bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disposal and simple living: exploring the circulation of goods and the development of sacred consumption
Authors: Cherrier Hélène 
Published: November 2009

Abstract

This study examines how consumers who engage in voluntary simplicity experience disposal in relation to changes in their values, identity, and lifestyle. The hermeneutic analysis shows disposal organized around three main themes: “desire for emancipation,” “sacrificing the surplus,” and “moving toward the sacred.” Each theme offers insights on disposal as a transcendental experience during which consumers relocate consumption meanings from the profane to the sacred. On the one hand, the practice of disposal symbolizes a distance from the profane marketplace and its constraining norms and on the other hand, it leads consumers to participate in the life of objects and to construct sacred consumption. Here, goods are removed from the profane commerce and transferred to sacredness with an eternal life of transit between hands and ownership. As such, goods can be regarded as alive, physically moving from one person to another. This article concludes that voluntary disposal can be seen as a form of empowerment. Through disposal, consumers participate in the life of objects. By contributing to the circulation of the material, consumers have the power to transform an act of pure elimination into a transcendental experience that prefigures the death of profane consumption and the birth of sacred consumption.

Copyright © 2009 John Wiley & Sons, Ltd.
Not moving things along: hoarding, clutter and other ambiguous matter
Authors: Maycroft Neil 
Published: November 2009

Abstract

Disposition and disposal are intriguing terms for, while they share the same roots, disposition is not usually understood popularly as a synonym of disposal. However, all disposal involves disposition as a prelude to destruction, reuse, recycling or redistribution of some sort. Here, however, disposition is considered in another sense; the relocation of an object without the attendant continuation of the disposal process. In particular, the paper considers the phenomena of the domestic hoarding of goods. Hoarding will be considered in relation to both opportunities for disposition and other types of ‘ambiguous’ stuff including clutter. Following this, hoarding as behaviour in relation to the spatial ‘disordering’ of material culture will be examined. Finally, the material nature of the hoard itself will be addressed. It is concluded that hoarding is an ambiguous concept without clear agreement as to its causes, characteristics, scope or significance. Its affinities with other forms of collecting, storing and ‘arranging’ matter also demand further attention. Finally, the paper calls for more empirical research as both adjunct and potential counterweight to its theoretical orientation.

Copyright © 2009 John Wiley & Sons, Ltd.
From trash to treasure and beyond: the meaning of voluntary disposition
Authors: Albinsson Pia A. , Perera B. Yasanthi 
Published: November 2009

Abstract

Extant consumer research literature focuses on the subtleties, multiplicity of meanings, and values consumers attach to acquisition of personal possessions. Researchers have devoted less attention to consumers' disposition behaviors, including factors that influence disposition decisions. This paper explores voluntary disposition using data gathered through participant observations and in‐depth interviews with a range of consumers, including those involved in clothing exchange (CE) events. The findings provide support for the a priori themes of values and consumption patterns, extending the life of self and goods, and consumers' self‐concept. Additionally, the findings yield emergent themes of role transitions, role models and family patterns, and shared community. Utilizing our findings, and extant literature, we propose a conceptual Framework of Voluntary Disposition that can be utilized to analyze further meanings of consumer disposition patterns in different contexts.

Copyright © 2009 John Wiley & Sons, Ltd.
Improving Compound Quality through in vitro and in silico Physicochemical Profiling
Authors: van de Waterbeemd Han 
Published: November 2009

