Measuring the spatial arrangement patterns of pathological lesions in histological sections of brain tissue

The development of abnormal protein aggregates in the form of extracellular plaques and intracellular inclusions is a characteristic feature of many neurodegenerative diseases such as Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD) and the fronto-temporal dementias (FTD). An important aspect of a pathological protein aggregate is its spatial topography in the tissue. Lesions may not be randomly distributed within a histological section but exhibit spatial pattern, a departure from randomness either towards regularity or clustering. Information on the spatial pattern of a lesion may be useful in elucidating its pathogenesis and in studying the relationships between different lesions. This article reviews the methods that have been used to study the spatial topography of lesions. These include simple tests of whether the distribution of a lesion departs significantly from random using randomized points or sample fields, and more complex methods that employ grids or transects of contiguous fields and which can detect the intensity of aggregation and the sizes, distribution and spacing of the clusters. The usefulness of these methods in elucidating the pathogenesis of protein aggregates in neurodegenerative disease is discussed.

Component scheduling for chip shooter machines: a hybrid genetic algorithm approach

A chip shooter machine for electronic component assembly has a movable feeder carrier, a movable X–Y table carrying a printed circuit board (PCB), and a rotary turret with multiple assembly heads. This paper presents a hybrid genetic algorithm (HGA) to optimize the sequence of component placements and the arrangement of component types to feeders simultaneously for a chip shooter machine, that is, the component scheduling problem. The objective of the problem is to minimize the total assembly time. The GA developed in the paper hybridizes different search heuristics including the nearest-neighbor heuristic, the 2-opt heuristic, and an iterated swap procedure, which is a new improved heuristic. Compared with the results obtained by other researchers, the performance of the HGA is superior in terms of the assembly time. Scope and purpose When assembling the surface mount components on a PCB, it is necessary to obtain the optimal sequence of component placements and the best arrangement of component types to feeders simultaneously in order to minimize the total assembly time. Since it is very difficult to obtain the optimality, a GA hybridized with several search heuristics is developed. The type of machines being studied is the chip shooter machine. This paper compares the algorithm with a simple GA. It shows that the performance of the algorithm is superior to that of the simple GA in terms of the total assembly time.

A hybrid genetic algorithm for component sequencing and feeder arrangement

This paper presents a hybrid genetic algorithm to optimize the sequence of component placements on a printed circuit board and the arrangement of component types to feeders simultaneously for a pick-and-place machine with multiple stationary feeders, a fixed board table and a movable placement head. The objective of the problem is to minimize the total travelling distance, or the travelling time, of the placement head. The genetic algorithm developed in the paper hybrisizes different search heuristics including the nearest neighbor heuristic, the 2-opt heuristic, and an iterated swap procedure, which is a new improving heuristic. Compared with the results obtained by other researchers, the performance of the hybrid genetic algorithm is superior to others in terms of the distance travelled by the placement head.

Synthesis and characterization of copper(II) complexes of pyridine-2-carboxamidrazones as potent antimalarial agents

Copper(II) complexes of some pyridine-2-carboxamidrazones have been prepared and characterized. The crystal structures of the copper complex cis-[dichloro(N1-2-acetylthiophene-pyridine-2-carboxamidrazone) copper(II)] 8a and one of the free ligands, viz. {(p-chloro-2-thioloxy-benzylidine-pyridine-2-carboxamidrazone)} 6, have been determined. The former shows a highly distorted square planar geometry around copper, with weak intermolecular coordination from the thiophenyl sulfur resulting in a stacking arrangement in the crystal lattice. The in vitro activities of the synthesized compounds against the malarial parasite Plasmodium falciparum are reported for the first time, which clearly shows the advantage of copper complexation and the requirement of four coordinate geometry around copper as some of the key structural features for designing such metal-based antimalarials. © 2003 Elsevier Science B.V. All rights reserved.

Area summation in human vision at and above detection threshold

The initial image-processing stages of visual cortex are well suited to a local (patchwise) analysis of the viewed scene. But the world's structures extend over space as textures and surfaces, suggesting the need for spatial integration. Most models of contrast vision fall shy of this process because (i) the weak area summation at detection threshold is attributed to probability summation (PS) and (ii) there is little or no advantage of area well above threshold. Both of these views are challenged here. First, it is shown that results at threshold are consistent with linear summation of contrast following retinal inhomogeneity, spatial filtering, nonlinear contrast transduction and multiple sources of additive Gaussian noise. We suggest that the suprathreshold loss of the area advantage in previous studies is due to a concomitant increase in suppression from the pedestal. To overcome this confound, a novel stimulus class is designed where: (i) the observer operates on a constant retinal area, (ii) the target area is controlled within this summation field, and (iii) the pedestal is fixed in size. Using this arrangement, substantial summation is found along the entire masking function, including the region of facilitation. Our analysis shows that PS and uncertainty cannot account for the results, and that suprathreshold summation of contrast extends over at least seven target cycles of grating. © 2007 The Royal Society.

