Quantifying intrinsic specificity: A potential complement to affinity in drug screening

We report here the investigation of a novel description of specificity in protein-ligand binding based on energy landscape theory. We define a new term, intrinsic specificity ratio (ISR), which describes the level of discrimination in binding free energies of the native basin for a protein-ligand complex from the weaker binding states of the same ligand. We discuss the relationship between the intrinsic specificity we defined here and the conventional definition of specificity. In a docking study of molecules with the enzyme COX-2, we demonstrate a statistical correspondence between ISR value and geometrical shapes of the small molecules binding to COX-2. We further observe that the known selective (nonselective) inhibitors of COX-2 have higher (lower) ISR values. We suggest that intrinsic specificity ratio may be a useful new criterion and a complement to affinity in drug screening and in searching for potential drug lead compounds.

Dynamics and intrinsic statistical fluctuations of a gene switch

We studied a simple gene regulatory network, the toggle switch. Specifically, we examined the means and statistical fluctuations in numbers of proteins. We found that when omega, the ratio of rates of protein-gene unbinding to protein degradation, was between similar to 10(-3) and similar to 10, the fluctuations were much larger than those we would have expected from Poisson statistics. In addition, we examined characteristic time values for system relaxation and found both that they increased with omega and that they have significant phase transition effects, with a secondary time scale appearing near the boundary between bistable and other phases. Last, we discuss the bistability of the toggle switch.

THERMAL BEHAVIORS OF INTRINSIC POLYANILINE AND ITS DERIVATIVES

Thermal properties of polyaniline (PAn), polytoluidine(POT) and polyanisidine(PAs) were examined by TG and DSC techniques. The weight-uptake of POT at 200-300 degrees C was observed and carefully discussed.

Recovering Intrinsic Images from a Single Image

We present an algorithm that uses multiple cues to recover shading and reflectance intrinsic images from a single image. Using both color information and a classifier trained to recognize gray-scale patterns, each image derivative is classified as being caused by shading or a change in the surface's reflectance. Generalized Belief Propagation is then used to propagate information from areas where the correct classification is clear to areas where it is ambiguous. We also show results on real images.

Altered of apoptotic markers of both extrinsic and intrinsic pathways induced by hepatitis C virus infection in peripheral blood mononuclear cells

Background: Chronic hepatitis C (CHC) has emerged as a leading cause of cirrhosis in the U. S. and across the world. To understand the role of apoptotic pathways in hepatitis C virus (HCV) infection, we studied the mRNA and protein expression patterns of apoptosis-related genes in peripheral blood mononuclear cells (PBMC) obtained from patients with HCV infection.Methods: the present study included 50 subjects which plasma samples were positive for HCV, but negative for human immunodeficiency virus (HIV) or hepatitis B virus (HBV). These cases were divided into four groups according to METAVIR, a score-based analysis which helps to interpret a liver biopsy according to the degree of inflammation and fibrosis. mRNA expression of the studied genes were analyzed by reverse transcription of quantitative polymerase chain reaction (RT-qPCR) and protein levels, analyzed by ELISA, was also conducted. HCV genotyping was also determined.Results: HCV infection increased mRNA expression and protein synthesis of caspase 8 in group 1 by 3 fold and 4 fold, respectively (p < 0.05). in group 4 HCV infection increased mRNA expression and protein synthesis of caspase 9 by 2 fold and 1,5 fold, respectively (p < 0.05). Also, caspase 3 mRNA expression and protein synthesis had level augumented by HCV infection in group 1 by 4 fold and 5 fold, respectively, and in group 4 by 6 fold and 7 fold, respectively (p < 0.05).Conclusions: HCV induces alteration at both genomic and protein levels of apoptosis markers involved with extrinsic and intrinsic pathways.

On the Intrinsic Locality Properties of Web Reference Streams

There has been considerable work done in the study of Web reference streams: sequences of requests for Web objects. In particular, many studies have looked at the locality properties of such streams, because of the impact of locality on the design and performance of caching and prefetching systems. However, a general framework for understanding why reference streams exhibit given locality properties has not yet emerged. In this work we take a first step in this direction, based on viewing the Web as a set of reference streams that are transformed by Web components (clients, servers, and intermediaries). We propose a graph-based framework for describing this collection of streams and components. We identify three basic stream transformations that occur at nodes of the graph: aggregation, disaggregation and filtering, and we show how these transformations can be used to abstract the effects of different Web components on their associated reference streams. This view allows a structured approach to the analysis of why reference streams show given properties at different points in the Web. Applying this approach to the study of locality requires good metrics for locality. These metrics must meet three criteria: 1) they must accurately capture temporal locality; 2) they must be independent of trace artifacts such as trace length; and 3) they must not involve manual procedures or model-based assumptions. We describe two metrics meeting these criteria that each capture a different kind of temporal locality in reference streams. The popularity component of temporal locality is captured by entropy, while the correlation component is captured by interreference coefficient of variation. We argue that these metrics are more natural and more useful than previously proposed metrics for temporal locality. We use this framework to analyze a diverse set of Web reference traces. We find that this framework can shed light on how and why locality properties vary across different locations in the Web topology. For example, we find that filtering and aggregation have opposing effects on the popularity component of the temporal locality, which helps to explain why multilevel caching can be effective in the Web. Furthermore, we find that all transformations tend to diminish the correlation component of temporal locality, which has implications for the utility of different cache replacement policies at different points in the Web.

