bluuebunny/crossref_metadata_2025 huggingface dataset:
CypScore: Quantitative Prediction of Reactivity toward Cytochromes P450 Based on Semiempirical Molecular Orbital Theory
Authors: Hennemann Matthias , Friedl Arno , Lobell Mario , Keldenich Jörg , Hillisch Alexander , Clark Timothy , Göller Andreas H.
Published: February 2009

CypScore predicts the reactivity of competing positions in the same and different molecules to a variety of cytochrome P450 metabolic reactions on a single reactivity scale.

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CypScore is an in silico approach for predicting the likely sites of cytochrome P450‐mediated metabolism of druglike organic molecules. It consists of multiple models for the most important P450 oxidation reactions such as aliphatic hydroxylation, N‐dealkylation, O‐dealkylation, aromatic hydroxylation, double‐bond oxidation, N‐oxidation, and S‐oxidation. Each of these models is based on atomic reactivity descriptors derived from surface‐based properties calculated with ParaSurfTM and based on AM1 semiempirical molecular orbital theory. The models were trained with data derived from Bayer Schering Pharma's in‐house MajorMetabolite Database with more than 2300 transformations and more than 800 molecules collected from the primary literature. The models have been balanced to allow the treatment of relative intramolecular, intra‐chemotype, and inter‐chemotype reactivities of the labile sites toward oxidation. The models were evaluated with promising hit rates on three public datasets of varying quality in the annotation of the experimental positions. For 39 well‐characterized compounds from 14 in‐house lead optimization programs, we could detect at least one major metabolite for the three highest‐ranked positions in 87 % of the compounds and overall more than 62 % of all major metabolites, with promising true‐ to false‐positive ratios of 0.9.
Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma
Authors: Reardon David A. , Egorin Merrill J. , Desjardins Annick , Vredenburgh James J. , Beumer Jan H. , Lagattuta Theodore F. , Gururangan Sridharan , Herndon James E. , Salvado August J. , Friedman Henry S.
Published: February 2009

BACKGROUND:

This study determined the maximum tolerated dose (MTD) and dose‐limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, vatalanib, when administered with imatinib and hydroxyurea on a continuous daily schedule among recurrent malignant glioma patients.

METHODS:

All patients received 500 mg of hydroxyurea twice daily. Imatinib was dosed at 400 mg per day for patients not taking enzyme‐inducing antiepileptic drugs (EIAEDs; stratum A) and at 500 mg twice‐a‐day for patients taking EIAEDs (stratum B). Vatalanib was escalated from 500 mg to 1250 mg twice daily in successive cohorts, independently for each stratum. Pharmacokinetics of each drug were assessed.

RESULTS:

A total of 37 recurrent patients, 34 (92%) with glioblastoma and 3 (8%) with grade 3 malignant glioma, were enrolled. Nineteen patients (51%) were taking EIAEDs. The MTD of vatalanib for all patients was 1000 mg twice‐a‐day. DLTs were hematologic, gastrointestinal, renal, and hepatic. No patients developed intracranial hemorrhage. Concurrent administration of imatinib and hydroxyurea did not affect vatalanib exposure, but EIAEDs decreased vatalanib and imatinib plasma exposures.

CONCLUSIONS:

Vatalanib doses up to 1000 mg twice‐a‐day combined with imatinib and hydroxyurea were well tolerated. Strategies to target tumor blood vessel endothelial cells and pericytes by inhibiting VEGFR and platelet‐derived growth factor, respectively, were safe among recurrent malignant glioma patients and may enhance antiangiogenesis activity. Cancer 2009. © 2009 American Cancer Society.
Non‐Covalent Interactions in Supramolecular Assemblies Investigated with Electron Spectroscopies
Authors: Ruiz‐Osés Miguel , de Oteyza Dimas G. , Fernández‐Torrente Isabel , Gonzalez‐Lakunza Nora , Schmidt‐Weber Phillipp M. , Kampen Thorsten , Horn Karsten , Gourdon André , Arnau Andrés , Ortega J. Enrique
Published: February 2009

A new view: A picture of the different non‐covalent interactions relevant for the self‐assembly of organic layers and their spectroscopic fingerprints is provided (see figure). In particular, state‐of‐the‐art spectroscopic measurements are performed for supramolecular assemblies, comparing the electronic structure of single‐component layers with that of binary organic layers.

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Development and validation of a male specific body checking questionnaire
Authors: Hildebrandt Tom , Walker D. Catherine , Alfano Lauren , Delinsky Sherrie , Bannon Katie
Published: February 2009

Objective:

Body checking may be an important behavioral consequence of body image disturbance. Despite the importance of body checking, few measurements of this construct exist, particularly for males. This study describes the development and validation of the Male Body Checking Questionnaire (MBCQ).

Method:

Convergent and divergent validity, factor structure, and reliability were tested in three separate samples of men and women.

Results:

Factor analyses suggested a reliable four‐factor structure with evidence of a higher order global checking factor for men, but not women. The MBCQ demonstrated good concurrent and divergent validity. Short‐term test‐retest reliability was good with high internal consistency across time.

