Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies: application to studies on the biotransformation of indinavir

Despite recent advances in the application of data-dependent liquid chromatography/tandem mass spectrometry (LC/MS/MS) to the identification of drug metabolites in complex biological matrixes, a prior knowledge of the likely routes of biotransformation of the therapeutic agent of interest greatly facilitates the detection and structural characterization of its metabolites. Thus, prediction of the [M + H]+ m/z values of expected metabolites allows for the construction of user-defined MS(n) protocols that frequently reveal the presence of minor drug metabolites, even in the presence of a vast excess of coeluting endogenous constituents. However, this approach suffers from inherent user bias, as a result of which additional "survey scans" (e.g., precursor ion and constant neutral loss scans) are required to ensure detection of as many drug-related components in the sample as possible. In the present study, a novel approach to this problem has been evaluated, in which knowledge-based predictions of metabolic pathways are first derived from a commercial database, the output from which is used to formulate a list-dependent LC/MS(n) data acquisition protocol. Using indinavir as a model drug, a substructure similarity search on the MDL metabolism database with a similarity index of 60% yielded 188 "hits", pointing to the possible operation of two hydrolytic, two N-dealkylation, three N-glucuronidation, one N-methylation, and several aromatic and aliphatic oxidation pathways. Integration of this information with data-dependent LC/MS(n) analysis using an ion trap mass spectrometer led to the identification of 18 metabolites of indinavir following incubation of the drug with human hepatic postmitochondrial preparations. This result was accomplished with only a single LC/MS(n) run, representing significant savings in instrument use and operator time, and afforded an accurate view of the complex in vitro metabolic profile of this drug.     

Pavlovian appetitive contingencies and approach versus withdrawal to conditioned stimuli in pigeons.

Investigated the directed skeletal movements of 21 female White Carneaux pigeons toward signals of food or no food in 3 experiments. Ss approached and pecked an illuminated key that was positively correlated with food delivery, and positioned themselves relatively far from an illuminated key that was negatively correlated with food delivery. Key illuminations alone, random presentations of key illuminations and food, and backward pairings of key illuminations and food did not produce keypecking or consistent approach-withdrawal. Therefore, directed skeletal behavior-often believed to be conditioned and maintained primarily or exclusively by operant procedures-also emerges on Pavlovian procedures. Several kinds of alternative explanations (e.g., conditioned reinforcement effects, and stimulus substitution) for these phenomena are considered, and some potential implications for operant discrimination learning are briefly explored. (17 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Securing the Operating System: Does lesser-known mean less at risk? Is the OS an example of security though obscurity?

It is no secret that Microsoft Windows NT is the hacker’s favourite Operating System (OS). According to defacement-tracking site Attrition.org, (www.Attrition.org) Windows NT received 54.41% of all recorded OS attacks between August 1999 and April 2001. In stark contrast, some of the lesser-known Operating Systems made up for as little as 0.1% of all OS attacks. However, despite the huge difference in the quantity of attacks, companies that employ the lesser-known systems may be at greater risk…     

Comparison of data gap-filling methods for Landsat ETM+ SLC-off imagery for monitoring forest degradation in a semi-deciduous tropical forest in Mexico

A number of methods to overcome the 2003 failure of the Landsat 7 Enhanced Thematic Mapper (ETM+) scan-line corrector (SLC) are compared in this article in a forest-monitoring application in the Yucatan Peninsula, Mexico. The objective of this comparison is to determine the best approach to accomplish SLC-off image gap-filling for the particular landscape in this region, and thereby provide continuity in the Landsat data sensor archive for forest-monitoring purposes. Four methods were tested: (1) local linear histogram matching (LLHM); (2) neighbourhood similar pixel interpolator (NSPI); (3) geostatistical neighbourhood similar pixel interpolator (GNSPI); and (4) weighted linear regression (WLR). All methods generated reasonable SLC-off gap-filling data that were visually consistent and could be employed in subsequent digital image analysis. Overall accuracy, kappa coefficients (κ), and quantity and allocation disagreement indices were used to evaluate unsupervised Iterative Self-Organizing Data Analysis (ISODATA) land-cover classification maps. In addition, Pearson correlation coefficients (r) and root mean squares of the error (RMSEs) were employed for estimates agreement with fractional land cover. The best results visually (overall accuracy > 85%, κ < 9%, quantity disagreement index < 5.5%, and allocation disagreement index < 12.5%) and statistically (r > 0.84 and RMSE < 7%) were obtained from the GNSPI method. These results suggest that the GNSPI method is suitable for routine use in reconstructing the imagery stack of Landsat ETM+ SLC-off gap-filled data for use in forest-monitoring applications in this type of heterogeneous landscape.     

