bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats
Authors: Lin Yu-Wei , Zhou Qi Tony , Hu Yang , Onufrak Nikolas J. , Sun Siping , Wang Jiping , Forrest Alan , Chan Hak-Kim , Li Jian 
Published: August 2017

ABSTRACTColistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 × 10−4liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, ≤10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (∼46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria.
Drug Susceptibility and Replicative Capacity of Multidrug-Resistant Recombinant Human Cytomegalovirus Harboring Mutations in
UL56
and
UL54
Genes
Authors: Piret Jocelyne , Goyette Nathalie , Boivin Guy 
Published: August 2017

ABSTRACT

Letermovir is an investigational antiviral agent with a novel mechanism of action involving the viral terminase (pUL56). We evaluated the impact of the V236M mutation in the
UL56
gene alone and in combination with the E756K mutation in the
UL54
gene on drug susceptibility and viral replicative capacity of recombinant human cytomegalovirus. The double mutant exhibited at least borderline resistance to all antivirals tested (ganciclovir, foscarnet, cidofovir, brincidofovir, and letermovir) and replicated less efficiently than the wild-type virus
in vitro
.
Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection
Authors: Berube Bryan J. , Murphy Katherine R. , Torhan Matthew C. , Bowlin Nicholas O. , Williams John D. , Bowlin Terry L. , Moir Donald T. , Hauser Alan R. 
Published: August 2017

ABSTRACT

Pseudomonas aeruginosa
is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or microabscess formation. The rising incidence of multidrug resistance among
P. aeruginosa
isolates has increased both the economic burden and the morbidity and mortality associated with
P. aeruginosa
disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells
in vitro
. In this study, we used a mouse model of
P. aeruginosa
abscess formation to test the
in vivo
efficacy of these compounds against the
P. aeruginosa
type III secretion system (T3SS). Bacteria used the T3SS to intoxicate infiltrating neutrophils to establish abscesses. Despite this antagonism, sufficient numbers of functioning neutrophils remained for proper containment of the abscesses, as neutrophil depletion resulted in an increased abscess size, the formation of dermonecrotic lesions on the skin, and the dissemination of
P. aeruginosa
to internal organs. Consistent with the specificity of the T3SS-neutrophil interaction,
P. aeruginosa
bacteria lacking a functional T3SS were fully capable of causing abscesses in a neutropenic host. Phenoxyacetamide inhibitors attenuated abscess formation and aided in the immune clearance of the bacteria. Finally, a
P. aeruginosa
strain resistant to the phenoxyacetamide compound was fully capable of causing abscess formation even in the presence of the T3SS inhibitors. Together, our results further define the role of type III secretion in murine abscess formation and demonstrate the
in vivo
efficacy of phenoxyacetamide inhibitors in
P. aeruginosa
infection.
Mediator Tail Module Is Required for Tac1-Activated
CDR1
Expression and Azole Resistance in Candida albicans
Authors: Liu Zhongle , Myers Lawrence C. 
Published: August 2017

ABSTRACT

The human fungal pathogen
Candida albicans
develops drug resistance after long-term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of-function (GOF) mutations in the transcription factor Tac1 and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which
C. albicans
acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C terminus of Tac1. GOF mutations within the Tac1 TAD, outside the context of full-length Tac1, generally do not enhance its absolute potential as a transcriptional activator. Negative regulation of the Tac1 TAD by the Tac1 middle region is necessary for the activating effect of GOF mutations or fluphenazine to be realized. We have found that full-length Tac1, when hyperactivated by xenobiotics or GOF mutations, facilitates the recruitment of the Mediator coactivator complex to the
CDR1
promoter. Azole resistance and the activation of Tac1 target genes, such as
CDR1
, are dependent on the Tac1 TAD and subunits of the Mediator tail module. The dependence of different Tac1 target promoters on the Mediator tail module, however, varies widely. Lastly, we show that hyperactivation of Tac1 is correlated with its Mediator-dependent phosphorylation, a potentially useful biomarker for Tac1 hyperactivation. The role of Mediator in events downstream of Tac1 hyperactivation in fluconazole-resistant clinical isolates is complex and provides opportunities and challenges for therapeutic intervention.
Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced
MDR1
Expression and Fluconazole Resistance
Authors: Liu Zhongle , Myers Lawrence C. 
Published: August 2017

