bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility Breakpoints for Amphotericin B and Aspergillus Species in an
In Vitro
Pharmacokinetic-Pharmacodynamic Model Simulating Free-Drug Concentrations in Human Serum
Authors: Elefanti A. , Mouton J. W. , Verweij P. E. , Zerva L. , Meletiadis J. 
Published: February 2014

ABSTRACT

Although conventional amphotericin B was for many years the drug of choice and remains an important agent against invasive aspergillosis, reliable susceptibility breakpoints are lacking. Three clinical
Aspergillus
isolates (
Aspergillus fumigatus
,
Aspergillus flavus
, and
Aspergillus terreus
) were tested in an
in vitro
pharmacokinetic-pharmacodynamic model simulating the biphasic 24-h time-concentration profile of free amphotericin B concentrations in human serum with free peak concentrations (
fC
max
) of 0.1, 0.3, 0.6, 1.2, and 2.4 mg/liter administered once daily. Drug concentrations were measured with a bioassay, and fungal growth was monitored for 72 h with galactomannan production. The
fC
max
/MIC corresponding to half-maximal activity (
P
50
) was determined for each species, and the percentage of target attainment was calculated for different MICs for the standard (1 mg/kg of body weight) and a lower (0.6-mg/kg) dose of amphotericin B with Monte Carlo simulation analysis. The
fC
max
/MICs (95% confidence intervals) corresponding to
P
50
were 0.145 (0.133 to 0.158), 0.371 (0.283 to 0.486), and 0.41 (0.292 to 0.522) for
A. fumigatus
,
A. flavus
, and
A. terreus
, respectively. The median percentages of
P
50
attainment were ≥88%, 47%, and 0% for
A. fumigatus
isolates with MICs of ≤0.5, 1, and ≥2 mg/liter, respectively, and ≥81%, 24%, and 0% and ≥75%, 15%, and 0% for
A. flavus
and
A. terreus
isolates with MICs of ≤0.25, 0.5, and ≥1 mg/liter, respectively. The lower dose of 0.6 mg/kg would retain efficacy for
A. fumigatus
,
A. flavus
, and
A. terreus
isolates with MICs of ≤0.25, ≤0.125, and ≤0.125 mg/liter, respectively. The susceptibility, intermediate susceptibility, and resistance breakpoints of ≤0.5, 1, and ≥2 mg/liter for
A. fumigatus
and ≤0.25, 0.5, and ≥1 mg/liter for
A. flavus
and
A. terreus
were determined for conventional amphotericin B with a pharmacokinetic-pharmacodynamic model simulating free-drug serum concentrations.
Identification of Cell Surface-Exposed Proteins Involved in the Fimbria-Mediated Adherence of Enteroaggregative Escherichia coli to Intestinal Cells
Authors: Izquierdo Mariana , Navarro-Garcia Fernando , Nava-Acosta Raul , Nataro James P. , Ruiz-Perez Fernando , Farfan Mauricio J. 
Published: February 2014

ABSTRACT

Fimbria-mediated adherence to the intestinal epithelia is a key step in enteroaggregative
Escherichia coli
(EAEC) pathogenesis. To date, four fimbriae have been described for EAEC; aggregative adherence fimbria II (AAF/II) is the most important adherence factor for EAEC prototype strain 042. Previously, we described results showing that extracellular matrix (ECM) components might be involved in the recognition of AAF/II fimbriae by intestinal cells. In this study, we sought to identify novel potential receptors on intestinal epithelial cells recognized by the AAF/II fimbriae. Purified AafA-
dsc
protein, the major subunit of AAF/II fimbriae, was incubated with a monolayer of T84 cells, cross-linked to the surface-exposed T84 cell proteins, and immunoprecipitated by using anti-AafA antibodies. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of cellular proteins bound to AafA-
dsc
protein identified laminin (previously recognized as a potential receptor for AAF/II) and cytokeratin 8 (CK8). Involvement of the major subunit of AAF/II fimbriae (AafA protein) in the binding to recombinant CK8 was confirmed by adherence assays with purified AAF/II fimbriae, AafA-
dsc
protein, and strain 042. Moreover, HEp-2 cells transfected with CK8 small interfering RNA (siRNA) showed reduced 042 adherence compared with cells transfected with scrambled siRNA as a control. Adherence of 042 to HEp-2 cells preincubated with antibodies against ECM proteins or CK8 was substantially reduced. Altogether, our results supported the idea of a role of CK8 as a potential receptor for EAEC.
A dynamic programming approach to dependent task clustering
Authors: Sharp Robert M. 
Published: February 2014

