bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrauterine growth restriction, human placental development and trophoblast cell death
Authors: Scifres Christina M. , Nelson D. Michael
Published: May 2009

Intrauterine growth restriction (IUGR) is a failure to achieve the growth potential of a fetus that is promised by the genetic constitution and environmental influences endogenous to the pregnancy. Optimal placental development and the ability of the placenta to compensate for stimulus‐induced injury are central in promotion of normal fetal growth. In this review, we will overview placental development with a focus on how villous structure relates to function. We will also describe the differentiation and turnover of villous trophoblast while highlighting selected features of microscopic placental injury. Histopathological studies of the placenta in IUGR indicate that abnormalities of the maternal spiral arterioles, dysregulated villous vasculogenesis, and abundant fibrin deposition are characteristic of the injuries associated with this condition. We identify selected insults, including oxidative stress and complement activation, and key pathways that regulate apoptosis in villous trophoblast, including increased p53 activity, altered translation of AKT and mTOR proteins, and the stress response of the endoplasmic reticulum. We surmise that trophoblast dysregulation at a subcellular level and loss of functional mass of villous trophoblast via cell death pathways are key contributors to the suboptimal placental performance that yields IUGR. We predict that a better understanding of placental dysfunction in IUGR will lead to targeted therapeutic options for this important clinical condition.
Analysis of Single-Nucleotide Polymorphisms in thecrt-oandmdr1Genes ofPlasmodium vivaxamong Chloroquine-Resistant Isolates from the Brazilian Amazon Region
Authors: Orjuela-Sánchez Pamela , de Santana Filho Franklin Simões , Machado-Lima Ariane , Chehuan Yonne Francis , Costa Mônica Regina Farias , Alecrim Maria das Graças Costa , del Portillo Hernando A.
Published: May 2009

Plasmodium vivaxparasites with chloroquine resistance (CQR) are already circulating in the Brazilian Amazon. Complete single-nucleotide polymorphism (SNP) analyses of coding and noncoding sequences of thepvmdr1andpvcrt-ogenes revealed no associations with CQR, even if some mutations had not been randomly selected. In addition, striking differences in the topologies and numbers of SNPs in these transporter genes betweenP. vivaxandP. falciparumreinforce the idea that mechanisms other than mutations may explain this virulent phenotype inP. vivax.
Pharmacokinetics of EDP-420 after Multiple Oral Doses in Healthy Adult Volunteers and in a Bioequivalence Study
Authors: Jiang Li-Juan , Or Yat Sun
Published: May 2009

EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI.
Cyclosporine Inhibits Flavivirus Replication through Blocking the Interaction between Host Cyclophilins and Viral NS5 Protein
Authors: Qing Min , Yang Feng , Zhang Bo , Zou Gang , Robida John M. , Yuan Zhiming , Tang Hengli , Shi Pei-Yong
Published: May 2009

Although flaviviruses cause significant human diseases, no effective therapy is currently available. Host factors essential for viral replication are potential targets for antiviral development. Here we report that cyclophilins (CyPs), a family of cellular peptidyl-prolyl isomerases (PPIases), play a role in flavivirus replication. Huh-7.5 cells with knockdown of different isoforms of CyP were less efficient than parental cells in supporting flavivirus replication, including West Nile virus (WNV), dengue virus, and yellow fever virus. The low viral replication in CyP A (CyPA) knockdown cells could be rescued by
trans
supplying of a wild-type CyPA but not by
trans
supplying of a mutant CyPA (defective in the PPIase activity), indicating that the isomerase activity of CyPA is critical for viral replication. Immunoprecipitation and biochemical pulldown analyses showed that CyPA interacts with WNV genomic RNA and viral NS5 protein in the replication complex. Furthermore, antiviral experiments demonstrated that cyclosporine (Cs; an 11-amino-acid cyclic peptide known to block the PPIase activity of CyPA) inhibits flavivirus replication in cell culture at nontoxic concentrations. Time-of-addition and transient replicon results indicated that Cs inhibits flavivirus at the step of viral RNA synthesis. Biochemical analysis showed that Cs directly blocks the interaction between CyPA and WNV NS5 protein. Our results suggest that host CyPA is a component of flavivirus replication complex and could be targeted for potential antiviral development.
First Report of Plasmid-Mediated Quinolone Resistance Determinant
qnrS1
in an
Escherichia coli
Strain of Animal Origin in Italy
Authors: Cerquetti Marina , García-Fernández Aurora , Giufrè Maria , Fortini Daniela , Accogli Marisa , Graziani Caterina , Luzzi Ida , Caprioli Alfredo , Carattoli Alessandra
Published: May 2009

A
qnrS1
-positive strain of
Escherichia coli
was detected among 73 poultry isolates showing ciprofloxacin MICs of ≥0.125 μg/ml. The
qnrS1
gene was associated with a Tn
3
-like transposon, as previously described to occur in a
Salmonella enterica
serovar Infantis strain of animal origin, but the plasmid scaffold carrying this element resembled that of a plasmid previously identified in
Salmonella enterica
serovar Dublin. These elements suggest genetic exchanges among
Salmonella
and
E. coli
and a potential animal reservoir for the
qnr
genes.
Efficacy of Liposomal Amphotericin B Combined with Gamma Interferon or Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Systemic Zygomycosis in Mice
Authors: Rodríguez M. Mar , Calvo Enrique , Mariné Marçal , Pastor F. Javier , Fernandez-Ballart Joan , Guarro Josep
Published: May 2009

