942 resultados para partial signatures


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Background
Connectivity mapping is a process to recognize novel pharmacological and toxicological properties in small molecules by comparing their gene expression signatures with others in a database. A simple and robust method for connectivity mapping with increased specificity and sensitivity was recently developed, and its utility demonstrated using experimentally derived gene signatures.

Results
This paper introduces sscMap (statistically significant connections' map), a Java application designed to undertake connectivity mapping tasks using the recently published method. The software is bundled with a default collection of reference gene-expression profiles based on the publicly available dataset from the Broad Institute Connectivity Map 02, which includes data from over 7000 Affymetrix microarrays, for over 1000 small-molecule compounds, and 6100 treatment instances in 5 human cell lines. In addition, the application allows users to add their custom collections of reference profiles and is applicable to a wide range of other 'omics technologies.

Conclusion
The utility of sscMap is two fold. First, it serves to make statistically significant connections between a user-supplied gene signature and the 6100 core reference profiles based on the Broad Institute expanded dataset. Second, it allows users to apply the same improved method to custom-built reference profiles which can be added to the database for future referencing. The software can be freely downloaded from http://purl.oclc.org/NET/sscMap

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Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

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We present near-infrared linear spectropolarimetry of a sample of persistent X-ray binaries, Sco X-1, Cyg X-2 and GRS 1915+105. For Sco X-1 and Cyg X-2, the polarization levels at 2.4 µm are 1.3+/-0.10% and 5.4+/-0.7%, respectively, which is greater than the polarization level at 1.65 µm. This cannot be explained by interstellar polarization or electron scattering in the anisotropic environment of the accretion flow. We propose that the most likely explanation is that this is the polarimetric signature of synchrotron emission arising from close to the base of the jet. For Sco X-1 the position angle of the radio jet on the sky is approximately perpendicular to the near-infrared position angle (electric vector), suggesting that the magnetic field is aligned with the jet. These observations may be a first step towards probing the ordering, alignment, and variability of the outflow magnetic field, in a region closer to the central accreting object than is observed in the radio band.

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In recent years, geophysical methods have been shown to be sensitive to microbial-induced mineralization processes. The spectral induced-polarization (SIP) method appears to be very promising for monitoring mineralization and microbial processes. With this work, we study the links of mineralization and SIP signals, in the absence of microbial activity. We recorded the SIP response during abiotic FeS precipitation. We show that the SIP signals are diagnostic of FeS mineralization and can be differentiated from SIP signals from biomineralization processes. More specifically, the imaginary conductivity shows almost linear dependence on the amount of FeS precipitating out of solution, above the threshold value 0.006 gr under our experimental conditions. This research has direct implications for the use of the SIP method as a monitoring and decision-making tool for sustainable remediation of metals in contaminated soils and groundwater.

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Strategies available to evaluate the performance of in situ permeable reactive barriers are currently not well developed and often rely on fluid and media sampling directly from the permeable reactive barrier (PRB). Here, we investigate the utility of the self-potential (SP) method as a technique to monitor in situ PRB performance. Our field study was conducted at in situ biological PRB in Portadown, Northern Ireland, UK, which was emplaced to assist in the remediation of groundwater contamination (e.g., hydrocarbons, ammonia) that resulted from the operations and waste disposal practices of a former gasworks. Borehole SP measurements were collected during the injection of contaminant groundwater slugs in an attempt to monitor/detect the response of the microbial activity associated with the breakdown of the added contaminants into the PRB. In addition, an uncontaminated groundwater slug was injected into a different portion of the PRB as a ‘control’ and SP measurements were collected for comparison to the SP response of the contaminant slugs. The results of the SP signals due to the contaminant injections show that the magnitude of the response was relatively small (<10 mV) yet showed a consistent decrease during both contaminant injections. The net decrease in SP recorded during the contaminant injections slowly rebounded to near background values through ~44 hours post-injection. The SP response during the uncontaminated injection showed a slight, albeit negligible (within the margin of error), 1 mV increase in the measured SP signals, in contrast to the contaminant injections. The results of the SP signals recorded from the uncontaminated groundwater injection also persisted through a period of ~47 hours after injection but show a net increase in SP relative to pre-injection values. Based on the difference in SP response between the contaminated and uncontaminated injections, we suggest that the responses are likely to be the result of differences in the chemistry of the injection types (contaminated versus uncontaminated) and in situ groundwater. We argue that the SP signals associated with the contaminated injections are dominated by diffusion (electrochemical) potential, possibly enhanced by a microbial effect. While the results of our investigation show a consistent SP response associated with the contaminant injections that is dominated by diffusional effects, further studies are required in order to better understand the effect of microbial activity on SP signals and the potential utility for the SP method to detect/monitor changes that may be indicative of biological PRB performance.

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Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2- methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino] propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]} -butanoate N-methyl-D-glucamine (PD135, 158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2- oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1- (2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoylmethyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

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We use many-body theory to find the asymptotic behaviour of second-order correlation corrections to the energies and positron annihilation rates in many- electron systems with respect to the angular momenta l of the single-particle orbitals included. The energy corrections decrease as 1/(l+1/2)4, in agreement with the result of Schwartz, whereas the positron annihilation rate has a slower 1/(l+1/2)2 convergence rate. We illustrate these results by numerical calculations of the energies of Ne and Kr and by examining results from extensive con?guration-interaction calculations of PsH binding and annihilation.

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We study the solution concepts of partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria. The partial cooperative Cournot-Nash equilibrium is axiomatically characterized by using notions of rationality, consistency and converse consistency with regard to reduced games. We also establish sufficient conditions for which partial cooperative Cournot-Nash equilibria and partial cooperative Stackelberg equilibria exist in supermodular games. Finally, we provide an application to strategic network formation where such solution concepts may be useful.

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This study investigates face recognition with partial occlusion, illumination variation and their combination, assuming no prior information about the mismatch, and limited training data for each person. The authors extend their previous posterior union model (PUM) to give a new method capable of dealing with all these problems. PUM is an approach for selecting the optimal local image features for recognition to improve robustness to partial occlusion. The extension is in two stages. First, authors extend PUM from a probability-based formulation to a similarity-based formulation, so that it operates with as little as one single training sample to offer robustness to partial occlusion. Second, they extend this new formulation to make it robust to illumination variation, and to combined illumination variation and partial occlusion, by a novel combination of multicondition relighting and optimal feature selection. To evaluate the new methods, a number of databases with various simulated and realistic occlusion/illumination mismatches have been used. The results have demonstrated the improved robustness of the new methods.