HLA-DP2 binding prediction by molecular dynamics simulations

Major histocompatibility complex (MHC) II proteins bind peptide fragments derived from pathogen antigens and present them at the cell surface for recognition by T cells. MHC proteins are divided into Class I and Class II. Human MHC Class II alleles are grouped into three loci: HLA-DP, HLA-DQ, and HLA-DR. They are involved in many autoimmune diseases. In contrast to HLA-DR and HLA-DQ proteins, the X-ray structure of the HLA-DP2 protein has been solved quite recently. In this study, we have used structure-based molecular dynamics simulation to derive a tool for rapid and accurate virtual screening for the prediction of HLA-DP2-peptide binding. A combinatorial library of 247 peptides was built using the "single amino acid substitution" approach and docked into the HLA-DP2 binding site. The complexes were simulated for 1 ns and the short range interaction energies (Lennard-Jones and Coulumb) were used as binding scores after normalization. The normalized values were collected into quantitative matrices (QMs) and their predictive abilities were validated on a large external test set. The validation shows that the best performing QM consisted of Lennard-Jones energies normalized over all positions for anchor residues only plus cross terms between anchor-residues.

The spatial arrangement patterns of senile plaques in senile dementia of the Alzheimer type (SDAT)

The spatial arrangement patterns of senile plaques have been studied in 10 micron cresyl violet stained sections cut from embedded portions of 20 brain regions from SDAT brains. Two studies are reported: an initial study using the Poisson distribution and a subsequent study using pattern analysis. The initial study indicated that plaques are arranged in discrete clumps in all brain regions when examined at x100 and x400 – suggesting that both small and larger scale clumping may be present. The pattern analysis study was applied to 8 cortical regions. This technique allows a more detailed study of pattern to be made. In all regions the technique revealed that the basic pattern of plaque arrangement is the regularly spaced discrete clump – which may be present on both large and small scales.

Spatial arrangement patterns of senile plaques in post-mortem senile dementia of the Alzheimer type brains

We have studied the spatial distribution of plaques in coronal and tangential sections of the parahippocampal gyrus (PHG), the hippocampus, the frontal lobe and the temporal lobe of five SDAT patients. Sections were stained with cresyl violet and examined at two magnifications (x100 and x400). in all cases (and at both magnifications) statistical analysis using the Poisson distribution showed that the plaques were arranged in clumps (x100: V/M = 1.48 - 4.49; x400 V/M = 1.17 - 1.95). this indicates that both large scale and small scale clumping occurs. Application of the statistical techniques of pattern analysis to coronal sections of frontal and temporal cortex and PHG showed. furthermore, that both large (3200-6400 micron) and small scale (100 - 400 micron) clumps were arranged with a high degree of regularity in the tissue. This suggests that the clumps of plaques reflect underlying neural structure.

The contract management responsibility system in China : an institutional interpretation

Thesis is about the enterprise reform in China in general, and the Contract Management Responsibility System (the CMRS) in particular. The latter is a new institutional arrangement to deal with the relation between the government and the state-owned enterprise which has always been at the centre of the enterprise reform. The focus of the research is on the process of institutionalization in order to study the problems of the emergence of a free enterprise system in China. The research is conducted by four in-depth case studies to reveal how the CMRS is running and what interaction is taking place between the government and the state-owned enterprise under the system. Drawing on the empirical work, the thesis analyzes the features of the CMRS and the characteristics of its implementation process with respect to the structural-institutional paradigm, and the property rights approach. The research shows that to establish a market-type relation between the government and the enterprise is a complicated and dynamic process. It involves the understanding of the two different economic mechanisms, market and planning, and the interations taken by two parties. It concludes that the CMRS is an unstable system, either going back to the previous system or moving towards a market system, because its dynamic and control dimension are dysfunctional.

Developing solid particulate vaccine adjuvants - surface bound antigen favouring a humoural response, whereas entrapped antigen shows a tendency for cell mediated immunity

This present study compares the efficacy of microsphere formulations, and their method of antigen presentation, for the delivery of the TB sub-unit vaccine antigen, Ag85B-ESAT-6. Microspheres based on poly(lactide-co-glycolide) (PLGA) and chitosan incorporating dimethyldioctadecylammonium bromide (DDA) were prepared by either the w/o/w double emulsion method (entrapped antigen) or the o/w single emulsion method (surface bound antigen), and characterised for their physico-chemical properties and their ability to promote an immune response to Ag85B-ESAT-6. The method of preparation, and hence method of antigen association, had a pronounced effect on the type of immune response achieved from the microsphere formulations, with surface bound antigen favouring a humoural response, whereas entrapped antigen favoured a cellular response.

Direct observation of R...R distances in rare-earth (R) phosphate glasses by magnetic difference neutron diffraction

A magnetic difference neutron diffraction study of a rare-earth (Tb) phosphate glass has revealed exclusively the Tb...Tb distances. The difference between data taken with and without an applied magnetic field of 4 T shows Tb...Tb pairwise atomic correlations at 3.9 and 6.4 A, respectively, with relative coordination numbers of 1:14. The first distance arises when two Tb3+ ions share a common oxygen neighbor, and indicates a clustering of rare-earth ions. The second distance arises when two Tb3+ ions are coordinated to different oxygens in the same PO4 group, in a near-linear arrangement.

