bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrotonic suppression of early afterdepolarizations in the neonatal rat ventricular myocyte monolayer
Authors: Himel Herman D. , Garny Alan , Noble Penelope J. , Wadgaonkar Raj , Savarese Joseph , Liu Nian , Bub Gil , El‐Sherif Nabil 
Published: September 2013

Key points
Early afterdepolarizations (EADs) are a known trigger for arrhythmias, but the effect of surrounding tissue on EADs is poorly understood.
Neurotoxin anthopleurin‐A (AP‐A) increases action potential duration and gives rise to EADs in isolated myocytes. We investigate the effect of AP‐A on connected networks of cultured cardiac cells.
We show that EADs are markedly suppressed in well‐coupled neonatal rat ventricular monolayers treated with AP‐A, but reappear when gap junction connectivity is blocked.
The ability of cell coupling to electrotonically damp EADs is confirmed in a two‐cell simulation where connectivity is systematically varied.
Taken together, these results suggest that cell–cell coupling can act to suppress EADs in normal cardiac tissue. Results also suggest that EADs may emerge and propagate in poorly coupled tissue.
Abstract  Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin‐A (AP‐A). AP‐A‐treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs. 610 ms at 1 Hz and 1200 ms at 0.5 Hz for AP‐A‐treated monolayers). In contrast, isolated single cells treated with AP‐A develop prominent irregular oscillations with a frequency of 2.5 Hz, and a variable prolongation of the action potential duration of up to several seconds. To investigate whether electrotonic interactions between coupled cells modulates EAD formation, cell connectivity was reduced by RNA silencing gap junction Cx43. In contrast to well‐connected monolayers, gap junction silenced monolayers display bradycardia‐dependent plateau oscillations consistent with EADs. Further, simulations of a cell displaying EADs electrically connected to a cell with normal action potentials show a coupling strength‐dependent suppression of EADs consistent with the experimental results. These results suggest that electrotonic effects may play a critical role in EAD‐mediated arrhythmogenesis.
Comprehensive Identification of Mutations Responsible for Heterogeneous Vancomycin-Intermediate Staphylococcus aureus (hVISA)-to-VISA Conversion in Laboratory-Generated VISA Strains Derived from hVISA Clinical Strain Mu3
Authors: Matsuo Miki , Cui Longzhu , Kim Jeeyoung , Hiramatsu Keiichi 
Published: September 2013

ABSTRACT

Heterogeneous vancomycin-intermediate
Staphylococcus aureus
(hVISA) spontaneously produces VISA cells within its cell population at a frequency of 10
−6
or greater. We established a total of 45 VISA mutant strains independently obtained from hVISA Mu3 and its related strains by one-step vancomycin selection. We then performed high-throughput whole-genome sequencing of the 45 strains and their parent strains to identify the genes involved in the hVISA-to-VISA phenotypic conversion. A comparative genome study showed that all the VISA strains tested carried a unique set of mutations. All of the 45 VISA strains carried 1 to 4 mutations possibly affecting the expression of a total of 48 genes. Among them, 32 VISA strains carried only one gene affected by a single mutation. As many as 20 genes in more than eight functional categories were affected in the 32 VISA strains, which explained the extremely high rates of the hVISA-to-VISA phenotypic conversion. Five genes,
rpoB
,
rpoC
,
walK
,
pbp4
, and
pp2c
, were previously reported as being involved in vancomycin resistance. Fifteen remaining genes were newly identified as associated with vancomycin resistance in this study. The gene most frequently affected (6 out of 32 strains) was
cmk
, which encodes cytidylate kinase, followed closely by
rpoB
(5 out of 32), encoding the β subunit of RNA polymerase. A mutation prevalence study also revealed a sizable number of
cmk
mutants among clinical VISA strains (7 out of 38 [18%]). Reduced cytidylate kinase activity in
cmk
mutant strains is proposed to contribute to the hVISA-to-VISA phenotype conversion by thickening the cell wall and reducing the cell growth rate.
Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection
Authors: Elfenbein Johanna R. , Endicott-Yazdani Tiana , Porwollik Steffen , Bogomolnaya Lydia M. , Cheng Pui , Guo Jinbai , Zheng Yi , Yang Hee-Jeong , Talamantes Marissa , Shields Christine , Maple Aimee , Ragoza Yury , DeAtley Kimberly , Tatsch Tyler , Cui Ping , Andrews Katharine D. , McClelland Michael , Lawhon Sara D. , Andrews-Polymenis Helene 
Published: September 2013

