bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple ascending dose study of BMS-790052, a nonstructural protein 5A replication complex inhibitor, in patients infected with hepatitis C virus genotype 1
Authors: Nettles Richard E. , Gao Min , Bifano Marc , Chung Ellen , Persson Anna , Marbury Thomas C. , Goldwater Ronald , DeMicco Michael P. , Rodriguez-Torres Maribel , Vutikullird Apinya , Fuentes Ernesto , Lawitz Eric , Lopez-Talavera Juan Carlos , Grasela Dennis M. 
Published: August 2011

Abstract

The antiviral activity, resistance profile, pharmacokinetics (PK), safety, and tolerability of BMS-790052, a nonstructural protein 5A (NS5A) replication complex inhibitor, were evaluated in a double-blind, placebo-controlled, sequential panel, multiple ascending dose study. Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from baseline in HCV RNA ranged from 2.8 to 4.1 log10 IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the

in vitro

replicon system. The PK profile was supportive of once-daily dosing with median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing. BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters.

Conclusion:

BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1. (Hepatology 2011
The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry
Authors: Ciesek Sandra , von Hahn Thomas , Colpitts Che C. , Schang Luis M. , Friesland Martina , Steinmann Jörg , Manns Michael P. , Ott Michael , Wedemeyer Heiner , Meuleman Philip , Pietschmann Thomas , Steinmann Eike 
Published: August 2011

Abstract

Hepatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Current antiviral therapy fails to clear infection in a substantial proportion of cases. Drug development is focused on nonstructural proteins required for RNA replication. Individuals undergoing orthotopic liver transplantation face rapid, universal reinfection of the graft. Therefore, antiviral strategies targeting the early stages of infection are urgently needed for the prevention of HCV infection. In this study, we identified the polyphenol, epigallocatechin-3-gallate (EGCG), as an inhibitor of HCV entry. Green tea catechins, such as EGCG and its derivatives, epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC), have been previously found to exert antiviral and antioncogenic properties. EGCG had no effect on HCV RNA replication, assembly, or release of progeny virions. However, it potently inhibited Cell-culture–derived HCV (HCVcc) entry into hepatoma cell lines as well as primary human hepatocytes. The effect was independent of the HCV genotype, and both infection of cells by extracellular virions and cell-to-cell spread were blocked. Pretreatment of cells with EGCG before HCV inoculation did not reduce HCV infection, whereas the application of EGCG during inoculation strongly inhibited HCV infectivity. Moreover, treatment with EGCG directly during inoculation strongly inhibited HCV infectivity. Expression levels of all known HCV (co-)receptors were unaltered by EGCG. Finally, we showed that EGCG inhibits viral attachment to the cell, thus disrupting the initial step of HCV cell entry.

Conclusion:

The green tea molecule, EGCG, potently inhibits HCV entry and could be part of an antiviral strategy aimed at the prevention of HCV reinfection after liver transplantation. (Hepatology 2011)
Developing country health systems and the governance of international HIV/AIDS funding
Authors: Poku Nana , Whitman Jim 
Published: August 2011

SUMMARYDonor country initiatives for the prevention and mitigation of HIV/AIDS are not a matter of simple burden sharing. Instead, they have brought in their wake many of the complexities and unforeseen effects that have long been associated with more general overseas development assistance. In the case of funding directed toward HIV/AIDS, these effects are by no means either secondary or easily calculable. It is widely acknowledged that there is no consensus framework on how these impacts may be defined, no framework/toolkit for the evaluation of impacts and no longitudinally significant data that could provide the substance for those evaluations.The subject of this study focuses not on the health outcomes of funding but on how donor–recipient relations could be better deliberated, negotiated and coordinated. We argue that effective leadership and governance of developing country health systems for HIV/AIDS work requires a reconfiguration of how donor–recipient relations are conceived and contracted, and for this purpose, we propose an adaptation of the Organisation for Economic Co‐operation and Development Paris Declaration principles of aid effectiveness. Copyright © 2011 John Wiley & Sons, Ltd.
Thermo‐solutal convection in an inclined porous cavity with various aspect ratios under mixed thermal and species boundary conditions
Authors: Chamkha Ali J. , Al‐Mudhaf Ali , Al‐Meshaiei Eisa 
Published: August 2011

