bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative genomic hybridization and transcriptome analysis with a pan‐genome microarray reveal distinctions between JP2 and non‐JP2 genotypes of Aggregatibacter actinomycetemcomitans
Authors: Huang Y. , Kittichotirat W. , Mayer M.P.A. , Hall R. , Bumgarner R. , Chen C. 
Published: September 2012

SummaryIt was postulated that the highly virulent JP2 genotype of Aggregatibacter actinomycetemcomitans may possess a constellation of distinct virulence determinants not found in non‐JP2 genotypes. This study compared the genome content and the transcriptome of the serotype b JP2 genotype and the closely related serotype b non‐JP2 genotype of A. actinomycetemcomitans. A custom‐designed pan‐genomic microarray of A. actinomycetemcomitans was constructed and validated against a panel of 11 sequenced reference strains. The microarray was subsequently used for comparative genomic hybridization of serotype b strains of JP2 (six strains) and non‐JP2 (six strains) genotypes, and for transcriptome analysis of strains of JP2 (three strains) and non‐JP2 (two strains). Two JP2‐specific and two non‐JP2‐specific genomic islands were identified. In one instance, distinct genomic islands were found to be inserted into the same locus among strains of different genotypes. Transcriptome analysis identified five operons, including the leukotoxin operon, to have at least two genes with an expression ratio of 2 or greater between genotypes. Two of the differentially expressed operons were members of the membrane‐bound nitrate reductase system (nap operon) and the Tol‐Pal system of gram‐negative bacterial species. This study is the first to demonstrate the differences in the full genome content and gene expression between A. actinomycetemcomitans strains of JP2 and non‐JP2 genotypes. The information is essential for designing hypothesis‐driven experiments to examine the pathogenic mechanisms of A. actinomycetemcomitans.
Cosubstrate Tolerance of the Aminoglycoside Resistance Enzyme Eis from Mycobacterium tuberculosis
Authors: Chen Wenjing , Green Keith D. , Garneau-Tsodikova Sylvie 
Published: September 2012

ABSTRACT

We previously demonstrated that aminoglycoside acetyltransferases (AACs) display expanded cosubstrate promiscuity. The enhanced intracellular survival (Eis) protein of
Mycobacterium tuberculosis
is responsible for the resistance of this pathogen to kanamycin A in a large fraction of clinical isolates. Recently, we discovered that Eis is a unique AAC capable of acetylating multiple amine groups on a large pool of aminoglycoside (AG) antibiotics, an unprecedented property among AAC enzymes. Here, we report a detailed study of the acyl-coenzyme A (CoA) cosubstrate profile of Eis. We show that, in contrast to other AACs, Eis efficiently uses only 3 out of 15 tested acyl-CoA derivatives to modify a variety of AGs. We establish that for almost all acyl-CoAs, the number of sites acylated by Eis is smaller than the number of sites acetylated. We demonstrate that the order of
n
-propionylation of the AG neamine by Eis is the same as the order of its acetylation. We also show that the 6′ position is the first to be
n
-propionylated on amikacin and netilmicin. By sequential acylation reactions, we show that AGs can be acetylated after the maximum possible
n
-propionylation of their scaffolds by Eis. The information reported herein will advance our understanding of the multiacetylation mechanism of inactivation of AGs by Eis, which is responsible for
M. tuberculosis
resistance to some AGs.
Use of Xylitol To Enhance the Therapeutic Efficacy of Polymethylmethacrylate-Based Antibiotic Therapy in Treatment of Chronic Osteomyelitis
Authors: Beenken Karen E. , Bradney Laura , Bellamy William , Skinner Robert A. , McLaren Sandra G. , Gruenwald M. Johannes , Spencer Horace J. , Smith James K. , Haggard Warren O. , Smeltzer Mark S. 
Published: September 2012

ABSTRACT

Using a rabbit model of postsurgical osteomyelitis, we demonstrate that incorporation of xylitol into polymethylmethacrylate (PMMA) bone cement enhances the elution of daptomycin under
in vivo
conditions. We also demonstrate that this can be correlated with an improved therapeutic outcome in the treatment of a chronic bone infection following surgical debridement.
Subtilase Cytotoxin Enhances Escherichia coli Survival in Macrophages by Suppression of Nitric Oxide Production through the Inhibition of NF-κB Activation
Authors: Tsutsuki Hiroyasu , Yahiro Kinnosuke , Suzuki Kotaro , Suto Akira , Ogura Kohei , Nagasawa Sayaka , Ihara Hideshi , Shimizu Takeshi , Nakajima Hiroshi , Moss Joel , Noda Masatoshi 
Published: September 2012

