Refinement of higher-order logic programs

A refinement calculus provides a method for transforming specifications to executable code, maintaining the correctness of the code with respect to its specification. In this paper we extend the refinement calculus for logic programs to include higher-order programming capabilities in specifications and programs, such as procedures as terms and lambda abstraction. We use a higher-order type and term system to describe programs, and provide a semantics for the higher-order language and refinement. The calculus is illustrated by refinement examples.

Higher-order CpG-DNA stimulation reveals distinct activation requirements for marginal zone and follicular B cells in lupus mice

Mouse follicular B cells express TLR9 and respond vigorously to stimulation with single-stranded CpG-oligodeoxynucleotides (ODN). Surprisingly, follicular B cells do not respond to direct stimulation with other TLR9 ligands, such as bacterial DNA or class A(D) CpG-ODN capable of forming higher-order structures, unless other cell types are present. Here, we show that priming with interferons or with B cell-activating factor, or simultaneous co-engagement of the B cell receptor for antigen (BCR), can overcome this unresponsiveness. The effect of interferons occurs at the transcriptional level and is mediated through an autocrine/paracrine loop, which is dependent on IRF-1, IL-6 and IL-12 p40. We hypothesize that the lack of bystander activation of follicular B cells with more complex CpG ligands may be an important safety mechanism for avoiding autoimmunity. This will prevent resting B cells from responding to foreign or self-derived hypomethylated double-stranded CpG ligands unless these ligands are either delivered through the B cell receptor or under conditions where B cells are simultaneously co-engaged by activated plasmacytoid dendritic cells or TH1 cells. A corollary is that the heightened responsiveness of lupus B cells to TLR9-induced stimulation cannot be ascribed to unprimed follicular B cells, but is rather mediated by hypersensitive marginal zone B cells.

New approximation for free surface flow of groundwater: capillarity correction

An existing capillarity correction for free surface groundwater flow as modelled by the Boussinesq equation is re-investigated. Existing solutions, based on the shallow flow expansion, have considered only the zeroth-order approximation. Here, a second-order capillarity correction to tide-induced watertable fluctuations in a coastal aquifer adjacent to a sloping beach is derived. A new definition of the capillarity correction is proposed for small capillary fringes, and a simplified solution is derived. Comparisons of the two models show that the simplified model can be used in most cases. The significant effects of higher-order capillarity corrections on tidal fluctuations in a sloping beach are also demonstrated. (c) 2004 Elsevier Ltd. All rights reserved.

Modulation of higher-plant NAD(H)-dependent glutamate dehydrogenase activity in transgenic tobacco via alteration of beta subunit levels

Glutamate dehydrogenase (GDH; EC 1.4.1.2-1.4.1.4) catalyses in vitro the reversible amination of 2-oxoglutarate to glutamate. In vascular plants the in vivo direction(s) of the GDH reaction and hence the physiological role(s) of this enzyme remain obscure. A phylogenetic analysis identified two clearly separated groups of higher-plant GDH genes encoding either the alpha- or beta-subunit of the GDH holoenzyme. To help clarify the physiological role(s) of GDH, tobacco (Nicotiana tabacum L.) was transformed with either an antisense or sense copy of a beta-subunit gene, and transgenic plants recovered with between 0.5- and 34-times normal leaf GDH activity. This large modulation of GDH activity (shown to be via alteration of beta-subunit levels) had little effect on leaf ammonium or the leaf free amino acid pool, except that a large increase in GDH activity was associated with a significant decrease in leaf Asp (similar to 51%, P=0.0045). Similarly, plant growth and development were not affected, suggesting that a large modulation of GDH beta-subunit titre does not affect plant viability under the ideal growing conditions employed. Reduction of GDH activity and protein levels in an antisense line was associated with a large increase in transcripts of a beta-subunit gene, suggesting that the reduction in beta-subunit levels might have been due to translational inhibition. In another experiment designed to detect post-translational up-regulation of GDH activity, GDH over-expressing plants were subjected to prolonged dark-stress. GDH activity increased, but this was found to be due more likely to resistance of the GDH protein to stress-induced proteolysis, rather than to post-translational up-regulation.

Modeling diffraction and imaging of laser beams by the mode-expansion method

We present a new method of modeling imaging of laser beams in the presence of diffraction. Our method is based on the concept of first orthogonally expanding the resultant diffraction field (that would have otherwise been obtained by the laborious application of the Huygens diffraction principle) and then representing it by an effective multimodal laser beam with different beam parameters. We show not only that the process of obtaining the new beam parameters is straightforward but also that it permits a different interpretation of the diffraction-caused focal shift in laser beams. All of the criteria that we have used to determine the minimum number of higher-order modes needed to accurately represent the diffraction field show that the mode-expansion method is numerically efficient. Finally, the characteristics of the mode-expansion method are such that it allows modeling of a vast array of diffraction problems, regardless of the characteristics of the incident laser beam, the diffracting element, or the observation plane. (C) 2005 Optical Society of America.

