under the hypothesis that the inner domain is strictly convex and $a1 > a2$ . As a consequence of this inequality, uniqueness and Lip- schitz stability are obtained for the inverse problem of retrieving a stationary potential for the wave equation with Dirichlet data and discontinuous principal coefficient from a single time-dependent Neumann boundary measurement

Rebuttal to published article “A review of ghost gear entanglement amongst marine mammals, reptiles and elasmobranchs” by M. Stelfox, J. Hudgins, and M. Sweet

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here under a nonexclusive, irrevocable, paid-up, worldwide license granted to WHOI. It is made available for personal use, not for redistribution. The definitive version was published in Marine Pollution Bulletin 117 (2017): 554-555, doi:10.1016/j.marpolbul.2016.11.052.We reviewed the findings of the recently published article by Stelfox et al. (2016): “A review of ghost gear entanglement amongst marine mammals, reptiles and elasmobranchs” published in this journal (Volume 111, pp 6–17) and found that they are both flawed and misleading as they do not accurately reflect the prevalence of “ghost gear” cases reported in the literature. While we commend the authors for recognizing the importance of attempting to quantify the threat and for recommending more comprehensive databases, the methods, results and conclusions of this review have not advanced the understanding of the issue. As authors of the papers on whale entanglements in the North Atlantic that were reviewed by Stelfox et al. (2016) and others who are knowledgeable about the topic, we provide specific comments regarding misrepresentations of both the source of entanglement (e.g., actively fished gear versus “ghost gear”) and the number of reported entanglements for whale species included in the North Atlantic

Don’t assume it’s ghost gear : accurate gear characterization is critical for entanglement mitigation [poster]

Presented at the Society for Marine Mammology 22nd Biennial Marine Mammal Conference, Halifax, Nova Scotia, October 23-27, 2017Entanglement is a significant conservation and welfare issue which is limiting the recovery of a number of marine species, including marine mammals. It is therefore important to reliably identify the causes of these events, including the nature of the entangling gear in order to reduce or prevent them in the future. A recently published review of marine debris assessed 76 publications and attributed a total of 1805 cases of cetacean entanglements in “ghost gear”, of which 78% (n=1413) were extracted from 13 peer reviewed publications. We examined the 13 publications cited in the review and found that the specific gear type or status of gear involved in the reported events was rarely mentioned beyond the fact that it was fishing related. This is likely due to the fact that determinations of debris as the entangling material are very difficult. In fact, in reviewing 10 years of large whale entanglement records for the U.S., the authors of another study reported that Hawaii was the only region in which any entangling gear was positively identified as ghost gear. The assumption that entangling gear is marine debris unless otherwise stated is dangerous because it could impact efforts to modify or restrict risk-prone fishing in key marine mammal habitats. Entanglement in actively fished gear poses a very real threat, and claims that only lost or abandoned fishing gear is responsible for entanglements can undermine conservation efforts.2017-10-2

Generalized Fourier Integral Operators on spaces of Colombeau type

Generalized Fourier integral operators (FIOs) acting on Colombeau algebras are defined. This is based on a theory of generalized oscillatory integrals (OIs) whose phase functions as well as amplitudes may be generalized functions of Colombeau type. The mapping properties of these FIOs are studied as the composition with a generalized pseudodifferential operator. Finally, the microlocal Colombeau regularity for OIs and the influence of the FIO action on generalized wave front sets are investigated. This theory of generalized FIOs is motivated by the need of a general framework for partial differential operators with non-smooth coefficients and distributional data

Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel

Background: Treatment selection for men with metastatic castration-resistant prostate cancer (mCRPC) has become increasingly challenging with the introduction of novel therapies at earlier disease stages. The purpose of this study was to identify prognostic factors for overall survival (OS) and PSA response in patients with mCRPC treated with cabazitaxel. Results: 224 mCRPC patients were included in the current analysis. In multivariable analysis, WHO performance status, baseline hemoglobin, alkaline phosphatase and albumin were all significantly associated with OS. Hemoglobin and alkaline phosphatase were significantly associated with PSA response. Conclusions: This study identified prognostic factors for OS and PSA response of men with mCRPC treated with cabazitaxel. In an increasingly complicated treatment landscape with several treatment options available our findings might serve to estimate the chance of survival of men qualifying for treatment with second-line chemotherapy in daily practice. Furthermore, these data can be used to risk-stratify patients in clinical trials. Methods: We performed a post-hoc analysis of a randomized phase II trial of mCRPC patients treated with cabazitaxel. Cox and logistic regression models were used to investigate the influence of clinical and biochemical variables on OS and PSA response. Nomograms were developed to estimate the chance of PSA response and OS