bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bactofencin A, a New Type of Cationic Bacteriocin with Unusual Immunity
Authors: O'Shea Eileen F. , O'Connor Paula M. , O'Sullivan Orla , Cotter Paul D. , Ross R. Paul , Hill Colin 
Published: October 2013

ABSTRACT

Bacteriocin production is an important probiotic trait of intestinal bacteria. In this study, we identify a new type of bacteriocin, bactofencin A, produced by a porcine intestinal isolate
Lactobacillus salivarius
DPC6502, and assess its potency against pathogenic species including
Staphylococcus aureus
and
Listeria monocytogenes
. Genome sequencing of the bacteriocin producer revealed
bfnA
, which encodes the mature and highly basic (pI 10.59), 22-amino-acid defensin-like peptide. Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) mass spectral analysis determined that bactofencin A has a molecular mass of 2,782 Da and contains two cysteine residues that form an intramolecular disulfide bond. Although an ABC transporter and transport accessory protein were also present within the bacteriocin gene cluster, a classical bacteriocin immunity gene was not detected. Interestingly, a
dltB
homologue was identified downstream of
bfnA
. DltB is usually encoded within the
dlt
operon of many Gram-positive bacteria. It is responsible for
d
-alanylation of teichoic acids in the cell wall and has previously been associated with bacterial resistance to cationic antimicrobial peptides. Heterologous expression of this gene conferred bactofencin A-specific immunity on sensitive strains of
L. salivarius
and
S. aureus
(although not
L. monocytogenes
), establishing its role in bacteriocin immunity. An analysis of the distribution of
bfnA
revealed that it was present in four additional isolates derived from porcine origin and absent from five human isolates, suggesting that its distribution is host specific. Given its novelty, we anticipate that bactofencin A represents the prototype of a new class of bacteriocins characterized as being cationic, with a DltB homologue providing a cognate immunity function.

IMPORTANCE
This study describes the identification, purification, and characterization of bactofencin A, a novel type of bacteriocin produced by
L. salivarius
DPC6502. Interestingly, bactofencin A is not similar to any other known bacteriocin but instead shares similarity with eukaryotic cationic antimicrobial peptides, and here, we demonstrate that it inhibits two medically significant pathogens. Genome sequence analysis of the producing strain also revealed the presence of an atypical
dltB
homologue in the bacteriocin gene cluster, which was lacking a classical bacteriocin immunity gene. Furthermore, cloning this gene rendered sensitive strains resistant to the bacteriocin, thereby establishing its role in providing cognate bacteriocin immunity. Four additional
L. salivarius
isolates, also of porcine origin, were found to contain the bacteriocin biosynthesis genes and successfully produced bactofencin A, while these genes were absent from five human-derived strains investigated.
Vitamin D status in recently arrived immigrants from Africa and Asia: a cross-sectional study from Norway of children, adolescents and adults
Authors: Eggemoen Åse R , Knutsen Kirsten V , Dalen Ingvild , Jenum Anne K 
Published: October 2013

ObjectivesTo estimate the prevalence of vitamin D deficiency (25(OH)D) <50 nmol/L among recently arrived immigrants from Africa and Asia in Oslo, and to explore 25(OH)D levels according to origin, gender and age.DesignA cross-sectional study.SettingPrimary healthcare unit in Oslo, Norway, offering family immigrants, asylum seekers, United Nations (UN) refugees or individuals granted asylum a free medical examination on arrival.ParticipantsAll individuals from African and Asian countries (n=591) referred to the Centre of Migrant Health, Health Agency, Oslo, Norway in 2010, estimated to cover 60% of the targeted population.Results25(OH)D <50 nmol/L was very prevalent in immigrants from the Middle East (81% (95% CI 75.4% to 86.6%)), South Sahara Africa (73% (CI 67.5% to 78.5%)) and South Asia (75% (CI 64.0% to 86.0%)), in contrast to East Asians (24% (CI 12.6% to 35.4%)), p<0.001 for differences. The prevalence of 25(OH)D<25 nmol/L was lower but followed the same pattern (Middle East: 38% (CI 31.1% to 45.0%), South Sahara Africa: 24% (CI 18.7% to 29.3%) and South Asia: 35% (CI 22.9% to 47.1%), although it was not observed in East Asians (p<0.001 for differences)). The ethnic differences persisted after adjusting for the duration of residence, seasonality and residence status in multiple linear regression analyses. Female adolescents from South Asia, the Middle East and South Sahara Africa had the lowest levels of 25(OH)D. Further, country-specific median levels of 25(OH)D were low (24–38 nmol/L) among groups from Somalia, Eritrea, Afghanistan and Iraq, the countries with the largest number of immigrants in our study.ConclusionsThe majority of recently settled immigrant groups from the Middle East, South Asia and Africa had 25(OH)D <50 nmol/L, in contrast to East Asians. Female adolescents from these regions had the lowest levels of 25(OH)D.
Reducing inpatient heritable thrombophilia testing using a clinical decision-making tool
Authors: Smith Tyler W , Pi David , Hudoba Monika , Lee Agnes Y Y 
Published: October 2013

