bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relebactam Is a Potent Inhibitor of the KPC-2 β-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae
Authors: Papp-Wallace Krisztina M. , Barnes Melissa D. , Alsop Jim , Taracila Magdalena A. , Bethel Christopher R. , Becka Scott A. , van Duin David , Kreiswirth Barry N. , Kaye Keith S. , Bonomo Robert A. 
Published: April 2018

ABSTRACT

The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by
Enterobacteriaceae
possessing complex β-lactamase backgrounds. Relebactam is a β-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the
Klebsiella pneumoniae
carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of
Enterobacteriaceae
. MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing
Enterobacteriaceae
(
K. pneumoniae
,
Klebsiella oxytoca
,
Enterobacter cloacae
,
Enterobacter aerogenes
,
Citrobacter freundii
,
Citrobacter koseri
, and
Escherichia coli
) were highly susceptible to imipenem-relebactam (MICs ≤ 2 mg/liter). Relebactam inhibited KPC-2 with a second-order onset of acylation rate constant (
k
2
/
K
) value of 24,750 M
−1
s
−1
and demonstrated a slow off-rate constant (
k
off
) of 0.0002 s
−1
. Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2–relebactam acyl-enzyme complex was stable for up to 24 h. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation have been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that the positioning of active-site water molecules is less favorable for desulfation in the KPC-2 active site than it is in the KPC-2–avibactam complex. In the acyl complexes, the water molecules are within 2.5 to 3 Å of the avibactam sulfate; however, they are more than 5 to 6 Å from the relebactam sulfate. As a result, we propose that the KPC-2–relebactam acyl complex is more stable than the KPC-2–avibactam complex. The clinical implications of this difference are not currently known.
In Vitro
and
In Vivo
Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus
Authors: Barman Tarani Kanta , Kumar Manoj , Mathur Tarun , Namba Eiko , Singh Diksha , Chaira Tridib , Kurosaka Yuichi , Yamada Makiko , Upadhyay Dilip Jatashankar , Masuda Nobuhisa 
Published: April 2018

ABSTRACT

DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the
in vitro
activity of DS-2969b and the
in vivo
activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant
Staphylococcus aureus
(MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of
S. aureus
DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram-negative aerobes, except for
Moraxella catarrhalis
and
Haemophilus influenzae
. DS-2969b was active against MRSA with an MIC
90
of 0.25 μg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 × 10
−10
in all four
S. aureus
isolates at 4× MIC of DS-2969b. In a neutropenic MRSA-induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC (
fT
MIC
) correlated best with
in vivo
efficacy, and the static percent
fT
MIC
was 43 to 49%. A sufficient
fT
MIC
was observed in a phase 1 multiple-ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to-oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid.
High-Yield Production of Herbicidal Thaxtomins and Thaxtomin Analogs in a Nonpathogenic Streptomyces Strain
Authors: Jiang Guangde , Zhang Yucheng , Powell Magan M. , Zhang Peilan , Zuo Ran , Zhang Yi , Kallifidas Dimitris , Tieu Albert M. , Luesch Hendrik , Loria Rosemary , Ding Yousong 
Published: April 2018

