bluuebunny/crossref_metadata_2025 huggingface dataset:
Tweets and Trades: the Information Content of Stock Microblogs
Authors: Sprenger Timm O. , Tumasjan Andranik , Sandner Philipp G. , Welpe Isabell M.
Published: May 2013

Microblogging forums (e.g., Twitter) have become a vibrant online platform for exchanging stock‐related information. Using methods from computational linguistics, we analyse roughly 250,000 stock‐related messages (so‐called tweets) on a daily basis. We find an association between tweet sentiment and stock returns, message volume and trading volume, as well as disagreement and volatility. In contrast to previous related research, we also analyse the mechanism leading to an efficient aggregation of information in microblogging forums. Our results demonstrate that users providing above average investment advice are retweeted (i.e., quoted) more often and have more followers, which amplifies their share of voice.
IRC and CRM: Modelling Framework for the ‘Basel 2.5’ Risk Measures
Authors: Wilkens Sascha , Brunac Jean‐Baptiste , Chorniy Vladimir
Published: May 2013

This paper presents a modelling framework for the Incremental Risk Charge (IRC) and Comprehensive Risk Measure (CRM) as the new capital requirements for market risks in a bank's trading book (‘Basel 2.5’). Both are Value‐at‐Risk‐type measures projecting losses over a one‐year capital horizon at a 99.9% confidence level and are applicable to credit flow and credit correlation instruments, respectively. With no consensus on industry standards for suitable internal models as yet, the article discusses selected risk factor models to derive simulation‐based loss distributions and the associated risk figures. Example calculations and implementation aspects complement the discussion.
Bank Regulations after the Global Financial Crisis: Good Intentions and Unintended Evil
Authors: Dermine Jean
Published: May 2013

In this essay, we analyse the impact of the capital and liquidity regulations and call attention to the fact that the banks' responses might create unintended evil: a reduced supply of bank loans, incentives to securitise assets, and adverse incentives on bank risk monitoring. The conclusion is that privately‐based mechanisms that put most creditors at risk are the best way to increase the soundness of banking markets. It is argued that interbank debt should be put at risk because banks have a comparative advantage in risk monitoring. As putting short‐term interbank at risk increases the danger of sudden deposit withdrawals, a mechanism is needed to extend the maturity of short‐term debt at the time of a credit‐led panic.
Weaving dreamcatchers: mothering among American Indian women who were teen mothers
Authors: Palacios Janelle F. , Strickland Carolyn J. , Chesla Catherine A. , Kennedy Holly P. , Portillo Carmen J.
Published: May 2013

Aims

The aim of this study was to explore the mothering experience and practice among reservation‐based adult American Indian women who had been adolescent mothers.

Background

Adolescent American Indian women are at an elevated risk for teen pregnancy and poor maternal/child outcomes. Identifying mothering practices among this population may help guide intervention development that will improve health outcomes.

Design

A collaborative orientation to community‐based participatory research approach.

Methods

Employing interpretive phenomenology, 30 adult American Indian women who resided on a Northwestern reservation were recruited. In‐depth, face‐to‐face and telephone interviews were conducted between 2007–2008.

Findings

Women shared their mothering experience and practice, which encompassed a lifespan perspective grounded in their American Indian cultural tradition. Four themes were identified as follows: mother hen, interrupted mothering and second chances, breaking cycles and mothering a community. Mothering originated in childhood, extended across their lifespan and moved beyond mothering their biological offspring.

Conclusion

These findings challenge the Western construct of mothering and charge nurses to seek culturally sensitive interventions that reinforce positive mothering practices and identify when additional mothering support is needed across a woman's lifespan.
Cognitive load causes people to react ineffectively to others' norm transgressions
Authors: Fonseca Anabel , Brauer Markus , Moisuc Alexandrina , Nugier Armelle
Published: May 2013

We examined whether cognitive resources are necessary to react effectively to norm transgressions of others. In Study 1, we showed that a polite verbal expression of disapproval was the most effective form of social control because perpetrators were least likely to engage in the same norm transgression again in the future. In Study 2, we manipulated cognitive load and asked participants how they would react when witnessing different uncivil behaviors. Compared to participants in the cognitive load condition, participants in the control condition were more likely to use effective forms of social control and less likely to use ineffective forms of social control. The findings are integrated with recent theorizing about normative pressures and people's reactions to deviance.
Origins of species richness in the Indo‐Malay‐Philippine biodiversity hotspot: evidence for the centre of overlap hypothesis
Authors: Gaither Michelle R. , Rocha Luiz A.
Published: May 2013