AbstractThe problem of laminar thermo‐solutal convective flow of a binary fluid mixture in an inclined rectangular cavity filled with a uniform porous medium is considered. Mixed heat and mass fluxes and uniform temperature and concentration conditions are applied on two opposing walls of the cavity while the other two walls are kept adiabatic and impermeable to mass transfer. The problem is put in terms of the stream function‐vorticity formulation. A numerical solution based on the finite‐difference methodology is obtained. Representative results illustrating the effects of the inclination angle of the cavity, buoyancy ratio, Darcy number, and the cavity aspect ratio on the contour maps of the streamline, temperature, and concentration as well as the profiles of velocity, temperature, and concentration at mid‐section of the cavity are reported. In addition, numerical results for the average Nusselt and Sherwood numbers as well as some useful correlations are presented for various parametric conditions and discussed. © 2011 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.20369
Combined use of spot samples and continuous integrated sampling in a study of storm runoff from a lowland catchment in the south of England
Authors: Gkritzalis‐Papadopoulos A. , Palmer M. R. , Mowlem M. C. 
Published: August 2011

AbstractWe have used two different sampling techniques to study the geochemical response of a small lowland rural catchment to episodic storm runoff. The first method involves traditional daily spot sampling and has been used to develop a standard end‐member mixing analysis (EMMA) of the relative contributions of ground water flow and surface runoff to the total stream flow. The second method utilizes a continuous sampling device, powered by an osmotic pump, to produce an integrated 24‐h sample of the stream flow. When combined with the EMMA results from the spot samples, analyses of the integrated samples reveal the presence of a third component that makes a significant contribution to the dissolved NO3, Ca and K export from the catchment during the rising limb of the hydrographic profile of a storm event following a prolonged dry period. The storm occurred in the middle of the night, so that the response of the stream chemistry was not captured by the daily samples. We hypothesize that this third component is derived from the flushing of stored soil water that contains the geochemical signature of decaying vegetation. Copyright © 2011 John Wiley & Sons, Ltd.
Comparative analysis of relationships between NLDAS‐2 forcings and model outputs
Authors: Xia Youlong , Ek Mike , Wei Helin , Meng Jesse 
Published: August 2011

AbstractThis study reports results from an analysis of the relationship between atmospheric forcing and model‐simulated water and energy fluxes for the North American Land Data Assimilation System Project Phase 2 (NLDAS‐2). The relationships between mean monthly precipitation and total runoff are stronger in the Sacramento (SAC) and variable infiltration capacity (VIC) models, which grew out of the hydrological community, than in the Noah and Mosaic models, which grew out of the soil‐vegetation‐atmosphere transfer (SVAT) community. The reverse is true for the relationship between mean monthly precipitation and evapotranspiration. In addition, surface energy fluxes in VIC are less sensitive to model forcing (except for air temperature) than those in the Noah and Mosaic model. Notwithstanding these general conclusions, the relationships between forcings and model‐simulated water and energy fluxes for all models vary for different seasons, variables, and regions. These findings will ultimately inspire a combination of SVAT‐type model energy components with hydrological model water components to develop a SVAT‐hydrology model to improve both evapotranspiration and total runoff simulations. Copyright © 2011 John Wiley & Sons, Ltd.
Impacts of riparian zone plant water use on temporal scaling of groundwater systems
Authors: Zhu Jianting , Young Michael H. , Osterberg John 
Published: August 2011

