Identification of the region of non-A beta component (NAC) of alzheimer's disease amyloid responsible for its aggregation and toxicity

The non-beta-amyloid (Aß) component of Alzheimer's disease amyloid (NAC) and its precursor a-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and a-synuclein both form ß-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3±18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8±18) and NAC(8±16) are toxic, whereas NAC(12±18), NAC(9±16) and NAC(8±15) are not. Circular dichroism indicates that none of the peptides displays ß-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce ß sheet, fragments NAC(8±18) and NAC(8±16) both form ß-sheet structure. Only NAC(8±18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8±16 of NAC, equivalent to residues 68±76 in a-synuclein, comprise the region crucial for toxicity.

An Investigation of the Flow Field through a Variable Geometry Turbine Stator with Vane Endwall Clearance

Variable geometry turbines provide an extra degree of flexibility in air management in turbocharged engines. The pivoting stator vanes used to achieve the variable turbine geometry necessitate the inclusion of stator vane endwall clearances. The consequent leakage flow through the endwall clearances impacts the flow in the stator vane passages and an understanding of the impact of the leakage flow on stator loss is required. A numerical model of a typical variable geometry turbine was developed using the commercial CFX-10 computational fluid dynamics software, and validated using laser doppler velocimetry and static pressure measurements from a variable geometry turbine with stator vane endwall clearance. Two different stator vane positions were investigated, each at three different operating conditions representing different vane loadings. The vane endwall leakage was found to have a significant impact on the stator loss and on the uniformity of flow entering the turbine rotor. The leakage flow changed considerably at different vane positions and flow incidence at vane inlet was found to have a significant impact.

A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders.

Convergent biochemical and genetic evidence suggests that the formation of alpha-synuclein (alpha-syn) protein deposits is an important and, probably, seminal step in the development of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). It has been reported that transgenic animals overexpressing human alpha-syn develop lesions similar to those found in the brain in PD, together with a progressive loss of dopaminergic cells and associated abnormalities of motor function. Inhibiting and/or reversing alpha-syn self-aggregation could, therefore, provide a novel approach to treating the underlying cause of these diseases. We synthesized a library of overlapping 7-mer peptides spanning the entire alpha-syn sequence, and identified amino acid residues 64-100 of alpha-syn as the binding region responsible for its self-association. Modified short peptides containing alpha-syn amino acid sequences from part of this binding region (residues 69-72), named alpha-syn inhibitors (ASI), were found to interact with full-length alpha-syn and block its assembly into both early oligomers and mature amyloid-like fibrils. We also developed a cell-permeable inhibitor of alpha-syn aggregation (ASID), using the polyarginine peptide delivery system. This ASID peptide was able to inhibit the DNA damage induced by Fe(II) in neuronal cells transfected with alpha-syn(A53T), a familial PD-associated mutation. ASI peptides without this delivery system did not reverse levels of Fe(II)-induced DNA damage. Furthermore, the ASID peptide increased (P

A VLSI Architecture for Variable Block Size Video Motion Estimation

With the advent of new video standards such as MPEG-4 part-10 and H.264/H.26L, demands for advanced video coding, particularly in the area of variable block size video motion estimation (VBSME), are increasing. In this paper, we propose a new one-dimensional (1-D) very large-scale integration architecture for full-search VBSME (FSVBSME). The VBS sum of absolute differences (SAD) computation is performed by re-using the results of smaller sub-block computations. These are distributed and combined by incorporating a shuffling mechanism within each processing element. Whereas a conventional 1-D architecture can process only one motion vector (MV), this new architecture can process up to 41 MV sub-blocks (within a macroblock) in the same number of clock cycles.

Correspondence between continuous-variable and discrete quantum systems of arbitrary dimensions

We establish a mapping between a continuous-variable (CV) quantum system and a discrete quantum system of arbitrary dimension. This opens up the general possibility to perform any quantum information task with a CV system as if it were a discrete system. The Einstein-Podolsky-Rosen state is mapped onto the maximally entangled state in any finite-dimensional Hilbert space and thus can be considered as a universal resource of entanglement. An explicit example of the map and a proposal for its experimental realization are discussed.