ABSTRACTSubtilase cytotoxin (SubAB), which is produced by certain strains of Shiga-toxigenicEscherichia coli(STEC), cleaves an endoplasmic reticulum (ER) chaperone, BiP/Grp78, leading to induction of ER stress and caspase-dependent apoptosis. SubAB alters the innate immune response. SubAB pretreatment of macrophages inhibited lipopolysaccharide (LPS)-induced production of both monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor α (TNF-α). We investigated here the mechanism by which SubAB inhibits nitric oxide (NO) production by mouse macrophages. SubAB suppressed LPS-induced NO production through inhibition of inducible NO synthase (iNOS) mRNA and protein expression. Further, SubAB inhibited LPS-induced IκB-α phosphorylation and nuclear localization of the nuclear factor-κB (NF-κB) p65/p50 heterodimer. Reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that SubAB reduced LPS-induced NF-κB p65/p50 heterodimer binding to an NF-κB binding site on the iNOS promoter. In contrast to the native toxin, a catalytically inactivated SubAB mutant slightly enhanced LPS-induced iNOS expression and binding of NF-κB subunits to the iNOS promoter. The SubAB effect on LPS-induced iNOS expression was significantly reduced in macrophages from NF-κB1 (p50)-deficient mice, which lacked a DNA-binding subunit of the p65/p50 heterodimer, suggesting that p50 was involved in SubAB-mediated inhibition of iNOS expression. Treatment of macrophages with an NOS inhibitor or expression of SubAB byE. coliincreasedE. colisurvival in macrophages, suggesting that NO generated by macrophages resulted in efficient killing of the bacteria and SubAB contributed toE. colisurvival in macrophages. Thus, we hypothesize that SubAB might represent a novel bacterial strategy to circumvent host defense during STEC infection.
Capsular Polysaccharide of Erysipelothrix rhusiopathiae, the Causative Agent of Swine Erysipelas, and Its Modification with Phosphorylcholine
Authors: Shi Fang , Harada Tomoyuki , Ogawa Yohsuke , Ono Hiroshi , Ohnishi-Kameyama Mayumi , Miyamoto Toru , Eguchi Masahiro , Shimoji Yoshihiro 
Published: September 2012

ABSTRACT

The capsule has been implicated in the virulence of the swine pathogen
Erysipelothrix rhusiopathiae
, a rod-shaped, intracellular Gram-positive bacterium that has a unique phylogenetic position in the phylum
Firmicutes
and is a close relative of
Mollicutes
(mycoplasma species). In this study, we analyzed the genetic locus and composition of the capsular polysaccharide (CPS) of the Fujisawa strain of
E. rhusiopathiae
. Genome analysis of the Fujisawa strain revealed that the genetic locus for capsular polysaccharide synthesis (
cps
) is located next to an
lic
operon, which is involved in the incorporation and expression of phosphorylcholine (PCho). Reverse transcription-PCR analysis showed that
cps
and
lic
are transcribed as a single mRNA, indicating that the loci form an operon. Using the cell surface antigen-specific monoclonal antibody (MAb) ER21 as a probe, the capsular materials were isolated from the Fujisawa strain by hot water extraction and treatment with DNase, RNase, pronase, and
N
-acetylmuramidase SG, followed by anion-exchange and gel filtration chromatography. The materials were then analyzed by high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance (NMR) spectroscopy. The CPS of
E. rhusiopathiae
is heterogeneous and consists of the major monosaccharides galacturonic acid, galactose, mannose, glucose, arabinose, xylose, and
N
-acetylglucosamine and some minor monosaccharides containing ribose, rhamnose, and
N
-acetylgalactosamine. In addition, the capsule is modified by PCho, which comigrates with the capsular materials, as determined by Western immunoblotting, and colocalizes on the cell surface, as determined by immunogold electron microscopy. Virulence testing of PCho-defective mutants in mice demonstrated that PCho is critical for the virulence of this organism.
Why RECIST Works and Why It Should Stay—Counterpoint
Authors: Fojo Antonio T. , Noonan Anne 
Published: September 2012

