bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutralizing Antibody Responses against Autologous and Heterologous Viruses in Acute versus Chronic Human Immunodeficiency Virus (HIV) Infection: Evidence for a Constraint on the Ability of HIV To Completely Evade Neutralizing Antibody Responses
Authors: Deeks Steven G. , Schweighardt Becky , Wrin Terri , Galovich Justin , Hoh Rebecca , Sinclair Elizabeth , Hunt Peter , McCune Joseph M. , Martin Jeffrey N. , Petropoulos Christos J. , Hecht Frederick M. 
Published: May 2006

ABSTRACT

Acute human immunodeficiency virus (HIV) infection is associated with the rapid development of neutralization escape mutations. The degree to which viral evolution persists in chronic infection has not been well characterized, nor is it clear if all patients develop high-level neutralization antibody escape. We therefore measured neutralizing antibody responses against autologous and heterologous viruses in a cohort of acutely and chronically infected subjects (
n
= 65). Neutralizing antibody responses against both autologous virus and heterologous viruses were lower among individuals with acute infection than among those with chronic infection. Among chronically infected individuals, there was a negative correlation between the level of neutralizing antibodies against autologous virus and the level of viremia. In contrast, there was a positive correlation between the level of neutralizing antibodies against a panel of heterologous viruses and the level of viremia. Viral evolution, as defined by the presence of higher neutralizing titers directed against earlier viruses than against contemporaneous viruses, was evident for subjects with recent infection but absent for those with chronic infection. In summary, neutralizing antibody responses against contemporaneous autologous viruses are absent in early HIV infection but can be detected at low levels in chronic infection, particularly among those controlling HIV in the absence of therapy. HIV replication either directly or indirectly drives the production of increasing levels of antibodies that cross-neutralize heterologous primary isolates. Collectively, these observations indicate that although HIV continuously drives the production of neutralizing antibodies, there may be limits to the capacity of the virus to evolve continuously in response to these antibodies. These observations also suggest that the neutralizing antibody response may contribute to the long-term control of HIV in some patients while protecting against HIV superinfection in most patients.
Modification of the Trypsin-Dependent Cleavage Activation Site of the Human Metapneumovirus Fusion Protein To Be Trypsin Independent Does Not Increase Replication or Spread in Rodents or Nonhuman Primates
Authors: Biacchesi Stéphane , Pham Quynh N. , Skiadopoulos Mario H. , Murphy Brian R. , Collins Peter L. , Buchholz Ursula J. 
Published: May 2006

ABSTRACT

The contribution of cleavage activation of the fusion F protein of human metapneumovirus (HMPV) to replication and pathogenicity in rodents and nonhuman primates was investigated. Recombinant HMPVs were generated in which the naturally occurring trypsin-dependent cleavage sequence (R-Q-S-R↓) was replaced by each of three sequences whose cleavage in vitro does not depend upon added trypsin. Two of these were multibasic sequences derived from avian metapneumovirus type A (R-R-R-R) or type C (R-K-A-R), with the former containing the consensus furin protease cleavage motif (R-X-R/K-R↓). The third one (R-Q-P-R) was derived from a recently described trypsin independent HMPV isolate (J. H. Schickli, J. Kaur, N. Ulbrandt, R. R. Spaete, and R. S. Tang, J. Virol.
79:
10678-10689, 2005). To preclude the possibility of conferring even greater virulence to this significant human pathogen, the modifications were done in an HMPV variant that was attenuated by the deletion of two of the three envelope glycoproteins, SH and G. Each of the introduced cleavage sequences conferred trypsin independent F cleavage and growth to HMPV in vitro. However, they differed in the efficiency of trypsin independent growth and plaque formation in vitro: R-R-R-R > R-K-A-R > R-Q-P-R > R-Q-S-R. The R-R-R-R mutant was the only one whose growth in vitro was not augmented by added trypsin, indicative of highly efficient trypsin independent cleavage. When inoculated intranasally into hamsters, there was essentially no difference in the magnitude of replication in the upper or lower respiratory tract between the mutants, and virus was not detected in organs outside of the respiratory tract. Evaluation of the most cleavage-efficient mutant, R-R-R-R, in African green monkeys showed that there was no detectable change in the magnitude of replication in the upper and lower respiratory tract or in immunogenicity and protective efficacy against HMPV challenge. These results suggest that cleavage activation is not a major determinant of HMPV virulence.
Double-Stranded RNA Binding May Be a General Plant RNA Viral Strategy To Suppress RNA Silencing
Authors: Mérai Zsuzsanna , Kerényi Zoltán , Kertész Sándor , Magna Melinda , Lakatos Lóránt , Silhavy Dániel 
Published: May 2006