The Indo‐Malay‐Philippine (IMP) biodiversity hotspot, bounded by the Philippines, the Malay Peninsula and New Guinea, is the epicentre of marine biodiversity. Hypotheses to explain the source of the incredible number of species found there include the centre of overlap hypothesis, which proposes that in this region the distinct faunas of the Pacific and Indian Oceans overlap. Here we review the biogeographical evidence in support of this hypothesis. We examined tropical reef fish distributions, paying particular attention to sister species pairs that overlap in the IMP hotspot. We also review phylogeographical studies of wide‐ranging species for evidence of lineage divergence and overlap in the IMP region. Our synthesis shows that a pattern of isolation between the Pacific and the Indian Ocean faunas is evident across a wide range of taxa. The occurrence of sister species, with one member in each ocean, indicates that the mechanism(s) of isolation has been in effect since at least the Miocene, while phylogeographical studies indicate more recent divergences in the Pleistocene. Divergence in isolation followed by population expansion has led to an overlap of closely related taxa or genetic lineages in the hotspot, contributing to diversity and species richness in the region. These findings are consistent with the centre of overlap hypothesis and highlight the importance of this process in generating biodiversity within the IMP.
Biogeography of scorpions in thePseudouroctonus minimuscomplex (Vaejovidae) from south‐western North America: implications of ecological specialization for pre‐Quaternary diversification
Authors: Bryson Robert W. , Savary Warren E. , Prendini Lorenzo
Published: May 2013

Aim

The aim of this study was to assess the impact of pre‐Quaternary tectonics and orogeny relative to that of Pleistocene climate change on diversification within thePseudouroctonus minimuscomplex, a group of vaejovid scorpions with stenotopic habitat requirements.

Location

South‐western North America (United States and Mexico).

Methods

Multilocus sequence data (1899 base pairs from two mitochondrial and two nuclear genes) were generated from 65 samples of scorpions in theminimuscomplex. Phylogeographical structure within theminimuscomplex was explored using model‐based phylogenetic methods and a general mixed Yule coalescent model to identify independent geographical clusters. A time‐calibrated multilocus species tree was reconstructed using a multispecies coalescent approach. Ancestral areas were estimated at divergence events across the tree using a probabilistic Bayesian approach.

Results

Extensive geographical structure was evident within two well‐supported clades. These clades probably diverged over 25 million years ago (Ma), based on estimated mean divergence dates, followed by 14 divergences in the Miocene (25–5 Ma) and 4 divergences in the Pliocene and Pleistocene (< 5 Ma). The ancestral origin of theminimuscomplex was reconstructed to be across California and the Mexican Highlands. The Chihuahuan Desert was colonized twice from the Mexican Highlands, and one dispersal event occurred from the Mexican Highlands back to California.

Main conclusions

Spatial and temporal patterns of evolution in theminimuscomplex support predictions that stenotopy promoted pre‐Quaternary diversification. Miocene and Pliocene geomorphology, perhaps in concert with climate change, induced allopatric divergence across the heterogeneous landscape of south‐western North America. Stenotopic scorpions such as theminimuscomplex provide a model for exploring correlations between Earth history and biological diversification.
International experiences of promoting generics use and its implications to China
Authors: Sun Jing
Published: May 2013

Objective

To summarize international experiences in promoting use of generics and to extract essence for China's reference.

Method

This is a commentary of two systematic reviews about policies to promote use of generics and its implications to China.

Result

Price, reimbursement, and generic substitution policies in European countries, and approaches in low and middle income countries in promoting market competition, appropriate intellectual property right protection strategy, and necessary demand side incentives, are all meaningful for China to contain soaring pharmaceutical expenditures, and to maintain the achievements and outcomes of the national health system reform.

Conclusion

Effective promotion of generics use must be practice based on the real situation. Tailor‐made and comprehensive measures are needed to address both demand and supply sides barriers before achieving tangible cost containment effect without unexpected side effects.
Deciphering Ascorbic Acid Regulatory Pathways in Ripening Tomato Fruit Using a Weighted Gene Correlation Network Analysis Approach
Authors: Gao Chao , Ju Zheng , Li Shan , Zuo Jinhua , Fu Daqi , Tian Huiqin , Luo Yunbo , Zhu Benzhong
Published: May 2013

Genotype is generally determined by the co‐expression of diverse genes and multiple regulatory pathways in plants. Gene co‐expression analysis combining with physiological trait data provides very important information about the gene function and regulatory mechanism. L‐Ascorbic acid (AsA), which is an essential nutrient component for human health and plant metabolism, plays key roles in diverse biological processes such as cell cycle, cell expansion, stress resistance, hormone synthesis, and signaling. Here, we applied a weighted gene correlation network analysis approach based on gene expression values and AsA content data in ripening tomato (Solanum lycopersicum L.) fruit with different AsA content levels, which leads to identification of AsA relevant modules and vital genes in AsA regulatory pathways. Twenty‐four modules were compartmentalized according to gene expression profiling. Among these modules, one negatively related module containing genes involved in redox processes and one positively related module enriched with genes involved in AsA biosynthetic and recycling pathways were further analyzed. The present work herein indicates that redox pathways as well as hormone‐signal pathways are closely correlated with AsA accumulation in ripening tomato fruit, and allowed us to prioritize candidate genes for follow‐up studies to dissect this interplay at the biochemical and molecular level.
Oestradiol Differentially Influences Feeding Behaviour Depending on Diet Composition in Female Rhesus Monkeys
Authors: Johnson Z. P. , Lowe J. , Michopoulos V. , Moore C. J. , Wilson M. E. , Toufexis D.
Published: May 2013

