bluuebunny/crossref_metadata_2025 huggingface dataset:
Cathepsin K in the bone microenvironment: link between obesity and prostate cancer?
Authors: Podgorski I. , Linebaugh B.E. , Sloane B.F.
Published: July 2007

The skeleton is the most common site of metastasis in patients with advanced prostate cancer. Despite many advances in targeting skeletal metastases, the mechanisms behind the attraction of prostate cancer cells to the bone are not known. Osteoclast cathepsin K, due to its ability to effectively degrade bone matrix collagen I, has been implicated in colonization and growth of prostate tumours in the bone. Identification of new cathepsin K substrates in the bone microenvironment and the recent findings demonstrating its involvement in obesity and inflammation suggest additional roles for this enzyme in skeletal metastases of prostate cancer.
Phagocytosis of collagen by fibroblasts and invasive cancer cells is mediated by MT1-MMP
Authors: Lee H. , Sodek K.L. , Hwang Q. , Brown T.J. , Ringuette M. , Sodek J.
Published: July 2007

Degradation of collagen is required for the physiological remodelling of connective tissues during growth and development, as well as in wound healing, inflammatory diseases, and cancer cell invasion. In remodelling adult tissues, degradation of collagen occurs primarily through a phagocytic pathway. While various steps in this pathway have been characterized, the enzyme required to fragment collagen fibrils for phagocytosis has not been identified. Laser confocal microscopy, transmission electron microscopy and biochemical assays were used to show that degradation of collagen substrates by fibroblasts correlated with the expression of the membrane-bound metalloproteinase MT1-MMP (membrane-type 1 matrix metalloproteinase). The MT1-MMP was localized to sites of collagen cleavage on the cell surface and also within the cells. In contrast with MT1-MMP, the gelatinase MMP-2 was not required for collagen phagocytosis. Similar analyses of several ovarian cancer, breast cancer and fibrosarcoma cells indicated that highly metastatic cells also degrade collagen through a phagocytic pathway that is mediated by MT1-MMP. Collectively, these studies demonstrate a pivotal role for catalytically active MT1-MMP in preparing collagen fibrils for phagocytic degradation by normal and transformed cells.
Family Resemblances? Ligand Binding and Activation of Family A and B G-Protein-Coupled Receptors
Authors: Poyner D.R. , Wheatley M.
Published: July 2007

In April 2007, the Biochemical Society held a meeting to compare and contrast ligand binding and activation of Family A and B GPCRs (G-protein-coupled receptors). Being the largest class, Family A GPCRs usually receive the most attention, although a previous Biochemical Society meeting has focused on Family B GPCRs. The aim of the present meeting was to bring researchers of both families together in order to identify commonalities between the two. The present article introduces the proceedings of the meeting, briefly commenting on the focus of each of the following articles.
Peptide binding at the GLP-1 receptor
Authors: Mann R. , Nasr N. , Hadden D. , Sinfield J. , Abidi F. , Al-Sabah S. , de Maturana R. López , Treece-Birch J. , Willshaw A. , Donnelly D.
Published: July 2007

The receptor for GLP-1 [glucagon-like peptide-1-(7–36)-amide] is a member of the ‘Family B’ of GPCRs (G-protein-coupled receptors) comprising an extracellular N-terminal domain containing six conserved cysteine residues (the N-domain) and a core domain (or J-domain) comprising the seven transmembrane helices and interconnecting loop regions. According to the two-domain model for peptide binding, the N-domain is primarily responsible for providing most of the peptide binding energy, whereas the core domain is responsible for binding the N-terminal region of the peptide agonists and transmitting the signal to the intracellular G-protein. Two interesting differences between the binding properties of two GLP-1 receptor agonists, GLP-1 and EX-4 (exendin-4), can be observed. First, while GLP-1 requires its full length to maintain high affinity, the eight N-terminal residues of EX-4 can be removed with little reduction in affinity. Secondly, EX-4 (but not GLP-1) can bind to the fully isolated N-domain of the receptor with an affinity matching that of the full-length receptor. In order to better understand these differences, we have studied the interaction between combinations of full-length or truncated ligands with full-length or truncated receptors.
Extracellular loops and ligand binding to a subfamily of Family A G-protein-coupled receptors
Authors: Wheatley M. , Simms J. , Hawtin S.R. , Wesley V.J. , Wootten D. , Conner M. , Lawson Z. , Conner A.C. , Baker A. , Cashmore Y. , Kendrick R. , Parslow R.A.
Published: July 2007

GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins which mediate their effects by coupling to G-proteins. The V1aR (V1a vasopressin receptor) is a member of a family of related GPCRs that are activated by vasopressin {AVP ([Arg8]vasopressin)}, OT (oxytocin) and related peptides. These receptors are members of a subfamily of Family A GPCRs called the neurohypophysial peptide hormone receptor family. GPCRs exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The cluster of TM helices is functionally important for ligand binding, and, furthermore, activation of GPCRs involves movement of these TM helices. Consequently, it might be assumed that the extracellular face of GPCRs is composed of peptide linkers that merely connect important TM helices. However, using a systematic mutagenesis approach and focusing on the N-terminus and the second ECL of the V1aR, we have established that these extracellular domains fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.
Molecular mechanisms involved in vasoactive intestinal peptide receptor activation and regulation: current knowledge, similarities to and differences from the A family of G-protein-coupled receptors
Authors: Langer I. , Robberecht P.
Published: July 2007