AbstractMany compounds entering clinical studies do not survive the numerous hurdles for a good pharmacological lead to a drug on the market. The reasons for attrition have been widely studied which resulted in more early attention to compound quality related to physical chemistry, drug metabolism and pharmacokinetics (DMPK), and toxicology/safety. This paper will briefly review current physicochemical in vitro assays and in silico predictions to support compound and library design through to lead optimization. The most important physicochemical properties include lipophilicity (log P/D), pKa, solubility, and permeability. These drive key ADMET properties such as absorption, cell penetration, access to the brain, volume of distribution, plasma protein binding, metabolism, and toxicity, as well as biopharmaceutical behavior. Much data are now available from medium‐ to high‐throughput physchem and ADMET in vitro assays, either in the public domain (see, e.g., PubChem, PubMed) or in drug companies' in‐house databases. Such data are increasingly being computer‐modelled and used in predictive chemistry. New pipelining technology makes it easier to build and update QSAR models so that such models can use the latest available data to produce robust local and global predictive in silico ADMET models.
Large‐Scale Evaluation of log P Predictors: Local Corrections May Compensate Insufficient Accuracy and Need of Experimentally Testing Every Other Compound
Authors: Tetko Igor V. , Poda Gennadiy I. , Ostermann Claude , Mannhold Raimund 
Published: November 2009

AbstractA large variety of log P calculation methods failed to produce sufficient accuracy in log P prediction for two in‐house datasets of more than 96000 compounds contrary to their significantly better performances on public datasets. The minimum Root Mean Squared Error (RMSE) of 1.02 and 0.65 were calculated for the Pfizer and Nycomed datasets, respectively, in the ‘out‐of‐box’ implementation. Importantly, the use of local corrections (LC) implemented in the ALOGPS program based on experimental in‐house log P data significantly reduced the RMSE to 0.59 and 0.48 for the Pfizer and Nycomed datasets, respectively, instantly without retraining the model. Moreover, more than 60% of molecules predicted with the highest confidence in each set had a mean absolute error (MAE) less than 0.33 log units that is only ca. 10% higher than the estimated variation in experimental log P measurements for the Pfizer dataset. Therefore, following this retrospective analysis, we suggest that the use of the predicted log P values with high confidence may eliminate the need of experimentally testing every other compound. This strategy could reduce the cost of measurements for pharmaceutical companies by a factor of 2, increase the confidence in prediction at the analog design stage of drug discovery programs, and could be extended to other ADMET properties.
Membrane Permeability in the Gastrointestinal Tract: The Interplay between Microclimate pH and Transporters
Authors: Kristl Albin 
Published: November 2009

AbstractSome examples of pH‐ and transporter‐dependent permeability, determined in side‐by‐side diffusion cells, are summarized. We investigated the polarized transport in the mucosal‐to‐serosal direction of monocarboxylic acid‐type drugs through the excised rat jejunal tissue and an artificial membrane. We established that,in vitro, these substances are most probably not transported by monocarboxylate transporter 1, but by passive pH‐dependent transport. We also studied various influences on the permeability of fluorescein, a low permeability marker, through isolated rat intestinal segments, Caco‐2 cell monolayers, and an artificial membrane. Polarized transport of fluorescein in the serosal‐to‐mucosal direction through the rat jejunum by multidrug resistance‐associated protein was triggered by the addition ofD‐glucose to the mucosal side, while the pH‐dependent increase of fluorescein influx is presumably the consequence of a monocarboxylate transporter and a member of the organic‐anion transporting polypeptide family. With permeability experiments through the excised segments of rat small intestine, we ascertained that ciprofloxacin is a low‐permeability drug and has higher and pH‐dependent transport in the mucosal‐to‐serosal direction than in the opposite direction. We also established that neither the permeability of fluoroquinolones nor their solubility in different buffers was influenced by the interactions with metal cations.
Miniaturization of Powder Dissolution Measurement and Estimation of Particle Size
Authors: Avdeef Alex , Tsinman Konstantin , Tsinman Oksana , Sun Na , Voloboy Dmytro 
Published: November 2009