Intersubject Regularity in the Intrinsic Shape of Human V1

Previous studies have reported considerable intersubject variability in the three-dimensional geometry of the human primary visual cortex (V1). Here we demonstrate that much of this variability is due to extrinsic geometric features of the cortical folds, and that the intrinsic shape of V1 is similar across individuals. V1 was imaged in ten ex vivo human hemispheres using high-resolution (200 μm) structural magnetic resonance imaging at high field strength (7 T). Manual tracings of the stria of Gennari were used to construct a surface representation, which was computationally flattened into the plane with minimal metric distortion. The instrinsic shape of V1 was determined from the boundary of the planar representation of the stria. An ellipse provided a simple parametric shape model that was a good approximation to the boundary of flattened V1. The aspect ration of the best-fitting ellipse was found to be consistent across subject, with a mean of 1.85 and standard deviation of 0.12. Optimal rigid alignment of size-normalized V1 produced greater overlap than that achieved by previous studies using different registration methods. A shape analysis of published macaque data indicated that the intrinsic shape of macaque V1 is also stereotyped, and similar to the human V1 shape. Previoud measurements of the functional boundary of V1 in human and macaque are in close agreement with these results.

Simulating Effects of Learning and Lesions with a Model of Intrinsic and Synaptically Gated Responses of Striatal Cholinergic Interneurons

The giant cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with characteristic pauses to novel events and to appetitive and aversive conditioned stimuli. Fluctuations in acetylcholine release by TANs modulate performance- and learning-related dynamics in the striatum. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from thalamic centromedian-parafascicular nuclei, and dopaminergic inputs from midbrain, are required for the generation of pause responses. No prior computational models encompass both intrinsic and synaptically-gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model, balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing, and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If the latter inhibition, presumably mediated by GABAergic interneurons, exceeds a threshold, its effect is amplified by a KIR current to generate a prolonged pause. In the model, the intrinsic mechanisms and external inputs are both modulated by learning-dependent dopamine (DA) signals and our simulations revealed that many learning-dependent behaviors of TANs are explicable without recourse to learning-dependent changes in synapses onto TANs. The "teaching signal" that modulates reinforcement learning at cortico-striatal synapses may be a sequence composed of an adaptively scaled DA burst, a brief ACh burst, and a scaled ACh pause. Such an interpretation is consistent with recent data on cholinergic control of LTD of cortical synapses onto striatal spiny projection neurons.

Using the institutional grammar tool to understand regulatory compliance: The case of Colorado aquaculture

What is the relationship between the design of regulations and levels of individual compliance? To answer this question, Crawford and Ostrom's institutional grammar tool is used to deconstruct regulations governing the aquaculture industry in Colorado, USA. Compliance with the deconstructed regulatory components is then assessed based on the perceptions of the appropriateness of the regulations, involvement in designing the regulations, and intrinsic and extrinsic motivations. The findings suggest that levels of compliance with regulations vary across and within individuals regarding various aspects of the regulatory components. As expected, the level of compliance is affected by the perceived appropriateness of regulations, participation in designing the regulations, and feelings of guilt and fear of social disapproval. Furthermore, there is a strong degree of interdependence among the written components, as identified by the institutional grammar tool, in affecting compliance levels. The paper contributes to the regulation and compliance literature by illustrating the utility of the institutional grammar tool in understanding regulatory content, applying a new Q-Sort technique for measuring individual levels of compliance, and providing a rare exploration into feelings of guilt and fear outside of the laboratory setting. © 2012 Blackwell Publishing Asia Pty Ltd.

Intrinsic measure of diversity gains in generalised distributed antenna systems with cooperative users

The diversity gains achievable in the generalised distributed antenna system with cooperative users (GDAS-CU) are considered. A GDAS-CU is comprised of M largely separated access points (APs) at one side of the link, and N geographically closed user terminals (UTs) at the other side. The UTs are collaborating together to enhance the system performance, where an idealised message sharing among the UTs is assumed. First, geometry-based network models are proposed to describe the topology of a GDAS-CU. The mean cross-correlation coefficients of signals received from non-collocated APs and UTs are calculated based on the network topology and the correlation models derived from the empirical data. The analysis is also extendable to more general scenarios where the APs are placed in a clustered form due to the constraints of street layout or building structure. Subsequently, a generalised signal attenuation model derived from several stochastic ray-tracing-based pathloss models is applied to describe the power-decaying pattern in urban built-up areas, where the GDAS-CU may be deployed. Armed with the cross-correlation and pathloss model preliminaries, an intrinsic measure of cooperative diversity obtainable from a GDAS-CU is then derived, which is the number of independent fading channels that can be averaged over to detect symbols. The proposed analytical framework would provide critical insight into the degree of possible performance improvement when combining multiple copies of the received signal in such systems.

An inquiry concerning the acceptance of intrinsic value theories of nature

This study empirically assesses the extent to which intrinsic value theories of nature are accepted and acknowledged outside the realm of academic environmental ethics. It focuses on twenty of the largest landowning organisations in England, including both conservation and non-conservation organisations and investigates the environmental philosophical beliefs and values held by representative individuals of these groups. An in-depth interview was held with a representative from each organisation. The interviews were analysed using qualitative data analysis software and the results compared against a backdrop of academic philosophical positions. The study found that an ecocentric position which acknowledges nature's intrinsic value was adopted by the majority of respondents, both from conservation and non-conservation organisations. However, it was also found that individuals felt the idea of nature's intrinsic value was generally not reflected in organisational policy.

Multi-ionization of helium and lithium using the independent electron and independent event models with intrinsic CDW

Cross sections for the multi-ionization of He and Li are presented for impact energies in the range of 50 to 1000 keV/amu. These are calculated using the eikonal initial state approximation to represent the input and exit channels of the active electrons. The ionization process is simulated in a variety of ways, most notably an attempt to account for the effects of electron correlation via the inclusion of a continuum density of states (CDS) term. Inadequacies, of the CDW formulation at small impact parameters, and of the models themselves, are discussed and conclusions are drawn on what repercussions this has for the cross sections calculated.