bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of BAL5788, a Prodrug of Cephalosporin BAL9141, in a Mouse Model of Acute Pneumococcal Pneumonia
Authors: Azoulay-Dupuis E. , Bédos J. P. , Mohler J. , Schmitt-Hoffmann A. , Schleimer M. , Shapiro S. 
Published: March 2004

ABSTRACT

BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10
7
CFU of clinical
Streptococcus pneumoniae
strains P-52181 (Pen
s
Cro
s
Ctx
s
), P-15986 (Pen
r
Cro
s
Ctx
s
), P-40422 (Pen
r
Cro
r
Ctx
r
), and P-40984 (Pen
r
Cro
r
Ctx
r
). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%;
P
< 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (
T
> MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of
T
> MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.
Aspergillus fumigatusVariant with Decreased Susceptibility to Multiple Antifungals
Authors: Balajee S. Arunmozhi , Weaver Molly , Imhof Alexander , Gribskov Jennifer , Marr Kieren A. 
Published: March 2004

ABSTRACTIsolates ofAspergillus fumigatusthat demonstrate resistance to itraconazole (ITZ) have been described previously; however, the prevalence and clinical significance of ITZ resistance are not completely understood. In this study we assessed the ITZ susceptibilities of 128A. fumigatusisolates that caused invasive infection in 82 stem cell transplant patients before and after the use of ITZ in our institution (study period, 1991 to 2000). The MICs for 10 isolates obtained from seven patients were high, ≥1 μg/ml. The average ITZ MIC increased after institutional use of the drug began in 1995. The majority of the isolates for which MICs were high (6 of 10) and one isolate for which the MIC was low (0.06 μg/ml) demonstrated an unusual phenotype, appearing as predominantly white colonies. For all seven atypical isolates, voriconazole MICs were high (≥2 μg/ml), and minimal effective concentrations of caspofungin were high (≥4 μg/ml). For two of the seven atypical isolates, amphotericin B MICs were high (≥2 μg/ml). The isolates appeared white due to slow sporulation; however, after prolonged incubations, the isolates sporulated with no difference in conidial color or conidiophore morphology compared with typical isolates. Randomly amplified polymorphic DNA-PCR patterns of these isolates were distinct compared with those of otherA. fumigatusisolates. Sequencing of 18S rRNA genes confirmed that all wereA. fumigatus; however, the mitochondrial cytochromebgene sequences of all the atypical isolates were unique. These data suggest the potential presence of a genetically unique, poorly sporulating variant ofA. fumigatusthat demonstrates decreased susceptibilities to several antifungals.
Dissemination of CTX-M-Type β-Lactamases among Clinical Isolates of
Enterobacteriaceae
in Paris, France
Authors: Eckert C. , Gautier V. , Saladin-Allard M. , Hidri N. , Verdet C. , Ould-Hocine Z. , Barnaud G. , Delisle F. , Rossier A. , Lambert T. , Philippon A. , Arlet G. 
Published: March 2004

ABSTRACT

We analyzed 19 clinical isolates of the family
Enterobacteriaceae
(16
Escherichia coli
isolates and 3
Klebsiella pneumoniae
isolates) collected from four different hospitals in Paris, France, from 2000 to 2002. These strains had a particular extended-spectrum cephalosporin resistance profile characterized by a higher level of resistance to cefotaxime and aztreonam than to ceftazidime. The
bla
CTX-M
genes encoding these β-lactamases were involved in this resistance, with a predominance of
bla
CTX-M-15
. Ten of the 19 isolates produced both TEM-1- and CTX-M-type enzymes. One strain (
E. coli
TN13) expressed CMY-2, TEM-1, and CTX-M-14.
bla
CTX-M
genes were found on large plasmids. In 15 cases the same insertion sequence, IS
Ecp1
, was located upstream of the 5′ end of the
bla
CTX-M
gene. In one case we identified an insertion sequence designated IS
26
. Examination of the other three
bla
CTX-M
genes by cloning, sequencing, and PCR analysis revealed the presence of a complex
sul1
-type integron that includes open reading frame ORF513, which carries the
bla
gene and the surrounding DNA. Five isolates had the same plasmid DNA fingerprint, suggesting clonal dissemination of CTX-M-15-producing strains in the Paris area.
Comparative Activities of Doripenem versus Isolates, Mutants, and Transconjugants of
Enterobacteriaceae
and
Acinetobacter
spp. with Characterized β-Lactamases
Authors: Mushtaq Shazad , Ge Yigong , Livermore David M. 
Published: March 2004