In females, cyclical changes in the ovarian hormone oestradiol are known to modulate feeding behaviour. However, what is less clear is how these behavioural effects of oestradiol are modified by the macronutrient content of a diet. In the present study, we report data showing that oestradiol treatment results in both significantly smaller meals and a reduced total calorie intake in ovariectomised, socially‐housed female rhesus macaques when only chow diet is available. Conversely, during a choice dietary condition where both palatable and chow options are available, oestradiol treatment had no observable, attenuating effect on calorie intake. During this choice dietary phase, all animals consumed more of the palatable diet than chow diet; however, oestradiol treatment appeared to further increase preference for the palatable diet. Finally, oestradiol treatment increased snacking behaviour (i.e. the consumption of calories outside of empirically defined meals), regardless of diet condition. These findings illustrate how oestradiol differentially influences feeding behaviour depending on the dietary environment and provides a framework in which we can begin to examine the mechanisms underlying these observed changes.
The study of sequence learning in individuals with schizophrenia: A critical review of the literature
Authors: Remillard Gilbert
Published: May 2013

The serial reaction time task (SRTT) has been used extensively to study implicit sequence learning. A number of studies have used the SRTT to examine sequence learning in schizophrenia patients. Despite these studies, it remains unclear whether sequence learning is impaired in patients, whether antipsychotic medications affect sequence learning, and what types of sequential information patients might have difficulty learning. Methodological limitations have made it difficult to obtain good answers to these questions. Methodological innovations from the general SRTT literature that have not yet been adopted in the schizophrenia literature could provide better answers.
An open‐label study of anidulafungin for the treatment of candidaemia/invasive candidiasis in Latin America
Authors: Nucci Marcio , Colombo Arnaldo L. , Petti Marco , Magana Martin , Abreu Paula , Schlamm Haran T. , Sanchez Sonia P.
Published: May 2013

Incidence and mortality of candidaemia/invasive candidiasis (C/IC) is relatively high in Latin America versus North America and Europe. To assess efficacy and safety of intravenous (IV) anidulafungin in Latin American adults with documented C/IC. All patients in this open‐label study received initial IV anidulafungin with optional step‐down to oral voriconazole after 5 days; total treatment duration was 14–42 days. The primary endpoint was global response (clinical + microbiological response) at end of treatment (EOT); missing/indeterminate responses were failures. The study enrolled 54 patients; 44 had confirmed C/IC within 96 h before study entry and comprised the modified intent‐to‐treat population. Global response at EOT was 59.1% (95% CI: 44.6, 73.6), with 13 missing/indeterminate assessments. Thirty‐day all‐cause mortality was 43.1%. Fourteen patients (31.8%) were able to step‐down to oral voriconazole; these patients had lower baseline acute physiological assessment and chronic health evaluation (APACHE) II scores and were less likely to have solid tumours or previous abdominal surgery. Anidulafungin was generally well tolerated with few treatment‐related adverse events. Anidulafungin was associated with relatively low response rates influenced by a high rate of missing/indeterminate assessments and mortality comparable to other recent candidaemia studies in Latin America. In a subset of patients with lower APACHE II scores, short‐course anidulafungin followed by oral voriconazole was successful.
Systemic inflammation with enhanced brain activation contributes to more severe delay in postoperative ileus
Authors: van Bree S. H. W. , Cailotto C. , Di Giovangiulio M. , Jansen E. , van der Vliet J. , Costes L. , Depoortere I. , Gomez‐Pinilla P. J. , Matteoli G. , Boeckxstaens G. E. E.
Published: May 2013

Background

The severity of postoperative ileus (POI) has been reported to result from decreased contractility of the muscularis inversely related to the number of infiltrating leukocytes. However, we previously observed that the severity of POI is independent of the number of infiltrating leukocytes, indicating that different mechanisms must be involved. Here, we hypothesize that the degree of tissue damage in response to intestinal handling determines the upregulation of local cytokine production and correlates with the severity of POI.

Methods

Intestinal transit, the inflammatory response, I‐FABP (marker for tissue damage) levels and brain activation were determined after different intensities of intestinal handling.

Key Results

Intense handling induced a more pronounced ileus compared with gentle intestinal manipulation (IM). No difference in leukocytic infiltrates in the handled and non‐handled parts of the gut was observed between the two intensities of intestinal handling. However, intense handling resulted in significantly more tissue damage and was accompanied by a systemic inflammation with increased plasma levels of pro‐inflammatory cytokines. In addition, intense but not gentle handling triggered enhanced c‐Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP). In patients, plasma levels of I‐FABP and inflammatory cytokines were significantly higher after open compared with laparoscopic surgery, and were associated with more severe POI.

