bluuebunny/crossref_metadata_2025 huggingface dataset:
Changing pattern of rotavirus G genotype distribution in Chiang Mai, Thailand from 2002 to 2004: Decline of G9 and reemergence of G1 and G2
Authors: Khamrin Pattara , Peerakome Supatra , Tonusin Supin , Malasao Rungnapa , Okitsu Shoko , Mizuguchi Masashi , Ushijima Hiroshi , Maneekarn Niwat
Published: September 2007

Group A rotaviruses are the most common cause of acute viral diarrhea in humans and animals throughout the world. Previous surveillance studies of group A rotaviruses in Thailand indicated that the dominant types of rotaviruses were changing from time to time. During 2000 and 2001, the G9 rotavirus emerged as the most prevalent genotype, with an exceptionally high frequency (91.6%) in Chiang Mai, Thailand. In the year 2002–2004, group A rotavirus was detected in 98 out of 263 (37.3%) fecal specimens collected from children hospitalized with diarrhea. Of these, 40 (40.8%) were G9P[8], 33 (33.7%) were G1P[8], 23 (23.5%) were G2P[4], and 2 (2.0%) were G3P[9]. The G9P[8] was found to be the most predominant strain in 2002, but the prevalence rate abruptly decreased during the period 2003–2004. In addition, G2P[4] reemerged in the epidemic season of 2003, whereas G1P[8] became the most predominant strain in the following year (2004). Phylogenetic analysis of the VP7 genes revealed that G1, G2, and G9 rotavirus strains clustered together with recently circulating strains, which were isolated from different regional settings in Thailand. In conclusion, the study demonstrated a decrease of incidence of G9P[8] and reemergence of G1P[8] and G2P[4] rotaviruses in Chiang Mai, Thailand during the period 2002–2004. These data imply that the distribution of group A rotavirus genotypes circulating in Chiang Mai, Thailand, changes over time. J. Med. Virol. 79:1775–1782, 2007. © 2007 Wiley‐Liss, Inc.
Mutations associated with lamivudine‐resistance in therapy‐naïve hepatitis B virus (HBV) infected patients with and without HIV co‐infection: Implications for antiretroviral therapy in HBV and HIV co‐infected South African patients
Authors: Selabe S. Gloria , Lukhwareni Azwidowi , Song Ernest , Leeuw Yeegan G.M. , Burnett Rosemary J. , Mphahlele M. Jeffrey
Published: September 2007

This was an exploratory study to investigate lamivudine‐resistant hepatitis B virus (HBV) strains in selected lamivudine‐naïve HBV carriers with and without human immunodeficiency virus (HIV) co‐infection in South African patients. Thirty‐five lamivudine‐naïve HBV infected patients with or without HIV co‐infection were studied: 15 chronic HBV mono‐infected patients and 20 HBV–HIV co‐infected patients. The latter group was further sub‐divided into 13 occult HBV (HBsAg‐negative) and 7 overt HBV (HBsAg‐ positive) patients. HBsAg, anti‐HBs, anti‐HBc, and anti‐HIV 1/2 were determined as part of routine diagnosis using Axsym assays (Abbott Laboratories, North Chicago, IL). Serum samples were PCR amplified with HBV reverse transcriptase (RT) primers, followed by direct sequencing across the tyrosine–methionine–aspartate–aspartate (YMDD) motif of the major catalytic region in the C domain of the HBV RT enzyme. HBV viral load was performed with Amplicor HBV Monitor® test v2.0 (Roche Diagnostics, Penzberg, Germany). HBV lamivudine‐resistant strains were detected in 3 of 15 mono‐infected chronic hepatitis B patients and 10 of 20 HBV–HIV co‐infected patients. To the best of our knowledge, this constitutes the first report of HBV lamivudine‐resistant strains in therapy‐naïve HBV–HIV co‐infected patients. The HBV viral loads for mono‐infected and co‐infected patients ranged from 3.32 × 102 to 3.82 × 107 and <200 to 4.40 × 103 copies/ml, respectively. It remains to be seen whether such pre‐existing antiviral mutations could result in widespread emergence of HBV resistant strains when lamivudine‐containing highly active antiretroviral (ARV) treatment (HAART) regimens become widely applied in South Africa, as this is likely to have potential implications in the management of HBV–HIV co‐infected patients. J. Med. Virol. 79:1750–1754, 2007. © 2007 Wiley‐Liss, Inc.
Fifteen years of Env C2V3C3 evolution in six individuals infected clonally with human immunodeficiency virus type 1
Authors: Kupfer Bernd , Sing Tobias , Schüffler Peter , Hall Rabea , Kurz Ralf , McKeown Astrid , Schneweis Karl‐Eduard , Eberl Wolfgang , Oldenburg Johannes , Brackmann Hans H. , Rockstroh Jürgen K. , Spengler Ulrich , Däumer Martin P. , Kaiser Rolf , Lengauer Thomas , Matz Bertfried
Published: September 2007