ABSTRACT

Doripenem (S-4661), a new parenteral carbapenem, was tested against over 250 clinical isolates, mutants, and transconjugants of
Enterobacteriaceae
and
Acinetobacter
spp., selected or derived for their β-lactamase expression characteristics. Imipenem, meropenem, and ertapenem were tested as comparators, along with cephalosporins and piperacillin-tazobactam, by using National Committee for Clinical Laboratory Standards agar dilution methodology. Doripenem MICs were from 0.03 to 0.25 μg/ml for
Klebsiella
isolates, irrespective of the presence of extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC or hyperproduced K1 β-lactamase. Similarly, MICs of doripenem for both AmpC-inducible and -derepressed
Enterobacter
isolates were 0.06 to 0.5 μg/ml. ESBL production did not raise the MICs of doripenem for
Escherichia coli
transconjugants, and studies with known expression mutants confirmed that neither inducible nor depressed AmpC β-lactamase expression was protective in
Enterobacter cloacae
,
Citrobacter freundii
,
Serratia marcescens
, or
Morganella morganii
. In all of these respects, doripenem resembled meropenem and imipenem, whereas the MICs of ertapenem were raised (but still ≤1 μg/ml) for many ESBL-producing klebsiellas and AmpC-derepressed
E. cloacae
and
C. freundii
strains. Resistance to all carbapenems, including doripenem (MICs of mostly 16 to 64 μg/ml, compared with 0.25 to 1 μg/ml for typical strains), was seen in
Acinetobacter
isolates with metallo-β-lactamases or OXA-carbapenemases. Isolates of
Klebsiella
and
Serratia
spp. with IMP, KPC, and SME β-lactamases also were resistant to doripenem (MICs, 8 to >64 μg/ml) and to other carbapenems, although the continued apparent susceptibility (MICs, ≤0.5 μg/ml) of
E. coli
derivatives with cloned IMP-1 and NMC-A β-lactamases suggested that carbapenem resistance might require other factors besides the enzymes.
Transactivator Protein BICP0 of Bovine Herpesvirus 1 (BHV-1) Is Blocked by Prostaglandin D2(PGD2), Which Points to a Mechanism for PGD2-Mediated Inhibition of BHV-1 Replication
Authors: Saydam Okay , Abril Carlos , Vogt Bernd , Ackermann Mathias , Schwyzer Martin 
Published: March 2004

ABSTRACTThe immediate-early protein, BICP0, of bovine herpesvirus 1 (BHV-1) transactivates a variety of viral and cellular genes. In a yeast two-hybrid cDNA library screening, we found that lipocalin-type prostaglandin D synthase, which catalyzes the production of prostaglandin D2(PGD2), is a cellular target of BICP0. We observed that, during wild-type BHV-1 infection, PGD2levels were increased intracellularly and decreased in the medium. These effects were absent upon infection with recombinant BHV-1 expressing β-galactosidase instead of BICP0 (A2G2). Transient-expression assays showed that BICP0 alone caused a significant increase in PGD2levels in the cell. PGD2repressed BHV-1 replication in cultured cells. Antiviral activities of prostaglandins have been documented long ago, but their mode of action remains to be clarified. Here we provide evidence that PGD2impairs the transactivation ability of BICP0 that is necessary for efficient virus replication.
Long-Lived Poxvirus Immunity, Robust CD4 Help, and Better Persistence of CD4 than CD8 T Cells
Authors: Amara Rama Rao , Nigam Pragati , Sharma Sunita , Liu Jinyan , Bostik Vanda 
Published: March 2004

ABSTRACT
The currently used smallpox vaccine is associated with a high incidence of adverse events, and there is a serious need for a safe and effective alternative vaccine. Here, we carried out a longitudinal evaluation of vaccinia virus-specific CD4 and CD8 T cells in smallpox-vaccinated individuals by using a highly sensitive intracellular cytokine staining assay. Our results demonstrate that, in addition to the CD8 response, the smallpox vaccinations raised a robust CD4 response with a Th1-dominant cytokine profile. These CD4 T cells were stable and exhibited only a twofold contraction between peak effector and memory phases compared with an approximate sevenfold contraction for CD8 cells. A significant proportion of vaccinated individuals lost detectable CD8 memory while maintaining CD4 memory. After a booster immunization, these individuals generated a robust CD8 response, which some of them rapidly lost. Thus, the current smallpox vaccine provides long-lasting CD4 help that may be critical for long-lived B-cell memory. We suggest that the provision of adequate CD4 help for CD8 and humoral effector functions will be critical to the success of the next generation of smallpox vaccines.
RoXaN, a Novel Cellular Protein Containing TPR, LD, and Zinc Finger Motifs, Forms a Ternary Complex with Eukaryotic Initiation Factor 4G and Rotavirus NSP3
Authors: Vitour Damien , Lindenbaum Pierre , Vende Patrice , Becker Michelle M. , Poncet Didier 
Published: March 2004

