bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maternal nutrient restriction during pregnancy and lactation leads to impaired right ventricular function in young adult baboons
Authors: Kuo Anderson H. , Li Cun , Huber Hillary F. , Schwab Matthias , Nathanielsz Peter W. , Clarke Geoffrey D. 
Published: April 2017

Key points
Maternal nutrient restriction induces intrauterine growth restriction (IUGR) and leads to heightened cardiovascular risks later in life.
We report right ventricular (RV) filling and ejection abnormalities in IUGR young adult baboons using cardiac magnetic resonance imaging.
Both functional and morphological indicators of poor RV function were seen, many of which were similar to effects of ageing, but also with a few key differences.
We observed more pronounced RV changes compared to our previous report of the left ventricle, suggesting there is likely to be a component of isolated RV abnormality in addition to expected haemodynamic sequelae from left ventricular dysfunction. In particular, our findings raise the suspicion of pulmonary hypertension after IUGR.
This study establishes that IUGR also leads to impairment of the right ventricle in addition to the left ventricle classically studied.
AbstractMaternal nutrient restriction induces intrauterine growth restriction (IUGR), increasing later life chronic disease including cardiovascular dysfunction. Our left ventricular (LV) CMRI studies in IUGR baboons (8 M, 8 F, 5.7 years – human equivalent approximately 25 years), control offspring (8 M, 8 F, 5.6 years), and normal elderly (OLD) baboons (6 M, 6 F, mean 15.9 years) revealed long‐term LV abnormalities in IUGR offspring. Although it is known that right ventricular (RV) function is dependent on LV health, the IUGR right ventricle remains poorly studied. We examined the right ventricle with cardiac magnetic resonance imaging in the same cohorts. We observed decreased ejection fraction (49 ± 2 vs. 33 ± 3%, P < 0.001), cardiac index (2.73 ± 0.27 vs. 1.89 ± 0.20 l min−1 m−2, P < 0.05), early filling rate/body surface area (BSA) (109.2 ± 7.8 vs. 44.6 ± 7.3 ml s−1 m−2, P < 0.001), wall thickening (61 ± 3 vs. 44 ± 5%, P < 0.05), and longitudinal shortening (26 ± 3 vs. 15 ± 2%, P < 0.01) in IUGR animals with increased chamber volumes. Many, but not all, of these changes share similarities to normal older animals. Our findings suggest IUGR‐induced pulmonary hypertension should be further investigated and that atrial volume, pulmonic outflow and interventricular septal motion may provide valuable insights into IUGR cardiovascular physiology. Overall, our findings reaffirm that gestational and neonatal challenges can result in long‐term programming of poor offspring cardiovascular health. To our knowledge, this is the first study reporting IUGR‐induced programmed adult RV dysfunction in an experimental primate model.
Identification of Antifungal H
+
-ATPase Inhibitors with Effect on Plasma Membrane Potential
Authors: Kjellerup Lasse , Gordon Sandra , Cohrt Karen O'Hanlon , Brown William Dalby , Fuglsang Anja Thoe , Winther Anne-Marie L. 
Published: April 2017

ABSTRACT

The plasma membrane H
+
-ATPase (Pma1) is an essential fungal protein and a proposed target for new antifungal medications. The compounds in a small-molecule library containing ∼191,000 commercially available compounds were screened for their ability to inhibit
Saccharomyces cerevisiae
plasma membranes containing Pma1. The overall hit rate was 0.2%, corresponding to 407 compounds. These hit compounds were further evaluated for ATPase selectivity and broad-spectrum antifungal activity. Following this work, one Pma1 inhibitor series based on compound 14 and analogs was selected for further evaluation. This compound series was able to depolarize the membrane and inhibit extracellular acidification in intact fungal cells concomitantly with a significant increase in intracellular ATP levels. Collectively, we suggest that these effects may be a common feature of Pma1 inhibitors. Additionally, the work uncovered a dual mechanism for the previously identified cationic peptide BM2, revealing fungal membrane disruption, in addition to Pma1 inhibition. The methods presented here provide a solid platform for the evaluation of Pma1-specific inhibitors in a drug development setting. The present inhibitors could serve as a starting point for the development of new antifungal agents with a novel mode of action.
New Macrolide-Lincosamide-Streptogramin B Resistance Gene
erm
(48) on the Novel Plasmid pJW2311 in Staphylococcus xylosus
Authors: Wipf Juliette R. K. , Riley Matthew C. , Kania Stephen A. , Bemis David A. , Andreis Sabrina , Schwendener Sybille , Perreten Vincent 
Published: April 2017