An actual paradigm for activation and regulation of the GPCR (G-protein-coupled receptors)/seven-transmembrane helix family of receptors essentially emerges from extensive studies of the largest family of receptors, the GPCR-A/rhodopsin family. The mechanisms regulating the GPCR-B family signal transduction are less precisely understood due in part to the lack of the conserved signatures of the GPCR-A family (E/DRY, NPXXY) and in part to the absence of a reliable receptor modelling, although some studies suggest that both families share similar features. Here, we try to highlight the current knowledge of the activation and the regulation of the VIP (vasoactive intestinal peptide) receptors, namely VPAC (VIP/pituitary adenylate cyclase-activating peptide receptor) 1 and 2. This includes search for amino acids involved in the stabilization of the receptor active conformation and in coupling to G-proteins, signalling pathways activated in response to VIP, agonist-dependent receptor down-regulation, phosphorylation and internalization as well as pharmacological consequences of receptor hetero-dimerization.
Ligand binding and activation of the CGRP receptor
Authors: Conner A.C. , Simms J. , Barwell J. , Wheatley M. , Poyner D.R.
Published: July 2007

The receptor for CGRP (calcitonin gene-related peptide) is a heterodimer between a GPCR (G-protein-coupled receptor), CLR (calcitonin receptor-like receptor) and an accessory protein, RAMP1 (receptor activity-modifying protein 1). Models have been produced of RAMP1 and CLR. It is likely that the C-terminus of CGRP interacts with the extracellular N-termini of CLR and RAMP1; the extreme N-terminus of CLR is particularly important and may interact directly with CGRP and also with RAMP1. The N-terminus of CGRP interacts with the TM (transmembrane) portion of the receptor; the second ECL (extracellular loop) is especially important. Receptor activation is likely to involve the relative movements of TMs 3 and 6 to create a G-protein-binding pocket, as in Family A GPCRs. Pro321 in TM6 appears to act as a pivot. At the base of TMs 2 and 3, Arg151, His155 and Glu211 may form a loose equivalent of the Family A DRY (Asp-Arg-Tyr) motif. Although the details of this proposed activation mechanism clearly do not apply to all Family B GPCRs, the broad outlines may be conserved.
Mechanisms underlying agonist efficacy
Authors: Strange P.G.
Published: July 2007

Agonist efficacy is a measure of how well an agonist can stimulate a response system linked to a receptor. Efficacy can be assessed in functional assays and various parameters (Emax, KA/EC50, Emax·KA/EC50) determined. The Emax·KA/EC50 parameter provides a good estimate of efficacy across the full range of efficacy. A convenient assay for the efficacy of agonists for some receptors is provided by the [35S]GTP[S] (guanosine 5′-[γ-[35S]thio]triphosphate)-binding assay. In this assay, the normal GTP-binding event in GPCR (G-protein-coupled receptor) activation is replaced by the binding of the non-hydrolysable analogue [35S]GTP[S]. This assay may be used to profile ligands for their efficacy, and an example here is the D2 dopamine receptor where an efficacy scale has been set up using this assay. The mechanisms underlying the assay have been probed. The time course of [35S]GTP[S] binding follows a pseudo-first-order reaction with [35S]GTP[S] binding reaching equilibrium after approx. 3 h. The [35S]GTP[S]-binding event is the rate-determining step in the assay. Agonists regulate the maximal level of [35S]GTP[S] bound, rather than the rate constant for binding. The [35S]GTP[S]-binding assay therefore determines agonist efficacy on the basis of the amount of [35S]GTP[S] bound rather than the rate of binding.
Computational studies of Family A and Family B GPCRs
Authors: Vohra S. , Chintapalli S.V. , Illingworth C.J.R. , Reeves P.J. , Mullineaux P.M. , Clark H.S.X. , Dean M.K. , Upton G.J.G. , Reynolds C.A.
Published: July 2007

A full picture of the similarities between Family A and Family B GPCRs (G-protein coupled receptors) has been frustrated by the lack of clear homology between the respective sequences. Here, we review previous computational studies on GPCR dimerization in which the putative dimerization interfaces have been analysed using entropy, the ET (evolutionary trace) method and related methods. The results derived from multiple sequence alignments of Family A subfamilies have been mapped on to the rhodopsin crystal structure using standard alignments. Similarly, the results for the Family B alignments have been mapped on to the rhodopsin crystal structure using the ‘cold-spot’ alignment. For both Family A and Family B GPCRs, the sequence analysis indicates that there are functional sites on essentially all transmembrane helices, consistent with the parallel daisy chain model of GPCR oligomerization in which each GPCR makes interactions with a number of neighbouring GPCRs. The results are not too sensitive to the quality of the alignment. Molecular Dynamics simulations of the activation process within a single transmembrane bundle of the rhodopsin and the β2-adrenergic receptor have been reviewed; the key observation, which is consistent with other computational studies, is that there is a translation and bending of helix 6, which contributes to a significant opening out of the intracellular face of the receptor, as shown in the accompanying movies. The simulations required the application of specific experiment-derived harmonic and half-harmonic distance restraints and so the application of such simulations to Family B GPCRs requires considerable care because of the alignment problem. Thus, in order to address the alignment problem, we have exploited the observation that GCR1, a plant GPCR, has homology with Family A, Family B and Family E GPCRs. The resulting alignment for transmembrane helix 3 is presented.
Monitoring interactions between G-protein-coupled receptors and β-arrestins
Authors: Pfleger K.D.G. , Dalrymple M.B. , Dromey J.R. , Eidne K.A.
Published: July 2007