The study of the evolution of human immunodeficiency virus type 1 (HIV‐1) requires blood samples collected longitudinally and data on the approximate time point of infection. Although these requirements were fulfilled in several previous studies, the infectious sources were either unknown or heterogeneous genetically. In the present study, HIV‐1 env C2V3C3 (nt 7029‐7315) evolution was examined retrospectively in a cohort of hemophiliacs. Compared to other cohorts, the area of interest here was the infection of six hemophiliacs by the same virus strain, that is, the infecting viruses shared an identical genome. As expected, divergence from the founder sequence as well as interpatient divergence of the predominant virus strains increased significantly over time. Based on the V3 nucleotide sequences, CCR5 usage was predicted exclusively throughout the whole period of infection in all patients. Interestingly, common patterns of viral evolution were detected in the patients of the cohort. Four amino acid substitutions within the V3 loop emerged and persisted subsequently in five (positions 305 and 308 of the HXB2 gp120 reference sequence) and six patients (positions 325 and 328 in HXB2 gp120), respectively. These common changes within the V3 loop are likely to be enforced by HIV‐1 specific immune response. J. Med. Virol. 79:1729–1739, 2007. © 2007 Wiley‐Liss, Inc.
Redetection of HBV lamivudine‐resistant mutations in a patient under entecavir therapy, who had been treated sequentially with nucleos(t)ide analogues
Authors: Rodriguez‐Frias Francisco , Jardi Rosendo , Schaper Melanie , Gimferrer Montserrat , Elefsiniotis Ioannis , Tabernero David , Esteban Rafael , Buti Maria
Published: September 2007

Development of hepatitis B virus (HBV)‐resistant strains following nucleos(t)ide analog treatment is a major medical concern. This report describes a case of an adult patient with chronic HBV infection, sequentially treated with the nucleos (t)ide analogues, lamivudine, adefovir, and entecavir. During monotherapy with lamivudine, the patient developed lamivudine‐resistant variants, which were undetectable during adefovir dipivoxil monotherapy. Twenty‐two months after discontinuing lamivudine therapy, the resistant variants were again detected while the patient was receiving entecavir monotherapy. Genotypic analysis by sequencing the HBV polymerase was confirmed with the INNO‐LiPA method. The results of this study suggest that entecavir treatment reselected residual lamivudine‐resistant HBV variants, possibly because lamivudine‐resistant HBV is less susceptible to entecavir than the wild‐type virus. Despite the presence of these variants, the patient has had a complete virological response. J. Med. Virol. 79:1671–1673, 2007. © 2007 Wiley‐Liss, Inc.
Structural variability of the carboxy‐terminus of Epstein–Barr virus encoded latent membrane protein 1 gene in Hodgkin's lymphomas
Authors: Guiretti Deisy M. , Chabay Paola A. , Valva Pamela , Stefanoff Claudio G. , Barros Mário H.M. , De Matteo Elena , Renault Ilana Zalcberg , Preciado Maria Victoria , Hassan Rocio
Published: September 2007

Epstein–Barr virus (EBV) is implicated in the pathogenesis of several lymphoid and epithelial neoplasms. Latent membrane protein 1 (LMP1) is the major viral oncogene and it is controversial whether tumor LMP1 variants reflect their geographical predominance or are associated with enhanced oncogenic properties. This study aimed to analyze LMP1 molecular variability of 62 EBV+ Hodgkin's lymphomas and 22 non‐neoplastic controls from Brazil and Argentina. EBV association was characterized by EBER‐ISH, LMP1 immunohistochemistry and PCR assays for EBNA2 and 3C (typing), LMP1 30 bp deletion (del30) and number of 33 bp tandem repeats. LMP1 C‐terminal sequencing was performed in 42 cases. EBV1 was the predominant strain in both geographical Hodgkin's lymphoma groups (average 82%). A higher frequency of del30 variant was observed in lymphomas (41/63) than in non‐neoplastic controls (6/22) (OR 4.97, CI 95% 1.53–16.79; P = 0.005, χ2 test). A large number (5–7) of 33 bp repeat units was characteristic of del30 LMP1 variants (P < 0.0001, Fisher's exact test). Sequence analysis showed a similar mutation spectrum to that described worldwide but none of the current classification schemes could be applied completely. A distinct structural pattern was observed in del30 variants, characterized by a large number of 33 bp repeat units and the presence of a 15 bp insertion encoding the JAK3 Box‐1a motif (3/15 wt vs. 16/20 del30; P = 0.001, χ2 test). The results suggest a pathogenic role for LMP1 del30 variants in Hodgkin's lymphoma from South America and point to particular virus‐host molecular mechanisms, such as genomic instability in LMP1 carboxy‐terminus, leading to enhanced production and selection of these deletion variants. J. Med. Virol. 79:1722–1730, 2007. © 2007 Wiley‐Liss, Inc.
A new method for simultaneous estimation of unsaponifiable constituents of rice bran oil using HPTLC
Authors: Afinisha Deepam Lawrence S. , Soban Kumar Dasiah R. , Sundaresan Andikkannu , Arumughan Chami
Published: September 2007

