bluuebunny/crossref_metadata_2025 huggingface dataset:
Unlocking the sources of the apparent episodic stationarity of the P/E ratio
Authors: Karras Georgios , Lee Jin‐Man , Neuburger Hugh
Published: September 2007

Purpose

The purpose of this paper is to investigate the sources of the apparent episodic stationarity of the P/E ratio.

Design/methodology/approach

The Stock–Watson procedure is used to decompose a VAR/VMA model into changes in structure and changes volatility. In theory, if the P/E ratio is properly anticipated and shocks are random, according to Samuelson's proof, it should exhibit the characteristics of a pure martingale and therefore it should not be possible to statistically reject trend nonstationary.

Findings

Using a rolling window, the P/E ratio is shown to have episodic periods when trend nonstationarity could be rejected and that the P/E ratio was not properly anticipated. However, if there were changes in the structure of the underlying P/E ratio model or changes in the volatility of the underlying model, it suggests that the shocks impacting the P/E ratio would not be random and it might be possible to reject nonstationarity. This is investigated further with the objective of determining whether there was underlying structural change or volatility changes that are associated with these periods when trend nonstationarity in the P/E ratio could be rejected. The results are tested and found to be robust to a number of different specifications examined, including different data periods and frequencies.

Research limitations/implications

Results findings should be tested in other countries and in other periods.

Originality/value

The paper developed a methodology whereby it is possible to detect periods there the P/E ratio is not properly anticipated.
Domain‐concept association rules mining for large‐scale and complex cellular manufacturing tasks
Authors: Kay Mahamaneerat Wannapa , Shyu Chi‐Ren , Ho Shih‐Chun , Alec Chang C.
Published: September 2007

Purpose

The purpose of this paper is to provide a novel domain‐concept association rules (DCAR) mining algorithm that offers solutions to complex cell formation problems, which consist of a non‐binary machine‐component (MC) matrix and production factors for fast and accurate decision support.

Design/methodology/approach

The DCAR algorithm first identifies the domain‐concept from the demand history and then performs association rule mining to find associations among machines. After that, the algorithm forms machine‐cells with a series of inclusion and exclusion processes to minimize inter‐cell material movement and intra‐cell void element costs as well as to maximize the grouping efficacy with the constraints of bill of material (BOM) and the maximum number of machines allowed for each cell.

Findings

The DCAR algorithm delivers either comparable or better results than the existing approaches using known binary datasets. The paper demonstrates that the DCAR can obtain satisfying machine‐cells with production costs when extra parameters are needed.

Research limitations/implications

The DCAR algorithm adapts the idea of the sequential forward floating selection (SFFS) to iteratively evaluate and arrange machine‐cells until the result is stabilized. The SFFS is an improvement over a greedy version of the algorithm, but can only ensure sub‐optimal solutions. Practical implications – The DCAR algorithm considers a wide range of production parameters, which make the algorithm suitable to the real‐world manufacturing system settings.

Originality/value

The proposed DCAR algorithm is unlike other array‐based algorithms. It can group non‐binary MC matrix with considerations of real‐world factors including product demand, BOM, costs, and maximum number of machines allowed for each cell.
Plug and play (PnP) modelling approach to throughput analysis
Authors: Hua Tan Kim , Noble James
Published: September 2007

Purpose

The purpose of this paper is to propose a “plug and play” (PnP) approach to decision modelling. An approach to building models from components based on a “LEGO block” style of manufacturing simulation and analysis. The objective of this paper is to present ideas central to PnP modelling for throughput analysis.

Design/methodology/approach

Firstly, the PnP concept is introduced and the proposed framework is described. Then different techniques adopted in the framework are explained, and their applications are illustrated using a case example on manufacturing throughput analysis. Finally, the implications of this research are discussed and plans for further work are outlined.

Findings

The proposed PnP approach for rapid decision modelling was capable to support two important goals: productivity improvement to ensure that managers can rapidly build up models, and increase communication and decision support efficiency to ensure that those who should be using it, can and will use it.

Research limitations/implications

This research has so far introduced, described, and explained the PnP approach. The idea of PnP to support manufacturing decision modelling is new and not yet well developed. It is recognised that there are a number of additional issues that must be addressed before the proposed PnP approach is ready to make a practical impact.

Originality/value

The paper introduces a PnP approach to decision modelling.
The cluster approach and SME competitiveness: a review
Authors: Karaev Aleksandar , Lenny Koh S.C. , Szamosi Leslie T.
Published: September 2007

Purpose

The purpose of this paper is to review the effect of a cluster approach on SMEs' competitiveness. The primary objective is to examine the use of a cluster approach among SMEs as a tool for meeting their challenges related to globalisation and trade liberalisation, as well as investigating its contributing factor in the process of increasing their competitiveness.

Design/methodology/approach

The methodology used for this paper is a literature review of published materials. The literature analysis was performed based on research objectivity, coverage and authority.

Findings

There is strong evidence to suggest that a cluster policy brings additional positive effect to existing SME policy in industrialised economies, but such effects have not been extensively researched in developing (transition) countries, particularly from the point of view of the SMEs, which are the main actors in the cluster development process, in relation to whether their performance has been improved as a result of cluster effects.

