bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in
Trypanosoma cruzi
, the Etiological Agent of Chagas' Disease
Authors: King-Keller Sharon , Li Minyong , Smith Alyssa , Zheng Shilong , Kaur Gurpreet , Yang Xiaochuan , Wang Binghe , Docampo Roberto 
Published: July 2010

ABSTRACT

Trypanosoma cruzi
phosphodiesterase (PDE) C (TcrPDEC), a novel and rather unusual PDE in which, unlike all other class I PDEs, the catalytic domain is localized in the middle of the polypeptide chain, is able to hydrolyze cyclic GMP (cGMP), although it prefers cyclic AMP (cAMP), and has a FYVE-type domain in its
N
-terminal region (S. Kunz et al., FEBS J.
272:
6412-6422, 2005). TcrPDEC shows homology to the mammalian PDE4 family members. PDE4 inhibitors are currently under development for the treatment of inflammatory diseases, such as asthma, chronic pulmonary diseases, and psoriasis, and for treating depression and serving as cognitive enhancers. We therefore tested a number of compounds originally synthesized as potential PDE4 inhibitors on
T. cruzi
amastigote growth, and we obtained several useful hits. We then conducted homology modeling of
T. cruzi
PDEC and identified other compounds as potential inhibitors through virtual screening. Testing of these compounds against amastigote growth and recombinant TcrPDEC activity resulted in several potent inhibitors. The most-potent inhibitors were found to increase the cellular concentration of cAMP. Preincubation of cells in the presence of one of these compounds stimulated volume recovery after hyposmotic stress, in agreement with their TcrPDEC inhibitory activity
in vitro
, providing chemical validation of this target. The compounds found could be useful tools in the study of osmoregulation in
T. cruzi
. In addition, their further optimization could result in the development of new drugs against Chagas' disease and other trypanosomiases.
Bioavailability and Efficacy of Levofloxacin against
Francisella tularensis
in the Common Marmoset (
Callithrix jacchus
)
Authors: Nelson Michelle , Lever Mark S. , Dean Rachel E. , Pearce Peter C. , Stevens Daniel J. , Simpson Andrew J. H. 
Published: July 2010

ABSTRACT

Pharmacokinetic and efficacy studies with levofloxacin were performed in the common marmoset (
Callithrix jacchus
) model of inhalational tularemia. Plasma levofloxacin pharmacokinetics were determined in six animals in separate single-dose and multidose studies. Plasma drug concentrations were analyzed using liquid chromatography-tandem mass spectrometry-electrospray ionization. On day 7 of a twice-daily dosing regimen of 40 mg/kg, the levofloxacin half-life, maximum concentration, and area under the curve in marmoset plasma were 2.3 h, 20.9 μg/ml, and 81.4 μg/liter/h, respectively. An efficacy study was undertaken using eight treated and two untreated control animals. Marmosets were challenged with a mean of 1.5 × 10
2
CFU of
Francisella tularensis
by the airborne route. Treated animals were administered 16.5 mg/kg levofloxacin by mouth twice daily, based on the pharmacokinetic parameters, beginning 24 h after challenge. Control animals had a raised core body temperature by 57 h postchallenge and died from infection by day 5. All of the other animals survived, remained afebrile, and lacked overt clinical signs. No bacteria were recovered from the organs of these animals at postmortem after culling at day 24 postchallenge. In conclusion, postexposure prophylaxis with orally administered levofloxacin was efficacious against acute inhalational tularemia in the common marmoset. The marmoset appears to be an appropriate animal model for the evaluation of postexposure therapies.
Comparative
In Vitro
Activity Profiles of Novel Bis-Indole Antibacterials against Gram-Positive and Gram-Negative Clinical Isolates
Authors: Butler Michelle M. , Williams John D. , Peet Norton P. , Moir Donald T. , Panchal Rekha G. , Bavari Sina , Shinabarger Dean L. , Bowlin Terry L. 
Published: July 2010

