An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro

G-protein-coupled receptors are desensitized by a two-step process. In a first step, G-protein-coupled receptor kinases (GRKs) phosphorylate agonist-activated receptors that subsequently bind to a second class of proteins, the arrestins. GRKs can be classified into three subfamilies, which have been implicated in various diseases. The physiological role(s) of GRKs have been difficult to study as selective inhibitors are not available. We have used SELEX (systematic evolution of ligands by exponential enrichment) to develop RNA aptamers that potently and selectively inhibit GRK2. This process has yielded an aptamer, C13, which bound to GRK2 with a high affinity and inhibited GRK2-catalyzed rhodopsin phosphorylation with an IC50 of 4.1 nM. Phosphorylation of rhodopsin catalyzed by GRK5 was also inhibited, albeit with 20-fold lower potency (IC50 of 79 nM). Furthermore, C13 reveals significant specificity, since almost no inhibitory activity was detectable testing it against a panel of 14 other kinases. The aptamer is two orders of magnitude more potent than the best GRK2 inhibitors described previously and shows high selectivity for the GRK family of protein kinases.

Effects of divided attention and speeded responding on implicit and explicit retrieval of artificial grammar knowledge

The artificial grammar (AG) learning literature (see, e.g., Mathews et al., 1989; Reber, 1967) has relied heavily on a single measure of implicitly acquired knowledge. Recent work comparing this measure (string classification) with a more indirect measure in which participants make liking ratings of novel stimuli (e.g., Manza & Bornstein, 1995; Newell & Bright, 2001) has shown that string classification (which we argue can be thought of as an explicit, rather than an implicit, measure of memory) gives rise to more explicit knowledge of the grammatical structure in learning strings and is more resilient to changes in surface features and processing between encoding and retrieval. We report data from two experiments that extend these findings. In Experiment 1, we showed that a divided attention manipulation (at retrieval) interfered with explicit retrieval of AG knowledge but did not interfere with implicit retrieval. In Experiment 2, we showed that forcing participants to respond within a very tight deadline resulted in the same asymmetric interference pattern between the tasks. In both experiments, we also showed that the type of information being retrieved influenced whether interference was observed. The results are discussed in terms of the relatively automatic nature of implicit retrieval and also with respect to the differences between analytic and nonanalytic processing (Whittlesea Price, 2001).

Prediction of Parkinson's disease tremor onset using artificial neural networks

In this paper we present the initial results using an artificial neural network to predict the onset of Parkinson's Disease tremors in a human subject. Data for the network was obtained from implanted deep brain electrodes. A tuned artificial neural network was shown to be able to identify the pattern of the onset tremor from these real time recordings.

Identification of Parkinson’s disease tremor onset using artificial neural networks

In this paper we consider the possibility of using an artificial neural network to accurately identify the onset of Parkinson’s Disease tremors in human subjects. Data for the network is obtained by means of deep brain implantation in the human brain. Results presented have been obtained from a practical study (i.e. real not simulated data) but should be regarded as initial trials to be discussed further. It can be seen that a tuned artificial neural network can act as an extremely effective predictor in these circumstances.

Cross-resistance following artificial selection for increased defense against parasitoids in Drosophila melanogaster

An increase in resistance to one natural enemy may result in no correlated change, a positive correlated change, or a negative correlated change in the ability of the host or prey to resist other natural enemies. The type of specificity is important in understanding the evolutionary response to natural enemies and was studied here in a Drosaphila-parasitoid system. Drosophila melanogaster lines selected for increased larval resistance to the endoparasitoid wasps Asobara tabida or Leptopilina boulardi were exposed to attack by A. tabida, L. boulardi and Leptopilina heterotama at 15 degrees C, 20 degrees C, and 25 degrees C. In general, encapsulation ability increased with temperature, with the exception of the lines selected against L. boulardi, which showed the opposite trend. Lines selected against L, boulardi showed large increases in resistance against all three parasitoid species, and showed similar levels of defense against A. tabida to the lines selected against that parasitoid. In contrast, lines selected against A. tabida showed a large increase in resistance to A. tabida and generally to L. heterotoma, but displayed only a small change in their ability to survive attack by L. boulardi. Such asymmetries in correlated responses to selection for increased resistance to natural enemies may influence host-parasitoid community structure.

Effect of molecule branching and glycosidic linkage on the degradation of polydextrose by gut microbiota.

