The architecture of amyloid-like peptide fibrils revealed by X-ray scattering, diffraction and electron microscopy

Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the GNNQQNY peptide fragment of a yeast prion protein. Data from small-angle X-ray solution scattering, fibre diffraction and electron microscopy are combined with existing high-resolution X-ray crystallographic structures to investigate the fibrillation process and the hierarchical fibril structure of the peptide fragment. The elongation of these fibrils proceeds without the accumulation of any detectable amount of intermediate oligomeric species, as is otherwise reported for, for example, glucagon, insulin and [alpha]-synuclein. Ribbons constituted of linearly arranged protofilaments are formed. An additional hierarchical layer is generated via the pairing of ribbons during fibril maturation. Based on the complementary data, a quasi-atomic resolution model of the protofilament peptide arrangement is suggested. The peptide structure appears in a [beta]-sheet arrangement reminiscent of the [beta]-zipper structures evident from high-resolution crystal structures, with specific differences in the relative peptide orientation. The complexity of protein fibrillation and structure emphasizes the need to use multiple complementary methods

Structure of the Dead Sea Pull-Apart Basin From Gravity Analyses

Analyses and modeling of gravity data in the Dead Sea pull-apart basin reveal the geometry of the basin and constrain models for its evolution. The basin is located within a valley which defines the Dead Sea transform plate boundary between Africa and Arabia. Three hundred kilometers of continuous marine gravity data, collected in a lake occupying the northern part of the basin, were integrated with land gravity data from Israel and Jordan to provide coverage to 30 km either side of the basin. Free-air and variable-density Bouguer anomaly maps, a horizontal first derivative map of the Bouguer anomaly, and gravity models of profiles across and along the basin were used with existing geological and geophysical information to infer the structure of the basin. The basin is a long (132 km), narrow (7-10 km), and deep (≤10 km) full graben which is bounded by subvertical faults along its long sides. The Bouguer anomaly along the axis of the basin decreases gradually from both the northern and southern ends, suggesting that the basin sags toward the center and is not bounded by faults at its narrow ends. The surface expression of the basin is wider at its center (≤16 km) and covers the entire width of the transform valley due to the presence of shallower blocks that dip toward the basin. These blocks are interpreted to represent the widening of the basin by a passive collapse of the valley floor as the full graben deepened. The collapse was probably facilitated by movement along the normal faults that bound the transform valley. We present a model in which the geometry of the Dead Sea basin (i.e., full graben with relative along-axis symmetry) may be controlled by stretching of the entire (brittle and ductile) crust along its long axis. There is no evidence for the participation of the upper mantle in the deformation of the basin, and the Moho is not significantly elevated. The basin is probably close to being isostatically uncompensated, and thermal effects related to stretching are expected to be minimal. The amount of crustal stretching calculated from this model is 21 km and the stretching factor is 1.19. If the rate of crustal stretching is similar to the rate of relative plate motion (6 mm/yr), the basin should be ~3.5 m.y. old, in accord with geological evidence

Rupture by damage accumulation in rocks

The deformation of rocks is associated with microcracks nucleation and propagation, i.e. damage. The accumulation of damage and its spatial localization lead to the creation of a macroscale discontinuity, so-called "fault" in geological terms, and to the failure of the material, i.e. a dramatic decrease of the mechanical properties as strength and modulus. The damage process can be studied both statically by direct observation of thin sections and dynamically by recording acoustic waves emitted by crack propagation (acoustic emission). Here we first review such observations concerning geological objects over scales ranging from the laboratory sample scale (dm) to seismically active faults (km), including cliffs and rock masses (Dm, hm). These observations reveal complex patterns in both space (fractal properties of damage structures as roughness and gouge), time (clustering, particular trends when the failure approaches) and energy domains (power-law distributions of energy release bursts). We use a numerical model based on progressive damage within an elastic interaction framework which allows us to simulate these observations. This study shows that the failure in rocks can be the result of damage accumulation

A novel syndrome of paediatric cataract, dysmorphism, ectodermal features, and developmental delay in Australian Aboriginal family maps to 1p35.3-p36.32

Background: A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family.Methods: Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations. Results: Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. Conclusions: The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.Kathryn Hattersley, Kate J Laurie, Jan E Liebelt, Jozef Gecz, Shane R Durkin, Jamie E Craig and Kathryn P Burdo

