bluuebunny/crossref_metadata_2025_split huggingface dataset:
Newly Designed Six-Membered Azasugar Nucleotide-Containing Phosphorothioate Oligonucleotides as Potent Human Immunodeficiency Virus Type 1 Inhibitors
Authors: Lee Dong-Seong , Jung Kyeong-Eun , Yoon Cheol-Hee , Lim Hong , Bae Yong-Soo 
Published: September 2005

ABSTRACT
A series of modified oligonucleotides (ONs), characterized by a phosphorothioate (P═S) backbone and a six-membered azasugar (6-AZS) as a sugar substitute in a nucleotide, were newly synthesized and assessed for their ability to inhibit human immunodeficiency virus type 1 (HIV-1) via simple treatment of HIV-1-infected cultures, without any transfection process. While unmodified P═S ONs exhibited only minor anti-HIV-1 activity, the six-membered azasugar nucleotide (6-AZN)-containing P═S oligonucleotides (AZPSONs) exhibited remarkable antiviral activity against HIV-1/simian-human immunodeficiency virus (SHIV) replication and syncytium formation (50% effective concentration = 0.02 to 0.2 μM). The AZPSONs exhibited little cytotoxicity at concentrations of up to 100 μM. DBM 2198, one of the most effective AZPSONs, exhibited antiviral activity against a broad spectrum of HIV-1, including T-cell-tropic, monotropic, and even drug-resistant HIV-1 variants. The anti-HIV-1 activities of DBM 2198 were similarly maintained in HIV-1-infected cultures of peripheral blood mononuclear cells. When we treated severely infected cultures with DBM 2198, syncytia disappeared completely within 2 days. Taken together, our results indicate that DBM 2198 and other AZPSONs may prove useful in the further development of safe and effective AIDS-therapeutic drugs against a broad spectrum of HIV-1 variants.
Comparative Mutant Prevention Concentrations of Pradofloxacin and Other Veterinary Fluoroquinolones Indicate Differing Potentials in Preventing Selection of Resistance
Authors: Wetzstein H.-G. 
Published: September 2005

ABSTRACT

Pradofloxacin (PRA) is an 8-cyano-fluoroquinolone (FQ) being developed to treat bacterial infections in dogs and cats. Its mutant prevention concentrations (MPC) were determined for
Escherichia coli
ATCC 8739 at 0.225 μg/ml, and for
Staphylococcus aureus
ATCC 6538 at 0.55 μg/ml. At drug concentrations equal to or above the MPC, growth (implying selective clonal expansion) of first-step FQ-resistant variants, naturally present in large bacterial populations, was inhibited. MPC
90
derived from 10 clinical isolates each of
E. coli
and
Staphylococcus intermedius
, the latter species being of greater clinical relevance than
S. aureus
in companion-animal medicine, amounted to 0.2 to 0.225 and 0.30 to 0.35 μg/ml, respectively. MPCs of other veterinary FQs were assessed to determine relative in vitro potencies. The MPCs of marbofloxacin, enrofloxacin, danofloxacin, sarafloxacin, orbifloxacin, and difloxacin were 1.2-, 1.4-, 2.3-, 2.4-, 5-, and 7-fold higher than the MPC of PRA for
E. coli
ATCC 8739, and 6-, 6-, 19-, 15-, 15-, and 31-fold higher than the MPC of PRA for
S. aureus
ATCC 6538, respectively. MPC curves revealed a pronounced heterogeneity in susceptibility within populations of ≥4 × 10
9
CFU employed, extending to 10-fold above the MICs. The duration of incubation and, for
S. aureus
, inoculum density profoundly affected the MPCs. With appropriate dosing, PRA may combine high therapeutic efficacy with a high potential for restricting the selection for FQ resistance under field conditions in the species analyzed.
Pharmacodynamics of Moxifloxacin against Anaerobes Studied in an In Vitro Pharmacokinetic Model
Authors: Noel Alan R. , Bowker Karen E. , MacGowan Alasdair P. 
Published: September 2005

