bluuebunny/crossref_metadata_2025_split huggingface dataset:
BEC, a Novel Enterotoxin of Clostridium perfringens Found in Human Clinical Isolates from Acute Gastroenteritis Outbreaks
Authors: Yonogi Shinya , Matsuda Shigeaki , Kawai Takao , Yoda Tomoko , Harada Tetsuya , Kumeda Yuko , Gotoh Kazuyoshi , Hiyoshi Hirotaka , Nakamura Shota , Kodama Toshio , Iida Tetsuya 
Published: March 2014

ABSTRACTClostridium perfringensis a causative agent of food-borne gastroenteritis for whichC. perfringensenterotoxin (CPE) has been considered an essential factor. Recently, we experienced two outbreaks of food-borne gastroenteritis in which non-CPE producers ofC. perfringenswere strongly suspected to be the cause. Here, we report a novel enterotoxin produced byC. perfringensisolates, BEC (binary enterotoxin ofC. perfringens). Culture supernatants of theC. perfringensstrains showed fluid-accumulating activity in rabbit ileal loop and suckling mouse assays. Purification of the enterotoxic substance in the supernatants and high-throughput sequencing of genomic DNA of the strains revealed BEC, composed of BECa and BECb. BECa and BECb displayed limited amino acid sequence similarity to other binary toxin family members, such as theC. perfringensiota toxin. ThebecABgenes were located on 54.5-kb pCP13-like plasmids. Recombinant BECb (rBECb) alone had fluid-accumulating activity in the suckling mouse assay. Although rBECa alone did not show enterotoxic activity, rBECa enhanced the enterotoxicity of rBECb when simultaneously administered in suckling mice. The entertoxicity of the mutant in which thebecBgene was disrupted was dramatically decreased compared to that of the parental strain. rBECa showed an ADP-ribosylating activity on purified actin. Although we have not directly evaluated whether BECb delivers BECa into cells, rounding of Vero cells occurred only when cells were treated with both rBECa and rBECb. These results suggest that BEC is a novel enterotoxin ofC. perfringensdistinct from CPE, and that BEC-producingC. perfringensstrains can be causative agents of acute gastroenteritis in humans. Additionally, the presence ofbecABon nearly identical plasmids in distinct lineages ofC. perfringensisolates suggests the involvement of horizontal gene transfer in the acquisition of the toxin genes.
Thermal, physiological and perceptual strain mediate alterations in match-play tennis under heat stress
Authors: Périard Julien D , Racinais Sébastien , Knez Wade L , Herrera Christopher P , Christian Ryan J , Girard Olivier 
Published: March 2014

ObjectivesThis study compared the thermal, physiological and perceptual responses associated with match-play tennis in HOT (∼34°C wet-bulb-globe temperature (WBGT)) and COOL (∼19°C WBGT) conditions, along with the accompanying alterations in match characteristics.Methods12 male tennis players undertook two matches for an effective playing time (ie, ball in play) of 20 min, corresponding to ∼119 and ∼102 min of play in HOT and COOL conditions, respectively. Rectal and skin temperatures, heart rate, subjective ratings of thermal comfort, thermal sensation and perceived exertion were recorded, along with match characteristics.ResultsEnd-match rectal temperature increased to a greater extent in the HOT (∼39.4°C) compared with the COOL (∼38.7°C) condition (p<0.05). Thigh skin temperature was higher throughout the HOT match (p<0.001). Heart rate, thermal comfort, thermal sensation and perceived exertion were also higher during the HOT match (p<0.001). Total playing time was longer in the HOT compared with the COOL match (p<0.05). Point duration (∼7.1 s) was similar between conditions, while the time between points was ∼10 s longer in the HOT relative to the COOL match (p<0.05). This led to a ∼3.4% lower effective playing percentage in the heat (p<0.05). Although several thermal, physiological and perceptual variables were individually correlated to the adjustments in time between points and effective playing percentage, thermal sensation was the only predictor variable associated with both adjustments (p<0.005).ConclusionsThese adjustments in match-play tennis characteristics under severe heat stress appear to represent a behavioural strategy adopted to minimise or offset the sensation of environmental conditions being rated as difficult.
The impact of match-play tennis in a hot environment on indirect markers of oxidative stress and antioxidant status
Authors: Knez Wade L , Périard JP 
Published: March 2014

