CD40 and dendritic cell function

CD40 has emerged as a key signaling pathway for the function of B cells, monocytes, and dendritic cells (DC) in the immune system, and plays a major role in inflammatory pathways of nonhemopoletic cells. CD40 is expressed by monocytes and DC and is up-regulated when DC migrate from the periphery to draining lymph nodes (DLN) in response to microbial challenge. CD154 signaling by MHC-restricted, activated CD4* T cells induces differentiation of DC, as defined by an increased surface expression of MHC, costimulatory, and adhesion molecules. Thus, CD40 functions in the adaptive immune response as a trigger for the expression of costimulatory molecules for efficient T-cell activation. CD40 ligation of DC also has the capacity to induce high levels of the cytokine IL-12, which polarizes CD4(+) T cells toward a T helper 1 (Th1) type, enhances proliferation of CD8(+) T cells, and activates NK cells. CD40 may also play an important role in the decision between tolerance and immunity and the generation of regulatory CD4(+) T cells that are thought to maintain peripheral self-tolerance in vivo.

Is maximizing resilience compatible with established ecological goal functions?

Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] used a simple phytoplanktonzooplankton-nutrient model and a genetic algorithm to determine the parameter values that would maximize the value of certain goal functions. These goal functions were to maximize biomass, maximize flux, maximize flux to biomass ratio, and maximize resilience. It was found that maximizing goal functions maximized resilience. The objective of this study was to investigate whether the Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] result was indicative of a general ecosystem principle, or peculiar to the model and parameter ranges used. This study successfully replicated the Cropp and Gabric [Ecosystem adaptation: do ecosystems maximise resilience? Ecology. In press] experiment for a number of different model types, however, a different interpretation of the results is made. A new metric, concordance, was devised to describe the agreement between goal functions. It was found that resilience has the highest concordance of all goal functions trialled. for most model types. This implies that resilience offers a compromise between the established ecological goal functions. The parameter value range used is found to affect the parameter versus goal function relationships. Local maxima and minima affected the relationship between parameters and goal functions, and between goal functions. (C) 2003 Elsevier B.V. All rights reserved.

Quadriceps activation in closed and in open kinetic chain exercise

Purpose: For treatment of various knee disorders, muscles are trained in open or closed kinetic chain tasks. Coordination between the heads of the quadriceps muscle is important for stability and optimal joint loading for both the tibiofemoral and the patellofemoral joint. The aim of this study was to examine whether the quadriceps femoris muscles are activated differently in open versus closed kinetic chain tasks. Methods: Ten healthy men and women (mean age 28.5 +/- 0.7) extended the knees isometrically in open and closed kinetic chain tasks in a reaction time paradigm using moderate force. Surface electromyography (EMG) recordings were made from four different parts of the quadriceps muscle. The onset and amplitude of EMG and force data were measured. Results: In closed chain knee extension, the onset of EMG activity of the four different muscle portions of the quadriceps was more simultaneous than in the open chain. In open chain, rectus femoris (RF) had the earliest EMG onset while vastus medialis obliquus was activated last (7 +/- 13 ms after RF EMG onset) and with smaller amplitude (40 +/- 30% of maximal voluntary contraction (MVC)) than in closed chain (46 +/- 43% MVC). Conclusions: Exercise in closed kinetic chain promotes more balanced initial quadriceps activation than does exercise in open kinetic chain. This may be of importance in designing training programs aimed toward control of the patellofemoral joint.

The t-SNARE syntaxin 4 is regulated during macrophage activation to function in membrane traffic and cytokine secretion

Activation of macrophages with lipopolysaccharide (LPS) induces the rapid synthesis and secretion of proinflammatory cytokines, such as tumor necrosis factor (TNFalpha), for priming the immune response [1, 2]. TNFalpha plays a key role in inflammatory disease [3]; yet, little is known of the intracellular trafficking events leading to its secretion. In order to identify molecules involved in this secretory pathway, we asked whether any of the known trafficking proteins are regulated by LPS. We found that the levels of SNARE proteins were rapidly and significantly up- or downregulated during macrophage activation. A subset of t-SNAREs (Syntaxin 4/SNAP23/Munc18c) known to control regulated exocytosis in other cell types [4, 5] was substantially increased by LPS in a temporal pattern coinciding with peak TNFalpha secretion. Syntaxin 4 formed a complex with Munc18c at the cell surface of macrophages. Functional studies involving the introduction of Syntaxin 4 cDNA or peptides into macrophages implicate this t-SNARE in a rate-limiting step of TNFalpha secretion and in membrane ruffling during macrophage activation. We conclude that in macrophages, SNAREs are regulated in order to accommodate the rapid onset of cytokine secretion and for membrane traffic associated with the phenotypic changes of immune activation. This represents a novel regulatory role for SNAREs in regulated secretion and in macrophage-mediated host defense.