Granulocyte-macrophage colony-stimulating factor enhanced the efficacy of liposomal amphotericin B (LAMB) in a murine model of disseminated infection by
Rhizopus oryzae
, significantly prolonging survival and reducing tissue burden. The use of gamma interferon (IFN-γ) alone was ineffective, and IFN-γ combined with LAMB did not improve the results obtained with LAMB alone.
Pharmacokinetics and Pharmacodynamics of a Novel Triazole, Isavuconazole: Mathematical Modeling, Importance of Tissue Concentrations, and Impact of Immune Status on Antifungal Effect
Authors: Warn Peter A. , Sharp Andrew , Parmar Arvind , Majithiya Jayesh , Denning David W. , Hope William W.
Published: May 2009

Isavuconazole is a triazole with broad-spectrum activity against medically important fungal pathogens. We investigated the pharmacokinetics and pharmacodynamics of isavuconazole in a murine model of disseminated candidiasis. We determined the pharmacokinetics in both plasma and kidney. The relationship between tissue concentrations and the resultant antifungal effect was described using a mathematical model. The pharmacodynamic parameter that optimally links drug exposure with the antifungal effect was determined using dose fractionation studies. The impact of the immune status of mice receiving isavuconazole was determined in persistently and temporarily neutropenic animals. The pharmacokinetics of 1.6 to 28 mg isavuconazole/kg of body weight were linear. Exposure-response relationships demonstrated near-maximal effect following the administration of >15 mg/kg. The mathematical model showed that exposures in the kidney were 5.77 times higher than those in plasma, and there was persistence of the drug at this site despite concentrations in plasma falling to undetectable levels. The in vitro and in vivo postantifungal effects were 2 to 5 and 8.41 h, respectively. The area under the concentration-time curve (AUC)/MIC ratio was the parameter that optimally linked drug exposure with the observed antifungal effect. The total drug AUC/MIC ratios associated with a 90% probability of survival in temporarily and persistently neutropenic mice were 270 and 670, respectively. Once corrected for protein binding, these values are similar to the magnitude of drug exposure associated with a high probability of a successful therapeutic outcome for other triazoles. This study provides the experimental foundation for the use of isavuconazole in patients with disseminated candidiasis.
Light-Microscopic Immunocytochemistry for Gentamicin and Its Use for Studying Uptake of the Drug in Kidney
Authors: Fujiwara Kunio , Shin Masashi , Matsunaga Hayato , Saita Tetsuya , Larsson Lars-Inge
Published: May 2009

Gentamicin (GM) is a widely used antibiotic but shows renal toxicity. We produced a serum against GM (anti-GM) conjugated to bovine serum albumin withN-(gamma-maleimidobutyryloxy)succinimide. The antiserum was monospecific for GM and did not cross-react with the analog streptomycin, tobramycin, kanamycin, or amikacin. The antiserum also detected glutaraldehyde-fixed GM, and this enabled us to develop an immunocytochemical method for detecting the uptake of GM in rat kidney. Twelve hours after a single intravenous administration of GM, immunocytochemistry revealed that GM accumulated in the S1, S2, and S3 segments of the proximal tubules, as well as in the distal tubules and collecting ducts. By 12 h after injection, the drug was detected in cytoplasmic granules of the proximal tubule cells. However, early (1 h) after injection, drug accumulation was detected in the microvilli of these cells. The distal tubules and collecting ducts contained scattered swollen cells, reminiscent of necrotic cells, in which both the nuclei and the cytoplasm reacted strongly with GM. No staining occurred in the kidneys of saline-injected control rats. These results agree with previous studies showing that GM is endocytosed in the proximal tubules and accumulates in lysosomes. Additionally, our results show that GM also accumulates in the distal tubules and collecting ducts. This was achieved by systematically varying the pretreatment conditions—an approach necessary for detecting GM in different subcellular compartments. This approach should be useful for accurately detecting the uptake and toxicity of the antibiotic in different tissues.
Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration
Authors: Oh Kook-Hwan , Kim Chiweon , Lee Hankyu , Lee Hajeong , Jung Ji Yong , Kim Nam Joong , Yu Kyung-Sang , Shin Kwang-Hee , Jang In-Jin , Ahn Curie
Published: May 2009

The pharmacokinetic characteristics of piperacillin sodium were studied in five volunteers undergoing on-line hemodiafiltration (HDF). The subjects were given 2 g of piperacillin sodium intravenously over 1 min and placed on on-line HDF for 4 h starting at 60 min after the piperacillin infusion. Noncompartmental models were employed for estimation of the pharmacokinetic parameters, and intradialytic piperacillin clearance was calculated by the recovery method. The mean volume of distribution and the elimination half-life were 0.27 ± 0.13 liter/kg (mean ± standard deviation) and 1.1 ± 0.6 h, respectively. The total body clearance of piperacillin was 0.19 ± 0.08 liter/h/kg. Piperacillin clearance through on-line HDF was 0.11 ± 0.06 liter/h/kg. The mean serum piperacillin concentration was 4.0 ± 1.9 μg/ml at the end of the 4-h on-line HDF session. The concentration of infused piperacillin recovered in the dialysate was 527 ± 236 mg (26.3% ± 11.8%). We suggest the replacement of 500 mg of piperacillin after each on-line HDF session.
Inhibitory Effects of Lactoferrin on Growth and Biofilm Formation ofPorphyromonas gingivalisandPrevotella intermedia
Authors: Wakabayashi Hiroyuki , Yamauchi Koji , Kobayashi Tetsuo , Yaeshima Tomoko , Iwatsuki Keiji , Yoshie Hiromasa
Published: May 2009