AbstractIn this work, we study groundwater system temporal scaling in relation to plant water use and near‐river‐stage fluctuations in riparian zones where phreatophytes exist. Using detrended fluctuation analysis (DFA), we investigate the influence of regular diurnal fluctuations due to phreatophyte water use on temporal scaling properties of groundwater level variations. We found that groundwater use by phreatophytes, at the field site on the Colorado River, USA, results in distinctive crossovers (slope changes when the plots are fitted with straight lines) in the logarithm plots of root‐mean‐square fluctuations of the detrended water level time series versus time scales of groundwater level dynamics. For groundwater levels monitored at wells close to the river, we identified one crossover at ∼1 day in the scaling characteristics of groundwater level variations. When time scale exceeds 1 day, the scaling properties decrease from persistent to close to 1/f noise, where f is the frequency. For groundwater levels recorded at wells further away from the river, the slope of the straight line fit (i.e. scaling exponent) is smallest when the time scale is between 1 and 3 days. When the time scale is < 1 day, groundwater variations become persistent. When the time scale is between 1 and 3 days, the variations are close to white noise, but return to persistent when the time scale is > 3 days. Copyright © 2011 John Wiley & Sons, Ltd.
Zinc–Homocysteine binding in cobalamin‐dependent methionine synthase and its role in the substrate activation: DFT, ONIOM, and QM/MM molecular dynamics studies
Authors: Abdel‐Azeim Safwat , Li Xin , Chung Lung Wa , Morokuma Keiji 
Published: August 2011

AbstractCobalamin‐dependent methionine synthase (MetH) is an important metalloenzyme responsible for the biosynthesis of methionine. It catalyzes methyl transfer from N5‐methyl‐tetrahydrofolate to homocysteine (Hcy) by using a zinc ion to activate the Hcy substrate. Density functional theory (B3LYP) calculations on the active‐site model in gas phase and in a polarized continuum model were performed to study the Zn coordination changes from the substrate‐unbound state to the substrate‐bound state. The protein effect on the Zn2+ coordination exchange was further investigated by ONIOM (B3LYP:AMBER)‐ME and EE calculations. The Zn2+‐coordination exchange is found to be highly unfavorable in the gas phase with a high barrier and endothermicity. In the water solution, the reaction becomes exothermic and the reaction barrier is drastically decreased to about 10.0 kcal/mol. A considerable protein effect on the coordination exchange was also found; the reaction is even more exothermic and occurs without barrier. The enzyme was suggested to constrain the zinc coordination sphere in the reactant state (Hcy‐unbound state) more than that in the product state (Hcy‐bound state), which promotes ligation of the Hcy substrate. Molecular dynamics simulations using molecular mechanics (MM) and PM3/MM potentials suggest a correlation between the flexibility of the Zn2+‐binding site and regulation of the enzyme function. Directed in silico mutations of selected residues in the active site were also performed. Our studies support a dissociative mechanism starting with the ZnO(Asn234) bond breaking followed by the ZnS(Hcy) bond formation; the proposed associative mechanism for the Zn2+‐coordination exchange is not supported. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Density functional theory study on electron and hole transport properties of organic pentacene derivatives with electron‐withdrawing substituent
Authors: Chai Shuo , Wen Shu‐Hao , Huang Jin‐Dou , Han Ke‐Li 
Published: August 2011

AbstractAttaching electron‐withdrawing substituent to organic conjugated molecules is considered as an effective method to produce n‐type and ambipolar transport materials. In this work, we use density functional theory calculations to investigate the electron and hole transport properties of pentacene (PENT) derivatives after substituent and simulate the angular resolution anisotropic mobility for both electron and hole transport. Our results show that adding electron‐withdrawing substituents can lower the energy level of lowest unoccupied molecular orbital (LUMO) and increase electron affinity, which are beneficial to the electron injection and ambient stability of the material. Also the LUMO electronic couplings for electron transport in these pentacene derivatives can achieve up to a hundred meV which promises good electron transport mobility, although adding electron‐withdrawing groups will introduce the increase of electron transfer reorganization energy. The final results of our angular resolution anisotropic mobility simulations show that the electron mobility of these pentacene derivatives can get to several cm2 V−1s−1, but it is important to control the orientation of the organic material relative to the device channel to obtain the highest electron mobility. Our investigation provide detailed information to assist in the design of n‐type and ambipolar organic electronic materials with high mobility performance. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
The evolution of heart gene delivery vectors
Authors: Wasala Nalinda B. , Shin Jin‐Hong , Duan Dongsheng 
Published: August 2011