ObjectivesThe purpose of this study was to determine the impact of changes in oxidative stress and antioxidant status in response to playing tennis in HOT (∼36°C and 35% relative humidity (RH)) and COOL (∼22°C and 70% RH) conditions.Methods10 male tennis players undertook two matches for an effective playing time (ie, ball in play) of 20 min, corresponding to ∼122 and ∼107 min of total play in HOT and COOL conditions, respectively. Core body temperature, body mass and indirect markers of oxidative stress (diacrons reactive oxygen metabolic test) and antioxidant status (biological antioxidant potential test) were assessed immediately prematch, midmatch and postmatch, and 24 and 48 h into recovery.ResultsRegardless of the condition, oxidative stress remained similar throughout play and into recovery. Likewise, match-play tennis in the COOL had no impact on antioxidant status. However, antioxidants status increased significantly in the HOT compared with COOL environment (p<0.05). Body mass losses (∼0.5 kg) were similar between conditions. Rectal temperature increased during both matches (p<0.05), but with a greater magnitude in the HOT (39.3±0.5°C) versus COOL (38.7±0.2°C) environment (p<0.05).ConclusionsMatch-play tennis in the heat does not exacerbate the development of oxidative stress, but significantly increases antioxidant status. These data suggest that the heat stress observed in the HOT environment may provide a necessary signal for the upregulation of antioxidant defence, dampening cellular damage.
Association of digital vascular function with cardiovascular risk factors: a population study
Authors: Kuznetsova Tatiana , Van Vlierberghe Eline , Knez Judita , Szczesny Gregory , Thijs Lutgarde , Jozeau Dominique , Balestra Costantino , D'hooge Jan , Staessen Jan A 
Published: March 2014

ObjectivesVasodilation of the peripheral arteries during reactive hyperaemia depends in part on release of nitric oxide from endothelial cells. Previous studies mainly employed a fingertip tonometric device to derive pulse wave amplitude (PWA) and PWA hyperaemic changes. An alternative approach is based on photoplethysmography (PPG). We sought to evaluate the correlates of digital PPG PWA hyperaemic responses as a measure of peripheral vascular function.DesignThe Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) is a population-based cohort study.SettingRespondents were examined at one centre in northern Belgium.ParticipantsFor this analysis, our sample consisted of 311 former participants (53.5% women; mean age 52.6 years; 43.1% hypertensive), who were examined from January 2010 until March 2012 (response rate 85.1%).Primary outcome measuresUsing a fingertip PPG device, we measured digital PWA at baseline and at 30 s intervals for 4 min during reactive hyperaemia induced by a 5 min forearm cuff occlusion. We performed stepwise regression to identify correlates of the hyperaemic response ratio for each 30 s interval after cuff deflation.ResultsThe maximal hyperaemic response was detected in the 30–60 s interval. The explained variance for the PPG PWA ratio ranged from 9.7% at 0–30 s interval to 22.5% at 60–90 s time interval. The hyperaemic response at each 30 s interval was significantly higher in women compared with men (p≤0.001). The PPG PWA changes at 0–90 s intervals decreased with current smoking (p≤0.0007) and at 0–240 s intervals decreased with higher body mass index (p≤0.035). These associations with sex, current smoking and body mass index were mutually independent.ConclusionsOur study is the first to implement the new PPG technique to measure digital PWA hyperaemic changes in a general population. Hyperaemic response, as measured by PPG, is inversely associated with traditional cardiovascular risk factors such as male sex, smoking and obesity.
Diagnostic accuracy of copeptin sensitivity and specificity in patients with suspected non-ST-elevation myocardial infarction with troponin I below the 99th centile at presentation
Authors: Duchenne Jonathan , Mestres Stéphanie , Dublanchet Nicolas , Combaret Nicolas , Marceau Geoffroy , Caumon Laurent , Dutoit Laurent , Ughetto Sylvie , Motreff Pascal , Sapin Vincent , Schmidt Jeannot 
Published: March 2014