Brain maps, great and small: lessons from comparative studies of primate visual cortical organization

In this paper, we review evidence from comparative studies of primate cortical organization, highlighting recent findings and hypotheses that may help us to understand the rules governing evolutionary changes of the cortical map and the process of formation of areas during development. We argue that clear unequivocal views of cortical areas and their homologies are more likely to emerge for 'core' fields, including the primary sensory areas, which are specified early in development by precise molecular identification steps. In primates, the middle temporal area is probably one of these primordial cortical fields. Areas that form at progressively later stages of development correspond to progressively more recent evolutionary events, their development being less firmly anchored in molecular specification. The certainty with which areal boundaries can be delimited, and likely homologies can be assigned, becomes increasingly blurred in parallel with this evolutionary/developmental sequence. For example, while current concepts for the definition of cortical areas have been vindicated in allowing a clarification of the organization of the New World monkey 'third tier' visual cortex (the third and dorsomedial areas, V3 and DM), our analyses suggest that more flexible mapping criteria may be needed to unravel the organization of higher-order visual association and polysensory areas.

Dinuclear cyano-bridged Co-III-Fe-II complexes as precursors for molecular mixed-valence complexes of higher nuclearity

The preparation and characterization of a series of trinuclear mixed-valence cyano-bridged Co-III-Fe-II-Co-III compounds derived from known dinuclear [{LnCoIII(mu-NC)}Fe-II(CN)(5)](-) complexes (L-n = N-5 or N3S2 n-membered pendant amine macrocycle) are presented. All of the new trinuclear complexes were fully characterized spectroscopically (UV-vis, IR, and C-13 NMR). Complexes exhibiting a trans and cis arrangement of the Co-Fe-Co units around the [Fe(CN)(6)](4-) center are described (i.e., cis/trans-[{LnCoIII(mu-NC)}(2)Fe-II(CN)(4)](2+)), and some of their structures are determined by X-ray crystallography. Electrochemical experiments revealed an expected anodic shift of the Fe-III/II redox potential upon addition of a tripositively charged {(CoLn)-L-III} moiety. The Co-III/II redox potentials do not change greatly from the di- to the trinuclear complex, but rather behave in a fully independent and noncooperative way. In this respect, the energies and extinction coefficients of the MMCT bands agree with the formal existence of two mixed-valence Fe-II-CN-Co-III units per molecule. Solvatochromic experiments also indicated that the MMCT band of these compounds behaves as expected for a class II mixed-valence complex. Nevertheless, its extinction coefficient is dramatically increased upon increasing the solvent donor number.

Cracks of higher modes in Cosserat continua

Rotational degrees of freedom in Cosserat continua give rise to higher fracture modes. Three new fracture modes correspond to the cracks that are surfaces of discontinuities in the corresponding components of independent Cosserat rotations. We develop a generalisation of J- integral that includes these additional degrees of freedom. The obtained path-independent integrals are used to develop a criterion of crack propagation for a special type of failure in layered materials with sliding layers. This fracture propagates as a progressive bending failure of layers – a “bending crack that is, a crack that can be represented as a distribution of discontinuities in the layer bending. This situation is analysed using a 2D Cosserat continuum model. Semi-infinite bending crack normal to layering is considered. The moment stress concentrates along the line that is a continuation of the crack and has a singularity of the power − 1/4. A model of process zone is proposed for the case when the breakage of layers in the process of bending crack propagation is caused by a crack (microcrack in our description) growing across the layer adjacent to the crack tip. This growth is unstable (in the moment-controlled loading), which results in a typical descending branch of moment stress – rotation discontinuity relationship and hence in emergence of a Barenblatt-type process zone at the tip of the bending crack.

Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with EphA3

Eph receptor tyrosine kinases (Ephs) function as molecular relays that interact with cell surface-bound ephrin ligands to direct the position of migrating cells. Structural studies revealed that, through two distinct contact surfaces on opposite sites of each protein, Eph and ephrin binding domains assemble into symmetric, circular heterotetramers. However, Eph signal initiation requires the assembly of higher order oligomers, suggesting additional points of contact. By screening a random library of EphA3 binding-compromised ephrin-A5 mutants, we have now determined ephrin-A5 residues that are essential for the assembly of high affinity EphA3 signaling complexes. In addition to the two interfaces predicted from the crystal structure of the homologous EphB2 center dot ephrin-B2 complex, we identified a cluster of 10 residues on the ephrin-A5 E alpha-helix, the E-F loop, the underlying H beta-strand, as well as the nearby B - C loop, which define a distinct third surface required for oligomerization and activation of EphA3 signaling. Together with a corresponding third surface region identified recently outside of the minimal ephrin binding domain of EphA3, our findings provide experimental evidence for the essential contribution of three distinct protein-interaction interfaces to assemble functional EphA3 signaling complexes.