β-Arrestins 1 and 2 are ubiquitously expressed intracellular adaptor and scaffolding proteins that play important roles in GPCR (G-protein-coupled receptor) desensitization, internalization, intracellular trafficking and G-protein-independent signalling. Recent developments in BRET (bioluminescence resonance energy transfer) technology enable novel insights to be gained from real-time monitoring of GPCR–β-arrestin complexes in live cells for prolonged periods. In concert with confocal microscopy, assays for studying internalization and recycling kinetics such as ELISAs, and techniques for measuring downstream signalling pathways such as those involving MAPKs (mitogen-activated protein kinases), investigators can now use a range of experimental tools to elucidate the ever-expanding roles of β-arrestins in mediating GPCR function.
The many futures for cell-penetrating peptides: how soon is now?
Authors: Howl J. , Nicholl I.D. , Jones S.
Published: July 2007

Studies of CPPs (cell-penetrating peptides), sequences that are also commonly designated as protein transduction domains, now extend to a second decade of exciting and far-reaching discoveries. CPPs are proven vehicles for the intracellular delivery of macromolecules that include oligonucleotides, peptides and proteins, low-molecular-mass drugs, nanoparticles and liposomes. The biochemical properties of different classes of CPP, including various sequences derived from the HIV-1 Tat (transactivator of transcription) [e.g. Tat-(48–60), GRKKRRQRRRPPQ], and the homeodomain of the Drosophila homeoprotein Antennapaedia (residues 43–58, commonly named penetratin, RQIKIWFQNRRMKWKK), also provide novel insights into the fundamental mechanisms of translocation across biological membranes. Thus the efficacy of CPP-mediated cargo delivery continues to provide valuable tools for biomedical research and, as witnessed in 2007, candidate and emerging therapeutics. Thus it is anticipated that the further refinement of CPP technologies will provide drug-delivery vectors, cellular imaging tools, nanoparticulate devices and molecular therapeutics that will have a positive impact on the healthcare arena. The intention of this article is to provide both a succinct overview of current developments and applications of CPP technologies, and to illustrate key developments that the concerted efforts of the many researchers contributing to the Biochemical Society's Focused Meeting in Telford predict for the future. The accompanying papers in this issue of Biochemical Society Transactions provide additional details and appropriate references. Hopefully, the important and eagerly anticipated biomedical and clinical developments within the CPP field will occur sooner rather than later.
Cell-penetrating-peptide-based delivery of oligonucleotides: an overview
Authors: Abes R. , Arzumanov A.A. , Moulton H.M. , Abes S. , Ivanova G.D. , Iversen P.L. , Gait M.J. , Lebleu B.
Published: July 2007

Cationic CPPs (cell-penetrating peptides) have been used largely for intracellular delivery of low-molecular-mass drugs, biomolecules and particles. Most cationic CPPs bind to cell-associated glycosaminoglycans and are internalized by endocytosis, although the detailed mechanisms involved remain controversial. Sequestration and degradation in endocytic vesicles severely limits the efficiency of cytoplasmic and/or nuclear delivery of CPP-conjugated material. Re-routing the splicing machinery by using steric-block ON (oligonucleotide) analogues, such as PNAs (peptide nucleic acids) or PMOs (phosphorodiamidate morpholino oligomers), has consequently been inefficient when ONs are conjugated with standard CPPs such as Tat (transactivator of transcription), R9 (nona-arginine), K8 (octalysine) or penetratin in the absence of endosomolytic agents. New arginine-rich CPPs such as (R-Ahx-R)4 (6-aminohexanoic acid-spaced oligo-arginine) or R6 (hexa-arginine)–penetratin conjugated to PMO or PNA resulted in efficient splicing correction at non-cytotoxic doses in the absence of chloroquine. SAR (structure–activity relationship) analyses are underway to optimize these peptide delivery vectors and to understand their mechanisms of cellular internalization.
Arginine-rich peptides and their internalization mechanisms
Authors: Futaki S. , Nakase I. , Tadokoro A. , Takeuchi T. , Jones A.T.
Published: July 2007

As the versatility and use of CPPs (cell-penetrating peptides) as intracellular delivery vectors have been widely accepted, the cellular uptake mechanisms that enable their efficient internalization have become the subject of much interest. Arginine-rich peptides, including HIV-1 Tatp (transactivator of transcription peptide), are regarded as a representative class of CPPs. Evidence suggests that macropinocytosis plays a crucial role in the cellular uptake of these peptides. We have recently shown that treatment of cells with arginine-rich peptides induces activation of Rac protein leading to F-actin (filamentous actin) organization and macropinocytosis. We have also shown that depletion of membrane-associated proteoglycans results in the failure of this signalling pathway, suggesting that membrane-associated proteoglycans may act as a potential receptor for the induction of macropinocytic uptake of arginine-rich peptides. However, when the macropinocytic pathway is inhibited at a low temperature or by cholesterol depletion, these peptides can be internalized by alternative mechanisms, one of which appears to be direct translocation of the peptides through the plasma membrane. This review summarizes the current theories on both endocytic and non-endocytic aspects of internalization of arginine-rich peptides.
all-D proline-rich cell-penetrating peptides: a preliminary in vivo internalization study
Authors: Pujals S. , Sabidó E. , Tarragó T. , Giralt E.
Published: July 2007