Polydextrose is a randomly linked complex glucose oligomer that is widely used as a sugar replacer, bulking agent, dietary fiber and prebiotic. Polydextrose is poorly utilized by the host and, during gastrointestinal transit, it is slowly degraded by intestinal microbes, although it is not known which parts of the complex molecule are preferred by the microbes. The microbial degradation of polydextrose was assessed by using a simulated model of colonic fermentation. The degradation products and their glycosidic linkages were measured by combined gas chromatography and mass spectrometry, and compared to those of intact polydextrose. Fermentation resulted in an increase in the relative abundance of non-branched molecules with a concomitant decrease in single-branched glucose molecules and a reduced total number of branching points. A detailed analysis showed a preponderance of 1,6 pyranose linkages. The results of this study demonstrate how intestinal microbes selectively degrade polydextrose, and provide an insight into the preferences of gut microbiota in the presence of different glycosidic linkages.

Artificial keys for botanical identification using a multilayer perceptron neural network (MLP)

In this paper, practical generation of identification keys for biological taxa using a multilayer perceptron neural network is described. Unlike conventional expert systems, this method does not require an expert for key generation, but is merely based on recordings of observed character states. Like a human taxonomist, its judgement is based on experience, and it is therefore capable of generalized identification of taxa. An initial study involving identification of three species of Iris with greater than 90% confidence is presented here. In addition, the horticulturally significant genus Lithops (Aizoaceae/Mesembryanthemaceae), popular with enthusiasts of succulent plants, is used as a more practical example, because of the difficulty of generation of a conventional key to species, and the existence of a relatively recent monograph. It is demonstrated that such an Artificial Neural Network Key (ANNKEY) can identify more than half (52.9%) of the species in this genus, after training with representative data, even though data for one character is completely missing.

Using self-organising feature maps for the control of artificial organisms

Variations on the standard Kohonen feature map can enable an ordering of the map state space by using only a limited subset of the complete input vector. Also it is possible to employ merely a local adaptation procedure to order the map, rather than having to rely on global variables and objectives. Such variations have been included as part of a hybrid learning system (HLS) which has arisen out of a genetic-based classifier system. In the paper a description of the modified feature map is given, which constitutes the HLSs long term memory, and results in the control of a simple maze running task are presented, thereby demonstrating the value of goal related feedback within the overall network.

Platelet endothelial cell adhesion molecule-1 regulates collagen-stimulated platelet function by modulating the association of phosphatidylinositol 3-kinase with Grb-2-associated binding protein-1 and linker for activation of T cells

Background: Platelet activation by collagen depends on signals transduced by the glycoprotein (GP)VI–Fc receptor (FcR)-chain collagen receptor complex, which involves recruitment of phosphatidylinositol 3-kinase (PI3K) to phosphorylated tyrosines in the linker for activation of T cells (LAT). An interaction between the p85 regulatory subunit of PI3K and the scaffolding molecule Grb-2-associated binding protein-1 (Gab1), which is regulated by binding of the Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) to Gab1, has been shown in other cell types to sustain PI3K activity to elicit cellular responses. Platelet endothelial cell adhesion molecule-1 (PECAM-1) functions as a negative regulator of platelet reactivity and thrombosis, at least in part by inhibiting GPVI–FcR-chain signaling via recruitment of SHP-2 to phosphorylated immunoreceptor tyrosine-based inhibitory motifs in PECAM-1. Objective: To investigate the possibility that PECAM-1 regulates the formation of the Gab1–p85 signaling complexes, and the potential effect of such interactions on GPVI-mediated platelet activation in platelets. Methods: The ability of PECAM-1 signaling to modulate the LAT signalosome was investigated with immunoblotting assays on human platelets and knockout mouse platelets. Results: PECAM-1-associated SHP-2 in collagen-stimulated platelets binds to p85, which results in diminished levels of association with both Gab1 and LAT and reduced collagen-stimulated PI3K signaling. We therefore propose that PECAM-1-mediated inhibition of GPVI-dependent platelet responses result, at least in part, from recruitment of SHP-2–p85 complexes to tyrosine-phosphorylated PECAM-1, which diminishes the association of PI3K with activatory signaling molecules, such as Gab1 and LAT.

Object detecting artificial retina

This paper describes the novel use of agent and cellular neural Hopfield network techniques in the design of a self-contained, object detecting retina. The agents, which are used to detect features within an image, are trained using the Hebbian method which has been modified for the cellular architecture. The success of each agent is communicated with adjacent agents in order to verify the detection of an object. Initial work used the method to process bipolar images. This has now been extended to handle grey scale images. Simulations have demonstrated the success of the method and further work is planned in which the device is to be implemented in hardware.