ABSTRACT

Long-term azole treatment of patients with chronic
Candida albicans
infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation of
MDR1
, a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We identified the Swi/Snf chromatin remodeling complex as a key coactivator for Mrr1, which is required to maintain basal and induced open chromatin, and Mrr1 occupancy, at the
MDR1
promoter. Deletion of
snf2
, the catalytic subunit of Swi/Snf, largely abrogates the increases in
MDR1
expression and fluconazole MIC observed in
MRR1
GOF
mutant strains. Mediator positively and negatively regulates key Mrr1 target promoters. Deletion of the Mediator tail module
med3
subunit reduces, but does not eliminate, the increased
MDR1
expression and fluconazole MIC conferred by
MRR1
GOF
mutations. Eliminating the kinase activity of the Mediator Ssn3 subunit suppresses the decreased
MDR1
expression and fluconazole MIC of the
snf2
null mutation in
MRR1
GOF
strains. Ssn3 deletion also suppresses
MDR1
promoter histone displacement defects in
snf2
null mutants. The combination of this work with studies on other hyperactive zinc cluster transcription factors that confer azole resistance in fungal pathogens reveals a complex picture where the induction of drug efflux pump expression requires the coordination of multiple coactivators. The observed variations in transcription factor and target promoter dependence of this process may make the search for azole sensitivity-restoring small molecules more complicated.
Relationships of Vancomycin Pharmacokinetics to Body Size and Composition Using a Novel Pharmacomorphomic Approach Based on Medical Imaging
Authors: Pai Manjunath P. , Derstine Brian A. , Lichty Matt , Ross Brian E. , Sullivan June A. , Su Grace L. , Wang Stewart C. 
Published: August 2017

ABSTRACT

Antibiotics such as vancomycin are empirically dosed on the basis of body weight, which may not be optimal across the expanding adult body size distribution. Our aim was to compare the relationships between morphomic parameters generated from computed tomography images to conventional body size metrics as predictors of vancomycin pharmacokinetics (PK). This single-center retrospective study included 300 patients with 1,622 vancomycin concentration (52% trough) measurements. Bayesian estimation was used to compute individual vancomycin volume of distribution of the central compartment (Vc) and clearance (CL). Approximately 45% of patients were obese with an overall median (5th, 95th percentile) weight and body mass index of 87.2 (54.7, 123) kg and 28.8 (18.9, 43.7) kg/m
2
, respectively. Morphomic parameters of body size such as body depth, total body area, and torso volume of the twelfth thoracic through fourth lumbar vertebrae (T12 to L4) correlated with Vc. The relationship of vancomycin Vc was poorly predicted by body size but was stronger with T12-to-L4 torso volume (coefficient of determination [
R
2
] = 0.11) than weight (
R
2
= 0.04). No relationships between vancomycin CL and traditional body size metrics could be discerned; however, relationships with skeletal muscle volume and total psoas area were found. Vancomycin CL independently correlated with total psoas area and inversely correlated with age. Thus, vancomycin CL was significantly related to total psoas area over age (
R
2
= 0.23,
P
< 0.0001). This proof-of-concept study suggests a potential role for translation of radiographic information into parameters predictive of drug pharmacokinetics. Prediction of individual antimicrobial pharmacokinetic parameters using analytic morphomics has the potential to improve antimicrobial dose selection and outcomes of obese patients.
RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus
Authors: Jain Ira , Miller Eric W. , Danger Jessica L. , Pflughoeft Kathryn J. , Sumby Paul 
Published: August 2017