ABSTRACT

Antimicrobial susceptibilities of 233 Gram-positive and 180 Gram-negative strains to two novel bis-indoles were evaluated. Both compounds were potent inhibitors of Gram-positive bacteria, with MIC
90
values of 0.004 to 0.5 μg/ml. One bis-indole, MBX 1162, exhibited potent activity against all Gram-negative strains, with MIC
90
values of 0.12 to 4 μg/ml, even against high-level-resistant pathogens, and compared favorably to all comparator antibiotics. The bis-indole compounds show promise for the treatment of multidrug-resistant clinical pathogens.
Antimicrobial Mechanism of Action of Transferrins: Selective Inhibition of H
+
-ATPase
Authors: Andrés María T. , Fierro José F. 
Published: July 2010

ABSTRACT

Two bacterial species with different metabolic features, namely,
Pseudomonas aeruginosa
and
Lactococcus lactis
, were used as a comparative experimental model to investigate the antimicrobial target and mechanism of transferrins. In anaerobiosis,
P. aeruginosa
cells were not susceptible to lactoferrin (hLf) or transferrin (hTf). In aerobiosis, the cells were susceptible but O
2
consumption was not modified, indicating that components of the electron transport chain (ETC) were not targeted. However, the respiratory chain inhibitor piericidin A significantly reduced the killing activity of both proteins. Moreover, 2,6-dichlorophenolindophenol (DCIP), a reducing agent that accepts electrons from the ETC coupled to H
+
extrusion, made
P. aeruginosa
susceptible to hLf and hTf in anaerobiosis. These results indicated that active cooperation of the cell was indispensable for the antimicrobial effect. For
L. lactis
cells lacking an ETC, the absence of a detectable transmembrane electrical potential in hLf-treated cells suggested a loss of H
+
-ATPase activity. Furthermore, the inhibition of ATPase activity and H
+
translocation (inverted membrane vesicles) provided direct evidence of the ability of hLf to inhibit H
+
-ATPase in
L. lactis
. Based on these data, we propose that hLf and hTf also inhibit the H
+
-ATPase of respiring
P. aeruginosa
cells. Such inhibition thereby interferes with reentry of H
+
from the periplasmic space to the cytoplasm, resulting in perturbation of intracellular pH and the transmembrane proton gradient. Consistent with this hypothesis, periplasmic H
+
accumulation was prevented by anaerobiosis or by piericidin A or was induced by DCIP in anaerobiosis. Collectively, these results indicate that transferrins target H
+
-ATPase and interfere with H
+
translocation, yielding a lethal effect
in vitro
.
Determination of CEM-101 Activity Tested against Clinical Isolates of
Neisseria meningitidis
from a Worldwide Collection
Authors: Biedenbach Douglas J. , Castanheira Mariana , Jones Ronald N. 
Published: July 2010

ABSTRACT

The activity of CEM-101, a fluoroketolide, was compared to those of 11 other antimicrobial agents using the reference broth microdilution method tested against 103
Neisseria meningitidis
strains, including ciprofloxacin-nonsusceptible isolates with confirmed
gyr
A
(T91I) mutations. Among the tested isolates, 79.6% were serogroup B or C and all isolates were susceptible to ceftriaxone, azithromycin, minocycline, and rifampin. However, penicillin-nonsusceptible strains were observed (15.5%) and susceptibility to trimethoprim-sulfamethoxazole was only 50.5%. CEM-101 was the most active macrolide-like compound (MIC
90
, ≤0.015 μg/ml) compared with MIC
90
s of telithromycin (MIC
90
, 0.03 μg/ml), azithromycin and clarithromycin (MIC
90
, 0.12 μg/ml), and erythromycin (MIC
90
, 0.25 μg/ml). CEM-101 could provide a potent alternative for the prophylaxis of meningococcal disease.
Use of a Mixture of Surrogates for Infectious Bioagents in a Standard Approach to Assessing Disinfection of Environmental Surfaces
Authors: Sabbah Safaa , Springthorpe Susan , Sattar Syed A. 
Published: July 2010

