bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of a mouse model for the West Nile virus group for the purpose of determining viral pathotypes
Authors: Bingham John , Payne Jean , Harper Jennifer , Frazer Leah , Eastwood Sarah , Wilson Susanne , Lowther Sue , Lunt Ross , Warner Simone , Carr Mary , Hall Roy A. , Durr Peter A.
Published: April 2014

West Nile virus (WNV; family Flaviviridae; genus Flavivirus) group members are an important cause of viral meningoencephalitis in some areas of the world. They exhibit marked variation in pathogenicity, with some viral lineages (such as those from North America) causing high prevalence of severe neurological disease, whilst others (such as Australian Kunjin virus) rarely cause disease. The aim of this study was to characterize WNV disease in a mouse model and to elucidate the pathogenetic features that distinguish disease variation. Tenfold dilutions of five WNV strains (New York 1999, MRM16 and three horse isolates of WNV-Kunjin: Boort and two isolates from the 2011 Australian outbreak) were inoculated into mice by the intraperitoneal route. All isolates induced meningoencephalitis in different proportions of infected mice. WNVNY99 was the most pathogenic, the three horse isolates were of intermediate pathogenicity and WNVKUNV-MRM16 was the least, causing mostly asymptomatic disease with seroconversion. Infectivity, but not pathogenicity, was related to challenge dose. Using cluster analysis of the recorded clinical signs, histopathological lesions and antigen distribution scores, the cases could be classified into groups corresponding to disease severity. Metrics that were important in determining pathotype included neurological signs (paralysis and seizures), meningoencephalitis, brain antigen scores and replication in extra-neural tissues. Whereas all mice infected with WNVNY99 had extra-neural antigen, those infected with the WNV-Kunjin viruses only occasionally had antigen outside the nervous system. We conclude that the mouse model could be a useful tool for the assessment of pathotype for WNVs.
HGTector: An automated method facilitating genome-wide discovery of putative horizontal gene transfers
Authors: Zhu Qiyun , Kosoy Michael , Dittmar Katharina
Published: April 2014

A new computational method of rapid, exhaustive and genome-wide detection of HGT was developed, featuring the systematic analysis of BLAST hit distribution patterns in the context of a priori defined hierarchical evolutionary categories. Genes that fall beyond a series of statistically determined thresholds are identified as not adhering to the typical vertical his-tory of the organisms in question, but instead having a putative horizontal origin. Tests on simulated genomic data suggest that this approach effectively targets atypically distributed genes that are highly likely to be HGT-derived, and exhibits robust performance compared to conventional BLAST-based approaches. This method was further tested on real genomic datasets, including Rickettsia genomes, and was compared to previous studies. Results show consistency with currently employed cat-egories of HGT prediction methods. In-depth analysis of both simulated and real genomic data suggests that the method is no-tably insensitive to stochastic events such as gene loss, rate variation and database error, which are common challenges to the current methodology. An automated pipeline was created to implement this approach and was made publicly available at: https://github.com/DittmarLab/HGTector. The program is versatile, easily deployed, has low requirements for computation-al resources, and is an effective tool for initial or standalone large-scale discovery of candidate HGT-derived genes.
New whole genome de novo assemblies of three divergent strains of rice (O. sativa) documents novel gene space of aus and indica
Authors: Schatz Michael C , Maron Lyza G , Stein Joshua C , Hernandez Wences Alejandro , Gurtowski James , Biggers Eric , Lee Hayan , Kramer Melissa , Antonio Eric , Ghiban Elena , Wright Mark H , Chia Jer-ming , Ware Doreen , McCouch Susan R , McCombie William Richard
Published: April 2014

The use of high throughput genome-sequencing technologies has uncovered a large extent of structural variation in eukaryotic genomes that makes important contributions to genomic diversity and phenotypic variation. Currently, when the genomes of different strains of a given organism are compared, whole genome resequencing data are aligned to an established reference sequence. However when the reference differs in significant structural ways from the individuals under study, the analysis is often incomplete or inaccurate. Here, we use rice as a model to explore the extent of structural variation among strains adapted to different ecologies and geographies, and show that this variation can be significant, often matching or exceeding the variation present in closely related human populations or other mammals. We demonstrate how improvements in sequencing and assembly technology allow rapid and inexpensive de novo assembly of next generation sequence data into high-quality assemblies that can be directly compared to provide an unbiased assessment. Using this approach, we are able to accurately assess the ?pan-genome? of three divergent rice varieties and document several megabases of each genome absent in the other two. Many of the genome-specific loci are annotated to contain genes, reflecting the potential for new biological properties that would be missed by standard resequencing approaches. We further provide a detailed analysis of several loci associated with agriculturally important traits, illustrating the utility of our approach for biological discovery. All of the data and software are openly available to support further breeding and functional studies of rice and other species.
Highly efficient RNA-guided genome editing in human cells via delivery of purified Cas9 ribonucleoproteins
Authors: Kim Sojung , Kim Daesik , Cho Seung Woo , Kim Jungeun , Kim Jin-Soo
Published: April 2014

