bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription
Authors: Kumari Namita , Iordanskiy Sergey , Kovalskyy Dmytro , Breuer Denitra , Niu Xiaomei , Lin Xionghao , Xu Min , Gavrilenko Konstantin , Kashanchi Fatah , Dhawan Subhash , Nekhai Sergei 
Published: August 2014

ABSTRACT
HIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (PPY)-based iron chelators were synthesized and examined for their effects on cellular iron, HIV-1 inhibition, and cytotoxicity. Activities of CDK2 and CDK9, expression of CDK9-dependent and CDK2-inhibitory mRNAs, NF-κB expression, and HIV-1- and NF-κB-dependent transcription were determined. PPY-based iron chelators significantly inhibited HIV-1, with minimal cytotoxicity, in cultured and primary cells chronically or acutely infected with HIV-1 subtype B, but they had less of an effect on HIV-1 subtype C. Iron chelators upregulated the expression of IκB-α, with increased accumulation of cytoplasmic NF-κB. The iron chelators inhibited CDK2 activity and reduced the amount of CDK9/cyclin T1 in the large P-TEFb complex. Iron chelators reduced HIV-1 Gag and Env mRNA synthesis but had no effect on HIV-1 reverse transcription. In addition, iron chelators moderately inhibited basal HIV-1 transcription, equally affecting HIV-1 and Sp1- or NF-κB-driven transcription. By virtue of their involvement in targeting several key steps in HIV-1 transcription, these novel iron chelators have the potential for the development of new therapeutics for the treatment of HIV-1 infection.
In Vivo
Monitoring of Staphylococcus aureus Biofilm Infections and Antimicrobial Therapy by [
18
F]Fluoro-Deoxyglucose–MicroPET in a Mouse Model
Authors: Garrido Victoria , Collantes María , Barberán Montserrat , Peñuelas Iván , Arbizu Javier , Amorena Beatriz , Grilló María-Jesús 
Published: August 2014

ABSTRACT

A mouse model was developed for
in vivo
monitoring of infection and the effect of antimicrobial treatment against
Staphylococcus aureus
biofilms, using the [
18
F]fluoro-deoxyglucose–MicroPET ([
18
F]FDG-MicroPET) image technique. In the model, sealed Vialon catheters were briefly precolonized with
S. aureus
strains ATCC 15981 or V329, which differ in cytotoxic properties and biofilm matrix composition. After subcutaneous implantation of catheters in mice, the
S. aureus
strain differences found in bacterial counts and the inflammatory reaction triggered were detected by the regular bacteriological and histological procedures and also by [
18
F]FDG-MicroPET image signal intensity determinations in the infection area and regional lymph node. Moreover, [
18
F]FDG-MicroPET imaging allowed the monitoring of the rifampin treatment effect, identifying the periods of controlled infection and those of reactivated infection due to the appearance of bacteria naturally resistant to rifampin. Overall, the mouse model developed may be useful for noninvasive
in vivo
determinations in studies on
S. aureus
biofilm infections and assessment of new therapeutic approaches.
The
msaABCR
Operon Regulates Resistance in Vancomycin-Intermediate Staphylococcus aureus Strains
Authors: Samanta Dhritiman , Elasri Mohamed O. 
Published: August 2014

ABSTRACT

Vancomycin-intermediate
Staphylococcus aureus
(VISA) strains present an increasingly difficult problem in terms of public health. However, the molecular mechanism for this resistance is not yet understood. In this study, we define the role of the
msaABCR
operon in vancomycin resistance in three clinical VISA strains, i.e., Mu50, HIP6297, and LIM2. Deletion of the
msaABCR
operon resulted in significant decreases in the vancomycin MIC (from 6.25 to 1.56 μg/ml) and significant reductions of cell wall thickness in strains Mu50 and HIP6297. Growth of the mutants in medium containing vancomycin at concentrations greater than 2 μg/ml resulted in decreases in the growth rate, compared with the wild-type strains. Mutation of the
msaABCR
operon also reduced the binding capacity for vancomycin. We conclude that the
msaABCR
operon contributes to resistance to vancomycin and cell wall synthesis in
S. aureus
.
Effect of Fosamprenavir-Ritonavir on the Pharmacokinetics of Dolutegravir in Healthy Subjects
Authors: Song Ivy , Borland Julie , Chen Shuguang , Peppercorn Amanda , Wajima Toshihiro , Piscitelli Stephen C. 
Published: August 2014