AbstractThe objective was to investigate the applicability and limitations of an approach for estimating particle size from powder dissolution measurement using as little as 50 μg of sample in 1 ml of buffer solutions. The powder dissolution profiles of five sparingly‐soluble drugs (hydrochlorothiazide, phenazopyridine hydrochloride, 2‐naphthoic acid, indomethacin, and dipyridamole) were evaluated with a novel biexponential spherical particle equation and also the Wang–Flanagan spherical particle non‐sink equation. The results were compared to particle sizing based on measured specific surface area by the Brunauer–Emmett–Teller (BET) method, and also based on Coulter counting. With the exception of hydrochlorothiazide, the model compounds indicated some agglomeration in the dissolution media. The dry‐state specific surface area was larger than expected from either the Coulter method or the powder‐dissolution data, especially for phenazopyridine hydrochloride. The particle radii estimated by the powder dissolution method ranged from 10 to 68 μm, with equilibrium solubilities spanning from 5 μg/ml (dipyridamole) to 911 μg/ml (hydrochlorothiazide). Powder dissolution data collected with the miniaturized apparatus can be used to determine particle size, with estimated values agreeing reasonably with those measured by the Coulter counter method.
Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept
Authors: Reichel Andreas 
Published: November 2009

AbstractDespite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK).To this day, PK support of CNS drug discovery heavily relies on improving the blood–brain barrier (BBB) permeabilityin vitroand/or the brain/plasma ratio (Kp)in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditionalKpratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non‐specific binding to brain lipids rather than free drug levels.To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measuredin vitroandin vivo, and integrated into a coherent model of brain penetration and distribution.The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic.
Prodrug Approaches for Enhancing the Bioavailability of Drugs with Low Solubility
Authors: Müller Christa E. 
Published: November 2009

AbstractLow water solubility and low bioavailability are frequent problems in drug development, particularly in the area of central nervous system (CNS) drugs. This short review describes selected prodrug approaches which have been developed to enhance the bioavailability of drugs, especially that of poorly soluble drugs. Some of the most successful drugs on the market are prodrugs. With a better understanding of active‐transport processes at cell membranes in the gut as well as at the blood–brain barrier, the importance of prodrug approaches will further increase in the future. Prodrug approaches will already be considered in the early phase of drug discovery.
The Unstirrable Water Layer Is Unstirrable because It Does Not Exist
Authors: Scherrer Robert A. 
Published: November 2009

AbstractA number of membrane‐permeation models require the incorporation of an unstirred or unstirrable water layer (UWL). An example occurs in PAMPA models when the effective permeation rate of lipophilic acids and bases, Pe, falls behind the expected permeation rate, Pm, at pH values providing a high concentration of unionized species in the donor phase. In such cases, the compound has an apparent pKa of a weaker acid or base. The explanation is that an UWL adjacent to the membrane provides a rate‐limiting diffusion barrier for such compounds. The thickness of the UWL is correlated with the difference between the aqueous pKa and the apparent pKa (pK$\rm{ {_{a}^{flux}}}$). Here, we provide an explanation for the pK$\rm{ {_{a}^{flux}}}$ term that requires no UWL. It comes from the fact that, in the process of passing into a membrane, an ionizable compound undergoes a change in pKa. At some point along its path into the membrane, the compound attains a maximum free energy, at which point it is as likely to continue into the membrane, as it is to return to the donor phase. This is the transition state for absorption. The pK$\rm{ {_{a}^{flux}}}$ is the pKa of the compound at the transition state. This is a testable hypothesis (see text). The relevance of absorption to permeation depends on the rate‐limiting step of permeation.
An Expert System Approach to the Assessment of Hepatotoxic Potential
Authors: Marchant Carol A. , Fisk Lilia , Note Reine R. , Patel Mukesh L. , Suárez Diana 
Published: November 2009

AbstractHepatotoxicity is a major cause of pharmaceutical drug attrition and is also a concern within other chemical industries. In silico approaches to the prediction of hepatotoxicity are an important tool in the early identification of adverse effects in the liver associated with exposure to a chemical. Here, we describe work in progress to develop an expert system approach to the prediction of hepatotoxicity, focussing particularly on the identification of structural alerts associated with its occurrence. The development of 74 such structural alerts based on public‐domain literature and proprietary data sets is described. Evaluation results indicate that, whilst these structural alerts are effective in identifying the hepatotoxicity of many chemicals, further research is needed to develop additional structural alerts to account for the hepatotoxicity of a number of chemicals which is not currently predicted. Preliminary results also suggest that the specificity of the structural alerts may be improved by the combined use of applicability domains based on physicochemical properties such as log P and molecular weight. In the longer term, the performance of predictive models is likely to benefit from the further integration of diverse data and prediction model types.
Predicting Ligand Interactions with ABC Transporters in ADME
Authors: Demel Michael A. , Krämer O. , Ettmayer Peter , Haaksma Eric E. J. , Ecker Gerhard F. 
Published: November 2009

AbstractABC‐type drug efflux pumps, e.g., ABCB1 (=P‐glycoprotein, =MDR1), ABCC1 (=MRP1), and ABCG2 (=MXR, =BCRP), confer a multi‐drug resistance (MDR) phenotype to cancer cells. Furthermore, the important contribution of ABC transporters for bioavailability, distribution, elimination, and blood–brain barrier permeation of drug candidates is increasingly recognized.This review presents an overview on the different computational methods and models pursued to predict ABC transporter substrate properties of drug‐like compounds. They encompass ligand‐based approaches ranging from ‘simple rule’‐based efforts to sophisticated machine learning methods. Many of these models show excellent performance for the data sets used. However, due to the complex nature of the applied methods, useful interpretation of the models that can be directly translated into chemical structures by the medicinal chemist is rather difficult.Additionally, very recent and promising attempts in the field of structure‐based modeling of ABC transporters, which embody homology modeling as well as recently published X‐ray structures of murine ABCB1, will be discussed.
Beyond Profiling: Using ADMET Models to Guide Decisions
Authors: Segall Matthew , Champness Edmund , Obrezanova Olga , Leeding Chris 
Published: November 2009

AbstractADMET Models, whether in silico or in vitro, are commonly used to ‘profile’ molecules, to identify potential liabilities or filter out molecules expected to have undesirable properties. While useful, this is the most basic application of such models. Here, we will show how models may be used to go ‘beyond profiling’ to guide key decisions in drug discovery. For example, selection of chemical series to focus resources with confidence or design of improved molecules targeting structural modifications to improve key properties.To prioritise molecules and chemical series, the success criteria for properties and their relative importance to a project's objective must be defined. Data from models (experimental or predicted) may then be used to assess each molecule's balance of properties against those requirements. However, to make decisions with confidence, the uncertainties in all of the data must also be considered. In silico models encode information regarding the relationship between molecular structure and properties. This is used to predict the property value of a novel molecule. However, further interpretation can yield information on the contributions of different groups in a molecule to the property and the sensitivity of the property to structural changes. Visualising this information can guide the redesign process. In this article, we describe methods to achieve these goals and drive drug‐discovery decisions and illustrate the results with practical examples.
Galectin‐1–Asialofetuin Interaction Is Inhibited by Peptides Containing the Tyr‐Xxx‐Tyr Motif Acting on the Glycoprotein
Authors: Wéber Edit , Hetényi Anasztázia , Váczi Balázs , Szolnoki Éva , Fajka‐Boja Roberta , Tubak Vilmos , Monostori Éva , Martinek Tamás A. 
Published: November 2009

AbstractGalectin‐1 (Gal‐1), a ubiquitous β‐galactoside‐binding protein expressed by various normal and pathological tissues, has been implicated in cancer and autoimmune/inflammatory diseases in consequence of its regulatory role in adhesion, cell viability, proliferation, and angiogenesis. The functions of Gal‐1 depend on its affinity for β‐galactoside‐containing glycoconjugates; accordingly, the inhibition of sugar binding blocks its functions, hence promising potential therapeutic tools. The Tyr‐Xxx‐Tyr peptide motifs have been reported to be glycomimetic sequences, mainly on the basis of their inhibitory effect on the Gal‐1–asialofetuin (ASF) interaction. However, the results regarding the efficacy of the Tyr‐Xxx‐Tyr motif as a glycomimetic inhibitor are still controversial. The present STD and trNOE NMR experiments reveal that the Tyr‐Xxx‐Tyr peptides studied do not bind to Gal‐1, whereas their binding to ASF is clearly detected. 15N,1H HSQC titrations with 15N‐labeled Gal‐1 confirm the absence of any peptide–Gal‐1 interaction. These data indicate that the Tyr‐Xxx‐Tyr peptides tested in this work are not glycomimetics as they interact with ASF via an unrevealed molecular linkage.
Electro‐Oxidation of Methanol on PtRu Nanostructured Catalysts Electrodeposited onto Electroactivated Carbon Fiber Materials
Authors: Sieben Juan M. , Duarte Marta M. E. , Mayer C. E. 
Published: November 2009

AbstractThe surface of different carbon substrates, such as glassy carbon (GC), graphite cloth (GC‐10), graphite felt (GF‐S2), and carbon fiber paper (CFP) was modified by electrochemical treatment to generate high concentrations of oxygenated functional groups. These activated carbons were used as substrates for the simultaneous electrodeposition of Pt and Ru by a double potentiostatic pulse program. The different catalyst/carbon systems were evaluated as electrodes for methanol oxidation in acid solution. Comparing the results for the oxidized and nonoxidized substrates, the oxidation of the different carbon materials prior to the catalyst deposition was found to lead to an increase in the electrode activity for methanol oxidation. This enhancement could be associated with a remarkable improvement of metal dispersion, reduction of particle size, and a higher active surface area of the catalyst. The electrodes prepared with oxidized graphite felt exhibited the greatest catalytic activity.
Tetrabrominated Lead Naphthalocyanine for Optical Power Limiting
Authors: Dini Danilo , Meneghetti Moreno , Calvete Mario J. F. , Arndt Thomas , Liddiard Colin , Hanack Michael 
Published: November 2009

AbstractThe complex 2,(3)‐tetrabromo‐3,(2)‐tetra[(3,5‐di‐tert‐butyl)phenyloxy]‐naphthalocyaninato lead [Br4(tBu2C6H3O)4NcPb, 1] has been prepared and its optical limiting properties for ns light pulses have been measured. Complex 1 behaves as a reverse saturable absorber within the spectral range 440–720 nm with a limiting threshold of 0.1 J cm−2 at 532 nm. The lifetime of the absorbing triplet excited state has been evaluated as 3.8×10−7 s and the quantum yield of triplet formation has been measured as 0.07 in toluene. The nonlinear optical transmission properties of complex 1 have also been determined in Plexiglas [naphthalocyanine content: 5.0×10−4 M (0.1 % by weight)]. A reversible nonlinear absorption was again observed for a fluence above 0.4 J cm−2, but through different excited‐state dynamics. This may be rationalized in terms of aggregation of the molecule in the polymer matrix.
Synthesis of Enantiopure Sulfonimidamides and Elucidation of Their Absolute Configuration by Comparison of Measured and Calculated CD Spectra and X‐Ray Crystal Structure Determination
Authors: Worch Christin , Atodiresei Iuliana , Raabe Gerhard , Bolm Carsten 
Published: November 2009

AbstractStraightforward syntheses of enantiopure N‐benzoyl‐ and N‐tert‐butyloxycarbonyl‐protected sulfonimidamides, which can be used as building blocks in newly designed catalysts, are presented. Key synthetic step is a dynamic resolution of a racemic sulfinic acid sodium salt. All subsequent transformations proceed stereospecifically. The absolute configurations at the sulfur atoms of both sulfonimidamides were determined by comparison of measured and calculated CD spectra. An X‐ray crystal structure determination of a sulfonimidoylguanidine derivative confirmed this result.