bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship Between Adaptive Morphological and Electrophysiological Remodeling of the Left Ventricle in Young Athletes After an 8-Month Period of Sports Training
Authors: Krenc Zbigniew 
Published: July 2015

Purpose:The aim of this investigation was to assess the influence of an 8-month physical training period on left ventricular voltages identified by resting ECG in relation to changes in left ventricle mass in adolescent athletes.Methods:The study encompassed 28 adolescents aged 13 years (14 boys and 14 girls) from a sports secondary school. Clinical assessment was performed on all athletes before and after 8 months of physical training.Results:Sokolov-Lyon voltage index, Cornell voltage index, and maximum spatial QRS vector magnitude demonstrated statistically significant decline during the study period. The specific potential of the myocardium also significantly decreased during 8 months of training. The Sokolov-Lyon voltage criterion for left ventricular hypertrophy was fulfilled in 9 athletes (32.1%) at the beginning of the observation and only in 3 athletes (10.7%) at the end of the study. On the other hand, mean left ventricular mass and mean left ventricular mass index significantly increased after long-term training. No statistically significant correlations were identified between relative changes in left ventricular mass and QRS voltages.Conclusion:An early period of intensive physical training in young athletes is associated with a decrease in QRS amplitude and a relative voltage deficit over the left ventricle.
Identification of a Novel NDM Variant, NDM-13, from a Multidrug-Resistant Escherichia coli Clinical Isolate in Nepal
Authors: Shrestha Basudha , Tada Tatsuya , Miyoshi-Akiyama Tohru , Shimada Kayo , Ohara Hiroshi , Kirikae Teruo , Pokhrel Bharat M. 
Published: July 2015

ABSTRACT

A novel New Delhi metallo-β-lactamase, NDM-13, was identified in a carbapenem-resistant
Escherichia coli
clinical isolate obtained from the urine of a patient in Nepal. The enzymatic activity of NDM-13 against β-lactams was similar to that of NDM-1. However, NDM-13 displayed significantly higher
k
cat
/

K
m

ratios for cefotaxime. The genetic environment of
bla
NDM-13
was determined to be
tnpA
-IS
30-bla
NDM-13
-
ble
MBL
-
trpF-dsbC-cutA-groES-groL
, with
bla
NDM-13
located within the chromosome.
Development of a Novel Formulation with Hypericin To Treat Cutaneous Leishmaniasis Based on Photodynamic Therapy inIn VitroandIn VivoStudies
Authors: Montoya Andrés , Daza Alejandro , Muñoz Diana , Ríos Karina , Taylor Viviana , Cedeño David , Vélez Iván D. , Echeverri Fernando , Robledo Sara M. 
Published: July 2015

ABSTRACTAn evaluation of the leishmanicidal activityin vitroandin vivoof hypericin, an expanded-spectrum photosensitizer found inHypericum perforatum, is presented. Hypericin was evaluated against intracellular amastigotesin vitroofLeishmania(Viannia)panamensis. A topical formulation containing 0.5% hypericin was developed and assayedin vivoin a hamster model of cutaneous leishmaniasis. Results demonstrate that hypericin induces a significant antiamastigote effectin vitroagainstL. panamensisby decreasing the number of parasites inside infected cells. The topical formulation of 0.5% hypericin allows healing ofL. panamensis-induced lesions upon a topical application of 40 mg/day plus visible-light irradiation (5 J/cm2, 15 min), twice a week for 3 weeks.
Discovery of Bacterial Fatty Acid Synthase Type II Inhibitors Using a Novel Cellular Bioluminescent Reporter Assay
Authors: Wallace Joselynn , Bowlin Nicholas O. , Mills Debra M. , Saenkham Panatda , Kwasny Steven M. , Opperman Timothy J. , Williams John D. , Rock Charles O. , Bowlin Terry L. , Moir Donald T. 
Published: July 2015