ABSTRACT

Dolutegravir (DTG) is an HIV integrase inhibitor (INI) with demonstrated activity in INI-naive and INI-resistant patients. The objective of this open-label, 2-period, single-sequence study was to evaluate the effect of fosamprenavir-ritonavir (FPV-RTV) on the steady-state plasma pharmacokinetics of DTG. Twelve healthy subjects received 50 mg DTG once daily for 5 days (period 1), followed by 10 days of 50 mg DTG once daily in combination with 700/100 mg FPV-RTV every 12 h (period 2). All doses were administered in the fasting state. Serial pharmacokinetic samples for DTG and amprenavir and safety assessments were obtained throughout the study. Noncompartmental pharmacokinetic analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated for within-subject treatment comparison. Fosamprenavir-ritonavir decreased the DTG area under the concentration-time curve, maximum concentration in plasma, and concentration in plasma at the end of the dosing interval by 35%, 24%, and 49%, respectively. Both DTG and DTG with FPV-RTV were well tolerated; no subject withdrew because of adverse events. The most frequently reported drug-related adverse events were rash, abnormal dreams, and nasopharyngitis. The modest decrease in DTG exposure when it was coadministered with FPV-RTV is not considered clinically significant, and DTG dose adjustment is not required with coadministration of FPV-RTV in INI-naive patient populations on the basis of established “no-effect” boundaries of DTG. In the INI-resistant population, as a cautionary measure, alternative combinations that do not include FPV-RTV should be considered. (This study has been registered at
ClinicalTrials.gov
under identifier NCT01209065.)
Plasmodium falciparum and Plasmodium vivax Genotypes and Efficacy of Intermittent Preventive Treatment in Papua New Guinea
Authors: Barnadas Celine , Senn Nicolas , Iga Jonah , Timinao Lincoln , Javati Sarah , Malau Elisheba , Rarau Patricia , Reeder John C. , Siba Peter , Karunajeewa Harin , Zimmerman Peter A. , Davis Timothy M. , Mueller Ivo 
Published: August 2014

ABSTRACT

Intermittent preventive treatment of infants (IPTi) reduces early childhood malaria-related morbidity. While genotypic drug resistance markers have proven useful in predicting the efficacy of antimalarial drugs in case management, there are few equivalent data relating to their protective efficacy when used as IPTi. The present data from an IPTi trial in Papua New Guinea demonstrate how these markers can predict protective efficacy of IPTi for both
Plasmodium falciparum
and
Plasmodium vivax
.
Linezolid-Resistant Staphylococcus aureus Strain 1128105, the First Known Clinical Isolate Possessing thecfrMultidrug Resistance Gene
Authors: Locke Jeffrey B. , Zuill Douglas E. , Scharn Caitlyn R. , Deane Jennifer , Sahm Daniel F. , Denys Gerald A. , Goering Richard V. , Shaw Karen J. 
Published: August 2014

ABSTRACTThe Cfr methyltransferase confers resistance to six classes of drugs which target the peptidyl transferase center of the 50S ribosomal subunit, including some oxazolidinones, such as linezolid (LZD). The mobilecfrgene was identified in European veterinary isolates from the late 1990s, although the earliest report of a clinicalcfr-positive strain was the 2005 Colombian methicillin-resistantStaphylococcus aureus(MRSA) isolate CM05. Here, through retrospective analysis of LZDrclinical strains from a U.S. surveillance program, we identified acfr-positive MRSA isolate, 1128105, from January 2005, predating CM05 by 5 months. Molecular typing of 1128105 revealed a unique pulsed-field gel electrophoresis (PFGE) profile most similar to that of USA100,spatype t002, and multilocus sequence type 5 (ST5). In addition tocfr, LZD resistance in 1128105 is partially attributed to the presence of a single copy of the 23S rRNA gene mutation T2500A. Transformation of the ∼37-kb conjugative p1128105cfr-bearing plasmid from 1128105 intoS. aureusATCC 29213 background strains was successful in recapitulating the Cfr antibiogram, as well as resistance to aminoglycosides and trimethoprim. A 7-kbcfr-containing region of p1128105 possessed sequence nearly identical to that found in the Chinese veterinaryProteus vulgarisisolate PV-01 and in U.S. clinicalS. aureusisolate 1900, although the presence of IS431-like sequences is unique to p1128105. Thecfrgene environment in this early clinicalcfr-positive isolate has now been identified in Gram-positive and Gram-negative strains of clinical and veterinary origin and has been associated with multiple mobile elements, highlighting the versatility of this multidrug resistance gene and its potential for further dissemination.
Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age
Authors: Zhao Wei , Hill Helen , Le Guellec Chantal , Neal Tim , Mahoney Sarah , Paulus Stephane , Castellan Charlotte , Kassai Behrouz , van den Anker Johannes N. , Kearns Gregory L. , Turner Mark A. , Jacqz-Aigrain Evelyne 
Published: August 2014