ABSTRACT

We used a mixture of surrogates (
Acinetobacter baumannii
,
Mycobacterium terrae
, hepatitis A virus, and spores of
Geobacillus stearothermophilus
) for bioagents in a standardized approach to test environmental surface disinfectants. Each carrier containing 10 μl of mixture received 50 μl of a test chemical or saline at 22 ± 2°C. Disinfectant efficacy criteria were ≥6 log
10
reduction for the bacteria and the spores and ≥3 log
10
reduction for the virus. Peracetic acid (1,000 ppm) was effective in 5 min against the two bacteria and the spores but not against the virus. Chlorine dioxide (CD; 500 and 1,000 ppm) and domestic bleach (DB; 2,500, 3,500, and 5,000 ppm) were effective in 5 min, except for sporicidal activity, which needed 20 min of contact with either 1,000 ppm of CD or the two higher concentrations of DB.
Identification of
Cryptosporidium
Species and Genotypes in Scottish Raw and Drinking Waters during a One-Year Monitoring Period
Authors: Nichols R. A. B. , Connelly L. , Sullivan C. B. , Smith H. V. 
Published: July 2010

ABSTRACT

We analyzed 1,042
Cryptosporidium
oocyst-positive slides (456 from raw waters and 586 from drinking waters) of which 55.7% contained 1 or 2 oocysts, to determine species/genotypes present in Scottish waters. Two nested PCR-restriction fragment length polymorphism (RFLP) assays targeting different loci (1 and 2) of the hypervariable region of the 18S rRNA gene were used for species identification, and 62.4% of samples were amplified with at least one of the PCR assays. More samples (577 slides; 48.7% from raw water and 51.3% from drinking water) were amplified at locus 1 than at locus 2 (419 slides; 50.1% from raw water and 49.9% from drinking water). PCR at loci 1 and 2 amplified 45.4% and 31.7% of samples containing 1 or 2 oocysts, respectively. We detected both human-infectious and non-human-infectious species/genotype oocysts in Scottish raw and drinking waters.
C
ryptosporidium
andersoni
,
C
ryptosporidium
parvum
, and the
Cryptosporidium
cervine genotype (now
C
ryptosporidium
ubiquitum
) were most commonly detected in both raw and drinking waters, with
C. ubiquitum
being most common in drinking waters (12.5%) followed by
C. parvum
(4.2%) and
C. andersoni
(4.0%). Numerous samples (16.6% total; 18.9% from drinking water) contained mixtures of two or more species/genotypes, and we describe strategies for unraveling their identity. Repetitive analysis for discriminating mixtures proved useful, but both template concentration and PCR assay influenced outcomes. Five novel
Cryptosporidium
spp. (SW1 to SW5) were identified by RFLP/sequencing, and
Cryptosporidium
sp. SW1 was the fourth most common contaminant of Scottish drinking water (3%).
Accidental Selection and Intentional Restoration of Sporulation-DeficientBacillus anthracisMutants
Authors: Sastalla Inka , Rosovitz M. J. , Leppla Stephen H. 
Published: July 2010

ABSTRACTWe demonstrate the frequent accidental enrichment of spontaneous sporulation-deficient mutants ofBacillus anthracison solid medium and identify contributing factors. Mutations inspo0A, encoding the master regulator of sporulation initiation, were found in 38 of 53 mutants. Transductions using bacteriophage CP51 propagated on sporogenic bacteria allowed for the restoration of sporulation phenotypes.
Yersinia enterocolitica
Infection and
tcaA
-Dependent Killing of
Caenorhabditis elegans
Authors: Spanier Britta , Starke Mandy , Higel Fabian , Scherer Siegfried , Fuchs Thilo M. 
Published: July 2010

