bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role of Alpha-Toxin and Protective Effects of Its Neutralization by a Human Antibody in Acute Bacterial Skin and Skin Structure Infections
Authors: Le Vien T. M. , Tkaczyk Christine , Chau Sally , Rao Renee L. , Dip Etyene Castro , Pereira-Franchi Eliane P. , Cheng Lily , Lee Sally , Koelkebeck Holly , Hilliard Jamese J. , Yu Xiang Qing , Datta Vivekananda , Nguyen Vien , Weiss William , Prokai Laszlo , O'Day Terrence , Stover C. Kendall , Sellman Bret R. , Diep Binh An 
Published: July 2016

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) causes large-scale epidemics of acute bacterial skin and skin structure infections (ABSSSI) within communities across the United States. Animal models that reproduce ABSSSI as they occur in humans are urgently needed to test new therapeutic strategies. Alpha-toxin plays a critical role in a variety of staphylococcal infection models in mice, but its role in the pathogenesis of ABSSSI remains to be elucidated in rabbits, which are similar to humans in their susceptibility to
S. aureus
superantigens and certain bicomponent pore-forming leukocidins. We report here a new rabbit model of ABSSSI and show that those infected with a mutant deficient in expression of alpha-toxin (Δ
hla
) developed a small dermonecrotic lesion, whereas those infected with isogenic USA300 MRSA wild-type or complemented Δ
hla
strains developed ABSSSI that mimic the severe infections that occur in humans, including the large central dermonecrotic core surrounded by erythema, induration, and marked subcutaneous hemorrhage. More importantly, immunoprophylaxis with MEDI4893*, an anti-alpha-toxin human monoclonal antibody, significantly reduced the severity of disease caused by a USA300 wild-type strain to that caused by the Δ
hla
mutant, indicating that this toxin could be completely neutralized during infection. Thus, this study illustrates a potential high standard for the development of new immunotherapeutic agents in which a toxin-neutralizing antibody provides protection to the same degree achieved with a toxin gene knockout. When MEDI4893* was administered as adjunctive therapy with a subtherapeutic dose of linezolid, the combination was significantly more efficacious than either agent alone in reducing the severity of ABSSSI.
Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity
Authors: Nankabirwa Joaniter I. , Conrad Melissa D. , Legac Jennifer , Tukwasibwe Stephen , Tumwebaze Patrick , Wandera Bonnie , Brooker Simon J. , Staedke Sarah G. , Kamya Moses R. , Nsobya Sam L. , Dorsey Grant , Rosenthal Philip J. 
Published: July 2016

ABSTRACT

Dihydroartemisinin-piperaquine (DP) offers prolonged protection against malaria, but its impact on
Plasmodium falciparum
drug sensitivity is uncertain. In a trial of intermittent preventive treatment in schoolchildren in Tororo, Uganda, in 2011 to 2012, monthly DP for 1 year decreased the incidence of malaria by 96% compared to placebo; DP once per school term offered protection primarily during the first month after therapy. To assess the impact of DP on selection of drug resistance, we compared the prevalence of key polymorphisms in isolates that emerged at different intervals after treatment with DP. Blood obtained monthly and at each episode of fever was assessed for
P. falciparum
parasitemia by microscopy. Samples from 160 symptomatic and 650 asymptomatic episodes of parasitemia were assessed at 4 loci (N86Y, Y184F, and D1246Y in
pfmdr1
and K76T in
pfcrt
) that modulate sensitivity to aminoquinoline antimalarials, utilizing a ligase detection reaction-fluorescent microsphere assay. For
pfmdr1
N86Y and
pfcrt
K76T, but not the other studied polymorphisms, the prevalences of mutant genotypes were significantly greater in children who had received DP within the past 30 days than in those not treated within 60 days (86Y, 18.0% versus 8.3% [
P
= 0.03]; 76T, 96.0% versus 86.1% [
P
= 0.05]), suggesting selective pressure of DP. Full sequencing of
pfcrt
in a subset of samples did not identify additional polymorphisms selected by DP. In summary, parasites that emerged soon after treatment with DP were more likely than parasites not under drug pressure to harbor
pfmdr1
and
pfcrt
polymorphisms associated with decreased sensitivity to aminoquinoline antimalarials. (This study has been registered at ClinicalTrials.gov under no. NCT01231880.)
Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams
Authors: Momper Jeremiah D. , Capparelli Edmund V. , Wade Kelly C. , Kantak Anand , Dhanireddy Ramasubbareddy , Cummings James J. , Nedrelow Jonathan H. , Hudak Mark L. , Mundakel Gratias T. , Natarajan Girija , Gao Jamie , Laughon Matt , Smith P. Brian , Benjamin Daniel K. 
Published: July 2016