Originality/value

The findings from this research will assist business managers in making more informed decisions regarding the adoption of a cluster approach and entering into cluster‐based relations, as well as assisting policy makers in designing more efficient cluster policies. The academic value will be added in the context of expanding knowledge in relation to the impact of clusters on economic development in transition countries and as such contribute in filling gaps within the existing body of knowledge.
An ANN‐based DSS system for quality assurance in production network
Authors: Chung Walter W.C. , Wong Kevin C.M. , Soon Paul T.K.
Published: September 2007

Purpose

The purpose of this paper is to propose an integrated model of decision support system (DSS), artificial neural network, information and communication technologies and statistical process control (SPC) to facilitate agreement by different stakeholders with special interests to commit to the decision that will be taken to stop the production line when something goes wrong somewhere in a supplier network environment.

Design/methodology/approach

A DSS is proposed to capture exceptional signals from source on deterioration of product quality to alert preventive actions needed before the problems are getting out of hand. The supervisors are given a set of guidelines to support making the decision. Real‐time SPC and rule‐based decision support procedures are used to trigger pre‐defined exceptional signals for forwarding to the most appropriate person (the knowledge holder in the problem domain) to make a decision to stop the line. All servers in all remote sites are internet‐connected and provide real‐time quality data to the regional supply chain manager. A case study is described to show how this is implemented in a lens manufacturing company.

Findings

A significant improvement in quality level can be achieved by holding the knowledge worker accountable for making the decision to stop the production line rather than made by default as is with most traditional operations.

Practical implications

To provide a concept to structure activities for decision support so that the persons responsible for making the decision to stop the production line is held accountable by all stakeholders.

Originality/value

Practitioners can replicate the approach used in this paper to their own situations involving decisions to be made to address un‐structured problems and unclear responsibilities.
The aggregation for enterprise distributed databases
Authors: Chiu Ruey‐Kei , Lenny Koh S.C. , Chang Chi‐Ming
Published: September 2007

Purpose

The purpose of this paper is to provide a data framework to support the incremental aggregation of, and an effective data refresh model to maintain the data consistency in, an aggregated centralized database.

Design/methodology/approach

It is based on a case study of enterprise distributed databases aggregation for Taiwan's National Immunization Information System (NIIS). Selective data replication aggregated the distributed databases to the central database. The data refresh model assumed heterogeneous aggregation activity within the distributed database systems. The algorithm of the data refresh model followed a lazy replication scheme but update transactions were only allowed on the distributed databases.

Findings

It was found that the approach to implement the data refreshment for the aggregation of heterogeneous distributed databases can be more effectively achieved through the design of a refresh algorithm and standardization of message exchange between distributed and central databases.

Research limitations/implications

The transaction records are stored and transferred in standardized XML format. It is more time‐consuming in record transformation and interpretation but it does have higher transportability and compatibility over different platforms in data refreshment with equal performance. The distributed database designer should manage these issues as well assure the quality.

Originality/value

The data system model presented in this paper may be applied to other similar implementations because its approach is not restricted to a specific database management system and it uses standardized XML message for transaction exchange.
Patient activation among Medicare beneficiaries
Authors: Williams Sunyna S. , Heller Amy
Published: September 2007

Purpose

The purpose of this research is to identify audience segments of Medicare beneficiaries, for the development of targeted and tailored communication activities to promote informed health care decision making.

Design/methodology/approach

Secondary analysis was conducted on data from the 2001 Medicare Current Beneficiary Survey. The 9,520 Medicare beneficiaries who had complete data on key variables constituted the analytic sample.

Findings

Cluster analysis identified four audience segments that varied separately with regard to health care decision‐making skills and motivation. Those in the active segment are skilled and motivated. Those in the passive segment are unskilled and unmotivated. Those in the high effort segment are motivated, but unskilled. And those in the complacent segment are skilled, but unmotivated. Additional analyses showed that the segments also varied on several additional variables of interest, such as knowledge, income, education, health behavior, health status, and preferred information sources. And finally, the segmentation screening tool was developed and shown to function adequately as a simple method to conduct segmentation in the field.

Research limitations/implications

Future research should further examine the reliability and validity of the segmentation scheme.

Originality/value

This research identified four segments of Medicare beneficiaries that vary with regard to health care decision‐making skills and motivation, and developed a simple tool to conduct segmentation.
The new Dutch health insurance system and its implications for pharmaceutical innovation
Authors: Cohen Joshua
Published: September 2007

Purpose

The purpose of this paper is to provide commentary on the state of affairs regarding implementation of Dutch health insurance reform, focusing on whether such reform is conducive to pharmaceutical innovation.

Design/methodology/approach

The general characteristics of the Dutch healthcare system is outlined, together with a brief synopsis of the 2006 health insurance reform initiative. This is followed by a description of the four market intervention mechanisms and their implications for pharmaceutical innovation. Finally, these implications and the potential for policy transfer to other European countries are discussed.