ABSTRACT

Novel, cellular, gain-of-signal, bioluminescent reporter assays for fatty acid synthesis type II (FASII) inhibitors were constructed in an efflux-deficient strain of
Pseudomonas aeruginosa
and based on the discovery that FASII genes in
P. aeruginosa
are coordinately upregulated in response to pathway disruption. A screen of 115,000 compounds identified a series of sulfonamidobenzamide (SABA) analogs, which generated strong luminescent signals in two FASII reporter strains but not in four control reporter strains designed to respond to inhibitors of pathways other than FASII. The SABA analogs selectively inhibited lipid biosynthesis in
P. aeruginosa
and exhibited minimal cytotoxicity to mammalian cells (50% cytotoxic concentration [CC
50
] ≥ 80 μM). The most potent SABA analogs had MICs of 0.5 to 7.0 μM (0.2 to 3.0 μg/ml) against an efflux-deficient
Escherichia coli
(Δ
tolC
) strain but had no detectable MIC against efflux-proficient
E. coli
or against
P. aeruginosa
(efflux deficient or proficient). Genetic, molecular genetic, and biochemical studies revealed that SABA analogs target the enzyme (AccC) catalyzing the biotin carboxylase half-reaction of the acetyl coenzyme A (acetyl-CoA) carboxylase step in the initiation phase of FASII in
E. coli
and
P. aeruginosa
. These results validate the capability and the sensitivity of this novel bioluminescent reporter screen to identify inhibitors of
E. coli
and
P. aeruginosa
FASII.
Novel Ranking System for Identifying Efficacious Anti-Influenza Virus PB2 Inhibitors
Authors: Tsai Alice W. , McNeil Colleen F. , Leeman Joshua R. , Bennett Hamilton B. , Nti-Addae Kwame , Huang Cassey , Germann Ursula A. , Byrn Randal A. , Berlioz-Seux Francoise , Rijnbrand Rene , Clark Michael P. , Charifson Paul S. , Jones Steven M. 
Published: July 2015

ABSTRACT

Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent
in vitro
and
in vivo
properties have been identified. To evaluate the
in vivo
efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients.
Caspofungin Treatment of Aspergillus fumigatus Results in ChsG-Dependent Upregulation of Chitin Synthesis and the Formation of Chitin-Rich Microcolonies
Authors: Walker Louise A. , Lee Keunsook K. , Munro Carol A. , Gow Neil A. R. 
Published: July 2015

ABSTRACT

Treatment of
Aspergillus fumigatus
with echinocandins such as caspofungin inhibits the synthesis of cell wall β-1,3-glucan, which triggers a compensatory stimulation of chitin synthesis. Activation of chitin synthesis can occur in response to sub-MICs of caspofungin and to CaCl
2
and calcofluor white (CFW), agonists of the protein kinase C (PKC), and Ca
2+
-calcineurin signaling pathways.
A. fumigatus
mutants with the
chs
gene (encoding chitin synthase) deleted (Δ
Afchs
) were tested for their response to these agonists to determine the chitin synthase enzymes that were required for the compensatory upregulation of chitin synthesis. Only the Δ
AfchsG
mutant was hypersensitive to caspofungin, and all other Δ
Afchs
mutants tested remained capable of increasing their chitin content in response to treatment with CaCl
2
and CFW and caspofungin. The resulting increase in cell wall chitin content correlated with reduced susceptibility to caspofungin in the wild type and all Δ
Afchs
mutants tested, with the exception of the Δ
AfchsG
mutant, which remained sensitive to caspofungin.
In vitro
exposure to the chitin synthase inhibitor, nikkomycin Z, along with caspofungin demonstrated synergistic efficacy that was again
Af
ChsG dependent. Dynamic imaging using microfluidic perfusion chambers demonstrated that treatment with sub-MIC caspofungin resulted initially in hyphal tip lysis. However, thickened hyphae emerged that formed aberrant microcolonies in the continued presence of caspofungin. In addition, intrahyphal hyphae were formed in response to echinocandin treatment. These
in vitro
data demonstrate that
A. fumigatus
has the potential to survive echinocandin treatment
in vivo
by
Af
ChsG-dependent upregulation of chitin synthesis. Chitin-rich cells may, therefore, persist in human tissues and act as the focus for breakthrough infections.
Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii?
Authors: García-Salguero Cristina , Rodríguez-Avial Iciar , Picazo Juan J. , Culebras Esther 
Published: July 2015

