bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of High-Titer RCAS Virus from DF1 Chicken Fibroblasts
Authors: Ahronian Leanne G. , Lewis Brian C.
Published: November 2014

RCAS viruses are replication-competent in avian cells, but are replication-deficient in mammalian cells. Therefore, high-titer RCAS virus stocks can be generated only in avian cells. The chicken fibroblast cell line DF1 is well suited for this purpose. Successful infection of target mammalian cells, particularly in vivo, is dependent on the production of high titer viruses by DF1 cells. Moreover, consistency in viral titer helps to ensure uniformity in results produced following the use of independent lots of virus producer cells. Therefore, it is critical to determine the viral titer before initiating these experiments. Because several factors, including insert size and the effect of the inserted gene product on the viability of DF1 cells, influence viral titer, the production of high virus titers cannot be assumed. For RCASBP-A-based viruses, a titer of >1 × 107 IU/mL is considered appropriate. Importantly, the virus reverse transcriptase is error prone; errors will accumulate in the virus produced over time. Therefore, virus producer cells should not be cultured for >4–6 wk before being replaced with fresh producer cells. Low passage virus producer cells may be frozen and stored at −80°C; thawed cells will not display a reduction in virus titer. Virus can be collected regularly, concentrated, and stored at −80°C for long-term use; thawed viral stocks typically show a 10-fold decrease in titer.
Isolating HeLa Cell Fractions Enriched for Clathrin-Coated Vesicles
Authors: Borner Georg H.H. , Fielding Andrew B.
Published: November 2014

HeLa cell lines can be experimentally manipulated using drugs or gene-silencing techniques such as RNA interference. Fractions enriched for clathrin-coated vesicles (CCVs) can be isolated from these cell lines and used to study the effects of these manipulations on the composition of CCVs. This protocol, originally developed in the laboratory of Margaret Robinson (Cambridge, United Kingdom), describes the preparation of a HeLa cell fraction that is enriched for a mixed population of CCVs and is suitable for analysis by mass spectroscopy, western blotting, or electron microscopy.
Methods for Processing High-Throughput RNA Sequencing Data
Authors: Ares Manuel
Published: November 2014

High-throughput sequencing (HTS) methods for analyzing RNA populations (RNA-Seq) are gaining rapid application to many experimental situations. The steps in an RNA-Seq experiment require thought and planning, especially because the expense in time and materials is currently higher and the protocols are far less routine than those used for other high-throughput methods, such as microarrays. As always, good experimental design will make analysis and interpretation easier. Having a clear biological question, an idea about the best way to do the experiment, and an understanding of the number of replicates needed will make the entire process more satisfying. Whether the goal is capturing transcriptome complexity from a tissue or identifying small fragments of RNA cross-linked to a protein of interest, conversion of the RNA to cDNA followed by direct sequencing using the latest methods is a developing practice, with new technical modifications and applications appearing every day. Even more rapid are the development and improvement of methods for analysis of the very large amounts of data that arrive at the end of an RNA-Seq experiment, making considerations regarding reproducibility, validation, visualization, and interpretation increasingly important. This introduction is designed to review and emphasize a pathway of analysis from experimental design through data presentation that is likely to be successful, with the recognition that better methods are right around the corner.
DevelopingWinXPRO: a software for determination of the multipole-model-based properties of crystals
Authors: Stash Adam I. , Tsirelson Vladimir G.
Published: November 2014

The new release of the computer program packageWinXPRO v.3xfor determination of the crystal properties from parameters of the multipole-modeled experimental electron density and anharmonic atomic displacement coefficients is described. The set of properties is significantly extended by using the density functional and information theories. In addition, a built-in multi-functional viewer and programs to display the output data, including the mapping of the chosen functional bonding descriptors onto surfaces of the other properties, are included.
FTA break new ground in response to grand challenges
Authors: Carabias Vicente , De Smedt Peter , Teichler Thomas
Published: November 2014

Purpose

This Guest Editorial aims to demonstrate the diversity of application fields in which FTA methods are being used and to offer a glimpse into possible consequences that grand challenges may imply for the development of FTA.

Design/methodology/approach

This introductory paper provides an overview of selected FTA 2011 Conference contributions for this Special Issue.

Findings

FTA approaches create spaces where an effective dialogue between key players in different policy domains facilitates vision‐building and consensus‐building for engineering major processes of transformation. Therefore, sound approaches of futures thinking will help to better address the grand challenges.

Research limitations/implications

From a large set of excellent papers presented at the FTA 2011 Conference, only a restricted number of papers could be included in this Special Issue highlighting the broad diversity of FTA application fields in response to grand challenges.