ABSTRACT
Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.
PBP2a Mutations Causing High-Level Ceftaroline Resistance in Clinical Methicillin-Resistant Staphylococcus aureus Isolates
Authors: Long S. Wesley , Olsen Randall J. , Mehta Shrenik C. , Palzkill Timothy , Cernoch Patricia L. , Perez Katherine K. , Musick William L. , Rosato Adriana E. , Musser James M. 
Published: August 2014

ABSTRACT

Ceftaroline is the first member of a novel class of cephalosporins approved for use in the United States. Although prior studies have identified eight ceftaroline-resistant methicillin-resistant
Staphylococcus aureus
(MRSA) isolates in Europe and Asia with MICs ranging from 4 to 8 mg/liter, high-level resistance to ceftaroline (>32 mg/liter) has not been described in MRSA strains isolated in the United States. We isolated a ceftaroline-resistant (MIC > 32 mg/liter) MRSA strain from the blood of a cystic fibrosis patient and five MRSA strains from the respiratory tract of this patient. Whole-genome sequencing identified two amino acid-altering mutations uniquely present in the ceftaroline-binding pocket of the transpeptidase region of penicillin-binding protein 2a (PBP2a) in ceftaroline-resistant isolates. Biochemical analyses and the study of isogenic mutant strains confirmed that these changes caused ceftaroline resistance. Thus, we identified the molecular mechanism of ceftaroline resistance in the first MRSA strain with high-level ceftaroline resistance isolated in the United States.
Efficacy of Entecavir-Tenofovir Combination Therapy for Chronic Hepatitis B Patients with Multidrug-Resistant Strains
Authors: Lee Yun Bin , Lee Jeong-Hoon , Lee Dong Hyeon , Cho Hyeki , Ahn Hongkeun , Choi Won-Mook , Cho Young Youn , Lee Minjong , Yoo Jeong-Ju , Cho Yuri , Cho Eun Ju , Yu Su Jong , Kim Yoon Jun , Yoon Jung-Hwan , Kim Chung Yong , Lee Hyo-Suk 
Published: August 2014

ABSTRACTThe emergence of multidrug-resistant (MDR) strains of hepatitis B virus (HBV) is a major concern. This study aimed to investigate the efficacy and safety of combination therapy with entecavir (ETV) plus tenofovir disoproxil fumarate (TDF) against MDR HBV. To adjust for differences in baseline characteristics, inverse probability weighting (IPW) using propensity scores for the entire cohort and weighted Cox proportional hazards models were applied. Ninety-three consecutive patients who were treated with ETV-TDF combination therapy for >6 months were included; at baseline, 45 were infected with HBV strains with genotypic resistance to lamivudine (LAM) and ETV (the LAM/ETV-R group), 28 with strains resistant to LAM and adefovir (ADV) (the LAM/ADV-R group), and 20 with strains resistant to LAM, ETV, and ADV (the LAM/ETV/ADV-R group). The median duration of rescue therapy was 13.0 (range, 6.7 to 31.7) months. Seventy-four of 93 patients (79.6%) achieved complete virologic suppression, after a median of 4.5 (95% confidence interval, 3.0 to 6.0) months. The cumulative probability of complete virologic suppression at month 6 was 63.6% (55.7%, 75.0%, and 65.0% in the LAM/ETV-R, LAM/ADV-R, and LAM/ETV/ADV-R groups, respectively). During the treatment period, these probabilities were not significantly different across the resistance profiles before and after IPW (P= 0.072 andP= 0.510, respectively). In multivariate analysis, a lower baseline HBV DNA level, but not resistance profiles, was an independent predictor of complete virologic suppression. Renal dysfunction was not observed during the treatment period. In conclusion, rescue therapy with ETV-TDF combination is efficient and safe in patients infected with MDR HBV strains regardless of the antiviral drug resistance profiles.
Dose Response of Listeria monocytogenes Invasion, Fetal Morbidity, and Fetal Mortality after Oral Challenge in Pregnant and Nonpregnant Mongolian Gerbils
Authors: Roulo Rebecca M. , Fishburn Jillian D. , Amosu Mayowa , Etchison Ashley R. , Smith Mary Alice 
Published: August 2014