Lactoferrin (LF) is an iron-binding antimicrobial protein present in saliva and gingival crevicular fluids, and it is possibly associated with host defense against oral pathogens, including periodontopathic bacteria. In the present study, we evaluated the in vitro effects of LF-related agents on the growth and biofilm formation of two periodontopathic bacteria,Porphyromonas gingivalisandPrevotella intermedia, which reside as biofilms in the subgingival plaque. The planktonic growth ofP. gingivalisandP. intermediawas suppressed for up to 5 h by incubation with ≥130 μg/ml of human LF (hLF), iron-free and iron-saturated bovine LF (apo-bLF and holo-bLF, respectively), and ≥6 μg/ml of bLF-derived antimicrobial peptide lactoferricin B (LFcin B); but those effects were weak after 8 h. The biofilm formation ofP. gingivalisandP. intermediaover 24 h was effectively inhibited by lower concentrations (≥8 μg/ml) of various iron-bound forms (the apo, native, and holo forms) of bLF and hLF but not LFcin B. A preformed biofilm ofP. gingivalisandP. intermediawas also reduced by incubation with various iron-bound bLFs, hLF, and LFcin B for 5 h. In an examination of the effectiveness of native bLF when it was used in combination with four antibiotics, it was found that treatment with ciprofloxacin, clarithromycin, and minocycline in combination with native bLF for 24 h reduced the amount of a preformed biofilm ofP. gingivaliscompared with the level of reduction achieved with each agent alone. These results demonstrate the antibiofilm activity of LF with lower iron dependency againstP. gingivalisandP. intermediaand the potential usefulness of LF for the prevention and treatment of periodontal diseases and as adjunct therapy for periodontal diseases.
Pharmacokinetics and Safety Profile of the Human Anti-
Pseudomonas aeruginosa
Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers
Authors: Lazar Hedvika , Horn Michael P. , Zuercher Adrian W. , Imboden Martin A. , Durrer Peter , Seiberling Michael , Pokorny Rolf , Hammer Christophe , Lang Alois B.
Published: May 2009

KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of
Pseudomonas aeruginosa
serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.
The Novel CXCR4 Antagonist KRH-3955 Is an Orally Bioavailable and Extremely Potent Inhibitor of Human Immunodeficiency Virus Type 1 Infection: Comparative Studies with AMD3100
Authors: Murakami Tsutomu , Kumakura Sei , Yamazaki Toru , Tanaka Reiko , Hamatake Makiko , Okuma Kazu , Huang Wei , Toma Jonathan , Komano Jun , Yanaka Mikiro , Tanaka Yuetsu , Yamamoto Naoki
Published: May 2009

The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1α binding to CXCR4 and Ca
2+
signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
Saccharomyces cerevisiae
Rbg1 Protein and Its Binding Partner Gir2 Interact on Polyribosomes with Gcn1
Authors: Wout P. K. , Sattlegger E. , Sullivan S. M. , Maddock J. R.
Published: May 2009

Rbg1 is a previously uncharacterized protein of
Saccharomyces cerevisiae
belonging to the Obg/CgtA subfamily of GTP-binding proteins whose members are involved in ribosome function in both prokaryotes and eukaryotes. We show here that Rbg1 specifically associates with translating ribosomes. In addition, in this study proteins were identified that interact with Rbg1 by yeast two-hybrid screening and include Tma46, Ygr250c, Yap1, and Gir2. Gir2 contains a GI (
G
cn2 and
I
mpact) domain similar to that of Gcn2, an essential factor of the general amino acid control pathway required for overcoming amino acid shortage. Interestingly, we found that Gir2, like Gcn2, interacts with Gcn1 through its GI domain, and overexpression of Gir2, under conditions mimicking amino acid starvation, resulted in inhibition of growth that could be reversed by Gcn2 co-overexpression. Moreover, we found that Gir2 also cofractionated with polyribosomes, and this fractionation pattern was partially dependent on the presence of Gcn1. Based on these findings, we conclude that Rbg1 and its interacting partner Gir2 associate with ribosomes, and their possible biological roles are discussed.
The Capsule-Encoding
viaB
Locus Reduces Intestinal Inflammation by a
Salmonella
Pathogenicity Island 1-Independent Mechanism
Authors: Haneda Takeshi , Winter Sebastian E. , Butler Brian P. , Wilson R. Paul , Tükel Çagla , Winter Maria G. , Godinez Ivan , Tsolis Renée M. , Bäumler Andreas J.
Published: May 2009