ABSTRACT
Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.
Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm
Authors: Meeker Daniel G. , Beenken Karen E. , Mills Weston B. , Loughran Allister J. , Spencer Horace J. , Lynn William B. , Smeltzer Mark S. 
Published: July 2016

ABSTRACT

We used
in vitro
and
in vivo
models of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistant
Staphylococcus aureus
(MRSA) in the specific context of an established biofilm. The results demonstrated that, under
in vitro
conditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when tested
in vivo
in a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associated
S. aureus
infections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.
Inhibition and Dispersal of Pseudomonas aeruginosa Biofilms by Combination Treatment with Escapin Intermediate Products and Hydrogen Peroxide
Authors: Santiago Ariel J. , Ahmed Marwa N. A. , Wang Shu-Lin , Damera Krishna , Wang Binghe , Tai Phang C. , Gilbert Eric S. , Derby Charles D. 
Published: July 2016

ABSTRACT

Escapin is an
l
-amino acid oxidase that acts on lysine to produce hydrogen peroxide (H
2
O
2
), ammonia, and equilibrium mixtures of several organic acids collectively called escapin intermediate products (EIP). Previous work showed that the combination of synthetic EIP and H
2
O
2
functions synergistically as an antimicrobial toward diverse planktonic bacteria. We initiated the present study to investigate how the combination of EIP and H
2
O
2
affected bacterial biofilms, using
Pseudomonas aeruginosa
as a model. Specifically, we examined concentrations of EIP and H
2
O
2
that inhibited biofilm formation or fostered disruption of established biofilms. High-throughput assays of biofilm formation using microtiter plates and crystal violet staining showed a significant effect from pairing EIP and H
2
O
2
, resulting in inhibition of biofilm formation relative to biofilm formation in untreated controls or with EIP or H
2
O
2
alone. Similarly, flow cell analysis and confocal laser scanning microscopy revealed that the EIP and H
2
O
2
combination reduced the biomass of established biofilms relative to that of the controls. Area layer analysis of biofilms posttreatment indicated that disruption of biomass occurs down to the substratum. Only nanomolar to micromolar concentrations of EIP and H
2
O
2
were required to impact biofilm formation or disruption, and these concentrations are significantly lower than those causing bactericidal effects on planktonic bacteria. Micromolar concentrations of EIP and H
2
O
2
combined enhanced
P. aeruginosa
swimming motility compared to the effect of either EIP or H
2
O
2
alone. Collectively, our results suggest that the combination of EIP and H
2
O
2
may affect biofilms by interfering with bacterial attachment and destabilizing the biofilm matrix.
High Level of Spinosad Production in the Heterologous Host Saccharopolyspora erythraea
Authors: Huang Jun , Yu Zhen , Li Mei-Hong , Wang Ji-Dong , Bai Hua , Zhou Jun , Zheng Yu-Guo 
Published: July 2016

ABSTRACT

Spinosad, a highly effective insecticide, has an excellent environmental and mammalian toxicological profile. Global market demand for spinosad is huge and growing. However, after much effort, there has been almost no improvement in the spinosad yield from the original producer,
Saccharopolyspora spinosa
. Here, we report the heterologous expression of spinosad using
Saccharopolyspora erythraea
as a host. The native erythromycin polyketide synthase (PKS) genes in
S. erythraea
were replaced by the assembled spinosad gene cluster through iterative recombination. The production of spinosad could be detected in the recombinant strains containing the whole biosynthesis gene cluster. Both metabolic engineering and UV mutagenesis were applied to further improve the yield of spinosad. The final strain, AT-ES04PS-3007, which could produce spinosad with a titer of 830 mg/liter, has significant potential in industrial applications.

IMPORTANCE
This work provides an innovative and promising way to improve the industrial production of spinosad. At the same time, it also describes a successful method of heterologous expression for target metabolites of interest by replacing large gene clusters.
Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants
Authors: Graça Telmo , Silva Marta G. , Kostyukova Alla S. , Palmer Guy H. 
Published: July 2016