Abstract
Assessing that the efficacy of a cancer therapeutic is an integral part of its path to regulatory approval, we review the history that led to our current assessment method, Response Evaluation Criteria in Solid Tumors (RECIST). We describe the efforts of Moertel and Hanley to standardize response assessments in lymphoid malignancies and how this was adapted in the World Health Organization (WHO) criteria. Two decades later, RECIST was advanced to streamline WHO and improve its reproducibility. We describe the ways in which thresholds established by Moertel and Hanley to provide accuracy and reproducibility evolved to become measures of efficacy and why they have been valuable. While we recognize RECIST is far from perfect—in need of modification as a measure of efficacy for some agents and in some diseases—for the majority of solid tumors, it is very valuable. We argue that over time, the efficacy thresholds established by WHO and then RECIST have proved their worth, and we summarize 10 years of U.S. Food and Drug Administration (FDA) approvals in solid tumors to support our position that current RECIST thresholds should be retained. Cancer Res; 72(20); 5151–7. ©2012 AACR.
Subtle Abnormalities in Contractile Function Are an Early Manifestation of Sarcomere Mutations in Dilated Cardiomyopathy
Authors: Lakdawala Neal K. , Thune Jens J. , Colan Steven D. , Cirino Allison L. , Farrohi Faranak , Rivero Jose , McDonough Barbara , Sparks Elizabeth , Orav E. J. , Seidman J. G. , Seidman Christine E. , Ho Carolyn Y. 
Published: September 2012

Background—
Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM.

Methods and Results—

Sixty-two genotyped individuals in families with sarcomeric DCM underwent clinical evaluation including strain echocardiography. The group included 12 subclinical DCM mutation carriers with normal cardiac dimensions and left ventricular ejection fraction (LVEF ≥55%), 21 overt DCM subjects, and 29 related mutation (-) normal controls. Results were compared with a previously characterized cohort of 60 subclinical HCM subjects (sarcomere mutation carriers without left ventricular hypertrophy). Systolic myocardial tissue velocity, longitudinal, circumferential, and radial strain, and longitudinal and radial strain rate were reduced by 10%–23% in subclinical DCM mutation carriers compared with controls (
P
<0.001 for all comparisons), after adjusting for age and family relations. No significant differences in diastolic parameters were identified comparing the subclinical and control cohorts. The opposite pattern of contractile abnormalities with reduced diastolic but preserved systolic function was seen in subclinical HCM.

Conclusions—
Subtle abnormalities in systolic function are present in subclinical DCM mutation carriers, despite normal left ventricular size and ejection fraction. In contrast, impaired relaxation and preserved systolic function appear to be the predominant early manifestations of sarcomere mutations that lead to HCM. These findings support the theory that the mutation’s intrinsic impact on sarcomere function influences whether a dilated or hypertrophic phenotype develops.
Five-year Clinical and Economic Outcomes Among Patients With Medically Managed Severe Aortic Stenosis
Authors: Clark Mary Ann , Arnold Suzanne V. , Duhay Francis G. , Thompson Ann K. , Keyes Michelle J. , Svensson Lars G. , Bonow Robert O. , Stockwell Benjamin T. , Cohen David J. 
Published: September 2012

Background—
Patients with severe, symptomatic aortic stenosis, who do not undergo valve replacement surgery have a poor long-term prognosis. Limited data exist on the medical resource utilization and costs during the final stages of the disease.

Methods and Results—
We used data from the 2003 Medicare 5% standard analytic files to identify patients with aortic stenosis and a recent hospitalization for heart failure, who did not undergo valve replacement surgery within the ensuing 2 calendar quarters. These patients (n=2150) were considered to have medically managed severe aortic stenosis and were tracked over 5 years to measure clinical outcomes, medical resource use, and costs (from the perspective of the Medicare Program). The mean age of the cohort was 82 years, 64% were female, and the estimated logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (a measure of predicted mortality with cardiac surgery) was 17%. During 5 years of follow-up, overall mortality was 88.4% with a mean survival duration of 1.8 years. During this time period, patients experienced an average of 4.4 hospital admissions, 52% were admitted to skilled nursing care, and 28% were admitted to hospice care. The total 5-year costs were $63 844 per patient, whereas mean annual follow-up costs (excluding the index quarter) per year alive were $29 278.