AimsTo evaluate the impact of a clinical decision-making tool, designed to educate physicians regarding heritable thrombophilia (HT) testing, on the volume of testing in hospitalised patients in the tertiary care setting.MethodsWe performed a retrospective cohort study over a 6-year period (2007–2012) at a single tertiary care centre intervention site and two regional control sites. In January 2010, the intervention site instituted a policy change whereby physicians ordering HT testing on inpatients needed to complete a pre-preprinted order (PPO) form that outlined the limitations of HT testing in the hospitalised setting. Failure to complete the PPO within 24 h resulted in test cancellation. Our main outcome measure was the volume of HT testing performed at the three study sites.ResultsIntroduction of the PPO resulted in a 79.4% (95% CI 71.2% to 87.6%) reduction in factor V Leiden (FVL) testing at the intervention site. This decrease was significantly greater compared with those in the two control teaching hospitals over the same time periods (33.7% and 43.6%; both p<0.001). Reductions in FVL testing postintervention were observed among all ordering specialists. Similar postintervention reductions in testing volumes were observed for antithrombin (57.4%), protein C (61.9%) and protein S (62.2%) activity assays.ConclusionsIn a large tertiary care hospital, the introduction of a clinical decision-making tool significantly reduced HT testing in inpatients across clinical specialties. The impact on patient outcome should be assessed in further studies.
EXPERIMENTAL VALIDATION OF A MEAN FILED MODEL OF MINERALIZED COLLAGEN FIBER ARRAYS AT TWO LEVELS OF HIERARCHY
Authors: SPIESZ EWA M. , REISINGER ANDREAS G. , ROSCHGER PAUL , ZYSSET PHILIPPE K. 
Published: October 2013

In the course of this study, stiffness of a fibril array of mineralized collagen fibrils modeled with a mean field method was validated experimentally at site-matched two levels of tissue hierarchy using mineralized turkey leg tendons (MTLT). The applied modeling approaches allowed to model the properties of this unidirectional tissue from nanoscale (mineralized collagen fibrils) to macroscale (mineralized tendon). At the microlevel, the indentation moduli obtained with a mean field homogenization scheme were compared to the experimental ones obtained with microindentation. At the macrolevel, the macroscopic stiffness predicted with micro finite element (μFE) models was compared to the experimental stiffness measured with uniaxial tensile tests. Elastic properties of the elements in μFE models were injected from the mean field model or two-directional microindentations. Quantitatively, the indentation moduli can be properly predicted with the mean-field models. Local stiffness trends within specific tissue morphologies are very weak, suggesting additional factors responsible for the stiffness variations. At macrolevel, the μFE models underestimate the macroscopic stiffness, as compared to tensile tests, but the correlations are strong.
Direct Inhibition of Retinoblastoma Phosphorylation by Nimbolide Causes Cell-Cycle Arrest and Suppresses Glioblastoma Growth
Authors: Karkare Swagata , Chhipa Rishi Raj , Anderson Jane , Liu Xiaona , Henry Heather , Gasilina Anjelika , Nassar Nicholas , Roychoudhury Jayeeta , Clark Jason P , Kumar Ashish , Pauletti Giovanni M. , Ghosh Pradip K. , Dasgupta Biplab 
Published: October 2013