Rice bran oil (RBO) is rich in a variety of bioactive phytochemicals otherwise known as unsaponifiable constituents (USC). Oryzanols, phytosterols, tocols, etc. are the major USC in RBO; the methods presently used for their estimation involve different techniques and require pretreatment of the sample. In this paper standardization of a simple method for simultaneous estimation of USC directly from RBO using HPTLC is presented. The method involves a two‐stage separation of USC on a precoated silica gel 60 F254 TLC plate viz.: TLC‐1 to separate sterols, oryzanols and tocols; TLC‐2 to separate steryl esters, wax, and squalene. Calibration plots using the respective standards were made to determine LOD, LOQ, and linear regression equations. Recovery studies were also conducted and the values ranged from 93.45 to 101.97%. The LOD and LOQ values showed the sensitivity of the method. The instrumental precision was found to be in the range of 0.30 to 1.18 CV%. Quantitative estimation of USC in crude RBO and refined RBO using this method gave a concentration of 52.80 mg/g of USC in the crude and 33.48 mg/g in the refined oil. The present method for estimation of USC using HPTLC is fast, simple, accurate, precise, and sensitive, as demonstrated here.
‘We're not the Barmy Army!’: reflections on the sports tourist experience
Authors: Morgan Michael
Published: September 2007

This paper explores the dynamics of the interaction between the sports tourist and the destination through the insights of experience management literature applied to the 2005 British and Irish Lions rugby tour of New Zealand. It contrasts the managerial view that sports tourism is something to be controlled and stage‐managed, with the consumer behaviour view of the experience as a subjective emotional journey full of personal, social and cultural meanings. A holistic model of the interactions between visitors and destinations is proposed. From this, it is suggested that rather than trying to channel sports tourists into special areas, planners should give them space to create their own experiences by encouraging them to explore for themselves. As a result, the positive impact of sports tourism will be spread wider in the economy of the region. Copyright © 2007 John Wiley & Sons, Ltd.
Running away from home: understanding visitor experiences and behaviour at sport tourism events
Authors: Shipway Richard , Jones Ian
Published: September 2007

Existing sport tourism research has been subject to claims of lacking coherence, theoretical underpinning and empirical support. This paper addresses these issues through an examination of a group of distance runners participating in theCyprus International Four‐day Challenge. Using the concepts of ‘serious leisure’ and social identification, the behaviours of this group of sport tourists are described and explained. The key finding was the strength of identification that participants had with the activity, and the nature of the event itself, which made this identity much more salient than other identities during the course of the event. This sense of identification was used to explain the unique ethos of the group, the use of significant personal effort, the perseverance of participants, the durable benefits obtained by the runners and the career structure associated with this social world. Copyright © 2007 John Wiley & Sons, Ltd.
Gas‐phase basicities of polyfunctional molecules. Part 1: Theory and methods
Authors: Bouchoux Guy
Published: September 2007

The experimental and theoretical methods of determination of gas‐phase basicities, proton affinities and protonation entropies are presented in a tutorial form. Particularities and limitations of these methods when applied to polyfunctional molecules are emphasized. Structural effects during the protonation process in the gas‐phase and their consequences on the corresponding thermochemistry are reviewed and classified. The role of the nature of the basic site (protonation on non‐bonded electron pairs or on π‐electron systems) and of substituent effects (electrostatic and resonance) are first examined. Then, linear correlations observed between gas‐phase basicities and ionization energies or substituent constants are recalled. Hydrogen bonding plays a special part in proton transfer reactions and in the protonation characteristics of polyfunctional molecules. A survey of the main properties of intermolecular and intramolecular hydrogen bonding in both neutral and protonated species is proposed. Consequences on the protonation thermochemistry, particularly of polyfunctional molecules are discussed. Finally, chemical reactions which may potentially occur inside protonated clusters during the measurement of gas‐phase basicities or inside a protonated polyfunctional molecule is examined. Examples of bond dissociations with hydride or alkyl migrations, proton transport catalysis, tautomerization, cyclization, ring opening and nucleophilic substitution are presented to illustrate the potentially complex chemistry that may accompany the protonation of polyfunctional molecules. © 2007 Wiley Periodicals, Inc., Mass Spec Rev 26:775–835, 2007
Impact of psychogenic movement disorders versus Parkinson's on disability, quality of life, and psychopathology
Authors: Anderson Karen E. , Gruber‐Baldini Ann L. , Vaughan Christopher G. , Reich Stephen G. , Fishman Paul S. , Weiner William J. , Shulman Lisa M.
Published: September 2007

Patients with psychogenic movement disorders (PMD) often report severe impairment, yet the impact of PMD on disability and quality of life has not been examined. We compared 66 patients with PMD and 704 patients with Parkinson's disease (PD) on measures of disability (Older Americans Resources and Services Scale, OARS); quality of life (QOL; SF‐12v2 Health Survey) and psychiatric symptomatology (Brief Symptom Inventory 18, BSI‐18). On the total OARS, PMD and PD patients reported similar levels of disability (17.6 ± 6.6, 19.8 ± 10.9, P = 0.490 at “best” function and 24.1 ± 11.2, 26.2 ± 14.3, P = 0.497 at their “worst” function). PMD patients reported similar Physical Health QOL to PD patients (38.9 ± 14.5, 39.8 ± 11.6, P = 0.652) but worse mental health QOL (41.6 ± 13.4 vs. 48.9 ± 11.0, P < 0.001). On the BSI‐18, PMD patients reported higher levels of distress on the Global Symptom Index (62.03 ± 9.6 vs. 53.7 ± 9.9, P < 0.001) and on Anxiety, Depression and Somatization subscales (PMD vs. PD scores: Anxiety 58.9 ± 12.0 vs. 52.3 ± 10.1, P < 0.001; Depression 58.8 ± 11.9 vs. 51.3 ± 10.3, P < 0.001; Somatization 60.5 ± 11.0 vs. 54.7 ± 8.7, P < 0.001). Thus, severity of disability reported by the PMD group was equal to that seen in a progressive neurodegenerative condition. Quality of life and mental health implications of PMD were also evident. PMD impacts several aspects of patient function and daily life. © 2007 Movement Disorder Society
Dietary advanced lipid oxidation endproducts are risk factors to human health
Authors: Kanner Joseph
Published: September 2007