ABSTRACT
Rotavirus mRNAs are capped but not polyadenylated, and viral proteins are translated by the cellular translation machinery. This is accomplished through the action of the viral nonstructural protein NSP3, which specifically binds the 3′ consensus sequence of viral mRNAs and interacts with the eukaryotic translation initiation factor eIF4G I. To further our understanding of the role of NSP3 in rotavirus replication, we looked for other cellular proteins capable of interacting with this viral protein. Using the yeast two-hybrid assay, we identified a novel cellular protein-binding partner for rotavirus NSP3. This 110-kDa cellular protein, named RoXaN (rotavirus X protein associated with NSP3), contains a minimum of three regions predicted to be involved in protein-protein or nucleic acid-protein interactions. A tetratricopeptide repeat region, a protein-protein interaction domain most often found in multiprotein complexes, is present in the amino-terminal region. In the carboxy terminus, at least five zinc finger motifs are observed, further suggesting the capacity of RoXaN to bind other proteins or nucleic acids. Between these two regions exists a paxillin leucine-aspartate repeat (LD) motif which is involved in protein-protein interactions. RoXaN is capable of interacting with NSP3 in vivo and during rotavirus infection. Domains of interaction were mapped and correspond to the dimerization domain of NSP3 (amino acids 163 to 237) and the LD domain of RoXaN (amino acids 244 to 341). The interaction between NSP3 and RoXaN does not impair the interaction between NSP3 and eIF4G I, and a ternary complex made of NSP3, RoXaN, and eIF4G I can be detected in rotavirus-infected cells, implicating RoXaN in translation regulation.
Superinfection Prevents Recombination of the Alphaherpesvirus Bovine Herpesvirus 1
Authors: Meurens François , Schynts Frédéric , Keil Günther M. , Muylkens Benoît , Vanderplasschen Alain , Gallego Pierre , Thiry Etienne 
Published: March 2004

ABSTRACTHomologous recombination between strains of the same alphaherpesvirus species occurs frequently both in vitro and in vivo. This process has been described between strains of herpes simplex virus type 1, herpes simplex virus type 2, pseudorabies virus, feline herpesvirus 1, varicella-zoster virus, and bovine herpesvirus 1 (BoHV-1). In vivo, the rise of recombinant viruses can be modulated by different factors, such as the dose of the inoculated viruses, the distance between inoculation sites, the time interval between inoculation of the first and the second virus, and the genes in which the mutations are located. The effect of the time interval between infections with two distinguishable BoHV-1 on recombination was studied in three ways: (i) recombination at the level of progeny viruses, (ii) interference induced by the first virus infection on β-galactosidase gene expression of a superinfecting virus, and (iii) recombination at the level of concatemeric DNA. A time interval of 2 to 8 h between two successive infections allows the establishment of a barrier, which reduces or prevents any successful superinfection needed to generate recombinant viruses. The dramatic effect of the time interval on the rise of recombinant viruses is particularly important for the risk assessment of recombination between glycoprotein E-negative marker vaccine and field strains that could threaten BoHV-1 control and eradication programs.
Identification of Epstein-Barr Virus (EBV) Nuclear Antigen 2 (EBNA2) Target Proteins by Proteome Analysis: Activation of EBNA2 in Conditionally Immortalized B Cells Reflects Early Events after Infection of Primary B Cells by EBV
Authors: Schlee Martin , Krug Tanja , Gires Olivier , Zeidler Reinhard , Hammerschmidt Wolfgang , Mailhammer Reinhard , Laux Gerhard , Sauer Guido , Lovric Josip , Bornkamm Georg W. 
Published: March 2004