Discussion:

Interpretation of psychometrics and recommendations for subsequent research are discussed. The MBCQ is likely to be an appropriate tool for investigating body image‐based pathology in males. © 2009 by Wiley Periodicals, Inc. Int J Eat Disord 2010
A simple framework for evaluating regional wetland ecohydrological response to climate change with case studies from Great Britain
Authors: Acreman M. C. , Blake J. R. , Booker D. J. , Harding R. J. , Reynard N. , Mountford J. O. , Stratford C. J.
Published: February 2009

It is widely accepted that the Earth's climate is changing more rapidly than it has in the past and that over the next 100 years temperatures will rise and patterns of precipitation will be altered. These predictions for the future have important implications for all ecosystems, particularly those, such as wetlands, whose ecological character is very dependent on its hydrological regime. The potential impacts of climate change on wetland hydrology are of interest to a wide range of stakeholders from wetland managers to international policy makers. Ecohydrological models that combine climate changes, hydrological processes and ecological response provide a means of estimating what might happen to some wetland functions and species in the future. This paper presents a framework that can be used for combining models and available data at a regional scale and is appropriate for different wetlands, in different countries and for different levels of data availability. The simple models are based on broad conceptual understanding of wetland hydrology and are intended to describe basic ecohydrological processes within the constraints of data availability; they are thus fit for the purpose of general assessment and do not pretend to provide precise results for specific wetland sites. Data from Great Britain (GB) have been used to demonstrate each step in the framework for two temperate wetland types: rain‐fed wetlands (wet heaths or degraded raised mires) and floodplain margins. Whilst GB may be considered to be relatively data rich, we believe that sufficient information is available in many countries to apply this framework for the regional assessment of climate change impacts on wetlands. Although the models successfully represent the baseline conditions, it is not possible to test whether they accurately predict the future vulnerability of the selected areas. Results for GB suggest that predictions of reduced summer rainfall and increased summer evaporation will put stress on wetland plant communities in late summer and autumn with greater impacts in the south and east of GB. In addition, impacts on rain‐fed wetlands will be greater than on those dominated by river inflows. Copyright © 2009 John Wiley & Sons, Ltd.
DAP10 associates with Ly49 receptors but contributes minimally to their expression and function in vivo
Authors: Tassi Ilaria , Le Friec Gaelle , Gilfillan Susan , Takai Toshiyuki , Yokoyama Wayne M. , Colonna Marco
Published: February 2009

NK cells recognize target cells through activating receptors, many of which rely on the transmembrane adaptors DAP10, DAP12 and FcR‐γ to deliver intracellular signals. Because these adaptors initiate distinct signaling pathways, they dictate the type of response mediated by receptor engagement. DAP10, for example, primarily triggers cytotoxicity, whereas DAP12 induces both cytotoxicity and IFN‐γ secretion. In mice, NKG2D signals through both DAP10 and DAP12, which broadens and modulates the type of response engendered by encounter with ligand. Although initial studies indicated that Ly49H and Ly49D recruit only DAP12, a recent report suggested that they also associate with DAP10. We asked whether this association occurs and is functionally significant under physiologic conditions. Our data demonstrate that DAP10 does associate with Ly49H and Ly49D in primary NK cells. While this association contributes slightly to cell surface expression of both receptors, it has no significant impact on Ly49H‐mediated control of murine cytomegalovirus infection. Thus, while many activating NK‐cell receptors are promiscuous in terms of adaptor association, our data indicate that the functional consequences of such promiscuity may vary widely and may not be evident in all cases.
The Variable Strength of the Sulfur–Sulfur Bond: 78 to 41 kcal – G3, CBS‐Q, and DFT Bond Energies of Sulfur (S8) and Disulfanes XSSX (X = H, F, Cl, CH3, CN, NH2, OH, SH)
Authors: Denk Michael K.
Published: February 2009

Experimental values for the strength of the sulfur–sulfur bond scatter over a wide range and are frequently in disagreement with each other. For S8, reliable experimental data seem to lack entirely. To check experimental data and establish the strength of the sulfur–sulfur bond in S8, high‐precision thermochemical calculations (G3, CBS‐Q) and DFT methods were employed. The calculations confirm a stunning range for the strength of the sulfur–sulfur bond with energies between 77.7 kcal for FSSF and only 41.8 kcal for tetrasulfane, HSS–SSH. For the pivotal bond energy of elemental sulfur, S8, the bond energy is 40.5 kcal but can be narrowed to 38.0–39.2 kcal mol–1 by including CBS‐QB3 data. While older DFT methods are not well suited to accurately reproduce the S–S bond energies, excellent data can be obtained with the recently introduced Boese–Martin (BMK) hybrid DFT method. Atoms in molecules (AIM) calculations reveal significant multiple bonding and spin delocalization in the sulfur radicals XS·. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
First Row Transition Metal Aminopyridinates – the Missing Complexes
Authors: Glatz Germund , Demeshko Serhiy , Motz Günter , Kempe Rhett
Published: February 2009