ABSTRACT

The antibacterial effects of moxifloxacin against
Bacteroides fragilis
,
Clostridium perfringens
, and gram-positive anaerobic cocci (GPAC) were studied in an in vitro pharmacokinetic model. Initially, a dose-ranging study with area under the concentration-time curve (AUC)/MIC ratios of 6.7 to 890 was used to investigate the effect of anaerobic conditions on the AUC/MIC antibacterial effect (ABE) relationship with
Escherichia coli
. The AUC/MIC ratios for 50% and 90% effects, using a log CFU drop at 24 h as the antibacterial effect measure, were 34 and 59, respectively, aerobic and 54 and 96, respectively, anaerobic. These values are not significantly different. Dose ranging at AUC/MIC ratios of 9 to 216 against the anaerobes indicated a differing AUC/MIC ABE pattern, and the AUC/MICs for 50% and 90% effects were lower: for
B. fragilis
, they were 10.5 and 25.7, respectively; for
C. perfringens
, they were 8.6 and 16.2; and for GPAC, they were 7.3 and 17.4. The maximum-effect log drops were as follows: for
B. fragilis
, −3.2 ± 0.2 logs; for
C. perfringens
, −3.7 ± 0.1 logs; and for GPAC, −2.5 ± 0.1 logs. Although the anaerobes were not eradicated, there was no emergence of resistance. Comparison of the ABE of moxifloxacin to that of ertapenem against
B. fragilis
indicated that moxifloxacin was superior at 24 h and 48 h. In contrast, ertapenem was superior to moxifloxacin against GPAC at 24 h and 48 h and against
C. perfringens
at 48 h. Both drugs performed equivalently against
C. perfringens
at 24 h. Monte Carlo simulations using human serum AUC data and an AUC/MIC anaerobe target of 7.5 suggests a >90% target achievement at MICs of <2 mg/liter. This divides the
B. fragilis
wild-type MIC distribution. The pharmacodynamic properties of moxifloxacin against anaerobes are different than those against aerobic species. The clinical implications of these differences need further exploration.
Inhibition of Coreceptor-Independent Cell-to-Cell Human Immunodeficiency Virus Type 1 Transmission by a CD4-Immunoglobulin G2 Fusion Protein
Authors: Bosch Berta , Blanco Julià , Pauls Eduardo , Clotet-Codina Imma , Armand-Ugón Mercedes , Grigorov Boyan , Muriaux Delphine , Clotet Bonaventura , Darlix Jean-Luc , Esté José A. 
Published: September 2005

ABSTRACTWe have previously shown (J. Blanco et al., J. Biol. Chem. 279:51305-51314, 2004) that the contact between HIV producing cells and primary CD4+T cells may induce the uptake of human immunodeficiency virus (HIV) particles by target cells in the absence of HIV envelope-mediated membrane fusion or productive HIV replication. HIV uptake by CD4+T cells was dependent on cellular contacts mediated by the binding of gp120 to CD4 but was independent of the expression of the appropriate HIV coreceptor, CCR5 or CXCR4. Here, we have characterized the effect of agents blocking gp120 binding to CD4 on cell-to-cell HIV transmission. A recombinant CD4-based protein (CD4-immunoglobulin G2 [IgG2]), that is currently being evaluated in clinical trials, completely inhibited the uptake of HIV particles by CD4+T cells from persistently infected cells expressing R5, X4, or X4/T-20-resistant HIV-1 envelope glycoproteins. Consequently, both the release of viral particles from endocytic vesicles and the infection of reporter U87-CD4 cells were also prevented. The polyanionic anti-HIV agent dextran sulfate failed to prevent the intracellular uptake of virions by CD4+T cells. Indeed, it increased HIV uptake in a dose-dependent manner, suggesting functional differences between the specific gp120-targeting CD4-IgG2 agent and nonspecific HIV binding inhibitors. Thus, the inhibition of the specific interaction between gp120 and CD4 protein could be an effective strategy to inhibit HIV binding to CD4+T cells, and the mechanism by which CD4+T cells lacking the appropriate coreceptor may be converted in HIV carriers.
Effect of Amphotericin B on Capsule and Cell Size inCryptococcus neoformansduring Murine Infection
Authors: Zaragoza Oscar , Mihu Coralia , Casadevall Arturo , Nosanchuk Joshua D. 
Published: September 2005