Proline-rich cell-penetrating peptides, particularly the SAP (sweet arrow peptide), (VRLPPP)3, have been proposed to be useful intracellular delivery vectors, as a result of their lack of cytotoxicity combined with their capacity to be internalized by cells. A common limitation of the therapeutic use of peptides is metabolic instability. In general, peptides are quickly degraded by proteases upon entry into the bloodstream. The use of all-D-peptide derivatives is emerging as a fruitful strategy to circumvent this degradation problem. In this context, we report on the internalization behaviour, protease-resistance enhancement and self-assembly properties of an all-D version of SAP [(vrlppp)3]. The cellular uptake of (vrlppp)3 was evaluated in an in vivo assay in mice. Both flow cytometry and confocal laser-scanning microscopy experiments showed that a carboxyfluoresceinated version of the molecule, carboxyfluorescein–(vrlppp)3, is internalized rapidly in white blood cells and kidney cells. Significant fluorescence was also detected in other organs such as the spleen and the liver. Finally, the toxicity of (vrlppp)3 was examined, and no significant differences in the main biochemical parameters nor in weight were detected compared with controls.
Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides
Authors: Gomez J.A. , Gama V. , Yoshida T. , Sun W. , Hayes P. , Leskov K. , Boothman D. , Matsuyama S.
Published: July 2007

We found that Ku70, a known DNA repair factor, has a novel function to bind and inhibit Bax (Bcl-2-associated X protein), a key mediator of apoptosis. Pentapeptides derived from the Bax-binding domain of Ku70 were cell-permeable and protected cells from Bax-mediated apoptosis. These pentapeptides were called BIPs (Bax-inhibiting peptides). BIPs may become a useful therapeutic tool to reduce cellular damage. We also generated BIP mutant pentapeptides that do not inhibit Bax, but retain their cell-penetrating activity. Since both BIPs and BIP mutants are cell-permeable, these peptides were designated CPP5s (cell-penetrating pentapeptides). Among the CPP5s discovered, VPTLK (BIP) and KLPVM (BIP mutant) were confirmed to possess protein transduction activity by examination of the delivery of GFP (green fluorescent protein) into cells by these peptides. The mechanism of cell penetration by CPP5s is not known. CPP5s enter the cell at 0 and 4°C. In preliminary studies, various inhibitors of endocytosis and pinocytosis did not show any significant suppression of CPP5 cell entry. CPP5s have very low toxicity in vitro and in vivo and so may be useful tools in order to develop non-toxic drug-delivery technologies.
Targeting aggressive B-cell lymphomas with cell-penetrating peptides
Authors: Melnick A.
Published: July 2007

DLBCL (diffuse large B-cell lymphoma) is the most common subtype of non-Hodgkin's lymphoma. Current therapy for patients includes chemotherapy and monoclonal antibodies. Although oncogene-targeted therapy is dramatically successful for patients with certain kinds of leukaemias, there are no such agents yet for DLBCL. One reason for this is that several key oncogenes involved in DLBCL pathogenesis are transcription factors, which are difficult to therapeutically target with small molecules. Recent advances in the structural and functional characterization of DLBCL oncogenes have facilitated design of CPPs (cellpenetrating peptides) with potent inhibitory effects on DLBCL and other aggressive lymphomas. CPPs targeting the Bcl (B-cell lymphoma)-6, Bcl-2, Myc and NF-κB (nuclear factor κB) oncogenic pathways, among others, could improve efficacy and reduce toxicity of anti-lymphoma therapy. Another barrier towards effective therapy in DLBCL is its profound molecular heterogeneity. Combinatorial administration of oncogene-targeted CPPs based on the molecular profiles of individual patient tumours could allow individualized targeted therapy regimens to be developed.
Cell-penetrating-peptide-mediated siRNA lung delivery
Authors: Moschos S.A. , Williams A.E. , Lindsay M.A.
Published: July 2007

The therapeutic application of siRNA (short interfering RNA) shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. A potential approach to solving this problem is the chemical conjugation of siRNA to the cationic CPPs (cell-penetrating peptides), Tat-(48–60) (transactivator of transcription) and penetratin, which have been shown previously to mediate protein and peptide delivery in a host of animal models. In this transaction, we review recent studies on the utility of siRNA for the investigation of protein function in the airways/lung. We show that, despite previous studies showing the utility of cationic CPPs in vitro, conjugation of siRNA to Tat-(48–60) and penetratin failed to increase residual siRNA-mediated knockdown of p38 MAPK (mitogen-activated protein kinase) (MAPK14) mRNA in mouse lung in vivo. Significantly, we will also discuss potential non-specific actions and the induction of immunological responses by CPPs and their conjugates and how this might limit their application for siRNA-mediated delivery in vivo.
Targeting the MHC II presentation pathway in allergy vaccine development
Authors: Rhyner C. , Kündig T. , Akdis C.A. , Crameri R.
Published: July 2007