Conclusions—
Elderly patients with severe aortic stenosis undergoing medical management have limited long-term survival and incur substantial costs to the Medicare Program. These results have important implications for policy makers interested in better understanding the cost-effectiveness of emerging treatment options such as transcatheter aortic valve replacement.
Television Watching, Leisure Time Physical Activity, and the Genetic Predisposition in Relation to Body Mass Index in Women and Men
Authors: Qi Qibin , Li Yanping , Chomistek Andrea K. , Kang Jae H. , Curhan Gary C. , Pasquale Louis R. , Willett Walter C. , Rimm Eric B. , Hu Frank B. , Qi Lu 
Published: September 2012

Background—

Previous studies on gene-lifestyle interaction and obesity have focused mostly on the
FTO
gene and physical activity, whereas little attention has been paid to sedentary behavior as indicated by television (TV) watching.

Methods and Results—

We analyzed interactions between TV watching, leisure time physical activity, and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: The Nurses' Health Study and the Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years before assessment of BMI. A weighted genetic risk score was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted genetic risk score was associated with 0.8 (SE, 0.4), 0.8 (SE, 0.2), 1.4 (SE, 0.2), 1.5 (SE, 0.2), and 3.4 (SE, 1.0) kg/m
2
higher BMI across the 5 categories of TV watching (0–1, 2–5, 6–20, 21–40, and >40 h/wk;
P
for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted genetic risk score was associated with 1.5 (SE, 0.2), 1.3 (SE, 0.2), 1.2 (SE, 0.2), 1.2 (SE, 0.2), and 0.8 (SE, 0.2) kg/m
2
higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other.

Conclusions—
A sedentary lifestyle, indicated by prolonged TV watching, may accentuate the predisposition to elevated adiposity, whereas greater leisure time physical activity may attenuate the genetic association.
Statistical Analysis of the Spatial Evolution of the Stationary Wind Wave Field
Authors: Zavadsky A. , Liberzon D. , Shemer L. 
Published: September 2012

Abstract
Detailed investigation of wind-generated water waves in a 5-m-long wind wave flume facility is reported. Careful measurements were carried out at a large number of locations along the test section and at numerous airflow rates. The evolution of the wind wave field was investigated using appropriate dimensionless parameters. When possible, quantitative comparison with the results accumulated in field measurements and in larger laboratory facilities was performed. Particular attention was given to the evolution of wave frequency spectra along the tank, distinguishing between the frequency domain around the spectral peak and the high-frequency tail of the spectrum. Notable similarity between the parameters of the evolving wind wave field in the present facility and in field measurements was observed.
Impacts of Mesonet Observations on Meteorological Surface Analyses
Authors: Tyndall Daniel P. , Horel John D. 
Published: September 2012

Abstract
Given the heterogeneous equipment, maintenance and reporting practices, and siting of surface observing stations, subjective decisions that depend on the application tend to be made to use some observations and to avoid others. This research determines objectively high-impact surface observations of 2-m temperature, 2-m dewpoint, and 10-m wind observations using the adjoint of a two-dimensional variational surface analysis over the contiguous United States. The analyses reflect a weighted blend of 1-h numerical forecasts used as background grids and available observations. High-impact observations are defined as arising from poor observation quality, observation representativeness errors, or accurate observed weather conditions not evident in the background field. The impact of nearly 20 000 surface observations is computed over a sample of 100 analysis hours during 25 major weather events. Observation impacts are determined for each station as well as within broad network categories. For individual analysis hours, high-impact observations are located in regions of significant weather—typically, where the background field fails to define the local weather conditions. Low-impact observations tend to be ones where there are many observations reporting similar departures from the background. When averaged over the entire 100 cases, observations with the highest impact are found within all network categories and depend strongly on their location relative to other observing sites and the amount of variability in the weather; for example, temperature observations have reduced impact in urban areas such as Los Angeles, California, where observations are plentiful and temperature departures from the background grids are small.
Would You Go Broke to Stay Alive in Singapore?
Authors: Quah Song Chiek 
Published: September 2012