ObjectiveTo determine whether copeptin-us can rule out diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) without prolonged monitoring and serial blood sampling in patients with high-sensitive cardiac troponin I (hs-cTnT) below the 99th centile at presentation to the emergency department (ED).DesignProspective, non-randomised, individual blinded diagnostic accuracy study.SettingTwo EDs of a rural region of France.ParticipantsPatients with chest pain suspected of NSTEMI with onset within the last 12 h were considered for enrolment.InterventionsSerial clinical, electrographical and biochemical investigations were performed at admission and after 2, 4, 6 and 12 h. Hs-cTnT was measured using an assay with Dimension VISTA, Siemens. Copeptin was measured by the BRAHMS copeptin-us assay on the KRYPTOR Compact Plus system. The follow-up period was 90 days.Primary and secondary outcome measuresCopeptin, troponin, myoglobin and creatine kinase values. Clinical and paraclinical events. The final diagnosis was adjudicated blinded to copeptin result.ResultsDuring 12 months, 102 patients were analysed. Final diagnosis was NSTEMI for 7.8% (n=8), unstable angina for 3.9% (n=4), cardiac but non-coronary artery disease for 8.8% (n=9), non-cardiac chest pain for 52% (n=53) and unknown for 27.5% (n=28). There was no statistical difference for copeptin values between patients with NSTEMI and others (respectively 5.5 pmol/L IQR (3.1–7.9) and 6.5 pmol/L IQR (3.9–12.1), p=0.49). Only one patient with NSTEMI had a copeptin value above the cut-off of 95th centile at admission.ConclusionsIn this study, copeptin does not add a diagnostic value at admission to ED for patients with suspected acute coronary syndrome without ST-segment elevation and with hs-cTnT below the 99th centile.Trial registration numberClinicaltrials.gov identifier:NCT01334645.
A stratigraphical basis for the Anthropocene?
Authors: Waters Colin N. , Zalasiewicz Jan A. , Williams Mark , Ellis Michael A. , Snelling Andrea M. 
Published: March 2014

Abstract
Recognition of intimate feedback mechanisms linking changes across the atmosphere, biosphere, geosphere and hydrosphere demonstrates the pervasive nature of humankind's influence, perhaps to the point that we have fashioned a new geological epoch, the Anthropocene. To what extent will these changes be evident as long-lasting signatures in the geological record?
To establish the Anthropocene as a formal chronostratigraphical unit it is necessary to consider a spectrum of indicators of anthropogenically induced environmental change, and to determine how these show as stratigraphic signals that can be used to characterize an Anthropocene unit and to recognize its base. It is important to consider these signals against a context of Holocene and earlier stratigraphic patterns. Here we review the parameters used by stratigraphers to identify chronostratigraphical units and how these could apply to the definition of the Anthropocene. The onset of the range of signatures is diachronous, although many show maximum signatures which post-date 1945, leading to the suggestion that this date may be a suitable age for the start of the Anthropocene.
Identification and Characterization of Small Molecules That Inhibit Nonsense-Mediated RNA Decay and Suppress Nonsense p53 Mutations
Authors: Martin Leenus , Grigoryan Arsen , Wang Ding , Wang Jinhua , Breda Laura , Rivella Stefano , Cardozo Timothy , Gardner Lawrence B. 
Published: March 2014