Lipid oxidation in foods is one of the major degradative processes responsible for losses in food quality. The oxidation of unsaturated fatty acids results in significant generation of dietary advanced lipid oxidation endproducts (ALEs) which are in part cytotoxic and genotoxic compounds. The gastrointestinal tract is constantly exposed to dietary oxidized food compounds, after digestion a part of them are absorbed into the lymph or directly into the blood stream. After ingestion of oxidized fats animals and human have been shown to excrete in urine increase amounts of malondialdehyde but also lipophilic carbonyl compounds. Oxidized cholesterol in the diet was found to be a source of oxidized lipoproteins in human serum. Some of the dietary ALEs, which are absorbed from the gut to the circulatory system, seems to act as injurious chemicals that activate an inflammatory response which affects not only circulatory system but also organs such as liver, kidney, lung, and the gut itself. We believe that repeated consumption of oxidized fat in the diet poses a chronic threat to human health. High concentration of dietary antioxidants could prevent lipid oxidation and ALEs generation not only in foods but also in stomach condition and thereby potentially decrease absorption of ALEs from the gut. This could explains the health benefit of diets containing large amounts of dietary antioxidants such those present in fruits and vegetables, or products such as red‐wine or tea consuming during the meal.

Introduction: http://dx.doi.org/10.1002/mnfr.200700030

Contra arguments: http://dx.doi.org/10.1002/mnfr.200600287
A method for calculating meshless finite difference weights
Authors: Roberts J. L.
Published: September 2007

An exact method for calculating the finite difference weights for arbitrary distributed points in multiple dimensions is presented. The method avoids the numerical ill conditioning associated with a small‐scale factor (ε) by delaying the limiting of ε → 0. The Gaussian Radial Basis function is approximated by a Taylor's series expansion in the variable ε, and the resultant matrix equation is solved using the Fraction Free LU decomposition method. Copyright © 2007 John Wiley & Sons, Ltd.
Down‐regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation
Authors: Bose S , Starczynski J , Chukwuma M , Baumforth K , Wei W , Morgan S , Byrd P , Ying J , Grundy R , Mann JR , Tao Q , Taylor AMR , Murray PG , Stankovic T
Published: September 2007

The tumour component of classical Hodgkin's lymphoma (cHL), Hodgkin Reed–Sternberg (HRS) cells, are believed to be derived from germinal centre (GC) B cells but intriguingly display a characteristic loss of B cell receptor (BCR) expression. The precise mechanisms by which BCR‐negative HRS cell progenitors survive negative selection during the GC reaction remain obscure. Individuals with ataxia telangiectasia, caused by biallelic inactivation of the DNA damage response gene, ataxia telangiectasia mutated (ATM), have a higher risk of cHL development. Here we show that, in contrast to normal GC B cells that expressed low but detectable ATM protein, ATM protein was not detected in HRS cells of 17/18 cases of paediatric cHL, all but one with nodular sclerosis (NS) subtype. A comprehensive analysis of the ATM gene in microdissected HRS cells of nine representative tumours showed no evidence of either loss of heterozygosity or consistent pathogenic mutations. Furthermore, bisulphite sequencing of the ATM promoter from HRS cells of five tumours also revealed the absence of hypermethylation. Since our microarray data suggested significantly reduced ATM transcription in HRS cells compared to GC B cells, we conclude that loss of ATM expression could be the result of alterations in upstream regulators of ATM transcription. Importantly, ATM loss in paediatric cHLs has clinical implications and could be potentially exploited to guide future, less toxic, tumour‐specific treatments. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Differential protein expression in male and female human lumbar cerebrospinal fluid using iTRAQ reagents after abundant protein depletion
Authors: Ogata Yuko , Charlesworth M. Cristine , Higgins LeeAnn , Keegan B. Mark , Vernino Steven , Muddiman David C.
Published: September 2007