ABSTRACT

Thaxtomins are virulence factors of most plant-pathogenic
Streptomyces
strains. Due to their potent herbicidal activity, attractive environmental compatibility, and inherent biodegradability, thaxtomins are key active ingredients of bioherbicides approved by the U.S. Environmental Protection Agency. However, the low yield of thaxtomins in native
Streptomyces
producers limits their wide agricultural applications. Here, we describe the high-yield production of thaxtomins in a heterologous host. The thaxtomin gene cluster from
S. scabiei
87.22 was cloned and expressed in
S. albus
J1074 after chromosomal integration. The production of thaxtomins and nitrotryptophan analogs was observed using liquid chromatography-mass spectrometry (LC-MS) analysis. When the engineered
S. albus
J1074 was cultured in the minimal medium Thx defined medium supplemented with 1% cellobiose (TDMc), the yield of the most abundant and herbicidal analog, thaxtomin A, was 10 times higher than that in
S. scabiei
87.22, and optimization of the medium resulted in the highest yield of thaxtomin analogs at about 222 mg/liter. Further engineering of the thaxtomin biosynthetic gene cluster through gene deletion led to the production of multiple biosynthetic intermediates important to the chemical synthesis of new analogs. Additionally, the versatility of the thaxtomin biosynthetic system in
S. albus
J1074 was capitalized on to produce one unnatural fluorinated analog, 5-fluoro-thaxtomin A (5-F-thaxtomin A), whose structure was elucidated by a combination of MS and one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) analyses. Natural and unnatural thaxtomins demonstrated potent herbicidal activity in radish seedling assays. These results indicated that
S. albus
J1074 has the potential to produce thaxtomins and analogs thereof with high yield, fostering their agricultural applications.

IMPORTANCE
Thaxtomins are agriculturally valuable herbicidal natural products, but the productivity of native producers is limiting. Heterologous expression of the thaxtomin gene cluster in
S. albus
J1074 resulted in the highest yield of thaxtomins ever reported, representing a significant leap forward in its wide agricultural use. Furthermore, current synthetic routes to thaxtomins and analogs are lengthy, and two thaxtomin biosynthetic intermediates produced at high yields in this work can provide precursors and building blocks to advanced synthetic routes. Importantly, the production of 5-F-thaxtomin A in engineered
S. albus
J1074 demonstrated a viable alternative to chemical methods in the synthesis of new thaxtomin analogs. Moreover, our work presents an attractive synthetic biology strategy to improve the supply of herbicidal thaxtomins, likely finding general applications in the discovery and production of many other bioactive natural products.
Using Preprints for Journal Clubs
Authors: Casadevall Arturo , Gow Neil 
Published: April 2018

ABSTRACT
Journal clubs are important mechanisms for teaching how to approach the scientific literature critically and for disseminating findings. Papers from high-impact journals often dominate journal club selections, a practice that reinforces the unscientific emphasis of placing high value on publishing venue rather than scientific content and critical analysis of the publications. We suggest improving journal clubs by including preprints rather than focusing completely on published papers. This change in practice might benefit the scientific enterprise in numerous ways, including by providing direct criticisms to preprint authors before publication, deemphasizing publishing venue, teaching students the art of reviewing papers, and making journal clubs more current by discussing unpublished data.
Two-year follow-up of corneal cross-linking and refractive surface ablation in patients with asymmetric corneal topography
Authors: Malta João Baptista N S , Kaz Soong H , Moscovici Bernardo Kaplan , Campos Mauro 
Published: April 2018

AimsTo evaluate the safety and efficacy of corneal cross-linking (CXL) followed by photorefractive keratectomy (PRK) for refractive correction in patients with bilateral asymmetric topography.MethodsForty-four patients (88 eyes) were enrolled in this prospective randomised clinical trial. CXL with subsequent PRK after 6 months was performed in one eye (study group), and PRK alone was performed in contralateral eyes (control group). Patients were followed for 24 months after PRK. Outcome measures investigated included visual acuity (VA), refraction, aberrometry, topography, pachymetry and endothelial cell count. Groups were compared with linear mixed regression and repeated measures logistic regression. Multiple comparison adjustment with the Holm procedure was performed.ResultsAt baseline, the logMAR VA (best spectacle corrected) in study and control groups was 0.12±0.13 (mean±SD) and 0.08D±0.14, respectively, and axial inferior–superior index (IS) (topographic IS) in study and control groups were 0.59D±0.31D and 0.58D±0.32D, respectively. After 24 months, a mean under correction of −0.50D was observed in both groups. Change from baseline in logMAR VA in study and control groups was 0.00D±0.08D and −0.02D±0.10D, respectively. Frequency of haze at 30 months in study and control group eyes was, respectively, 18.2% and 4.6% (p=0.05). There was no statistical difference between groups in spherical aberration and coma after adjustment for multiple comparisons.ConclusionsNon-simultaneous CXL followed by PRK may be performed safely, and refractive results over a 2-year follow-up are highly similar in virgin and previously cross-linked corneas. Despite using mitomycin C, corneal haze can be significantly higher in the first year after PRK in eyes pretreated with CXL.
Rise and fall of NT-proBNP in aortic valve intervention
Authors: Hultkvist Henrik , Holm Jonas , Svedjeholm Rolf , Vánky Farkas 
Published: April 2018