ABSTRACT

Nosocomial pathogens can be associated with a variety of infections, particularly in intensive care units (ICUs) and in immunocompromised patients. Usually these pathogens are resistant to multiple drugs and pose therapeutic challenges. Among these organisms,
Acinetobacter baumannii
is one of the most frequent being encountered in the clinical setting. Carbapenems are very useful to treat infections caused by these drug-resistant Gram-negative bacilli, but carbapenem resistance is increasing globally. Combination therapy is frequently given empirically for hospital-acquired infections in critically ill patients and is usually composed of an adequate beta-lactam and an aminoglycoside. The purpose of this study was to evaluate the
in vitro
activity of plazomicin against carbapenem-resistant
Acinetobacter baumannii
. Amikacin was used as a comparator. The activity of plazomicin in combination with several different antibiotics was tested by disk diffusion, the checkerboard method, and time-kill studies. Synergy was consistently observed with carbapenems (meropenem and/or imipenem) along with plazomicin or amikacin. When the aminoglycosides were combined with other classes of antibiotics, synergy was observed in some cases, depending on the strain and the antibiotic combination; importantly, there was no antagonism observed in any case. These findings indicate the potential utility of plazomicin in combination with other antibiotics (mainly carbapenems) for the treatment of
A. baumannii
infections, including those caused by carbapenem-resistant isolates.
Noninvasive Pneumococcal Clones Associated with Antimicrobial Nonsusceptibility Isolated from Children in the Era of Conjugate Vaccines
Authors: McElligott Martha , Vickers Imelda , Meehan Mary , Cafferkey Mary , Cunney Robert , Humphreys Hilary 
Published: July 2015

ABSTRACT

Carriage and noninvasive pneumococcal isolates frequently have a higher prevalence of antimicrobial nonsusceptibility than invasive isolates. From 2009 to 2014, we determined the associated clones in 169 pediatric noninvasive nonsusceptible pneumococci from a total of 506 isolates collected after 7- and 13-valent conjugate vaccine introduction (PCV7/13) to the Irish childhood immunization schedule in 2008 and 2010, respectively. We compared our results to those from 25 noninvasive pediatric pneumococcal isolates collected in 2007, the year before introduction of conjugate vaccines. In 2007, England
14
-9 and Spain
9V
-3 accounted for 12% and 32% of nonsusceptible clones, respectively, but in 2009 to 2014, their prevalence fell to 0% and 2.4%. Furthermore, there was a significant decline in Spain
6B
-2 and its variants from 2009 to 2014 (
P
= 0.0024). Fluctuations occurred in clonal complex 320 associated with serotype 19A. The prevalence of Sweden
15A
-25 and its variants and ST558 (a single-locus variant of Utah
35B
-24) associated with nonvaccine serotypes (NVT) 15A and 35B increased from 0% and 8% in 2007 to 19% and 16% in 2013 to 2014, respectively. Pilus locus 1 (PI-1) is associated with the spread of some nonsusceptible pneumococcal clones. PI-1 was more frequently associated with PCV7/13 serotypes than NVT (
P
= 0.0020). Our data highlight the value of surveillance of noninvasive pneumococci following conjugate vaccine introduction. Importantly, emerging clones associated with NVT may limit the effectiveness of PCV7/13 in reducing the high rate of nonsusceptibility among pediatric noninvasive pneumococci, with implications for empirical treatment strategies.
Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance
Authors: Pitout Johann D. D. , Nordmann Patrice , Poirel Laurent 
Published: July 2015

ABSTRACT

The management of infections due to
Klebsiella pneumoniae
has been complicated by the emergence of antimicrobial resistance, especially to carbapenems. Resistance to carbapenems in
K. pneumoniae
involves multiple mechanisms, including the production of carbapenemases (e.g., KPC, NDM, VIM, OXA-48-like), as well as alterations in outer membrane permeability mediated by the loss of porins and the upregulation of efflux systems. The latter two mechanisms are often combined with high levels of other types of β-lactamases (e.g., AmpC).
K. pneumoniae
sequence type 258 (ST258) emerged during the early to mid-2000s as an important human pathogen and has spread extensively throughout the world. ST258 comprises two distinct lineages, namely, clades I and II, and it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Incompatibility group F plasmids with
bla
KPC
have contributed significantly to the success of ST258. The optimal treatment of infections due to carbapenemase-producing
K. pneumoniae
remains unknown. Some newer agents show promise for treating infections due to KPC producers; however, effective options for the treatment of NDM producers remain elusive.
Ex VivoBioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4+T Cells from Aviremic Patients
Authors: Spivak Adam M. , Bosque Alberto , Balch Alfred H. , Smyth David , Martins Laura , Planelles Vicente 
Published: July 2015