Conclusions & Inferences

Not the influx of leukocytes, rather the manipulation‐induced damage and subsequent inflammatory response determine the severity of POI. The release of tissue damage mediators and pro‐inflammatory cytokines into the systemic circulation most likely contribute to the impaired motility of non‐manipulated intestine.
Gingipain‐dependent degradation of mammalian target of rapamycin pathway proteins by the periodontal pathogen Porphyromonas gingivalis during invasion
Authors: Stafford P. , Higham J. , Pinnock A. , Murdoch C. , Douglas C.W.I. , Stafford G.P. , Lambert D.W.
Published: May 2013

Porphyromonas gingivalis and Tannerella forsythia are gram‐negative pathogens strongly associated with periodontitis. Their abilities to interact, invade and persist within host cells are considered crucial to their pathogenicity, but the mechanisms by which they subvert host defences are not well understood. In this study, we set out to investigate whether P. gingivalis and T. forsythia directly target key signalling molecules that may modulate the host cell phenotype to favour invasion and persistence. Our data identify, for the first time, that P. gingivalis, but not T. forsythia, reduces levels of intracellular mammalian target of rapamycin (mTOR) in oral epithelial cells following invasion over a 4‐h time course, via the action of gingipains. The ability of cytochalasin D to abrogate P. gingivalis‐mediated mTOR degradation suggests that this effect is dependent upon cellular invasion. We also show that levels of several other proteins in the mTOR signalling pathway are modulated by gingipains, either directly or as a consequence of mTOR degradation including p‐4E‐BP1. Taken together, our data suggest that P. gingivalis manipulates the mTOR pathway, providing evidence for a potentially novel mechanism by which P. gingivalis mediates its effects on host cell responses to infection.
Knowledge, Credit, and Cognitive Agency
Authors: Breyer Daniel S.
Published: May 2013

According to credit theories of knowledge, S knows that p only if S deserves credit for truly believing that p. This article argues that any adequate credit theory has to explain the conditions under which beliefs are attributable to subjects. It then presents a general account of these conditions and defends two models of cognitive agency. Finally, the article explains how an agent‐based approach rescues the credit theory from an apparent counterexample. The article's defense of the credit theory is qualified, however, for one lesson that emerges is that credit theories are theories of subjective justification, not theories of knowledge.
Hematopoietic stem cell transplantation with a reduced‐intensity conditioning regimen in pediatric patients withGriscelli syndrome type 2
Authors: Hamidieh Amir Ali , Pourpak Zahra , Yari Kolsoum , Fazlollahi Mohammad Reza , Hashemi Susan , Behfar Maryam , Moin Mostafa , Ghavamzadeh Ardeshir
Published: May 2013

Partial albinism with variable immunodeficiency are the two major characteristics ofGriscelli syndrome type 2 (GS‐2). This syndrome is usually associated with a high mortality rate and commonly results in early childhood death. Patients suffer from different infections and experience crisis ofHLH.HSCTremains the sole curative treatment forGS‐2. We prospectively analyzed the outcomes of transplantation withRICregimen in five patients. The median age at transplantation was 21.6 months (range: 12–30). All of the patients underwentHSCTfromHLA‐matched related donors. Currently, four patients are cured, and symptoms of recurrent infections andHLHcrisis are not seen in them. The only patient who died had undergoneHSCTin the accelerated phase ofHLH. One patient who developed acuteGvHDhad a favorable response to therapy. No chronicGvHDoccurred in patients. It seems that the use ofRICregimen as a method of transplant preparation is effective and tolerable in this group of patients with various comorbidities. It is recommended to carry outHSCTin these patients at lower ages, before presentations of different infections andHLHcrisis.
Nontuberculous mycobacteria‐associated spindle cell pseudotumor of the nasal cavity: A case report
Authors: Ohara Kentaro , Kimura Tokuhiro , Sakamoto Koji , Okada Yasunori
Published: May 2013

Mycobacterial spindle cell pseudotumor (MSP) is a rare mass‐forming lesion caused by mycobacterial infection, mostly in immunocompromised patients. Since it is composed of a proliferation of spindle‐shaped fibrohistiocytic cells without forming epithelioid cell granulomas, histological distinction from other spindle cell lesions is often difficult and its pathophysiology is poorly understood. MSP arising in the nasal cavity is extremely rare, and only two cases have been reported previously. Here we report a case of MSP of the nasal cavity in an 83‐year‐old man with no evidence of immunodeficient state. The resected tumor consisted of spindle cells, which contained numerous acid‐fast bacilli in the cytoplasm. By polymerase chain reaction and sequencing using DNA extracted from the paraffin sections, the bacilli were identified as Mycobacterium intracellulare. Immunohistochemistry revealed that the spindle cells were positive for CD68, CD11c and S100 protein, confirming the histiocytic nature of these cells. They were also positive for CD163 and CD204, suggesting that they showed a phenotype similar to alternatively activated (M2) macrophages and the phenotype might contribute to the maintenance of mycobacterial infection despite apparent immunocompetence of the host.
Characterization of the Exonic Regions of the JY‐1 Gene in Zebu Cattle and Buffaloes
Authors: de Camargo GMF , Baldi F , Regitano LCA , Tonhati H
Published: May 2013