Abstract
Many of the gene mutations found in genetic disorders, including cancer, result in premature termination codons (PTC) and the rapid degradation of their mRNAs by nonsense-mediated RNA decay (NMD). We used virtual library screening, targeting a pocket in the SMG7 protein, a key component of the NMD mechanism, to identify compounds that disrupt the SMG7–UPF1 complex and inhibit NMD. Several of these compounds upregulated NMD-targeted mRNAs at nanomolar concentrations, with minimal toxicity in cell-based assays. As expected, pharmacologic NMD inhibition disrupted SMG7–UPF1 interactions. When used in cells with PTC-mutated p53, pharmacologic NMD inhibition combined with a PTC “read-through” drug led to restoration of full-length p53 protein, upregulation of p53 downstream transcripts, and cell death. These studies serve as proof-of-concept that pharmacologic NMD inhibitors can restore mRNA integrity in the presence of PTC and can be used as part of a strategy to restore full-length protein in a variety of genetic diseases. Cancer Res; 74(11); 3104–13. ©2014 AACR.
Mislocalization of the Cell Polarity Protein Scribble Promotes Mammary Tumorigenesis and Is Associated with Basal Breast Cancer
Authors: Feigin Michael E. , Akshinthala S. Dipikaa , Araki Kiyomi , Rosenberg Avi Z. , Muthuswamy Lakshmi B. , Martin Bernard , Lehmann Brian D. , Berman Hal K. , Pietenpol Jennifer A. , Cardiff Robert D. , Muthuswamy Senthil K. 
Published: March 2014

Abstract
Scribble (SCRIB) localizes to cell–cell junctions and regulates establishment of epithelial cell polarity. Loss of expression of SCRIB functions as a tumor suppressor in Drosophila and mammals; conversely, overexpression of SCRIB promotes epithelial differentiation in mammals. Here, we report that SCRIB is frequently amplified, mRNA overexpressed, and protein is mislocalized from cell–cell junctions in human breast cancers. High levels of SCRIB mRNA are associated with poor clinical prognosis, identifying an unexpected role for SCRIB in breast cancer. We find that transgenic mice expressing a SCRIB mutant [Pro 305 to Leu (P305L)] that fails to localize to cell–cell junctions, under the control of the mouse mammary tumor virus long terminal repeat promoter, develop multifocal hyperplasia that progresses to highly pleomorphic and poorly differentiated tumors with basal characteristics. SCRIB interacts with phosphatase and tensin homolog (PTEN) and the expression of P305L, but not wild-type SCRIB, promotes an increase in PTEN levels in the cytosol. Overexpression of P305L, but not wild-type SCRIB, activates the Akt/mTOR/S6K signaling pathway. Human breast tumors overexpressing SCRIB have high levels of S6K but do not harbor mutations in PTEN or PIK3CA, identifying SCRIB amplification as a mechanism of activating PI3K signaling in tumors without mutations in PIK3CA or PTEN. Thus, we demonstrate that high levels of mislocalized SCRIB functions as a neomorph to promote mammary tumorigenesis by affecting subcellular localization of PTEN and activating an Akt/mTOR/S6kinase signaling pathway. Cancer Res; 74(11); 3180–94. ©2014 AACR.
GWAS-Identified Common Variants for Obesity Are Not Associated with the Risk of Developing Colorectal Cancer
Authors: Sainz Juan , Frank Bernd , da Silva Filho Miguel I. , Hoffmeister Michael , Rudolph Anja , Butterbach Katja , Chang-Claude Jenny , Brenner Hermann , Hemminki Kari , Försti Asta 
Published: March 2014