Lithiated 4‐methyl‐2‐[(trimethylsilyl)amino]pyridine (ApTMSH) undergoes a salt metathesis reaction with [ScCl3(thf)3] and FeCl3, at low temperature in thf, to yield the homoleptic complexes [Sc(ApTMS)3] (1) and [Fe(ApTMS)3] (2). An analogous reaction with MnCl2, CoCl2 and FeCl2 using two equivalents of 4‐tert‐butylpyridine (tBuPy) as additional donor ligand affords the structurally analogous cis complexes [Mn(ApTMS)2(tBuPy)2] (3), [Co(ApTMS)2(tBuPy)2] (4) and [Fe(ApTMS)2(tBuPy)2] (5). If FeCl2 is used without tBuPy, the highly symmetric trinuclear complex [Fe3(ApTMS)6Li2O] (6) is obtained. Furthermore, the use of ZnCl2 in a reaction with lithiated ApTMSH yields the dimeric complex [Zn2(ApTMS)4] (7) in which two ApTMS ligands bridge the two metals. All complexes have been characterised by X‐ray crystal structure analysis. To the best of our knowledge, complexes 1 and 2 and 5 are the first scandium and iron aminopyridinates, respectively, and complex 3 is the first manganese aminopyridinate complex which contains no additional anionic ligand. Complexes 4 and 7 are rare examples of cobalt and zinc aminopyridinates. This study proves that aminopyridinato ligands are highly universal ligands since they are able to stabilize early and late transition metals. Aminopyridinates of every first row transition metal are now available. The magnetic properties of all paramagnetic complexes were investigated. All complexes are high‐spin complexes and the trinuclear iron complex 6 exhibits a weak antiferromagnetic coupling.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Anionic Lanthanide Complexes Bearing a Bis(phenoxy)‐Functionalized N‐Heterocyclic Carbene Ligand: Syntheses and Molecular Structures
Authors: Yao Haisheng , Zhang Yong , Sun Hongmei , Shen Qi
Published: February 2009

A series of anionic lanthanide complexes supported by bis(phenoxy)‐functionalized N‐heterocyclic carbene (NHC) ligand L, where L = 1,3‐bis[O‐4,6‐di‐tBu‐C6H2‐2‐CH2][C{N(CHCH)N}], were synthesized by the amine‐elimination reaction. The in situ reaction of LH3Cl with Li(thf)Ln(NiPr2)4 and nBuLi in a 2:1:2 molar ratio in thf afforded the discrete ion‐pair complexes [L2Ln][Li(dme)3] (Ln = Sm 1, Er 2, Yb 3) upon crystallization from dme/toluene (10 mL:15 mL). The reaction of LH3Cl with Li(thf)Sm(NiPr2)4 and nBuLi in a 2:1:2 molar ratio proceeded in thf, followed by crystallization from thf/toluene (2 mL:15 mL), to yield an “ate” complex [(thf)Li(μ‐L)SmL] (4). The analogous “ate” complex with sodium metal [(Et2O)Na(μ‐L)SmL] (5) was also prepared by the in situ treatment of LH3Cl with Sm[N(SiMe3)2]3 and NaN(SiMe3)2 in a 2:1:3 molar ratio. Single‐crystal X‐ray structural analyses of 1–5 revealed that complexes 1–3 have ion‐pair structure consisting of an anion [L2Ln]– and a cation [Li(dme)3]+, in which the coordination geometries about each lanthanide metal ion can be best described as a distorted octahedron, while the samarium ion and the alkali metal ion in complexes 4 and 5 are connected together by two phenoxide oxygen bridges, and each alkali metal ion is bound to anadditional oxygen atom of one thf (for 4) and one Et2O (for 5).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
2,3‐Di‐n‐undecylanthracene and 2,3‐Di‐n‐decyloxyanthracene (DDOA) – on the Connecting Link between the Aromatic Substrate and the Aliphatic Chain in Self‐Assembling Systems
Authors: Hopf Henning , Greiving Helmut , Bouas‐Laurent Henri , Desvergne Jean‐Pierre
Published: February 2009

In contrast to its bis(oxa) analog 1 (DDOA), the hydrocarbon 11 was not found to form organogels with linear alcohols, alkanes, toluene, acetonitrile and other solvents. Whereas the photoreactivity of 1 did not follow the usual behaviour of anthracene derivatives, compound 11, irradiated in cyclohexane, produced the two expected [4+4]cycloadducts 12 and 13 (anti and syn photodimers, respectively). These facts point to the role of the connecting link between the rigid core and the flexible chain for some self‐assembled systems.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Simulation of multiple shock–shock interference using implicit anti‐diffusive WENO schemes
Authors: Hsieh Tsang‐Jen , Wang Ching‐Hua , Yang Jaw‐Yen
Published: February 2009

Accurate computations of two‐dimensional turbulent hypersonic shock–shock interactions that arise when single and dual shocks impinge on the bow shock in front of a cylinder are presented. The simulation methods used are a class of lower–upper symmetric‐Gauss–Seidel implicit anti‐diffusive weighted essentially non‐oscillatory (WENO) schemes for solving the compressible Navier–Stokes equations with Spalart–Allmaras one‐equation turbulence model. A numerical flux of WENO scheme with anti‐diffusive flux correction is adopted, which consists of first‐order and high‐order fluxes and allows for a more flexible choice of first‐order dissipative methods. Experimental flow fields of type IV shock–shock interactions with single and dual incident shocks by Wieting are computed. By using the WENO scheme with anti‐diffusive flux corrections, the present solution indicates that good accuracy is maintained and contact discontinuities are sharpened markedly as compared with the original WENO schemes on the same meshes. Computed surface pressure distribution and heat transfer rate are also compared with experimental data and other computational results and good agreement is found. Copyright © 2009 John Wiley & Sons, Ltd.
A streamfunction–velocity approach for 2D transient incompressible viscous flows
Authors: Kalita Jiten C. , Gupta Murli M.
Published: February 2009

We recently proposed (J. Comput. Phys. 2005; 207(1):52–68) a new paradigm for solving the steady‐state two‐dimensional (2D) Navier–Stokes (N–S) equations using a streamfunction–velocity (ψ–v) formulation. This formulation was shown to avoid the difficulties associated with the traditional formulations (primitive variables and streamfunction‐vorticity formulations). The new formulation was found to be second‐order accurate and was found to yield accurate solutions of a number of fluid flow problems.