Contents

Protein JY‐1 is an oocyte‐specific protein that plays an important regulatory role in the granulosa cell layer and during the early embryo development stages. It is the first specific protein of maternal origin discovered in a single‐ovulating species. In this study, the exon regions of the JY‐1 gene were characterized by sequencing in 20 unrelated cattle (Bos taurus indicus) and 20 unrelated buffaloes (Bubalus bubalis). Eighteen polymorphisms were detected in cattle and 10 polymorphisms in buffaloes. Some of the polymorphisms were identified in codifying regions and caused amino acid changes. The insertion of a thymine was detected in the codifying region of exon 3 of the buffalo sequence when compared to the cattle one. This insertion causes a change in the codons frameshift from this point onwards, modifying the 19 terminal amino acids of the buffalo protein and creating a premature stop codon. This finding may explain reproductive differences between cattle and buffaloes in terms of follicle recruitment, embryo development and incidence of twin pregnancies.
Improving Causal Inferences in Risk Analysis
Authors: Cox Louis Anthony (Tony)
Published: May 2013

Recent headlines and scientific articles projecting significant human health benefits from changes in exposures too often depend on unvalidated subjective expert judgments and modeling assumptions, especially about the causal interpretation of statistical associations. Some of these assessments are demonstrably biased toward false positives and inflated effects estimates. More objective, data‐driven methods of causal analysis are available to risk analysts. These can help to reduce bias and increase the credibility and realism of health effects risk assessments and causal claims. For example, quasi‐experimental designs and analysis allow alternative (noncausal) explanations for associations to be tested, and refuted if appropriate. Panel data studies examine empirical relations between changes in hypothesized causes and effects. Intervention and change‐point analyses identify effects (e.g., significant changes in health effects time series) and estimate their sizes. Granger causality tests, conditional independence tests, and counterfactual causality models test whether a hypothesized cause helps to predict its presumed effects, and quantify exposure‐specific contributions to response rates in differently exposed groups, even in the presence of confounders. Causal graph models let causal mechanistic hypotheses be tested and refined using biomarker data. These methods can potentially revolutionize the study of exposure‐induced health effects, helping to overcome pervasive false‐positive biases and move the health risk assessment scientific community toward more accurate assessments of the impacts of exposures and interventions on public health.
Goodness‐of‐fit Test for Directional Data
Authors: Boente Graciela , Rodriguez Daniela , Manteiga Wenceslao González
Published: May 2013

In this paper, we study the problem of testing the hypothesis on whether the density f of a random variable on a sphere belongs to a given parametric class of densities. We propose two test statistics based on the L2 and L1 distances between a non‐parametric density estimator adapted to circular data and a smoothed version of the specified density. The asymptotic distribution of the L2 test statistic is provided under the null hypothesis and contiguous alternatives. We also consider a bootstrap method to approximate the distribution of both test statistics. Through a simulation study, we explore the moderate sample performance of the proposed tests under the null hypothesis and under different alternatives. Finally, the procedure is illustrated by analysing a real data set based on wind direction measurements.
Moment estimation in discrete shifting level model applied to fast array‐CGH segmentation
Authors: Gandolfi A. , Benelli M. , Magi A. , Chiti S.
Published: May 2013

We develop a mathematical theory needed for moment estimation of the parameters in a general shifting level process (SLP) treating, in particular, the finite state space case geometric finite normal (GFN) SLP. For the SLP, we give expressions for the moment estimators together with asymptotic (co)variances, following, completing, and correcting Cline (Journal of Applied Probability 20, 1983, 322–337); formulae are then made more explicit for the GFN‐SLP. To illustrate the potential uses, we then apply the moment estimation method to a GFN‐SLP model of array comparative genomic hybridization data. We obtain encouraging results in the sense that a segmentation based on the estimated parameters turns out to be faster than with other currently available methods, while being comparable in terms of sensitivity and specificity.
Using Reverse Viewshed Analysis to Assess the Location Correctness of Visually Generated VGI
Authors: Senaratne Hansi , Bröring Arne , Schreck Tobias
Published: May 2013

With the increased availability of user generated data, assessing the quality and credibility of such data becomes important. In this article, we propose to assess the location correctness of visually generated Volunteered Geographic Information (VGI) as a quality reference measure. The location correctness is determined by checking the visibility of the point of interest from the position of the visually generated VGI (observer point); as an example we utilize Flickr photographs. Therefore we first collect all Flickr photographs that conform to a certain point of interest through their textual labelling. Then we conduct a reverse viewshed analysis for the point of interest to determine if it lies within the area of visibility of the observer points. If the point of interest lies outside the visibility of a given observer point, the respective geotagged image is considered to be incorrectly geotagged. In this way, we analyze sample datasets of photographs and make observations regarding the dependency of certain user/photo metadata and (in)correct geotags and labels. In future the dependency relationship between the location correctness and user/photo metadata can be used to automatically infer user credibility. In other words, attributes such as profile completeness, together with location correctness, can serve as a weighted score to assess credibility.
Inductively coupled plasma mass‐spectrometric determination of platinum in excretion products of client‐owned pet dogs
Authors: Janssens T. , Brouwers E. E. M. , de Vos J. P. , de Vries N. , Schellens J. H. M. , Beijnen J. H.
Published: May 2013