RNA-guided engineered nucleases (RGENs) derived from the prokaryotic adaptive immune system known as CRISPR (clustered, regularly interspaced, short palindromic repeat)/Cas (CRISPR-associated) enable genome editing in human cell lines, animals, and plants, but are limited by off-target effects and unwanted integration of DNA segments derived from plasmids encoding Cas9 and guide RNA at both on-target and off-target sites in the genome. Here, we deliver purified recombinant Cas9 protein and guide RNA into cultured human cells including hard-to-transfect fibroblasts and pluripotent stem cells. RGEN ribonucleoproteins (RNPs) induce site-specific mutations at frequencies of up to 79%, while reducing off-target mutations associated with plasmid transfection at off-target sites that differ by one or two nucleotides from on-target sites. RGEN RNPs cleave chromosomal DNA almost immediately after delivery and are degraded rapidly in cells, reducing off-target effects. Furthermore, RNP delivery is less stressful to human embryonic stem cells, producing at least twofold more colonies than does plasmid transfection.
Multigene Engineering of Triacylglycerol Metabolism Boosts Seed Oil Content in Arabidopsis
Authors: van Erp Harrie , Kelly Amélie A. , Menard Guillaume , Eastmond Peter J.
Published: April 2014

Increasing the yield of oilseed crops is an important objective for biotechnologists. A number of individual genes involved in triacylglycerol metabolism have previously been reported to enhance the oil content of seeds when their expression is altered. However, it has yet to be established whether specific combinations of these genes can be used to achieve an additive effect and whether this leads to enhanced yield. Using Arabidopsis (Arabidopsis thaliana) as an experimental system, we show that seed-specific overexpression of WRINKLED1 (a transcriptional regulator of glycolysis and fatty acid synthesis) and DIACYLGLYCEROL ACYLTRANSFERASE1 (a triacylglycerol biosynthetic enzyme) combined with suppression of the triacylglycerol lipase SUGAR-DEPENDENT1 results in a higher percentage seed oil content and greater seed mass than manipulation of each gene individually. Analysis of total seed yield per plant suggests that, despite a reduction in seed number, the total yield of oil is also increased.
Who is more likely to become business angels?
Authors: Li Yaokuang , Ling Li , Wu Juan , Li Peng
Published: April 2014

Purpose

– The paper is aimed to obtain a clear understanding of influence factors that can increase the possibility to be business angels (BA).

Design/methodology/approach

– This study develops the 3A model in the Chinese context to design questionnaire, and 334 questionnaires are obtained via focus group sample and targeted snowball approach, and the multinomial logit analysis is used to test a serious of hypotheses.

Findings

– The paper confirmed that the entrepreneurial experience and wealth are determinants of investment for potential BA, and the wealth have both directly and indirectly positive influence on investment activity through risk preference, namely that richer people prefer risk which impel them to invest as BA.

Research limitations/implications

– There are two limitations in the paper: first, the macro environment in China has not been taken into consideration in the model; second, the source of the sample focuses on the developed cities in the middle and eastern of China, only reflect the characteristic of angels in these areas, which may somewhat diverges from the reality.

Practical implications

– The paper would contribute to form the policy which could promote the development of angel investment in China.

Originality/value

– This paper conducts a preliminary exploration of the factors that have impact on Chinese BA' investment activity based on current research.
A US-China comparative study of cloud computing adoption behavior
Authors: Ratten Vanessa
Published: April 2014

Purpose

– The purpose of this paper is to examine the effects of privacy concerns and consumer innovativeness towards consumer's adoption of a technological innovation in the form of cloud computing technology.

Design/methodology/approach

– A cross-cultural comparison between consumers in the USA and China is made through a study of consumers intending to adopt cloud computing services. A review of the technology innovation adoption literature forms the basis of the research propositions, which are based on the extant literature and focused on the innovative adoption behaviour of consumers. A comparative approach is taken to analyse the differences between US and Chinese consumers intending to adopt cloud computing services.

Findings

– Findings suggest that there are more similarities than differences between US and Chinese consumers adopting cloud computing services. The survey suggests that the performance expectancy, perceived usefulness and perceived ease of use can help predict intention to adopt cloud computing services in both the USA and China, but consumer innovativeness is a better indicator in the USA than in China for consumers adopting technological innovations.