ABSTRACTThe Epstein-Barr virus (EBV) is a ubiquitous B-lymphotropic herpesvirus associated with several malignant tumors, e.g., Burkitt's lymphoma and Hodgkin's disease, and is able to efficiently immortalize primary B lymphocytes in vitro. The growth program of infected B cells is initiated and maintained by the viral transcription factor EBV nuclear antigen 2 (EBNA2), which regulates viral and cellular genes, including the proto-oncogene c-myc. In our study, patterns of protein expression in B cells with and without EBNA2 were analyzed by two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. For this purpose, we used a conditional immortalization system for EBV, a B cell line (EREB2-5) that expresses an estrogen receptor-EBNA2 fusion protein. In order to discriminate downstream targets of c-Myc from c-Myc-independent EBNA2 targets, we used an EREB2-5-derived cell line, P493-6, in which c-Myc is expressed under the control of a tetracycline-regulated promoter. Of 20 identified EBNA2 target proteins, 11 were c-Myc dependent and therefore most probably associated with proliferation, and one of these proteins was a posttranslationally modified protein, i.e., hypusinylated eIF5a. Finally, to estimate the relevance of EBNA2 targets during early EBV infection, we analyzed the proteomes of primary B cells before and after infection with EBV. The protein expression pattern induced upon EBV infection was similar to that following EBNA2 activation. These findings underscore the value of EREB2-5 cells as an appropriate model system for the analysis of early events in the process of EBV-mediated B-cell immortalization.
Selective Modification of Variable Loops Alters Tropism and Enhances Immunogenicity of Human Immunodeficiency Virus Type 1 Envelope
Authors: Yang Zhi-yong , Chakrabarti Bimal K. , Xu Ling , Welcher Brent , Kong Wing-pui , Leung Kwanyee , Panet Amos , Mascola John R. , Nabel Gary J. 
Published: March 2004

ABSTRACTAlthough the B clade of human immunodeficiency virus type 1 (HIV-1) envelopes (Env) includes five highly variable regions, each of these domains contains a subset of sequences that remain conserved. The V3 loop has been much studied for its ability to elicit neutralizing antibodies, which are often restricted to a limited number of closely related strains, likely because a large number of antigenic structures are generated from the diverse amino acid sequences in this region. Despite these strain-specific determinants, subregions of V3 are highly conserved, and the effects of different portions of the V3 loop on Env tropism and immunogenicity have not been well delineated. For this report, selective deletions in V3 were introduced by shortening of the stem of the V3 loop. These mutations were explored in combination with deletions of selected V regions. Progressive shortening of the stem of V3 abolished the immunogenicity as well as the functional activity of HIV Env; however, two small deletions on both arms of the V3 stem altered the tropism of the dualtropic 89.6P viral strain so that it infected only CXCR4+cells. When this smaller deletion was combined with removal of the V1 and V2 loops and used as an immunogen in guinea pigs, the antisera were able to neutralize multiple independent clade B isolates with a higher potency. These findings suggest that highly conserved subregions within V3 may be relevant targets for eliciting neutralizing antibody responses, affecting HIV tropism, and increasing the immunogenicity of AIDS vaccines.
Herpes Simplex Virus 1 Gene Products Occlude the Interferon Signaling Pathway at Multiple Sites
Authors: Chee Ana Virginia , Roizman Bernard 
Published: March 2004

ABSTRACTEarlier studies have shown that herpes simplex virus 1 (HSV-1) blocks the interferon response pathways, at least at two sites, by circumventing the effects of activation of protein kinase R by double-stranded RNA and interferon and through the degradation of promyelocytic leukemia protein (PML) since interferon has no antiviral effects in PML−/−cells. Here we report on two effects of viral genes on other sites of the interferon signaling pathway. (i) In infected cells, Jak1 kinase associated with interferon receptors and Stat2 associated with the interferon signaling pathway rapidly disappear from infected cells. The level of interferon alpha receptor is also reduced, albeit less drastically at times after 4 h postinfection. Other members of the Stat family of proteins were either decreased in amount or posttranslationally processed in a manner different from those of mock-infected cells. The decrease in the levels of Jak1 and Stat2 may account for the decrease in the formation of complexes consisting of Stat1 or ISGF3 and DNA sequences containing the interferon-stimulated response elements after exposure to interferon. (ii) The disappearance of Jak1 and Stat2 was related at least in part to the function of the virion host shutoff protein, the product of the viral UL41 gene. Consistent with this observation, a mutant lacking the UL41 gene and treated with interferon produced lesser amounts of a late protein (UL38) than the wild-type parent. We conclude that HSV-1 blocks the interferon signaling pathways at several sites.
Early Activation of the Kaposi's Sarcoma-Associated Herpesvirus RTA, RAP, and MTA Promoters by the Tetradecanoyl Phorbol Acetate-Induced AP1 Pathway
Authors: Wang Shizhen Emily , Wu Frederick Y. , Chen Honglin , Shamay Meir , Zheng Qizhi , Hayward Gary S. 
Published: March 2004