Findings

The new Dutch health insurance system represents a novel approach that closely follows Enthoven's managed competition model. Certain features of the new system are conducive to pharmaceutical innovation. These positive features include more flexibility on the part of private insurers to deviate from the national formulary, speedier reimbursement appraisals, and more earmarked funding for certain highly innovative pharmaceutical products. Other features, however, appear detrimental to drug innovation. These include direct price controls, reference pricing, and the still highly centralized nature of decision making with respect to drug reimbursement. On the whole, one could say that, despite many challenges, Dutch health insurance reform is a step in the right direction that may prove to be a boon to biopharmaceutical innovation if further steps are taken to remove obstacles.

Research limitations/implications

It is premature to draw firm conclusions on whether Dutch health insurance reform is conducive to pharmaceutical innovation. The new system is at an early stage in its evolution. Further, one should be cautious about the extent to which lessons can be drawn from the new Dutch system for other European countries, given the limited size of the Dutch biopharmaceutical industry relative to some of its European neighbors.

Originality/value

While much is known about how changes in the drug regulatory framework impact pharmaceutical innovation, very little is known about how changes in health care insurance impact pharmaceutical innovation. This paper aims to fill that void by examining the impact of the new Dutch health insurance system on drug innovation.
Web‐enabled product ID system as a tool in pharmaceutical marketing
Authors: Browe Christopher , Lu Wang Cheng
Published: September 2007

Purpose

The purpose of this paper is to explore how a web‐enabled product ID system can be applied to pharmaceutical marketing and consumer relationship management.

Design/methodology/approach

As a technical paper, it first introduces and describes the product ID system and then explores various marketing applications of this interactive communication tool in the pharmaceutical industry. Finally, it concludes with managerial implications and caveats.

Findings

The web‐based product ID system is able to provide a means for product validation and database marketing, facilitate interactive marketing communication and viral marketing, and collect customer information and feedback for research activities.

Research limitations/implications

The perceived lack of security of public networks and customer confidence about drug sourcing are always concerns when applied to online technology in pharmaceutical marketing. Caveats about building such a system of coded ID product are discussed.

Practical implications

The use of uniquely coded packaging would impact marketing research activities, enhance consumer promotions, allow end‐users to authenticate a drug's validity, provide a means for early reporting of unforeseen risks or benefits, and build/maintain customer relationship.

Originality/value

The proposed web‐based product ID system is an innovative concept that can have important marketing implications in the pharmaceutical industry.
The marketing concept, patient dumping and EMTALA
Authors: Bonnici Joseph
Published: September 2007

Purpose

The purpose of this paper is to show that in the presence of the marketing concept something is fundamentally wrong in our national health care system where patients are denied emergency medical treatment or are prematurely transferred from one hospital to another because they cannot guarantee payment.

Design/methodology/approach

A viewpoint is discussed citing supporting literature.

Findings

The literature suggests an adverse relationship between the marketing concept and the Emergency Medical Treatment and Active Labor Act (EMTALA) and further suggests that the two are failing indigent patients. The marketing concept as a driving business philosophy is too simplistic and commercially oriented to befit an emergency setting. At the same time, EMTALA suffers from serious shortcomings, shackles hospitals' freedom of contract and threatens the economics of health care.

Research limitations/implications

The paper lacks quantitative research to back its position.

Practical implications

It is not enough to coin positively sounding theories within healthcare marketing when these theories are inadequate in addressing the stark realities behind supply and demand. EMTALA as a remedial measure falls short in correcting the situation and a fresh outlook at the problem is warranted.

Originality/value

The paper taps into marketing and legal expertise in bringing together the marketing concept and EMTALA, two subjects that have never been twinned before in the literature. The subjects are of special interest in understanding the treatment of indigent patients.
Healthcare marketing: what is salient?
Authors: Kay Mark J.
Published: September 2007

Purpose

The purpose of this paper is to develop a perspective on what is “salient” or critical to the discipline of healthcare marketing by analyzing and contrasting the consumer (or patient) perspective with the institutional (or organizational) perspective. This “salience issue” is complicated by the structural problems in healthcare such as societal service systems, advances in medical technology, and the escalating costs of care. Reviewing selected studies, the paper examines how consumers face increasingly difficult health choices.

Design/methodology/approach

The paper examines the different priorities and goals for marketing that are implied by both patient and organizational perspectives in healthcare, focusing primarily on the excesses of the more “market‐based” US healthcare system.

Findings

Healthcare organizations need to better utilize marketing tools to inform consumers and assist their healthcare decisions. This effort needs to be balanced by healthcare organizations that can support the demand to improve quality and increase accessibility of care.