In Complex Data Management Systems, the program generator must consider segmentation of the data processing program resulting from the generation. There are well-defined breaking points where the only dependency between program segments is the use of external data files. If program segments sharing data files were to be grouped together in the same processing unit, a record constructed for, or read from, a shared file could be routed to each segment using that file, eliminating redundant reading of the file.
This paper considers the optimization of clustering program segments into processing units. It is a dynamic or selective trial and error approach which considers constraints of execution order, both implicit and explicit.
An integrated approach to automated computer maintenance
Authors: Hackl F. J. , Shirk R. W. 
Published: February 2014

This paper describes a method for applying automatic fault locating techniques to a computer system. Although the techniques described here are generally applicable, they have been specifically applied to IBM System/360 Model 50. Hardcore considerations are stressed and levels of hardcore are defined. Implementation objectives include both minimization of hardcore and minimization of additional circuitry. The design philosophy is to alter existing hardware where possible, keeping hardcore restrictions in mind. Hardware is added only where function does not exist or where hardcore restrictions are violated.
A bootstrap approach is used whereby subsystems are tested before being used for checkout of other subsystems. A special program load is used to bypass CPU and channel circuitry to enter tests into storage. With tests in storage, a mode of operation is defined to permit use of main storage as both a data and control storage. In this mode, tests are performed on the read-only storage controls. The read-only storage, once checked, is used to control test execution on the remainder of the CPU. The entire CPU is then used as a test vehicle for channel checkout purposes.
Finally, the same techniques and circuitry are shown to be applicable to other maintenance functions, including logging of errors and checking of certain storage subsystems.
Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers
Authors: Yamamoto Yukiya , Abe Akihiro , Emi Nobuhiko 
Published: February 2014

Abstract
The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479–84. ©2014 AACR.
Autophagy-Dependent Production of Secreted Factors Facilitates Oncogenic RAS-Driven Invasion
Authors: Lock Rebecca , Kenific Candia M. , Leidal Andrew M. , Salas Eduardo , Debnath Jayanta 
Published: February 2014

Abstract
The tumor-promoting functions of autophagy are primarily attributed to its ability to promote cancer cell survival. However, emerging evidence suggests that autophagy plays other roles during tumorigenesis. Here, we uncover that autophagy promotes oncogenic RAS-driven invasion. In epithelial cells transformed with oncogenic RAS, depletion of autophagy-related genes suppresses invasion in three-dimensional culture, decreases cell motility, and reduces pulmonary metastases in vivo. Treatment with conditioned media from autophagy-competent cells rescues the invasive capacity of autophagy-deficient cells, indicating that these cells fail to secrete factors required for RAS-driven invasion. Reduced autophagy diminishes the secretion of the promigratory cytokine interleukin-6 (IL-6), which is necessary to restore invasion of autophagy-deficient cells. Moreover, autophagy-deficient cells exhibit reduced levels of matrix metalloproteinase 2 and WNT5A. These results support a previously unrecognized function for autophagy in promoting cancer cell invasion via the coordinate production of multiple secreted factors.
Significance: Our results delineate a previously unrecognized function for autophagy in facilitating oncogenic RAS-driven invasion. We demonstrate that an intact autophagy pathway is required for the elaboration of multiple secreted factors favoring invasion, including IL-6. Cancer Discov; 4(4); 466–79. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 377
The Contested Fifth Liquid in Malayalam: A Window into the Lateral-Rhotic Relationship in Dravidian Languages
Authors: Punnoose Reenu , Khattab Ghada , Al-Tamimi Jalal 
Published: February 2014

Abstract
Apart from Tamil, Malayalam is the only Dravidian language that still retains a fifth liquid in its inventory (denoted as /ʐ/), a sound that can be traced back to Proto-Dravidian. The phonetic and phonological status of this sound has been the subject of considerable debate, both in terms of its rhotic versus lateral status and its phonetic realisation. Studies to date have been impressionistic, so this is the first acoustic study of all five liquids in Malayalam. Production data from 8 male speakers reveal that while /ʐ/ is realised as a central post-alveolar approximant, its ambiguous phonotactic patterning and mixed acoustic profile are contributors to its mixed identity. An understanding of the complex patterning of this sound, which straddles the rhotic/lateral divide, requires an appreciation of the role of secondary acoustic resonance in distinguishing members of a crowded liquid system and in preventing a /ʐ/-/ɭ/ merger.
Perceptual Learning of Phonetic Information That Indicates Morphological Structure
Authors: Barden Katharine , Hawkins Sarah 
Published: February 2014