ABSTRACTIn plants, RNA silencing (RNA interference) is an efficient antiviral system, and therefore successful virus infection requires suppression of silencing. Although many viral silencing suppressors have been identified, the molecular basis of silencing suppression is poorly understood. It is proposed that various suppressors inhibit RNA silencing by targeting different steps. However, as double-stranded RNAs (dsRNAs) play key roles in silencing, it was speculated that dsRNA binding might be a general silencing suppression strategy. Indeed, it was shown that the related aureusvirus P14 and tombusvirus P19 suppressors are dsRNA-binding proteins. Interestingly, P14 is a size-independent dsRNA-binding protein, while P19 binds only 21-nucleotide ds-sRNAs (small dsRNAs having 2-nucleotide 3′ overhangs), the specificity determinant of the silencing system. Much evidence supports the idea that P19 inhibits silencing by sequestering silencing-generated viral ds-sRNAs. In this study we wanted to test the hypothesis that dsRNA binding is a general silencing suppression strategy. Here we show that many plant viral silencing suppressors bind dsRNAs.Beet yellows virus PeanutP21,clump virusP15,Barley stripe mosaic virusγB, andTobacco etch virusHC-Pro, like P19, bind ds-sRNAs size-selectively, whileTurnip crinkle virusCP is a size-independent dsRNA-binding protein, which binds long dsRNAs as well as ds-sRNAs. We propose that size-selective ds-sRNA-binding suppressors inhibit silencing by sequestering viral ds-sRNAs, whereas size-independent dsRNA-binding suppressors inactivate silencing by sequestering long dsRNA precursors of viral sRNAs and/or by binding ds-sRNAs. The findings that many unrelated silencing suppressors bind dsRNA suggest that dsRNA binding is a general silencing suppression strategy which has evolved independently many times.
Functional Correlation between a Novel Amino Acid Insertion at Codon 19 in the Protease of Human Immunodeficiency Virus Type 1 and Polymorphism in the p1/p6 Gag Cleavage Site in Drug Resistance and Replication Fitness
Authors: Brann Terrence W. , Dewar Robin L. , Jiang Min-Kan , Shah Akram , Nagashima Kunio , Metcalf Julia A. , Falloon Judith , Lane H. Clifford , Imamichi Tomozumi 
Published: May 2006

ABSTRACT
Population-based sequence analysis revealed the presence of a variant of human immunodeficiency virus type 1 (HIV-1) containing an insertion of amino acid Ile in the protease gene at codon 19 (19I) and amino acid substitutions in the protease at codons 21 (E21D) and 22 (A22V) along with multiple mutations associated with drug resistance, M46I/P63L/A71V/I84V/I93L, in a patient who had failed protease inhibitor (PI) therapy. Longitudinal analysis revealed that the P63L/A71V/I93L changes were present prior to PI therapy. Polymorphisms in the Gag sequence were only seen in the p1/p6 cleavage site at the P1′ position (Leu to Pro) and the P5′ position (Pro to Leu). To characterize the role of these mutations in drug susceptibility and replication capacity, a chimeric HIV-1 strain containing the 19I/E21D/A22V mutations with the M46I/P63L/A71V/I84V/I93L and p1/p6 mutations was constructed. The chimera displayed high-level resistance to multiple PIs, but not to lopinavir, and grew to 30% of that of the wild type. To determine the relative contribution of each mutation to the phenotypic characteristic of the virus, a series of mutants was constructed using site-directed mutagenesis. A high level of resistance was only seen in mutants containing the 19I/A22V and p1/p6 mutations. The E21D mutation enhanced viral replication. These results suggest that the combination of the 19I/E21D/A22V mutations may emerge and lead to high-level resistance to multiple PIs. The combination of the 19I/A22V mutations may be associated with PI resistance; however, the drug resistance may be caused by the presence of a unique set of mutations in the p1/p6 mutations. The E21D mutation contributes to replication fitness rather than drug resistance.
The Cysteine-Rich Region and Secreted Form of the Attachment G Glycoprotein of Respiratory Syncytial Virus Enhance the Cytotoxic T-Lymphocyte Response despite Lacking Major Histocompatibility Complex Class I-Restricted Epitopes
Authors: Bukreyev Alexander , Serra Maria Elina , Laham Federico R. , Melendi Guillermina A. , Kleeberger Steven R. , Collins Peter L. , Polack Fernando P. 
Published: May 2006