ABSTRACT

Whole-genome sequencing of
Staphylococcus xylosus
strain JW2311 from bovine mastitis milk identified the novel 49.3-kb macrolide-lincosamide-streptogramin B (MLS
B
) resistance plasmid pJW2311. It contained the macrolide resistance gene
mph
(C), the macrolide-streptogramin B resistance gene
msr
(A), and the new MLS
B
resistance gene
erm
(48) and could be transformed into
Staphylococcus aureus
by electroporation. Functionality of
erm
(48) was demonstrated by cloning and expression in
S. aureus
.
Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media
Authors: Hoberman Alejandro , Paradise Jack L. , Rockette Howard E. , Jeong Jong-Hyeon , Kearney Diana H. , Bhatnagar Sonika , Shope Timothy R. , Muñiz Gysella , Martin Judith M. , Kurs-Lasky Marcia , Haralam MaryAnn , Pope Marcia A. , Nagg Jennifer P. , Zhao Wenchen , Miah Mohammad Kowser , Beumer Jan , Venkataramanan Raman , Shaikh Nader 
Published: April 2017

ABSTRACT

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (
P
= 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (
P
= 0.04) and of AOM treatment failure were 12% and 16% (
P
= 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit β-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.)
Multihospital Occurrence of Pan-Resistant Klebsiella pneumoniae Sequence Type 147 with an IS
Ecp1
-Directed
bla
OXA-181
Insertion in the
mgrB
Gene in the United Arab Emirates
Authors: Sonnevend Ágnes , Ghazawi Akela , Hashmey Rayhan , Haidermota Aliasgher , Girgis Safinaz , Alfaresi Mubarak , Omar Mohammed , Paterson David L. , Zowawi Hosam M. , Pál Tibor 
Published: April 2017

ABSTRACT

The emergence of pan-resistant
Klebsiella pneumoniae
strains is an increasing concern. In the present study, we describe a cluster of 9 pan-resistant
K. pneumoniae
sequence type 147 (ST147) isolates encountered in 4 patients over nearly 1 year in 3 hospitals of the United Arab Emirates (UAE). The isolates exhibited highly similar genotypes. All produced chromosomally encoded OXA-181, and the majority also produced the NDM-5 carbapenemase. As with the previously described single isolate from the UAE, MS6671, the
mgrB
was disrupted by a functional, IS
Ecp1
-driven
bla
OXA-181
insertion causing resistance to carbapenems. The mutation was successfully complemented with an intact
mgrB
gene, indicating that it was responsible for colistin resistance.
bla
NDM-5
was located within a resistance island of an approximately 100-kb IncFII plasmid carrying
ermB
,
mph
(A),
bla
TEM-1B
,
rmtB
,
bla
NDM-5
,
sul1
,
aadA2
, and
dfrA12
resistance genes. Sequencing this plasmid (pABC143-NDM) revealed that its backbone was nearly identical to that of plasmid pMS6671E from which several resistance genes, including
bla
NDM-5
, had been deleted. More extensive similarities of the backbone and the resistance island were found between pABC143C-NDM and the
bla
NDM-5
-carrying IncFII plasmids of two
K. pneumoniae
ST147 isolates from South Korea, one of which was colistin resistant, and both also produced OXA-181. Notably, one of these strains was isolated from a patient transferred from the UAE. Our data show that this pan-resistant clone has an alarming capacity to maintain itself over an extended period of time and is even likely to be transmitted internationally.
Identification of Mycobacterial Genes Involved in Antibiotic Sensitivity: Implications for the Treatment of Tuberculosis with β-Lactam-Containing Regimens
Authors: Viswanathan Gopinath , Yadav Sangya , Raghunand Tirumalai R. 
Published: April 2017

ABSTRACT

In a
Mycobacterium smegmatis
mutant library screen, transposon mutants with insertions in
fhaA
,
dprE2
,
rpsT
, and
parA
displayed hypersusceptibility to antibiotics, including the β-lactams meropenem, ampicillin, amoxicillin, and cefotaxime. Sub-MIC levels of octoclothepin, a psychotic drug inhibiting ParA, phenocopied the
parA
insertion and enhanced the bactericidal activity of meropenem against
Mycobacterium tuberculosis
in combination with clavulanate. Our study identifies novel factors associated with antibiotic resistance, with implications in repurposing β-lactams for tuberculosis treatment.
Potassium Iodide Potentiates Antimicrobial Photodynamic Inactivation Mediated by Rose Bengal in
In Vitro
and
In Vivo
Studies
Authors: Wen Xiang , Zhang Xiaoshen , Szewczyk Grzegorz , El-Hussein Ahmed , Huang Ying-Ying , Sarna Tadeusz , Hamblin Michael R. 
Published: April 2017