ObjectivesTo describe the dynamics of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from preoperative evaluation to 6-month follow-up in patients undergoing aortic valve intervention, and to evaluate NT-proBNP with regard to 1-year mortality.MethodsAt preoperative evaluation, we prospectively included 462 patients accepted for aortic valve intervention. The median time to surgical aortic valve replacement (SAVR; n=336) or transcatheter aortic valve implantation (TAVI; n=126) was 4 months. NT-proBNP was measured at enrolment for preoperative evaluation, on the day of surgery, postoperatively on day 1, day 3 and at the 6-month follow-up. Subgroups of patients undergoing SAVR with aortic regurgitation and aortic stenosis with and without coronary artery bypass were also analysed.ResultsNT-proBNP remained stable in all subgroups during the preoperative waiting period, but displayed a substantial transient early postoperative increase with a peak on day 3 except in the TAVI group, which peaked on day 1. At the 6-month follow-up, NT-proBNP had decreased to or below the preoperative level in all groups. In the SAVR group, NT-proBNP preoperatively and on postoperative days 1 and 3 revealed significant discriminatory power with regard to 1-year mortality (area under the curve (AUC)=0.79, P=0.0001; AUC=0.71, P=0.03; and AUC=0.79, P=0.002, respectively). This was not found in the TAVI group, which had higher levels of NT-proBNP both preoperatively and at the 6-month follow-up compared with the SAVR group.ConclusionsThe dynamic profile of NT-proBNP differed between patients undergoing TAVI and SAVR. NT-proBNP in the perioperative course was associated with increased risk of 1-year mortality in SAVR but not in TAVI.
Single attosecond pulse generation by using plasmon-driven double optical gating technology in crossed metal nanostructures
Authors: Feng Liqiang , Liu Katheryn 
Published: April 2018

An effective method to obtain the single attosecond pulses (SAPs) by using the multi-cycle plasmon-driven double optical gating (DOG) technology in the specifically designed metal nanostructures has been proposed and investigated. It is found that with the introduction of the crossed metal nanostructures along the driven and the gating polarization directions, not only the harmonic cutoff can be extended, but also the efficient high-order harmonic generation (HHG) at the very highest orders occurs only at one side of the region inside the nanostructure. As a result, a 93 eV supercontinuum with the near stable phase can be found. Further, by properly introducing an ultraviolet (UV) pulse into the driven laser polarization direction (which is defined as the DOG), the harmonic yield can be enhanced by two orders of magnitude in comparison with the singe polarization gating (PG) technology. However, as the polarized angle or the ellipticity of the UV pulse increase, the enhancement of the harmonic yield is slightly reduced. Finally, by superposing the selected harmonics from the DOG scheme, a 30 as SAP with intensity enhancement of two orders of magnitude can be obtained.
Advances on the BRAF Front in Colorectal Cancer
Authors: Janku Filip 
Published: April 2018