AbstractGene therapy holds promise for treating numerous heart diseases. A key premise for the success of cardiac gene therapy is the development of powerful gene transfer vehicles that can achieve highly efficient and persistent gene transfer specifically in the heart. Other features of an ideal vector include negligible toxicity, minimal immunogenicity and easy manufacturing. Rapid progress in the fields of molecular biology and virology has offered great opportunities to engineer various genetic materials for heart gene delivery. Several nonviral vectors (e.g. naked plasmids, plasmid lipid/polymer complexes and oligonucleotides) have been tested. Commonly used viral vectors include lentivirus, adenovirus and adeno‐associated virus. Among these, adeno‐associated virus has shown many attractive features for pre‐clinical experimentation in animal models of heart diseases. We review the history and evolution of these vectors for heart gene transfer. Copyright © 2011 John Wiley & Sons, Ltd.
Ventilation‐based segmentation of the lungs using hyperpolarized 3He MRI
Authors: Tustison Nicholas J. , Avants Brian B. , Flors Lucia , Altes Talissa A. , de Lange Eduard E. , Mugler John P. , Gee James C. 
Published: August 2011

AbstractPurpose:To develop an automated segmentation method to differentiate the ventilated lung volume on 3He magnetic resonance imaging (MRI).Materials and Methods:Computational processing (CP) for each subject consisted of the following three essential steps: 1) inhomogeneity bias correction, 2) whole lung segmentation, and 3) subdivision of the lung segmentation into regions of similar ventilation. Evaluation consisted of two comparative analyses: i) comparison of the number of defects scored by two human readers in 43 subjects, and ii) simultaneous truth and performance level estimation (STAPLE) in 18 subjects in which the ventilation defects were manually segmented by four human readers.Results:There was excellent correlation between the number of ventilation defects tabulated by CP and reader #1 (intraclass correlation coefficient [ICC] = 0.86), CP and reader #2 (ICC = 0.85), and between the two readers (ICC = 0.97). The STAPLE results from the second analysis yielded the following sensitivity/specificity numbers: CP (0.898/0.905), radiologist #1 (0.743/0.897), radiologist #2 (0.501/0.985), radiologist #3 (0.898/0.848), and the first author (0.600/0.984).Conclusion:We developed and evaluated an automated method for quantifying the ventilated lung volume on 3He MRI. The findings strongly indicate that our proposed algorithmic processing may be a reliable, automatic method for quantitating ventilation defects. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.
Mutations in two PKR‐binding domains in chronic hepatitis C of genotype 3a and correlation with viral loads and interferon responsiveness
Authors: Yokozaki Shouichi , Katano Yoshiaki , Hayashi Kazuhiko , Ishigami Masatoshi , Itoh Akihiro , Hirooka Yoshiki , Nakano Isao , Goto Hidemi 
Published: August 2011

AbstractInterferon (IFN) induces the double‐stranded RNA‐dependent protein kinase (PKR) to inhibit viral replication. Two motifs of the PKR‐binding domain exist in the E2 and the NS5A regions of the hepatitis C virus (HCV). These regions are called the PKR‐eukaryotic transcription factor (elF2‐alpha) phosphorylation homology domain (PePHD), and the IFN sensitivity‐determining region (ISDR). Both regions are inhibited by PKR. Thus, several studies have reported the relationship between these regions and IFN responsiveness and the HCV viral load. However, the data obtained from these studies remain controversial. The aim of this study was to investigate the genomic heterogeneity of the PePHD and the ISDR in patients with genotype 3a and how this impacts HCV replication and the response to IFN therapy. Twenty‐one male patients infected with HCV genotype 3a were studied. The PePHD was well conserved, and mutations were found in only one amino acid position in two patients. Patients with three or more mutations in the ISDR had lower viral loads than those with fewer than two mutations (192.2 ± 176.7 vs. 1279.4 ± 997.6 KIU/ml, P = 0.0277). Ten (71.4%) of 14 patients achieved a sustained virological response to IFN therapy. No specific amino acid substitutions in the PePHD and the ISDR were associated with IFN responsiveness; however, the number of mutations in the ISDR was significantly associated with the HCV viral load. The findings from this study suggest that the ISDR plays an important role in regulating viral replication in patients infected with HCV genotype 3a. J. Med. Virol. 83:1727–1732, 2011. © 2011 Wiley‐Liss, Inc.
Elevated Epstein–Barr virus seroreactivity among unaffected members of families with nasopharyngeal carcinoma
Authors: Qin Hai‐De , Jia Wei‐Hua , Zhang Lin‐Lin , Liu Na , Zhou Xin‐Xi , Wang Ming‐Hsi , Feng Qi‐Sheng , Chen Li‐Zhen , Zhang Ying , Jorgensen Timothy J. , Zeng Yi‐Xin , Shugart Yin Yao 
Published: August 2011

AbstractSerum antibodies to Epstein–Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA‐IgA) were compared to those of 904 controls from the general population. The VCA‐IgA titer was correlated among sibling pairs to a high significance in both family types (P < 0.0001 and P = 0.0005 for the multiplex and the sporadic families, respectively); parent–offspring pairs also showed significant correlation (P < 0.0001 and P = 0.0002, respectively); and spouse pairs were correlated, but at lower significance levels (P = 0.0790 and P = 0.0040, respectively). When compared to the controls, among first‐degree relatives in the multiplex families, the age‐ and gender‐adjusted odds ratio (OR) was 2.06 (95% confidence interval 1.56–2.71), 3.55 (2.24–5.64), and 2.25 (1.57–3.23) for siblings, parents, and children, respectively. In the sporadic families, the adjusted OR was 1.55 (1.21–2.00) and 2.08 (1.51–2.86) for siblings and parents, respectively. The adjusted P‐value of spouses lost significance in the multiplex families, but remained significant in the sporadic families (P = 0.0146). In conclusion, EBV seropositivity rates were elevated among unaffected family members in both multiplex and sporadic families with NPC. J. Med. Virol. 83:1792–1798, 2011. © 2011 Wiley‐Liss, Inc.
Antibody response and avidity of respiratory syncytial virus‐specific total IgG, IgG1, and IgG3 in young children
Authors: Freitas G.R.O. , Silva D.A.O. , Yokosawa J. , Paula N.T. , Costa L.F. , Carneiro B.M. , Ribeiro L.Z.G. , Oliveira T.F.M. , Mineo J.R. , Queiróz D.A.O. 
Published: August 2011

AbstractRespiratory syncytial virus (RSV) is a major cause of acute respiratory disease in infants and young children. Considering that several aspects of the humoral immune response to RSV infection remain unclear, this study aimed to investigate the occurrence, levels, and avidity of total IgG, IgG1, and IgG3 antibodies against RSV in serum samples from children ≤5 years old. In addition, a possible association between antibody avidity and severity of illness was examined. The occurrence and levels of RSV‐specific IgG depended on age, with infants <3 months old displaying high levels of antibodies, which were probably acquired from the mother. Children ≥24 months old also showed frequent occurrence and high levels of IgG, which was produced actively during infection. In addition, the avidity assay showed that the avidity of RSV‐specific total IgG and IgG1 was lower in infants <3 months old who had acute respiratory disease than in age‐matched controls. The avidity of RSV‐specific IgG detected in children ≥24 months old with lower respiratory infection was lower than that in children with upper respiratory infection. These results indicate that the presence of high avidity RSV‐specific IgG antibodies may lead to better protection against RSV infection in children <3 months old, who may have a lower probability of developing disease of increased severity. In addition, children ≥24 months old with RSV‐specific IgG antibodies of low avidity tended to develop more severe RSV illness. These findings may be helpful in establishing vaccination schedules when a vaccine becomes available. J. Med. Virol. 83:1826–1833, 2011. © 2011 Wiley‐Liss, Inc.