In this paper, we extend the ideas and propose a second‐order implicit, unconditionally stable ψ–v formulation for the unsteady incompressible N–S equations. The method is used to solve several 2D time‐dependent fluid flow problems, including the flow decayed by viscosity problem with analytical solution, the lid‐driven square cavity problem, the backward‐facing step problem and the flow past a square prism problem. For the problems with known exact solutions, our coarse grid transient solutions are extremely close to the analytical ones even for high Reynolds numbers (Re). For the driven cavity problem, our time‐marching steady‐state solutions up to Re=7500 provide excellent matches with established numerical results, and for Re=10000, our study concludes that the asymptotic stable solution is periodic as has been found by other authors in recent studies. For the backward step problem, our numerical results are in excellent agreement with established numerical and experimental results. Finally, for the flow past a square prism, we have very successfully simulated the von Kármán vortex street for Re=200. Copyright © 2009 John Wiley & Sons, Ltd.
Comparison of sequential data assimilation methods for the Kuramoto–Sivashinsky equation
Authors: Jardak M. , Navon I. M. , Zupanski M.
Published: February 2009

The Kuramoto–Sivashinsky equation plays an important role as a low‐dimensional prototype for complicated fluid dynamics systems having been studied due to its chaotic pattern forming behavior. Up to now, efforts to carry out data assimilation with this 1‐D model were restricted to variational adjoint methods domain and only Chorin and Krause (Proc. Natl. Acad. Sci. 2004; 101(42):15013–15017) tested it using a sequential Bayesian filter approach. In this work we compare three sequential data assimilation methods namely the Kalman filter approach, the sequential Monte Carlo particle filter approach and the maximum likelihood ensemble filter methods. This comparison is to the best of our knowledge novel. We compare in detail their relative performance for both linear and nonlinear observation operators. The results of these sequential data assimilation tests are discussed and conclusions are drawn as to the suitability of these data assimilation methods in the presence of linear and nonlinear observation operators. Copyright © 2009 John Wiley & Sons, Ltd.
Spending on new drug development1
Authors: Adams Christopher Paul , Brantner Van Vu
Published: February 2009

This paper replicates DiMasi et al. (J. Health Econ. 2003; 22: 151–185; Drug Inf. J. 2004; 38: 211–223) estimates of expenditure on new drug development using publicly available data. The paper estimates that average expenditure on drugs in human clinical trials is around $27m per year, with $17m per year on drugs in Phase I, $34m on drugs in Phase II and $27m per year on drugs in Phase III of the human clinical trials. The paper's estimated expenditure on new drug development is somewhat greater than suggested by the survey results presented in DiMasi et al. (J. Health Econ. 2003; 22: 151–185; Drug Inf. J. 2004; 38: 211–223). The paper combines a 12‐year panel of research and development expenditure for 183 publicly traded firms in the pharmaceutical industry with panel of drugs in human clinical trials for each firm over the same period. The paper estimates drug expenditure by estimating the relationship between research and development expenditure and the number of drugs in development for 1682 company/years (183 firms multiplied by the number of years for which we have financial and drug development information). The paper also estimates expenditure on drugs in various therapeutic categories. Copyright © 2009 John Wiley & Sons, Ltd.
Statistical implications of utility weighted and equally weighted HRQL measures: an empirical study
Authors: Wilke Caitlyn T. , Pickard A. Simon , Walton Surrey M. , Moock Joern , Kohlmann Thomas , Lee Todd A.
Published: February 2009

The utility‐based approach to health measurement, exemplified by EQ‐5D and Health Utilities Index (HUI), has been challenged on a theoretical basis, but the statistical implications of such an approach have received little attention. To empirically investigate this issue, psychometric properties and statistical efficiency of the EQ‐5D and HUI Mark 3 (HUI3) classifiers were compared when scored using preference weighted (WPS) and equally weighted summary scores using two longitudinal datasets (nstroke=124; nrehabilitation=264). Test–retest reliability, construct validity, responsiveness, and relative efficiency (RE) ratios (with bootstrapped 95% confidence intervals) were examined. WPS had slightly lower test–retest reliability, particularly for EQ‐5D (intraclass correlation coefficient=0.61 vs 0.72). For known‐groups comparisons, WPS had greater inferential power for both EQ‐5D and HUI3 (RE>1). No significant differences in sensitivity to change were observed for EQ‐5D [0.71 (95% CI: 0.29,1.33)≤RE≤0.96(95% CI: 0.69,1.32)] or HUI3 [0.97 (95% CI: 0.89,1.03)≤RE≤1.23 (95% CI: 0.98,1.72)]. Implications of weighted scoring will depend on whether the weights are greater or less than equal weights where patients fall along the health state classifier continuum. Because utility weights can affect the statistical properties and significance of results, the summary score selected should be appropriate to the purpose of the study and population of interest. Copyright © 2009 John Wiley & Sons, Ltd.
Central nervous system dissemination in immunocompetent patients with aggressive lymphomas: incidence, risk factors and therapeutic options
Authors: Ferreri Andrés J. M. , Assanelli Andrea , Crocchiolo Roberto , Ciceri Fabio
Published: February 2009