ABSTRACT

Caenorhabditis elegans
is a validated model to study bacterial pathogenicity. We report that
Yersinia enterocolitica
strains W22703 (biovar 2, serovar O:9) and WA314 (biovar 1B, serovar O:8) kill
C. elegans
when feeding on the pathogens for at least 15 min before transfer to the feeding strain
Escherichia coli
OP50. The killing by
Yersinia enterocolitica
requires viable bacteria and, in contrast to that by
Yersinia pestis
and
Yersinia pseudotuberculosis
strains, is biofilm independent. The deletion of
tcaA
encoding an insecticidal toxin resulted in an OP50-like life span of
C. elegans
, indicating an essential role of TcaA in the nematocidal activity of
Y. enterocolitica
. TcaA alone is not sufficient for nematocidal activity because
E. coli
DH5α overexpressing TcaA did not result in a reduced
C. elegans
life span. Spatial-temporal analysis of
C. elegans
infected with green fluorescent protein-labeled
Y. enterocolitica
strains showed that
Y. enterocolitica
colonizes the nematode intestine, leading to an extreme expansion of the intestinal lumen. By low-dose infection with W22703 or DH5α followed by transfer to
E. coli
OP50, proliferation of
Y. enterocolitica
, but not
E. coli
, in the intestinal lumen of the nematode was observed. The titer of W22703 cells within the worm increased to over 10
6
per worm 4 days after infection while a significantly lower number of a
tcaA
knockout mutant was recovered. A strong expression of
tcaA
was observed during the first 5 days of infection.
Y. enterocolitica
WA314 (biovar 1B, serovar O:8) mutant strains lacking the
yadA
,
inv
,
yopE
, and
irp1
genes known to be important for virulence in mammals were not attenuated or only slightly attenuated in their toxicity toward the nematode, suggesting that these factors do not play a significant role in the colonization and persistence of this pathogen in nematodes. In summary, this study supports the hypothesis that
C. elegans
is a natural host and nutrient source of
Y. enterocolitica
.
APorphyromonas gingivalisMutant Defective in a Putative Glycosyltransferase Exhibits Defective Biosynthesis of the Polysaccharide Portions of Lipopolysaccharide, Decreased Gingipain Activities, Strong Autoaggregation, and Increased Biofilm Formation
Authors: Yamaguchi Mikiyo , Sato Keiko , Yukitake Hideharu , Noiri Yuichiro , Ebisu Shigeyuki , Nakayama Koji 
Published: July 2010

ABSTRACTThe Gram-negative anaerobic bacteriumPorphyromonas gingivalisis a major pathogen in periodontal disease, one of the biofilm-caused infectious diseases. The bacterium possesses potential virulence factors, including fimbriae, proteinases, hemagglutinin, lipopolysaccharide (LPS), and outer membrane vesicles, and some of these factors are associated with biofilm formation; however, the precise mechanism of biofilm formation is still unknown. Colonial pigmentation of the bacterium on blood agar plates is related to its virulence. In this study, we isolated a nonpigmented mutant that had an insertion mutation within the new gene PGN_1251 (gtfB) by screening a transposon insertion library. The gene shares homology with genes encoding glycosyltransferase 1 of several bacteria. ThegtfBmutant was defective in biosynthesis of both LPSs containing O side chain polysaccharide (O-LPS) and anionic polysaccharide (A-LPS). The defect in the gene resulted in a complete loss of surface-associated gingipain proteinases, strong autoaggregation, and a marked increase in biofilm formation, suggesting that polysaccharide portions of LPSs influence attachment of gingipain proteinases to the cell surface, autoaggregation, and biofilm formation ofP. gingivalis.
Effects ofInVitroHIV-1 Infection on Mycobacterial Growth in Peripheral Blood Monocyte-Derived Macrophages
Authors: Pathak Sharad , Wentzel-Larsen Tore , Åsjö Birgitta 
Published: July 2010