Abstract
Purpose: Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica, controls glioblastoma growth.
Experimental Design: Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma.
Results: We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against glioblastoma multiforme in vitro and in vivo. Azt caused cell-cycle arrest, most prominently at the G1–S stage in glioblastoma multiforme cells expressing EGFRvIII, an oncogene present in about 20% to 25% of glioblastoma multiformes. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma protein, cell-cycle arrest at G1—S, and cell death. Independent of retinoblastoma hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of glioblastoma multiforme cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, extracellular signal-regulated kinase 1/2, and STAT3. These effects were specific because Azt did not affect mTOR or other cell-cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of glioblastoma multiforme growth.
Conclusions: Our preclinical findings demonstrate nimbolide as a potent anti-glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo. Clin Cancer Res; 20(1); 199–212. ©2013 AACR.
BAY 80-6946 Is a Highly Selective Intravenous PI3K Inhibitor with Potent p110α and p110δ Activities in Tumor Cell Lines and Xenograft Models
Authors: Liu Ningshu , Rowley Bruce R. , Bull Cathy O. , Schneider Claudia , Haegebarth Andrea , Schatz Christoph A. , Fracasso Paul R. , Wilkie Dean P. , Hentemann Martin , Wilhelm Scott M. , Scott William J. , Mumberg Dominik , Ziegelbauer Karl 
Published: October 2013

Abstract
Because of the complexity derived from the existence of various phosphoinositide 3-kinase (PI3K) isoforms and their differential roles in cancers, development of PI3K inhibitors with differential pharmacologic and pharmacokinetic profiles would allow best exploration in different indications, combinations, and dosing regimens. Here, we report BAY 80-6946, a highly selective and potent pan-class I PI3K inhibitor with sub-nanomolar IC50s against PI3Kα and PI3Kδ. BAY 80-6946 exhibited preferential inhibition (about 10-fold) of AKT phosphorylation by PI3Kα compared with PI3Kβ in cells. BAY 80-6946 showed superior antitumor activity (&gt;40-fold) in PIK3CA mutant and/or HER2 overexpression as compared with HER2-negative and wild-type PIK3CA breast cancer cell lines. In addition, BAY 80-6946 revealed potent activity to induce apoptosis in a subset of tumor cells with aberrant activation of PI3K as a single agent. In vivo, single intravenous administration of BAY 80-6946 exhibited higher exposure and prolonged inhibition of pAKT levels in tumors versus plasma. BAY 80-6946 is efficacious in tumors with activated PI3K when dosed either continuously or intermittently. Thus, BAY 80-6946 induced 100% complete tumor regression when dosed as a single agent every second day in rats bearing HER2-amplified and PIK3CA-mutated KPL4 breast tumors. In combination with paclitaxel, weekly dosing of BAY 80-6946 is sufficient to reach sustained response in all animals bearing patient-derived non–small cell lung cancer xenografts, despite a short plasma elimination half-life (1 hour) in mice. Thus, BAY 80-6946 is a promising agent with differential pharmacologic and pharmacokinetic properties for the treatment of PI3K-dependent human tumors. Mol Cancer Ther; 12(11); 2319–30. ©2013 AACR.
Genes with Aberrant Expression in Murine Preneoplastic Intestine Show Epigenetic and Expression Changes in Normal Mucosa of Colon Cancer Patients
Authors: Leclerc Daniel , Lévesque Nancy , Cao Yuanhang , Deng Liyuan , Wu Qing , Powell Jasmine , Sapienza Carmen , Rozen Rima 
Published: October 2013