ABSTRACTCattle are naturally infected withSalmonella entericaserotype Typhimurium and exhibit pathological features of enteric salmonellosis that closely resemble those in humans. Cattle are the most relevant model of gastrointestinal disease resulting from nontyphoidalSalmonellainfection in an animal with an intact microbiota. We utilized this model to screen a library of targeted single-gene deletion mutants to identify novel genes ofSalmonellaTyphimurium required for survival during enteric infection. Fifty-four candidate mutants were strongly selected, including numerous mutations in genes known to be important for gastrointestinal survival of salmonellae. Three genes with previously unproven phenotypes in gastrointestinal infection were tested in bovine ligated ileal loops. Two of these mutants,STM3602andSTM3846, recapitulated the phenotype observed in the mutant pool. Complementation experiments successfully reversed the observed phenotypes, directly linking these genes to the colonization defects of the corresponding mutant strains.STM3602encodes a putative transcriptional regulator that may be involved in phosphonate utilization, andSTM3846encodes a retron reverse transcriptase that produces a unique RNA-DNA hybrid molecule called multicopy single-stranded DNA. The genes identified in this study represent an exciting new class of virulence determinants for further mechanistic study to elucidate the strategies employed bySalmonellato survive within the small intestines of cattle.
The effectiveness of geophysical techniques in detecting a range of buried metallic weapons at various depths and orientations
Authors: Richardson Thomas , Cheetham Paul N. 
Published: September 2013

Abstract
The use of weapons in violent crime in the UK is well attested by crime statistics. It has been demonstrated by previous experimental studies that geophysical techniques have the potential for use in the search and detection of buried metallic weapons. Previous research has focused on only one weapon type, or the depths at which weapons can be detected, while this study also considers weapon orientation. This study employs magnetometry (fluxgate gradiometry), Slingram electromagnetic (both phases in both horizontal magnetic dipole (HMD) and vertical magnetic dipole (VMD) orientations) and ground-penetrating radar (500 and 800 MHz) methods to investigate the detectability of a wide variety of weapon types when buried in the ground in different orientations and depths. This study demonstrates that there were limitations for each instrument employed resulting from the orientation of the weapon in the ground, with none of the techniques in this work being able to detect all of the weapons in all orientations. A second limitation was the inability of all these instruments to detect smaller weapons. This study shows that a combination of techniques is required to increase the chances of successful detection. Blind searching trials in a range of environments are now required to quantify the level of successful detection that can be achieved in practice. The influence of metal composition of the weapons also needs to be further investigated.
Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children
Authors: Triscott Joanna , Lee Cathy , Foster Colleen , Manoranjan Branavan , Pambid Mary Rose , Berns Rachel , Fotovati Abbas , Venugopal Chitra , O'Halloran Katrina , Narendran Aru , Hawkins Cynthia , Ramaswamy Vijay , Bouffet Eric , Taylor Michael D. , Singhal Ash , Hukin Juliette , Rassekh Rod , Yip Stephen , Northcott Paul , Singh Sheila K. , Dunham Christopher , Dunn Sandra E. 
Published: September 2013

Abstract
Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition. Cancer Res; 73(22); 6734–44. ©2013 AACR.
Longitudinal Changes in IGF-I and IGFBP-3, and Mammographic Density among Postmenopausal Women
Authors: Woolcott Christy G. , Courneya Kerry S. , Boyd Norman F. , Yaffe Martin J. , McTiernan Anne , Brant Rollin , Jones Charlotte A. , Stanczyk Frank Z. , Terry Tim , Cook Linda S. , Wang Qinggang , Friedenreich Christine M. 
Published: September 2013