ABSTRACT

Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease. This is true for the group A
Streptococcus
(GAS), a pathogen that causes both invasive (e.g., necrotizing fasciitis) and noninvasive (e.g., pharyngitis) diseases. The
c
ontrol
o
f
v
irulence (CovRS) two-component system has a major role in regulating GAS virulence factor expression. The
r
egulator
o
f
c
ov (RocA) protein, which is a predicted kinase, functions in an undetermined manner through CovRS to alter gene expression and reduce invasive disease virulence. Here, we show that the ectopic expression of a truncated RocA derivative, harboring the membrane-spanning domains but not the dimerization or HATPase domain, is sufficient to complement a
rocA
mutant strain. Coupled with a previous bioinformatic study, the data are consistent with RocA being a pseudokinase. RocA reduces the ability of serotype M1 GAS isolates to express capsule and to evade killing in human blood, phenotypes that are not observed for M3 or M18 GAS due to isolates of these serotypes naturally harboring mutant
rocA
alleles. In addition, we found that varying the RocA concentration attenuates the regulatory activity of Mg
2+
and the antimicrobial peptide LL-37, which positively and negatively regulate CovS function, respectively. Thus, we propose that RocA is an accessory protein to the CovRS system that influences the ability of GAS to modulate gene expression in response to host factors. A model of how RocA interacts with CovRS, and of the regulatory consequences of such activity, is presented.
Cytosolic Phospholipase A2α Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection
Authors: Bhowmick Rudra , Clark Stacie , Bonventre Joseph V. , Leong John M. , McCormick Beth A. 
Published: August 2017

ABSTRACTPulmonary infection byStreptococcus pneumoniaeis characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A3(HXA3) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge withS. pneumoniae. As phospholipase A2(PLA2) promotes the release of AA, we investigated the role of PLA2in local and systemic disease duringS. pneumoniaeinfection. The group IVA cytosolic isoform of PLA2(cPLA2α) was activated uponS. pneumoniaeinfection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blockedS. pneumoniae-induced PMN transepithelial migrationin vitro. Genetic ablation of the cPLA2isoform cPLA2α dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge withS. pneumoniae. The cPLA2α-deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA2α plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection followingS. pneumoniaelung challenge.
Listeria monocytogenes Has Both Cytochrome
bd
-Type and Cytochrome
aa
3
-Type Terminal Oxidases, Which Allow Growth at Different Oxygen Levels, and Both Are Important in Infection
Authors: Corbett David , Goldrick Marie , Fernandes Vitor E. , Davidge Kelly , Poole Robert K. , Andrew Peter W. , Cavet Jennifer , Roberts Ian S. 
Published: August 2017

ABSTRACT

Listeria monocytogenes
is a foodborne pathogen responsible for a number of life-threatening infections of humans. During an infection, it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here, we demonstrate that
L. monocytogenes
has two terminal oxidases, a cytochrome
bd
-type (CydAB) and a cytochrome
aa
3
-type menaquinol (QoxAB) oxidase, and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB
bd
-type oxidase is essential for aerobic respiration and intracellular replication, and
cydAB
mutants are highly attenuated in mice. In contrast, the QoxAB
aa
3
-type oxidase is required neither for aerobic respiration in air nor for intracellular growth. However, the
qoxAB
mutants are attenuated in mice, with a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB
aa
3
-type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (vol/vol), both oxidases are functional, and the presence of either is sufficient for aerobic respiration and intracellular replication. However, at 0.2% (vol/vol), both oxidases are necessary for maximum growth. These findings are consistent with the ability of
L. monocytogenes
to switch between terminal oxidases under different oxygen conditions, providing exquisite adaptation to different conditions encountered within the infected host.
Meeting Report on the ASM Conference on Mechanisms of Interbacterial Cooperation and Competition
Authors: Lories Bram , Parijs Ilse , Foster Kevin R. , Steenackers Hans P. 
Published: August 2017

ABSTRACT
The American Society for Microbiology Conference on Mechanisms of Interbacterial Cooperation and Competition was held in Washington, DC, from 1 to 4 March 2017. The conference provided an international forum for sociomicrobiologists from different disciplines to present and discuss new findings. The meeting covered a wide range of topics, spanning molecular mechanisms, ecology, evolution, computation, and manipulation of interbacterial interactions, and encompassed social communities in medicine, the natural environment, and industry. This report summarizes the presentations and emerging themes.
Bacteriophages of
Gordonia
spp. Display a Spectrum of Diversity and Genetic Relationships
Authors: Pope Welkin H. , Mavrich Travis N. , Garlena Rebecca A. , Guerrero-Bustamante Carlos A. , Jacobs-Sera Deborah , Montgomery Matthew T. , Russell Daniel A. , Warner Marcie H. ,   Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES), Hatfull Graham F. 
Published: August 2017