AbstractAn understanding of early genetic/epigenetic changes in colorectal cancer would aid in diagnosis and prognosis. To identify these changes in human preneoplastic tissue, we first studied our mouse model in which Mthfr+/− BALB/c mice fed folate-deficient diets develop intestinal tumors in contrast to Mthfr+/+ BALB/c mice fed control diets. Transcriptome profiling was performed in normal intestine from mice with low or high tumor susceptibility. We identified 12 upregulated and 51 downregulated genes in tumor-prone mice. Affected pathways included retinoid acid synthesis, lipid and glucose metabolism, apoptosis and inflammation. We compared murine candidates from this microarray analysis, and murine candidates from an earlier strain-based comparison, with a set of human genes that we had identified in previous methylome profiling of normal human colonic mucosa, from colorectal cancer patients and controls. From the extensive list of human methylome candidates, our approach uncovered five orthologous genes that had shown changes in murine expression profiles (PDK4, SPRR1A, SPRR2A, NR1H4, and PYCARD). The human orthologs were assayed by bisulfite-pyrosequencing for methylation at 14 CpGs. All CpGs exhibited significant methylation differences in normal mucosa between colorectal cancer patients and controls; expression differences for these genes were also observed. PYCARD and NR1H4 methylation differences showed promise as markers for presence of polyps in controls. We conclude that common pathways are disturbed in preneoplastic intestine in our animal model and morphologically normal mucosa of patients with colorectal cancer, and present an initial version of a DNA methylation-based signature for human preneoplastic colon. Cancer Prev Res; 6(11); 1171–81. ©2013 AACR.
Exposure to Excess Estradiol or Leptin during Pregnancy Increases Mammary Cancer Risk and Prevents Parity-Induced Protective Genomic Changes in Rats
Authors: de Assis Sonia , Wang Mingyue , Jin Lu , Bouker Kerrie B. , Hilakivi-Clarke Leena A. 
Published: October 2013

Abstract
Using a preclinical model, we investigated whether excess estradiol (E2) or leptin during pregnancy affects maternal mammary tumorigenesis in rats initiated by administering carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) on day 50. Two weeks later, rats were mated, and pregnant dams were treated daily with 10 μg of 17β-estradiol, 15 μg of leptin, or vehicle from gestation day 8 to 19. Tumor development was assessed separately during weeks 1 to 12 and 13 to 22 after DMBA administration, because pregnancy is known to induce a transient increase in breast cancer risk, followed by a persistent reduction. Parous rats developed less (32%) mammary tumors than nulliparous rats (59%, P &lt; 0.001), and the majority (93%) of tumors in the parous rats appeared before week 13 (vs. 41% in nulliparous rats), indicating that pregnancy induced a transient increase in breast cancer risk. Parous rats exposed to leptin (final tumor incidence 65%) or E2 (45%) during pregnancy developed mammary tumors throughout the tumor-monitoring period, similar to nulliparous control rats, and the incidence was significantly higher in both the leptin- and E2-exposed dams after week 12 than in the vehicle-exposed parous dams (P &lt; 0.001). The mammary glands of the exposed parous rats contained significantly more proliferating cells (P &lt; 0.001). In addition, the E2- or leptin-treated parous rats did not exhibit the protective genomic signature induced by pregnancy and seen in the parous control rats. Specifically, these rats exhibited downregulation of genes involved in differentiation and immune functions and upregulation of genes involved in angiogenesis, growth, and epithelial-to-mesenchymal transition. Cancer Prev Res; 6(11); 1194–211. ©2013 AACR.
High-Density Lipoprotein Maintains Skeletal Muscle Function by Modulating Cellular Respiration in Mice
Authors: Lehti Maarit , Donelan Elizabeth , Abplanalp William , Al-Massadi Omar , Habegger Kirk M. , Weber Jon , Ress Chandler , Mansfeld Johannes , Somvanshi Sonal , Trivedi Chitrang , Keuper Michaela , Ograjsek Teja , Striese Cynthia , Cucuruz Sebastian , Pfluger Paul T. , Krishna Radhakrishna , Gordon Scott M. , Silva R.A. Gangani D. , Luquet Serge , Castel Julien , Martinez Sarah , D’Alessio David , Davidson W. Sean , Hofmann Susanna M. 
Published: October 2013

Background—
Abnormal glucose metabolism is a central feature of disorders with increased rates of cardiovascular disease. Low levels of high-density lipoprotein (HDL) are a key predictor for cardiovascular disease. We used genetic mouse models with increased HDL levels (apolipoprotein A-I transgenic [apoA-I tg]) and reduced HDL levels (apoA-I–deficient [apoA-I ko]) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle.

Methods and Results—
ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose tolerance test compared with wild-type mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved glucose tolerance test, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of endurance capacity compared with wild-type mice. Circulating levels of fibroblast growth factor 21, a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high-fat diet–induced impairment of glucose homeostasis.