AbstractA relation between the breast cancer risk factors, insulin-like growth factor-I (IGF-I) and mammographic density, is biologically plausible, but results from cross-sectional epidemiologic studies have been mixed. Our objective was to examine the relation in a longitudinal manner, that is, between the change in circulating IGF-I concentrations and the change in mammographic measures over one year. Data from an exercise intervention trial conducted in 302 postmenopausal women ages 50 to 74 years were used. Blood drawn at baseline and postintervention was assessed for IGF-I and its binding protein (IGFBP-3) by direct chemiluminscent immunoassay. Area and volumetric measurements of mammographic dense fibroglandular and nondense fatty tissue were made. Statistical analyses were based on multiple linear regression. A one SD (20.2 ng/mL) change in IGF-I over one year was associated with small changes in percent dense area [mean: 0.8%; 95% confidence interval (CI), 0.1–1.4] and dense area (mean: 1.2 cm2; 95% CI, 0.2–2.1). Change in IGFBP-3 was also associated with percent and absolute dense area. Absolute and percent dense volume, and mammographic measures representing fatty tissue (nondense area and volume) were not associated with changes in IGF-I and IGFBP-3. Longitudinal associations may be more detectable than cross-sectional associations due to the absence of confounding by invariant personal factors. Absolute and percent dense area, measures that are related to breast cancer risk, may be affected by IGF-I. Confirmation should be sought in further longitudinal studies in which larger changes in the IGF system are evoked. Cancer Epidemiol Biomarkers Prev; 22(11); 2116–20. ©2013 AACR.
Lack of Evidence for Human T-Lymphotropic Virus Type 1 and Mouse Mammary Tumor–Like Virus Involvement in the Genesis of Childhood Acute Lymphoblastic Leukemia
Authors: Morales-Sánchez Abigail , Bernáldez-Ríos Roberto , Álvarez-Rodríguez Francisco Javier , Bekker-Méndez Vilma Carolina , Fajardo-Gutiérrez Arturo , de Diego Flores-Chapa José , Flores-Lujano Janet , Jiménez-Hernández Elva , Peñaloza-González José Gabriel , del Carmen Rodríguez-Zepeda María , Torres-Nava José Refugio , Velázquez-Aviña Martha Margarita , Amador-Sánchez Raquel , Alvarado-Ibarra Martha , Reyes-Zepeda Nancy , Espinosa-Elizondo Rosa Martha , Fuentes-Pananá Ezequiel M. , Mejía-Aranguré Juan Manuel 
Published: September 2013

Abstract
Background: In Mexico City, the incidence of childhood acute lymphoblastic leukemia (ALL) is one of the highest in the world; epidemiologic evidence suggests that infectious agents could be involved in the genesis of this disease. Early transmitted oncogenic retroviruses infecting lymphocytes are important candidates.
Methods: PCR-based assays were used to screen viral genomic sequences of human T-cell lymphotrophic virus, type 1 (HTLV1) and mouse mammary tumor virus (MMTV)–like virus (MMTV-LV) in leukemic cells from 67 pediatric patients with ALL.
Results: Viral genomic sequences were not detected in any sample by neither standard nor nested PCR.
Conclusions: Because of the methodologic strictness and high statistical power of the study, these results suggest that HTLV1 and MMTV-LV are not involved in the genesis of childhood ALL in Mexican children.
Impact: To our knowledge, this is the first work exploring the direct participation of HTLV1 and MMTV-LV retroviruses in childhood ALL development. Cancer Epidemiol Biomarkers Prev; 22(11); 2130–3. ©2013 AACR.
CYP2C19 Poor Metabolizer Is Associated With Clinical Outcome of Clopidogrel Therapy in Acute Myocardial Infarction But Not Stable Angina
Authors: Kim Ho-Sook , Chang Kiyuk , Koh Yoon-Seok , Park Mahn-Won , Choi Yun-Seok , Park Chul-Soo , Oh Minkyung , Kim Eun-Young , Shon Ji-Hong , Shin Jae-Gook , Seung Ki-Bae 
Published: September 2013

Background—
More intensive platelet suppression is required in patients with acute myocardial infarction (AMI) than in those with stable angina because of differential platelet activation between AMI and stable angina. In this context, CYP2C19 genotype leading to reduced active metabolite formation may profoundly affect the clinical outcome of clopidogrel therapy in patients with AMI compared with those with stable angina.

Methods and Results—

Effects of CYP2C19 genotypes on the clinical outcome of clopidogrel therapy were evaluated in 2188 patients (532 patients with AMI and 1656 patients with stable angina) undergoing percutaneous coronary intervention. The primary clinical outcome was a composite of major adverse cardiac and cerebrovascular events defined as death from any cause, nonfatal myocardial infarction, or stroke during 1 year of clopidogrel therapy. Compared with extensive metabolizer, the CYP2C19 poor metabolizer was significantly associated with higher risk of major adverse cardiac and cerebrovascular events in patients with AMI (hazard ratio, 2.88; 95% confidence interval, 1.27–6.53;
P
=0.011). However, this finding was not seen in patients with stable angina. A significant interaction between CYP2C19 genotypes and disease subsets of AMI and stable angina was identified with respect to major adverse cardiac and cerebrovascular events (adjusted interaction
P
=0.045). The patients with AMI showed lower percent inhibition of P2Y12 compared with patients with stable angina in CYP2C19 poor metabolizer or CYP2C19 intermediate metabolizer genotype groups but not in CYP2C19 extensive metabolizer genotype group.

Conclusions—
CYP2C19 poor metabolizer is associated with poor clinical outcome of clopidogrel therapy in Asian patients with AMI but not in those with stable angina possibly because of differential requirement of platelet suppression in patients with AMI and stable angina.

