bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo
Effect of Flucloxacillin in Experimental Endocarditis Caused by
mecC
-positive Staphylococcus aureus Showing Temperature-Dependent Susceptibility
In Vitro
Authors: Mancini Stefano , Laurent Frédéric , Veloso Tiago R. , Giddey Marlyse , Vouillamoz Jacques , Vandenesch François , Moreillon Philippe , Entenza José M. 
Published: January 2015

ABSTRACT

Methicillin-resistant
Staphylococcus aureus
(MRSA) carrying the
mecC
gene (
mecC
-MRSA) exhibited at 37°C MICs of oxacillin close to those of methicillin-susceptible
S. aureus
(MSSA). We investigated whether at this temperature,
mecC
-MRSA strains respond to flucloxacillin treatment like MSSA strains, using a rat model of endocarditis. Flucloxacillin (human-like kinetics of 2 g intravenously every 6 h) cured 80 to 100% of aortic vegetations infected with five different
mecC
-MRSA strains. These results suggest that
mecC
-MRSA infections may successfully respond to treatment with β-lactams.
Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens
Authors: Rice Christopher A. , Colon Beatrice L. , Alp Mehmet , Göker Hakan , Boykin David W. , Kyle Dennis E. 
Published: January 2015

ABSTRACT

Naegleria fowleri
is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new
in vitro
assays suitable for medium- or high-throughput drug discovery and used these for
N. fowleri
. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC
50
) of 177 nM. Similarly, we identified 10 additional analogues with IC
50
s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with
N. fowleri
.
Ribonucleotide Reductase NrdR as a Novel Regulator for Motility and Chemotaxis during Adherent-Invasive Escherichia coli Infection
Authors: Dreux Nicolas , Cendra Maria del Mar , Massier Sébastien , Darfeuille-Michaud Arlette , Barnich Nicolas , Torrents Eduard 
Published: January 2015

ABSTRACT

A critical step in the life cycle of all organisms is the duplication of the genetic material during cell division. Ribonucleotide reductases (RNRs) are essential enzymes for this step because they control the
de novo
production of the deoxyribonucleotides required for DNA synthesis and repair.
Enterobacteriaceae
have three functional classes of RNRs (Ia, Ib, and III), which are transcribed from separate operons and encoded by the genes
nrdAB
,
nrdHIEF
, and
nrdDG
, respectively. Here, we investigated the role of RNRs in the virulence of adherent-invasive
Escherichia coli
(AIEC) isolated from Crohn's disease (CD) patients. Interestingly, the LF82 strain of AIEC harbors four different RNRs (two class Ia, one class Ib, and one class III). Although the
E. coli
RNR enzymes have been extensively characterized both biochemically and enzymatically, little is known about their roles during bacterial infection. We found that RNR expression was modified in AIEC LF82 bacteria during cell infection, suggesting that RNRs play an important role in AIEC virulence. Knockout of the
nrdR
and
nrdD
genes, which encode a transcriptional regulator of RNRs and class III anaerobic RNR, respectively, decreased AIEC LF82's ability to colonize the gut mucosa of transgenic mice that express human CEACAM6 (
c
arcino
e
mbryonic
a
ntigen-related
c
ell
a
dhesion
m
olecule 6). Microarray experiments demonstrated that NrdR plays an indirect role in AIEC virulence by interfering with bacterial motility and chemotaxis. Thus, the development of drugs targeting RNR classes, in particular NrdR and NrdD, could be a promising new strategy to control gut colonization by AIEC bacteria in CD patients.
Neither Primary nor Memory Immunity to Mycobacterium tuberculosis Infection Is Compromised in Mice with Chronic Enteric Helminth Infection
Authors: Rafi Wasiulla , Bhatt Kamlesh , Gause William C. , Salgame Padmini 
Published: January 2015