Abstract
Summary: Colorectal cancer with BRAFV600E mutation can be effectively treated with combination approaches involving inhibition of BRAF, MEK, and EGFR proteins. However, activation of the MAPK pathway, often due to emergence of previously undetected molecular alterations, ultimately leads to adaptive therapeutic resistance. Novel combination strategies combining inhibition of BRAF, ERK, and EGFR can be used to prevent MAPK pathway–driven resistance and warrant further investigation. Cancer Discov; 8(4); 389–91. ©2018 AACR.
See related article by Corcoran et al., p. 428.
See related article by Hazar-Rethinam et al., p. 417.
Re(de)fining Innate Lymphocyte Lineages in the Face of Cancer
Authors: Chou Chun , Li Ming O. 
Published: April 2018

Abstract
Innate lymphocytes play critical roles in maintaining tissue homeostasis and integrity of the host at steady state and during pathogenic insults. The successive identification of new innate lymphocyte subsets has revealed an incredible diversity within the family. While this heterogeneous population can be grouped based on their cytotoxic potential into exclusively cytokine-producing helpers and cytolytic killers, the exact developmental relationships between the subsets are not fully understood. The former group is enriched at mucosal surfaces, whereas innate lymphocytes with cytotoxic potential can be identified in a wider array of tissues, including tumors. Although their cytotoxicity suggests an antitumor role, the nature of tumor-elicited innate lymphocyte responses has only begun to be investigated, and the identities of participating subsets still remain contentious. In this review, we provide a brief overview of innate lymphocyte biology, review the current knowledge on their ontogeny, and discuss their roles in tumor immunosurveillance. Cancer Immunol Res; 6(4); 372–7. ©2018 AACR.
Probable Maximum Precipitation: Its Estimation and Uncertainty Quantification Using Bivariate Extreme Value Analysis
Authors: Ben Alaya M. A. , Zwiers F. , Zhang X. 
Published: April 2018

AbstractProbable maximum precipitation (PMP) is the key parameter used to estimate the probable maximum flood (PMF), both of which are important for dam safety and civil engineering purposes. The usual operational procedure for obtaining PMP values, which is based on a moisture maximization approach, produces a single PMP value without an estimate of its uncertainty. We therefore propose a probabilistic framework based on a bivariate extreme value distribution to aid in the interpretation of these PMP values. This 1) allows us to evaluate estimates from the operational procedure relative to an estimate of a plausible distribution of PMP values, 2) enables an evaluation of the uncertainty of these values, and 3) provides clarification of the impact of the assumption that a PMP event occurs under conditions of maximum moisture availability. Results based on a 50-yr Canadian Centre for Climate Modelling and Analysis Regional Climate Model (CanRCM4) simulation over North America reveal that operational PMP estimates are highly uncertain and suggest that the assumption that PMP events have maximum moisture availability may not be valid. Specifically, in the climate simulated by CanRCM4, the operational approach applied to 50-yr data records produces a value that is similar to the value that is obtained in our approach when assuming complete dependence between extreme precipitation efficiency and extreme precipitable water. In contrast, our results suggest weaker than complete dependence. Estimates from the operational approach are 15% larger on average over North America than those obtained when accounting for the dependence between precipitation efficiency and precipitable water extremes realistically. A difference of this magnitude may have serious implications in engineering design.
The Effect of Hydrometeors on MSU/AMSU Temperature Observations over the Tropical Ocean
Authors: Pahlavan Hamid A. , Fu Qiang , Wallace John M. 
Published: April 2018