ABSTRACT
Kaposi's sarcoma-associated herpesvirus (KSHV) maintains a latent infection in primary effusion lymphoma (PEL) cells, but treatment with tetradecanoyl phorbol acetate (TPA) can trigger the full lytic-cycle replication in some of these cells. During lytic-cycle replication, the KSHV-encoded replication and transcription activator (RTA or ORF50), the mRNA transport and accumulation protein (MTA), and the replication-associated protein (RAP) all play crucial roles in expression of downstream viral genes as well as in mediation of viral DNA replication. The cellular CCAAT/enhancer-binding protein alpha (C/EBPα) is induced in TPA-treated PEL cells and contributes to transactivation of the promoters for all of these genes through both direct binding and cooperative interactions with RTA and RAP targeted to upstream C/EBP sites. However, little is known about how RTA expression is triggered initially at the earliest stages after TPA induction when the C/EBPα levels are still limited. Treatment with TPA proved to significantly induce both AP1 DNA-binding activity and levels of activated phosphorylated cJUN in PEL cells and ectopic expression of cJUN-plus-cFOS-induced RTA protein expression in PEL cells. Cotransfected cJUN plus cFOS or TPA treatment transactivated the KSHV RTA, RAP, and MTA promoters in an AP1-binding site-dependent manner in all three promoters. Chromatin immunoprecipitation assays confirmed that cJUN associates with these KSHV target promoters in PEL cells as early as 4 h after TPA treatment. Furthermore, the KSHV RTA and RAP proteins both interact with cJUN or both cJUN and cFOS in vitro or by coimmunoprecipitation from induced PEL cells and enhance cJUN-plus-cFOS-mediated transactivation of these viral promoters. Both increased phosphorylated cJUN and AP1 DNA-binding activity was detected as early as 1 h after TPA treatment in PEL cells, suggesting that AP1 activity may be crucial for very early activation of the RAP, MTA, and RTA promoters during the KSHV lytic cycle. Finally, expression of RTA alone increased cJUN protein levels severalfold in DG75 cells but did not induce cJUN phosphorylation. Therefore, we suggest that the initiating effects of TPA via the AP1 pathway in PEL cells need to be amplified by RTA for full lytic-cycle induction.
The Leader Protein of Theiler's Virus Interferes with Nucleocytoplasmic Trafficking of Cellular Proteins
Authors: Delhaye Sophie , van Pesch Vincent , Michiels Thomas 
Published: March 2004

ABSTRACT
The leader protein of Theiler's virus was previously shown to block the production of alpha/beta interferon by infected cells. Here, we observed that expression of the leader protein in infected cells triggered subcellular redistribution of a nucleus-target green fluorescent protein. It enhanced redistribution of the nuclear polypyrimidine tract-binding protein but had no influence on the localization of the nuclear splicing factor SC-35. The leader protein also interfered with trafficking of the cytoplasmic interferon regulatory factor 3, a factor critical for transcriptional activation of alpha/beta interferon genes.
DNA Vaccines: Influenza Virus Challenge of a Th2/Tc2 Immune Response Results in a Th2/Tc1 Response in the Lung
Authors: Oran Alp E. , Robinson Harriet L. 
Published: March 2004

ABSTRACTFor this study, we used DNA-based immunizations to elicit gamma interferon-producing (Tc1) or interleukin 4 (IL-4)-producing (Tc2) CD8 T cells to the influenza virus nucleoprotein. We examined the response of these cells to an intranasal viral challenge. Both the Tc2- and Tc1-biased responses were present in mice with predominantly IL-4-producing (Th2) CD4 T cells. After viral challenge, Tc1 cells underwent more efficient expansion than did Tc2 cells, and only Tc1 cells were detected at the site of infection. In contrast, the CD4 response remained IL-4 biased. However, only a limited number of CD4 cells appeared in the postchallenge lung, and these were strongly enriched for the Th1 phenotype. Thus, the type of memory T-cell response induced by DNA vaccination does not determine the type of response that will predominate at the site of an infection.