Practical implications

– This paper is important for cloud service technology marketers by indicating how social influencers can influence consumer's usage of cloud computing by affecting their social network of friends and family. In addition, insight into how consumers adopt cloud computing by focusing on privacy concerns of personal information being shared can help future technology innovations enter the marketplace at a faster rate.

Originality/value

– This paper fills the gap in the current technology marketing and innovation literature on how consumers adopt technological innovations and highlights the importance of increasing the perceptions of performance expectation of service innovations.
Evaluating the readability of marketing research textbooks: an international comparison
Authors: Berndt Adele , P. Wayland Jane
Published: April 2014

Purpose

– Locally authored textbooks are used at tertiary South African institutions to assist in marketing research studies. The purpose of this paper is to investigate the readability of locally authored marketing research textbooks in South Africa and compare them with international (USA) texts.

Design/methodology/approach

– South African marketing research textbooks (authored locally) used at South African institutions were identified. Electronic versions of the textbooks were used and analysed using accepted readability formulae. The same procedure was used with texts produced in the USA and the findings of each were compared.

Findings

– The South Africa texts scored higher on the Flesch Reading Ease score than US texts, which links to the target audience of these books (undergraduate students), while also being cognisant of the reading skills of the target audience but their score still describes them as “difficult”.

Research limitations/implications

– The original formulae and theory tend to be dated, though there are recent studies into readability in other areas of business studies. There are also those that question the applicability of readability formulae in the tertiary environment.

Practical implications

– Instructors need to ensure that material is at a suitable reading level to maximise the student's learning. For publishers and authors, this means that the examples and illustrations used need to be linked to the context in which the student lives and functions, and not just focus on the English used in the text.

Originality/value

– While studies have been conducted into the readability of US textbooks, there is little published research into the readability of regional marketing research textbooks in other contexts to facilitate comparison.
Students achieving intercultural competence through group work: realised or idealised?
Authors: Burdett Jane
Published: April 2014

Purpose

– The purpose of this study was to explore local and international business students' perceptions of their intercultural group work experience as a mechanism for developing intercultural competence and group work skills.

Design/methodology/approach

– Using qualitative interviews, the group work experiences of 11 final-year undergraduate local and international students in a business program in a large Australian university were analysed.

Findings

– The findings suggest that international and local students working together on group assignments create social and academic situations that result in “at best” limited positive intercultural learning and relationships. Differences in expectations, motivations, language fluency, trust and relationship issues were evident when students collaborated on group assignments. Thus, it appears that group assignments are potentially flawed mechanisms for delivering the goals of intercultural competence and group work skills in business students.

Practical implications

– Although this exploratory study is limited in scope, the research has implications for pedagogical strategies, in particular, the use and design of group assignments and the preparation of students for working on group tasks in intercultural groups. It also has implications for developing effective learning mechanisms that lead to improved student intercultural competence, greater socio-cultural engagement and the academic success of international and local business students, as well as positive learning experiences for all.

Originality/value

– The findings of this study are likely to be a useful resource for university staff considering the use of group work assignments for the development of intercultural understanding and competence and collaborative skills.
Candidates' integration of individual psychological assessment feedback
Authors: Boudrias Jean-Sébastien , Bernaud Jean-Luc , Plunier Patrick
Published: April 2014

Purpose

– The purpose of this paper is to empirically verify a theoretical model of candidates' feedback integration in the context of individual psychological assessment (IPA).

Design/methodology/approach

– Structural equation modeling analyses were conducted in a two-wave longitudinal study. A total of 97 candidates completed questionnaires immediately after their feedback session as well as three months later.

Findings

– Results indicate that candidates' motivational intention to act on IPA feedback is a pivotal variable linking feedback perceptions and post-feedback behaviors. Source credibility, assessment face validity, as well as perception that the feedback helped increase candidate's awareness were related to motivational intention. Conversely, feedback acceptance was not related to candidates' motivation to act on feedback and post-feedback behaviors.

Research limitations/implications

– Because the authors relied on self-report questionnaires, future studies would benefit from including externally assessed behavioral outcomes. Future research efforts should continue distinguishing candidates' acceptance and awareness based on their distinctive contributions in the feedback integration process.

Practical implications

– The results indicate that motivation created during the feedback session is a stronger predictor of day-to-day behavioral changes than it is of involvement in specific developmental activities.

Originality/value

– This research fills a gap in IPA literature by highlighting some IPA benefits and the processes involved in increasing feedback value for the participant.
The identity-based explanation of affective commitment
Authors: W. Lam Long , Liu Yan
Published: April 2014

Purpose

– Drawing on social identity and self-categorization theories and building on Meyer and Herscovitch's (2001) work on affective commitment, this study aimed to examine the relationship between organizational identification and affective commitment, and the relationships between these two variables and employees' attitude and behavior.