Abstract
Background: Observational studies have consistently associated obesity with colorectal cancer risk. Because both traits are genetically determined and share some metabolic biomarkers, we hypothesized that obesity-related polymorphisms could also influence the risk of developing colorectal cancer.
Methods: We conducted a comprehensive population-based case–control study in 1,792 German colorectal cancer cases and 1,805 controls to explore associations between 28 obesogenic variants identified through genome-wide association studies (GWAS) and colorectal cancer risk. We also evaluated interactions between polymorphisms and body mass index (BMI), type II diabetes (T2D), and gender.
Results: No evidence of association between obesogenic variants and colorectal cancer risk was observed after correction for multiple testing. There was only a remarkable interaction between the LTArs1041981 polymorphism and gender, which modified the risk of colorectal cancer [Pinteraction = 0.002; males: odds ratio (OR), 1.14; 95% confidence intervals (CI), 1.00–1.30 vs. females: OR, 0.83; 95% CI, 0.71–0.97].
Conclusions: Our findings showed that obesogenic variants are not a major pathogenetic risk factor for colorectal cancer.
Impact: This comprehensive population-based case–control study does not provide evidence of a shared genetic component between obesity and colorectal cancer. Cancer Epidemiol Biomarkers Prev; 23(6); 1125–8. ©2014 AACR.
Complete Protection against Aflatoxin B1-Induced Liver Cancer with a Triterpenoid: DNA Adduct Dosimetry, Molecular Signature, and Genotoxicity Threshold
Authors: Johnson Natalie M. , Egner Patricia A. , Baxter Victoria K. , Sporn Michael B. , Wible Ryan S. , Sutter Thomas R. , Groopman John D. , Kensler Thomas W. , Roebuck Bill D. 
Published: March 2014

Abstract
In experimental animals and humans, aflatoxin B1 (AFB1) is a potent hepatic toxin and carcinogen. The synthetic oleanane triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a powerful activator of Keap1-Nrf2 signaling, protects against AFB1-induced toxicity and preneoplastic lesion formation (GST-P–positive foci). This study assessed and mechanistically characterized the chemoprotective efficacy of CDDO-Im against AFB1-induced hepatocellular carcinoma (HCC). A lifetime cancer bioassay was undertaken in F344 rats dosed with AFB1 (200 μg/kg rat/day) for four weeks and receiving either vehicle or CDDO-Im (three times weekly), one week before and throughout the exposure period. Weekly, 24-hour urine samples were collected for analysis of AFB1 metabolites. In a subset of rats, livers were analyzed for GST-P foci. The comparative response of a toxicogenomic RNA expression signature for AFB1 was examined. CDDO-Im completely protected (0/20) against AFB1-induced liver cancer compared with a 96% incidence (22/23) observed in the AFB1 group. With CDDO-Im treatment, integrated level of urinary AFB1-N7-guanine was significantly reduced (66%) and aflatoxin-N-acetylcysteine, a detoxication product, was consistently elevated (300%) after the first AFB1 dose. In AFB1-treated rats, the hepatic burden of GST-P–positive foci increased substantially (0%–13.8%) over the four weeks, but was largely absent with CDDO-Im intervention. The toxicogenomic RNA expression signature characteristic of AFB1 was absent in the AFB1 + CDDO-Im–treated rats. The remarkable efficacy of CDDO-Im as an anticarcinogen is established even in the face of a significant aflatoxin adduct burden. Consequently, the absence of cancer requires a concept of a threshold for DNA damage for cancer development. Cancer Prev Res; 7(7); 658–65. ©2014 AACR.
Permanent Leadless Cardiac Pacing
Authors: Reddy Vivek Y. , Knops Reinoud E. , Sperzel Johannes , Miller Marc A. , Petru Jan , Simon Jaroslav , Sediva Lucie , de Groot Joris R. , Tjong Fleur V.Y. , Jacobson Peter , Ostrosff Alan , Dukkipati Srinivas R. , Koruth Jacob S. , Wilde Arthur A.M. , Kautzner Josef , Neuzil Petr 
Published: March 2014

Background—
Conventional cardiac pacemakers are associated with several potential short- and long-term complications related to either the transvenous lead or subcutaneous pulse generator. We tested the safety and clinical performance of a novel, completely self-contained leadless cardiac pacemaker.