ABSTRACTThe cytotoxic T-lymphocyte (CTL) response is important for the control of viral replication during respiratory syncytial virus (RSV) infection. The attachment glycoprotein (G) of RSV does not encode major histocompatibility complex class I-restricted epitopes in BALB/c mice (H-2d). Furthermore, studies to date have described an absence of significant CTL activity directed against this protein in humans. Therefore, G previously was not considered necessary for the generation of RSV-specific CTL responses. In this study, we demonstrate that, despite lacking H-2d-restricted epitopes, G enhances the generation of an effective CTL response against RSV. Furthermore, we show that this stimulatory effect is independent of virus titers and RSV-induced inflammation; that it is associated primarily with the secreted form of G; and that the effect depends on the cysteine-rich region of G (GCRR), a segment conserved in wild-type isolates worldwide. These findings reveal a novel function for the GCRR with potential implications for the generation of protective cellular responses and vaccine development.
Medians for second-trimester maternal serum markers: geographical differences and variation caused by median multiples-of-median equations
Authors: Vranken G , Reynolds T , Van Nueten J 
Published: May 2006

Objectives:To establish gestational age-specific mid-trimester normal medians for the prenatal serum markers α fetoprotein (AFP), human chorionic gonadotropin (HCG) and unconjugated oestriol (uE3) for a Belgian population by using the Beckman Coulter Access chemiluminiscent immunoassays; to compare these data with data obtained from other geographical regions; to propose regression coefficients for regressed medians and analyse variation induced by different regression equations; to evaluate the effect of formulas used for gestation correction on estimating risk in Down’s syndrome.Design:Data derived from 862 fresh serum samples from women being screened for Down’s syndrome pregnancy, composed of selected pregnancies deemed to be normal, were examined in a retrospective study. Regressed medians were calculated by using a first-degree logarithmic–linear fit of the raw data. Multiples-of-median (MoM) values estimated by using a simple logarithmic–linear equation were compared with those calculated with higher-degree polynomials chosen with a goodness-of-fit analysis. Model-specific variation was estimated and the effect on risk for Down’s syndrome was evaluated.Results:Regressed medians (Y) for Access serum markers AFP (IU/ml), HCG (IU/ml) and uE3 (nmol/l) for a Belgian population can be estimated with the equation Y = 10(A+BX)with X = decimal weeks. The best fit was obtained with a third-degree and a second-degree polynomial for AFP and uE3, respectively. Differences between the medians and among the slopes of the geographical populations were found to be significant (analysis of covariance, p<0.001).Conclusions:Belgian marker medians versus gestational time are found to show a pattern that is similar to that in the literature. The log–linear equation is observed to give a good fit and can be suggested as a tool for calculating median MoM values for Belgian laboratories that use Access biochemical prenatal markers.
Long hours in paid and domestic work and subsequent sickness absence: does control over daily working hours matter?
Authors: Ala-Mursula L , Vahtera J , Kouvonen A , Väänänen A , Linna A , Pentti J , Kivimäki M 
Published: May 2006

