274 research outputs found

    Ultrastructural cellular signatures: does cellular form follow function?

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    Cognitive behavior therapy in panic disorder and comorbid major depression - A naturalistic study

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    Background: There is a lack of evidence about the effectiveness of cognitive behavior therapies (CBT) in settings of routine clinical care as well as in the treatment of panic and comorbid disorders. Methods: We investigated a group-oriented CBT approach for 80 patients with panic disorder including 35 patients with current comorbid major depression. Assessments took place 6 months before treatment, at the beginning and end of treatment, and 1 year later. Structured interviews and multiple clinical self-rating scales were used. Results: Panic patients with comorbid major depression showed higher anxiety-specific and nonspecific pathology. The most striking benefits were in reducing avoidance behavior, while improvements concerning catastrophic beliefs were smaller, but still significant. For most self-rating scale results, patients with and without comorbid depression improved to a comparable degree. However, the end-state functioning of patients with panic disorder and current comorbid depression at admission is significantly lower than for patients with panic disorder alone, Conclusions: The results point to the necessity to develop and improve treatment approaches for patients with comorbidity of panic disorder and current major depression. Copyright (C) 2000 S.Karger AG, Basel

    SimilarityLab:Molecular similarity for sar exploration and target prediction on the web

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    Exploration of chemical space around hit, experimental, and known active compounds is an important step in the early stages of drug discovery. In academia, where access to chemical synthesis efforts is restricted in comparison to the pharma-industry, hits from primary screens are typically followed up through purchase and testing of similar compounds, before further funding is sought to begin medicinal chemistry efforts. Rapid exploration of druglike similars and structure‚Äďactivity relationship profiles can be achieved through our new webservice SimilarityLab. In addition to searching for commercially available molecules similar to a query compound, SimilarityLab also enables the search of compounds with recorded activities, generating consensus counts of activities, which enables target and off-target prediction. In contrast to other online offerings utilizing the USRCAT similarity measure, SimilarityLab‚Äôs set of commercially available small molecules is consistently updated, currently containing over 12.7 million unique small molecules, and not relying on published databases which may be many years out of date. This ensures researchers have access to up-to-date chemistries and synthetic processes enabling greater diversity and access to a wider area of commercial chemical space. All source code is available in the SimilarityLab source repository

    Development of Multiscale Biological Image Data Analysis: Review of 2006 International Workshop on Multiscale Biological Imaging, Data Mining and Informatics, Santa Barbara, USA (BII06)

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    The 2006 International Workshop on Multiscale Biological Imaging, Data Mining and Informatics was held at Santa Barbara, on Sept 7‚Äď8, 2006. Based on the presentations at the workshop, we selected and compiled this collection of research articles related to novel algorithms and enabling techniques for bio- and biomedical image analysis, mining, visualization, and biology applications

    CLAffinity:A software tool for identification of optimum ligand affinity for competition-based primary screens

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    [Image: see text] A simplistic assumption in setting up a competition assay is that a low affinity labeled ligand can be more easily displaced from a target protein than a high affinity ligand, which in turn produces a more sensitive assay. An often-cited paper correctly rallies against this assumption and recommends the use of the highest affinity ligand available for experiments aiming to determine competitive inhibitor affinities. However, we have noted this advice being applied incorrectly to competition-based primary screens where the goal is optimum assay sensitivity, enabling a clear yes/no binding determination for even low affinity interactions. The published advice only applies to secondary, confirmatory assays intended for accurate affinity determination of primary screening hits. We demonstrate that using very high affinity ligands in competition-based primary screening can lead to reduced assay sensitivity and, ultimately, the discarding of potentially valuable active compounds. We build on techniques developed in our PyBindingCurve software for a mechanistic understanding of complex biological interaction systems, developing the ‚ÄúCLAffinity tool‚ÄĚ for simulating competition experiments using protein, ligand, and inhibitor concentrations common to drug screening campaigns. CLAffinity reveals optimum labeled ligand affinity ranges based on assay parameters, rather than general rules to optimize assay sensitivity. We provide the open source CLAffinity software toolset to carry out assay simulations and a video summarizing key findings to aid in understanding, along with a simple lookup table allowing identification of optimal dynamic ranges for competition-based primary screens. The application of our freely available software and lookup tables will lead to the consistent creation of more performant competition-based primary screens identifying valuable hit compounds, particularly for difficult targets

    MRlogP:Transfer learning enables accurate logP prediction using small experimental training datasets

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    Small molecule lipophilicity is often included in generalized rules for medicinal chemistry. These rules aim to reduce time, effort, costs, and attrition rates in drug discovery, allowing the rejection or prioritization of compounds without the need for synthesis and testing. The availability of high quality, abundant training data for machine learning methods can be a major limiting factor in building effective property predictors. We utilize transfer learning techniques to get around this problem, first learning on a large amount of low accuracy predicted logP values before finally tuning our model using a small, accurate dataset of 244 druglike compounds to create MRlogP, a neural network-based predictor of logP capable of outperforming state of the art freely available logP prediction methods for druglike small molecules. MRlogP achieves an average root mean squared error of 0.988 and 0.715 against druglike molecules from Reaxys and PHYSPROP. We have made the trained neural network predictor and all associated code for descriptor generation freely available. In addition, MRlogP may be used online via a web interface

    √Ėffnungsklauseln in der tariflichen Lohnpolitik √Ėsterreichs - Umsetzung in Betriebsvereinbarungen und politische Einsch√§tzung

