bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship of Pleconaril Susceptibility and Clinical Outcomes in Treatment of Common Colds Caused by Rhinoviruses
Authors: Pevear Daniel C. , Hayden Frederick G. , Demenczuk Tina M. , Barone Linda R. , McKinlay Mark A. , Collett Marc S. 
Published: October 2005

ABSTRACTPleconaril, a specific inhibitor of human picornaviruses, showed therapeutic efficacy against community-acquired colds caused by rhinoviruses in two placebo-controlled trials. Virological assessments were conducted during these trails, including virus culture and drug susceptibility testing. Nasal mucus samples collected from the enrolled patients were tested for the presence of picornavirus by reverse transcriptase PCR and culture. In total, 827 baseline nasal mucus samples were positive by virus culture (420 in the placebo group and 407 in the pleconaril group). Pleconaril treatment was associated with a more rapid loss of culturable virus. By study day 3, the number of samples positive by culture fell to 282 for the placebo-treated subjects and 202 for the pleconaril-treated subjects (P< 0.0001); and by day 6, the number of samples in the two groups positive by culture fell to 196 and 165, respectively (P= 0.07). The clinical benefit correlated strongly with the pleconaril susceptibility of the baseline virus isolate. Pleconaril-treated subjects infected with the more highly susceptible viruses (50% effective concentration ≤ 0.38 μg/ml) experienced a median 1.9- to 3.9-day reduction in symptom duration compared with that for the placebo-treated subjects. By contrast, subjects whose baseline virus isolate susceptibility was >0.38 μg/ml did not benefit from pleconaril treatment. These results indicate that the magnitude of symptomatic improvement in pleconaril-treated subjects with community-acquired colds is related to the drug susceptibility of the infecting virus, clearly linking the antiviral effects of the drug to clinical efficacy. Postbaseline virus isolates with reduced susceptibility or full resistance to pleconaril were recovered from 10.7% and 2.7% of drug-treated subjects, respectively. These patients shed low levels of virus and had no unusual clinical outcomes. Nevertheless, studies on the biologic properties and transmissibility of these variant viruses are warranted.
TAK-652 Inhibits CCR5-Mediated Human Immunodeficiency Virus Type 1 Infection In Vitro and Has Favorable Pharmacokinetics in Humans
Authors: Baba Masanori , Takashima Katsunori , Miyake Hiroshi , Kanzaki Naoyuki , Teshima Koichiro , Wang Xin , Shiraishi Mitsuru , Iizawa Yuji 
Published: October 2005

ABSTRACT

The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1α (MIP-1α), and MIP-1β to CCR5-expressing cells at nanomolar concentrations. TAK-652 could also suppress the binding of monocyte chemotactic protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on ligand binding to other chemokine receptors was limited. TAK-652 was active against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4) HIV-1. The compound was active against R5 HIV-1 clinical isolates containing reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50% effective concentration (EC
50
) and EC
90
of 0.061 and 0.25 nM, respectively. In addition, recombinant R5 viruses carrying different subtype (A to G) envelope proteins were equally susceptible to TAK-652. A single oral administration of TAK-652 up to 100 mg was safe and well tolerated in humans. The compound displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml (9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a promising candidate as a novel entry inhibitor of HIV-1.
Expression of the
mef
(E) Gene Encoding the Macrolide Efflux Pump Protein Increases in
Streptococcus pneumoniae
with Increasing Resistance to Macrolides
Authors: Wierzbowski Aleksandra K. , Boyd Dave , Mulvey Michael , Hoban Daryl J. , Zhanel George G. 
Published: October 2005