Residues of antineoplastic drugs in canine excretion products may represent exposure risks to veterinary personnel, owners of pet dogs and other animal care‐takers. The aim of this study was to measure the extent and duration of platinum (Pt) excretion in pet dogs treated with carboplatin. Samples were collected before and up to 21 days after administration of carboplatin. We used validated, ultra‐sensitive, inductively coupled plasma‐mass spectrometry assays to measure Pt in canine urine, faeces, saliva, sebum and cerumen. Results showed that urine is the major route of elimination of Pt in dogs. In addition, excretion occurs via faeces and saliva, with the highest amounts eliminated during the first 5 days. The amount of excreted Pt decreased over time but was still quantifiable at 21 days after administration of carboplatin. In conclusion, increased Pt levels were found in all measured excretion products up to 21 days after administration of carboplatin to pet dogs, with urine as the main route of excretion. These findings may be used to further adapt current veterinary guidelines on safe handling of antineoplastic drugs and treated animals.
Automated Identification of a Mechatronic System Model Using Genetic Programming and Bond Graphs
Authors: Behbahani Saeed , de Silva Clarence W.
Published: May 2013

Modeling, identification (experimental modeling), and design of dynamic systems and the associated problem of controller design are common problems in the field of mechatronics. A typical mechatronic problem entails finding the best topology as well as parameter values of the desired solution. In view of dynamic interactions in a mechatronic system, which involves more than one domain, it is desirable to use concurrent and integrated methodology in the solution. The powerful search ability of genetic programming (GP) along with the domain independence and the open architecture of bond graph (BG) modeling can be integrated to develop an evolutionary mechatronic tool for identification of a complex mechatronic system. This paper extends this integrated approach to nonlinear mechatronic problems and develops a software tool for this purpose. It is illustrated how the developed technique and the corresponding software tool can be used in the automated synthesis and identification of a nonlinear mechatronic system. The performance of the software tool is validated by applying it to a nonlinear electrohydraulic manipulator, which falls into the class of multidomain systems. The results obtained from the application are quite encouraging, and form a rationale for the extension of the tool for concurrent and optimal design of mechatronic systems.
Micromirrors connected in series for low voltage operation in vacuum
Authors: Kotani Seibou , Manh Chu Hoang , Sasaki Takashi , Hane Kazuhiro
Published: May 2013

Micromirrors connected in series were fabricated and studied for decreasing operation voltage and investigating an energy loss of resonant mirror. Three identical mirrors (center-mirror and side-mirrors) were connected by torsion bars. The torsion bars of center-mirror were not fixed to substrate; the other sides of the torsion bars of side-mirrors were fixed to the substrate. The motions of the mirrors connected in series were studied. Using the third-mode resonance of series-mirror, the motion of center-mirror was identical to that of a single mirror in the first-mode resonance. The energy loss of mirror was studied by comparing the quality-factors of the series-mirror in the third-mode resonance and the single mirror in the first-mode resonance in vacuum. The quality-factor of the series-mirror was higher than that of the single mirror. The operation voltage of the series-mirror was decreased under the resonant condition in vacuum. The improvements in quality-factor and operation voltage of the series-mirror in the third-mode resonance were explained by the reduced anchor loss due to the virtual supporting of the center-mirror.
Glycosylations in the Globular Head of the Hemagglutinin Protein Modulate the Virulence and Antigenic Properties of the H1N1 Influenza Viruses
Authors: Medina Rafael A. , Stertz Silke , Manicassamy Balaji , Zimmermann Petra , Sun Xiangjie , Albrecht Randy A. , Uusi-Kerttula Hanni , Zagordi Osvaldo , Belshe Robert B. , Frey Sharon E. , Tumpey Terrence M. , García-Sastre Adolfo
Published: May 2013

Hemagglutinin glycosylations modulate the virulence and antigenicity of H1N1 influenza viruses.
Methylation of 23S rRNA Nucleotide G748 by RlmA
II
Methyltransferase Renders Streptococcus pneumoniae Telithromycin Susceptible
Authors: Takaya Akiko , Sato Yoshiharu , Shoji Tatsuma , Yamamoto Tomoko
Published: May 2013