Design/methodology/approach

– Data were collected on-site from 158 automobile dealership employees in central China. Regression analysis and hierarchical linear modeling were used to analyze the survey data.

Findings

– Organizational identification was positively related to affective commitment. Affective commitment was negatively related to turnover intention and positively related to job performance. Affective commitment mediated the relationship between organizational identification and turnover intention, but did not mediate the relationship between organizational identification and job performance.

Research limitations/implications

– This study contributes to the literature by integrating organizational identification and affective commitment, the two distinct types of employees' organizational attachment. However, results should be cautioned with the limitations of the study.

Practical implications

– Managers can use employees' organizational identification to foster affective commitment since it leads to a variety of positive work attitudes and behavior.

Social implications

– Society as a whole may benefit by having more loyal and committed workforce in organisations.

Originality/value

– This study develops a model that aligns employee commitment and identification. Doing so answers the call for more efforts to integrate the two forms of organizational attachment in order to make more progress in this line of research.
Both biotic and abiotic factors influence floral longevity in three species of Epidendrum (Orchidaceae)
Authors: Vega Yesenia , Marques Isabel
Published: April 2014

Extended flower longevity has been widely defended to occur as a consequence of low pollination activity. To test this hypothesis in Neotropical rainforests, we selected three species of Epidendrum that flower during rainy conditions and commonly exhibit low levels of insect visits. Experimental studies carried out in 15 populations distributed along a wide spatial gradient detected the presence of pollinator limitation in all populations. Pollinia removal without pollen deposition increased longevity, and thus extended longevity could apparently be considered as an ecological advantage for these orchids. Nevertheless, flower longevity was severely shortened by abiotic factors like precipitation and humidity. Comparison with other tropical orchids showed that flower longevity was higher even in species that flower during periods of more pollinator activity than the ones studied here, which is contrary to the hypothesis that pollinators are the only driving force for long‐lived flowers in Epidendrum. Thus, although long floral longevities are apparently favorable for the reproductive success of these species, the high maintenance costs experienced during rainy conditions are also an important factor constraining the selection of long‐lived flowers in Epidendrum.
The Stalking of Lawyers: A Survey Amongst Professionals in Milan
Authors: Merzagora Betsos Isabella , Marchesi Matteo
Published: April 2014

This is the first study focused on the stalking of lawyers. The authors hypothesized that these professionals are at risk of being stalked by their clients and that this stalking is ascribable to RECON type I.B. A random sample of lawyers was survived. 37.3% of 166 respondents revealed to have been stalked: not only by clients, but also by adversaries and colleagues. Data seem to confirm that the stalking of lawyers mainly belongs to RECON type I.B. Female lawyers were at greater risk than male lawyers. In family law cases, the professionals tended to be stalked by the former husbands of the lawyers' clients (p < 0.01). Several female lawyers—but no male lawyers—were threatened with harm to their family members (p < 0.05). Most of the stalking victims described psychological effects of being stalked. Who suffered physical aggression or repercussions on work was more likely to lodge a complaint (p < 0.01).
Acute Benztropine Intoxication and Fatality
Authors: McIntyre Iain M. , Mallett Phyllis , Burton Christopher G. , Morhaime Jacquelyn
Published: April 2014

A woman was found unresponsive with an empty bottle of Cogentin® prescribed to another. Admitted to an area hospital, her condition steadily declined until death 29 h after admission. Following toxicological screening on hospital (admission) whole blood, the only significant compound detected was benztropine. Benztropine was confirmed at 0.28 mg/L – the highest antemortem blood concentration recorded in a case of toxicity or fatality uniquely associated with benztropine. A second serum antemortem specimen showed a benztropine concentration of 0.19 mg/L. Despite over 24 h in the hospital, benztropine was also found in the postmortem specimens collected at autopsy. Peripheral blood, central blood, liver, and gastric concentrations were 0.47 mg/L, 0.36 mg/L, 9.6 mg/kg, and 44 mg, respectively. These results indicate that benztropine exhibited a potential difference between whole‐blood and serum (plasma) concentrations. Additionally, in consideration of literature data, benztropine was found indicative of a compound prone to at least some postmortem redistribution.
Challenges in the sequencing of therapies for the management of metastatic castration‐resistant prostate cancer
Authors: Parente Phillip , Parnis Francis , Gurney Howard
Published: April 2014

Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration‐resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel‐T) and radium‐233 (for symptomatic bone metastases). With several other agents in the pipeline for late‐stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient‐focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.
The Roles of Economic Freedom and Regulatory Quality in Creating a Favorable Environment for Investment in EnergyR&D, Infrastructure, and Capacity
Authors: Cebula Richard J. , Mixon Franklin G.
Published: April 2014