ABSTRACTAntifungal drugs can affect the cellular morphology ofCryptococcus neoformansin culture, which alters its interactions with phagocytes. We examined the effects of amphotericin B onC. neoformansduring murine infection. The antifungal reduced capsule size and serum polysaccharide, which suggests an additional mechanism for amphotericin B's efficacy in cryptococcosis.
AbeM, an H
+
-Coupled
Acinetobacter baumannii
Multidrug Efflux Pump Belonging to the MATE Family of Transporters
Authors: Su Xian-Zhong , Chen Jing , Mizushima Tohru , Kuroda Teruo , Tsuchiya Tomofusa 
Published: September 2005

ABSTRACT

We cloned a gene,
abeM
, for a multidrug efflux pump from
Acinetobacter baumannii
using
Escherichia coli
as the host. Sequence analysis revealed that AbeM is a member of the MATE family of pumps. AbeM was found to be an H
+
-coupled multidrug efflux pump and a unique member of the MATE family.
Vancomycin-Resistant
Enterococcus faecium
Strains Isolated from Community Wastewater from a Semiclosed Agri-Food System in Texas
Authors: Poole T. L. , Hume M. E. , Campbell L. D. , Scott H. M. , Alali W. Q. , Harvey R. B. 
Published: September 2005

ABSTRACT

Vancomycin-resistant
Enterococcus faecium
strains (VRE) were isolated from human wastewater but not swine fecal waste from a semiclosed agri-food system in Texas. Forty-nine VRE isolates possessed
vanA
, and one possessed
vanB
. Twenty-one pulsed-field gel electrophoresis types were identified and segregated into three groups. There was evidence of clonal dissemination among geographically separated sites.
Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist
Authors: Best Sonja M. , Morris Keely L. , Shannon Jeffrey G. , Robertson Shelly J. , Mitzel Dana N. , Park Gregory S. , Boer Elena , Wolfinbarger James B. , Bloom Marshall E. 
Published: September 2005

ABSTRACTThe tick-borne encephalitis (TBE) complex of viruses, genusFlavivirus, can cause severe encephalitis, meningitis, and/or hemorrhagic fevers. Effective interferon (IFN) responses are critical to recovery from infection with flaviviruses, and the mosquito-borne flaviviruses can inhibit this response. However, little is known about interactions between IFN signaling and TBE viruses. Langat virus (LGTV), a member of the TBE complex of viruses, was found to be highly sensitive to the antiviral effects of IFN. However, LGTV infection inhibited IFN-induced expression of a reporter gene driven by either IFN-α/β- or IFN-γ-responsive promoters. This indicated that LGTV can inhibit the IFN-mediated JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway of signal transduction. The mechanism of inhibition was due to blocks in the phosphorylation of both Janus kinases, Jak1 and Tyk2, during IFN-α signaling and at least a failure of Jak1 phosphorylation following IFN-γ stimulation. To determine the viral protein(s) responsible, we individually expressed all nonstructural (NS) proteins and examined their ability to inhibit signal transduction. Expression of NS5 alone inhibited STAT1 phosphorylation in response to IFN, thus identifying NS5 as a potential IFN antagonist. Examination of interactions between NS5 and cellular proteins revealed that NS5 associated with IFN-α/β and -γ receptor complexes. Importantly, inhibition of JAK-STAT signaling and NS5-IFN receptor interactions were demonstrated in LGTV-infected human monocyte-derived dendritic cells, important target cells for early virus replication. Because NS5 may interfere with both innate and acquired immune responses to virus infection, this protein may have a significant role in viral pathogenesis.
Structure of the Fab Fragment of F105, a Broadly Reactive Anti-Human Immunodeficiency Virus (HIV) Antibody That Recognizes the CD4 Binding Site of HIV Type 1 gp120
Authors: Wilkinson Royce A. , Piscitelli Chayne , Teintze Martin , Cavacini Lisa A. , Posner Marshall R. , Lawrence C. Martin 
Published: September 2005