Salmonella enterica
serotype Typhimurium elicits acute neutrophil influx in the human intestinal mucosa within 1 or 2 days after infection, resulting in inflammatory diarrhea. In contrast, no overt symptoms are observed within the first 1 or 2 weeks after infection with
S. enterica
serotype Typhi. Here we show that introduction of the capsule-encoding
viaB
locus of serotype Typhi reduced the ability of serotype Typhimurium to elicit acute intestinal inflammation in a streptomycin-pretreated mouse model. Serotype Typhimurium requires a functional invasion-associated type III secretion system (type III secretion system 1 [T3SS-1]) to elicit cecal inflammation within 48 h after infection of streptomycin-pretreated mice, and the presence of the
viaB
locus reduced its invasiveness for human intestinal epithelial cells in vitro. However, a reduced activity of T3SS-1 could not account for the ability of the
viaB
locus to attenuate cecal inflammation, because introduction of the
viaB
locus into an invasion-deficient serotype Typhimurium strain (
invA
mutant) resulted in a significant reduction of pathology and inflammatory cytokine expression in the cecum 5 days after infection of mice. We conclude that a T3SS-1-independent mechanism contributes to the ability of the
viaB
locus to reduce intestinal inflammation.
CspA-Mediated Binding of Human Factor H Inhibits Complement Deposition and Confers Serum Resistance in
Borrelia burgdorferi
Authors: Kenedy Melisha R. , Vuppala Santosh R. , Siegel Corinna , Kraiczy Peter , Akins Darrin R.
Published: May 2009

Borrelia burgdorferi
has developed efficient mechanisms for evading the innate immune response during mammalian infection and has been shown to be resistant to the complement-mediated bactericidal activity of human serum. It is well recognized that
B. burgdorferi
expresses multiple lipoproteins on its surface that bind the human complement inhibitors factor H and factor H-like protein 1 (FH/FHL-1). The binding of FH/FHL-1 on the surface of
B. burgdorferi
is thought to enhance its ability to evade serum-mediated killing during the acute phase of infection. One of the key
B. burgdorferi
FH/FHL-1 binding proteins identified thus far was designated CspA. While it is known that CspA binds FH/FHL-1, it is unclear how the interaction between CspA and FH/FHL-1 specifically enhances serum resistance. To better understand how CspA mediates serum resistance in
B. burgdorferi
, we inactivated
cspA
in a virulent strain of
B. burgdorferi
. An affinity ligand blot immunoassay and indirect immunofluorescence revealed that the CspA mutant does not efficiently bind human FH to its surface. Consistent with the lack of FH binding, the CspA mutant was also highly sensitive to killing by human serum. Additionally, the deposition of complement components C3, C6, and C5b-9 was enhanced on the surface of the CspA mutant compared to that of the wild-type strain. The combined data lead us to conclude that the CspA-mediated binding of human FH confers serum resistance by directly inhibiting complement deposition on the surface of
B. burgdorferi
.
Identification of a Simple Chemical Structure Associated with Protective Human Antibodies against Multiple Pneumococcal Serogroups
Authors: Park Saeyoung , Parameswar Archana R. , Demchenko Alexei V. , Nahm Moon H.
Published: May 2009

Streptococcus pneumoniae, a major human pathogen, expresses at least 91 serologically distinct carbohydrate capsules. Since pneumococcal vaccines are designed to elicit antibodies against many different capsular polysaccharides (PSs), it is important to identify the epitopes involved in eliciting anti-capsular PS antibodies. We investigated the epitopes recognized by Dob1, which is a hybridoma-secreting human immunoglobulin G2 antibody to the PS of serotype 6B (Y. Sun et al., Infect. Immun. 67:1172-1179, 1999). We found that Dob1 bound synthetic capsular carbohydrates Gal(1→3)α-d-Glcp(1→3)α-l-Rhap(1→3)Rib-ol and α-d-Glcp(1→3)α-l-Rhap(1→3)Rib-ol but did not bind α-l-Rhap(1→3)Rib-ol. The critical epitope α-d-Glcp(1→3)α-l-Rhapis found in the capsular PSs of serotypes 6A, 6B, 6C, and 19A but not in the 19F PS. Consistent with this observation, Dob1 bound to the PSs of serotypes 6A, 6B, 6C, and 19A but did not bind the 19F PS and 23 additional unrelated pneumococcal capsular PSs. Also, Dob1 could opsonize pneumococci expressing serotypes 6A, 6B, 6C, and 19A but did not opsonize 19F pneumococci. In addition, ca. 7% of immune sera (12 of 175 sera) had significant amounts of Dob1-like antibodies, i.e., reacted with 6B and 19A PSs, but not with 19F PS. Humans can produce antibodies to the Dob1 epitope and the antibodies to that epitope cross-react with the four serotypes 6A, 6B, 6C, and 19A that belong to different serogroups. This epitope may be useful for producing a totally synthetic, simple chemical structure that is capable of generating protective antibodies to multiple pneumococcal serogroups.
Urothelial Cultures Support Intracellular Bacterial Community Formation by UropathogenicEscherichia coli
Authors: Berry Ruth E. , Klumpp David J. , Schaeffer Anthony J.
Published: May 2009