Cerebrospinal fluid (CSF) has become one of the most frequently used biological medium for physiological studies for neurological disorders due to its proximity to the brain and clinical availability; however, before undertaking a rational approach to biomarker discovery or diagnostics, it is crucial to understand the underlying characteristics of CSF proteome in subpopulations. In this study, we examined the differential expression of proteins in pooled male and female CSF utilizing isobaric tags for relative and absolute quantification (iTRAQ™) reagents after the depletion of six high abundant proteins using a multiple affinity removal system (MARS). A total of 219 proteins were identified (95% confidence level), and 12 proteins showed difference in expression levels. Eleven out of 12 differentially expressed proteins showed ratios of male/female between 1.15 and 1.29 (duplicate average), indicating a remarkable similarity between male and female CSF. One notable exception was the slightly lower expression level of ceruloplasmin (ferroxidase) in male CSF (0.81), a copper containing protein that catalyzes the conversion of ferrous iron to ferric iron with antioxidant properties. We also examined the levels of ceruloplasmin in each individual patient sample which constituted the pooled CSF using Western blot analysis which confirmed the lower expression levels of ceruloplasmin in male CSF.
On‐plate digestion of proteins using novel trypsin‐immobilized magnetic nanospheres for MALDI‐TOF‐MS analysis
Authors: Li Yan , Yan Bo , Deng Chunhui , Tang Jia , Liu Junyan , Zhang Xiangmin
Published: September 2007

In this study, a novel method of on‐plate digestion using trypsin‐immobilized magnetic nanospheres was developed followed by MALDI‐TOF‐MS for rapid and effective analysis and identification of proteins. We utilized a facile one‐pot method for the direct preparation of amine‐functionalized magnetic nanospheres with highly magnetic properties and the amino groups on the outer surface. Through the reaction of the aldehyde groups with amine groups, trypsin was simply and stably immobilized onto the magnetic nanospheres. The obtained trypsin‐linked magnetic nanospheres were then applied for on‐plate digestion of sample proteins (myoglobin and Cytochrome c). Moreover, after digestion, the trypsin‐linked nanospheres could be easily removed from the plate due to their magnetic property, which would avoid causing contamination on the ion source chamber in MS. The effects of the temperature and incubation time on the digestion efficiency were characterized. Within only 5 min, proteins could be efficiently digested with the peptide sequence coverage higher than or equal to that of the traditional in‐solution digestion for 12 h. Furthermore, RPLC fractions of rat liver extract were also successfully processed using this novel method. These results suggested that our improved on‐plate digestion protocol for MALDI‐MS may find further application in automated analysis of large sets of proteins.
Multiphoton‐gated photochromic reaction of diarylethene derivatives in PMMA solid film
Authors: Ryo Senichi , Ishibashi Yukihide , Murakami Masataka , Miyasaka Hiroshi , Kobatake Seiya , Irie Masahiro
Published: September 2007

Cycloreversion (ring‐opening) process of a photochromic diarylethene derivative in PMMA polymer solid film was investigated by means of picosecond laser photolysis. As was observed in our previous work in solution phase, the drastic enhancement of the cycloreversion reaction yield was observed under picosecond laser exposure. The excitation intensity effect of the reaction profiles revealed that the successive multiphoton absorption process leading to higher excited states opened the efficient cycloreversion process with reaction yield of (50 ± 10)%. These results indicate that the multiphoton‐gated reaction takes place also in the polymer solid and its efficiency was almost comparable with that in solution phase. Copyright © 2007 John Wiley & Sons, Ltd.
A stroma targeted therapy enhances castration effects in a transplantable rat prostate cancer model
Authors: Johansson Anna , Jones Jonathan , Pietras Kristian , Kilter Sigrid , Skytt Åsa , Rudolfsson Stina Häggström , Bergh Anders
Published: September 2007

BACKGROUND

Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration‐induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma.

METHODS

Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies.

RESULTS

In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF‐Rβ were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF‐Rβ simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone.

CONCLUSIONS

The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced. Prostate 67: 1664–1676, 2007. © 2007 Wiley‐Liss, Inc.
Receptor‐specific scoring functions derived from quantum chemical models improve affinity estimates for in‐silico drug discovery
Authors: Fischer Bernhard , Fukuzawa Kaori , Wenzel Wolfgang
Published: September 2007

The adaptation of forcefield‐based scoring function to specific receptors remains an important challenge for in‐silico drug discovery. Here we compare binding energies of forcefield‐based scoring functions with models that are reparameterized on the basis of large‐scale quantum calculations of the receptor. We compute binding energies of eleven ligands to the human estrogen receptor subtype α (ERα) and four ligands to the human retinoic acid receptor of isotype γ (RARγ). Using the FlexScreen all‐atom receptor‐ligand docking approach, we compare docking simulations parameterized by quantum‐mechanical calculation of a large protein fragment with purely forcefield‐based models. The use of receptor flexibility in the FlexScreen permits the treatment of all ligands in the same receptor model. We find a high correlation between the classical binding energy obtained in the docking simulation and quantum mechanical binding energies and a good correlation with experimental affinities R=0.81 for ERα and R=0.95 for RARγ using the quantum derived scoring functions. A significant part of this improvement is retained, when only the receptor is treated with quantum‐based parameters, while the ligands are parameterized with a purely classical model. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Full correlation analysis of conformational protein dynamics
Authors: Lange Oliver F. , Grubmüller Helmut
Published: September 2007