ABSTRACTWe have determined the crystal structure of the Fab fragment from F105, a broadly reactive human antibody with limited potency that recognizes the CD4 binding site of gp120. The structure reveals an extended CDR H3 loop with a phenylalanine residue at the apex and shows a striking pattern of serine and tyrosine residues. Modeling the interaction between gp120 and F105 suggests that the phenylalanine may recognize the binding pocket of gp120 used by Phe43of CD4 and that numerous tyrosine and serine residues form hydrogen bonds with the main chain atoms of gp120. A comparison of the F105 structure to that of immunoglobulin G1 b12, a much more potent and broadly neutralizing antibody with an overlapping epitope, suggests similarities that contribute to the broad recognition of human immunodeficiency virus by both antibodies. While the putative epitope for F105 shows significant overlap with that predicted for b12, it appears to differ from the b12 epitope in extending across the interface between the inner and outer domains of gp120. In contrast, the CDR loops of b12 appear to interact predominantly with the outer domain of gp120. The difference between the predicted epitopes for b12 and F105 suggests that the unique potency of b12 may arise from its ability to avoid the interface between the inner and outer domains of gp120.
An Orally Bioavailable Antipoxvirus Compound (ST-246) Inhibits Extracellular Virus Formation and Protects Mice from Lethal Orthopoxvirus Challenge
Authors: Yang Guang , Pevear Daniel C. , Davies Marc H. , Collett Marc S. , Bailey Tom , Rippen Susan , Barone Linda , Burns Chris , Rhodes Gerry , Tohan Sanjeev , Huggins John W. , Baker Robert O. , Buller R. L. Mark , Touchette Erin , Waller Kem , Schriewer Jill , Neyts Johan , DeClercq Erik , Jones Kevin , Hruby Dennis , Jordan Robert 
Published: September 2005

ABSTRACT

ST-246 is a low-molecular-weight compound (molecular weight = 376), that is potent (concentration that inhibited virus replication by 50% = 0.010 μM), selective (concentration of compound that inhibited cell viability by 50% = >40 μM), and active against multiple orthopoxviruses, including vaccinia, monkeypox, camelpox, cowpox, ectromelia (mousepox), and variola viruses. Cowpox virus variants selected in cell culture for resistance to ST-246 were found to have a single amino acid change in the V061 gene. Reengineering this change back into the wild-type cowpox virus genome conferred resistance to ST-246, suggesting that V061 is the target of ST-246 antiviral activity. The cowpox virus V061 gene is homologous to vaccinia virus F13L, which encodes a major envelope protein (p37) required for production of extracellular virus. In cell culture, ST-246 inhibited plaque formation and virus-induced cytopathic effects. In single-cycle growth assays, ST-246 reduced extracellular virus formation by 10 fold relative to untreated controls, while having little effect on the production of intracellular virus. In vivo oral administration of ST-246 protected BALB/c mice from lethal infection, following intranasal inoculation with 10× 50% lethal dose (LD
50
) of vaccinia virus strain IHD-J. ST-246-treated mice that survived infection acquired protective immunity and were resistant to subsequent challenge with a lethal dose (10× LD
50
) of vaccinia virus. Orally administered ST-246 also protected A/NCr mice from lethal infection, following intranasal inoculation with 40,000× LD
50
of ectromelia virus. Infectious virus titers at day 8 postinfection in liver, spleen, and lung from ST-246-treated animals were below the limits of detection (<10 PFU/ml). In contrast, mean virus titers in liver, spleen, and lung tissues from placebo-treated mice were 6.2 × 10
7
, 5.2 × 10
7
, and 1.8 × 10
5
PFU/ml, respectively. Finally, oral administration of ST-246 inhibited vaccinia virus-induced tail lesions in Naval Medical Research Institute mice inoculated via the tail vein. Taken together, these results validate F13L as an antiviral target and demonstrate that an inhibitor of extracellular virus formation can protect mice from orthopoxvirus-induced disease.
Mucosal and Systemic Antibody Responses in Humans Infected with Simian Foamy Virus
Authors: Cummins James E. , Boneva Roumiana S. , Switzer William M. , Christensen Logan L. , Sandstrom Paul , Heneine Walid , Chapman Louisa E. , Dezzutti Charlene S. 
Published: September 2005