UropathogenicEscherichia coli(UPEC) causes most community-acquired and nosocomial urinary tract infections (UTI). In a mouse model of UTI, UPEC invades superficial bladder cells and proliferates rapidly, forming biofilm-like structures called intracellular bacterial communities (IBCs). Using a gentamicin protection assay and fluorescence microscopy, we developed an in vitro model for studying UPEC proliferation within immortalized human urothelial cells. By pharmacologic manipulation of urothelial cells with the cholesterol-sequestering drug filipin, numbers of intracellular UPEC CFU increased 8 h and 24 h postinfection relative to untreated cultures. Enhanced UPEC intracellular proliferation required that the urothelial cells, but not the bacteria, be filipin treated prior to infection. However, neither UPEC frequency of invasion nor early intracellular trafficking events to a Lamp1-positive compartment were modulated by filipin. Upon inspection by fluorescence microscopy, cultures with enhanced UPEC intracellular proliferation exhibited large, dense bacterial aggregates within cells that resembled IBCs but were contained with Lamp1-positive vacuoles. While an isogenicfimHmutant was capable of forming these IBC-like structures, the mutant formed significantly fewer than wild-type UPEC. Similar to IBCs, expression ofE. coliiron acquisition systems was upregulated by intracellular UPEC. Expression of other putative virulence factors, includinghlyA,cnf1,fliC,kpsD, and the biofilm adhesinyfaLalso increased, while expression offimAdecreased and that offludid not change. These results indicate that UPEC differentially regulates virulence factors in the intracellular environment. Thus, immortalized urothelial cultures that recapitulate IBC formation in vitro represent a novel system for the molecular and biochemical characterization of the UPEC intracellular life cycle.
Chlamydial and Periodontal Pathogens Induce Hepatic Inflammation and Fatty Acid Imbalance in Apolipoprotein E-Deficient Mice
Authors: Hyvärinen Kati , Tuomainen Anita M. , Laitinen Saara , Bykov Igor L. , Törmäkangas Liisa , Lindros Kai , Käkelä Reijo , Alfthan Georg , Salminen Irma , Jauhiainen Matti , Kovanen Petri T. , Leinonen Maija , Saikku Pekka , Pussinen Pirkko J.
Published: May 2009

Periodontitis and
Chlamydia pneumoniae
infection are independent risk factors for cardiovascular diseases. The aim of this study was to investigate the effect of
C. pneumoniae
and
Aggregatibacter actinomycetemcomitans
infection on hepatic inflammation and lipid homeostasis of apolipoprotein E-deficient mice. Mice were infected with viable
C. pneumoniae
intranasally three times for chronic infection or once for acute infection. Viable
A. actinomycetemcomitans
was administered 10 times intravenously alone or in concert with
C. pneumoniae
. Hepatic alterations were assessed by histochemistry, lipid quantification, and fatty acid profile analysis. The RNA expression levels and the presence of pathogens in the livers and lungs were detected by quantitative real-time PCR. Both pathogens were detected in the livers of the infected animals. Chronic
C. pneumoniae
infection induced marked changes in hepatic lipid homeostasis.
A. actinomycetemcomitans
infection resulted in inflammatory cell infiltration into the liver, accompanied by elevated hepatic RNA expression levels of inflammation-related genes and higher serum amyloid A and lipopolysaccharide concentrations. Our results indicate that proatherogenic pathogens infect the liver, causing proinflammatory alterations and lipid disturbances. This infection may maintain chronic systemic inflammation attributable to atherogenesis.
Characterization of a Novel ADAM Protease Expressed byPneumocystis carinii
Authors: Kennedy Cassie C. , Kottom Theodore J. , Limper Andrew H.
Published: May 2009

Pneumocystisspecies are opportunistic fungal pathogens that cause severe pneumonia in immunocompromised hosts. Recent evidence has suggested that unidentified proteases are involved inPneumocystislife cycle regulation. Proteolytically active ADAM (named for “a disintegrin and metalloprotease”) family molecules have been identified in some fungal organisms, such asAspergillus fumigatusandSchizosaccharomyces pombe, and some have been shown to participate in life cycle regulation. Accordingly, we sought to characterize ADAM-like molecules in the fungal opportunistic pathogen,Pneumocystis carinii(PcADAM). After an in silico search of theP. cariniigenomic sequencing project identified a 329-bp partial sequence with homology to known ADAM proteins, the full-length PcADAMsequence was obtained by PCR extension cloning, yielding a final coding sequence of 1,650 bp. Sequence analysis detected the presence of a typical ADAM catalytic active site (HEXXHXXGXXHD). Expression of PcADAMover thePneumocystislife cycle was analyzed by Northern blot. Southern and contour-clamped homogenous electronic field blot analysis demonstrated its presence in theP. cariniigenome. Expression of PcADAMwas observed to be increased inPneumocystiscysts compared to trophic forms. The full-length gene was subsequently cloned and heterologously expressed inSaccharomyces cerevisiae. Purified PcADAMp protein was proteolytically active in casein zymography, requiring divalent zinc. Furthermore, native PcADAMp extracted directly from freshly isolatedPneumocystisorganisms also exhibited protease activity. This is the first report of protease activity attributable to a specific, characterized protein in the clinically important opportunistic fungal pathogenPneumocystis.
CovS Simultaneously Activates and Inhibits the CovR-Mediated Repression of Distinct Subsets of Group A
Streptococcus
Virulence Factor-Encoding Genes
Authors: Treviño Jeanette , Perez Nataly , Ramirez-Peña Esmeralda , Liu Zhuyun , Shelburne Samuel A. , Musser James M. , Sumby Paul
Published: May 2009