ABSTRACTCoinfection with human immunodeficiency virus type 1 (HIV-1) and opportunistic mycobacteria, especiallyMycobacteriumtuberculosis, is a cause of high morbidity and mortality worldwide. Both mycobacteria and HIV-1 may infect macrophages, and thus, coinfection may generate conditions that reciprocally influence the intracellular replication of the pathogens. Elucidation of the interaction between HIV-1 and mycobacteria in their common target cell is important for understanding pathogenesis in coinfected individuals. In this study, we investigated the effects ofinvitroHIV-1 infection on the growth ofM.tuberculosis,M.avium, andM.paratuberculosisin human peripheral blood monocyte-derived macrophages. Interestingly, HIV-1 infection induced a greater bacterial burden in coinfected cell cultures for all of the mycobacterial species tested and specifically induced accelerated growth ofM.tuberculosiswith a reduced mean generation time. The interaction of HIV-1 andM.tuberculosiswas especially detrimental to the host cell, causing a significant synergistic reduction in macrophage viability. Also, inM.tuberculosis/HIV-1-coinfected cultures, increased levels of interleukin-1β (IL-1β), IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor were observed and viral replication was enhanced. Overall, the present data suggest that HIV-1 infection of macrophages may impair their ability to contain mycobacterial growth. Furthermore, coinfection with HIV-1 andM.tuberculosisseems to give rise to synergistic effects at the cellular level that mutually enhance the replication of both pathogens. This may, in part, contribute to the increased morbidity and mortality seen in coinfected individuals.
Cytotoxicity of the
Bacillus cereus
Nhe Enterotoxin Requires Specific Binding Order of Its Three Exoprotein Components
Authors: Lindbäck Toril , Hardy Simon P. , Dietrich Richard , Sødring Marianne , Didier Andrea , Moravek Maximilian , Fagerlund Annette , Bock Stefanie , Nielsen Carina , Casteel Maximilian , Granum Per Einar , Märtlbauer Erwin 
Published: July 2010

ABSTRACT

This study focuses on the interaction of the three components of the
Bacillus cereus
Nhe enterotoxin with particular emphasis on the functional roles of NheB and NheC. The results demonstrated that both NheB and NheC were able to bind to Vero cells directly while NheA lacked this ability. It was also shown that Nhe-induced cytotoxicity required a specific binding order of the individual components whereby the presence of NheC in the priming step as well as the presence of NheA in the final incubation step was mandatory. Priming of cells with NheB alone and addition of NheA plus NheC in the second step failed to induce toxic effects. Furthermore, in solution, excess NheC inhibited binding of NheB to Vero cells, whereas priming of cells with excess NheC resulted in full toxicity if unbound NheC was removed before addition of NheB. By using mutated NheC proteins where the two cysteine residues in the predicted β-tongue were replaced with glycine (NheC
cys−
) or where the entire hydrophobic stretch was deleted (NheC
hr−
), the predicted hydrophobic β-tongue of NheC was found essential for binding to cell membranes but not for interaction with NheB in solution. All data presented here are compatible with the following model. The first step in the mode of action of Nhe is associated with binding of NheC and NheB to the cell surface and probably accompanied by conformational changes. These events allow subsequent binding of NheA, leading to cell lysis.
The Effects of Auricular Acupressure on Weight Loss and Serum Lipid Levels in Overweight Adolescents
Authors: Hsieh Ching Hsiu 
Published: July 2010