Abstract
Familiarity with a talker or accent can facilitate speech perception, but little is known about the acoustic-phonetic knowledge that is acquired during exposure to an unfamiliar talker, particularly with respect to how a talker realises grammatical and prosodic distinctions. The present experiment used relatively natural stimuli and tasks to investigate listeners' adaptation to a phonetic variant that is systematically associated with a morphological context, specifically the English /ri:/ prefix. Results showed that listeners who had previously been exposed to the atypical variant in /ri:/ prefixes in stories scored higher than control listeners in an intelligibility-in-noise task that included instances of the atypical variant. Perceptual learning was partly specific to the /ri:/ prefix, though there was weak generalisation of learning to word-initial /ri:/ syllables that were not prefixes. These results emphasise the value of developing context-sensitive, probabilistic models of speech perception which include multiple, parallel levels of representation.
Methodological Issues in Cohort Studies That Relate Sodium Intake to Cardiovascular Disease Outcomes
Authors: Cobb Laura K. , Anderson Cheryl A.M. , Elliott Paul , Hu Frank B. , Liu Kiang , Neaton James D. , Whelton Paul K. , Woodward Mark , Appel Lawrence J. 
Published: February 2014

Background—
The results of cohort studies relating sodium (Na) intake to blood pressure–related cardiovascular disease (CVD) are inconsistent. To understand whether methodological issues account for the inconsistency, we reviewed the quality of these studies.

Methods and Results—
We reviewed cohort studies that examined the association between Na and CVD. We then identified methodological issues with greatest potential to alter the direction of association (reverse causality, systematic error in Na assessment), some potential to alter the direction of association (residual confounding, inadequate follow-up), and the potential to yield false null results (random error in Na assessment, insufficient power). We included 26 studies with 31 independent analyses. Of these, 13 found direct associations between Na and CVD, 8 found inverse associations, 2 found J-shaped associations, and 8 found null associations only. On average there were 3 to 4 methodological issues per study. Issues with greater potential to alter the direction of association were present in all but 1 of the 26 studies (systematic error, 22; reverse causality, 16). Issues with lesser potential to alter the direction of association were present in 18 studies, whereas those with potential to yield false null results were present in 23.

Conclusions—
Methodological issues may account for the inconsistent findings in currently available observational studies relating Na to CVD. Until well-designed cohort studies in the general population are available, it remains appropriate to base Na guidelines on the robust body of evidence linking Na with elevated blood pressure and the few existing general population trials of the effects of Na reduction on CVD.
Trends in Cause of Death After Percutaneous Coronary Intervention
Authors: Spoon Daniel B. , Psaltis Peter J. , Singh Mandeep , Holmes David R. , Gersh Bernard J. , Rihal Charanjit S. , Lennon Ryan J. , Moussa Issam D. , Simari Robert D. , Gulati Rajiv 
Published: February 2014

Background—
The impact of changing demographics on causes of long-term death after percutaneous coronary intervention (PCI) remains incompletely defined.

Methods and Results—

We evaluated trends in cause-specific long-term mortality after index PCI performed at a single center from 1991 to 2008. Deaths were ascertained by scheduled prospective surveillance. Cause was determined via telephone interviews, medical records, autopsy reports, and death certificates. Competing-risks analysis of cause-specific mortality was performed using 3 time periods of PCI (1991–1996, 1997–2002, and 2003–2008). Final follow-up was December 31, 2012. A total of 19 077 patients survived index PCI hospitalization, of whom 6988 subsequently died (37%, 4.48 per 100 person-years). Cause was determined in 6857 (98.1%). Across 3 time periods, there was a 33% decline in cardiac deaths at 5 years after PCI (incidence: 9.8%, 7.4%, and 6.6%) but a 57% increase in noncardiac deaths (7.1%, 8.5%, and 11.2%). Only 36.8% of deaths in the recent era were cardiac. Similar trends were observed regardless of age, extent of coronary disease, or PCI indication. After adjustment for baseline variables, there was a 50% temporal decline in cardiac mortality but no change in noncardiac mortality. The decline in cardiac mortality was driven by fewer deaths from myocardial infarction/sudden death (
P
<0.001) but not heart failure (
P
=0.85). The increase in noncardiac mortality was primarily attributable to cancer and chronic diseases (
P
<0.001).

Conclusions—
This study found a marked temporal switch from predominantly cardiac to predominantly noncardiac causes of death after PCI over 2 decades. The decline in cardiac mortality was independent of changes in baseline clinical characteristics. These findings have implications for patient care and clinical trial design.
Sovereign Immunity v. Redress for War Crimes: The Judgment of the International Court of Justice in the Case Concerning Jurisdictional Immunities of the State (Germany v. Italy)
Authors: Negri Stefania 
Published: February 2014

Abstract
In the judgment delivered in the case concerning Jurisdictional Immunities of the State (Germany v. Italy), the International Court of Justice held that under the present state of international customary law State immunity encompasses all acta jure imperii, regardless of whether they are unlawful. Following the ruling that States are entitled to jurisdictional immunities before foreign courts even if their sovereign acts amount to violations of peremptory norms, the Court found that Italy had violated Germany’s immunity from jurisdiction and enforcement. In rendering such a conservative judgment, the Court missed a double opportunity: to contribute to the development of international law by interpreting the rule on sovereign immunity in harmony with international human rights law and its dynamics, and to finally serve justice for the victims of war crimes.
A Critical History of Internet Activism and Social Protest in Malaysia, 1998-2011
Authors: Postill John 
Published: February 2014