To colonize and cause disease at distinct anatomical sites, bacterial pathogens must tailor gene expression in a microenvironment-specific manner. The molecular mechanisms that control the ability of the human bacterial pathogen group A
Streptococcus
(GAS) to transition between infection sites have yet to be fully elucidated. A key regulator of GAS virulence gene expression is the CovR-CovS two-component regulatory system (also known as CsrR-CsrS).
covR
and
covS
mutant strains arise spontaneously during invasive infections and, in in vivo models of infection, rapidly become dominant. Here, we compared wild-type GAS with
covR
,
covS
, and
covRS
isogenic mutant strains to investigate the heterogeneity in the types of natural mutations that occur in
covR
and
covS
and the phenotypic consequences of
covR
or
covS
mutation. We found that the response regulator CovR retains some regulatory function in the absence of CovS and that CovS modulates CovR to significantly enhance repression of one group of genes (e.g., the
speA
,
hasA
, and
ska
genes) while it reduces repression of a second group of genes (e.g., the
speB
,
grab
, and
spd3
genes). We also found that different in vivo-induced
covR
mutations can lead to strikingly different transcriptomes. While
covS
mutant strains show increased virulence in several invasive models of infection, we determined that these mutants are significantly outcompeted by wild-type GAS during growth in human saliva, an ex vivo model of upper respiratory tract infection. We propose that CovS-mediated regulation of CovR activity plays an important role in the ability of GAS to cycle between pharyngeal and invasive infections.
Natural Antibody to Conserved Targets ofHaemophilus influenzaeLimits Colonization of the Murine Nasopharynx
Authors: Zola Tracey A. , Lysenko Elena S. , Weiser Jeffrey N.
Published: May 2009

Nasopharyngeal colonization represents the initial interaction betweenHaemophilus influenzaeand its human host. Factors that influence bacterial carriage likely affect transmission and incidence of infection. Therefore, we investigated host factors involved in limitingH. influenzaecolonization in BALB/c mice, as colonization can be established in this genetic background. Unlike what is observed in the C57BL/6 background, initial colonization of BALB/c mice was mainly limited by adaptive immune components. This effect on colonization did not require either CD4- or CD8-positive T cells. Instead, initial colonization by genetically diverse strains was limited by preexisting natural antibody with a lesser contribution of complement activity and the presence of neutrophils. Natural serum immunoglobulin from mice was able to bind to the bacterial surface and exhibited complement-dependent bactericidal activity against these genetically diverseH. influenzaestrains. Moreover, natural immunoglobulin G (IgG) recognizing these strains was detected at the nasopharyngeal mucosal surface. This antibody-mediated effect required exposure to the normal mouse microbial flora, since mice raised under germfree (GF) conditions showed increased levels ofH. influenzaecolonization that were not limited by adaptive immunity. In addition, serum IgG from GF mice exhibited less surface binding toH. influenzae, suggesting that natural antibody, induced through prior exposure to the microbial flora, mediated the observed reduction in initial colonization. The broad effect of natural IgG against genetically diverse isolates suggests the presence of conserved species-wide protective targets of antibody.
Analysis of DNA Binding by a Eubacterial Zinc Finger Transcription Factor
Authors: McAlister Victor J. , Christie Gail E.
Published: May 2009

The
Serratia marcescens
NucC protein is structurally and functionally homologous to the P2 Ogr family of eubacterial zinc finger transcription factors required for late gene expression in P2- and P4-related bacteriophages. These activators exhibit site-specific binding to a conserved DNA sequence, TGT-N
3
-R-N
4
-Y-N
3
-aCA, that is located upstream of NucC-dependent
S. marcescens
promoters and the late promoters of P2-related phages. In this report we describe the interactions of NucC with the P2
FETUD
late operon promoter P

F

. NucC is shown to bind P

F

as a tetramer and to make 12 symmetrical contacts to the DNA phosphodiester backbone. The backbone contacts are centered on the TGT-N
3
-R-N
4
-Y-N
3
-aCA motif. Major groove base contacts can be seen at most positions within the ∼24-bp binding site. Minor groove contacts map to adjacent positions in the downstream half of the binding site, which corresponds to the area in which the DNA also appears to be bent by NucC binding. NucC binding provides a new example of protein-DNA interaction that is strikingly different from the DNA binding demonstrated for eukaryotic zinc-finger transcription factors.
Quantitative health impact assessment of transport policies: two simulations related to speed limit reduction and traffic re-allocation in the Netherlands
Authors: Schram-Bijkerk D , van Kempen E , Knol A B , Kruize H , Staatsen B , van Kamp I
Published: May 2009

Background:

Few quantitative health impact assessments (HIAs) of transport policies have been published so far and there is a lack of a common methodology for such assessments.

Objective:

To evaluate the usability of existing HIA methodology to quantify health effects of transport policies at the local level.

Methods:

Health impact of two simulated but realistic transport interventions — speed limit reduction and traffic re-allocation — was quantified by selecting traffic-related exposures and health endpoints, modelling of population exposure, selecting exposure-effect relations and estimating the number of local traffic-related cases and disease burden, expressed in disability-adjusted life-years (DALYs), before and after the intervention.

Results:

Exposure information was difficult to retrieve because of the local scale of the interventions, and exposure-effect relations for subgroups and combined effects were missing. Given uncertainty in the outcomes originating from this kind of missing information, simulated changes in population health by two local traffic interventions were estimated to be small (<5%), except for the estimated reduction in DALYs by less traffic accidents (60%) due to speed limit reduction.