Sustainable investment in energy requires a favorable economic and regulatory environment. A random effects model (PLSestimations), using a four‐year panel, reveals the growth rate in real per capitaGDPforOECDnations as an increasing function of both economic freedom and regulatory quality. These results underscore the critical roles that economic freedom and regulatory quality play, directly and indirectly, in creating an environment conducive to sustainable investment in energyR&Dand infrastructure.
Public Choice and the EPA, 20 Years Later: An Exploratory Study
Authors: Cebula Richard J. , Mixon Franklin G. , Upadhyaya Kamal P.
Published: April 2014

Nearly 20 years ago, Mixon (1995) found that urban warming is positively related to the probability of an EPA citation for a violation of carbon emissions standards, whereas lobbying effort reduces the probability of such a citation. This study revisits the Mixon (1995) framework by using data on ozone violations. The results indicate that EPA citations for ozone violations are not significantly related to lobbying effort.
Is the U.S. Supreme Court's Legitimacy Grounded in Performance Satisfaction and Ideology?
Authors: Gibson James L. , Nelson Michael J.
Published: April 2014

Bartels and Johnston have recently presented evidence suggesting that the legitimacy of the U.S. Supreme Court is grounded in the ideological preferences and perceptions of the American people. In addition, they offer experimental data purporting to show that dissatisfaction with a single Court decision substantially diminishes the institution's legitimacy. These findings strongly break with earlier research on the Court's institutional support, as the authors recognize. The theoretical implications of their findings are profound. If the authors are correct that legitimacy is strongly dependent upon satisfying the policy preferences and ideological predilections of the American people, the essence of legitimacy is fundamentally transformed. Consequently, we reinvestigate the relationships among ideology, performance satisfaction, and Court legitimacy, unearthing empirical findings that diverge markedly from theirs. We conclude with some thoughts about how the Court's “countermajoritarian dilemma” can be reconceptualized and recalculated, once more drawing conclusions sharply at odds with those of Bartels and Johnston.
EAACI Food Allergy and Anaphylaxis Guidelines. Primary prevention of food allergy
Authors: Muraro A. , Halken S. , Arshad S. H. , Beyer K. , Dubois A. E. J. , Du Toit G. , Eigenmann P. A. , Grimshaw K. E. C. , Hoest A. , Lack G. , O'Mahony L. , Papadopoulos N. G. , Panesar S. , Prescott S. , Roberts G. , de Silva D. , Venter C. , Verhasselt V. , Akdis A. C. , Sheikh A. ,   EAACI Food Allergy and Anaphylaxis Guidelines Group
Published: April 2014

Food allergy can have significant effects on morbidity and quality of life and can be costly in terms of medical visits and treatments. There is therefore considerable interest in generating efficient approaches that may reduce the risk of developing food allergy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Prevention and is part of the EAACI Guidelines for Food Allergy and Anaphylaxis. It aims to provide evidence‐based recommendations for primary prevention of food allergy. A wide range of antenatal, perinatal, neonatal, and childhood strategies were identified and their effectiveness assessed and synthesized in a systematic review.

Based on this evidence, families can be provided with evidence‐based advice about preventing food allergy, particularly for infants at high risk for development of allergic disease. The advice for all mothers includes a normal diet without restrictions during pregnancy and lactation. For all infants, exclusive breastfeeding is recommended for at least first 4–6 months of life. If breastfeeding is insufficient or not possible, infants at high‐risk can be recommended a hypoallergenic formula with a documented preventive effect for the first 4 months. There is no need to avoid introducing complementary foods beyond 4 months, and currently, the evidence does not justify recommendations about either withholding or encouraging exposure to potentially allergenic foods after 4 months once weaning has commenced, irrespective of atopic heredity. There is no evidence to support the use of prebiotics or probiotics for food allergy prevention.
Exhaled carbon dioxide can be used to guide respiratory support in the delivery room
Authors: van Os Sylvia , Cheung Po‐Yin , Pichler Gerhard , Aziz Khalid , O'Reilly Megan , Schmölzer Georg M.
Published: April 2014

Respiratory support in the delivery room remains challenging. Assessing chest rise is imprecise, and mask leak and airway obstruction are common problems. We describe recordings of respiratory signals during delivery room resuscitations and discuss guidance on positive‐pressure ventilation using respiratory parameters and exhaled carbon dioxide (ECO2) during neonatal resuscitations.