ABSTRACT

The global bacteriophage population is large, dynamic, old, and highly diverse genetically. Many phages are tailed and contain double-stranded DNA, but these remain poorly characterized genomically. A collection of over 1,000 phages infecting
Mycobacterium smegmatis
reveals the diversity of phages of a common bacterial host, but their relationships to phages of phylogenetically proximal hosts are not known. Comparative sequence analysis of 79 phages isolated on
Gordonia
shows these also to be diverse and that the phages can be grouped into 14 clusters of related genomes, with an additional 14 phages that are “singletons” with no closely related genomes. One group of six phages is closely related to Cluster A mycobacteriophages, but the other
Gordonia
phages are distant relatives and share only 10% of their genes with the mycobacteriophages. The
Gordonia
phage genomes vary in genome length (17.1 to 103.4 kb), percentage of GC content (47 to 68.8%), and genome architecture and contain a variety of features not seen in other phage genomes. Like the mycobacteriophages, the highly mosaic
Gordonia
phages demonstrate a spectrum of genetic relationships. We show this is a general property of bacteriophages and suggest that any barriers to genetic exchange are soft and readily violable.

IMPORTANCE
Despite the numerical dominance of bacteriophages in the biosphere, there is a dearth of complete genomic sequences. Current genomic information reveals that phages are highly diverse genomically and have mosaic architectures formed by extensive horizontal genetic exchange. Comparative analysis of 79 phages of
Gordonia
shows them to not only be highly diverse, but to present a spectrum of relatedness. Most are distantly related to phages of the phylogenetically proximal host
Mycobacterium smegmatis
, although one group of
Gordonia
phages is more closely related to mycobacteriophages than to the other
Gordonia
phages. Phage genome sequence space remains largely unexplored, but further isolation and genomic comparison of phages targeted at related groups of hosts promise to reveal pathways of bacteriophage evolution.
Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer
Authors: Balyasnikova Svetlana , Read James , Wotherspoon Andrew , Rasheed S , Tekkis Paris , Tait Diana , Cunningham David , Brown G 
Published: August 2017

IntroductionEarly rectal cancer (ERC) assessment should include prediction of the potential excision plane to safely remove lesions with clear deep margins and feasibility of organ preservation.MethodMRI accuracy for differentiating ≤T1sm2 (partially preserved submucosa) or ≤T2 (partially preserved muscularis) versus >T2 tumours was compared with the gold standard of pT stage T1sm1/2 versus ≤pT2 versus >pT2. N stage was also compared. The MRI protocol employed a standard surface phased array coil with a high resolution (0.6×0.6×3 mm resolution). The staging data were analysed from a prospectively recorded database of all ERC (≤mrT3b) treated by primary surgery.ResultsOf 65 <mrT3b tumours, 45 were ≤pT2 and 14 were ≤pT1sm2. MRI accuracy for ≤T1sm2 was 89% (95% CI 63% to 87%), positive predictive value (PPV) 77% and negative predictive value (NPV) 92%, and for ≤T2 89% (95% CI 79% to 95%), PPV 93% and NPV 81%. Interobserver agreement between two experienced radiologists was >0.7 suggesting good agreement. 44 out of 65 patients underwent radical surgery and 22 out of 44 were ≤mrT2. MRI accuracy to predict lymph node status was 84% (95% CI 70% to 92%), PPV 71% and NPV 90%. Among the 21 out of 65 (32%) patients undergoing local excision or TEM, 20 out of 21 were staged as MR≤T2 and confirmed as such by pathology. On follow-up, none had relapse. If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment, a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95% CI 9% to 35%).ConclusionsMRI is a useful tool for multidisciplinary teams (MDTs) wishing to optimise treatment options for ERC; these study findings will be validated in a prospective multicentre trial.
Systematic reassessment of the first Jurassic pterosaur from Thailand
Authors: Unwin David M. , Martill David M. 
Published: August 2017

Abstract
A pterosaur humerus (PRC 64) from the Upper Jurassic of Thailand was initially assigned to the Azhdarchoidea, an important clade of edentulous Cretaceous pterodactyloid pterosaurs. Here it is reassigned, on the basis of morphological comparisons and a phylogenetic analysis, to the Rhamphorhynchidae, a widely distributed clade of small to medium-sized seemingly piscivorous basal pterosaurs. This record extends the geographical range of rhamphorhynchids and confirms recent findings that these pterosaurs inhabited continental as well as marginal marine ecosystems.