Central nervous system (CNS) dissemination is a rare (4–5%) but usually fatal complication of aggressive lymphomas. Prophylaxis modalities to prevent CNS dissemination in aggressive lymphomas cannot be widely applied to every lymphoma patient since it is associated with increased risk of neurotoxicity. Therefore, identification of high‐risk patients as the best candidates to receive CNS prophylaxis constitutes a major endpoint in the management of these malignancies. Various risk factors and models for CNS recurrence have been described. Parameters reflecting the extent and proliferation of the disease, like elevated serum lactate dehydrogenase levels, involvement of multiple extranodal sites, advanced stage and high age‐adjusted International Prognostic Index (IPI) score, as well as the involvement of specific anatomic sites, like testes, orbit, paranasal sinuses, have been identified and confirmed as important to predict CNS dissemination. Management of this complication in aggressive lymphomas with conventional‐dose chemotherapy is associated with disappointing results, while some preliminary but encouraging experiences suggest a potential role of high‐dose chemotherapy and stem cell transplantation. The analysis of recent clinical studies could lead to advancement in the prognosis of aggressive lymphomas, but several questions regarding the optimum chemotherapy combination, the best conditioning regimen and the role of radiation therapy and intrathecal chemotherapy remain still unanswered. The purposes of the present review are to critically analyse current data on the risk of CNS dissemination in aggressive lymphomas, the clinical presentation of secondary CNS lymphomas and the efficacy of CNS prophylaxis as well as to discuss the available therapeutic options for this devastating event. Copyright © 2009 John Wiley & Sons, Ltd.
Modeling the adhesion of human embryonic stem cells to poly(lactic‐co‐glycolic acid) surfaces in a 3D environment
Authors: Gao Steven Y. , Lees Justin G. , Wong Jennifer C. Y. , Croll Tristan I. , George Peter , Cooper‐White Justin J. , Tuch Bernard E.
Published: February 2009

Human embryonic stem cells (hESCs) have previously been cultured on three dimensional (3D) biodegradable polymer scaffolds. Although complex structures were formed from the hESCs, very little is known about the mechanism of adhesion of these cells to the surfaces of the scaffolds. In this study, we achieved the efficient adhesion of pluripotent hESCs to 3D poly(lactic‐co‐glycolic acid) (PLGA) scaffolds based on our data from a novel two dimensional (2D) model that imitates the surface properties of the scaffolds. In the 2D model, single cell preparations of pluripotent hESCs adhered efficiently and predominantly to PLGA surfaces coated with laminin in comparison to collagen I, collagen IV, or fibronectin‐coated surfaces. Flow cytometry analysis revealed that almost all of the pluripotent single cells expressed the integrin α6, with a small percentage also expressing α3ß1, which facilitates adhesion to laminin. This data was then translated into the 3D environment, with the efficient binding of single pluripotent hESCs to PLGA scaffolds coated with laminin. The utility of this system was shown by the directed differentiation of single hESCs seeded within laminin‐coated scaffolds toward the endoderm lineage. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res 2010
Recombinant retrovirus‐like particle forming DNA vaccines in prime‐boost immunization and their use for hepatitis C virus vaccine development
Authors: Desjardins Delphine , Huret Christophe , Dalba Charlotte , Kreppel Florian , Kochanek Stefan , Cosset François‐Loïc , Tangy Frédéric , Klatzmann David , Bellier Bertrand
Published: February 2009

Background

The expression of Moloney murine leukemia virus (Mo‐MLV) gag proteins is sufficient to generate retrovirus‐like particles (retroVLPs) that can be used as antigen‐display platforms by pseudotyping with heterologous envelope proteins or by insertion of epitopes in structural constituents. To circumvent the in vitro production of such retroVLPs, we used DNA plasmids generating recombinant retroVLPs (plasmo‐retroVLPs) as immunogens. We previously demonstrated that plasmo‐retroVLPs induce significantly better antigen‐specific T cell responses and antiviral immune protection than plasmids bearing a single mutation preventing retroVLPs assembly. In the present study, we investigated the possibility of using such plasmo‐retroVLPs in prime‐boost immunization strategies for hepatitis C virus (HCV) vaccine development.

Methods

To define the best immunization regimen with plasmo‐retroVLPs and serotype 5 recombinant adenovirus vectors (rAd5), we used standardized methodologies measuring immune responses to the GP33–41 ‘gold standard’ antigen. The protective efficacy of these immunization schedules was also evaluated in mice after tumor challenge. We then applied the optimal prime‐boost immunization strategy using vectors expressing HCV‐E1/E2 envelope glycoproteins.

Results

Using vectors expressing the model antigen, we demonstrated that rAd5GP33–41/plasmo‐retroVLPGP33–41 regimen induced significantly higher cellular immune responses than plasmo‐retroVLPGP33–41/rAd5GP33–41. Consequently, HCV‐specific plasmo‐retroVLPs (plasmo‐retroVLPE1E2) were used as boost in mice primed with rAd5E1E2 and we observed that plasmo‐retroVLPE1E2 significantly increased E1/E2‐specific interferon‐γ cellular responses and E2‐specific antibody generation. By contrast, plasmids unable to form E1/E2‐pseudotyped retroVLPs had no boosting effect, revealing the importance of presenting E1/E2 in a particulate form.