ABSTRACT

Active macrolide efflux is a major mechanism of macrolide resistance in
Streptococcus pneumoniae
in many parts of the world, especially North America. In Canada, this active macrolide efflux in
S. pneumoniae
is predominantly due to acquisition of the
mef
(E) gene. In the present study, we assessed the
mef
(E) gene sequence as well as
mef
(E) expression in variety of low- and high-level macrolide-resistant, clindamycin-susceptible (M-phenotype)
S. pneumoniae
isolates (erythromycin MICs, 1 to 32 μg/ml; clindamycin MICs, ≤0.25 μg/ml). Southern blot hybridization with
mef
(E) probe and EcoRI digestion and relative real-time reverse transcription-PCR were performed to study the
mef
(E) gene copy number and expression. Induction of
mef
(E) expression was analyzed by Etest susceptibility testing pre- and postincubation with subinhibitory concentrations of erythromycin, clarithromycin, azithromycin, telithromycin, and clindamycin. The macrolide efflux gene,
mef
(E), was shown to be a single-copy gene in all 23 clinical
S. pneumoniae
isolates tested, and expression post-macrolide induction increased 4-, 6-, 20-, and 200-fold in isolates with increasing macrolide resistance (erythromycin MICs 2, 4, 8, and 32 μg/ml, respectively). Sequencing analysis of the macrolide efflux genetic assembly (mega) revealed that
mef
(E) had a 16-bp deletion 153 bp upstream of the putative start codon in all 23 isolates. A 119-bp intergenic region between
mef
(E) and
mel
was sequenced, and a 99-bp deletion was found in 11 of the 23 M-phenotype
S. pneumoniae
isolates compared to the published mega sequence. However, the
mef
(E) gene was fully conserved among both high- and low-level macrolide-resistant isolates. In conclusion, increased expression of
mef
(E) is associated with higher levels of macrolide resistance in macrolide-resistant
S. pneumoniae.
A Class of Pantothenic Acid Analogs Inhibits
Plasmodium falciparum
Pantothenate Kinase and Represses the Proliferation of Malaria Parasites
Authors: Spry Christina , Chai Christina L. L. , Kirk Kiaran , Saliba Kevin J. 
Published: October 2005

ABSTRACT

The growth and proliferation of the human malaria parasite
Plasmodium falciparum
are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B
5
). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic
P. falciparum
parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 μM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with

K
i

values in the nanomolar range.
Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5
Authors: Nishikawa Masao , Takashima Katsunori , Nishi Toshiya , Furuta Rika A. , Kanzaki Naoyuki , Yamamoto Yoshio , Fujisawa Jun-ichi 
Published: October 2005

ABSTRACT
G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.
Activities of Flucytosine, Fluconazole, Amphotericin B, and Micafungin in a Murine Model of Disseminated Infection by
Candida glabrata
Authors: Mariné Marçal , Serena Carolina , Fernández-Torres Belkys , Pastor F. Javier , Guarro Josep 
Published: October 2005

ABSTRACT

We compared the efficacies of amphotericin B, fluconazole, flucytosine, and micafungin in a systemic murine infection by three isolates of
Candida glabrata.
Amphotericin B showed the best results, although none of the drugs dramatically reduced mortality or tissue burden in liver or spleen.
AmpC and OprD Are Not Involved in the Mechanism of Imipenem Hypersusceptibility among
Pseudomonas aeruginosa
Isolates Overexpressing the
mexCD
-
oprJ
Efflux Pump
Authors: Wolter Daniel J. , Hanson Nancy D. , Lister Philip D. 
Published: October 2005

ABSTRACT

Pseudomonas aeruginosa
strains that overexpress
mexCD
-
oprJ
become hypersusceptible to imipenem. Disruption of AmpC induction has been suggested to cause this phenotype. However, data from this study demonstrate that hypersusceptibility to imipenem can develop without changes in
ampC
expression or AmpC activity. Furthermore, hypersusceptibility is not caused by changes in expression of the outer membrane porin, OprD.
Differential Antibiotic Susceptibilities of Starved
Mycobacterium tuberculosis
Isolates
Authors: Xie Zhifang , Siddiqi Noman , Rubin Eric J. 
Published: October 2005