AbstractThis article asks two related questions. First, to what extent has internet activism shaped social protest in Malaysia from the late 1990s to the present? Second, what can the history of internet activism and social protest in Malaysia tell us, if anything, about the 2011 global wave of protests? To address these questions I distinguish three key moments in Malaysia’s eventful history of internet activism and social protest, namely the 1998-1999 reformasi movement, the electoral ‘tsunami’ of 2008 (in which the ruling coalition lost its two-thirds majority), and the Bersih 2.0 rallies of 2011. I argue that Bersih 2.0 is best explained as both the latest episode in a series of uniquely Malaysian techno-political events and as a local variant of the global wave of protests of 2011 – a wave in which hackers, online journalists, and technology lawyers, as well as ordinary citizens using digital media, played an important part. The article ends with a summary and with suggestions for further research.
Global Stochastic Tropical Cyclone Model Based on Principal Component Analysis and Cluster Analysis
Authors: Nakajo Sota , Mori Nobuhito , Yasuda Tomohiro , Mase Hajime 
Published: February 2014

AbstractA global stochastic tropical cyclone model was developed as a means for preparing a large number of artificial tropical cyclone (TC) samples with different values for parameters such as track, minimum sea level pressure, and translation speed. In this paper, the model and the results of its verification are presented in detail. The proposed stochastic model is sensitive to approximations of the joint probability distribution functions (PDFs) of TC parameters and temporal correlations. A newly introduced accurate method for approximating joint PDFs by using principal component analysis and cluster analysis resulted in improved reproducibility of TC parameters. The simulation results were compared with historical observational data from the northwestern Pacific, southwestern Pacific, and North Atlantic Oceans. The grid-averaged mean values and distribution patterns of PDFs of TC parameters were in agreement with observational data.
Multivariate Minimum Residual Method for Cloud Retrieval. Part II: Real Observations Experiments
Authors: Auligné Thomas 
Published: February 2014

Abstract
In Part I of this two-part paper, the multivariate minimum residual (MMR) scheme was introduced to retrieve profiles of cloud fraction from satellite infrared radiances and identify clear observations. In this paper it is now validated with real observations from the Atmospheric Infrared Sounder (AIRS) instrument. This new method is compared with the cloud detection scheme presented earlier by McNally and Watts and operational at the European Centre for Medium-Range Weather Forecasts (ECMWF). Cloud-top pressures derived from both algorithms are comparable, with some differences at the edges of the synoptic cloud systems. The population of channels considered as clear is less contaminated with residual cloud for the MMR scheme. Further procedures, based on the formulation of the variational quality control, can be applied during the variational analysis to reduce the weight of observations that have a high chance of being contaminated by cloud. Finally, the MMR scheme can be used as a preprocessing step to improve the assimilation of cloud-affected infrared radiances.
Radar Data Assimilation in the Canadian High-Resolution Ensemble Kalman Filter System: Performance and Verification with Real Summer Cases
Authors: Chang Weiguang , Chung Kao-Shen , Fillion Luc , Baek Seung-Jong 
Published: February 2014

Abstract
An 80-member high-resolution ensemble Kalman filter (HREnKF) is implemented for assimilating radar observations with the Canadian Meteorological Center’s (CMC’s) Global Environmental Multiscale Limited-Area Model (GEM-LAM). This system covers the Montréal, Canada, region and assimilates radar data from the McGill Radar Observatory with 4-km data thinning. The GEM-LAM operates in fully nonhydrostatic mode with 58 hybrid vertical levels and 1-km horizontal grid spacing. As a first step toward full radar data assimilation, only radial velocities are directly assimilated in this study. The HREnKF is applied on three 2011 summer cases having different precipitation structures: squall-line structure, isolated small-scale structures, and widespread stratiform precipitation. The short-term (&lt;2 h) accuracy of the HREnKF analyses and forecasts is examined.
In HREnKF, the ensemble spread is sufficient to cover the estimated error from innovations and lead to filter convergence. It results in part from a realistic initiation of HREnKF data assimilation cycle by using a Canadian regional EnKF system (itself coupled to a global EnKF) working at meso- and synoptic scales. The filter convergence is confirmed by the HREnKF background fields gradually approaching to radar observations as the assimilation cycling proceeds. At each analysis step, it is clearly shown that unobserved variables are significantly modified through HREnKF cross correlation of errors from the ensemble. Radar reflectivity observations are used to verify the improvements in analyses and short-term forecasts achievable by assimilating only radial velocities. Further developments of the analysis system are discussed.