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    "Bei den Verhandlungen √ľber die Entgeltkollektivvertr√§ge f√ľr die Metallarbeiter bzw. f√ľr die Industrieangestellten (ca. 310.000 Besch√§ftigte) im Herbst 1993 haben sich die √∂sterreichischen Kollektivvertragsparteien auf eine sogenannte √Ėffnungsklausel geeinigt. Dadurch war es m√∂glich, anstelle der grunds√§tzlich ausgehandelten Ist- Lohn/Gehaltserh√∂hung durch Betriebsvereinbarungen "besch√§ftigungsf√∂rdernde Ma√ünahmen" festzulegen. Der vorliegende Beitrag analysiert in der Folge die im Zusammenhang mit der √Ėffnungsklausel abgeschlossenen Betriebsvereinbarungen sowie die Auswirkungen der (teilweisen) Verlagerung der Lohnpolitik auf die betriebliche Ebene. Zentrale Ergebnisse der Untersuchung der Betriebsvereinbarungen sind der Ma√ünahmenschwerpunkt bei Investitionen im Bereich der technischen Ausstattung der Betriebe, das √ľberwiegend geringe Ma√ü an Konkretheit der vereinbarten Regelungen sowie das weitgehende Fehlen von Regelungen zur Durchf√ľhrung bzw. Kontrolle der besch√§ftigungsf√∂rdernden Ma√ünahmen. Die politischen Konsequenzen bestehen erstens in einer Machtverschiebung innerhalb der Arbeitnehmervertretung und zweitens in massiven Ver√§nderungen f√ľr die Mitbestimmung des Betriebsrates - sowohl was seinen Kompetenzbereich als auch seine Durchsetzungsf√§higkeit betrifft." (Autorenreferat)"In the negotiation on the collective pay agreement for the metal-industry blue collar workers and for the industrial white collar workers in autumn 1993 the Austrian Principal Interest Associations agreed on a so called "opening clause". Thereby it is possible to fix in formal plant agreements measures which are conducive to occupation instead of the basic bargained rise of the real wages. This article analyses the formal plant agreements which were using the "opening clause" as well as the implications of the (partial) transfer of the wage policy to the company level. The main results of the study are the priority of the measures at industrial equipment's investments of the companies, the predominant low degree of precision of the agreed regulations as well as the absence of regulations about the realization and control of the measures. The political consequences are displacement of power inside the employee's representation and in massive changes to works council codetermination - concerning both its competence and its ability to assert." (author's abstract

    Quantitative microdialysis:Experimental protocol and software for small molecule protein affinity determination and for exclusion of compounds with poor physicochemical properties

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    Quantitative microdialysis is a traditional biophysical affinity determination technique. In the development of the detailed experimental protocol presented, we used commercially available equipment, rapid equilibrium dialysis (RED) devices (ThermoFisher Scientific), which means that it is open to most laboratories. The target protein and test compound are incubated in a chamber partitioned to allow only small molecules to transition to a larger reservoir chamber, then reversed-phase high performance liquid chromatography (RP-HPLC) or liquid chromatography–mass spectrometry (LC–MS) is used to determine the abundance of compound in each chamber. A higher compound concentration measured in the chamber that contains the target protein indicates binding. As a novel, and differentiating contribution, we present a protocol for mathematical analysis of experimental data. We provide the equations and the software to yield dissociation constants for the test compound-target protein complex up to 0.5 mM KD, and we quantitatively discuss the limitations of affinities in relation to measured compound concentrations

    Die Verteilungsoption in Kollektivverträgen der österreichischen Industrie: ein erfolgreiches Instrument organisierter Dezentralisierung?

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    "Bei den Verhandlungen √ľber die Entgeltkollektivvertr√§ge f√ľr die Metallarbeiter bzw. Industrieangestellten (√ľber 300.000 Besch√§ftigte) haben sich die √∂sterreichischen Kollektivvertragsparteien seit Herbst 1997 j√§hrlich auf eine sogenannte Verteilungsoption geeinigt. Sie erlaubt es, einen Teil der kollektivvertraglichen Ist-Entgelterh√∂hung innerbetrieblich nach leistungsbezogenen und sozialen Gesichtspunkten zu verteilen. Die formelle Grundlage daf√ľr bildet eine Betriebsvereinbarung. Dieser Beitrag analysiert die betriebliche Umsetzung dieser √Ėffnungsklausel und diskutiert kritische Faktoren f√ľr den (Miss)Erfolg der Verteilungsoption als Instrument organisierter Dezentralisierung industrieller Beziehungen. Die wesentlichen Elemente f√ľr den Erfolg der Verteilungsoption bilden die Interaktionsbeziehungen zwischen den Akteuren auf der Verbands- und der betrieblichen Ebene, die politischen und √∂konomischen Interessenlagen des Managements und des Betriebsrats, deren Kooperationsmuster sowie die vorherrschende Unternehmenskultur. Die empirische Basis dieser Analyse bildet vor allem eine schriftliche Befragung des (Personal) Managements der betroffenen Betriebe √ľber die (Nicht)Anwendung der Verteilungsoption in den Jahren 1997 und 1998." (Autorenreferat)"In the annual pay negotiations for metal industry blue-collar workers and all whitecollar workers in the manufacturing sector (together more than 300,000 employees) from 1997 to 2000, the unions and employer organisations agreed to a specific opening clause ('Verteilungsoption', VO). These allow formal workplace agreements about the distribution of a specified part of the increase of contractual pay for efficiency or social reasons. This paper investigates the implementation of such opening clauses and discusses to what extent they can be regarded as successful method of organised decentralisation. Particularly important are the relationships between unions and employer associations and the main actors at company level (management, works councils), economic and political interests of management and works councils, and their dominant patterns of co-operation and corporate culture. The study is based on a survey of personnel managers of the affected companies about their application or refusal of opening clauses in 1997 and 1998." (author's abstract
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