ABSTRACTSequential expression of outer membrane protein antigenic variants is an evolutionarily convergent mechanism used by bacterial pathogens to escape host immune clearance and establish persistent infection. Variants must be sufficiently structurally distinct to escape existing immune effectors yet retain the core structural elements required for localization and function within the outer membrane. We examined this balance usingAnaplasma marginale, which generates antigenic variants in the outer membrane protein Msp2 using gene conversion. The overwhelming majority of Msp2 variants expressed during long-term persistent infection are mosaics, derived by recombination of oligonucleotide segments from multiple alleles to form unique hypervariable regions (HVR). As a result, the mosaics are not under long-term selective pressure to encode a functional protein; consequently, we hypothesized that the Msp2 HVR is structurally permissive for mosaic expression. Using an integrated approach of predictive modeling with determination of the native Msp2 protein structure and function, we demonstrate that structured elements, most notably, β-sheets, are significantly concentrated in the highly conserved N- and C-terminal domains. In contrast, the HVR is overwhelmingly a random coil, with the structured α-helices and β-sheets being confined to the genomically defined structural tethers that separate the antigenically variable microdomains. This structure is supported by the surface exposure of the HVR microdomains and the slow diffusion-type porin function in native Msp2. Importantly, the predominance of the random coil provides plasticity for the formation of functional HVR mosaics and realization of the full potential of segmental gene conversion to dramatically expand the variant repertoire.
Spermidine Inversely Influences Surface Interactions and Planktonic Growth in Agrobacterium tumefaciens
Authors: Wang Yi , Kim Sok Ho , Natarajan Ramya , Heindl Jason E. , Bruger Eric L. , Waters Christopher M. , Michael Anthony J. , Fuqua Clay 
Published: July 2016

ABSTRACT

In bacteria, the functions of polyamines, small linear polycations, are poorly defined, but these metabolites can influence biofilm formation in several systems. Transposon insertions in an ornithine decarboxylase (
odc
) gene in
Agrobacterium tumefaciens
, predicted to direct synthesis of the polyamine putrescine from ornithine, resulted in elevated cellulose. Null mutants for
odc
grew somewhat slowly in a polyamine-free medium but exhibited increased biofilm formation that was dependent on cellulose production. Spermidine is an essential metabolite in
A. tumefaciens
and is synthesized from putrescine in
A. tumefaciens
via the stepwise actions of carboxyspermidine dehydrogenase (CASDH) and carboxyspermidine decarboxylase (CASDC). Exogenous addition of either putrescine or spermidine to the
odc
mutant returned biofilm formation to wild-type levels. Low levels of exogenous spermidine restored growth to CASDH and CASDC mutants, facilitating weak biofilm formation, but this was dampened with increasing concentrations. Norspermidine rescued growth for the
odc
, CASDH, and CASDC mutants but did not significantly affect their biofilm phenotypes, whereas in the wild type, it stimulated biofilm formation and depressed spermidine levels. The
odc
mutant produced elevated levels of cyclic diguanylate monophosphate (c-di-GMP), exogenous polyamines modulated these levels, and expression of a c-di-GMP phosphodiesterase reversed the enhanced biofilm formation. Prior work revealed accumulation of the precursors putrescine and carboxyspermidine in the CASDH and CASDC mutants, respectively, but unexpectedly, both mutants accumulated homospermidine; here, we show that this requires a homospermidine synthase (
hss
) homologue.

IMPORTANCE
Polyamines are small, positively charged metabolites that are nearly ubiquitous in cellular life. They are often essential in eukaryotes and more variably in bacteria. Polyamines have been reported to influence the surface-attached biofilm formation of several bacteria. In
Agrobacterium tumefaciens
, mutants with diminished levels of the polyamine spermidine are stimulated for biofilm formation, and exogenous provision of spermidine decreases biofilm formation. Spermidine is also essential for
A. tumefaciens
growth, but the related polyamine norspermidine exogenously rescues growth and does not diminish biofilm formation, revealing that the growth requirement and biofilm control are separable. Polyamine control of biofilm formation appears to function via effects on the cellular second messenger cyclic diguanylate monophosphate, regulating the transition from a free-living to a surface-attached lifestyle.
Origin and time evolution of subduction polarity reversal from plate kinematics of Southeast Asia
Authors: von Hagke Christoph , Philippon Mélody , Avouac Jean-Philippe , Gurnis Michael 
Published: July 2016

Abstract
We present a regional model of plate geometry and kinematics of Southeast Asia since the Late Cretaceous, embedded in a global plate model. The model involves subduction polarity reversals and sheds new light on the origin of the subduction polarity reversal currently observed in Taiwan. We show that this subduction zone reversal is inherited from subduction of the proto–South China Sea plate and owes its current location to triple junction migration and slab rollback. This analysis sheds new light on the plate tectonic context of the Taiwan orogeny and questions the hypothesis that northern Taiwan can be considered an older, more mature equivalent of southern Taiwan.
The minimum scale of grooving on faults
Authors: Candela Thibault , Brodsky Emily E. 
Published: July 2016