Objectives:To explore the associations of working hours (paid, domestic, commuting, and total) with sickness absence, and to examine whether these associations vary according to the level of employee control over daily working hours.Methods:Prospective cohort study among 25 703 full-time public sector employees in 10 towns in Finland. A survey of working hours and control over working hours was carried out in 2000–01. The survey responses were linked with register data on the number of self-certified (⩽3 days) and medically certified (>3 days) sickness absences until the end of 2003. Poisson regression analyses with generalised estimating equations were used to take into account the fact that the employees were nested within work units. Adjustments were made for work and family characteristics and health behaviour. The mean follow-up period was 28.1 (SD 8.1) months.Results:Long domestic and total working hours were associated with higher rates of medically certified sickness absences among both genders. In contrast, long paid working hours were associated with lower rates of subsequent self-certified sickness absences. Long commuting hours were related to increased rates of sickness absence of both types. Low control over daily working hours predicted medically certified sickness absences for both the women and men and self-certified absences for the men. In combinations, high control over working hours reduced the adverse associations of long domestic and total working hours with medically certified absences.Conclusions:Employee control over daily working hours may protect health and help workers successfully combine a full-time job with the demands of domestic work.
Decline in respiratory symptoms in service workers five months after a public smoking ban
Authors: Eagan T M L , Hetland J , Aarø L E 
Published: May 2006

Objective:To evaluate the effect of a total ban on smoking indoors in restaurants and other hospitality business premises in Norway, on respiratory symptoms among workers in the industry.Methods:Phone interviews with 1525 employees in the hospitality business were conducted immediately before the enacting of the law. In a follow-up study five months later, 906 of the workers from the baseline sample participated. Questions were asked on demographic variables, passive smoking exposure, personal smoking, attitudes towards the law, and five respiratory symptoms. Change in symptom prevalence was analysed with McNemar’s test and with analysis of variance (ANOVA) for repeated measures.Results:The prevalence of all five symptoms declined after the ban; for morning cough from 20.6% to 16.2% (p < 0.01); for daytime cough from 23.2% to 20.9%; for phlegm cough from 15.3% to 11.8% (p < 0.05); for dyspnoea from 19.2% to 13.0% (p < 0.01); and for wheezing from 9.0% to 7.8%. ANOVA showed that the largest decline in symptom prevalence was seen among workers who themselves gave up smoking, and subjects with a positive attitude towards the law before it took effect.Conclusion:A significant decrease in respiratory symptoms among service industry workers was found five months after the enacting of a public smoking ban.
HIGHER-ORDER QUASILINEAR PARABOLIC EQUATIONS WITH SINGULAR INITIAL DATA
Authors: GALAKTIONOV V. A. , SHISHKOV A. E. 
Published: May 2006

As a basic model, we study the 2mth-order quasilinear parabolic equation of diffusion-absorption type [Formula: see text] where Δm,pis the 2mth-order p-Laplacian [Formula: see text].We consider the Cauchy problem in RN× R+with arbitrary singular initial data u0≠ 0 such that u0(x) = 0 for any x ≠ 0. We prove that, in the most delicate case p = q and [Formula: see text], this Cauchy problem admits the unique trivial solution u(·, t) = 0 for t > 0. For λ < λ0, such nontrivial very singular solutions are known to exist for some semilinear higher-order models. This extends the well-known result by Brezis and Friedman established in 1983 for the semilinear heat equation with p = q = m = 1.
Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non–small cell lung cancer cells
Authors: Van Schaeybroeck Sandra , Kyula Joan , Kelly Donal M. , Karaiskou-McCaul Anthi , Stokesberry Susan A. , Van Cutsem Eric , Longley Daniel B. , Johnston Patrick G. 
Published: May 2006

AbstractActivating epidermal growth factor receptor (EGFR) mutations have been linked with sensitivity to gefitinib and erlotinib; however, there are no established predictive markers for response to the combination of EGFR inhibitors with standard chemotherapy in non–small cell lung cancer (NSCLC) patients. In this study, we characterized a panel of human EGFR wild-type and mutant NSCLC cells for their sensitivity to gefitinib alone and in combination with cisplatin or Taxol. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and crystal violet cell viability assays. Cell cycle distribution was measured by flow cytometry. EGFR expression was measured by flow cytometry, real-time PCR, and Western blotting. EGFR/Her2/Akt and extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation were measured by Western blotting. Two of nine EGFR wild type and one of two EGFR mutant NSCLC cells were sensitive to gefitinib, and this was associated with a decrease in phospho (p)–Akt and pErk1/2 following gefitinib exposure. There was no correlation between constitutive EGFR expression or activity and sensitivity to gefitinib nor was there a correlation between Her2/Akt and Erk1/2 activity and gefitinib sensitivity. However, in cells displaying a synergistic interaction between gefitinib and chemotherapy (cisplatin or Taxol), a dose-dependent increase in pEGFR was observed following chemotherapy exposure. In contrast, in cells where no change or a decrease in pEGFR following drug treatment was observed, we found an antagonistic or (at best) an additive interaction between the two compounds. Furthermore, the nature of this interaction was not dependent on the presence of a mutant EGFR. These novel findings suggest that modulation of EGFR activity following drug treatment determines response to gefitinib in combination with chemotherapy in NSCLC cells. [Mol Cancer Ther 2006;5(5):1154–65]
Aspirin reduces the outcome of anticancer therapy in Meth A–bearing mice through activation of AKT-glycogen synthase kinase signaling
Authors: di Palma Antonella , Matarese Giuseppe , Leone Vincenza , Di Matola Tiziana , Acquaviva Fabio , Acquaviva Angela Maria , Ricchi Paolo 
Published: May 2006