Originality/value

The perspective on the consumer (or patient) often becomes clouded amid the operation of increasingly complex and convoluted healthcare systems. A new perspective on healthcare marketing needs to be considered. Greater consumer access to healthcare information could improve patient decision making. To accomplish this, greater institutional diffusion of evidence‐based healthcare practices is needed to improve organizational performance.
Structure of a designed, right‐handed coiled‐coil tetramer containing all biological amino acids
Authors: Sales Mark , Plecs Joseph J. , Holton James M. , Alber Tom
Published: September 2007

The previous design of an unprecedented family of two‐, three‐, and four‐helical, right‐handed coiled coils utilized nonbiological amino acids to efficiently pack spaces in the oligomer cores. Here we show that a stable, right‐handed parallel tetrameric coiled coil, called RH4B, can be designed entirely using biological amino acids. The X‐ray crystal structure of RH4B was determined to 1.1 Å resolution using a designed metal binding site to coordinate a single Yb2+ ion per 33‐amino acid polypeptide chain. The resulting experimental phases were particularly accurate, and the experimental electron density map provided an especially clear, unbiased view of the molecule. The RH4B structure closely matched the design, with equivalent core rotamers and an overall root‐mean‐square deviation for the N‐terminal repeat of the tetramer of 0.24 Å. The clarity and resolution of the electron density map, however, revealed alternate rotamers and structural differences between the three sequence repeats in the molecule. These results suggest that the RH4B structure populates an unanticipated variety of structures.
The rigid connecting loop stabilizes hairpin folding of the two helices of the ATP synthase subunit c
Authors: Dmitriev Oleg Y. , Fillingame Robert H.
Published: September 2007

We have tested the role of the polar loop of subunit c of the Escherichia coli ATP synthase in stabilizing the hairpin structure of this protein. The structure of the c32–52 peptide corresponding to the cytoplasmic region of subunit c bound to the dodecylphosphocholine micelles was solved by high‐resolution NMR. The region comprising residues 41–47 forms a well‐ordered structure rather similar to the conformation of the polar loop region in the solution structure of the full‐length subunit c and is flanked by short α‐helical segments. This result suggests that the rigidity of the polar loop significantly contributes to the stability of the hairpin formed by the two helices of subunit c. This experimental system may be useful for NMR studies of interactions between subunit c and subunits γ and ε, which together form the rotor of the ATP synthase.
The crystal structure of the ligand‐binding module of human TAG‐1 suggests a new mode of homophilic interaction
Authors: Mörtl Mario , Sonderegger Peter , Diederichs Kay , Welte Wolfram
Published: September 2007

Human TAG‐1 is a neural cell adhesion molecule that is crucial for the development of the nervous system during embryogenesis. It consists of six immunoglobulin‐like and four fibronectin III‐like domains and is anchored to the membrane by glycosylphosphatidylinositol. Herein we present the crystal structure of the four N‐terminal immunoglobulin‐like domains of TAG‐1 (TAG‐1Ig1–4), known to be important in heterophilic and homophilic macromolecular interactions. The contacts of neighboring molecules within the crystal were investigated. A comparison with the structure of the chicken ortholog resulted in an alternative mode for the molecular mechanism of homophilic TAG‐1 interaction. This mode of TAG‐1 homophilic interaction is based on dimer formation rather than formation of a molecular zipper as proposed for the chicken ortholog.
Solution structure of the hypothetical protein TA0095 from Thermoplasma acidophilum: A novel superfamily with a two‐layer sandwich architecture
Authors: León Esther , Yee Adelinda , Ortíz Angel R. , Santoro Jorge , Rico Manuel , Jiménez M. Angeles
Published: September 2007

TA0095 is a 96‐residue hypothetical protein from Thermoplasma acidophilum that exhibits no sequence similarity to any protein of known structure. Also, TA0095 is a member of the COG4004 orthologous group of unknown function found in Archaea bacteria. We determined its three‐dimensional structure by NMR methods. The structure displays an α/β two‐layer sandwich architecture formed by three α‐helices and five β‐strands following the order β1‐α1‐β2‐β3‐β4‐β5‐α2‐α3. Searches for structural homologs indicate that the TA0095 structure belongs to the TBP‐like fold, constituting a novel superfamily characterized by an additional C‐terminal helix. The TA0095 structure provides a fold common to the COG4004 proteins that will obviously belong to this new superfamily. Most hydrophobic residues conserved in the COG4004 proteins are buried in the structure determined herein, thus underlying their importance for structure stability. Considering that the TA0095 surface shows a large positively charged patch with a high degree of residue conservation within the COG4004 domain, the biological function of TA0095 and the rest of COG4004 proteins might occur through binding a negatively charged molecule. Like other TBP‐like fold proteins, the COG4004 proteins might be DNA‐binding proteins. The fact that TA0095 is shown to interact with large DNA fragments is in favor of this hypothesis, although nonspecific DNA binding cannot be ruled out.
A cross‐strand Trp–Trp pair stabilizes the hPin1 WW domain at the expense of function
Authors: Jäger Marcus , Dendle Maria , Fuller Amelia A. , Kelly Jeffery W.
Published: September 2007