Conclusion

Observing tidal volume and ECO2 waveforms adds objectivity to clinical assessments. ECO2 could help assess lung aeration and improve lung recruitment immediately after birth.
ALK gene aberrations and the JUN/JUNB/PDGFR axis in metastatic NSCLC
Authors: Berghoff Anna Sophie , Birner Peter , Streubel Berthold , Kenner Lukas , Preusser Matthias
Published: April 2014

Anaplastic lymphoma kinase (ALK) gene aberrations are found in several tumor types including anaplastic large cell lymphoma (ALCL) and non‐small cell lung cancer (NSCLC). Crizotinib, an inhibitor of ALK‐fusion proteins, has shown clinical activity, but resistance mechanisms limit long‐lasting disease control. It has been shown that ALK‐NPM fusion upregulates platelet‐derived growth factor receptor beta (PDGFRB) via JUN and transcription factor Jun B (JUNB) in ALCL. PDGFRB inhibition has been identified as therapy option for ALK‐positive ALCL. Here, we investigated the ALK/JUN/JUNB/transcription factor Jun C (JUNC)/PDGFR axis in metastatic NSCLC with regard to ALK aberrations. We performed immunohistochemical analysis of platelet‐derived growth factor receptor alpha (PDGFRA), PDGFRB, JUNB and JUNC expression in formalin‐fixed, paraffin‐embedded specimens of 15 NSCLC brain metastases (5 ALK translocations, 3 of them involving EML4, 5 ALK amplifications, 5 without ALK aberrations). We did not find a statistically significant difference in expression of PDGFRA, PDGFRB, JUNB or JUNC in tumor samples with normal ALK status, ALK amplification or ALK translocations (Kruskal–Wallis test p > 0.05). Interestingly, PDGFRB was not expressed in tumor cells (but in vascular and stromal cells) in any of our cases. Our data argue against PDGFRB activation in association with ALK gene aberrations in metastatic NSCLC and thus seem to imply differential pathobiological roles of ALK alterations in lung cancer and lymphoma, possibly depending on different fusion partner genes. These results may be relevant for targeted therapies, as they indicate that inhibition of PDGFRB in ALK translocated NSCLC seems to be no therapeutic opportunity.
Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen
Authors: ter Heine Rob , Binkhorst Lisette , de Graan Anne Joy M. , de Bruijn Peter , Beijnen Jos H. , Mathijssen Ron H. J. , Huitema Alwin D. R.
Published: April 2014

Aims

Tamoxifen is considered a pro‐drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen.

Methods

We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non‐linear mixed effects modelling.

Results

Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter‐individual variability reduced from 55% to 25%).

Conclusions

We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti‐oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach
Authors: Wunnapuk Klintean , Mohammed Fahim , Gawarammana Indika , Liu Xin , Verbeeck Roger K. , Buckley Nicholas A. , Roberts Michael S. , Musuamba Flora T.
Published: April 2014

Aims

Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self‐poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat‐intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population.

Methods

A non‐linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients.

Results

The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half‐life were 1.17 l h−1, 2.4 l kg−1 and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l−1 caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function.

Conclusion

The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development.
ECONOMIES OF SCALE AND SCOPE: THE CASE OF SPECIALTY HOSPITALS
Authors: Carey Kathleen , Burgess James F. , Young Gary J.
Published: April 2014

The recent growth of physician‐owned hospitals specializing in orthopedic and surgical specialty services in the United States has generated considerable controversy, yet there is little understanding of the economic logic of organizing hospital services around these single specialties. This article takes a multiple output hospital cost function approach to an empirical investigation of whether single specialty hospitals (SSHs) exhibit economies of scale and economies of scope as keys to new insights into that logic. We applied generalized estimating equation techniques to a sample of 80SSHsand 883 general hospital competitors over the 1998–2008 period. Results indicated large underlying scale differences across the organizational types. Simulation analysis revealed the potential for exploitation of economies of scope gained from shifting output fromSSHsto general hospitals. (JELI18, L23)
Relative Contributions of the Logging, Fiber, Oil Palm, and Mining Industries to Forest Loss in Indonesia
Authors: Abood Sinan A. , Lee Janice Ser Huay , Burivalova Zuzana , Garcia‐Ulloa John , Koh Lian Pin
Published: April 2014