Correlated motions in biomolecules are often essential for their function, for example, allosteric signal transduction or mechanical/thermodynamic energy transport. Principal component analysis (PCA) is a widely used method to extract functionally relevant collective motions from a molecular dynamics (MD) trajectory. Being based on the covariance matrix, however, PCA detects only linear correlations. Here we present a new method, full correlation analysis (FCA), which is based on mutual information and thus quantifies all correlations, including nonlinear and higher order correlations. For comparison, we applied both, PCA and FCA, to ∼100 ns MD trajectories of T4 lysozyme and the hexapeptide neurotensin. For both systems, FCA yielded better resolved conformational substates and aligned its modes more often with actual transition pathways. This improved resolution is shown to be due to a strongly increased anharmonicity of FCA modes as compared to the respective PCA modes. The high anharmonicity further suggests that the motions extracted by FCA are functionally more relevant than those captured by PCA. In summary, FCA should provide improved collective degrees of freedom for dimension‐reduced descriptions of macromolecular dynamics. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Position‐resolved free energy of solvation for amino acids in lipid membranes from molecular dynamics simulations
Authors: Johansson Anna C.V. , Lindahl Erik
Published: September 2007

Studies of insertion and interactions of amino acids in lipid membranes are pivotal to our understanding of membrane protein structure and function. Calculating the insertion cost as a function of transmembrane helix sequence is thus an important step towards improved membrane protein prediction and eventually drug design. Here, we present position‐dependent free energies of solvation for all amino acid analogs along the membrane normal. The profiles cover the entire region from bulk water to hydrophobic core, and were produced from all‐atom molecular dynamics simulations. Experimental differences corresponding to mutations and costs for entire segments match experimental data well, and in addition the profiles provide the spatial resolution currently not available from experiments.

 Polar side‐chains largely maintain their hydration and assume quite ordered conformations, which indicates the solvation cost is mainly entropic. The cost of solvating charged side‐chains is not only significantly lower than for implicit solvation models, but also close to experiments, meaning these could well maintain their protonation states inside the membrane. The single notable exception to the experimental agreement is proline, which is quite expensive to introduce in vivo despite its hydrophobicity—a difference possibly explained by kinks making it harder to insert helices in the translocon. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Exploring the extremes of sequence/structure space with ensemble fold recognition in the program Phyre
Authors: Bennett‐Lovsey Riccardo M. , Herbert Alex D. , Sternberg Michael J. E. , Kelley Lawrence A.
Published: September 2007

Structural and functional annotation of the large and growing database of genomic sequences is a major problem in modern biology. Protein structure prediction by detecting remote homology to known structures is a well‐established and successful annotation technique. However, the broad spectrum of evolutionary change that accompanies the divergence of close homologues to become remote homologues cannot easily be captured with a single algorithm. Recent advances to tackle this problem have involved the use of multiple predictive algorithms available on the Internet. Here we demonstrate how such ensembles of predictors can be designed in‐house under controlled conditions and permit significant improvements in recognition by using a concept taken from protein loop energetics and applying it to the general problem of 3D clustering. We have developed a stringent test that simulates the situation where a protein sequence of interest is submitted to multiple different algorithms and not one of these algorithms can make a confident (95%) correct assignment. A method of meta‐server prediction (Phyre) that exploits the benefits of a controlled environment for the component methods was implemented. At 95% precision or higher, Phyre identified 64.0% of all correct homologous query–template relationships, and 84.0% of the individual test query proteins could be accurately annotated. In comparison to the improvement that the single best fold recognition algorithm (according to training) has over PSI‐Blast, this represents a 29.6% increase in the number of correct homologous query–template relationships, and a 46.2% increase in the number of accurately annotated queries. It has been well recognised in fold prediction, other bioinformatics applications, and in many other areas, that ensemble predictions generally are superior in accuracy to any of the component individual methods. However there is a paucity of information as to why the ensemble methods are superior and indeed this has never been systematically addressed in fold recognition. Here we show that the source of ensemble power stems from noise reduction in filtering out false positive matches. The results indicate greater coverage of sequence space and improved model quality, which can consequently lead to a reduction in the experimental workload of structural genomics initiatives. Proteins 2008. © 2007 Wiley‐Liss, Inc.
Safer use of anticoagulants: the NPSA patient safety alert
Authors: Chaplin Steve
Published: September 2007

Steve Chaplin describes the NPS's anticoagulant patient safety alert and the measures it recommends for making the supply and administration of anticoagulant therapy safer. Copyright © 2007 Wiley Interface Ltd
Diuretics: their properties and efficacy in hypertension
Authors: Girvin Briegeen , Johnston Dennis
Published: September 2007

Diuretics are as effective as newer treatments in hypertension and they still remain drugs of first choice. This Drug review considers their mode of action and properties, followed by sources of further information, a review of prescription data and the Datafile. Copyright © 2007 Wiley Interface Ltd
Electronic structure of the Co4Sn6Te6ternary skutterudite phase
Authors: Bertini Luca , Cenedese Simone
Published: September 2007

The electronic structure of Co4Sn6–xTe6+x(x= 0, 1) ternary skutterudite systems has been investigated usingab‐initioband structure computation. Thex= 0 system is a semiconductor like the binary Co4Sb12, but with a lower band gap. The best dopant concentration for Co4Sn6Te6is estimated to be lower than that of Co4Sb12, with the highest electronic fig‐ ure‐of‐meritZeTfor the n‐doped system. Finally, the increased charge transfer between the 8cCo and 24gSn and Te atoms in Co4Sn6Te6compared to that of Co4Sb12could be one reason for the observed decrease of thermal conductivity in ternary skutterudite systems. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Unified Physicochemical QSPR Model of the Partitioning and Solubility of Chemicals in the Triple System “Water–Octanol–Air”
Authors: Raevsky Oleg A. , Schaper Klaus‐J.
Published: September 2007