ABSTRACTSimian foamy virus (SFV) infection and the subsequent immune response are not well characterized. Blood plasma, saliva, and urine were obtained from four humans and nine chimpanzees persistently infected with chimpanzee-type SFV for an unknown length of time. SFV-specific immunoglobulin G (IgG) antibodies, but not IgA antibodies, against the Gag and Bet proteins were detected, by Western blotting, in all sample types from infected humans and chimpanzees. Overall, chimpanzee samples had higher anti-SFV IgG titers than humans. These results provide a first comparative evaluation of SFV-specific host mucosal humoral immunity in infected humans and chimpanzees that is characterized by a predominant IgG response and a virtually absent IgA response.
Conjugation of Lentivirus to Paramagnetic Particles via Nonviral Proteins Allows Efficient Concentration and Infection of Primary Acute Myeloid Leukemia Cells
Authors: Chan Lucas , Nesbeth Darren , MacKey Taylor , Galea-Lauri Joanna , Gäken Joop , Martin Francisco , Collins Mary , Mufti Ghulam , Farzaneh Farzin , Darling David 
Published: September 2005

ABSTRACTNonviral producer cell proteins incorporated into retroviral vector surfaces profoundly influence infectivity and in vivo half-life. We report the purification and concentration of lentiviral vectors using these surface proteins as an efficient gene transduction strategy. Biotinylation of these proteins and streptavidin paramagnetic particle concentration enhances titer 400- to 2,500-fold (to 109CFU/ml for vesicular stomatitis virus G protein and 5 × 108for amphotropic murine leukemia virus envelope). This method also uses newly introduced membrane proteins (B7.1 and ΔLNGFR) directed to lentiviral surfaces, allowing up to 17,000-fold concentrations. Particle conjugation of lentivirus allows facile manipulation in vitro, resulting in the transduction of 48 to 94% of human acute myeloid leukemia blasts.
Maximum oxygen uptake and objectively measured physical activity in Danish children 6–7 years of age: the Copenhagen school child intervention study
Authors: Eiberg S , Hasselstrom H , Grønfeldt V , Froberg K , Svensson J , Andersen L B 
Published: September 2005

Objectives:To provide normative data on maximum oxygen uptake (V˙o2max) and physical activity in children 6–7 years of age and analyse the association between these variables.Methods:V˙o2maxwas measured in 366 boys (mean (SD) 6.8 (0.4) years of age) and 332 girls (6.7 (0.4) years of age) from preschool classes in two suburban communities in Copenhagen, during a progressive treadmill exercise. Habitual physical activity was measured with accelerometers.Results:Boys had higher V˙o2maxboth in absolute values (1.19 (0.18)v1.06 (0.16) litres/min (+11%), p<0.001) and relative to body weight (48.5 (6.0)v44.8 (5.6) ml/kg/min (+8%); p<0.001) than girls. The difference in V˙o2maxbetween boys and girls decreased to +2% when expressed relative to lean body mass (LBM). Absolute V˙o2maxwas related to LBM, body mass, and stature (all p<0.001). Boys were more physically active than girls (mean counts +9.4%, p<0.001), and even when boys and girls with the same V˙o2maxwere compared, boys were more active. The difference in physical activity between the sexes was higher when sustained activity of higher intensity was compared.Conclusions:V˙o2maxis higher in boys than girls (+11%), even when related to body mass (+8%) and LBM (+2%). Most of the difference in V˙o2maxrelative to body mass was explained by the larger percentage body fat in girls. When boys and girls with the same V˙o2maxwere compared, boys engaged in more minutes of exercise of at least moderate intensity.
Establishment of a protocol to test fatigue of the trunk muscles
Authors: Corin G , Strutton P H , McGregor A H 
Published: September 2005