Conclusions

Altogether, combining plasmo‐retroVLPs that represent a new class of genetic vaccines in a heterologous prime‐boost vaccination strategy appears to be a promising strategy for HCV vaccine development. Copyright © 2009 John Wiley & Sons, Ltd.
HPLC methods for the purification of [11C]‐labelled radiopharmaceuticals: reversal of the retention order of products and precursors
Authors: Lehel Szabolcs , Madsen Jacob , Gillings Nic
Published: February 2009

Preparative HPLC methods have been developed for a number of [11C]‐methylated PET tracers, which enable elution of the labelled compounds prior to their precursors, thus reducing the overall synthesis time and avoiding contamination of the final product with precusor. This reversal of retention order has been achieved for [11C]DASB, [11C]raclopride, [11C]FLB 457, [11C]carfentanil, and 2‐fluoro‐[N‐methyl‐11C]apomorphine, enabling collection of the purified radiopharmaceuticals from the HPLC system after 5–7 min. Furthermore, by using ethanol as the organic modifier, residual solvent analysis prior to human injection could be avoided and three of the radiopharmaceuticals could be injected directly following simple dilution and sterile filtration. Copyright © 2009 John Wiley & Sons, Ltd.
Synthesis and biodistribution of novel 99mTc‐nitrido methylpiperidine dithioformate derivatives as potential brain imaging agents
Authors: Lu Jie , Xu Mingyan , Jia Hongmei , Xi Shuxia , Wang Yimeng , Wang Xuebin
Published: February 2009

Three dithioformate ligands with methyl substituted on the piperidine rings, potassium 1‐(2‐methylpiperidine‐1‐yl)‐dithioformate (2‐mp), potassium 1‐(3‐methylpiperidine‐1‐yl)‐dithioformate (3‐mp) and potassium 1‐(4‐methylpiperidine‐1‐yl)‐dithioformate (4‐mp) were synthesized. The corresponding 99mTc‐nitrido complexes were prepared in high yield (>95%) through the [99mTcN] intermediate and characterized by thin layer chromatography and high‐performance liquid chromatography. All the neutral 99mTc‐nitrido complexes were stable under physiological conditions and lipophilic with log P values between 1.40 and 1.58. In vivo biodistribution results showed that all the 99mTc‐nitrido complexes displayed high brain uptakes and long retention times. Among them, 99mTcN‐4mp, demonstrated the best properties for brain imaging with the brain uptake 3.40±0.24, 3.22±0.31, 2.72±0.28 and 2.22±0.18% ID/g at 5, 30, 60 and 120 min p.i., respectively. Moreover, the influence of stereochemistry of the 99mTcN complexes with methyl substitution on ortho, meta and para positions on piperidine ring on the biodistribution properties were investigated with B3LYP/6‐31G*(LANL2DZ for Tc) method using the Gaussian 03 program package. Copyright © 2009 John Wiley & Sons, Ltd.
Structure of male accessory glands of Bolivarius siculus (fischer) (Orthoptera, Tettigoniidae) and protein analysis of their secretions
Authors: Marchini Daniela , Brundo Maria Violetta , Sottile Lorenzo , Viscuso Renata
Published: February 2009

In Tettigoniidae (Orthoptera), male reproductive accessory glands are involved in the construction of a two‐part spermatophore; one part, the spermatophylax, is devoid of sperm and considered a nuptial gift. The morphology, ultrastructure, and secretion protein content of the male reproductive accessory glands from Bolivarius siculus were investigated. Two main groups of gland tubules open into the ejaculatory duct: the “first‐order” glands, a number of large anterior tubules, and the “second‐order” glands, smaller and more numerous tubules positioned posteriorly. Along with a further subdivision of the gland tubules, we here describe for the first time an additional gland group, the intermediate tubules, which open between first and second‐order glands. The mesoderm‐derived epithelium of all glands is a single layer of microvillated cells, which can be either flattened or cylindric in the proximal or distal region of the same gland. Epithelial cells, very rich in RER and Golgi systems, produce secretions of both electron‐dense granules and globules or electron‐transparent material, discharged into the gland lumen by apocrine or merocrine mechanisms, respectively. With one exception, a unique electrophoresis protein profile was displayed by each of the gland types, paralleling their unique morphologies. To assess the contribution of different types of accessory glands to the construction of the spermatophore, the protein patterns of the gland secretions were compared with those of the extracts from the two parts of the spermatophore. All samples showed bands distributed in a wide range of molecular weight, including proteins of very low molecular mass. However, one major high molecular weight protein band (>180 kDa) is seen exclusively in extracts from the first‐order glands, and corresponds to an important protein component of the spermatophylax. J. Morphol., 2009. © 2009 Wiley‐Liss, Inc.
Morphological characterization of the testicular cells and seminiferous epithelium cycle in six species of Neotropical bats
Authors: Beguelini Mateus R. , Moreira Paula R.L. , Faria Karina C. , Marchesin Sandra R.C. , Morielle‐Versute Eliana
Published: February 2009