For the three‐phase system “water–octanol–air” a unified physicochemical Quantitative Structure–Property Relationship (QSPR) model of the pertinent three partition coefficients [log P(octanol–water), log P(air–octanol), and log P(air–water)] of monofunctional chemicals and of their solubilities in the three phases was generated on the basis of three Hydrogen Bond Thermodynamics (HYBOT) descriptors: molecular polarizability, H‐bond acceptor, and H‐bond donor factors. Within the framework of the water–octanol–air system, it is possible to construct separate QSPR models for any single property on the basis of different combinations of QSPR models for other properties. This mutual derivation of relationships provides a better recognition of their physical meaning and also enables a test of their stability.
Prediction of Solubility of Nonionic Solutes in Anionic Micelle (SDS) Using a QSPR Model
Authors: Ghasemi Jahanbakhsh , Abdolmaleki Azizeh , Asadpour Saeid , Shiri Fereshteh
Published: September 2007

A Quantitative structure–property relationships analysis has been applied to a series of chemical compounds which were of interest because of their roles in environmental samples. The incorporation neutral solute (log Ks) in anionic micelle (SDS) has been predicted by using molecular structural descriptors for a heterogeneous set of 62 neutral solutes with a range of more than 4log units. Two linear correlating models, Multiple Linear Regression (MLR) and Partial Least Squares (PLS) regression methods were used. The stepwise MLR of SPSS software was used for the selection of the variables. After variables selection, MLR and PLS methods used leave‐one‐out cross‐validation for building the regression models. Appropriate models with low standard errors and high correlation coefficients were selected. The results showed that both MLR and PLS methods could model the relationship between solubility and their electronic and thermodynamic descriptors perfectly. The predictive quality of the QSPR models were tested for an external prediction set of 11 compounds randomly chosen from 62 compounds. The squared regression coefficients of prediction for the MLR and PLS regression methods were 0.9679 and 0.9728 respectively.
Description and Application of Similarity‐Based Methods for Fast and Simple QSAR Model Development
Authors: Urbano‐Cuadrado Manuel , Luque Ruiz Irene , Gómez‐Nieto Miguel Ángel
Published: September 2007

A molecular similarity‐based approximation to fast methodologies for developing QSAR models is presented in this paper with the aim of evaluating reliability of different similarity proposals. Inhibition of carbonic anhydrase presented by a dataset of 47 sulfonamides was the chemical framework employed to build QSAR models. A view of different chemical isomorphism extraction methods, similarity metrics, and structural difference‐based approaches is given in order to provide pharmacological chemists with fast modeling and predictive tools. Recent isomorphism detection approaches which account for dissimilarity between border atoms and bonds were also employed to analyze differences involved in scaffold substitution positions. Thus, the compounds characterization attending to several chemical criteria has been studied by principal component analysis and prediction of the inhibitory activity was carried out by partial least squares regression processes. Fingerprint‐based and approximate similarities gave the best statistical results (Q2>0.70). The latter demonstrated to be useful to detect anomalous behavior presented by very similar molecules which show very different activities. External validations (test r2≈0.90) were also carried out in order to evaluate predictions obtained for molecules which have not participated in the fitting stage.
A robust approach to the UAV task assignment problem
Authors: Alighanbari Mehdi , How Jonathan P.
Published: September 2007

This paper presents a new robust approach to the task assignment of unmanned aerial vehicles (UAVs) operating in uncertain dynamic environments for which the optimization data, such as target cost and target–UAV distances, are time varying and uncertain. The impact of this uncertainty in the data is mitigated by tightly integrating two approaches for improving the robustness of the assignment algorithm. One approach is to design task assignment plans that are robust to the uncertainty in the data, which reduces the sensitivity to errors in the situational awareness (SA), but can be overly conservative for long duration plans. A second approach is to replan as the SA is updated, which results in the best plan given the current information, but can lead to a churning type of instability if the updates are performed too rapidly. The strategy proposed in this paper combines robust planning with the techniques developed to eliminate churning. This combination results in the robust filter‐embedded task assignment algorithm that uses both proactive techniques that hedge against the uncertainty, and reactive approaches that limit churning behavior by the vehicles. Numerous simulations are shown to demonstrate the performance benefits of this new algorithm. Copyright © 2007 John Wiley & Sons, Ltd.
A hybrid Bayesian‐frequentist approach to evaluate clinical trial designs for tests of superiority and non‐inferiority
Authors: Shao Yongzhao , Mukhi Vandana , Goldberg Judith D.
Published: September 2007