The worldwide increase in the incidence of allergic diseases and the limited efficacy of current vaccines require the development of new efficient vaccination strategies. Based on PTD (protein transduction domain) technology, we have engineered MAT (modular antigen translocation) molecules, aimed to enhance antigen presentation through intracellular targeting of the MHC II presentation pathway. MAT vaccines consist of a cloning cassette, which fuses Tat (transactivator of transcription) peptide to a truncated Ii (invariant chain), which is able to target antigens to the nascent MHC II molecules in the trans-Golgi compartment. To test the efficacy of intracellular targeting, we engineered arrays of MAT-fusions and compared the effects of recombinant allergens, Tat-conjugated allergens and MAT-conjugated allergens for the ability to stimulate T-cell proliferation and cytokine production in human PBMC (peripheral blood mononuclear cell) cultures derived from allergic individuals, and to elicit protective immune responses in mice. MAT–vaccines induced a strong proliferation of PBMCs at a low concentration and induced a Th2/Treg (regulatory T-cell) cell shift in the cytokine profile, reflecting those reported in successfully desensitized allergic individuals. In allergic mouse models, we showed that MAT–vaccines are highly efficient in desensitizing mice and protect them from anaphylactic shock. The technology is applicable not only for the treatment of allergies, but also for the development of preventive vaccines in general.
Attention API Suppliers: Quality Agreements are here to Stay
Authors: Sayre Stephen D. , Gattoni Todd Grant
Published: July 2007

US pharmaceutical manufacturers are increasingly requiring their active pharmaceutical ingredient (API) suppliers to sign quality agreements. This trend — if properly managed by finished-dosage manufacturers — should enable them to enhance the quality of their products without unduly burdening API suppliers. As many of these suppliers are now located in developing industrial countries, this trend will have a significant impact on global supply chains in the pharmaceutical industry. This paper, examining quality agreements from the vantage point of the contract lawyer, will discuss (1) the regulatory basis for requiring quality agreements, including recent changes prompting more finished-dosage manufacturers to require API suppliers to sign quality agreements, (2) hot-button issues in quality agreements and (3) best practices for drafting effective quality agreements. Because the authors are US lawyers, the paper is written from the perspective of US federal laws except where specific reference is made to the laws of other jurisdictions.
Data Protection: The New IP Frontier — An Overview of Existing Laws and Regulations
Authors: Cullen Dolores
Published: July 2007

The paper provides an overview of laws and regulations for the protection of data submitted by pharmaceutical companies for the purposes of obtaining marketing approval for a drug in Member States of the World Trade Organization, which must comply with intellectual property provisions set in the Agreement on Trade Related Aspects of Intellectual Property Rights (TRIPS). Article 39.3 of the agreement requires countries to protect undisclosed test or other data against unfair commercial use but not the adoption of exclusivity periods to protect such data. In general terms, today all developed countries have implemented an array of data exclusivity provisions with specific periods of protection, whereas most developing and least developed countries have often adopted language similar to that of Article 39.3. There are exceptions to this, mainly those countries that have negotiated free trade agreements with the United States such as Chile, Morocco and Jordan, and others that have agreed to adopt periods of exclusivity under pressure from other governments and industry groups. Furthermore, trade agreements have gradually broadened the scope of the protection thus undermining generic competition and therefore consumers' access to more affordable drugs.
A Computer Scientist's Reactions to NPfIT
Authors: Randell Brian
Published: July 2007

This paper contains a set of personal views relating to NHS Connecting for Health's National Programme for IT (NPfIT), and in particular its Care Records Service, written from the point of view of a computer scientist, not a medical informatics expert. The principal points made are as follows: Centralisation: Pulling lots of data together (for individual patients and then for large patient populations) harms safety and privacy – it is one byproduct of excessive use of identification when in fact all that is usually needed is authentication. Large centralized data storage facilities can be useful for reliability, but risk exchanging lots of small failures for a lesser number of much larger failures. A much more decentralised approach to electronic patient record (EPR) data and its storage should be investigated. Evolutionary acquisition: Specifying, implementing, deploying and evaluating a sequence of ever more complete IT systems is the best way of ending up with well-accepted and well-trusted systems – especially when this process is controlled by the stakeholders who are most directly involved, rather than by some distant central bureaucracy. Thus authority as well as responsibility should be left with hospital and general practitioner trusts to acquire IT systems that suit their environments and priorities – subject to adherence to minimal interoperability constraints – and to use centralized services (e.g., for system support and back-up) as if and when they choose. Socio-technical issues: Ill-chosen imposed medical IT systems impede patient care, are resisted, result in lots of accidental faults, and lose user support and trust. All these points are attested to by rigorous studies involving expertise from the social sciences (psychology, ethnography, etc.) as well as by technical (medical and computer) experts – much more attention needs to be paid to such studies, and more such studies encouraged. Constructive reviews: A constructive expert review, working closely with Connecting for Health, could be very helpful, but should be evidently independent and open and thus essentially different in nature to past and current inquiries. A review of this nature could not just recommend appropriate changes of plan, and speed progress. It could also contribute to the vital task of helping to restore the trust and confidence of the public and the media in the programme and in the government officials involved.
Differential calculi on some quantum prehomogeneous vector spaces
Authors: Sinel’shchikov S. , Stolin A. , Vaksman L.
Published: July 2007