ABSTRACTPreviously we had reported thatNippostrongylus brasiliensis, a helminth with a lung migratory phase, affected host resistance againstMycobacterium tuberculosisinfection through the induction of alternatively activated (M2) macrophages. Several helminth species do not have an obligatory lung migratory phase but establish chronic infections in the host that include potent immune downregulatory effects, in part mediated through induction of a FoxP3+T regulatory cell (Treg) response. Treg cells exhibit duality in their functions in host defense againstM. tuberculosisinfection since their depletion leads to enhanced priming of T cells in the lymph nodes and attendant improved control ofM. tuberculosisinfection, while their presence in the lung granuloma protects against excessive inflammation.Heligmosomoides polygyrusis a strictly murine enteric nematode that induces a strong FoxP3 Treg response in the host. Therefore, in this study we investigated whether host immunity toM. tuberculosisinfection would be modulated in mice with chronicH. polygyrusinfection. We report that neither primary nor memory immunity conferred byMycobacterium bovisBCG vaccination was affected in mice with chronic enteric helminth infection, despite a systemic increase in FoxP3+T regulatory cells. The findings indicate that anti-M. tuberculosisimmunity is not similarly affected by all helminth species and highlight the need to consider this inequality in human coinfection studies.
Biosynthesis and Transport of the Lantibiotic Mutacin 1140 Produced by Streptococcus mutans
Authors: Escano Jerome , Stauffer Byron , Brennan Jacob , Bullock Monica , Smith Leif 
Published: January 2015

ABSTRACTLantibiotics are ribosomally synthesized peptide antibiotics composed of an N-terminal leader peptide that is cleaved to yield the active antibacterial peptide. Significant advancements in molecular tools that promote the study of lantibiotic biosynthesis can be used inStreptococcus mutans. Herein, we further our understanding of leader peptide sequence and core peptide structural requirements for the biosynthesis and transport of the lantibiotic mutacin 1140. Our study on mutacin 1140 biosynthesis shows a dedicated secondary cleavage site within the leader peptide and the dependency of transport on core peptide posttranslational modifications (PTMs). The secondary cleavage site on the leader peptide is found at the −9 position, and secondary cleavage occurs before the core peptide is transported out of the cell. The coordinated cleavage at the −9 position was absent in alanTdeletion strain, suggesting that the core peptide interaction with the LanT transporter enables uniform cleavage at the −9 position. Following transport, the LanP protease was found to be tolerant to a wide variety of amino acid substitutions at the primary leader peptide cleavage site, with the exception of arginine at the −1 position. Several leader and core peptide mutations produced core peptide variants that had intermediate stages of PTM enzyme modifications, supporting the concept that PTM enzyme modifications, secondary cleavage, and transport are occurring in a highly coordinated fashion.IMPORTANCEMutacin 1140 belongs to the class I lantibiotic family of ribosomally synthesized and posttranslationally modified peptides (RiPPs). The biosynthesis of mutacin 1140 is a highly efficient process which does not lead to a discernible level of production of partially modified core peptide variants. The products isolated from an extensive mutagenesis study on the leader and core peptides of mutacin 1140 show that the posttranslational modifications (PTMs) on the core peptide occur under a highly coordinated dynamic process. PTMs are dictated by the distance of the core peptide modifiable residues from PTM enzyme active sites. The formation of lanthionine rings aids in the formation of successive PTMs, as was observed in a peptide variant lacking a C-terminal decarboxylation.
Burnout in emergency department healthcare professionals is associated with coping style: a cross-sectional survey
Authors: Howlett M , Doody K , Murray J , LeBlanc-Duchin D , Fraser J , Atkinson PR 
Published: January 2015