Several posttranscriptional modifications of bacterial rRNAs are important in determining antibiotic resistance or sensitivity. In all Gram-positive bacteria, dimethylation of nucleotide A2058, located in domain V of 23S rRNA, by the dimethyltransferase Erm(B) results in low susceptibility and resistance to telithromycin (TEL). However, this is insufficient to produce high-level resistance to TEL in
Streptococcus pneumoniae
. Inactivation of the methyltransferase RlmA
II
, which methylates the N-1 position of nucleotide G748, located in hairpin 35 of domain II of 23S rRNA, results in increased resistance to TEL in
erm
(B)-carrying
S. pneumoniae
. Sixteen TEL-resistant mutants (MICs, 16 to 32 μg/ml) were obtained from a clinically isolated
S. pneumoniae
strain showing low TEL susceptibility (MIC, 2 μg/ml), with mutation resulting in constitutive dimethylation of A2058 because of nucleotide differences in the regulatory region of
erm
(B) mRNA. Primer extension analysis showed that the degree of methylation at G748 in all TEL-resistant mutants was significantly reduced by a mutation in the gene encoding RlmA
II
to create a stop codon or change an amino acid residue. Furthermore, RNA footprinting with dimethyl sulfate and a molecular modeling study suggested that methylation of G748 may contribute to the stable interaction of TEL with domain II of 23S rRNA, even after dimethylation of A2058 by Erm(B). This novel finding shows that methylation of G748 by RlmA
II
renders
S. pneumoniae
TEL susceptible.
Two Multidrug-Resistant Clinical Isolates of Bacteroides fragilis Carry a Novel Metronidazole Resistance
nim
Gene (
nimJ
)
Authors: Husain Fasahath , Veeranagouda Yaligara , Hsi Justin , Meggersee Rosemary , Abratt Valerie , Wexler Hannah M.
Published: May 2013

Two multidrug-resistant
Bacteroides fragilis
clinical isolates contain and express a novel
nim
gene,
nimJ
, that is not recognized by the “universal”
nim
primers and can confer increased resistance to metronidazole when introduced into a susceptible strain on a multicopy plasmid. HMW615, an appendiceal isolate, contains at least two copies of
nimJ
on its genome, while HMW616, an isolate from a patient with sepsis, contains one genomic copy of
nimJ. B. fragilis
NimJ is phylogenetically closer to
Prevotella baroniae
NimI and
Clostridium botulinum
NimA than to the other known
Bacteroides
Nim proteins. The predicted protein structure of NimJ, based on fold recognition analysis, is consistent with the crystal structures derived for known Nim proteins, and specific amino acid residues important for substrate binding in the active site are conserved. This study demonstrates that the “universal”
nim
primers will not detect all
nim
genes with the ability to confer metronidazole resistance, but
nimJ
alone cannot account for the very high metronidazole MICs of these resistant clinical isolates.
Multicenter Study of Isavuconazole MIC Distributions and Epidemiological Cutoff Values for Aspergillus spp. for the CLSI M38-A2 Broth Microdilution Method
Authors: Espinel-Ingroff A. , Chowdhary A. , Gonzalez G. M. , Lass-Flörl C. , Martin-Mazuelos E. , Meis J. , Peláez T. , Pfaller M. A. , Turnidge J.
Published: May 2013

Epidemiological cutoff values (ECVs) were established for the new triazole isavuconazole andAspergillusspecies wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) that were defined with 855Aspergillus fumigatus, 444A. flavus, 106A. nidulans, 207A. niger, 384A. terreus, and 75A. versicolorspecies complex isolates; 22AspergillussectionUstiisolates were also included. CLSI broth microdilution MIC data gathered in Europe, India, Mexico, and the United States were aggregated to statistically define ECVs. ECVs were 1 μg/ml for theA. fumigatusspecies complex, 1 μg/ml for theA. flavusspecies complex, 0.25 μg/ml for theA. nidulansspecies complex, 4 μg/ml for theA. nigerspecies complex, 1 μg/ml for theA. terreusspecies complex, and 1 μg/ml for theA. versicolorspecies complex; due to the small number of isolates, an ECV was not proposed forAspergillussectionUsti. These ECVs may aid in detecting non-WT isolates with reduced susceptibility to isavuconazole due tocyp51A(anA. fumigatusspecies complex resistance mechanism among the triazoles) or other mutations.
Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase
Authors: Harris Michael T. , Walker Dawn M. , Drew Mark E. , Mitchell William G. , Dao Kevin , Schroeder Chad E. , Flaherty Daniel P. , Weiner Warren S. , Golden Jennifer E. , Morris James C.
Published: May 2013

Parasites in the genus
Plasmodium
cause disease throughout the tropic and subtropical regions of the world.
P. falciparum
, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa
P. falciparum
HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (∼26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC
50
s) of <1 μM. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited
P. falciparum
growth
in vitro
(50% effective concentration [EC
50
] of ≥0.6 and <6.8 μM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against
P. falciparum
.
Nationwide Surveillance of Macrolide-Resistant Mycoplasma pneumoniae Infection in Pediatric Patients
Authors: Kawai Yasuhiro , Miyashita Naoyuki , Kubo Mika , Akaike Hiroto , Kato Atsushi , Nishizawa Yoko , Saito Aki , Kondo Eisuke , Teranishi Hideto , Wakabayashi Tokio , Ogita Satoko , Tanaka Takaaki , Kawasaki Kozo , Nakano Takashi , Terada Kihei , Ouchi Kazunobu
Published: May 2013