Specification of the study objective of superiority or non‐inferiority at the design stage of a phase III clinical trial can sometimes be very difficult due to the uncertainty that surrounds the efficacy level of the experimental treatment. This uncertainty makes it tempting for investigators to design a trial that would allow testing of both superiority and non‐inferiority hypotheses. However, when a conventional single‐stage design is used to test both hypotheses, the sample size is based on the chosen primary objective of either superiority or non‐inferiority. In this situation, the power of the test for the secondary objective can be low, which may lead to a large loss of resources. Potentially low reproducibility is another major concern for the single‐stage design in phase III trials, because significant findings of confirmatory trials are required to be reproducible. In this paper, we propose a hybrid Bayesian‐frequentist approach to evaluate reproducibility and power in single‐stage designs for phase III trials to test both superiority and non‐inferiority. The essence of the proposed approach is to express the uncertainty that surrounds the efficacy of the experimental treatment as a probability distribution. Then one can use Bayes formula with simple graphical techniques to evaluate reproducibility and power adequacy. Copyright © 2007 John Wiley & Sons, Ltd.
“Hairy” Single‐Walled Carbon Nanotubes Prepared by Atom Transfer Radical Polymerization
Authors: Wu Wei , Tsarevsky Nicolay V. , Hudson Jared L. , Tour James M. , Matyjaszewski Krzysztof , Kowalewski Tomasz
Published: September 2007

“Hairy nano‐objects” are hybrid nanostructures comprising a core surrounded by a “hairlike” corona of flexible polymer chains, the role of which is typically to improve the solubility of the core material or to improve its dispersability and adhesion in other polymer matrices. Both aspects could be particularly useful with carbon nanotubes, especially in their applications as reinforcing agents. The controlled synthesis of hairy carbon nanotubes is accomplished by chemical modification with 2‐bromopropionate followed by extension with poly(n‐butyl acrylate) through atom transfer radical polymerization. The obtained hairy nanotubes are visualized at nearly molecular resolution with tapping‐mode atomic force microscopy, providing insight into the uniformity of grafted chain lengths and grafting density. The grafting densities vary from ≈1.0–10.0 chains nm−1 along the nanotubes. Such a wide range of grafting density may indicate some chemical heterogeneity along and between the nanotubes; it may be also an indication of the challenges associated with carrying out chemical modification of nano‐objects having high tendency to aggregate.
In Situ Raman Spectroelectrochemical Study of 13C‐Labeled Fullerene Peapods and Carbon Nanotubes
Authors: Kalbáč Martin , Kavan Ladislav , Zukalová Markéta , Dunsch Lothar
Published: September 2007

C60 fullerene peapods and double‐walled carbon nanotubes (DWCNTs) containing highly 13C enriched C60 and inner tubes, respectively, are studied using Raman spectroscopy and in situ Raman spectroelectrochemistry in order to follow the influence of 13C enrichment on the vibrational pattern of these carbon nanostructures. The Raman response of 13C60 after encapsulation in fullerene peapods differs from that of isotope‐natural species, NatC60. The Raman Ag(2) mode of encapsulated 13C60 is upshifted in frequency compared to that of the NatC60 peapods with the same filling factor. The chemical doping of 13C60 peapods (peapod=C60@SWCNT) with K‐vapor leads to the downshift of the Ag(2) mode, similar to the case of NatC60 peapods. The 13C60 peapods were successfully transformed into DWCNTs, which confirms high filling of single‐walled (SW) CNTs with 13C60. The DWCNTs exhibited distinctly downshifted G and D Raman modes for inner tubes, which proves that only inner tubes were enriched by 13C. The in situ Raman spectroelectrochemistry of NatC60 exhibits strong anodic enhancement, while for 13C60 peapods the enhancement is only weak. On the other hand, the electrochemical charging of the inner‐tube‐labeled DWCNTs (13Ci‐DWCNTs) followed the behavior of ordinary NatCi‐DWCNTs as indicated by in situ Raman spectroelectrochemistry. In addition, the spectroelectrochemical behavior of the G mode of inner tubes in 13 Ci‐DWCNTs is followed from the start of the electrochemical doping, which was not feasible for NatCi‐DWCNTs.
Morphology Control of Structured Polymer Brushes
Authors: Steenackers Marin , Küller Alexander , Ballav Nirmalya , Zharnikov Michael , Grunze Michael , Jordan Rainer
Published: September 2007

The surface‐initiated photopolymerization (SIPP) of vinyl monomers on structured self‐assembled monolayers, as defined by two‐dimensional (2D) initiator templates for polymer growth, is investigated. The 2D templates are prepared by electron‐beam chemical lithography (EBCL) of 4′‐nitro‐4‐mercaptobiphenyl (NBT) and chemical conversion to an asymmetric azo initiator (4′‐azomethylmalonodinitrile‐1,1′‐biphenyl‐4‐thiol). Ex situ kinetic studies of the SIPP process reveal a linear increase in the thickness of the polymer layer with the irradiation/polymerization time. The effect of the applied electron dosage during the EBCL process upon the final thickness of the polymer layer is also studied. The correlation between the electron‐induced conversion of the 4′‐nitro to the 4′‐amino group and the layer thickness of the resulting polymer brush indicates that the polymer‐brush grafting density can be directly controlled by the EBCL process. NBT‐based template arrays are used for the combinatorial study of the influence of the lateral structure size and the irradiation dosage on the morphology of the resulting polymer‐brush layer. Analysis of the array topography reveals the dependence of the thickness of the dry polymer layer on both electron dosage and structure size. This unique combination of EBCL as a lithographic technique to locally manipulate the surface chemistry and SIPP to amplify the created differences allows the preparation of defined polymer‐brush layers of controlled morphologies.