ABSTRACT

Listeria monocytogenes
is a food-borne pathogen that can result in adverse pregnancy outcomes, such as stillbirth or premature delivery. The Mongolian gerbil was recently proposed as the most appropriate small-animal model of listeriosis due to its susceptibility to the same invasion pathways as humans. The objectives of this study were to investigate invasion and adverse pregnancy outcomes in gerbils orally exposed to
L. monocytogenes
, to compare the dose-response data to those of other animal models, and to investigate differences in the responses of pregnant versus nonpregnant gerbils. Gerbils were orally exposed to 0 (control), 10
3
, 10
5
, 10
7
, or 10
9
CFU
L. monocytogenes
in whipping cream.
L. monocytogenes
was recovered in a dose-dependent manner from fecal samples, adult organs, and pregnancy-associated tissues. Dams exposed to 10
9
CFU had more invaded organs and higher concentrations of
L. monocytogenes
in almost all organs than nonpregnant animals, though no differences in fecal shedding were seen between the two groups. Adverse pregnancy outcomes occurred only in the dams treated with 10
9
CFU. A 50% infectivity dose (ID
50
) of 2.60 × 10
6
CFU for fetuses was calculated by fitting the data to a logistic model. Our results suggest that the 50% lethal dose (LD
50
) falls within the range of 5 × 10
6
to 5 × 10
8
CFU. This range includes the guinea pig and nonhuman primate LD
50
s, but the observation that
L. monocytogenes
-induced stillbirths can be seen in guinea pigs and primates exposed to lower doses than those at which stillbirths were seen in gerbils indicates that gerbils are not more sensitive to
L. monocytogenes
invasion.
SSP3 Is a Novel Plasmodium yoelii Sporozoite Surface Protein with a Role in Gliding Motility
Authors: Harupa Anke , Sack Brandon K. , Lakshmanan Viswanathan , Arang Nadia , Douglass Alyse N. , Oliver Brian G. , Stuart Andrew B. , Sather D. Noah , Lindner Scott E. , Hybiske Kevin , Torii Motomi , Kappe Stefan H. I. 
Published: August 2014

ABSTRACTPlasmodiumsporozoites develop within oocysts in the mosquito midgut wall and then migrate to the salivary glands. After transmission, they embark on a complex journey to the mammalian liver, where they infect hepatocytes. Proteins on the sporozoite surface likely mediate multiple steps of this journey, yet only a few sporozoite surface proteins have been described. Here, we characterize a novel, conserved sporozoite surface protein (SSP3) in the rodent malaria parasitePlasmodium yoelii. SSP3 is a putative type I transmembrane protein unique toPlasmodium. By using epitope tagging and SSP3-specific antibodies in conjunction with immunofluorescence microscopy, we showed that SSP3 is expressed in mosquito midgut oocyst sporozoites, exhibiting an intracellular localization. In sporozoites derived from the mosquito salivary glands, however, SSP3 localized predominantly to the sporozoite surface as determined by immunoelectron microscopy. However, the ectodomain of SSP3 appeared to be inaccessible to antibodies in nonpermeabilized salivary gland sporozoites. Antibody-induced shedding of the major surface protein circumsporozoite protein (CSP) exposed the SSP3 ectodomain to antibodies in some sporozoites. Targeted deletion ofSSP3adversely affectedin vitrosporozoite gliding motility, which, surprisingly, impacted neither their cell traversal capacity, host cell invasionin vitro, nor infectivityin vivo. Together, these data reveal a previously unappreciated complexity of thePlasmodiumsporozoite surface proteome and the roles of surface proteins in distinct biological activities of sporozoites.
Involvement of Stress-Related Genes
polB
and
PA14_46880
in Biofilm Formation of Pseudomonas aeruginosa
Authors: Alshalchi Sahar A. , Anderson Gregory G. 
Published: August 2014