We conducted nationwide surveillance to investigate regional differences in macrolide-resistant (MR)
Mycoplasma pneumoniae
strains in Japan. The prevalence of MR
M. pneumoniae
in pediatric patients gradually increased between 2008 and 2012. Although regional differences were observed, high levels of MR genes were detected in all seven surveillance areas throughout Japan and ranged in prevalence from 50% to 93%. These regional differences were closely related to the previous administration of macrolides.
Synergistic Activity of Colistin and Rifampin Combination against Multidrug-Resistant Acinetobacter baumannii in an
In Vitro
Pharmacokinetic/Pharmacodynamic Model
Authors: Lee Hee Ji , Bergen Phillip J. , Bulitta Jurgen B. , Tsuji Brian , Forrest Alan , Nation Roger L. , Li Jian
Published: May 2013

Combination therapy may be required for multidrug-resistant (MDR)
Acinetobacter baumannii
. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR
A. baumannii
. Studies were conducted over 72 h in an
in vitro
pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ∼10
6
and ∼10
8
CFU/ml using two MDR clinical isolates of
A. baumannii
, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [
C
max
] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10
6
-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 10
8
-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ∼2.5 to 7.5 and ∼2.5 to 5 log
10
CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR
A. baumannii
.
The Francisella tularensis migR,
trmE
, and
cphA
Genes Contribute to F. tularensis Pathogenicity Island Gene Regulation and Intracellular Growth by Modulation of the Stress Alarmone ppGpp
Authors: Faron Matthew , Fletcher Joshua R. , Rasmussen Jed A. , Long Matthew E. , Allen Lee-Ann H. , Jones Bradley D.
Published: May 2013

The
Francisella tularensis
pathogenicity island (FPI) encodes many proteins that are required for virulence. Expression of these genes depends upon the FevR (PigR) regulator and its interactions with the MglA/SspA and RNA polymerase transcriptional complex. Experiments to identify how transcription of the FPI genes is activated have led to identification of mutations within the
migR
,
trmE
, and
cphA
genes that decrease FPI expression. Recent data demonstrated that the small alarmone ppGpp, produced by RelA and SpoT, is important for stabilizing MglA/SspA and FevR (PigR) interactions in
Francisella
. Production of ppGpp is commonly known to be activated by cellular and nutritional stress in bacteria, which indicates that cellular and nutritional stresses act as important signals for FPI activation. In this work, we demonstrate that mutations in
migR
,
trmE
, or
cphA
significantly reduce ppGpp accumulation. The reduction in ppGpp levels was similar for each of the mutants and correlated with a corresponding reduction in
iglA
reporter expression. In addition, we observed that there were differences in the ability of each of these mutants to replicate within various mammalian cells, indicating that the
migR
,
trmE
, and
cphA
genes are likely parts of different cellular stress response pathways in
Francisella
. These results also indicate that different nutritional and cellular stresses exist in different mammalian cells. This work provides new information to help understand how
Francisella
regulates its virulence genes in response to host cell environments, and it contributes to our growing knowledge of this highly successful bacterial pathogen.
Comparison of Genomes of Brucella melitensis M28 and the B. melitensis M5-90 Derivative Vaccine Strain Highlights the Translation Elongation Factor Tu Gene
tuf2
as an Attenuation-Related Gene
Authors: Wang Fangkun , Qiao Zujian , Hu Sen , Liu Wenxing , Zheng Huajun , Liu Sidang , Zhao Xiaomin , Bu Zhigao
Published: May 2013

Brucella melitensis
causes brucellosis, a disease affecting sheep, cattle, and sometimes humans. Attenuated
B. melitensis
strain M5-90, derived from virulent strain M28, is widely used as a live vaccine in ruminants in China. Genetic differences between the strains may cast light on the mechanism of attenuation. We recently reported the complete genomic sequences of M28 and M5-90. Genome organization is highly conserved between these isolates, and also with virulent strains 16 M and ATCC 23457. Analysis revealed 23 open reading frames (ORFs) with consistent differences between M5-90 and the virulent strains. Notably, the
tuf2
gene encoding translation elongation factor EF-Tu from M5-90 contained 50 single nucleotide polymorphisms (SNPs) and 9 gaps (indels) compared to
tuf2
of M28 or of the other virulent strains. There were no changes in
tuf1
. To evaluate the potential role of EF-Tu in pathogenesis,
tuf1
and
tuf2
mutants of M28 and an M5-90 strain harboring wild-type
tuf2
were constructed, and their virulence/attenuation was evaluated
in vivo
. We report that the
tuf2
gene plays an important role in the attenuation of M5-90 virulence.