Using the human Pin1 WW domain (hPin1 WW), we show that replacement of two nearest neighbor non‐hydrogen‐bonded residues on adjacent β‐strands with tryptophan (Trp) residues increases β‐sheet thermodynamic stability by 4.8 kJ mol−1 at physiological temperature. One‐dimensional NMR studies confirmed that introduction of the Trp–Trp pair does not globally perturb the structure of the triple‐stranded β‐sheet, while circular dichroism studies suggest that the engineered cross‐strand Trp–Trp pair adopts a side‐chain conformation similar to that first reported for a designed “Trp‐zipper” β‐hairpin peptide, wherein the indole side chains stack perpendicular to each other. Even though the mutated side chains in wild‐type hPin1 WW are not conserved among WW domains and compose the β‐sheet surface opposite to that responsible for ligand binding, introduction of the cross‐strand Trp–Trp pair effectively eliminates hPin1 WW function as assessed by the loss of binding affinity toward a natural peptide ligand. Maximizing both thermodynamic stability and the domain function of hPin1 WW by the above mentioned approach appears to be difficult, analogous to the situation with loop 1 optimization explored previously. That introduction of a non‐hydrogen‐bonded cross‐strand Trp–Trp pair within the hPin1 WW domain eliminates function may provide a rationale for why this energetically favorable pairwise interaction has not yet been identified in WW domains or any other biologically evolved protein with known three‐dimensional structure.
The dominant‐negative effect of the Q218K variant of the prion protein does not require protein X
Authors: Lee Cheng I. , Yang Qingyuan , Perrier Veronique , Baskakov Ilia V.
Published: September 2007

Previous studies identified several single‐point mutants of the prion protein that displayed dominant‐negative effects on prion replication. The dominant‐negative effect was assumed to be mediated by protein X, an as‐yet‐unknown cellular cofactor that is believed to be essential for prion replication. To gain insight into the mechanism that underlies the dominant‐negative phenomena, we evaluated the effect of the Q218K variant of full‐length recombinant prion protein (Q218K rPrP), one of the dominant‐negative mutants, on cell‐free polymerization of wild‐type rPrP into amyloid fibrils. We found that both Q218K and wild‐type (WT) rPrPs were incorporated into fibrils when incubated as a mixture; however, the yield of polymerization was substantially decreased in the presence of Q218K rPrP. Furthermore, in contrast to fibrils produced from WT rPrP, the fibrils generated in the mixture of WT and Q218K rPrPs did not acquire the proteinase K‐resistant core of 16 kDa that was shown previously to encompass residues 97–230 and was similar to that of PrPSc. Our studies demonstrate that the Q218K variant exhibits the dominant‐negative effect in cell‐free conversion in the absence of protein X, and that this effect is, presumably, mediated by physical interaction between Q218K and WT rPrP during the polymerization process.
Interactions between homopolymeric amino acids (HPAAs)
Authors: Oma Yoko , Kino Yoshihiro , Toriumi Kazuya , Sasagawa Noboru , Ishiura Shoichi
Published: September 2007

Many human proteins contain consecutive amino acid repeats, known as homopolymeric amino acid (HPAA) tracts. Some inherited diseases are caused by proteins in which HPAAs are expanded to an excessive length. To this day, nine polyglutamine‐related diseases and nine polyalanine‐related diseases have been reported, including Huntington's disease and oculopharyngeal muscular dystrophy. In this study, potential HPAA–HPAA interactions were examined by yeast two‐hybrid assays using HPAAs of ∼30 residues in length. The results indicate that hydrophobic HPAAs interact with themselves and with other hydrophobic HPAAs. Previously, we reported that hydrophobic HPAAs formed large aggregates in COS‐7 cells. Here, those HPAAs were shown to have significant interactions with each other, suggesting that hydrophobicity plays an important role in aggregation. Among the observed HPAA–HPAA interactions, the Ala28–Ala29 interaction was notable because polyalanine tracts of these lengths have been established to be pathogenic in several polyalanine‐related diseases. By testing several constructs of different lengths, we clarified that polyalanine self‐interacts at longer lengths (>23 residues) but not at shorter lengths (six to ∼23 residues) in a yeast two‐hybrid assay and a GST pulldown assay. This self‐interaction was found to be SDS sensitive in SDS‐PAGE and native‐PAGE assays. Moreover, the intracellular localization of these long polyalanine tracts was also observed to be disturbed. Our results suggest that long tracts of polyalanine acquire SDS‐sensitive self‐association properties, which may be a prerequisite event for their abnormal folding. The misfolding of these tracts is thought to be a common molecular aspect underlying the pathogenesis of polyalanine‐related diseases.
Structure‐based design of robust glucose biosensors using a Thermotoga maritima periplasmic glucose‐binding protein
Authors: Tian Yaji , Cuneo Matthew J. , Changela Anita , Höcker Birte , Beese Lorena S. , Hellinga Homme W.
Published: September 2007

We report the design and engineering of a robust, reagentless fluorescent glucose biosensor based on the periplasmic glucose‐binding protein obtained from Thermotoga maritima (tmGBP). The gene for this protein was cloned from genomic DNA and overexpressed in Escherichia coli, the identity of its cognate sugar was confirmed, ligand binding was studied, and the structure of its glucose complex was solved to 1.7 Å resolution by X‐ray crystallography. TmGBP is specific for glucose and exhibits high thermostability (midpoint of thermal denaturation is 119 ± 1°C and 144 ± 2°C in the absence and presence of 1 mM glucose, respectively). A series of fluorescent conjugates was constructed by coupling single, environmentally sensitive fluorophores to unique cysteines introduced by site‐specific mutagenesis at positions predicted to be responsive to ligand‐induced conformational changes based on the structure. These conjugates were screened to identify engineered tmGBPs that function as reagentless fluorescent glucose biosensors. The Y13C•Cy5 conjugate is bright, gives a large response to glucose over concentration ranges appropriate for in vivo monitoring of blood glucose levels (1–30 mM), and can be immobilized in an orientation‐specific manner in microtiter plates to give a reversible response to glucose. The immobilized protein retains its response after long‐term storage at room temperature.
Models of S/π interactions in protein structures: Comparison of the H2S–benzene complex with PDB data
Authors: Ringer Ashley L. , Senenko Anastasia , Sherrill C. David
Published: September 2007