ABSTRACT

Chronic infections of
Pseudomonas aeruginosa
are generally established through production of biofilm. During biofilm formation, production of an extracellular matrix and establishment of a distinct bacterial phenotype make these infections difficult to eradicate. However, biofilm studies have been hampered by the fact that most assays utilize nonliving surfaces as biofilm attachment substrates. In an attempt to better understand the mechanisms behind
P. aeruginosa
biofilm formation, we performed a genetic screen to identify novel factors involved in biofilm formation on biotic and abiotic surfaces. We found that deletion of genes
polB
and
PA14_46880
reduced biofilm formation significantly compared to that in the wild-type strain PA14 in an abiotic biofilm system. In a biotic biofilm model, wherein biofilms form on cultured airway cells, the Δ
polB
and Δ
PA14_46880
strains showed increased cytotoxic killing of the airway cells independent of the total number of bacteria bound. Notably, deletion mutant strains were more resistant to ciprofloxacin treatment. This phenotype was linked to decreased expression of
algR
, an alginate transcriptional regulatory gene, under ciprofloxacin pressure. Moreover, we found that pyocyanin production was increased in planktonic cells of mutant strains. These results indicate that inactivation of
polB
and
PA14_46880
may inhibit transition of
P. aeruginosa
from a more acute infection lifestyle to the biofilm phenotype. Future investigation of these genes may lead to a better understanding of
P. aeruginosa
biofilm formation and chronic biofilm infections.
Acidosis Potentiates the Host Proinflammatory Interleukin-1β Response to Pseudomonas aeruginosa Infection
Authors: Torres Iviana M. , Patankar Yash R. , Shabaneh Tamer B. , Dolben Emily , Hogan Deborah A. , Leib David A. , Berwin Brent L. 
Published: August 2014

ABSTRACTInfection byPseudomonas aeruginosa, and bacteria in general, frequently promotes acidification of the local microenvironment, and this is reinforced by pulmonary exertion and exacerbation. However, the consequence of an acidic environment on the host inflammatory response toP. aeruginosainfection is poorly understood. Here we report that the pivotal cellular and host proinflammatory interleukin-1β (IL-1β) response, which enables host clearance of the infection but can produce collateral inflammatory damage, is increased in response toP. aeruginosainfection within an acidic environment. Synergistic mechanisms that promote increased IL-1β release in response toP. aeruginosainfection in an acidic environment are increased pro-IL-1β induction and increased caspase-1 activity, the latter being dependent upon a functional type III secretion system of the bacteria and the NLRC4 inflammasome of the host. Using anin vivoperitonitis model, we have validated that the IL-1β inflammatory response is increased in mice in response toP. aeruginosainfection within an acidic microenvironment. These data reveal novel insights into the regulation and exacerbation of inflammatory responses toP. aeruginosa.
Immunoproteomic Analysis To Identify Shiga Toxin-Producing Escherichia coli Outer Membrane Proteins Expressed during Human Infection
Authors: Montero David , Orellana Paz , Gutiérrez Daniela , Araya Daniela , Salazar Juan Carlos , Prado Valeria , Oñate Ángel , del Canto Felipe , Vidal Roberto 
Published: August 2014

ABSTRACT

Shiga-toxin producing
Escherichia coli
(STEC) is the etiologic agent of acute diarrhea, dysentery, and hemolytic-uremic syndrome (HUS). There is no approved vaccine for STEC infection in humans, and antibiotic use is contraindicated, as it promotes Shiga toxin production. In order to identify STEC-associated antigens and immunogenic proteins, outer membrane proteins (OMPs) were extracted from STEC O26:H11, O103, O113:H21, and O157:H7 strains, and commensal
E. coli
strain HS was used as a control. SDS-PAGE, two-dimensional-PAGE analysis, Western blot assays using sera from pediatric HUS patients and controls, and matrix-assisted laser desorption ionization–tandem time of flight analyses were used to identify 12 immunogenic OMPs, some of which were not reactive with control sera. Importantly, seven of these proteins have not been previously reported to be immunogenic in STEC strains. Among these seven proteins, OmpT and Cah displayed IgG and IgA reactivity with sera from HUS patients. Genes encoding these two proteins were present in a majority of STEC strains. Knowledge of the antigens produced during infection of the host and the immune response to those antigens will be important for future vaccine development.