Abstract
Aspirin displays, at millimolar concentrations, several mechanisms independent from its ability to inhibit cyclooxygenases. Occasionally, the mechanisms displayed in vitro have been clearly related to an effect of clinical relevance in vivo. An expanding literature has been focusing on the cytoprotective effect of aspirin in neurodegenerative disorders and the activation of AKT pathway in neuroprotection and induction of resistance to anticancer drugs. In this work, we tested the ability of aspirin to activate the AKT survival pathway in methylcholanthrene-induced fibrosarcoma cells (Meth A) transplanted into BALB/c nude mice and the clinical effect of aspirin cotreatment during etoposide (VP-16)–based anticancer therapy. We found that cotreatment with aspirin reduced VP-16-induced apoptosis and activated AKT in vitro and in vivo. In Meth A–bearing mice, aspirin administration also activated glycogen synthase kinase-3 and reduced the activity and the efficacy of anticancer therapy in VP-16 cotreated animals. Our data suggest that the antiapoptotic effect of aspirin operates in vivo through the activation of AKT-glycogen synthase kinase pathway causing a decrease in the outcome of VP-16-based therapy. These findings could have clinical relevance in treatment of human malignancies. [Mol Cancer Ther 2006;5(5):1318–24]
Detection of histone deacetylase inhibition by noninvasive magnetic resonance spectroscopy
Authors: Sankaranarayanapillai Madhuri , Tong William P. , Maxwell David S. , Pal Ashutosh , Pang Jihai , Bornmann William G. , Gelovani Juri G. , Ronen Sabrina M. 
Published: May 2006

Abstract
Histone deacetylase (HDAC) inhibitors are new and promising antineoplastic agents. Current methods for monitoring early response rely on invasive biopsies or indirect blood-derived markers. Our goal was to develop a magnetic resonance spectroscopy (MRS)–based method to detect HDAC inhibition. The fluorinated lysine derivative Boc-Lys-(Tfa)-OH (BLT) was investigated as a 19F MRS molecular marker of HDAC activity together with 31P MRS of endogenous metabolites. In silico modeling of the BLT-HDAC interaction and in vitro MRS studies of BLT cleavage by HDAC confirmed BLT as a HDAC substrate. BLT did not affect cell viability or HDAC activity in PC3 prostate cancer cells. PC3 cells were treated, in the presence of BLT, with the HDAC inhibitor p-fluoro-suberoylanilide hydroxamic acid (FSAHA) over the range of 0 to 10 μmol/L, and HDAC activity and MRS spectra were monitored. Following FSAHA treatment, HDAC activity dropped, reaching 53% of control at 10 μmol/L FSAHA. In parallel, a steady increase in intracellular BLT from 14 to 32 fmol/cell was observed. BLT levels negatively correlated with HDAC activity consistent with higher levels of uncleaved BLT in cells with inhibited HDAC. Phosphocholine, detected by 31P MRS, increased from 7 to 16 fmol/cell following treatment with FSAHA and also negatively correlated with HDAC activity. Increased phosphocholine is probably due to heat shock protein 90 inhibition as indicated by depletion of client proteins. In summary, 19F MRS of BLT, combined with 31P MRS, can be used to monitor HDAC activity in cells. In principle, this could be applied in vivo to noninvasively monitor HDAC activity. [Mol Cancer Ther 2006;5(5):1325–34]