ABSTRACTThe human immunodeficiency virus type 1 (HIV-1) latent reservoir in resting CD4+T cells represents a major barrier to viral eradication. Small compounds capable of latency reversal have not demonstrated uniform responses acrossin vitroHIV-1 latency cell models. Characterizing compounds that demonstrate latency-reversing activity in resting CD4+T cells from aviremic patientsex vivowill help inform pilot clinical trials aimed at HIV-1 eradication. We have optimized a rapidex vivoassay using resting CD4+T cells from aviremic HIV-1+patients to evaluate both the bioactivity and latency-reversing potential of candidate latency-reversing agents (LRAs). Using this assay, we characterize the properties of two candidate compounds from promising LRA classes, ingenol 3,20-dibenzoate (a protein kinase C agonist) and panobinostat (a histone deacetylase inhibitor), in cells from HIV-1+antiretroviral therapy (ART)-treated aviremic participants, including the effects on cellular activation and cytotoxicity. Ingenol induced viral release at levels similar to those of the positive control (CD3/28 receptor stimulation) in cells from a majority of participants and represents an exciting LRA candidate, as it combines a robust viral reactivation potential with a low toxicity profile. At concentrations that blocked histone deacetylation, panobinostat displayed a wide range of potency among participant samples and consistently induced significant levels of apoptosis. The protein kinase C agonist ingenol 3,20-dibenzoate demonstrated significant promise in a rapidex vivoassay using resting CD4+T cells from treated HIV-1-positive patients to measure latent HIV-1 reactivation.
Inhibition of Aminoglycoside 6′-
N
-Acetyltransferase Type Ib-Mediated Amikacin Resistance in Klebsiella pneumoniae by Zinc and Copper Pyrithione
Authors: Chiem Kevin , Fuentes Brooke A. , Lin David L. , Tran Tung , Jackson Alexis , Ramirez Maria S. , Tolmasky Marcelo E. 
Published: July 2015

ABSTRACT

The
in vitro
activity of the aminoglycoside 6′-
N
-acetyltransferase type Ib [AAC(6′)-Ib] was inhibited by CuCl
2
with a 50% inhibitory concentration (IC
50
) of 2.8 μM. The growth of an amikacin-resistant
Klebsiella pneumoniae
strain isolated from a neonate with meningitis was inhibited when amikacin was supplemented by the addition of Zn
2+
or Cu
2+
in complex with the ionophore pyrithione. Coordination complexes between cations and ionophores could be developed for their use, in combination with aminoglycosides, to treat resistant infections.
Determination of [
11
C]Rifampin Pharmacokinetics within Mycobacterium tuberculosis-Infected Mice by Using Dynamic Positron Emission Tomography Bioimaging
Authors: DeMarco Vincent P. , Ordonez Alvaro A. , Klunk Mariah , Prideaux Brendan , Wang Hui , Zhuo Zhang , Tonge Peter J. , Dannals Robert F. , Holt Daniel P. , Lee Carlton K. K. , Weinstein Edward A. , Dartois Véronique , Dooley Kelly E. , Jain Sanjay K. 
Published: July 2015

ABSTRACT

Information about intralesional pharmacokinetics (PK) and spatial distribution of tuberculosis (TB) drugs is limited and has not been used to optimize dosing recommendations for new or existing drugs. While new techniques can detect drugs and their metabolites within TB granulomas, they are invasive, rely on accurate resection of tissues, and do not capture dynamic drug distribution in the tissues of interest. In this study, we assessed the
in situ
distribution of
11
C-labeled rifampin in live,
Mycobacterium tuberculosis
-infected mice that develop necrotic lesions akin to human disease. Dynamic positron emission tomography (PET) imaging was performed over 60 min after injection of [
11
C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [
11
C]rifampin was rapidly distributed to all parts of the body and quickly localized to the liver. Areas under the concentration-time curve for the first 60 min (AUC
0–60
) in infected and uninfected mice were similar for liver, blood, and brain compartments (
P
> 0.53) and were uniformly low in brain (10 to 20% of blood values). However, lower concentrations were noted in necrotic lung tissues of infected mice than in healthy lungs (
P
= 0.03).
Ex vivo
two-dimensional matrix-assisted laser desorption ionization (MALDI) imaging confirmed restricted penetration of rifampin into necrotic lung lesions. Noninvasive bioimaging can be used to assess the distribution of drugs into compartments of interest, with potential applications for TB drug regimen development.
Novel Riboswitch-Binding Flavin Analog That Protects Mice against Clostridium difficile Infection without Inhibiting Cecal Flora
Authors: Blount Kenneth F. , Megyola Cynthia , Plummer Mark , Osterman David , O'Connell Tim , Aristoff Paul , Quinn Cheryl , Chrusciel R. Alan , Poel Toni J. , Schostarez Heinrich J. , Stewart Catherine A. , Walker Daniel P. , Wuts Peter G. M. , Breaker Ronald R. 
Published: July 2015