S/π interactions are prevalent in biochemistry and play an important role in protein folding and stabilization. Geometries of cysteine/aromatic interactions found in crystal structures from the Brookhaven Protein Data Bank (PDB) are analyzed and compared with the equilibrium configurations predicted by high‐level quantum mechanical results for the H2S–benzene complex. A correlation is observed between the energetically favorable configurations on the quantum mechanical potential energy surface of the H2S–benzene model and the cysteine/aromatic configurations most frequently found in crystal structures of the PDB. In contrast to some previous PDB analyses, configurations with the sulfur over the aromatic ring are found to be the most important. Our results suggest that accurate quantum computations on models of noncovalent interactions may be helpful in understanding the structures of proteins and other complex systems.
Conformational changes induced by a single amino acid substitution in the trans‐membrane domain of Vpu: Implications for HIV‐1 susceptibility to channel blocking drugs
Authors: Park Sang Ho , Opella Stanley J.
Published: September 2007

The channel‐forming trans‐membrane domain of Vpu (Vpu TM) from HIV‐1 is known to enhance virion release from the infected cells and is a potential target for ion‐channel blockers. The substitution of alanine at position 18 by a histidine (A18H) has been shown to render HIV‐1 infections susceptible to rimantadine, a channel blocker of M2 protein from the influenza virus. In order to describe the influence of the mutation on the structure and rimantadine susceptibility of Vpu, we determined the structure of A18H Vpu TM, and compared it to those of wild‐type Vpu TM and M2 TM. Both isotropic and orientationally dependent NMR frequencies of the backbone amide resonance of His18 were perturbed by rimantadine, and those of Ile15 and Trp22 were also affected, suggesting that His18 is the key residue for rimantadine binding and that residues located on the same face of the TM helix are also involved. A18H Vpu TM has an ideal, straight α‐helix spanning residues 6–27 with an average tilt angle of 41° in C14 phospholipid bicelles, indicating that the tilt angle is increased by 11° compared to that of wild‐type Vpu TM. The longer helix formed by the A18H mutation has a larger tilt angle to compensate for the hydrophobic mismatch with the length of the phospholipids in the bilayer. These results demonstrate that the local change of the primary structure plays an important role in secondary and tertiary structures of Vpu TM in lipid bilayers and affects its ability to interact with channel blockers.
Functional implications of tetraspanin proteins in cancer biology
Authors: Lazo Pedro A.
Published: September 2007

Human tetraspanin proteins are a group of 33 highly hydrophobic membrane proteins that can form complexes in cholesterol‐rich microdomains, distinct from lipid rafts, on the cell surface in a dynamic and reversible way. These complexes are composed of a core of several tetraspanin proteins that organize other membrane proteins such as integrins, human leukocyte antigen (HLA) antigens and some growth factor receptors. Although most tetraspanin proteins have been studied individually, tetraspanin proteins and their complexes can have effects on cellular adhesion and motility, interactions with stroma or affect signaling by growth factors, and for most of them no ligand has been identified. Functionally these proteins have been mostly studied in cells of lymphoid lineage, but they are present in all cell types. Data is also available for some tumors, where some tetraspanins have been identified as metastasis suppressors, but their significance is still not clear. Some of their implications in tumor biology and the areas that deserve further study are outlined. (Cancer Sci 2007; 98: 1666–1677)
Soy‐derived isoflavones inhibit the growth of adult T‐cell leukemia cells in vitro and in vivo
Authors: Yamasaki Masao , Fujita Satoshi , Ishiyama Erina , Mukai Ayako , Madhyastha Harishkumar , Sakakibara Yoichi , Suiko Masahito , Hatakeyama Kinta , Nemoto Takayuki , Morishita Kazuhiro , Kataoka Hiroaki , Tsubouchi Hirohito , Nishiyama Kazuo
Published: September 2007