Rise and Fall of a Multi-sheet Intrusive Complex, Elba Island, Italy

Elba Island intrusive complex: multisheet laccoliths, sheeted pluton, mafic dyke swarm. Laccolith magma fed from dykes and emplaced in crustal discontinuities (traps). Pluton growth by downward stacking of three magma pulses. Laccoliths and plutons: different outcomes of similar processes in different conditions. Emplacement of excess magma in a short time led to massive gravity slide

Multiphoton absorption in amyloid protein fibres

Fibrillization of peptides leads to the formation of amyloid fibres, which, when in large aggregates, are responsible for diseases such as Alzheimer's and Parkinson's. Here, we show that amyloids have strong nonlinear optical absorption, which is not present in native non-fibrillized protein. Z-scan and pump-probe experiments indicate that insulin and lysozyme β-amyloids, as well as α-synuclein fibres, exhibit either two-photon, three-photon or higher multiphoton absorption processes, depending on the wavelength of light. We propose that the enhanced multiphoton absorption is due to a cooperative mechanism involving through-space dipolar coupling between excited states of aromatic amino acids densely packed in the fibrous structures. This finding will provide the opportunity to develop nonlinear optical techniques to detect and study amyloid structures and also suggests that new protein-based materials with sizable multiphoton absorption could be designed for specific applications in nanotechnology, photonics and optoelectronics

Amyloid as a Depot for the Formulation of Long-Acting Drugs

Amyloids are highly organized protein aggregates that are associated with both neurodegenerative diseases such as Alzheimer disease and benign functions like skin pigmentation. Amyloids self-polymerize in a nucleation-dependent manner by recruiting their soluble protein/peptide counterpart and are stable against harsh physical, chemical, and biochemical conditions. These extraordinary properties make amyloids attractive for applications in nanotechnology. Here, we suggest the use of amyloids in the formulation of long-acting drugs. It is our rationale that amyloids have the properties required of a long-acting drug because they are stable depots that guarantee a controlled release of the active peptide drug from the amyloid termini. This concept is tested with a family of short- and long-acting analogs of gonadotropin-releasing hormone (GnRH), and it is shown that amyloids thereof can act as a source for the sustained release of biologically active peptides

Effects of crystallographic anisotropy on fracture development and acoustic emission in quartz

Transgranular microcracking is fundamental for the initiation and propagation of all fractures in rocks. The geometry of these microcracks is primarily controlled by the interaction of the imposed stress field with the mineral elastic properties. However, the effects of anisotropic elastic properties of minerals on brittle fracture are not well understood. This study examines the effects of elastic anisotropy of quartz on the geometry of brittle fracture and related acoustic emissions (AE) developed during indentation experiments on single crystals at ambient pressure and temperature. A Hertzian cone crack developed during blunt indentation of a single crystal of flawless Brazilian quartz parallel to the c axis shows geometric deviation away from predictions based on the isotropic case, consistent with trigonal symmetry. The visible cone crack penetration depth varies from 3 to 5 mm and apical angle from 53 to 40. Electron backscatter diffraction (EBSD) mapping of the crack tip shows that fracturing initiates along a ~40 μm wide process zone, comprising damage along overlapping en echelon high-index crystallographic planes, shown by discrete bands of reduced electron backscatter pattern (EBSP) quality (band contrast).Coalescence of these surfaces results in a stepped fracture morphology. Monitoring of AE during indentation reveals that the elastic anisotropy of quartz has a significant effect on AE location and focal mechanisms. Ninety-four AE events were recorded during indentation and show an increasing frequency with increasing load. They correspond to the development of subsidiary concentric cracks peripheral to the main cone crack. The strong and complex anisotropy in seismic velocity (~28% Vp, ~43% Vs with trigonal symmetry) resulted in inaccurate and high uncertainty in AE locations using Geiger location routine with an isotropic velocity model. This problem was overcome by using a relative (master event) location algorithm that only requires a priori knowledge of the velocity structure within the source volume. The AE location results correlate reasonably well to the extent of the observed cone crack. Decomposition of AE source mechanisms of the Geiger relocated events shows dominantly end-member behavior between tensile and compressive vector dipole events, with some double-couple-dominated events and no purely tensile or compressive events. The same events located by the master event algorithm yield greater percentage of vector dipole components and no double-couple events, indicating that AE source mechanism solutions can depend on AE location accuracy, and therefore, relocation routine that is utilized. Calculations show that the crystallographic anisotropy of quartz causes apparent deviation of the moment tensors away from double-couple and pure tensile/compressive sources consistent with the observations. Preliminary modeling of calcite anisotropy shows a response distinct from quartz, indicating that the effects of anisotropy on interpreting AE are complex and require detailed further study