Indonesia contributes significantly to deforestation in Southeast Asia. However, much uncertainty remains over the relative contributions of various forest‐exploiting sectors to forest losses in the country. Here, we compare the magnitudes of forest and carbon loss, and forest and carbon stocks remaining within oil palm plantation, logging, fiber plantation (pulp and paper), and coal mining concessions in Indonesia. Forest loss in all industrial concessions, including logging concessions, relate to the conversion of forest to nonforest land cover. We found that the four industries accounted for ∼44.7% (∼6.6 Mha) of forest loss in Kalimantan, Sumatra, Papua, Sulawesi, and Moluccas between 2000 and 2010. Fiber plantation and logging concessions accounted for the largest forest loss (∼1.9 Mha and ∼1.8 Mha, respectively). Although the oil palm industry is often highlighted as a major driver of deforestation, it was ranked third in terms of deforestation (∼1 Mha), and second in terms of carbon dioxide emissions (∼1,300–2,350 Mt CO2). Crucially, ∼34.6% (∼26.8 Mha) of Indonesia's remaining forests is located within industrial concessions, the majority of which is found within logging concessions (∼18.8 Mha). Hence, future development plans within Indonesia's industrial sectors weigh heavily on the fate of Southeast Asia's remaining forests and carbon stocks.
A highly selective ratiometric fluorescent sensor for Hg2+ based on 1,8‐naphthalimide
Authors: Li Xiangzhi , Zheng Chunling , Yuan Ailing , Yang Lu , Wang Han , Wang Haibo
Published: April 2014

A sulfur probe based on 1,8‐naphthalimide was designed and synthesised, and its sensing behaviour towards a mercury ion was investigated by fluorescence spectroscopy. The probe showed higher selective recognition towards Hg2+ than towards other metal ions in methanol solution. Compared with 4‐amino‐substituted naphthalimide derivatives, the probe exhibited different fluorescent characteristics for sensing Hg2+. The novel, reaction‐based probe is recommended for selective recognition of Hg2+ with significant fluorescence change.
Motor impairment in very preterm infants: implications for clinical practice and research
Authors: Zwicker Jill G
Published: April 2014

This commentary is on the original article by Van Hus et al. on pages 587–594 of this issue.
BILATERAL OLIGOPOLY IN POLLUTION PERMIT MARKETS: EXPERIMENTAL EVIDENCE
Authors: SCHNIER KURT , DOYLE MARTIN , RIGBY JAMES R. , YATES ANDREW J.
Published: April 2014

We experimentally investigate behavior in a bilateral oligopoly using a supply function equilibria model discussed by Klemperer and Meyer (1989), Hendricks and McAfee (2010), and Malueg and Yates (2009). We focus on the role that market size and the degree of firm heterogeneity have on the market equilibrium. Our results indicate that subjects within the experiment recognize the strategic incentives in a bilateral oligopoly, but they do not exploit these incentives to the exact magnitude predicted by theory. We find weaker support for predicted market outcomes, as market efficiency does not depend on market size, and in some cases buyers or sellers are more successful at extracting the rents from the market. (JEL L13, Q5, C9)
Visual system integrity and cognition in early Huntington's disease
Authors: Wolf Robert C. , Sambataro Fabio , Vasic Nenad , Baldas Eva‐Maria , Ratheiser Iris , Bernhard Landwehrmeyer Georg , Depping Malte S. , Thomann Philipp A. , Sprengelmeyer Reiner , Süssmuth Sigurd D. , Orth Michael
Published: April 2014

Posterior cortical volume changes and abnormal visuomotor performance are present in patients with Huntington's disease (HD). However, it is unclear whether posterior cortical volume loss contributes to abnormal neural activity, and whether activity changes predict cognitive dysfunction. Using magnetic resonance imaging (MRI), we investigated brain structure and visual network activity at rest in patients with early HD (n = 20) and healthy controls (n = 20). The symbol digit modalities test (SDMT) and subtests of the Visual Object and Space Perception Battery were completed offline. For functional MRI data, a group independent component analysis was used. Voxel‐based morphometry was employed to assess regional brain atrophy, and ‘biological parametric mapping’ analyses were included to investigate the impact of atrophy on neural activity. Patients showed significantly worse visuomotor and visual object performance than controls. Structural analyses confirmed occipitotemporal atrophy. In patients and controls, two spatiotemporally distinct visual systems were identified. Patients showed decreased activity in the left fusiform cortex, and increased left cerebellar activity. These findings remained stable after correction for brain atrophy. Lower fusiform cortex activity was associated with lower SDMT performance and with higher disease burden scores. These associations were absent when cerebellar function was related to task performance and disease burden. The results of this study suggest that regionally specific functional abnormalities of the visual system can account for the worse visuomotor cognition in HD patients. However, occipital volume changes cannot sufficiently explain abnormal neural function in these patients.
Neural correlates of endogenous attention, exogenous attention and inhibition of return in touch
Authors: Jones Alexander , Forster Bettina
Published: April 2014