Conclusions—
In view of impaired mitochondrial function and decreased HDL levels in type 2 diabetes mellitus, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of type 2 diabetes mellitus beyond cardiovascular disease.
Multiscale Simulation of a Prescribed Fire Event in the New Jersey Pine Barrens Using ARPS-CANOPY
Authors: Kiefer Michael T. , Heilman Warren E. , Zhong Shiyuan , Charney Joseph J. , Bian Xindi , Skowronski Nicholas S. , Hom John L. , Clark Kenneth L. , Patterson Matthew , Gallagher Michael R. 
Published: October 2013

AbstractSmoke prediction products are one of the tools used by land management personnel for decision making regarding prescribed fires. This study documents the application to a prescribed fire of a smoke prediction system that employs ARPS-CANOPY, a modified version of the Advanced Regional Prediction System (ARPS) model containing a canopy submodel, as the meteorological driver. In this paper, the performance of ARPS-CANOPY in simulating meteorological fields in the vicinity of a low-intensity fire is assessed using flux-tower data collected prior to and during a low-intensity prescribed fire in the New Jersey Pine Barrens in March 2011. A three-dimensional high-resolution plant area density dataset is utilized to define the characteristics of the canopy, and the fire is represented in ARPS-CANOPY as a heat flux to the atmosphere. The standard ARPS model is compared with reanalysis and upper-air data to establish that the model can simulate the observed synoptic-mesoscale and planetary boundary layer features that are salient to this study. ARPS-CANOPY profiles of mean turbulent kinetic energy, wind speed/direction, and temperature exhibit patterns that appear in the flux-tower observations during both the preburn phase of the experiment and the period of time the flux tower experienced perturbed atmospheric conditions due to the impinging fire. Last, the character and source of turbulence in and around the fire line are examined. These results are encouraging for smoke prediction efforts since transport of smoke from low-intensity fires is highly sensitive to the near-surface meteorological conditions and, in particular, turbulent flows.
A Note on the Stability Indicator of the Atlantic Meridional Overturning Circulation
Authors: Liu Wei , Liu Zhengyu 
Published: October 2013

Abstract
This study examines the validity of the net freshwater transport ΔMov as a stability indicator of the Atlantic meridional overturning circulation (AMOC) in a low-resolution version of the NCAR Community Climate System Model, version 3 (CCSM3). It is shown that the sign of ΔMov indicates the monostability or bistability of the AMOC, which is based on a hypothesis that a collapsed AMOC induces a zero net freshwater transport. In CCSM3, this hypothesis is satisfied in that the collapsed AMOC, with a nonzero strength, induces a zero net freshwater transport ΔMov across the Atlantic basin by generating equivalent freshwater export MovS and freshwater import MovN at the southern and northern boundaries, respectively. Because of the satisfaction of the hypothesis, ΔMov is consistent with a generalized indicator L for a slowly evolving AMOC, both of which correctly monitor the AMOC stability.
Tornado Warning Trade-Offs: Evaluating Choices for Visually Communicating Risk
Authors: Ash Kevin D. , Schumann Ronald L. , Bowser Gregg C. 
Published: October 2013

Abstract
Recent improvements in weather observation and monitoring have increased the precision of tornado warnings. The National Weather Service currently issues storm-based tornado warnings, and even more geographically specific warnings that include probability information are under development. At the same time, the widespread proliferation of smartphone and mobile computing technology supports the rapid dissemination of graphical weather warning information. Some broadcasters and private companies have already begun using probabilistic-style tornado warning graphics. However, the development of these new types of warnings has occurred with limited research on how users interpret probabilistic visualizations.
This study begins filling this void by examining responses to color scheme and relative position using probabilistic tornado warning designs. A survey of university students is used to measure the level of perceived fear and likelihood of protective action for a series of hypothetical warning scenarios. Central research questions investigate 1) differences in responses across warning designs, 2) clustering of extreme responses in each design, 3) trends in responses with respect to probability levels, 4) differences in responses inside versus outside the warnings, and 5) differences in responses near the edges of the warning designs. Results suggest a variety of trade-offs in viewer responses to tornado warnings based on visual design choices. These findings underscore the need for more comprehensive research on visualizations in weather hazard communication that can aid meteorologists in effectively warning the public and spur appropriate tornado protection behaviors in a timely manner.