Conclusions:

Quantitative HIA of transport policies at a local scale is possible, provided that data on exposures, the exposed population and their baseline health status are available. The interpretation of the HIA information should be carried out in the context of the quality of input data and assumptions and uncertainties of the analysis.
NORMAL DOMAINS WITH MONOMIAL PRESENTATIONS
Authors: GOFFA ISABEL , JESPERS ERIC , OKNIŃSKI JAN
Published: May 2009

Let A be a finitely generated commutative algebra over a field K with a presentation A = K 〈X1,…, Xn | R〉, where R is a set of monomial relations in the generators X1,…, Xn. So A = K[S], the semigroup algebra of the monoid S = 〈X1,…, Xn | R〉. We characterize, purely in terms of the defining relations, when A is an integrally closed domain, provided R contains at most two relations. Also the class group of such algebras A is calculated.
COMMENT ON A FREQUENT ERROR IN CALCULATIONS OF THE Γn/Γf RATIO
Authors: SIWEK-WILCZYŃSKA K. , WILCZYŃSKI J.
Published: May 2009

In the last decade some 20–30 publications in leading journals appeared in which cross sections for production of super-heavy elements are calculated with an erroneous formula for the Γn/Γf ratio. The erroneous treatment of shell structure corrections leads to an energy-dependent fission barrier that is inserted to the expression for the fission width Γf. In this approach the shell effect in the residual nucleus that emitted the neutron is ignored. We give examples of calculations that illustrate the deviations of the erroneous formula from the correct one. The errors reach several orders of magnitude, especially for low excitation energies and those compound nuclei for which large ground-state shell effect exceeds the neutron binding energy.
FISSION BARRIERS AT FINITE TEMPERATURE: A THEORETICAL DESCRIPTION WITH THE GOGNY FORCE
Authors: MARTIN V. , ROBLEDO L. M.
Published: May 2009

The evolution with temperature of nuclear properties relevant to fission are analyzed in the case of the 240 Pu nucleus by using the standard finite temperature mean field approximation (including pairing correlations) and the Gogny D1S force. To be more specific, potential energy curves, pairing correlation energies, level density parameter a, collective quadrupole mass, etc are considered. The impact of their evolution with temperature in the quantum decay rate, meaningful only in the low temperature regime, is also considered.
SYMMETRY ENERGY IN NUCLEAR SURFACE
Authors: DANIELEWICZ PAWEL , LEE JENNY
Published: May 2009

Interplay between the dependence of symmetry energy on density and the variation of nucleonic densities across nuclear surface is discussed. That interplay gives rise to the mass dependence of the symmetry coefficient in an energy formula. Charge symmetry of the nuclear interactions allows to introduce isoscalar and isovector densities that are approximately independent of the magnitude of neutron-proton asymmetry.
CHAOS AND STRUCTURE OF LEVEL DENSITIES
Authors: ÅBERG SVEN , UHRENHOLT HENRIK , ICHIKAWA TAKATOSHI , MÖLLER PETER
Published: May 2009

Two coexisting facets of warm nuclei, quantum chaos and structure of the level density, are considered. A newly developed combinatorial level-density model is presented, and the role of collective enhancements discussed. An example of extreme parity enhancement is shown.
A NEW EQUATION OF MOTION METHOD FOR MULTIPHONON NUCLEAR SPECTRA
Authors: ANDREOZZI F. , KNAPP F. , LO IUDICE N. , PORRINO A. , KVASIL J.
Published: May 2009

A method which generates a multiphonon basis through the construction and the iterative solution of a set of equations of motion is adopted to investigate the negative parity spectrum and the structure of the giant dipole resonance in 16 O .
ISOSPIN MIXING OF ISOSPIN-PROJECTED SLATER DETERMINANTS: FORMALISM AND PRELIMINARY APPLICATIONS
Authors: RAFALSKI M. , SATUŁA W. , DOBACZEWSKI J.
Published: May 2009

We report on the development of a new theoretical tool that allows for isospin projection of Slater determinants and we present its first applications. In particular, we determine the isospin mixing in ground states of N = Z nuclei and discuss its dependence on the size of the harmonic-oscillator basis used in the calculations. We also discuss the unphysical contribution to the isospin mixing caused by the spurious isospin-symmetry breaking inherent to the mean-field approach. We show that these contributions may be as large as 30% of the value of the isospin-mixing parameter.
LORENTZIAN-LIKE MODELS OF E1 RADIATIVE STRENGTH FUNCTIONS
Authors: PLUJKO V. A. , GORBACHENKO O. M. , KULICH E. V.
Published: May 2009

Photoabsorption cross sections and dipole γ-decay strength functions are calculated and compared with experimental data to test Lorentzian-like models of their description in the middle-weight and heavy atomic nuclei. Approaches with asymmetric shape of the radiative strength function are recommended for overall estimation of the dipole γ-strengths. The ready-to-use table of giant dipole resonance parameters and their errors are obtained from fitting the theoretical calculations for photoabsorption cross sections to the experimental data. Systematics for giant dipole resonance parameters are given.
COLLECTIVE STATES IN LIGHT Kr ISOTOPES
Authors: PRÓCHNIAK L.
Published: May 2009