This paper is devoted to study of differential calculi over quadratic algebras, which arise in the theory of quantum bounded symmetric domains. We prove that in the quantum case dimensions of the homogeneous components of the graded vector spaces of k-forms are the same as in the classical case. This result is well known for quantum matrices. The quadratic algebras, which we consider in the present paper, are q-analogs of the polynomial algebras on prehomogeneous vector spaces of commutative parabolic type. This enables us to prove that the de Rham complex is isomorphic to the dual of a quantum analog of the generalized Bernstein-Gelfand-Gelfand resolution [Lie Goups and Their Representations (Summer School of the Bolyai Janos Mathematical Society), edited by I. M. Gelfand (Halsted, New York, 1975), pp. 21–64].
Infrared-active vibron bands associated with rare gas atom dopants isolated in solid parahydrogen
Authors: Raston P. L. , Anderson D. T.
Published: July 2007

We report high-resolution infrared absorption spectroscopic studies of the dopant-induced Q1(0) vibron band in solid parahydrogen crystals doped with low concentrations of rare gas atoms. The frequency, line shape, and integrated absorption coefficient for the rare gas atom-induced Q1(0) vibron band are measured for Ne, Ar, Kr, and Xe. The observed line shapes and peak maxima frequencies are sensitive to the H2 vibrational dependence of the dopant–H2 isotropic intermolecular potential. Trends observed for Ar, Kr, and Xe indicate that the vibrational dependence is strong enough for Xe to trap the infrared-active vibron in its first solvation shell, while for Ar the vibron remains delocalized. The Ne-induced feature displays a qualitatively different line shape which is attributed to the weak intramolecular vibrational dependence of the Ne–H2 intermolecular potential relative to the H2–H2 interaction. The line shapes of the Ar, Kr, and Xe dopant-induced Q1(0) pure vibrational features agree well with recent first-principles calculations.
Structural formation and thermal relaxation of quench-condensed Kr films: effect on EPR spectrum of trapped hydrogen atoms
Authors: Dmitriev Yu. A.
Published: July 2007

Hydrogen atoms are trapped in a quench-condensed Kr matrix and investigated by EPR. Each hyperfine component is a superposition of a broad and a narrow line. The spectrum of narrow lines shows an axial anisotropy of the hyperfine structure constant. The degree of anisotropy is found to depend on both the deposition temperature, Tdep, and the temperature of the solid sample, Tsample. As Tdep increases, the broad lines diminish while the anisotropy of the spectrum of narrow lines becomes less pronounced. The spectrum of narrow lines originate from H atoms in well-defined environments and is attributed to a superposition of two spectra given by the atoms in substitutional fcc and hcp sites. The spectrum of broad lines is assumed to originate from the atoms trapped in highly disordered regions in the lattice. These regions are found to start relaxing at Tsample as low as 12K.
Structure of quench condensed nH2–N2 binary alloys: isotope effect
Authors: Galtsov N. N. , Prokhvatilov A. I. , Strzhemechny M. A.
Published: July 2007

The structure of quench condensed nH2–N2 alloys is investigated by powder x-ray diffraction over a wide range of temperatures, compositions, and rates of deposition. The structure of the deposits is shown to depend on the condensation regime. Under a mild regime, no solid nitrogen reflections from hydrogen-rich deposits are observed. When the temperature is increased to the hydrogen triple point, nitrogen lines appear at substantially larger angles compared to pure N2, which suggests presence of dissolved hydrogen. The quantum nature of this hydrogen is suppressed in the nitrogen matrix. The samples grown in the mild regime exhibit the highest apparent solubility (up to 25%) of hydrogen in solid N2. When H2 is substituted by D2, the isotope effect consists in a wider range of single-phase states based on the nitrogen cubic lattice, which can accommodate up to 70% deuterium, if grown under the mild regime.
Plasticity of parahydrogen with reduced deuterium contents
Authors: Alekseeva L. A.
Published: July 2007

The plasticity of solid parahydrogen with lowered deuterium contents under stepwise uniaxial extension at liquid helium temperatures 1.8–4.2K is investigated. Work hardening curves for single crystals are measured. The maximum possible values of the elongation of the samples without their fracture at minimum stress values are reached. Features of super-plastic irreversible deformation of samples are observed. Anomalous temperature dependence of deformation parameters is found. The character of this anomaly exhibits evidence of the coherent motion of dislocation kinks in Peierls relief, modified by residual ortho and deuterium impurities.
Plateau effect in the thermal conductivity of solid hydrogen with neon impurity
Authors: Zholonko N. N.
Published: July 2007