Unsaturated diffusivity functions for concrete derived from NMR images

Deterioration of concrete or reinforcing steel through excessive contaminant concentration is often the result of repeated wetting and drying cycles. At each cycle, the absorption of water carries new contaminants into the unsaturated concrete. Nuclear Magnetic Resonance (NMR) is used with large concrete samples to observe the shape of the wetting profile during a simple one-dimensional wetting process. The absorption of water by dry concrete is modelled by a nonlinear diffusion equation with the unsaturated hydraulic diffusivity being a strongly nonlinear function of the moisture content. Exponential and power functions are used for the hydraulic diffusivity and corresponding solutions of the diffusion equation adequately predict the shape of the experimental wetting profile. The shape parameters, describing the wetting profile, vary little between different blends and are relatively insensitive to subsequent re-wetting experiments allowing universal parameters to be suggested for these concretes.

Asymmetric contribution of α and β subunits to the activation of αβ heteromeric glycine receptors

This study investigated the role of beta subunits in the activation of alphabeta heteromeric glycine receptor (GlyR) chloride channels recombinantly expressed in HEK293 cells. The approach involved incorporating mutations into corresponding positions in alpha and beta subunits and comparing their effects on receptor function. Although cysteine-substitution mutations to residues in the N-terminal half of the alpha subunit M2-M3 loop dramatically impaired the gating efficacy, the same mutations exerted little effect when incorporated into corresponding positions of the beta subunit. Furthermore, although the alpha subunit M2-M3 loop cysteines were modified by a cysteine-specific reagent, the corresponding beta subunit cysteines showed no evidence of reactivity. These observations suggest structural or functional differences between alpha and beta subunit M2-M3 loops. In addition, a threonine-->leucine mutation at the 9' position in the beta subunit M2 pore-lining domain dramatically increased the glycine sensitivity. By analogy with the effects of the same mutation in other ligand-gated ion channels, it was concluded that the mutation affected the GlyR activation mechanism. This supports the idea that the GlyR beta subunit is involved in receptor gating. In conclusion, this study demonstrates that beta subunits contribute to the activation of the GlyR, but that their involvement in this process is significantly different to that of the alpha subunit.

Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons

The origin of intracellular Ca2+ concentration ([Ca2+](i)) transients stimulated by nicotinic ( nAChR) and muscarinic ( mAChR) receptor activation was investigated in fura-2-loaded neonatal rat intracardiac neurons. ACh evoked [Ca2+](i) increases that were reduced to similar to 60% of control in the presence of either atropine ( 1 muM) or mecamylamine ( 3 muM) and to < 20% in the presence of both antagonists. Removal of external Ca2+ reduced ACh-induced responses to 58% of control, which was unchanged in the presence of mecamylamine but reduced to 5% of control by atropine. The nAChR-induced [Ca2+](i) response was reduced to 50% by 10 μM ryanodine, whereas the mAChR-induced response was unaffected by ryanodine, suggesting that Ca2+ release from ryanodine-sensitive Ca2+ stores may only contribute to the nAChR-induced [Ca2+](i) responses. Perforated-patch whole cell recording at - 60 mV shows that the rise in [Ca2+](i) is concomitant with slow outward currents on mAChR activation and with rapid inward currents after nAChR activation. In conclusion, different signaling pathways mediate the rise in [Ca2+](i) and membrane currents evoked by ACh binding to nicotinic and muscarinic receptors in rat intracardiac neurons.

The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-activation, Coactivator Recruitment, and Activation by the Purine Anti-metabolite 6-Mercaptopurine

NOR-1/NR4A3 is an orphan member of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell- and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the C-terminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hRORbeta, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity.

Mapping the royal road and other hierarchical functions

In this paper we present a technique for visualising hierarchical and symmetric, multimodal fitness functions that have been investigated in the evolutionary computation literature. The focus of this technique is on landscapes in moderate-dimensional, binary spaces (i.e., fitness functions defined over {0, 1}(n), for n less than or equal to 16). The visualisation approach involves an unfolding of the hyperspace into a two-dimensional graph, whose layout represents the topology of the space using a recursive relationship, and whose shading defines the shape of the cost surface defined on the space. Using this technique we present case-study explorations of three fitness functions: royal road, hierarchical-if-and-only-if (H-IFF), and hierarchically decomposable functions (HDF). The visualisation approach provides an insight into the properties of these functions, particularly with respect to the size and shape of the basins of attraction around each of the local optima.