Background:Muscle fatigue has high relevance in human performance yet little research has evaluated how it should be assessed.Objective:To perform a pilot study to identify suitable methods of generating and assessing fatigue of the trunk flexor and extensor muscles.Methods:Sixteen university rugby players (mean (SEM) age 21.9 (0.2) years) were recruited and subjected to four protocols (A, B, C, D), separated by a week to allow recovery, with peak torque being recorded during each test: A, isokinetic measurements before and after fatigue, with a 10 repetition isokinetic fatigue period; B, isokinetic measurements before and after fatigue with a 45 second isometric fatigue period; C, isometric measurements before and after fatigue with a 10 repetition isokinetic fatigue period; D, isometric measurements before and after fatigue with a 45 second isometric fatigue period. All were conducted during flexion and extension of the trunk on the Cybex Norm Isokinetic Dynamometer trunk flexion-extension unit.Results:All subjects completed all four protocols. Fatigue induction appeared more effective in flexion than extension. Significant differences in mean peak torque before and after fatigue were seen in protocols A, B, and D in flexion and only in protocol D for extension. In flexion, protocol D produced the greatest fatigue, peak torque being 16.2% less after than before fatigue, suggesting greatest sensitivity.Conclusions:Protocol D, which incorporates isometric testing and fatigue protocols, appears to be able to produce fatigue most effectively, and therefore may provide the most valid assessment of fatigue in the trunk flexor and extensor muscles.
Effect of anticipation during unknown or unexpected exercise duration on rating of perceived exertion, affect, and physiological function
Authors: Baden D A , McLean T L , Tucker R , Noakes T D , St Clair Gibson A 
Published: September 2005

Objectives:To determine the effect of unknown exercise duration and an unexpected increase in exercise duration on rating of perceived exertion (RPE), affect, and running economy during treadmill running.Methods:Sixteen well trained male and female runners completed three bouts of treadmill running at 75% of their peak treadmill running speed. In the first trial, they were told to run for 20 minutes and were stopped at 20 minutes (20 MIN). In another trial, they were told to run for 10 minutes, but at 10 minutes were told to run for a further 10 minutes (10 MIN). In the final trial, they were not told for how long they would be running but were stopped after 20 minutes (unknown, UN). During each of the running bouts, RPE, oxygen consumption (ml/kg/min), heart rate (beats/min), stride frequency (min−1), affect scores (arbitrary units), and attentional focus (percentage associative thought scores) were recorded.Results:RPE increased significantly between 10 and 11 minutes in the 10 MIN compared with the 20 MIN and UN trials (p<0.05). The affect score decreased significantly between 10 and 11 minutes in the 10 MIN compared with the 20 MIN trial (p<0.05). Running economy, as measured by oxygen consumption, was significantly lower in the UN compared with the 20 MIN trial from 10 to 19 minutes (p<0.05).Conclusions:The change in RPE between 10 and 11 minutes in the 10 MIN trial suggests that RPE is not purely a measure of physical exertion, as treadmill speed was maintained at a constant pace both before and after the unexpected increase in exercise duration. The associated changes in affect score at similar times in the 10 MIN trial supports the hypothesis that RPE has an affective component.