The thermal conductivity of solid hydrogen with 1–2ppm Ne impurity is investigated in the temperature range 1.5–10K on samples grown from the liquid phase at various growth rates. The results differ qualitatively from those obtained on samples grown from the gas phase: the thermal conductivity curve exhibited a dip in a broad plateau. A relaxation model is proposed to explain the effect, which is presumed to be due to linear impurity structures arranged on dislocation lines. A comparison with the case of isolated neon atoms homogeneously distributed in the solid hydrogen is made.
Electronically induced modification of thin layers on surfaces
Authors: Bauer U. , Neppl S. , Menzel D. , Feulner P. , Shaporenko A. , Zharnikov M.
Published: July 2007

Interactions of thermally and electronically stimulated reactions in thin layers on surfaces are investigated. For self-assembled monolayers, thermal activation promotes many processes primarily induced by electronic excitations. We demonstrate that the film temperature is an important parameter for steering these reactions towards different final products. Using chemisorbed water on Ru(001) as an example, we investigate how the products of an irradiation induced reaction catalyze thermally stimulated dissociation of water molecules.
Kinetic study of inelastic radiation-induced processes in rare-gas cryocrystals
Authors: Ogurtsov A. N. , Masalitina N. Yu. , Bliznjuk O. N.
Published: July 2007

The processes of large-scale atomic displacements induced by exciton self-trapping are studied by the selective vacuum ultraviolet luminescence method. Models of Frenkel pairs creation in rare-gas crystals are discussed, with a focus on excited-state mechanisms of defect formation. A simple kinetic model of defect accumulation in rare-gas samples is proposed.
Thermally stimulated exoelectron emission from solid Xe
Authors: Khyzhniy I. V. , Grigorashchenko O. N. , Savchenko E. V. , Ponomaryov A. N. , Bondybey V. E.
Published: July 2007

Thermally stimulated emission of exoelectrons and photons from solid Xe pre-irradiated by low-energy electrons are studied. A high sensitivity of thermally stimulated luminescence (TSL) and thermally stimulated exoelectron emission (TSEE) to sample prehistory is demonstrated. It is shown that electron traps in unannealed samples are characterized by a much broader distribution of trap levels in comparison with annealed samples and their concentration exceeds in number that in annealed samples. Both phenomena, TSL and TSEE, are found to be triggered by release of electrons from the same kind of traps. The data obtained suggest a competition between two relaxation channels: charge recombination and electron transport terminated by TSL and TSEE. It is found that TSEE predominates at low temperatures, while at higher temperatures TSL prevails. An additional relaxation channel, a photon-stimulated exoelectron emission from pre-irradiated solid Xe, is revealed.
Shift of close-packed basal planes as an order parameter of transitions between antiferromagnetic phases in solid oxygen: II. Temperature/pressure dependence of sound velocities and lattice parameters
Authors: Gomonay E. V. , Loktev V. M.
Published: July 2007

In the present paper we generalize a phenomenological model developed by Gomonay and Loktev (Fiz. Nizk. Temp. 31, 1002 (2005) [Low Temp. Phys. 31, 763 (2005)]) for the description of magnetostructural phase transitions and related peculiarities of the elastic properties of solid oxygen under high pressure and/or temperature below 40K. We show that the variation of all the lattice parameters in the vicinity of the α–β phase transition is due to both the shift of basal closed-packed planes and appearance of long-range magnetic order. Competition between these two factors, on the one hand, and the lattice compression below Tαβ on the other, produces nonmonotonic temperature dependence of lattice parameter b (along the monoclinic axis). A steep decrease of the sound velocities in the vicinity of Tαβ can be explained by a softening of the lattice with respect to shift of the close-packed planes (described by the constant K2) prior to the phase transition point. We anticipate an analogous softening of the sound velocities in the vicinity of the α–δ phase transition and nonmonotonic pressure dependence of sound velocities in the α phase.
Many-body interactions and high-pressure equations of state in rare-gas solids
Authors: Freiman Yu. A. , Tretyak S. M.
Published: July 2007

The T=0K equations of state (EOS) of rare-gas solids (RGS) (He, Ne, Ar, Kr, and Xe) are calculated in the experimentally studied ranges of pressures with the two- and three-body interatomic forces taken into account. Solid-state corrections to the pure two-body Aziz et al. potentials included the long-range Axilrod–Teller three-body interaction and short-range three-body exchange interaction. The energy-scale and length-scale parameters of the latter were taken as adjustable parameters of theory. The calculated T=0K EOS for all RGS are in excellent agreement with experiment in the whole range of pressures. The calculated EOS for Ar, Kr, and Xe exhibit inflection points where the isothermal bulk moduli have non-physical maxima, indicating that account of only three-body forces becomes insufficient. These points lie at pressures 250, 200, and 175GPa (volume compressions of approximately 4.8, 4.1, and 3.6) for Ar, Kr, and Xe, respectively. No such points were found in the calculated EOS of He and Ne. The relative magnitude of the three-body contribution to the ground-state energy with respect to the two-body one as a function of the volume compression was found to be nonmonotonic in the sequence Ne–Ar–Kr–Xe. In a large range of compressions, Kr has the highest value of this ratio. This anomalously high three-body exchange force contributes to the EOS a negative pressure so large that the EOS for Kr and Ar as a function of compression nearly coincide. At compressions higher than approximately 3.5 the curves intersect, and further on, the EOS of Kr lies lower than that of Ar.
Phase transitions in Kr–CH4 solid solutions and rotational excitations in phase II
Authors: Bagatskii M. I. , Mashchenko D. A. , Dudkin V. V.
Published: July 2007