Activation energy distribution of thermal annealing of a bituminous coal

A bituminous coal was pyrolyzed in a nitrogen stream in an entrained flow reactor at various temperatures from 700 to 1475 degreesC. Char samples were collected at different positions along the reactor. Each collected sample was oxidized nonisothermally in a TGA for reactivity determination. The reactivity of the coal char was found to decrease rapidly with residence time until 0.5 s, after which it decreased only slightly. On the bases of the reactivity data at various temperatures, a new approach was utilized to obtaining the true activation energy distribution function for thermal annealing without the assumption of any distribution function form or a constant preexponential factor. It appears that the true activation energy distribution function consists of two separate parts corresponding to different temperature ranges, suggesting different mechanisms in different temperature ranges. Partially burnt coal chars were also collected along the reactor when the coal was oxidized in air at various temperatures from 700 to 1475 degreesC. The collected samples were analyzed for the residual carbon content and the specific reaction rate was estimated. The characteristic time of thermal deactivation was compared with that of oxidation under realistic conditions. The characteristic times were found to be close to each other, indicating the importance of thermal deactivation during combustion of the coal studied.

Validation of percutaneous puncture trajectory during renal access using 4D ultrasound reconstruction

Background: An accurate percutaneous puncture is essential for disintegration and removal of renal stones. Although this procedure has proven to be safe, some organs surrounding the renal target might be accidentally perforated. This work describes a new intraoperative framework where tracked surgical tools are superimposed within 4D ultrasound imaging for security assessment of the percutaneous puncture trajectory (PPT). Methods: A PPT is first generated from the skin puncture site towards an anatomical target, using the information retrieved by electromagnetic motion tracking sensors coupled to surgical tools. Then, 2D ultrasound images acquired with a tracked probe are used to reconstruct a 4D ultrasound around the PPT under GPU processing. Volume hole-filling was performed in different processing time intervals by a tri-linear interpolation method. At spaced time intervals, the volume of the anatomical structures was segmented to ascertain if any vital structure is in between PPT and might compromise the surgical success. To enhance the volume visualization of the reconstructed structures, different render transfer functions were used. Results: Real-time US volume reconstruction and rendering with more than 25 frames/s was only possible when rendering only three orthogonal slice views. When using the whole reconstructed volume one achieved 8-15 frames/s. 3 frames/s were reached when one introduce the segmentation and detection if some structure intersected the PPT. Conclusions: The proposed framework creates a virtual and intuitive platform that can be used to identify and validate a PPT to safely and accurately perform the puncture in percutaneous nephrolithotomy.

Health education: the role and functions of the specialist and the generalist

Education for health is a process in which all public health and medical care personnel are involved. People learn both formally (planned learning experiences) and informally (unplanned learning experiences). Since the patient, the client, the consummer and the community expect public health and medical care personnel to assist them with health and disease issues and problems, the response of the professional "educates" the customer whether the professional intends to educate or not. Therefore, it is incumbent on all public health and medical care professionals to understand their educational functions and their role in health education. It is also important that the role of the specialist in education be clear. The specialist, as to all other specialists, has an in-depth knowledge of his area of expertise, i.e., the teaching/learning process; s/he may function as a consultant to others to enhance the educational potential of their role or s/he may work with a team or with communities or groups of patients. Specific competencies and knowledge are required of the health education specialist; and there is a body of learning and social change theory which provides a frame of reference for planning, implementing and evaluating educational programs. Working with others to enhance their potential to learn and to make informed decisions about health/disease issues is the hallmark of the health education specialist.

Equilibrium self-assembly of colloids with distinct interaction sites: Thermodynamics, percolation, and cluster distribution functions

We calculate the equilibrium thermodynamic properties, percolation threshold, and cluster distribution functions for a model of associating colloids, which consists of hard spherical particles having on their surfaces three short-ranged attractive sites (sticky spots) of two different types, A and B. The thermodynamic properties are calculated using Wertheim's perturbation theory of associating fluids. This also allows us to find the onset of self-assembly, which can be quantified by the maxima of the specific heat at constant volume. The percolation threshold is derived, under the no-loop assumption, for the correlated bond model: In all cases it is two percolated phases that become identical at a critical point, when one exists. Finally, the cluster size distributions are calculated by mapping the model onto an effective model, characterized by a-state-dependent-functionality (f) over bar and unique bonding probability (p) over bar. The mapping is based on the asymptotic limit of the cluster distributions functions of the generic model and the effective parameters are defined through the requirement that the equilibrium cluster distributions of the true and effective models have the same number-averaged and weight-averaged sizes at all densities and temperatures. We also study the model numerically in the case where BB interactions are missing. In this limit, AB bonds either provide branching between A-chains (Y-junctions) if epsilon(AB)/epsilon(AA) is small, or drive the formation of a hyperbranched polymer if epsilon(AB)/epsilon(AA) is large. We find that the theoretical predictions describe quite accurately the numerical data, especially in the region where Y-junctions are present. There is fairly good agreement between theoretical and numerical results both for the thermodynamic (number of bonds and phase coexistence) and the connectivity properties of the model (cluster size distributions and percolation locus).