ABSTRACT

Novel mechanisms of action and new chemical scaffolds are needed to rejuvenate antibacterial drug discovery, and riboswitch regulators of bacterial gene expression are a promising class of targets for the discovery of new leads. Herein, we report the characterization of 5-(3-(4-fluorophenyl)butyl)-7,8-dimethylpyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione (5FDQD)—an analog of riboflavin that was designed to bind riboswitches that naturally recognize the essential coenzyme flavin mononucleotide (FMN) and regulate FMN and riboflavin homeostasis.
In vitro
, 5FDQD and FMN bind to and trigger the function of an FMN riboswitch with equipotent activity. MIC and time-kill studies demonstrated that 5FDQD has potent and rapidly bactericidal activity against
Clostridium difficile
. In C57BL/6 mice, 5FDQD completely prevented the onset of lethal antibiotic-induced
C. difficile
infection (CDI). Against a panel of bacteria representative of healthy bowel flora, the antibacterial selectivity of 5FDQD was superior to currently marketed CDI therapeutics, with very little activity against representative strains from the
Bacteroides
,
Lactobacillus
,
Bifidobacterium
,
Actinomyces
, and
Prevotella
genera. Accordingly, a single oral dose of 5FDQD caused less alteration of culturable cecal flora in mice than the comparators. Collectively, these data suggest that 5FDQD or closely related analogs could potentially provide a high rate of CDI cure with a low likelihood of infection recurrence. Future studies will seek to assess the role of FMN riboswitch binding to the mechanism of 5FDQD antibacterial action. In aggregate, our results indicate that riboswitch-binding antibacterial compounds can be discovered and optimized to exhibit activity profiles that merit preclinical and clinical development as potential antibacterial therapeutic agents.
Genetically Modified Live Attenuated Leishmania donovani Parasites Induce Innate Immunity through Classical Activation of Macrophages That Direct the Th1 Response in Mice
Authors: Bhattacharya Parna , Dey Ranadhir , Dagur Pradeep K. , Kruhlak Michael , Ismail Nevien , Debrabant Alain , Joshi Amritanshu B. , Akue Adovi , Kukuruga Mark , Takeda Kazuyo , Selvapandiyan Angamuthu , McCoy John Philip , Nakhasi Hira L. 
Published: July 2015

ABSTRACTVisceral leishmaniasis (VL) causes significant mortality and there is no effective vaccine. Previously, we have shown that genetically modifiedLeishmania donovaniparasites, here described as live attenuated parasites, induce a host protective adaptive immune response in various animal models. In this study, we demonstrate an innate immune response upon infection with live attenuated parasites in macrophages from BALB/c mice bothin vitroandin vivo. In vitroinfection of macrophages with live attenuated parasites (compared to that with wild-type [WT]L. donovaniparasites) induced significantly higher production of proinflammatory cytokines (tumor necrosis factor alpha [TNF-α], interleukin-12 [IL-12], gamma interferon [IFN-γ], and IL-6), chemokines (monocyte chemoattractant protein 1/CCL-2, macrophage inflammatory protein 1α/CCL-3, and IP-10), reactive oxygen species (ROS), and nitric oxide, while concomitantly reducing anti-inflammatory cytokine IL-10 and arginase-1 activities, suggesting a dominant classically activated/M1 macrophage response. The classically activated response in turn helps in presenting antigen to T cells, as observed with robust CD4+T cell activationin vitro. Similarly, parasitized splenic macrophages from live attenuated parasite-infected mice also demonstrated induction of an M1 macrophage phenotype, indicated by upregulation of IL-1β, TNF-α, IL-12, and inducible nitric oxide synthase 2 and downregulation of genes associated with the M2 phenotype, i.e., the IL-10, YM1, Arg-1, and MRC-1 genes, compared to WTL. donovani-infected mice. Furthermore, anex vivoantigen presentation assay showed macrophages from live attenuated parasite-infected mice induced higher IFN-γ and IL-2 but significantly less IL-10 production by ovalbumin-specific CD4+T cells, resulting in proliferation of Th1 cells. These data suggest that infection with live attenuated parasites promotes a state of classical activation (M1 dominant) in macrophages that leads to the generation of protective Th1 responses in BALB/c mice.