IntroductionIneffective coping may lead to impaired job performance and burnout, with adverse consequences to staff well-being and patient outcomes. We examined the relationship between coping styles and burnout in emergency physicians, nurses and support staff at seven small, medium and large emergency departments (ED) in a Canadian health region (population 500 000).MethodsLinear regression with the Coping Inventory for Stressful Situations (CISS) and Maslach Burnout Inventory (MBI) was used to evaluate the effect of coping style on levels of burnout in a cross-sectional survey of 616 ED staff members. CISS measures coping style in three categories: task-oriented, emotion-oriented and avoidance-oriented coping; MBI, in use for 30 years, assesses the level of burnout in healthcare workers.ResultsTask-oriented coping was associated with decreased risk of burnout, while emotion-oriented coping was associated with increased risk of burnout.DiscussionSpecific coping styles are associated with varied risk of burnout in ED staff across several different types of hospitals in a regional network. Coping style intervention may reduce burnout, while leading to improvement in staff well-being and patient outcomes. Further studies should focus on building and sustaining task-oriented coping, along with alternatives to emotion-oriented coping.
Shiga toxin‐producing Escherichia coli O157, O26 and O111 in cattle faeces and hides in Italy
Authors: Bonardi S. , Alpigiani I. , Tozzoli R. , Vismarra A. , Zecca V. , Greppi C. , Bacci C. , Bruini I. , Brindani F. 
Published: January 2015

IntroductionRuminants are regarded as the natural reservoir for Shiga toxin‐producing Escherichia coli (STEC), especially of serogroup O157.Materials and methodsDuring 2011 and 2012, 320 samples (160 faecal samples from the rectum and 160 hide samples from the brisket area) were collected from 160 cattle at slaughter in Northern Italy during warm months (May to October). Cattle were reared in different farms and their age at slaughter ranged between nine months and 15 years, most of them being culled cattle (median age: six years; average age: 4.6 years). Samples were tested by immunomagnetic‐separation technique for E coli O157 and O26 and by a screening PCR for stx genes followed by cultural detection of STEC. The virulence genes stx1, stx2, eae, and e‐hlyA were detected and among stx2‐positive isolates the presence of the stx2a and stx2c variants was investigated.ResultsTwenty‐one of 160 cattle (13.1 per cent; 95 per cent CI 8.3 to 19.4 per cent) were found to be faecal carriers of STEC. STEC O157 was found in 10 (6.3 per cent) samples, STEC O26 in six (3.8 per cent) and STEC O111 in one (0.6 per cent). Four isolates (2.5 per cent) were O not determined (OND). Six out of 160 (3.8 per cent; 95 per cent CI 1.4 to 8.0 per cent) hide samples were positive for STEC; four hides (2.5 per cent) were contaminated by STEC O157 and two (1.3 per cent) by STEC O26. In three cattle (1.9 per cent) STEC from both faeces and hides were detected. Among STEC O157, 87.5 per cent of them carried the stx2c gene and 12.5 per cent carried both stx1 and stx2c genes. No O157 isolate harboured stx2a variant. STEC O26 and O111 carried the stx1 gene only. One OND strain carried both the stx2a and stx2c genes.ConclusionsThis study shows that STEC O157 from cattle can harbour the stx2c variant, which is associated with haemolytic uraemic syndrome in humans, and that cattle hides may be a source of human pathogenic STEC O157 and O26 in the slaughterhouse environment.
The use of palaeomagnetism and rock magnetism to understand volcanic processes: introduction
Authors: Ort M. H. , Porreca M. , Geissman J. W. 
Published: January 2015

Abstract
This Special Publication provides a snapshot of our understanding of volcanic processes through the use of palaeomagnetic and rock magnetic techniques. Here, we provide a context for the book, placing individual chapters within the milieu of previous work, including some magnetic techniques that were not used in the particular studies described herein. Thermoremanent magnetization is a powerful tool to understand processes related to heating and cooling of rocks, including estimating the temperature of emplacement of pyroclastic deposits, which may allow us to better understand the rates of cooling during eruption and transport. Anisotropy of magnetic susceptibility and anisotropy of remanence are used primarily to investigate rock fabrics, and allow the interpretation of flow dynamics in dykes, lava flows and pyroclastic deposits, as well as the location of the eruptive vents. Rock magnetic characteristics can help in the correlation of volcanic deposits but also provide means to date volcanic deposits and to better understand the processes of cooling of the deposits, as the magnetic minerals can change with temperature. In addition, volcanic rocks may be key recorders of past magnetic fields, allowing a better understanding of changes in field intensity and, perhaps, providing clues of how the magnetic field is formed.
The Heat Shock Protein 90 Inhibitor, (−)-Epigallocatechin Gallate, Has Anticancer Activity in a Novel Human Prostate Cancer Progression Model
Authors: Moses Michael A. , Henry Ellen C. , Ricke William A. , Gasiewicz Thomas A. 
Published: January 2015