Clinical Trial Registration Information—

URL:
clinicaltrials.gov
. Identifier: NCTO1239914.
Origins of the Solar Radiation Biases over the Southern Ocean in CFMIP2 Models*
Authors: Bodas-Salcedo A. , Williams K. D. , Ringer M. A. , Beau I. , Cole J. N. S. , Dufresne J.-L. , Koshiro T. , Stevens B. , Wang Z. , Yokohata T. 
Published: September 2013

AbstractCurrent climate models generally reflect too little solar radiation over the Southern Ocean, which may be the leading cause of the prevalent sea surface temperature biases in climate models. The authors study the role of clouds on the radiation biases in atmosphere-only simulations of the Cloud Feedback Model Intercomparison Project phase 2 (CFMIP2), as clouds have a leading role in controlling the solar radiation absorbed at those latitudes. The authors composite daily data around cyclone centers in the latitude band between 40° and 70°S during the summer. They use cloud property estimates from satellite to classify clouds into different regimes, which allow them to relate the cloud regimes and their associated radiative biases to the meteorological conditions in which they occur. The cloud regimes are defined using cloud properties retrieved using passive sensors and may suffer from the errors associated with this type of retrievals. The authors use information from the Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) lidar to investigate in more detail the properties of the “midlevel” cloud regime. Most of the model biases occur in the cold-air side of the cyclone composite, and the cyclone composite accounts for most of the climatological error in that latitudinal band. The midlevel regime is the main contributor to reflected shortwave radiation biases. CALIPSO data show that the midlevel cloud regime is dominated by two main cloud types: cloud with tops actually at midlevel and low-level cloud. Improving the simulation of these cloud types should help reduce the biases in the simulation of the solar radiation budget in the Southern Ocean in climate models.
Ocean Circulation under Globally Glaciated Snowball Earth Conditions: Steady-State Solutions
Authors: Ashkenazy Yosef , Gildor Hezi , Losch Martin , Tziperman Eli 
Published: September 2013

Abstract
Between ~750 and 635 million years ago, during the Neoproterozoic era, the earth experienced at least two significant, possibly global, glaciations, termed “Snowball Earth.” While many studies have focused on the dynamics and the role of the atmosphere and ice flow over the ocean in these events, only a few have investigated the related associated ocean circulation, and no study has examined the ocean circulation under a thick (~1 km deep) sea ice cover, driven by geothermal heat flux. Here, a thick sea ice–flow model coupled to an ocean general circulation model is used to study the ocean circulation under Snowball Earth conditions. The ocean circulation is first investigated under a simplified zonal symmetry assumption, and (i) strong equatorial zonal jets and (ii) a strong meridional overturning cell are found, limited to an area very close to the equator. The authors derive an analytic approximation for the latitude–depth ocean dynamics and find that the extent of the meridional overturning circulation cell only depends on the horizontal eddy viscosity and β (the change of the Coriolis parameter with latitude). The analytic approximation closely reproduces the numerical results. Three-dimensional ocean simulations, with reconstructed Neoproterozoic continental configuration, confirm the zonally symmetric dynamics and show additional boundary currents and strong upwelling and downwelling near the continents.
Auditory Azimuthal Localization Performance in Water as a Function of Prior Exposure
Authors: Savel Sophie , Drake Carolyn 
Published: September 2013

Objective: We report two psychoacoustical experiments that assessed the relationship between auditory azimuthal localization performance in water and duration of prior exposure to the milieu. Background: The adaptability of spatial hearing abilities has been demonstrated in air for both active and passive exposures to altered localization cues. Adaptability occurred faster and was more complete for elevation perception than for azimuth perception. In water, spatial hearing is believed to solely rely on smaller than normal cues-to-azimuth: interaural time differences. This should produce a medial bias in localization judgments toward the center of the horizontal plane, unless the listeners have adapted to the environment. Method: Azimuthal localization performance was measured in seawater for eight azimuthal directions of a low-frequency (<500 Hz) auditory target. Seventeen participants performed a forced-choice task in Experiment 1. Twenty-eight other participants performed a pointing task in Experiment 2. Results: In both experiments we observed poor front/back discrimination but accurate left/right discrimination, regardless of prior exposure. A medial bias was found in azimuth perception, whose size decreased as the exposure duration of the participant increased. Conclusion: The study resembles earlier results showing that passive exposure to altered azimuth cues elicits the adaptability of internal audio-spatial maps, that is, the behavioral plasticity of spatial hearing abilities. Application: Studies of the adaptability of the auditory system to altered spatial information may yield practical implications for scuba divers, hearing-impaired listeners with reduced sensitivity to spatial cues, and various normal-hearing users of virtual auditory displays.