Abstract
At the field scale, nearly all fault surfaces contain grooves generated as one side of the fault slips past the other. Grooves are so common that they are one of the key indicators of principal slip surfaces. Here, we show that at sufficiently small scales, grooves do not exist on fault surfaces. A transition to isotropic roughness occurs at 4–500 μm. Although the scale of the transition can vary even between locales on a single fault, the aspect ratio of the roughness at the transition is well defined for a given fault. We interpret the transition between grooved and ungrooved scales as a transition in deformation mode of asperities on the slip surface. Grooves can form when a hard indenter slides past a softer surface. At small scales, the asperities appear to yield plastically and therefore do not generate grooves as hard indenters. The plastic yielding can be a consequence of the high shear strains required to deform the surfaces at small scales where the aspect ratio (roughness) is high. The transition to plastic yielding is predicted to occur at a specific aspect ratio for each fault, as observed. The new observation both shows a limit to one of the most commonly observed features of faults and suggests a change in the mode of failure of faults as a function of scale.
Structural segmentation controlled the 2015 Mw 7.8 Gorkha earthquake rupture in Nepal
Authors: Hubbard Judith , Almeida Rafael , Foster Anna , Sapkota Soma Nath , Bürgi Paula , Tapponnier Paul 
Published: July 2016

Abstract
The ongoing collision of India with Asia is partly accommodated by slip on the Main Himalayan Thrust (MHT). The 25 April 2015, Mw 7.8 Gorkha earthquake is the most recent major event to rupture the MHT, which dips gently northward beneath central Nepal. Although the geology of the range has been studied for decades, fundamental aspects of its deep structure remain disputed. Here, we develop a structural cross section and a three-dimensional, geologically informed model of the MHT that are consistent with seismic observations from the Gorkha earthquake. A comparison of our model to a detailed slip inversion data set shows that the slip patch closely matches an oval-shaped, gently dipping fault surface bounded on all sides by steeper ramps. The Gorkha earthquake rupture seems to have been limited by the geometry of that fault segment. This is a significant step forward in understanding the deep geometry of the MHT and its effect on earthquake nucleation and propagation. Published models of fault locking do not correlate with the slip patch or our fault model in the vicinity of the earthquake, further suggesting that fault geometry was the primary control on this event. Our result emphasizes the importance of adequately constraining subsurface fault geometry in megathrusts in order to better assess the sizes and locations of future earthquakes.
Temporal and genetic link between incremental pluton assembly and pulsed porphyry Cu-Mo formation in accretionary orogens
Authors: Rezeau Hervé , Moritz Robert , Wotzlaw Jörn-Frederik , Tayan Rodrik , Melkonyan Rafael , Ulianov Alexey , Selby David , d’Abzac François-Xavier , Stern Richard A. 
Published: July 2016

Abstract
Economically important porphyry Cu-Mo deposits (PCDs) are generally hosted by upper-crustal plutons of variable chemical compositions related to distinct geodynamic settings. The absolute timing and duration of pluton assembly and PCD formation are critical to understanding the genetic relationship between these interrelated processes. Here, we present new comprehensive zircon U-Pb and molybdenite Re-Os ages that tightly constrain the timing and duration of pluton assembly and the age of mineralization in one of the largest ore-bearing plutons of the central Tethyan metallogenic belt, the Meghri-Ordubad pluton, southern Armenia and Nakhitchevan, Lesser Caucasus. This composite pluton was incrementally assembled during three compositionally distinct magmatic episodes over ∼30 m.y., comprising Middle Eocene (48.9–43.1 Ma) calc-alkaline subduction-related magmatism lasting 5.8 ± 0.8 m.y., followed by postsubduction Late Eocene–Middle Oligocene (37.8–28.1 Ma) shoshonitic magmatism over 9.7 ± 0.9 m.y., and Late Oligocene–Early Miocene (26.6–21.2 Ma) adakitic magmatism consisting of shoshonitic dikes and high-K calc-alkaline granodioritic magmas emplaced over 5.4 ± 0.4 m.y. Despite the distinct geodynamic settings and magma compositions, each intrusive suite culminated in the formation of variably sized PCDs, including the giant Oligocene Kadjaran porphyry Cu-Mo deposit associated with high-Sr/Y shoshonitic magmas. Complementary in situ zircon hafnium (εHfzircon = +8 to +11.3) and oxygen (δ18Ozircon = +4.6‰ to +6.0‰) isotope data support a mantle-dominated magma source with limited crustal contribution and/or cannibalization of young and juvenile lower-crustal cumulates. We conclude that, independent of geodynamic setting and magma composition, long-lived (5–10 m.y.) incremental mantle-derived magmatism is a prerequisite to form fertile magmatic-hydrothermal systems, and especially giant PCDs.