Does Local Television News Coverage Cultivate Fatalistic Beliefs About Cancer Prevention?

Many U.S. adults hold fatalistic beliefs about cancer prevention despite evidence that a large proportion of cancer deaths are preventable. We report findings from two studies that assess the plausibility of the claim that local television (TV) news cultivates fatalistic beliefs about cancer prevention. Study 1 features a content analysis of an October 2002 national sample of local TV and newspaper coverage about cancer. Study 2 describes an analysis of the 2005 Annenberg National Health Communication Survey (ANHCS). Overall, findings are consistent with the claim that local TV news coverage may promote fatalistic beliefs about cancer prevention. We conclude with a discussion of study implications for cultivation theory and the knowledge gap hypothesis and suggest foci for future research.     

Optimization of carbon nanotube synthesis from porous anodic Al-Fe-Al templates

A parametric study of carbon nanotube (CNT) synthesis from catalytically active porous anodic Al-Fe-Al multilayer templates was conducted with respect to pore aspect ratio, Fe layer thickness, CNT synthesis temperature, and pre-anodization thermal annealing. Performance metrics included CNT catalytic activity and the pore wall integrity at the Al-Fe-Al interface. The observed CNT density was a strong function of pore diameter, synthesis temperature and pre-anodization annealing of the catalyst film. Vertical pore wall integrity at the Al-Fe-Al interface was optimized by selection of pre-anodization annealing conditions, with interfacial void formation observed in the absence of this technique. Based on CNT growth rates, an activation energy of 0.52 eV was observed for CNT synthesis for all film structures, regardless of pore aspect ratio. The optimization of templated CNT synthesis is expected to assist in the development of high-density vertically oriented CNT-based devices.     

A behaviour instantiation agent architecture

This paper presents a novel agent architecture, the VM-architecture, that chooses its actions via a behaviour instantiation mechanism inspired by Maes?s behaviour networks. The VM-architecture enables an agent, VMattie, built upon it, actively to gather information from humans using email in natural language, to compose announcements of next week?s seminars and to mail them each week to a list that she keeps updated. VMattie does all this without the supervision of a human. Implemented and tested in a UNIX environment, the system?s performance surpassed the authors? fondest hopes.     

The social construction of housing management

Although housing management as an occupational role has existed for over a century it has never received an adequate definition, and its scope and emphasis have varied over time. This paper locates housing management within the debates on the nature of the professions and bureaucracy, and suggests that these analyses are inadequate. It is proposed that a more fruitful approach in understanding the nature of housing management is derived from a consideration of its ‘social construction’. In support of this interpretation material from qualitative empirical research with practitioners is presented and analysed. Key respondents were identified as people working at the boundaries of housing management, such as in a caring or support role, since it was felt that the perceptions of such boundaries were important in defining the limits and limitations of housing management. In conclusion it is suggested that this is a critical moment for housing management in terms of achieving a more rigorous definition of its activities, and of seeking to resolve the conflict between the pressures to organise around commercial objectives and to provide a welfare service. Meanwhile there remains a somewhat paradoxical situation in that whilst the lack of consistent practice within housing management weakens its claims to occupational strength and legitimacy, these same inconsistencies permit individual practitioners the flexibility to offer a more responsive service to those in need.     

On the stability of adaptive pole-placement controllers with asaturating actuator

The authors examine how existing pole-placement algorithms work in the case of a saturating input. The stability of such algorithms and the modifications needed to make them work in the case of saturation are examined. The net result is that the analysis of G.C. Goodwin and K.S. Sin (1984) can be slightly modified to prove the stability of adaptive pole-placement, but only for the case where the plant is stable. It is shown that, for unstable plants, it is possible to push the plant into a state from which it cannot be returned to the origin (with a saturating input). Thus, it is fairly easy to generate examples of instability in the adaptive control system that would not exist with unbounded control authority