Adult T‐cell leukemia occurs in human T‐lymphotropic virus type I‐infected individuals and is endemic to the south‐western area of Kyushu in Japan. In this communication, we examined the effect of soy isoflavones on the growth of adult T‐cell leukemia cells in vitro and in vivo. In the in vitro study, daidzein and genistein but not glycitein significantly inhibited the proliferation of ED‐40515 and Hut102 cells in a dose‐dependent manner. Among the isoflavones studied, genistein had the highest growth‐inhibitory effect; however, genistein did not exert an apparent growth‐inhibitory effect on Jurkat and Molt‐4 cells, which were non‐adult T‐cell leukemia cells. Genistein prevented the G1/S or G2/M transition at 3 and 10 or 30 µM, respectively. Genistein upregulated p21 protein expression together with p53 accumulation. In addition, treatment with 30 µM genistein strongly induced phosphorylation of checkpoint kinase (CHK) 2 and p53 at serines 15, 20 and 37. Caffeine, an inhibitor of ataxia‐telangiectasia mutated protein kinase, alleviated the genistein‐induced p53 and CHK2 phosphorylation, suggesting the involvement of DNA damage at 30 µM. However, marked phosphorylation of CHK2 and p53 could not be detected at 3 and 10 µM genistein. These data indicate that genistein has biphasic growth‐inhibitory properties. The in vivo studies demonstrated that soy‐derived isoflavones significantly inhibit ED‐40515 cell growth and infiltration into various organs in non‐obese diabetic severe combined‐immunodeficiency common γ‐chain knockout mice. Taken together, it is evident that soy isoflavones might serve as a promising compound for the treatment of adult T‐cell leukemia. (Cancer Sci 2007; 98: 1740–1746)
CCAAT/enhancer binding protein‐β promotes the survival of intravascular rat pancreatic tumor cells via antiapoptotic effects
Authors: Shimizu Yasuhito , Kishimoto Takashi , Ohtsuka Masayuki , Kimura Fumio , Shimizu Hiroaki , Yoshidome Hiroyuki , Miyazaki Masaru
Published: September 2007

A transcriptional factor, CCAAT/enhancer binding protein‐β (C/EBP‐β), regulates a variety of cell functions in normal and neoplastic cells. Although the involvement of C/EBP‐β in metastasis has been demonstrated clinicopathologically in several types of human cancer, the mechanism by which it functions during the multistep process of metastasis remains largely unknown. We investigated the role of C/EBP‐β in the intravascular step of hematogenous metastasis in a rat pancreatic tumor cell line, AR42J‐B13, as this step profoundly affects metastatic efficiency. C/EBP‐β‐transfected AR42J‐B13 (βB13) cells acquired considerable resistance against serum toxicity, which was primarily mediated by apoptosis in vitro. Upregulated expression of Bcl‐2 and Bcl‐xL was seen in βB13 cells. Enhanced early survival of intraportally injected βB13 cells in the BALB/c nu/nu male mice liver, detected by the mRNA of a vector‐specific gene, was observed. Nick‐end labeling analysis of the tumor‐injected liver revealed significantly lower rates of apoptosis among intravascular βB13 tumor cells than among empty vector‐transfected AR42J‐B13 (mB13) cells. Finally, intrasplenically injected βB13 cells established a larger number of colonies in the liver than did the mB13 cells. These findings suggest that C/EBP‐β may enhance hematogenous metastasis and its antiapoptotic effects may promote the survival of intravascular tumor cells. (Cancer Sci 2007; 98: 1706–1713)
Nuclear translocation of ADAM‐10 contributes to the pathogenesis and progression of human prostate cancer
Authors: Arima Takashi , Enokida Hideki , Kubo Hiroyuki , Kagara Ichiro , Matsuda Ryouichirou , Toki Kazuki , Nishimura Hiroaki , Chiyomaru Takeshi , Tatarano Shuichi , Idesako Toshihiko , Nishiyama Kenryu , Nakagawa Masayuki
Published: September 2007

A disintegrin and metalloproteases (ADAM) are cell membrane‐anchored proteins with potential implications for the metastasis of human cancer cells via cell adhesion and protease activities. In prostate cancer (PC), the ADAM‐10 protein showed a nuclear localization whereas in benign prostate hypertrophy (BPH) it was predominantly bound to the cell membrane. We hypothesized that the pathogenesis and progression of PC are attributable to the nuclear translocation of ADAM‐10. Immunoblotting revealed that after 5α‐dihydrotestosterone treatment, a 60‐kDa active form of ADAM‐10 was increased in the nuclear fraction but decreased in the cell membrane and cytoplasmic fractions of human androgen‐dependent PC cells. Immunocytochemistry revealed that after 5α‐dihydrotestosterone treatment, the ADAM‐10 protein was translocated from the cell membrane to the nucleus. Coimmunoprecipitation of androgen receptor and ADAM‐10 was detected in the nuclear fraction but not in the cell membrane and cytoplasmic fractions. Immunohistochemical study of 64 PC and 20 BPH samples showed that the intensity of ADAM‐10 staining was significantly higher in the nuclei of PC cells than in the nuclei of BPH cells (P < 0.0001). It was also significantly lower in the cell membrane of PC cells than in the cell membrane of BPH cells (P = 0.0017). Nuclear staining intensity was significantly correlated with the clinical T‐factor (P = 0.004), the Gleason score (P < 0.0001) and preoperative prostate‐specific antigen levels (P = 0.0061). ADAM‐10 small interfering RNA transfectants showed a significant decrease in cell growth compared to the controls. Our results suggest that in human PC, the nuclear translocation of ADAM‐10 coupled with the androgen receptor is involved in tumor growth and progression. (Cancer Sci 2007; 98: 1720–1726)
Testing long‐term patterns of basin sedimentation by detrital zircon geochronology, Centralian Superbasin, Australia
Authors: Maidment D. W. , Williams I. S. , Hand M.
Published: September 2007