Predicting class II MHC-Peptide binding:a kernel based approach using similarity scores

Background - Modelling the interaction between potentially antigenic peptides and Major Histocompatibility Complex (MHC) molecules is a key step in identifying potential T-cell epitopes. For Class II MHC alleles, the binding groove is open at both ends, causing ambiguity in the positional alignment between the groove and peptide, as well as creating uncertainty as to what parts of the peptide interact with the MHC. Moreover, the antigenic peptides have variable lengths, making naive modelling methods difficult to apply. This paper introduces a kernel method that can handle variable length peptides effectively by quantifying similarities between peptide sequences and integrating these into the kernel. Results - The kernel approach presented here shows increased prediction accuracy with a significantly higher number of true positives and negatives on multiple MHC class II alleles, when testing data sets from MHCPEP [1], MCHBN [2], and MHCBench [3]. Evaluation by cross validation, when segregating binders and non-binders, produced an average of 0.824 AROC for the MHCBench data sets (up from 0.756), and an average of 0.96 AROC for multiple alleles of the MHCPEP database. Conclusion - The method improves performance over existing state-of-the-art methods of MHC class II peptide binding predictions by using a custom, knowledge-based representation of peptides. Similarity scores, in contrast to a fixed-length, pocket-specific representation of amino acids, provide a flexible and powerful way of modelling MHC binding, and can easily be applied to other dynamic sequence problems.

Linear stability of flow past two circular cylinders in a side-by-side arrangement

The linear stability of flow past two circular cylinders in a side-by-side arrangement is investigated theoretically, numerically and experimentally under the assumption of a two-dimensional flow field, in order to explore the origin of in-phase and antiphase oscillatory flows. Steady symmetric flow is realized at a small Reynolds number, but becomes unstable above a critical Reynolds number though the solution corresponding to the flow still satisfies the basic equations irrespective of the magnitude of the Reynolds number. We obtained the solution numerically and investigated its linear stability. We found that there are two kinds of unstable modes, i.e., antisymmetric and symmetric modes, which lead to in-phase and antiphase oscillatory flows, respectively. We determined the critical Reynolds numbers for the two modes and evaluated the critical distance at which the most unstable disturbance changes from the antisymmetric to the symmetric mode, or vice versa. ©2005 The Physical Society of Japan.

Developing solid particulate vaccine adjuvants:surface bound antigen favouring a humoural response, whereas entrapped antigen shows a tendency for cell mediated immunity

This present study compares the efficacy of microsphere formulations, and their method of antigen presentation, for the delivery of the TB sub-unit vaccine antigen, Ag85B-ESAT-6. Microspheres based on poly(lactide-co-glycolide) (PLGA) and chitosan incorporating dimethyldioctadecylammonium bromide (DDA) were prepared by either the w/o/w double emulsion method (entrapped antigen) or the o/w single emulsion method (surface bound antigen), and characterised for their physico-chemical properties and their ability to promote an immune response to Ag85B-ESAT-6. The method of preparation, and hence method of antigen association, had a pronounced effect on the type of immune response achieved from the microsphere formulations, with surface bound antigen favouring a humoural response, whereas entrapped antigen favoured a cellular response.

Background synaptic activity in rat entorhinal cortex shows a progressively greater dominance of inhibition over excitation from deep to superficial layers

The entorhinal cortex (EC) controls hippocampal input and output, playing major roles in memory and spatial navigation. Different layers of the EC subserve different functions and a number of studies have compared properties of neurones across layers. We have studied synaptic inhibition and excitation in EC neurones, and we have previously compared spontaneous synaptic release of glutamate and GABA using patch clamp recordings of synaptic currents in principal neurones of layers II (L2) and V (L5). Here, we add comparative studies in layer III (L3). Such studies essentially look at neuronal activity from a presynaptic viewpoint. To correlate this with the postsynaptic consequences of spontaneous transmitter release, we have determined global postsynaptic conductances mediated by the two transmitters, using a method to estimate conductances from membrane potential fluctuations. We have previously presented some of this data for L3 and now extend to L2 and L5. Inhibition dominates excitation in all layers but the ratio follows a clear rank order (highest to lowest) of L2>L3>L5. The variance of the background conductances was markedly higher for excitation and inhibition in L2 compared to L3 or L5. We also show that induction of synchronized network epileptiform activity by blockade of GABA inhibition reveals a relative reluctance of L2 to participate in such activity. This was associated with maintenance of a dominant background inhibition in L2, whereas in L3 and L5 the absolute level of inhibition fell below that of excitation, coincident with the appearance of synchronized discharges. Further experiments identified potential roles for competition for bicuculline by ambient GABA at the GABAA receptor, and strychnine-sensitive glycine receptors in residual inhibition in L2. We discuss our results in terms of control of excitability in neuronal subpopulations of EC neurones and what these may suggest for their functional roles. © 2014 Greenhill et al.