We know little about the process of spermatogenesis in bats, a great and diverse clade of mammals that presents different reproductive strategies. In the present study, spermatogenesis in six species of Neotropical bats was investigated by light microscopy. On the basis of chromatin condensation, nuclear morphology, relative position to the basal membrane and formation of the flagellum, three types of spermatogonia were recognized: dark type A (Ad), pale type A (Ap), and type B; the development of spermatids was divided into seven steps. With the exception of Myotis nigricans, the seminiferous epithelium cycle of the other five species studied was similar to those of other mammals, showing gradual stages by the tubular morphology method. Asynchrony was observed in the seminiferous epithelium cycle of M. nigricans, shown by overlapping stages and undefined cycles. The frequencies found in the three phases of the cycle were variable with the greatest frequency occurring in the postmeiotic phase (>50%) and the least in the meiotic phase (<10%). The similarities observed in the five species of Phyllostomidae appeared to be related to their phylogenetic relationship and shorter divergence times, whereas the differences in M. nigricans appeared to be related to its greater phylogenetic distance because the Vespertilionidae family diverged earlier. J. Morphol., 2009. © 2009 Wiley‐Liss, Inc.
Regional climate model simulation of winter climate over Central–Southwest Asia, with emphasis on NAO and ENSO effects
Authors: Syed F. S. , Giorgi F. , Pal J. S. , Keay Kevin
Published: February 2009

We present a regional climate modeling study of the winter climate of Central–Southwest Asia (CSWA), focusing on the mean model climatology of temperature and precipitation, the simulated storm characteristics and the effects of El‐Nino Southern Oscillation (ENSO) and North Atlantic Oscillation (NAO) on storm activity and precipitation. Forty‐three winter seasons are simulated with the model RegCM3 driven by ERA40 reanalysis fields over a region encompassing CSWA and the Mediterranean sector. The model shows a good performance in reproducing the observed mean surface climate of the region as well as the characteristics of the western disturbances affecting CSWA. Observations show that both the NAO and ENSO have a substantial influence on the CSWA climate, particularly in the region of Northern Pakistan, Afghanistan and Tajikistan, where precipitation increases (decreases) during the positive (negative) NAO phase and warm (cold) ENSO phase. The model captures well the observed signals and a detailed storm analysis shows that they are mostly associated with an intensification of western disturbances originating in the Eastern Mediterranean and Middle East regions and moving eastward across a 500 hPa trough situated over the CSWA during the positive NAO and warm ENSO phases. The NAO and ENSO signals are reinforced by enhanced moisture sources from the Mediterranean, Caspian and Arabian Seas. Our study provides encouraging indications towards the use of the model RegCM3 for climate simulations over CSWA. Copyright © 2009 Royal Meteorological Society
Thermoelastic rolling contact problem with temperature dependent friction
Authors: Chudzikiewicz Andrzej , Myslinski Andrzej
Published: February 2009

The paper is concerned with the numerical solution of a thermoelastic rolling contact problem with wear. The friction between the bodies is governed by Coulomb law. A frictional heat generation and heat transfer across the contact surface as well as Archard's law of wear in contact zone are assumed. The friction coefficient is assumed to depend on temperature. In the paper quasistatic approach to solve this contact problem is employed. This approach is based on the assumption that for the observer moving with the rolling body the displacement of the supporting foundation is independent on time. The original thermoelastic contact problem described by the hyperbolic inequality governing the displacement and the parabolic equation governing the heat flow is transformed into elliptic inequality and elliptic equation, respectively. In order to solve numerically this system we decouple it into mechanical and thermal parts. Finite element method is used as a discretization method. Numerical examples showing the influence of the temperature dependent friction coefficient on the temperature distribution and the length of the contact zone are provided. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Stability calculation of travelling waves in a simplified brake model
Authors: Steindl Alois
Published: February 2009

We consider a system composed of an elastic tube, which is fixed at the outer boundary and in frictional contact with a rigid cylinder, rotating inside the tube about the common axis.

Using a 1–mode Galerkin ansatz in radial direction, a non–smooth PDE for the tangential and radial deformations at the contact between the two bodies is obtained. It has been shown ([1]) that different types of travelling stick–slip–separation waves exist, but these waves are unstable for most parameter values. In this investigation we first enlarge the model by viscuous damping and second we introduce a larger number of nodes in radial direction for the numerical analysis. The influence of these two effects on the shape and stability of the travelling waves is studied. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Weight Functions Method in Stability Study of Systems
Authors: Stroe Ion , Parvu Petrisor
Published: February 2009

A new method for systems stability analysis is presented. This method is called weight functions method and it replaces the problem of Liapunov function finding with a problem of finding a number of functions (weight functions) equal to the number of first order differential equations describing the system. It is known that there are not general methods for finding Liapunov functions. The weight functions method is simpler than the classical method since one function at a time has to found. Conditions of solution stability for linear and nonlinear systems and some examples are presented. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Zum Einfluss von Fahrzeugparametern auf die Schädigung von Straßen
Authors: Vogt Heike , Seemann Wolfgang
Published: February 2009

Bedingt durch erhöhte Transportnachfragen und höhere Achslasten hat in den vergangenen Jahren die Belastung der Straßen stetig zugenommen. Unter diesem Aspekt ist es wichtig, die grundlegenden Mechanismen, die zur Schädigung der Straße beitragen, zu verstehen, um Verbesserungsmöglichkeiten aufzuzeigen. Während schon seit längerem experimentelle Arbeiten durchgeführt werden, sind grundlegende analytische Untersuchungen bisher eher rar (siehe beispielsweise [1]).

In dieser Arbeit werden deshalb die Wechselwirkungen zwischen Straße und Fahrzeug genauer betrachtet. Die Straße wird dabei als viskoelastische Schicht modelliert, während als Fahrzeugmodell ein Einmassenschwinger gewählt wird.