ABSTRACT

We compared the efficacies of 17 agents against rapidly growing and starved
Mycobacterium tuberculosis
H37Rv. Few compounds have significant activity at attainable concentrations. However, two phenothiazine compounds at similar concentrations were bactericidal for starved and growing cells. These drugs appear to target a process important in both replicating and nonreplicating bacteria.
Impact of Mass Distribution of Azithromycin on the Antibiotic Susceptibilities of Ocular
Chlamydia trachomatis
Authors: Solomon Anthony W. , Mohammed Zeena , Massae Patrick A. , Shao John F. , Foster Allen , Mabey David C. W. , Peeling Rosanna W. 
Published: October 2005

ABSTRACT

In a community of Tanzania where trachoma is endemic, we cultured conjunctival swabs from all residents who had active trachoma and were PCR positive for ocular
Chlamydia trachomatis
, both before (43 isolates) and 2 months after (9 isolates) mass antibiotic treatment. No clinically or programmatically significant increase in azithromycin or tetracycline resistance was observed.
Gene Silencing and Overexpression of Porcine Peptidoglycan Recognition Protein Long Isoforms: Involvement in β-Defensin-1 Expression
Authors: Sang Yongming , Ramanathan Balaji , Ross Christopher R. , Blecha Frank 
Published: October 2005

ABSTRACTPeptidoglycan recognition proteins (PGRPs) are a group of newly identified proteins with emerging functions in mammalian innate immunity. Here we report the identification and characterization of two long isoforms of porcine PGRP. Their complete cDNA sequences encode predicted peptides of 252 and 598 residues and are named pPGRP-L1 and pPGRP-L2, respectively. These porcine isoforms share identical PGRP domains at their C terminus, which are highly conserved with human and mouse orthologs. pPGRP-L1 is expressed constitutively in several tissues, including bone marrow, intestine, liver, spleen, kidney, and skin. pPGRP-L2 is highly expressed in the duodenum and liver, and expression in intestinal tissues is increased bySalmonellainfection. In intestinal cells, expression of both pPGRP-L1 and pPGRP-L2 is increased by bacterial infection. Recombinant pPGRP-L1 and pPGRP-L2 haveN-acetylmuramoyl-L-alanine amidase activity. Loss-of-function and gain-of-function experiments indicate that these two pPGRPs are involved in expression of the antimicrobial peptide β-defensin-1. Silencing of pPGRP-L2 in intestinal cells challenged withListeria monocytogenesresults in downregulation of β-defensin-1. Conversely, overexpression of pPGRP-L1 or pPGRP-L2 dramatically upregulates expression of β-defensin-1. Collectively, these findings suggest that porcine PGRPs are involved in antimicrobial peptide expression.
Identification of
gmhA
, a
Yersinia pestis
Gene Required for Flea Blockage, by Using a
Caenorhabditis elegans
Biofilm System
Authors: Darby Creg , Ananth Sandya L. , Tan Li , Hinnebusch B. Joseph 
Published: October 2005

ABSTRACT

Yersinia pestis
, the cause of bubonic plague, blocks feeding by its vector, the flea. Recent evidence indicates that blockage is mediated by an in vivo biofilm.
Y. pestis
and the closely related
Yersinia pseudotuberculosis
also make biofilms on the cuticle of the nematode
Caenorhabditis elegans
, which block this laboratory animal's feeding. Random screening of
Y. pseudotuberculosis
transposon insertion mutants with a
C. elegans
biofilm assay identified
gmhA
as a gene required for normal biofilms.
gmhA
encodes phosphoheptose isomerase, an enzyme required for synthesis of heptose, a conserved component of lipopolysaccharide and lipooligosaccharide. A
Y. pestis gmhA
mutant was constructed and was severely defective for
C. elegans
biofilm formation and for flea blockage but only moderately defective in an in vitro biofilm assay. These results validate use of the
C. elegans
biofilm system to identify genes and pathways involved in
Y. pestis
flea blockage.
Studies of Fibronectin-Binding Proteins of
Streptococcus equi
Authors: Lannergård Jonas , Flock Margareta , Johansson Staffan , Flock Jan-Ingmar , Guss Bengt 
Published: October 2005