Abstract
(−)-Epigallocatechin gallate (EGCG), a major tea polyphenol, elicits anticancer effects. However, the mechanism of action is not fully understood. Our laboratory previously showed that EGCG inhibits heat shock protein 90 (HSP90). We used nontumorigenic (NT), tumorigenic, and metastatic cancer cells from a novel human prostate cancer progression model to test the hypotheses that certain stages are more or less sensitive to EGCG and that sensitivity is related to HSP90 inhibition. Treatment of cells with EGCG, novobiocin, or 17-AAG resulted in more potent cytotoxic effects on tumorigenic and metastatic cells than NT cells. When tumorigenic or metastatic cells were grown in vivo, mice supplemented with 0.06% EGCG in drinking water developed significantly smaller tumors than untreated mice. Furthermore, EGCG prevented malignant transformation in vivo using the full prostate cancer model. To elucidate the mechanism of EGCG action, we performed binding assays with EGCG-Sepharose, a C-terminal HSP90 antibody, and HSP90 mutants. These experiments revealed that EGCG-Sepharose bound more HSP90 from metastatic cells compared with NT cells and binding occurred through the HSP90 C-terminus. In addition, EGCG bound HSP90 mutants that mimic both complexed and uncomplexed HSP90. Consistent with HSP90 inhibitory activity, EGCG, novobiocin, and 17-AAG induced changes in HSP90-client proteins in NT cells and larger differences in metastatic cells. These data suggest that EGCG may be efficacious for the treatment of prostate cancer because it preferentially targets cancer cells and inhibits a molecular chaperone supportive of the malignant phenotype. Cancer Prev Res; 8(3); 249–57. ©2015 AACR.
Perfect in Every Sense
Authors: Gaulke Karsten 
Published: January 2015

At the center of this article is an iconographic analysis of the eight silver reliefs on the sides of a table clock made in 1591 by Jost Bürgi, the court clockmaker of Landgrave Wilhelm IV of Hessen-Kassel. The reliefs present an astronomical ancestral picture gallery, running from the Patriarchs of the Old Testament to Copernicus. The author argues that the “storyboard” for this sequence of images must have been conceived down to its smallest details by the Kassel court astronomer Christoph Rothmann; indeed, many of the scenes shown, along with many particular details depicted within them, are literally described in Rothmann’s never-published manuscript Observationes stellarum fixarum of 1589. The final section of the essay compares these reliefs to the images created for Tycho Brahe at his Uraniborg and Stjerneborg observatories. The author concludes that the sequence of the reliefs in Kassel, culminating in the representation of Copernicus and his world view, is a reflection of the acrimonious debate extending over many years between the heliocentrist Rothmann and the geo-heliocentrist Brahe regarding the veracity of the heliocentric world view.
Environmental Analysis of GOES-R Proving Ground Convection-Initiation Forecasting Algorithms
Authors: Apke Jason M. , Nietfeld Daniel , Anderson Mark R. 
Published: January 2015