The heat capacity CP of Kr-nCH4 solid solutions with CH4 concentrations n=0.82, 0.86, and 0.90 and of solutions with n=0.90, 0.95 doped with 0.002 O2 impurity is investigated under equilibrium vapor pressure over the interval 1–24K. The (T,n) phase diagram of Kr-nCH4 solid solutions is refined, and the region of two-phase states is determined. The contribution of the rotational subsystem, Crot, to the heat capacity of the solutions is separated. Analysis of Crot(T) at T<3K makes it possible to estimate the effective conversion times τ and the energy gaps E1 and E2 between the tunneling levels of the A,T and A,E nuclear-spin species of CH4 molecules in the orientationally ordered subsystem and to determine the effective energy gaps E1 between the lowest levels of the A and T species. The relations τ(n) and E1(n) stem from changes of the effective potential field in result of the replacement of CH4 molecules by Kr atoms at sites of the ordered sublattices. The effective gaps EL between a group of tunneling levels of the librational ground state and the nearest group of excited levels of the librational state of the ordered CH4 molecules in the solutions with n=0.90 (EL=52K) and 0.95 (EL=55K) is estimated.
Quantum trajectories in complex phase space: Multidimensional barrier transmission
Authors: Wyatt Robert E. , Rowland Brad A.
Published: July 2007

The quantum Hamilton-Jacobi equation for the action function is approximately solved by propagating individual Lagrangian quantum trajectories in complex-valued phase space. Equations of motion for these trajectories are derived through use of the derivative propagation method (DPM), which leads to a hierarchy of coupled differential equations for the action function and its spatial derivatives along each trajectory. In this study, complex-valued classical trajectories (second order DPM), along which is transported quantum phase information, are used to study low energy barrier transmission for a model two-dimensional system involving either an Eckart or Gaussian barrier along the reaction coordinate coupled to a harmonic oscillator. The arrival time for trajectories to reach the transmitted (product) region is studied. Trajectories launched from an “equal arrival time surface,” defined as an isochrone, all reach the real-valued subspace in the transmitted region at the same time. The Rutherford-type diffraction of trajectories around poles in the complex extended Eckart potential energy surface is described. For thin barriers, these poles are close to the real axis and present problems for computing the transmitted density. In contrast, for the Gaussian barrier or the thick Eckart barrier where the poles are further from the real axis, smooth transmitted densities are obtained. Results obtained using higher-order quantum trajectories (third order DPM) are described for both thick and thin barriers, and some issues that arise for thin barriers are examined.
A numerical study of intrusive compositional gravity currents
Authors: Ooi Seng Keat , Constantinescu George , Weber Larry
Published: July 2007

The formation, evolution, and structure of intrusive Boussinesq gravity currents propagating into a two-layer fluid with a sharp interface are investigated using highly resolved large eddy simulation at Reynolds numbers defined with the front velocity in the range of Ref=3000–5000. Two cases are studied in which the density of the lock fluid is equal to the depth-weighted mean of the densities inside the two layers of ambient fluid. In the first one (case SC) the depths of the two layers of ambient fluid are equal. In the second one (case NSC) the depths of the two layers are different. The propagation speed in the slumping phase and the evolution of the currents are found to be close to both experiments and theory. Experimental observations showed the front continued to propagate for some time after the bore has caught the head region with the same constant velocity observed during the slumping phase. The present simulations show the reason is that unmixed lock fluid is still left inside the head region at the end of the slumping phase. This is in contrast to the case of gravity currents propagating over no-slip surfaces. It is also confirmed that even after the end of the slumping phase the local dissipation rate inside the region of unmixed fluid present inside the head remains very small compared to typical values observed in the interfacial layers behind the head. However, the size of the head and the region of unmixed fluid inside the head and dissipative-wake continue to decrease after the end of the slumping phase. The growth of three-dimensional (3D) instabilities at the front of the intrusion currents is observed to generate large-scale structures similar to the lobes observed in the case of gravity currents propagating over a no-slip surface. The dominant wavelength present in the initial growth stages of the 3D front instability in case SC is about half the one predicted by stability theory for a current propagating over a no-slip surface at the same Grashof number. The length scales of the front structures during the slumping phase are found to be smaller than the ones observed for currents propagating over no-slip surfaces at similar Grashof numbers.
Quantumlike representation of extensive form games: Probabilistic aspects
Authors: Khrennikov Andrei
Published: July 2007

We consider an application of the mathematical formalism of quantum mechanics outside physics, namely, to game theory. We present a simple game between macroscopic players, say, Alice and Bob (or in a more complex form—Alice, Bob, and Cecilia), which can be represented in the quantumlike (QL) way—by using a complex probability amplitude (game’s “wave function”) and noncommutative operators. The crucial point is that games under consideration are so-called extensive form games. Here the order of actions of players is important; such a game can be represented by the tree of actions. The QL probabilistic behavior of players is a consequence of incomplete information (which is available to, e.g., Bob) about the previous action of Alice. In general one could not construct a classical probability space underlying a QL game. This can happen even in a QL game with two players. In a QL game with three players Bell’s inequality can be violated. The most natural probabilistic description is given by the so-called contextual probability theory completed by the frequency definition of probability.