ABSTRACT

Streptococcus equi
subsp.
equi
is the causative agent of strangles, a disease of the upper respiratory tract in horses. The initiation of
S. equi
subsp.
equi
infection is likely to involve cell surface-anchored molecules mediating bacterial adhesion to the epithelium of the host. The present study describes the cloning and characterization of FNEB, a fibronectin-binding protein with cell wall-anchoring motifs. FNEB can thus be predicted as cell surface located, contrary to the two previously characterized fibronectin-binding proteins in
S. equi
subsp.
equi
, FNE and SFS. Assays of antibody titers in horses and in experimentally infected mice indicate that the protein is immunogenic and expressed in vivo during
S. equi
subsp.
equi
infection. Using Western ligand blotting, it was shown that FNEB binds to the N-terminal 29-kDa fragment of fibronectin, while SFS and FNE both bind to the adjacent 40-kDa fragment.
S. equi
subsp.
equi
is known to bind fibronectin to a much lower degree than the closely related
S. equi
subsp.
zooepidemicus
, but the binding is primarily directed to the 29-kDa fragment. Inhibition studies using
S. equi
subsp.
equi
cells indicate that FNEB mediates cellular binding to fibronectin in this species.
LruA and LruB, Novel Lipoproteins of PathogenicLeptospira interrogansAssociated with Equine Recurrent Uveitis
Authors: Verma Ashutosh , Artiushin Sergey , Matsunaga James , Haake David A. , Timoney John F. 
Published: October 2005

ABSTRACTRecurrent uveitis as a sequela toLeptospirainfection is the most common infectious cause of blindness and impaired vision of horses worldwide. Leptospiral proteins expressed during prolonged survival in the eyes of horses with lesions of chronic uveitis were identified by screening a phage library ofLeptospira interrogansDNA fragments with eye fluids from uveitic horses. Inserts of reactive phages encoded several known leptospiral proteins and two novel putative lipoproteins, LruA and LruB. LruA was intrinsically labeled during incubation ofL. interrogansin medium containing [14C]palmitic acid, confirming that it is a lipoprotein.lruAandlruBwere detected by Southern blotting in infectiousLeptospira interrogansbut not in nonpathogenicLeptospira biflexa. Fractionation data from culturedLeptospiraindicate that LruA and LruB are localized in the inner membrane. Uveitic eye fluids contained significantly higher levels of immunoglobulin A (IgA) and IgG specific for each protein than did companion sera, indicating strong local antibody responses. Moreover, LruA- and LruB-specific antisera reacted with equine ocular components, suggesting an immunopathogenic role in leptospiral uveitis.
Selection of Protective Epitopes for
Brucella melitensis
by DNA Vaccination
Authors: Yang Xinghong , Hudson Mary , Walters Nancy , Bargatze Robert F. , Pascual David W. 
Published: October 2005

ABSTRACT

The
Brucella melitensis
16M genome was examined for proteins in excess of 100 amino acids and for immunogenicity-associated genes. One subset of 32 annotated genes or open reading frames was identified, and each of these were cloned into the eukaryotic vector pcDNA3.1. Purified recombinant plasmids were used to intramuscularly (i.m.) immunize BALB/c mice. After challenge with
B. melitensis
16M strain, two protective antigens were found: the periplasmic protein, bp26, and the chaperone protein, trigger factor (TF). Protective efficacy was confirmed with DNA vaccines for these two
B. melitensis
proteins and, when combined, protection against wild-type challenge was significantly enhanced. Both proteins were found to be immunogenic since elevated serum immunoglobulin G (IgG) antibodies without a specific IgG subclass bias were induced subsequent to i.m. DNA immunization. Antigen-restimulation assays revealed that bp26 and TF stimulated gamma interferon and only bp26 induced interleukin-4 (IL-4), IL-5, and IL-6 cytokines as measured by cytokine enzyme-linked immunospot assay. These collective results suggest that both bp26 and TF are excellent candidates for use in future vaccination studies against brucellosis.
Endotoxin Priming Improves Clearance ofPseudomonas aeruginosain Wild-Type and Interleukin-10 Knockout Mice
Authors: Varma Tushar K. , Durham Megan , Murphey Erle D. , Cui Weihua , Huang Zhiyu , Lin Cheng Y. , Toliver-Kinsky Tracy , Sherwood Edward R. 
Published: October 2005

ABSTRACTEndotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-γ) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogenPseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance ofPseudomonas aeruginosawas measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-γ and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-γ and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice clearedPseudomonas aeruginosafrom lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearingPseudomonas aeruginosaafter systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance ofPseudomonas aeruginosaand that this effect was augmented by neutralization of IL-10.
Borrelia burgdorferiRegulates Expression of Complement Regulator-Acquiring Surface Protein 1 during the Mammal-Tick Infection Cycle
Authors: von Lackum Kate , Miller Jennifer C. , Bykowski Tomasz , Riley Sean P. , Woodman Michael E. , Brade Volker , Kraiczy Peter , Stevenson Brian , Wallich Reinhard 
Published: October 2005

ABSTRACTDuring the natural mammal-tick infection cycle, the Lyme disease spirocheteBorrelia burgdorfericomes into contact with components of the alternative complement pathway.B. burgdorferi, like many other human pathogens, has evolved the immune evasion strategy of binding two host-derived fluid-phase regulators of complement, factor H and factor H-like protein 1 (FHL-1). The borrelial complement regulator-acquiring surface protein 1 (CRASP-1) is a surface-exposed lipoprotein that binds both factor H and FHL-1. Analysis of CRASP-1 expression during the mammal-tick infectious cycle indicated thatB. burgdorferiexpresses this protein during mammalian infection, supporting the hypothesized role for CRASP-1 in immune evasion. However, CRASP-1 synthesis was repressed in bacteria during colonization of vector ticks. Analysis of cultured bacteria indicated that CRASP-1 is differentially expressed in response to changes in pH. Comparisons of CRASP-1 expression patterns with those of other infection-associatedB. burgdorferiproteins, including the OspC, OspA, and Erp proteins, indicated that each protein is regulated through a unique mechanism.
Murine Macrophages Kill the Vegetative Form of
Bacillus anthracis
Authors: Kang Tae Jin , Fenton Matthew J. , Weiner Matthew A. , Hibbs Stephen , Basu Subhendu , Baillie Les , Cross Alan S. 
Published: October 2005

ABSTRACT

Anti-protective antigen antibody was reported to enhance macrophage killing of ingested
Bacillus anthracis
spores, but it was unclear whether the antibody-mediated macrophage killing mechanism was directed against the spore itself or the vegetative form emerging from the ingested and germinating spore. To address this question, we compared the killing of germination-proficient (gp) and germination-deficient (Δ
gerH
) Sterne 34F2 strain spores by murine peritoneal macrophages. While macrophages similarly ingested both spores, only gp Sterne was killed at 5 h (0.37 log kill). Pretreatment of macrophages with gamma interferon (IFN-γ) or opsonization with immunoglobulin G (IgG) isolated from a subject immunized with an anthrax vaccine enhanced the killing of Sterne to 0.49 and 0.73 log, respectively, but the combination of IFN-γ and IgG was no better than either treatment alone. Under no condition was there killing of Δ
gerH
spores. To examine the ability of the exosporium to protect spores from macrophages, we compared the macrophage-mediated killing of nonsonicated (exosporium
+
) and sonicated (exosporium
−
) Sterne 34F2 spores. More sonicated spores than nonsonicated spores were killed at 5 h (0.98 versus 0.37 log kill, respectively). Pretreatment with IFN-γ increased the sonicated spore killing to 1.39 log. However, the opsonization with IgG was no better than no treatment or pretreatment with IFN-γ. We conclude that macrophages appear unable to kill the spore form of
B. anthracis
and that the exosporium may play a role in the protection of spores from macrophages.