The ATDHFB theory was applied to study properties of collective quadrupole states in the 72–76 Kr isotopes. The calculations were performed for SIII, Sly4 and SkP variants of the Skyrme interaction with a seniority, volume δ or surface δ pairing force. Obtained energies and B(E2) transition probabilities are in a reasonable agreement with experimental data, with exception of those of the SkP interaction.
MASS AND ENERGY CORRELATIONS IN FAST TERNARY BREAK-UP OF 197Au + 197Au SYSTEM
Authors:   for CHIMERA Collaboration, SKWIRA-CHALOT I. , SIWEK-WILCZYŃSKA K. , WILCZYŃSKI J.
Published: May 2009

Detailed characteristics of a new reaction mechanism of fast ternary break-up in collisions of a heavy nucleus-nucleus system 197 Au + 197 Au at 15 MeV/nucleon, studied in experiments at the INFN LNS Laboratory in Catania by using the multidetector array CHIMERA are presented. Results of an analysis of mass and energy correlations complement our earlier report that demonstrated the mechanism of aligned re-separation of the Au + Au system into three massive fragments in semi-peripheral collisions.
NON-AXIAL OCTUPOLE DEFORMATION OF A HEAVY NUCLEUS
Authors: JACHIMOWICZ P. , KOWAL M. , ROZMEJ P. , SKALSKI J. , SOBICZEWSKI A.
Published: May 2009

The effect of the non-axial octupole deformation a32(Y32+Y3-2) of heavy nuclei on their potential energy is studied. The study is performed within a macroscopic-microscopic approach. It is found that the largest effect appears for the nucleus 238 Fm and consists in a lowering of the energy by more than 3 MeV with respect to the energy at the spherical configuration.
NEUTRALINO INDUCED MAJORANA NEUTRINO TRANSITION MAGNETIC MOMENTS
Authors: GÓŹDŹ MAREK , KAMIŃSKI WIESŁAW A.
Published: May 2009

We calculate the effect of neutrino-neutralino mixing on the neutrino magnetic moment and compare it with the contribution of pure particle-sparticle loop. We have found that the dominated mechanism is still the bare loop, and that the bilinear insertions on the external neutrino lines contribute at least one order of magnitude weaker.
SMALLEST IRREDUCIBLE OF THE FORM x2-dy2
Authors: DING SHANSHAN
Published: May 2009

It is a classical result that prime numbers of the form x2 + ny2 can be characterized via class field theory for an infinite set of n. In this paper, we derive the function field analogue of the classical result. Then, we apply an effective version of the Chebotarev density theorem to bound the degree of the smallest irreducible of the form x2 - dy2, where x, y, and d are elements of a polynomial ring over a finite field.
INFINITE SERIES WITH HARMONIC NUMBERS AND CENTRAL BINOMIAL COEFFICIENTS
Authors: CHU WENCHANG , ZHENG DEYIN
Published: May 2009

By means of two hypergeometric summation formulae, we establish two large classes of infinite series identities with harmonic numbers and central binomial coefficients. Up to now, these numerous formulae have hidden behind very few known identities of Apéry-like series for Riemann-zeta function, discovered mainly by Lehmer [14] and Elsner [12] as well as Borwein et al. [4, 5, 7]. All the computation and verification are carried out by an appropriately-devised Mathematica package.
PRINCIPALIZATION OF IDEALS IN ABELIAN EXTENSIONS OF NUMBER FIELDS
Authors: BOSCA SÉBASTIEN
Published: May 2009

We give a self-contained proof of a general conjecture of Gras on principalization of ideals in Abelian extensions of a given field L, which was solved by Kurihara in the case of totally real extensions L of the rational field ℚ.

More precisely, for any given extension L/K of number fields, in which at least one infinite place of K totally splits, and for any ideal class cL of L, we construct a finite Abelian extension F/K, in which all infinite places totally split, such that cL become principal in the compositum M = LF.
RESEARCH ON THE MOIRE CHROMATOGRAPHY TECHNIQUE AND ITS APPLICATION
Authors: LI TIANZE , WANG SHUYUN
Published: May 2009

This paper explains the Moire chromatography technique and the optical characteristics when the light crosses the 3D air flow field. Based on this, taking grating, CCD camera, optical filter and diaphragm as the main device, a multi-direction Moire chromatography optical system was designed. The system consists of five detective light paths, in each detective light path there is parallel and same periodic grating and filtering minipore placed on the lens' focal length plane; the grating is used to adjust the space length and angle between the two gratings, and the filtering minipore is used to remove the unorderly high frequency intermix in the Moire fringe. Utilizing the computer escalator method to convert the tested value, the vivid interference fringe of tested parameter can be obtained. The application of this system in precision measurement and medicine is also analyzed and discussed.
NEAR-INFRARED OPTICAL TOMOGRAPHY IMAGE RECONSTRUCTION APPROACH BASED ON TWO-LAYERED BP NEURAL NETWORK
Authors: LI TING , LI WEITAO , QIAN ZHIYU
Published: May 2009

An image-reconstruction approach for optical tomography is presented, in which a two-layered BP neural network is used to distinguish the tumor location. The inverse problem is solved as optimization problem by Femlab software and Levenberg–Marquardt algorithm. The concept of the average optical coefficient is proposed in this paper, which is helpful to understand the distribution of the scattering photon from tumor. The reconstructive [Formula: see text] by the trained network is reasonable for showing the changes of photon number transporting inside tumor tissue. It realized the fast reconstruction of tissue optical properties and provided optical OT with a new method.