Changing the Viewpoint: Re-Indexing by Introspective Questioning

Various cognitive and compuUtional models have addressed the use of previous experience to understand a new domain. In particular, research in case-based reasoning has explored the ideas of retrieving and adapting previous experience in the form of cases, which can only be retrieved when they are appropriately indexed. In contrast to learning new indexes, reindexing of existing cases has received little attention. The need for re-indexing a case arises when a previous situation has been incorrectly or incompletely understood. W e describe a novel approach to re-indexing which integrates results from two different areas: multiple viewpoints used in intelUgent tutoring systems and introspective questioning used in metacognitive activities. Furthermore, we apply ideas from CaseBased Reasoning to the re-indexing process itself. The revised index can be tested by active interaction with the agent's environment. An example of our implementation, JULIAN, will illustrate the re-indexing process

Isospectral domains with mixed boundary conditions

We construct a series of examples of planar isospectral domains with mixed Dirichlet-Neumann boundary conditions. This is a modification of a classical problem proposed by M. Kac.Comment: 9 figures. Statement of Theorem 5.1 correcte

Condensation properties of stress granules and processing bodies are compromised in Myotonic Dystrophy Type 1

RNA regulation in mammalian cells requires complex physical compartmentalisation, using structures thought to be formed by liquid-liquid phase separation. Disruption of these structures is implicated in numerous degenerative diseases. Myotonic dystrophy type 1 (DM1) is a multi-systemic trinucleotide repeat disorder resulting from an expansion of nucleotides CTG (CTGexp) in the DNA encoding DM1 protein kinase (DMPK). The cellular hallmark of DM1 is the formation of nuclear foci that contain expanded DMPK RNA (CUGexp) (with thymine instead of uracil). We report here the deregulation of stress granules (SGs) and processing bodies (P-bodies), two cytoplasmic structures key for mRNA regulation, in cell culture models of DM1. Alterations to the rates of formation and dispersal of SGs suggest an altered ability of cells to respond to stress associated with DM1, while changes to the structure and dynamics of SGs and P-bodies suggest that a widespread alteration to the biophysical properties of cellular structures is a consequence of the presence of CUGexp RNA.</p

Exact and quasiexact solvability of second-order superintegrable quantum systems: I. Euclidean space preliminaries

We show that second-order superintegrable systems in two-dimensional and three-dimensional Euclidean space generate both exactly solvable (ES) and quasiexactly solvable (QES) problems in quantum mechanics via separation of variables, and demonstrate the increased insight into the structure of such problems provided by superintegrability. A principal advantage of our analysis using nondegenerate superintegrable systems is that they are multiseparable. Most past separation of variables treatments of QES problems via partial differential equations have only incorporated separability, not multiseparability. Also, we propose another definition of ES and QES. The quantum mechanical problem is called ES if the solution of Schrödinger equation can be expressed in terms of hypergeometric functions mFn and is QES if the Schrödinger equation admits polynomial solutions with coefficients necessarily satisfying a three-term or higher order of recurrence relations. In three dimensions we give an example of a system that is QES in one set of separable coordinates, but is not ES in any other separable coordinates. This example encompasses Ushveridze's tenth-order polynomial QES problem in one set of separable coordinates and also leads to a fourth-order polynomial QES problem in another separable coordinate set

Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients

OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases

Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

Coupling models of cattle and farms with models of badgers for predicting the dynamics of bovine tuberculosis (TB)

Bovine TB is a major problem for the agricultural industry in several countries. TB can be contracted and spread by species other than cattle and this can cause a problem for disease control. In the UK and Ireland, badgers are a recognised reservoir of infection and there has been substantial discussion about potential control strategies. We present a coupling of individual based models of bovine TB in badgers and cattle, which aims to capture the key details of the natural history of the disease and of both species at approximately county scale. The model is spatially explicit it follows a very large number of cattle and badgers on a different grid size for each species and includes also winter housing. We show that the model can replicate the reported dynamics of both cattle and badger populations as well as the increasing prevalence of the disease in cattle. Parameter space used as input in simulations was swept out using Latin hypercube sampling and sensitivity analysis to model outputs was conducted using mixed effect models. By exploring a large and computationally intensive parameter space we show that of the available control strategies it is the frequency of TB testing and whether or not winter housing is practised that have the most significant effects on the number of infected cattle, with the effect of winter housing becoming stronger as farm size increases. Whether badgers were culled or not explained about 5%, while the accuracy of the test employed to detect infected cattle explained less than 3% of the variance in the number of infected cattle

IER2-induced senescence drives melanoma invasion through osteopontin

Expression of the immediate-early response gene IER2 has been associated with the progression of several types of cancer, but its functional role is poorly understood. We found that increased IER2 expression in human melanoma is associated with shorter overall survival, and subsequently investigated the mechanisms through which IER2 exerts this effect. In experimental melanoma models, sustained expression of IER2 induced senescence in a subset of melanoma cells in a p53/MAPK/AKT-dependent manner. The senescent cells produced a characteristic secretome that included high levels of the extracellular phosphoglycoprotein osteopontin. Nuclear localization of the IER2 protein was critical for both the induction of senescence and osteopontin secretion. Osteopontin secreted by IER2-expressing senescent cells strongly stimulated the migration and invasion of non-senescent melanoma cells. Consistently, we observed coordinate expression of IER2, p53/p21, and osteopontin in primary human melanomas and metastases, highlighting the pathophysiological relevance of IER2-mediated senescence in melanoma progression. Together, our study reveals that sustained IER2 expression drives melanoma invasion and progression through stimulating osteopontin secretion via the stochastic induction of senescence

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo