bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of downstream integration in the US pharmaceutical industry
Authors: Simonet Daniel 
Published: June 2007

PurposeThis paper aims to review the vertical or quasi‐vertical integration that characterized the pharmaceutical industry in the mid‐1990s. The acquisitions and vertical partnerships that linked pharmacy benefits managers and drug manufacturers modified the structure of the market at that time. What were the motivations of those agreements? Did they induce any distortion on competition in the drug market? And why did they fail to achieve their desired strategic advantages?Design/methodology/approachThe paper uses established theoretical perspectives, such as the resource‐based view and the theory of contestable markets, as the basis for a descriptive analysis, documenting strategic decisions of vertical integration using supporting literature in marketing and strategy.FindingsVertical integration did not obtain the intended results (e.g. acquisition of competitive advantages). This perspective provides a framework to examine vertical integration strategies, applicable to other industries.Originality/valueThe paper reviews the objectives of vertical integration strategies of US drug firms in the 1990s and their hidden agendas.
Pharmaceutical marketing return‐on‐investment: a European perspective
Authors: Rod Michel , Ashill Nicholas J. , Carruthers Janet 
Published: June 2007

PurposeA key objective of the 5th Annual Pharmaceutical Congress “Marketing ROI for Pharma” conference was to illustrate how in the midst of a very turbulent environment, and with higher demand for pharmaceutical marketers to deliver bigger profits from increasingly smaller promotional budgets, there are a few critical decision areas that, if addressed appropriately, can help to deliver better return on investment (ROI). This commentary paper aims to provide a summary of what was discussed.Design/methodology/approachGiven access to the conference presenters' original materials, the authors condensed the presentations into a summary article with reference to some recent academic work in the area.FindingsThe article summarises the presentations of a number of European pharmaceutical industry practitioners, healthcare professionals and government policy personnel in their assessments of the turbulent European pharmaceutical industry environment and the challenges associated with optimising ROI from promotional spending.Practical implicationsThe entire paper summarises recent industry practice in Europe regarding how to optimise pharmaceutical ROI with respect to marketing activities and provides actual examples of how to do this.Originality/valuePrimarily targeting pharmaceutical industry practitioners, this paper provides a timely and thorough resource for those industry personnel charged with the mission of maximizing pharmaceutical marketing ROI.
Women customers in pubs: still a business opportunity
Authors: Pratten J.D. , Lovatt C.J. 
Published: June 2007

PurposeThe aim of this paper was to outline the changes in the 20th century public house, where the simultaneous development of pub products and facilities and a changing environment have encouraged a growth of the female customer.Design/methodology/approachThere has been a heavy use of secondary sources drawn from the whole of the period studied. This has been augmented by discussions with licensees, retired licensees and older pub customers, to collect their reflections on the industry.FindingsThe public house of 60 years ago had a largely male, working class beer drinking clientele. Over the years, it has become accessible to women and children, the hungry and those seeking entertainment. These changes have been effected by the owners, introducing new products and altering the premises, licensees seeking to attract trade, government legislation and external factors. This paper attempts to identify the changes and their causes, with particular reference to the female customer.Research limitations/implicationsThe work reports the changes in the industry and examines some of the causes. Further work could examine such causes more carefully, and could include regional studies for comparison purposes.Practical implicationsThe paper demonstrates the extent of change, and suggests that further women‐friendly moves could be welcomed; it further suggests some strategies to develop the female customer base.Originality/valueThe topic could be of interest to the general reader as well as practitioners and students of the hospitality industry. It suggests that pubs can become even more women‐friendly, which could represent a business opportunity to some practitioners.
Revealed preference analysis of red wine attributes using polarisation
Authors: Jarvis Wade , Rungie Cam , Lockshin Larry 
Published: June 2007

PurposeThe usual method of analysis of product attributes in marketing is to fit a multinomial logit model within a stated choice experiment, to determine the impact of attributes on the choice probability, which is equivalent to market share. The market share is intuitive and is based on each single choice in the study. However, revealed preference allows for a study into repeat purchase and loyalty, which can also be rich constructs for determining consumer preference.Design/methodology/approachThe authors introduce a loyalty measure, polarisation, and show results based on a wine data set of revealed preference. Polarisation is a function of the beta binomial distribution (BBD) and can also be a function of the Dirichlet multinomial distribution (DMD). The DMD provides a standardised or average loyalty effect for each attribute (such as wine variety), and the BBD an individual effect for each attribute level (such as cabernet) within the attribute. While the DMD results provide a rich “first‐pass” of the data, it is the individual results which can classify levels as reinforcing, niche, or change‐of‐pace in nature, with subsequent different marketing implications. These implications are drawn out in this study.FindingsSpecifically, the DMD results show higher loyalty towards price and variety rather than to region and brand. The BBD results show that segmented preferences in the wine market are influenced more by the price attribute levels and that the two key single varietals in the red wine category tend to behave as reinforcing attribute levels with important marketing implications for small and large wine brands.Originality/valueThe authors extend the work of stated choice experiments into the realm of actual consumer purchase behaviour for wine. They also find that consumers’ repeat purchasing is based on attributes other than brand. This provides a useful platform for both researchers to further investigate loyalty/repurchasing using attributes as well as for marketing practitioners to better position their products to consumers.
The wine consumer's behaviour in selected stores of Italian major retailing chains
Authors: Seghieri Chiara , Casini Leonardo , Torrisi Francesco 
Published: June 2007

PurposeThe principal aim of this article is to examine attitudes of Italian consumers in relation to wine, identifying specific types of wine buyers.Design/methodology/approachA sample of 442 Italian wine consumers has been surveyed and three measurement instruments have been developed for grouping the observations by means of multivariate statistical analysis. The study then investigates both the consumer and product characteristics that significantly differentiate between the derived clusters of buyers and finally provides an external validity check.FindingsAlthough the study is exploratory in nature, there is evidence that four wine‐related consumer segments exist in our sample. These segments are habitual wine buyers, rational buyers, interested consumers, and professionals of promotions.Originality/valueFor wine marketers, the results of this research clearly support the need for a targeted approach to their consumer market. The study identifies the principal consequences of the results in order to provide both retailers and producers some useful marketing suggestions.
Significance of mutations on the structural perturbation of thymidylate synthase: Implications for their involvement in subunit exchange
Authors: Saxl Ruth L. , Maley Gladys F. , Hauer Charles R. , Maccoll Robert , Changchien Liming , Maley Frank 
Published: June 2007

AbstractWild‐type thymidylate synthase (WT‐TS) from Escherichia coli and several of its mutants showed varying degrees of susceptibility to trypsin. While WT‐TS was resistant to trypsin as were the mutants C146S, K48E, and R126K, others such as Y94A, Y94F, C146W, and R126E were digested but at different rates from one another. The peptides released from the mutants were identified by mass spectrometry and Edman sequence analysis. The known crystal structures for WT‐TS, Y94F, and R126E, surprisingly, showed no structural differences that could explain the difference in their susceptibility to trypsin. One explanation is that the mutations could perturb the dynamic equilibrium of the dimeric state of the mutants as to increase their dissociation to monomers, which being less structured than the dimer, would be hydrolyzed more readily by trypsin. Earlier studies appear to support this proposal since conditions that promote subunit dissociation in solutions of R126E with other inactive mutants, such as dilution, low concentrations of urea, and elevated pH, greatly enhance the rate of restoration of TS activity. Analytic ultracentrifuge studies with various TSs in urea, or at pH 9.0, or that have been highly diluted are, for the most part, in agreement with this thesis, since these conditions are associated with an increase in dissociation to monomers, particularly with the mutant TSs. However, these studies do not rule out the possibility that conformation differences among the various TS dimers are responsible for the differences in susceptibility to trypsin, particularly at high concentrations of protein where the WT‐TS and mutants are mainly dimers.
Configurational entropy elucidates the role of salt‐bridge networks in protein thermostability
Authors: Missimer John H. , Steinmetz Michel O. , Baron Riccardo , Winkler Fritz K. , Kammerer Richard A. , Daura Xavier , van Gunsteren Wilfred F. 
Published: June 2007

AbstractDetailed knowledge of how networks of surface salt bridges contribute to protein thermal stability is essential not only to understand protein structure and function but also to design thermostable proteins for industrial applications. Experimental studies investigating thermodynamic stability through measurements of free energy associated with mutational alterations in proteins provide only macroscopic evidence regarding the structure of salt‐bridge networks and assessment of their contribution to protein stability. Using explicit‐solvent molecular dynamics simulations to provide insight on the atomic scale, we investigate here the structural stability, defined in terms of root‐mean‐square fluctuations, of a short polypeptide designed to fold into a stable trimeric coiled coil with a well‐packed hydrophobic core and an optimal number of intra‐ and interhelical surface salt bridges. We find that the increase of configurational entropy of the backbone and side‐chain atoms and decreased pair correlations of these with increased temperature are consistent with nearly constant atom‐positional root‐mean‐square fluctuations, increased salt‐bridge occupancies, and stronger electrostatic interactions in the coiled coil. Thus, our study of the coiled coil suggests a mechanism in which well‐designed salt‐bridge networks could accommodate stochastically the disorder of increased thermal motion to produce thermostability.
The 2.2 Å resolution crystal structure of Bacillus cereus Nif3‐family protein YqfO reveals a conserved dimetal‐binding motif and a regulatory domain
Authors: Godsey Michael H. , Minasov George , Shuvalova Ludmilla , Brunzelle Joseph S. , Vorontsov Ivan I. , Collart Frank R. , Anderson Wayne F. 
Published: June 2007

AbstractYqfO of Bacillus cereus is a member of the widespread Nif3 family of proteins, which has been highlighted as an important target for structural genomics. The N‐ and C‐terminal domains are conserved across the family and contain a dimetal‐binding motif in a putative active site. YqfO contains an insert in the middle of the protein, present in a minority of bacterial family members. The structure of YqfO was determined at a resolution of 2.2 Å and reveals conservation of the putative active site. It also reveals the previously unknown structure of the insert, which despite extremely limited sequence conservation, bears great similarity to PII, CutA, and a number of other trimeric regulatory proteins. Our results suggest that this domain acts as a signal sensor to regulate the still‐unknown catalytic activity of the more‐conserved domains.
Using surface envelopes to constrain molecular modeling
Authors: Dugan Jonathan M. , Altman Russ B. 
Published: June 2007

AbstractMolecular density information (as measured by electron microscopic reconstructions or crystallographic density maps) can be a powerful source of information for molecular modeling. Molecular density constrains models by specifying where atoms should and should not be. Low‐resolution density information can often be obtained relatively quickly, and there is a need for methods that use it effectively. We have previously described a method for scoring molecular models with surface envelopes to discriminate between plausible and implausible fits. We showed that we could successfully filter out models with the wrong shape based on this discrimination power. Ideally, however, surface information should be used during the modeling process to constrain the conformations that are sampled. In this paper, we describe an extension of our method for using shape information during computational modeling. We use the envelope scoring metric as part of an objective function in a global optimization that also optimizes distances and angles while avoiding collisions. We systematically tested surface representations of proteins (using all nonhydrogen heavy atoms) with different abundance of distance information and showed that the root mean square deviation (RMSD) of models built with envelope information is consistently improved, particularly in data sets with relatively small sets of short‐range distances.
Nonbonded terms extrapolated from nonlocal knowledge‐based energy functions improve error detection in near‐native protein structure models
Authors: Ferrada Evandro , Melo Francisco 
Published: June 2007

AbstractThe accurate assessment of structural errors plays a key role in protein structure prediction, constitutes the first step of protein structure refinement, and has a major impact on subsequent functional inference from structural data. In this study, we assess and compare the ability of different full atom knowledge‐based potentials to detect small and localized errors in comparative protein structure models of known accuracy. We have evaluated the effect of incorporating close nonbonded pairwise atom terms on the task of classifying residue modeling accuracy. Since the direct and unbiased derivation of close nonbonded terms from current experimental data is not possible, we extrapolated those terms from the corresponding pseudo‐energy functions of a nonlocal knowledge‐based potential. It is shown that this methodology clearly improves the detection of errors in protein models, suggesting that a proper description of close nonbonded terms is important to achieve a more complete and accurate description of native protein conformations. The use of close nonbonded terms directly derived from experimental data exhibited a poor performance, demonstrating that these terms cannot be accurately obtained by using the current data and methodology. Some external knowledge‐based energy functions that are widely used in model assessment also performed poorly, which suggests that the benchmark of models and the specific error detection task tested in this study constituted a difficult challenge. The methodology presented here could be useful to detect localized structural errors not only in high‐quality protein models, but also in experimental protein structures.
Structural and biochemical characterization of a novel Mn2+‐dependent phosphodiesterase encoded by the yfcE gene
Authors: Miller Darcie J. , Shuvalova Ludmilla , Evdokimova Elena , Savchenko Alexei , Yakunin Alexander F. , Anderson Wayne F. 
Published: June 2007

AbstractEscherichia coli YfcE belongs to a conserved protein family within the calcineurin‐like phosphoesterase superfamily (Pfam00149) that is widely distributed in bacteria and archaea. Superfamily members are metallophosphatases that include monoesterases and diesterases involved in a variety of cellular functions. YfcE exhibited catalytic activity against bis‐p‐nitrophenyl phosphate, a general substrate for phosphodiesterases, and had an absolute requirement for Mn2+. However, no activity was observed with phosphodiesters and over 50 naturally occurring phosphomonoesters. The crystal structure of the YfcE phosphodiesterase has been determined to 2.25 Å resolution. YfcE has a β‐sandwich architecture similar to metallophosphatases of common ancestral origin. Unlike its more complex homologs that have added structural elements for regulation and substrate recognition, the relatively small 184‐amino‐acid protein has retained its ancestral simplicity. The tetrameric protein carries two zinc ions per active site from the E. coli extract that reflect the conserved di‐Mn2+ active site geometry. A cocrystallized sulfate inhibitor mimics the binding of phosphate moeities in known ligand/phosphatase complexes. Thus, YfcE has a similar active site and biochemical mechanism as well‐characterized superfamily members, while the YfcE phosphodiester‐containing substrate is unique.
OPUS‐Ca: A knowledge‐based potential function requiring only Cα positions
Authors: Wu Yinghao , Lu Mingyang , Chen Mingzhi , Li Jialin , Ma Jianpeng 
Published: June 2007

AbstractIn this paper, we report a knowledge‐based potential function, named the OPUS‐Ca potential, that requires only Cα positions as input. The contributions from other atomic positions were established from pseudo‐positions artificially built from a Cα trace for auxiliary purposes. The potential function is formed based on seven major representative molecular interactions in proteins: distance‐dependent pairwise energy with orientational preference, hydrogen bonding energy, short‐range energy, packing energy, tri‐peptide packing energy, three‐body energy, and solvation energy. From the testing of decoy recognition on a number of commonly used decoy sets, it is shown that the new potential function outperforms all known Cα‐based potentials and most other coarse‐grained ones that require more information than Cα positions. We hope that this potential function adds a new tool for protein structural modeling.
The leucine‐rich repeat (LRR) protein, CaLRR1, interacts with the hypersensitive induced reaction (HIR) protein, CaHIR1, and suppresses cell death induced by the CaHIR1 protein
Authors: JUNG HO WON , HWANG BYUNG KOOK 
Published: June 2007

SUMMARYLeucine‐rich repeat proteins (LRRs) function in a number of signal transduction pathways via protein–protein interactions. The gene encoding a small protein of pepper, CaLRR1, is specifically induced upon pathogen challenge and treatment with pathogen‐associated molecular patterns (PAMPs). We identified a pepper hypersensitive induced reaction (CaHIR1) protein that interacts with the LRR domain of the CaLRR1 protein using yeast two‐hybrid screening. Ectopic expression of the pepper CaHIR1 gene induces cell death in tobacco and Arabidopsis, indicating that the CaHIR1 protein may be a positive regulator of HR‐like cell death. Because transformation is very difficult in pepper plants, we over‐expressed CaLRR1 and CaHIR1 in Arabidopsis to determine cellular functions of the two genes. The over‐expression of the CaHIR1 gene, but not the CaLRR1 gene, in transgenic Arabidopsis confers disease resistance in response to Pseudomonas syringae infection, accompanied by the strong expression of PR genes, the accumulation of both salicylic acid and H2O2, and K+ efflux in plant cells. In Arabidopsis and tobacco plants over‐expressing both CaHIR1 and CaLRR1, the CaLRR1 protein suppresses not only CaHIR1‐induced cell death, but also PR gene expression elicited by CaHIR1 via its association with HIR protein. We propose that the CaLRR1 protein functions as a novel negative regulator of CaHIR1‐mediated cell death responses in plants.
Comparative transcript profiling by cDNA‐AFLP reveals similar patterns of Avr4/Cf‐4‐ and Avr9/Cf‐9‐dependent defence gene expression
Authors: HONG WEI , XU YOU‐PING , ZHENG ZHONG , CAO JIA‐SHU , CAI XIN‐ZHONG 
Published: June 2007

SUMMARYTomato Cf genes confer resistance to the fungal pathogen Cladosporium fulvum. Although the Cf‐4 and Cf‐9 proteins are very similar, the Cf‐4‐ and Cf‐9‐dependent hypersensitive responses (HRs) are distinct in cell death pattern, intensity and sensitivity to environmental conditions. To investigate the mechanism leading to these differences, comparative transcript profiling of Avr4/Cf‐4‐ and Avr9/Cf‐9‐dependent defence gene expression was performed. To do this, cDNA‐AFLP analysis was conducted on Avr/Cf tomato seedlings undergoing early HR. Both Avr4/Cf‐4 and Avr9/Cf‐9 signalling elicited the same spectrum of genes, referred to here as Avr/Cf‐elicited (ACE) genes. Of approximately 25 000 transcript‐derived fragments (TDFs), 367 (1.5%) showed significant differential expression between HR+ and HR− seedlings (either Avr4/Cf‐4‐ or Avr9/Cf‐9‐dependent). However, 42.8% of the ACE TDFs (157/367 in total) showed quantitatively different expression in the two types of HR+ seedlings. The majority of these (135/157, 86.0%) displayed significantly greater differential expression (either induced or repressed) in Avr4/Cf‐4 HR+ seedlings than in Avr9/Cf‐9 HR+ seedlings. Our results are consistent with the previous observation that Avr4/Cf‐4‐dependent HR is more severe than Avr9/Cf‐9‐dependent HR, and indicate that the distinction between Avr4/Cf‐4‐ and Avr9/Cf‐9‐dependent HR is most probably a result of events upstream of the defence responses. Sequencing of 189 ACE fragments identified genes associated with: defence and resistance (33.3%), signal transduction (7.4%), HR and cell death (5.3%), transcriptional regulation and post‐transcriptional modification (4.3%). Expression data revealed that defence response, respiration and biological oxidation are strongly induced while photosynthesis is severely repressed in the HR+ seedlings.
Surface complex structures modelled with quantum chemical calculations: carbonate, phosphate, sulphate, arsenate and arsenite
Authors: Kubicki J. D. , Kwon K. D. , Paul K. W. , Sparks D. L. 
Published: June 2007

SummaryHybrid molecular orbital/density functional theory (MO/DFT) calculations on molecular clusters were used to model infrared (IR) vibrational frequencies and interatomic distances obtained via extended X‐ray absorption fine structure (EXAFS) spectroscopy. Molecular clusters were found to provide good agreement with experimental observations for the oxyanions carbonate, phosphate, sulphate, arsenate and arsenite. The results show a consistent tendency to form bidentate bridging surface complexes at low pH, but the protonation and hydration states play a significant role in the results obtained from calculation as various protonation states of monodentate surface complexes are also predicted to be stable as pH increases (i.e. the number of H+ ions in the model are decreased). A method for estimating the Gibbs free energy of adsorption (ΔGads) is discussed to complement the comparisons of experimental and theoretical spectroscopic parameters. Calculated ΔGads values were consistent with the interpretations based on modelling observed spectra.