Selective attention helps process the myriad of information constantly touching our body. Both endogenous and exogenous mechanisms are relied upon to effectively process this information; however, it is unclear how they relate in the sense of touch. In three tasks we contrasted endogenous and exogenous event‐related potential (ERP) and behavioural effects. Unilateral tactile cues were followed by a tactile target at the same or opposite hand. Clear behavioural effects showed facilitation of expected targets both when the cue predicted targets at the same (endogenous predictive task) and opposite hand (endogenous counter‐predictive task), and these effects also correlated with ERP effects of endogenous attention. In an exogenous task, where the cue was non‐informative, inhibition of return (IOR) was observed. The electrophysiological results demonstrated early effects of exogenous attention followed by later endogenous attention modulations. These effects were independent in both the endogenous predictive and exogenous tasks. However, voluntarily directing attention away from a cued body part influenced the early exogenous marker (N80). This suggests that the two mechanisms are interdependent, at least when the task requires more demanding shifts of attention. The early marker of exogenous tactile attention, the N80, was not directly related to IOR, which may suggest that exogenous attention and IOR are not necessarily two sides of the same coin. This study adds valuable new insight into how we process and select information presented to our body, showing both independent and interdependent effects of endogenous and exogenous attention in touch.
Reaching and Acquiring Valuable Resources: The Entrepreneur's Use of Brokerage, Cohesion, and Embeddedness
Authors: Ozdemir Salih Zeki , Moran Peter , Zhong Xing , Bliemel Martin J.
Published: April 2014

Entrepreneurs have two key aims in managing their ego–networks: extending reach to valuable resources and facilitating resource acquisition. This study provides a synthesis of the brokerage, cohesion, and embeddedness literatures to develop and present a multilevel theoretical framework and analytical model that treat both aims jointly. It makes three contributions. First, it highlights a trade–off that entrepreneurs face in allocating their available networking time and energy while pursuing these two aims. Second, it explores the central role of two types of embeddedness—relational and structural—in resolving this trade–off. Third, it helps entrepreneurs decide when to embed a particular dyadic connection relationally or structurally. We show that entrepreneurs can better balance their dual aim by structurally embedding some ties rather than trying to relationally embed all. The resultant network is one that meshes characteristics of brokerage and cohesive ego–network structures.
International Analysis of Venture Capital Programs of Large Corporations and Financial Institutions
Authors: Da Gbadji Luc Armel G. , Gailly Benoit , Schwienbacher Armin
Published: April 2014

In this article, we investigate what drives large companies (nonfinancial corporations and financial institutions) worldwide to run venture capital (VC) programs, specifically targeting Fortune Global 500 companies. Such a decision involves trade–offs between expected strategic and financial benefits and costs of managing and financing a portfolio of ventures, which are influenced by the institutions and regulations that affect innovation–oriented entrepreneurship. We determine that companies are more likely to run a program if they are based in countries in which the market for early–stage investments is well developed and innovation–related resources are more widely available. Moreover, companies based in countries with costly personal bankruptcy regulations are less likely to run a VC program, which is consistent with the prediction that these regulations discourage entrepreneurial initiatives. These findings emphasize the importance of favorable local conditions for an affiliated VC program. We observe no evidence, however, that unfavorable local conditions affect the degree of internationalization of programs, suggesting that running international programs entails significant extra costs. Finally, no significant difference emerges between U.S.–based and Western European–based companies.
Bleomycin‐induced fibrosis in MC1 signalling‐deficient C57BL/6J‐Mc1re/e mice further supports a modulating role for melanocortins in collagen synthesis of the skin
Authors: Böhm Markus , Stegemann Agatha
Published: April 2014

The melanocortin‐1 receptor (MC1) binds α‐melanocyte‐stimulating hormone (α‐MSH) with high affinity and has a physiological role in cutaneous melanin pigmentation. Previously, we reported that human dermal fibroblasts also express functional MC1. α‐MSH suppressed transforming growth factor‐β1‐ and bleomycin (BLM)‐induced collagen synthesis in vitro and in vivo. Using MC1 signalling‐deficient C57BL/6J‐Mc1re/e mice, we tested as to whether MC1 has a regulatory role on dermal collagen synthesis in the BLM model of scleroderma. Notably, mice with a C57BL/6J genetic background were previously shown to be BLM‐non‐susceptible. Interestingly, treatment of C57BL/6J‐Mc1re/e but not of C57BL/6J‐wild‐type mice with BLM increased cutaneous collagen type I content at RNA and protein level along with development of skin fibrosis. Cutaneous levels of connective tissue growth factor and monocyte chemotactic protein‐1 were also increased in BLM‐treated C57BL/6J‐Mc1re/e mice. Primary dermal fibroblasts from C57BL/6J‐wt mice further expressed MC1, suggesting that these cells are directly targeted by melanocortins to affect collagen production of the skin. Our findings support the concept that MC1 has an endogenous regulatory function in collagen synthesis and controls the extent of fibrotic stress responses of the skin.