ABSTRACT

Rose bengal (RB) is a halogenated xanthene dye that has been used to mediate antimicrobial photodynamic inactivation for several years. While RB is highly active against Gram-positive bacteria, it is largely inactive in killing Gram-negative bacteria. We have discovered that addition of the nontoxic salt potassium iodide (100 mM) potentiates green light (540-nm)-mediated killing by up to 6 extra logs with the Gram-negative bacteria
Escherichia coli
and
Pseudomonas aeruginosa
, the Gram-positive bacterium methicillin-resistant
Staphylococcus aureus
, and the fungal yeast
Candida albicans
. The mechanism is proposed to be singlet oxygen addition to iodide anion to form peroxyiodide, which decomposes into radicals and, finally, forms hydrogen peroxide and molecular iodine. The effects of these different bactericidal species can be teased apart by comparing the levels of killing achieved in three different scenarios: (i) cells, RB, and KI are mixed together and then illuminated with green light; (ii) cells and RB are centrifuged, and then KI is added and the mixture is illuminated with green light; and (iii) RB and KI are illuminated with green light, and then cells are added after illumination with the light. We also showed that KI could potentiate RB photodynamic therapy in a mouse model of skin abrasions infected with bioluminescent
P. aeruginosa
.
Evaluation of the Ability of a Novel Miconazole Formulation To Penetrate Nail by Using Three
In Vitro
Nail Models
Authors: Christensen Luisa , Turner Rob , Weaver Sean , Caserta Francesco , Long Lisa , Ghannoum Mahmoud , Brown Marc 
Published: April 2017

ABSTRACT

In an effort to increase the efficacy of topical medications for treating onychomycosis, several new nail penetration enhancers were recently developed. In this study, the ability of 10% (wt/wt) miconazole nitrate combined with a penetration enhancer formulation to permeate the nail is demonstrated by the use of a selection of
in vitro
nail penetration assays. These assays included the bovine hoof, TurChub zone of inhibition, and infected-nail models.
Position of O-Acetylation within the Capsular Repeat Unit Impacts the Biological Properties of Pneumococcal Serotypes 33A and 33F
Authors: Spencer Brady L. , Saad Jamil S. , Shenoy Anukul T. , Orihuela Carlos J. , Nahm Moon H. 
Published: April 2017

ABSTRACT

Streptococcus pneumoniae
(pneumococcus) produces many capsule types that differ in their abilities to evade host immune recognition. To explain these serotype-dependent protective capacities, many studies have investigated capsular thickness or the interaction of the capsule with complement proteins, but the effects of small chemical modifications of the capsule on its function have not been studied. One small chemical modification found frequently among pneumococcal capsules is O-acetylation. Pneumococcal serotype 33A has two membrane-bound
O
-acetyltransferase genes,
wciG
and
wcjE
. A 33A
wcjE
-deficient variant, 33F, occurs naturally and is increasing in prevalence in the wake of widespread conjugate vaccine use, but no
wciG
-deficient variants have been reported. To study the biological consequence of the loss of O-acetylation, we created
wciG
-deficient variants in both serotypes 33A and 33F, which we named 33X1 (Δ
wciG
) and 33X2 (Δ
wciG
Δ
wcjE
). Serotypes 33X1 and 33X2 express novel capsule types based on serological and biochemical analyses. We found that loss of WcjE-mediated O-acetylation appears not to affect cell wall shielding, since serotypes 33A and 33F exhibit comparable nonspecific opsonophagocytic killing, biofilm production, and adhesion to nasopharyngeal cells, though serotype 33F survived short-term drying better than serotype 33A. Loss of WciG-mediated O-acetylation in serotypes 33X1 and 33X2, however, resulted in a phenotype resembling that of nonencapsulated strains: increased cell wall accessibility, increased nonspecific opsonophagocytic killing, enhanced biofilm formation, and increased adhesion to nasopharyngeal cells. We conclude that WciG-mediated, but not WcjE-mediated, O-acetylation is important for producing protective capsules in 33A and that small chemical changes to the capsule can drastically affect its biological properties.
Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model
Authors: Jaswal Dharmvir S. , Cui Xizhong , Torabi-Parizi Parizad , Ohanjanian Lernik , Sampath-Kumar Hannish , Fitz Yvonne , Li Yan , Xu Wanying , Eichacker Peter Q. 
Published: April 2017

ABSTRACT

Bacillus anthracis
edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (
n
= 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (
P
≤ 0.04, except for sodium reabsorption under constant pressure [
P
= 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (
P
≤ 0.03 except for urine output with raxibacumab [
P
= 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 ± 1.06 ng/ml versus 1.51 ± 0.44 ng/ml [means ± standard errors of the means {SEM};
P
= 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.
Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis
Authors: Ripamonti Chiara , Bishop Lisa R. , Kovacs Joseph A. 
Published: April 2017