Detrital zircon geochronology of Neoproterozoic to Devonian sedimentary rocks from the Georgina and Amadeus basins has been used to track changes in provenance that reflect the development and inversion of the former Australian Superbasin. Through much of the Neoproterozoic, sediments appear to have been predominantly derived from local sources in the Arunta and Musgrave inliers. Close similarities between the detrital age signatures of late Neoproterozoic sedimentary rocks in the two basins suggests that they were contiguous at this time. A dominant population of 1.2–1.0 Ga zircon in Early Cambrian sediments of the Amadeus Basin reflects the uplift of the Musgrave Inlier during the Petermann Orogeny between 560 and 520 Ma, which shed a large volume of detritus northwards into the Amadeus Basin. Early Cambrian sedimentary rocks in the Georgina Basin have a much smaller proportion of 1.2–1.0 Ga detritus, possibly due to the formation of sub‐basins along the northern margin of the Amadeus Basin which might have acted as a barrier to sediment transfer. An influx of 0.6–0.5 Ga zircon towards the end of the Cambrian coincides with the transgression of the Larapintine Sea across central Australia, possibly as a result of intracratonic rifting. Detrital zircon age spectra of sedimentary rocks deposited within this epicontinental sea are very similar to those of coeval sedimentary rocks from the Pacific Gondwana margin, implying that sediment was transported into central Australia from the eastern continental margin. The remarkably consistent ‘Pacific Gondwana’ signature of Cambro‐Ordovician sediments in central and eastern Australia reflects a distal source, possibly from east Antarctica or the East African Orogen. The peak of the marine incursion into central Australia in the early to mid Ordovician coincides with granulite‐facies metamorphism at mid‐crustal depths between the Amadeus and Georgina basins (the Larapinta Event). The presence of the epicontinental sea, the relative lack of a local basement zircon component in Cambro‐Ordovician sedimentary rocks and their maturity suggest that metamorphism was not accompanied by mountain building, consistent with an extensional or transtensional setting for this tectonism. Sediments deposited at ∼435–405 and ∼365 Ma during the Alice Springs Orogeny have detrital age signatures similar to those of Cambro‐Ordovician sedimentary rocks, reflecting uplift and reworking of the older succession into narrow foreland basins adjacent to the orogen.
Orthogonal to oblique rifting: effect of rift basin orientation in the evolution of the North basin, Malawi Rift, East Africa
Authors: Mortimer E. , Paton D. A. , Scholz C. A. , Strecker M. R. , Blisniuk P.
Published: September 2007

The East African Rift system has long been considered the best modern example of the initial stages of continental rifting. The Malawi Rift is characteristic of the western branch of the East African Rift system, composed of half‐grabens of opposing asymmetry along its length. There are striking similarities between basins within the Malawi Rift, and others along the western branch. Each exhibits similar bathymetry, border‐fault length, rift zone width and fault segment length. The North Basin of the Malawi Rift differs from others in the rift only in its orientation: trending NW–SE as opposed to N–S. Although there is general agreement as to the geometry of the Malawi Rift; debate as to the amount of strike–slip vs. dip–slip deformation and the influence of underlying Pan‐African foliation remains. This study presents new data from a closely spaced shallow [2 s two‐way travel time (TWT)] seismic reflection data set integrated with basin‐scale deeper (6 s TWT) seismic reflection data that document the structural evolution of the border and intra‐basin faults. These data reveal that the different trend of the North Basin, most likely to have been influenced by the underlying Pan‐African foliation, has played an extremely important role in the structural style of basin evolution. The border‐fault and intra‐basin structures nucleated during extension that was initially orthogonal (ENE). During this time (>8.6 to ∼0.5–0.4 Ma) intra‐basin faults synthetic to the west‐dipping border‐fault nucleated, whereas strain was localised on the segmented border‐fault early on. A later rotation of extension orientation (to NW) led to these established faults orienting oblique to rifting. This generated an overall dextral strike–slip setting that led to the development of transfer faults adjacent to the border‐fault, and the generation of flower structures and folds over the greater displacement intra‐basin faults.
Late‐ to post‐orogenic exhumation of the Central Pyrenees revealed through combined thermochronological data and modelling
Authors: Gibson M. , Sinclair H. D. , Lynn G. J. , Stuart F. M.
Published: September 2007

Apatite (U–Th)/He and fission track thermochronometry have been combined with 3D thermal modelling to constrain the late‐ to post‐orogenic exhumation history of the Central Pyrenees, Spain. Data from four massifs immediately north and south of the present drainage divide of the mountain belt reveal a diachroneity in the transition from syn‐ to post‐orogenic forcing of exhumation. Immediately south of the drainage divide, rapid exhumation of ∼1.5 mm year−1 decelerated after ∼30 Ma to ∼0.03 mm year−1. A similar transition occurred immediately north of the drainage divide at the same time. Further south, in the core of the Axial Zone antiformal stack of the Pyrenees, rapid (∼1 mm year−1), syn‐orogenic exhumation continued to ∼20 Ma, but slowed to ∼0.1–0.2 mm year−1 soon after that time. This order of magnitude decrease in exhumation rates across the orogen records the diachronous transition into a post‐orogenic state for the mountain belt. These data do not record rejuvenation of exhumation in Late Miocene or Pliocene times driven either by large‐scale base‐level change or an evolution to more erosive climatic conditions.