Auricular acupressure is widely used to reduce body weight. The current study was designed to test the efficacy of auricular acupressure on weight reduction and serum total cholesterol (TC), total triglycerides (TG), high density lipids (HDL) and low density lipids (LDL) in an eight-week, randomized controlled trial of three groups of 84 adolescents aged 18–20 with a body mass index (BMI) of 23 or higher. The control group received tape treatment only and the other two experimental groups were administered acupressure using either Japanese Magnetic Pearls or vaccaria seeds. All three groups were educated on reduced calorie diets, physical activity, weight loss, and lifestyle modification. During the eight-week trial, all participants were seen weekly for 10 min per session. Anthropometric measurements of BMI and TC, TG, HDL, and LDL were performed at weeks 0 and 8 for all participants. Changes in BMI, TC, TG, HDL, and LDL were calculated from baseline to trial completion. BMI was significantly increased in the control group by +0.0457 ( p < 0.0001), it was decreased in the Japanese Magnetic Pearl group by -0.6982 ( p < 0.0001) and the vaccaria seed group by -1.2341 ( p < 0.0001). All three groups showed significant increases in TC, TG, HDL, and LDL. In conclusion, the current study shows that auricular acupressure employing Japanese Magnetic Pearls or vaccaria seeds can decrease BMI, with the vaccaria seed method showing the greatest reduction. Auricular acupressure did not result in decreased TC, TG, HDL, or LDL in the current eight-week protocol.
EARLY BUFFER PLANNING WITH CONGESTION CONTROL USING BUFFER REQUIREMENT MAP
Authors: JAHANIAN ALI , ZAMANI MORTEZA SAHEB 
Published: July 2010

Buffer insertion plays an important role in circuit performance and signal integrity especially in deep submicron technologies. The stage at which buffers are inserted in a design has a large impact on the design quality. Early buffer insertion may cause misestimation due to unknown cell locations whereas buffer insertion after placement may not be very effective because the cell locations have been fixed and buffer resources may be distributed inappropriately. In this paper, a buffer planning algorithm for floor-placement design flow is presented. This algorithm creates a map of buffer requirements in various regions of the design at the floorplanning stage and then enforces the detailed placer to distribute white spaces with respect to the estimated buffer requirement map. Experimental results show that the proposed method improves the performance of attempted circuits with fewer buffers. Furthermore, results show that congestion, routability and design convergence are improved and the auxiliary loops are avoided in the proposed design flow. Our analyses and experiments show that the CPU time overhead of this algorithm is very small.
Carotid Plaque Inflammation Is Associated With Cerebral Microembolism in Patients With Recent Transient Ischemic Attack or Stroke
Authors: Moustafa Ramez Reda , Izquierdo-Garcia David , Fryer Tim D. , Graves Martin J. , Rudd James H.F. , Gillard Jonathan H. , Weissberg Peter L. , Baron Jean-Claude , Warburton Elizabeth A. 
Published: July 2010

Background—

Cerebral infarcts distal to carotid stenoses are thought to be caused by emboli from inflamed, destabilized plaques. We hypothesized that microembolic signals (MES) on transcranial Doppler will be associated with carotid plaque inflammation on
18
F fluorodeoxyglucose positron-emission tomography (FDG PET) in recently symptomatic patients.

Methods and Results—

Sixteen patients presenting with recent (47±31 days) anterior circulation transient ischemic attack or minor stroke and 50% to 99% stenosis of the ipsilateral carotid bifurcation underwent FDG PET, high-resolution black-blood carotid MRI, and transcranial Doppler for detection of MES. Patients with potential cardiac sources of emboli or contralateral MES were excluded. Regions of interest defined on the coregistered MRI were used to measure FDG standardized uptake values (with Rousset partial volume correction) from the index and contralateral carotid plaques and artery. Ipsilateral MES were detected in 7 patients (MES+ group) and absent in 8 (MES− group). There was a significant difference in index-to-contralateral plaque standardized uptake value ratio between MES+ (median, 1.05; first to third quartile, 0.96 to 1.32) and MES− (median, 0.76; first to third quartile, 0.62 to 0.94) patients (
P
=0.005). The interval from symptom onset to PET and percent index carotid stenosis were not different between the 2 groups (
P
=0.68 and
P
=0.48, respectively).

Conclusions—
In this sample of recently symptomatic patients with carotid stenosis, an association was found between in vivo measures of plaque inflammation detected by FDG PET and the presence of transcranial Doppler MES. These findings strengthen the notion that embolic events distal to carotid stenoses are related to plaque inflammation, and FDG PET may be useful in the investigation of culprit carotid lesions.