Aims: This study attempts to explore how high treatment costs can result in people foregoing necessary treatment. Methods: Health care professionals (HCPs) were invited to complete a questionnaire survey, in which they were requested to imagine that they had locally recurrent head and neck cancers. They were then asked to choose a treatment in each of the 3 scenarios, which differed only in the cost of treatment. Results: Majority would choose the cheapest treatment option if treatment costs mirrored that in real life. But majority would opt for the treatment that gave the greatest median survival, if cost was not an issue. Conclusion: High cost of treatment can be a strong deterrent to patients who need and can benefit from those treatments.
Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial
Authors: Tan King L. , Scott David W. , Hong Fangxin , Kahl Brad S. , Fisher Richard I. , Bartlett Nancy L. , Advani Ranjana H. , Buckstein Rena , Rimsza Lisa M. , Connors Joseph M. , Steidl Christian , Gordon Leo I. , Horning Sandra J. , Gascoyne Randy D. 
Published: September 2012

Abstract
Increased tumor-associated macrophages (TAMs) are reported to be associated with poor prognosis in classic Hodgkin lymphoma (CHL). We investigated the prognostic significance of TAMs in the E2496 Intergroup trial, a multicenter phase 3 randomized controlled trial comparing ABVD and Stanford V chemotherapy in locally extensive and advanced stage CHL. Tissue microarrays were constructed from formalin-fixed, paraffin-embedded tumor tissue and included 287 patients. Patients were randomly assigned into training (n = 143) and validation (n = 144) cohorts. Immunohistochemistry for CD68 and CD163, and in situ hybridization for EBV-encoded RNA were performed. CD68 and CD163 IHC were analyzed by computer image analysis; optimum thresholds for overall survival (OS) were determined in the training cohort and tested in the independent validation cohort. Increased CD68 and CD163 expression was significantly associated with inferior failure-free survival and OS in the validation cohort. Increased CD68 and CD163 expression was associated with increased age, EBV-encoded RNA positivity, and mixed cellularity subtype of CHL. Multivariate analysis in the validation cohort showed increased CD68 or CD163 expression to be significant independent predictors of inferior failure-free survival and OS. We demonstrate the prognostic significance of TAMs in locally extensive and advanced-stage CHL in a multicenter phase 3 randomized controlled clinical trial.
Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL
Authors: Le Noir Sandrine , Ben Abdelali Raouf , Lelorch Marc , Bergeron Julie , Sungalee Stephanie , Payet-Bornet Dominique , Villarèse Patrick , Petit Arnaud , Callens Céline , Lhermitte Ludovic , Baranger Laurence , Radford-Weiss Isabelle , Grégoire Marie-José , Dombret Hervé , Ifrah Norbert , Spicuglia Salvatore , Romana Serge , Soulier Jean , Nadel Bertrand , Macintyre Elizabeth , Asnafi Vahid 
Published: September 2012

Abstract
Chromosomal translocations involving the TCR loci represent one of the most recurrent oncogenic hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) and are generally believed to result from illegitimate V(D)J recombination events. However, molecular characterization and evaluation of the extent of recombinase involvement at the TCR-oncogene junction has not been fully evaluated. In the present study, screening for TCRβ and TCRα/δ translocations by FISH and ligation-mediated PCR in 280 T-ALLs allowed the identification of 4 previously unreported TCR-translocated oncogene partners: GNAG, LEF1, NKX2-4, and IL2RB. Molecular mapping of genomic junctions from TCR translocations showed that the majority of oncogenic partner breakpoints are not recombinase mediated and that the regulatory elements predominantly used to drive oncogene expression differ markedly in TCRβ (which are exclusively enhancer driven) and TCRα/δ (which use an enhancer-independent cryptic internal promoter) translocations. Our data also imply that oncogene activation takes place at a very immature stage of thymic development, when Dδ2-Dδ3/Dδ3-Jδ1 and Dβ-Jβ rearrangements occur, whereas the bulk leukemic maturation arrest occurs at a much later (cortical) stage. These observations have implications for T-ALL therapy, because the preleukemic early thymic clonogenic population needs to be eradicated and its disappearance monitored.