Der Einfluss unterschiedlicher Parameter auf die Verformung der Straße wird untersucht. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Dynamic response analysis of the two stators hybrid transducer type piezoelectric ultrasonic motor using finite element simulation
Authors: Nantawatana Weerayuth , Seemann Wolfgang
Published: February 2009

This paper presents the finite element simulation with an aim to analyse the dynamic response of the two stators hybrid transducer type piezoelectric ultrasonic motor. The three dimensional–model which includes the effects of piezoelectric coupling are formulated. The dynamic behaviours of a motor stator are calculated and later compared to the experimental results measured from the prototype of this motor. The impedance characteristic of the complete stator is validated using HP4294A precision impedance analyzer. In addition to the electrical measurements, the mechanical displacement and the mechanical velocity of the stator are measured directly using a single point laser Doppler vibrometer. This is to verify that finite element modelling is an appropriate approach to analyse the dynamic behaviour of this piezoelectric ultrasonic motor. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Realisation and Modelling of Geotechnical Experiments
Authors: Avci O. , Ehlers W.
Published: February 2009

The realistic description of slope failure due to critical superimposed loads or heavy rainfall events remains a challenging research topic in soil mechanics. Here, the investigations concern granular materials, such as sand, which undergo a highly complex deformation behaviour that can be characterised via homogeneous triaxial experiments. Within this contribution, benchmark tests of base and slope failure situations will be presented, which are simulated by using the FE–tool PANDAS. The solid skeleton is described within the Theory of Porous Media (TPM) as a linear elasto–plastic material exhibiting an isotropic hardening–softening effect and a non–associated plastic flow behaviour.

On the basis of triaxial experiments, the material parameters of the elastic as well as the plastic constitutive equations are determined using a gradient–based optimisation method, which is coupled with PANDAS. Finally, the simulations of the benchmark experiments and the localisation of the shear bands are carried out using either a biphasic model including a deformable solid skeleton and pore air or a triphasic model with an additional water phase (pore water) depending on the type of experiment. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A Multi‐phase‐field model including inelastic deformation for solid state transformations
Authors: Benke Stefan
Published: February 2009

A multi phase field model is presented in order to take the plastic deformation during a solid state transformation into account and to investigate its effect on the transformation kinetics and morphology in a multi phase material. The model is formulated consistently with the multi phase field model for diffusional and surface driven phase transformations [1]. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Effiziente FEM‐Adaption des Konzepts repräsentativer Raumrichtungen
Authors: Freund M. , Ihlemann J.
Published: February 2009

Das Konzept repräsentativer Raumrichtungen dient der Verallgemeinerung eindimensionaler Stoffgesetze zu vollständigen dreidimensionalen Materialmodellen für die Finite–Elemente–Methode und basiert auf der numerischen Integration einachsiger Spannungszustände über diskret verteilte Raumrichtungen. Zur Reduzierung der Programmlaufzeit einer FE–Simulation ist eine möglichst geringe Anzahl dieser Richtungen anzustreben, was jedoch aufgrund des Diskretisierungsfehlers zu einer entsprechenden Richtungsabhängigkeit des Spannungs–Dehnungs–Verhaltens des resultierenden Stoffgesetzes führt. Ziel ist es, die Effizienz der numerischen Integration derart zu steigern, dass sich für eine hinreichend genaue FE–Simulation ähnliche Berechnungszeiten wie bei herkömmlichen Stoffgesetzen ergeben. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Experimental Investigations on and Modelling of the Transient Phenomena of the Payne‐Effect.
Authors: Höfer Philipp , Lion Alexander
Published: February 2009

The wide majority of industrially–used rubber is filled with a considerable amount of active fillers like carbon black or silica. Due to this, the material is strengthend and mechanical key features like stiffness and strength are significantly increased. In contrast to unfilled rubber, filled elastomers show a pronounced amplitude dependence, which is widely known as Fletcher–Gent or Payne effect. Besides that, some recently published works show a significant history dependence of this effect with distinctive relaxation phenomena.

In the present work, some experiments on typical tyre rubber compounds with focus on these amplitude dependent phenomena are presented. On this basis, an appropriate thermodynamic consistent phenomenological material model of finite viscoelasticity is introduced. In order to incorporate the history dependent phenomena of the amplitude dependence, this model is generalized with intrinsic time scales on the basis of inner structure variables, which are a measure of the materials microstructure. The performance of the model is critically demonstrated by a few simulation results. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Plastic deformation of bicrystals within continuum dislocation theory
Authors: Kochmann D. M. , Le K. C.
Published: February 2009

We analyze the evolution of the plastic distortion and the nucleation and accumulation of dislocations within a model bicrystal with one active slip system in each single crystal (symmetric with respect to the interface), which is subject to prescribed displacements of plane–strain shear and extension, and we present closed–form analytical solutions. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Elastomeric materials: Theoretical investigation and experiments
Authors: Koprowski Nadine , Diebels Stefan , Johlitz Michael
Published: February 2009

In this contribution we investigate an incompressible carbon–filled rubber experimentally and theoretically. On the experimental side we perform uniaxial tension tests and theoretically we use two different constitutive models, the Arruda–Boyce–Model and the Yeoh–Model, to describe the experimental observed behaviour. The model parameters are identified by a comercial fitting tool Origin Pro from National Instruments. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)