ABSTRACTPneumocystisremains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection withPneumocystismurina. We also examined the clearance ofPneumocystisinfection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peakPneumocystislevels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+T cells for the former compared to ∼15% for the latter. Both CD4+T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance ofPneumocystisinfection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice clearedPneumocystisinfection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased duringPneumocystisinfection in immunocompetent mice, IL-17A is not required for control ofPneumocystisinfection.
Peptoanaerobacter stomatis Primes Human Neutrophils and Induces Granule Exocytosis
Authors: Jimenez Flores E. , Tian S. , Sizova M. , Epstein S. S. , Lamont R. J. , Uriarte S. M. 
Published: April 2017

ABSTRACTPeptoanaerobacter stomatisis a newly appreciated taxon associated with periodontal diseases; however, little is known about the organism's pathogenic potential or its interaction with the host immune response. Neutrophils are the most abundant innate immune cell present in the gingival tissue and function to constrain the oral microbial challenge. However, some periodontal pathogens have developed strategies to evade phagocytosis and killing by neutrophils. Therefore, to begin to understand the role ofP. stomatisin periodontitis, we studied its interactions with human neutrophils. Our data showed that after 30 min of incubation, neutrophils failed to engulfP. stomatisefficiently; however, whenP. stomatiswas internalized, it was promptly eradicated.P. stomatischallenge induced a robust intracellular respiratory burst; however, this response did not contribute to bacterial killing. Minimal superoxide release was observed by direct bacterial challenge; however,P. stomatissignificantly increasedN-formyl-methionyl-leucyl phenylalanine (fMLF)-stimulated superoxide release to an extent similar to that of cells primed with tumor necrosis factor alpha (TNF-α). When neutrophils were challenged withP. stomatis, 52% of the bacterium-containing phagosomes were enriched for the specific granule marker lactoferrin and 82% with the azurophil granule marker elastase.P. stomatischallenge stimulated exocytosis of the four neutrophil granule subtypes. Moreover,P. stomatissusceptibility to extracellular killing could be attributed to the exocytosis of antimicrobial components present in neutrophil granules. Priming neutrophils for an enhanced respiratory burst together with promoting granule content release could contribute to the chronic inflammation and tissue destruction that characterize periodontal diseases.
Inactivation of Transcriptional Regulators during Within-Household Evolution of Escherichia coli
Authors: Kisiela Dagmara I. , Radey Matthew , Paul Sandip , Porter Stephen , Polukhina Kseniya , Tchesnokova Veronika , Shevchenko Sofiya , Chan Diana , Aziz Maliha , Johnson Timothy J. , Price Lance B. , Johnson James R. , Sokurenko Evgeni V. 
Published: April 2017

ABSTRACT

We analyzed the within-household evolution of two household-associated
Escherichia coli
strains from pandemic clonal group ST131-
H
30, using isolates recovered from five individuals within two families, each of which had a distinct strain. Family 1's strain was represented by a urine isolate from the index patient (older sister) with recurrent cystitis and a blood isolate from her younger sister with fatal urosepsis. Family 2's strain was represented by a urine isolate from the index patient (father) with pyelonephritis and renal abscesses, blood and kidney drainage isolates from the daughter with emphysematous pyelonephritis, and urine and fecal isolates from the mother with cystitis. Collectively, the several variants of each family's strain had accumulated a total of 8 (family 1) and 39 (family 2) point mutations; no two isolates were identical. Of the 47 total mutations, 36 resulted in amino acid changes or truncation of coded proteins. Fourteen such mutations (39%) targeted genes encoding transcriptional regulators, and 9 (25%) involved DNA-binding transcription factors (TFs), which significantly exceeded the relative contribution of TF genes to the isolates' genomes (∼6%). At least one-half of the transcriptional regulator mutations were inactivating, based on phenotypic and/or transcriptional analysis. In particular, inactivating mutations in the global regulator LrhA (repressor of type 1 fimbriae and flagella) occurred in the blood isolates from both households and increased the virulence of
E. coli
strains in a murine sepsis model. The results indicate that
E. coli
undergoes adaptive evolution between and/or within hosts, generating subpopulations with distinctive phenotypes and virulence potential.

IMPORTANCE
The clonal evolution of bacterial strains associated with interhost transmission is poorly understood. We characterized the genome sequences of clonal descendants of two
Escherichia coli
strains, recovered at different time points from multiple individuals within two households who had different types of urinary tract infection. We found evidence that the
E. coli
strains underwent extensive mutational diversification between and within these individuals, driven disproportionately by inactivation of transcriptional regulators. In urosepsis isolates, the mutations observed in the global regulator LrhA increased bacterial virulence in a murine sepsis model. Our findings help in understanding the adaptive dynamics and strategies of
E. coli
during short-term natural evolution.