AbstractThe temperature of Earth’s atmosphere has been monitored continuously since late 1978 by the Microwave Sounding Unit (MSU) and the Advanced Microwave Sounding Unit (AMSU) flown on polar-orbiting weather satellites. It is well known that these measurements are affected by the scattering and emission from hydrometeors, including cloud water, precipitation, and ice particles. In this study the hydrometeor effects on MSU/AMSU temperature observations are investigated by comparing satellite-observed temperature of the middle troposphere (TMT) with synthetic TMT constructed using temperature fields from ECMWF Interim [ERA-Interim (ERA-I)]. Precipitation data have been used to estimate how much of the difference between these two TMT fields is due to hydrometeor contamination effects. It is shown that there exists a robust linear proportionality between TMT deficit (i.e., the measured TMT minus the synthetic TMT) and precipitation at individual grid points in monthly mean fields. The linear correlation is even stronger in the annual mean and seasonally varying climatology and also in the spatial pattern of ENSO-related anomalies. The linear regression coefficient obtained in all of these analyses is virtually identical: −0.042 K (mm day−1)−1. The channel that senses lower-tropospheric temperature (TLT) is more sensitive to precipitation than the TMT channel: the regression coefficient is −0.059 K (mm day−1)−1. It is shown that correcting the TMT or TLT monthly anomalies by removing the hydrometeor contamination does not significantly influence estimates of tropical mean temperature trends, but it could affect the pattern of temperature trend over the tropical oceans.
Evolution of GLM-Observed Total Lightning in Hurricane Maria (2017) during the Period of Maximum Intensity
Authors: Fierro Alexandre O. , Stevenson Stephanie N. , Rabin Robert M. 
Published: April 2018

Total lightning data obtained from the Geostationary Lightning Mapper (GLM) were analyzed to present a first glimpse of relationships with intensity variations and convective evolution in Hurricane Maria (2017). The GLM has made it possible, for the first time, to analyze total lightning within a major hurricane for a long period, far from ground-based detection networks. It is hoped that these observations could enlighten some of the complex relationships existing between intensity fluctuations and the distribution of electrified convection in these systems. Prior to rapidly intensifying from a category 1 to category 5 storm, Maria produced few inner-core flashes. Increases in total lightning in the inner core ( r ≤ 100 km) occurred during both the beginning and end of an intensification cycle, while lightning increases in the outer region (100 < r ≤ 500 km) occurred earlier in the intensification cycle and during weakening. Throughout the analysis period, the largest lightning rates in the outer region were consistently located in the southeastern quadrant, a pattern consistent with modeling studies of electrification within hurricanes. Lightning in the inner core was generally tightly clustered within a 50-km radius from the center and most often found in the southeastern portion of the eyewall, which is atypical. Bootstrapped correlation statistics revealed that the most robust and systematic relationship with storm intensity was obtained for inner-core lightning and maximum surface wind speed. A brief comparison between flash rates from GLM and a very low-frequency ground-based network revealed that not all lightning peaks are seen equally, with hourly flash-rate ratios between both systems sometimes exceeding two orders of magnitude.
Validation of Mountain Precipitation Forecasts from the Convection-Permitting NCAR Ensemble and Operational Forecast Systems over the Western United States
Authors: Gowan Thomas M. , Steenburgh W. James , Schwartz Craig S. 
Published: April 2018

Abstract
Convection-permitting ensembles can capture the large spatial variability and quantify the inherent uncertainty of precipitation in areas of complex terrain; however, such systems remain largely untested over the western United States. In this study, we assess the capabilities of deterministic and probabilistic cool-season quantitative precipitation forecasts (QPFs) produced by the 10-member, convection-permitting (3-km horizontal grid spacing) NCAR Ensemble using observations collected by SNOTEL stations at mountain locations across the western United States and precipitation analyses from PRISM. We also examine the performance of operational forecast systems run by NCEP including the High Resolution Rapid Refresh (HRRR) model, the NAM forecast system with a 3-km continental United States (CONUS) nest, GFS, and the Short-Range Ensemble Forecast system (SREF). Overall, we find that higher-resolution models, such as the HRRR, NAM-3km CONUS nest, and an individual member of the NCAR Ensemble, are more deterministically skillful than coarser models, especially over the narrow interior ranges of the western United States, likely because they better resolve topography and thus better simulate orographic precipitation. The 10-member NCAR Ensemble is also more probabilistically skillful than 13-member subensembles composed of each SREF dynamical core, but less probabilistically skillful than the full 26-member SREF, as a result of insufficient spread. These results should help guide future short-range model development and inform forecasters about the capabilities and limitations of several widely used deterministic and probabilistic modeling systems over the western United States.