Methods and Results—
The primary safety end point was freedom from complications at 90 days. Secondary performance end points included implant success rate, implant time, and measures of device performance (pacing/sensing thresholds and rate-responsive performance). The mean age of the patient cohort (n=33) was 77±8 years, and 67% of the patients were male (n=22/33). The most common indication for cardiac pacing was permanent atrial fibrillation with atrioventricular block (n=22, 67%). The implant success rate was 97% (n=32). Five patients (15%) required the use of >1 leadless cardiac pacemaker during the procedure. One patient developed right ventricular perforation and cardiac tamponade during the implant procedure, and eventually died as the result of a stroke. The overall complication-free rate was 94% (31/33). After 3 months of follow-up, the measures of pacing performance (sensing, impedance, and pacing threshold) either improved or were stable within the accepted range.

Conclusions—
In a prospective nonrandomized study, a completely self-contained, single-chamber leadless cardiac pacemaker has shown to be safe and feasible. The absence of a transvenous lead and subcutaneous pulse generator could represent a paradigm shift in cardiac pacing.

Clinical Trial Registration—

URL:
http://clinicaltrials.gov
. Unique identifier: NCT01700244.
Coinhibitory Suppression of T Cell Activation by CD40 Protects Against Obesity and Adipose Tissue Inflammation in Mice
Authors: Wolf Dennis , Jehle Felix , Michel Nathaly Anto , Bukosza Eva Nora , Rivera Jennifer , Chen Yung Chih , Hoppe Natalie , Dufner Bianca , Rodriguez Alexandra Ortiz , Colberg Christian , Nieto Leandro , Rupprecht Benjamin , Wiedemann Ansgar , Schulte Lisa , Peikert Alexander , Bassler Nicole , Lozhkin Andrey , Hergeth Sonja Patricia , Stachon Peter , Hilgendorf Ingo , Willecke Florian , von zur Mühlen Constantin , von Elverfeldt Dominik , Binder Christoph J. , Aichele Peter , Varo Nerea , Febbraio Mark A. , Libby Peter , Bode Christoph , Peter Karlheinz , Zirlik Andreas 
Published: March 2014

Background—
Costimulatory cascades such as the CD40L-CD40 dyad enhance immune cell activation and inflammation during atherosclerosis. Here, we tested the hypothesis that CD40 directly modulates traits of the metabolic syndrome in diet-induced obesity in mice.

Methods and Results—

To induce the metabolic syndrome, wild-type or CD40
−/−
mice consumed a high-fat diet for 20 weeks. Unexpectedly, CD40
−/−
mice exhibited increased weight gain, impaired insulin secretion, augmented accumulation of inflammatory cells in adipose tissue, and enhanced proinflammatory gene expression. This proinflammatory and adverse metabolic phenotype could be transplanted into wild-type mice by reconstitution with CD40-deficient lymphocytes, indicating a major role for CD40 in T or B cells in this context. Conversely, therapeutic activation of CD40 signaling by the stimulating antibody FGK45 abolished further weight gain during the study, lowered glucose levels, improved insulin sensitivity, and suppressed adipose tissue inflammation. Mechanistically, CD40 activation decreased the expression of proinflammatory cytokines in T cells but not in B cells or macrophages. Finally, repopulation of lymphocyte-free Rag1
−/−
mice with CD40
−/−
T cells provoked dysmetabolism and inflammation, corroborating a protective role of CD40 on T cells in the metabolic syndrome. Finally, levels of soluble CD40 showed a positive association with obesity in humans, suggesting clinical relevance of our findings.

Conclusions—
We present the surprising finding that CD40 deficiency on T cells aggravates whereas activation of CD40 signaling improves adipose tissue inflammation and its metabolic complications. Therefore, positive modulation of the CD40 pathway might describe a novel therapeutic concept against cardiometabolic disease.