AbstractEnhanced temporal and spatial resolution of the Geostationary Operational Environmental Satellite–R Series (GOES-R) will allow for the use of cloud-top-cooling-based convection-initiation (CI) forecasting algorithms. Two such algorithms have been created on the current generation of GOES: the University of Wisconsin cloud-top-cooling algorithm (UWCTC) and the University of Alabama in Huntsville’s satellite convection analysis and tracking algorithm (SATCAST). Preliminary analyses of algorithm products have led to speculation over preconvective environmental influences on algorithm performance. An objective validation approach is developed to separate algorithm products into positive and false indications. Seventeen preconvective environmental variables are examined for the positive and false indications to improve algorithm output. The total dataset consists of two time periods in the late convective season of 2012 and the early convective season of 2013. Data are examined for environmental relationships using principal component analysis (PCA) and quadratic discriminant analysis (QDA). Data fusion by QDA is tested for SATCAST and UWCTC on five separate case-study days to determine whether application of environmental variables improves satellite-based CI forecasting. PCA and significance testing revealed that positive indications favored environments with greater vertically integrated instability (CAPE), less stability (CIN), and more low-level convergence. QDA improved both algorithms on all five case studies using significantly different variables. This study provides an examination of environmental influences on the performance of GOES-R Proving Ground CI forecasting algorithms and shows that integration of QDA in the cloud-top-cooling-based algorithms using environmental variables will ultimately generate a more skillful product.
How Climate Change Affects Extremes in Maize and Wheat Yield in Two Cropping Regions
Authors: Ummenhofer Caroline C. , Xu Hong , Twine Tracy E. , Girvetz Evan H. , McCarthy Heather R. , Chhetri Netra , Nicholas Kimberly A. 
Published: January 2015

Abstract
Downscaled climate model projections from phase 5 of the Coupled Model Intercomparison Project (CMIP5) were used to force a dynamic vegetation agricultural model (Agro-IBIS) and simulate yield responses to historical climate and two future emissions scenarios for maize in the U.S. Midwest and wheat in southeastern Australia. In addition to mean changes in yield, the frequency of high- and low-yield years was related to changing local hydroclimatic conditions. Particular emphasis was on the seasonal cycle of climatic variables during extreme-yield years and links to crop growth.
While historically high (low) yields in Iowa tend to occur during years with anomalous wet (dry) growing season, this is exacerbated in the future. By the end of the twenty-first century, the multimodel mean (MMM) of growing season temperatures in Iowa is projected to increase by more than 5°C, and maize yield is projected to decrease by 18%. For southeastern Australia, the frequency of low-yield years rises dramatically in the twenty-first century because of significant projected drying during the growing season. By the late twenty-first century, MMM growing season precipitation in southeastern Australia is projected to decrease by 15%, temperatures are projected to increase by 2.8°–4.5°C, and wheat yields are projected to decline by 70%. Results highlight the sensitivity of yield projections to the nature of hydroclimatic changes. Where future changes are uncertain, the sign of the yield change simulated by Agro-IBIS is uncertain as well. In contrast, broad agreement in projected drying over southern Australia across models is reflected in consistent yield decreases for the twenty-first century. Climatic changes of the order projected can be expected to pose serious challenges for continued staple grain production in some current centers of production, especially in marginal areas.
Current Status of Clinical Trials in Head and Neck Cancer 2014
Authors: Liu Jeffrey C. , Ridge John A. , Brizel David M. , O’Sullivan Brian , Cohen Ezra W. , Mann Bhupinder S. , Adelstein David J. 
Published: January 2015

IntroductionThe last few years have seen significant increase in the number of available clinical trials in head and neck cancer. It has been difficult to stay abreast of these efforts because multiple cooperative groups and institutions are engaged in their recruitment. This review presents the state of the art of available clinical trials organized around major research themes.Data SourcesPublished literature, published cooperative group monographs, expert review.Review MethodsInitial themes in head and neck cancer clinical trial development were first identified along with examples. Opinions from an international panel of multidisciplinary experts were then solicited.Results/DiscussionCurrent major themes of head and neck clinical trials centered on 5 major themes: (1) recognition of human papillomavirus oropharynx cancer and optimal treatment strategies, (2) defining the role of transoral surgery in head and neck cancer treatment, (3) improving postoperative adjuvant treatment, (4) investigation of rare malignancies, and (5) the importance of biomarker‐driven, innovative, and targeted therapy investigation.ConclusionsA number of exciting clinical trials are currently in development or accrual with the potential for tremendous impact and improvement of the treatment of head and neck cancer.Implications for PracticeAwareness by practicing otolaryngologists and trainees of these current themes will be essential for study accrual, success, and improvement in the care of head and neck cancer.