Palaeoecology of the Spathian Virgin Formation (Utah, USA) and its implications for the Early Triassic recovery

The Spathian (late Early Triassic) Virgin Formation of south-western Utah (U.S.A.) yields a comparatively diverse benthic fauna that flourished ~2 Ma after the end-Permian mass extinction. In this study, we present quantitative palaeoecological data, which are analysed in the context of their depositional environments. This integrated approach helps to discriminate between effects of the end-Permian mass extinction event and local environmental factors on alpha diversity and ecological structure of the Virgin Fauna. Shallow subtidal environments yield the highest species richness and lowest dominance values as recorded in two benthic associations, the Eumorphotis sp. A Association and the Protogusarella smithi Association, both of which contain 20 benthic species (bivalves, gastropods, brachiopods, echinoderms, and porifers). Tidal inlet deposits yield a low diverse fauna (Piarorhynchella triassica Association) with a very high dominance of filter feeders adapted to high energy conditions. Another comparably low diverse fauna is recorded by the Bakevellia exporrecta Association, which is recorded in deposits of the offshore transition zone, most likely reflecting unconsolidated substrates. A single sample containing five bivalve species (Bakevellia costata Assemblage) is recorded from a marginal-marine setting. The Virgin fauna yields a bulk diversity of 30 benthic species (22 genera) of body fossils and 14 ichnogenera and, thus, represents the most diverse marine bottom fauna known so far from the Early Triassic. Our results suggest that oceanographic conditions during the early Spathian enabled ecosystems to rediversify without major abiotic limitations. However, taxonomical differentiation between habitats was still low, indicating a time lag between increasing within-habitat diversity (alpha diversity) and the onset of taxonomical differentiation between habitats (beta diversity). We suggest that taxonomical habitat differentiation after mass extinction events starts only when within-habitat competition exceeds a certain threshold, which was not yet reached in the Spathian of the investigated area. This interpretation is an alternative to previous suggestions that the prevalence of generalistic taxa in the aftermath of mass extinction events reflects protracted environmental stress. The onset of increasing beta diversity is a potential criterion for distinguishing two major recovery phases, the first ending with habitat saturation and the second ending with the completion of ecosystem differentiation

The [Het-s] Prion, an Amyloid Fold as a Cell Death Activation Trigger

International audienc

Cleavage Fracture of Brittle Semiconductors from the Nanometer to the Centimeter Scale

The objective of this paper is to present the fundamental phenomena occurring during the scribing and subsequent fracturing process usually performed when preparing surfaces of brittle semiconductors. In the first part, an overview of nano-scratching experiments of different semiconductor surfaces (InP, Si and GaAs) is given. It is shown how phase transformation can occur in Si under a diamond tip, how single dislocations can be induced in InP wafers and how higher scratching load of GaAs wafer leads to the apparition of a crack network below the surface. A nano-scratching device, inside a scanning electron microscope (SEM), has been used to observe how spalling (crack and detachment of chips) and/or ductile formation of chips may happen at the semiconductor surface. In the second part cleavage experiments are described. The breaking load of thin GaAs (100) wafers is directly related to the presence of initial sharp cracks induced by scratching. By performing finite element modelling (FEM) of samples under specific loading conditions, it is found that the depth of the median crack below the scratch determines quantitatively the onset of crack propagation. By carefully controlling the position and measuring the force during the cleavage, it is demonstrated that crack propagation through a wafer can be controlled. Besides, the influence of the loading configuration on crack propagation and on the cleaved surface quality is explained. © 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K.

PMCID: PMC3591419This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Parkinson's disease (PD) is pathologically characterized by the presence of Lewy bodies (LBs) in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS), a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT) protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils

Self-assembled amyloid fibrils with controllable conformational heterogeneity

Amyloid fibrils are a hallmark of neurodegenerative diseases and exhibit a conformational diversity that governs their pathological functions. Despite recent findings concerning the pathological role of their conformational diversity, the way in which the heterogeneous conformations of amyloid fibrils can be formed has remained elusive. Here, we show that microwave-assisted chemistry affects the self-assembly process of amyloid fibril formation, which results in their conformational heterogeneity. In particular, microwave-assisted chemistry allows for delicate control of the thermodynamics of the self-assembly process, which enabled us to tune the molecular structure of ??-lactoglobulin amyloid fibrils. The heterogeneous conformations of amyloid fibrils, which can be tuned with microwave-assisted chemistry, are attributed to the microwave-driven thermal energy affecting the electrostatic interaction during the self-assembly process. Our study demonstrates how microwave-assisted chemistry can be used to gain insight into the origin of conformational heterogeneity of amyloid fibrils as well as the design principles showing how the molecular structures of amyloid fibrils can be controlledopen0

Targeting CD47 in Anaplastic Thyroid Carcinoma Enhances Tumor Phagocytosis by Macrophages and Is a Promising Therapeutic Strategy.

Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human cancers, with a median survival of only three to six months. Standard treatment options and even targeted therapies have so far failed to improve long-term overall survival. Thus, novel treatment modalities for ATC, such as immunotherapy, are urgently needed. CD47 is a "don't eat me" signal, which prevents cancer cells from phagocytosis by binding to signal regulatory protein alpha on macrophages. So far, the role of macrophages and the CD47-signal regulatory protein alpha signaling axis in ATC is not well understood. Methods: This study analyzed 19 primary human ATCs for macrophage markers, CD47 expression, and immune checkpoints by immunohistochemistry. ATC cell lines and a fresh ATC sample were assessed by flow cytometry for CD47 expression and macrophage infiltration, respectively. CD47 was blocked in phagocytosis assays of co-cultured macrophages and ATC cell lines. Anti-CD47 antibody treatment was administered to ATC cell line xenotransplanted immunocompromised mice, as well as to tamoxifen-induced ATC double-transgenic mice. Results: Human ATC samples were heavily infiltrated by CD68- and CD163-expressing tumor-associated macrophages (TAMs), and expressed CD47 and calreticulin, the dominant pro-phagocytic molecule. In addition, ATC tissues expressed the immune checkpoint molecules programmed cell death 1 and programmed death ligand 1. Blocking CD47 promoted the phagocytosis of ATC cell lines by macrophages in vitro. Anti-CD47 antibody treatment of ATC xenotransplanted mice increased the frequency of TAMs, enhanced the expression of macrophage activation markers, augmented tumor cell phagocytosis, and suppressed tumor growth. In double-transgenic ATC mice, CD47 was expressed on tumor cells, and blocking CD47 increased TAM frequencies. Conclusions: Targeting CD47 or CD47 in combination with programmed cell death 1 may potentially improve the outcomes of ATC patients and may represent a valuable addition to the current standard of care

Fractional deuteration applied to biomolecular solid-state NMR spectroscopy

Solid-state Nuclear Magnetic Resonance can provide detailed insight into structural and dynamical aspects of complex biomolecules. With increasing molecular size, advanced approaches for spectral simplification and the detection of medium to long-range contacts become of critical relevance. We have analyzed the protonation pattern of a membrane-embedded ion channel that was obtained from bacterial expression using protonated precursors and D2O medium. We find an overall reduction of 50% in protein protonation. High levels of deuteration at Hα and Hβ positions reduce spectral congestion in (1H,13C,15N) correlation experiments and generate a transfer profile in longitudinal mixing schemes that can be tuned to specific resonance frequencies. At the same time, residual protons are predominantly found at amino-acid side-chain positions enhancing the prospects for obtaining side-chain resonance assignments and for detecting medium to long-range contacts. Fractional deuteration thus provides a powerful means to aid the structural analysis of complex biomolecules by solid-state NMR

Inter-Allelic Prion Propagation Reveals Conformational Relationships among a Multitude of [PSI] Strains

Immense diversity of prion strains is observed, but its underlying mechanism is less clear. Three [PSI] prion strains—named VH, VK, and VL—were previously isolated in the wild-type yeast genetic background. Here we report the generation and characterization of eight new [PSI] isolates, obtained by propagating the wild-type strains with Sup35 proteins containing single amino-acid alterations. The VH strain splits into two distinct strains when propagated in each of the three genetic backgrounds, harboring respectively single mutations of N21L, R28P, and Gi47 (i.e. insertion of a glycine residue at position 47) on the Sup35 N-terminal prion-forming segment. The six new strains exhibit complex inter-conversion patterns, and one of them continuously mutates into another. However, when they are introduced back into the wild-type background, all 6 strains revert to the VH strain. We obtain two more [PSI] isolates by propagating VK and VL with the Gi47 and N21L backgrounds, respectively. The two isolates do not transmit to other mutant backgrounds but revert to their parental strains in the wild-type background. Our data indicate that a large number of [PSI] strains can be built on three basic Sup35 amyloid structures. It is proposed that the three basic structures differ by chain folding topologies, and sub-strains with the same topology differ in distinct ways by local structural adjustments. This “large number of variations on a small number of basic themes” may also be operative in generating strain diversities in other prion elements. It thus suggests a possible general scheme to classify a multitude of prion strains