Practical implications

FTA can contribute not only to the steering of diverse innovation systems, but also to their adjustment, adaptability and ability to shape responses to grand challenges.

Social implications

The papers of this Special Issue point to the need for FTA to take into account user perspectives and to shape the social context.

Originality/value

This Special Issue brings together papers that explore not only the opportunities and limitations of implementing FTA methods in a variety of policy domains, but also their benefits in enabling a better understanding of complex systems that interact in each situation and in defining effective policy responses.
A GIS-microscopic simulation approach for optimizing road barrier placement and configuration in university campus emergency evacuation
Authors: Cai Hubo , Rahman Asadur , Su Xing , Zhang Hongtao
Published: November 2014

Purpose

– The purpose of this study is to create a framework that integrates GIS and microscopic simulation to optimize the placement of road barriers in emergency evacuation and assess the effectiveness via simulation. Human populations are at risk from many hazards including man-made and natural disasters, sudden events that are difficult to predict and prevent, but have catastrophic consequences. A critical issue in disaster management is timely evacuation that considers the dynamic traffic demand and congestions under dynamic hazard conditions. University campuses face a unique challenge in developing effective emergency evacuation plans due to their complex site configurations, high-dense buildings and dynamic spatial-temporal distribution of population.

Design/methodology/approach

– The framework was implemented and tested on the main campus of the Western Michigan University to optimize the placement and configuration of road barriers to achieve an effective utilization of road network when the demand way exceeds the capacity. The resulting system was also used to test the effectiveness of the phased evacuation notification strategy, both with and without the optimal road barrier strategy.

Findings

– It concluded that the newly created framework and its implementation could assist emergency evacuation planning for university campuses. It also concluded that placing road barriers at appropriate locations could reduce the evacuation time by 20 per cent or more under a variety of evacuation scenarios.

Originality/value

– The originality of this research lies in three aspects of: a university campus context, the integration of GIS and microscopic simulation in emergency evacuation and the simulation based turn restriction strategy.
Internationalisation of service firms through corporate social entrepreneurship and networking
Authors: Ghauri Pervez , Tasavori Misagh , Zaefarian Reza
Published: November 2014

Purpose

– The purpose of this paper is to explore how employing corporate social entrepreneurship and developing a network of relationships with non-governmental organisations (NGOs) can support and contribute towards the internationalisation of service firms into the base of the pyramid (BOP) markets in emerging markets.

Design/methodology/approach

– This research adopts an exploratory approach employing qualitative multiple case studies. Three service firms that have targeted the BOP markets in India were studied. In total, 25 in-depth interviews were conducted with multinational corporations (MNCs) and their NGO partners. Data analysis was facilitated through pattern matching and systematic case comparison.

Findings

– The findings reveal that, by engaging in social entrepreneurship, these MNCs have focused on the neglected needs of the BOP population, developed sustainable solutions and empowerment, and started with social value creation and postponed value capturing. The pursuit of corporate social entrepreneurship has paved the way for them to establish relationships with NGOs. While the MNCs have mainly had the technical knowledge and financial resources required, collaboration with NGOs have allowed them to learn about the BOP’s specific needs and benefit from the NGOs’ knowledge, human resources and good relationships in this market.

Originality/value

– This research unravels how service firms can seize opportunities at the BOP. The authors build on social entrepreneurship theory and bring new insights to the field of international business. In addition, the authors broaden the network view and show how networking with social actors such as NGOs enables the mobilisation of resources, actors and activities in emerging markets.
AACSB International’s 2013 accreditation standards
Authors: P. Miles Morgan , McClure Franklin Geralyn , Heriot Kirk , Hadley Linda , Hazeldine Mary
Published: November 2014

Purpose

– The purpose of this paper is to consider the implications of the 2013 Association to Advance Collegiate Schools of Business (AACSB) Accreditation Standards for both business faculty and their deans who are responsible for implementing these changes.

Design/methodology/approach

– This paper is a speculative viewpoint on the implications of the 2013 AACSB standards by a set of a co-authors that include AACSB deans who are active in accreditation reviews and serve as mentors to schools in the accreditation process and senior faculty who have written self-studies for AACSB and served as consultants for schools seeking AACSB accreditation internationally.

Findings

– The implications of the 2013 AACSB business accreditation standards are arguably positive for active scholars holding a relevant doctoral degree. For example, active and engaged scholarly faculty should appreciate the ability to use additional indicators of the impact of their career’s intellectual contributions (IC) including, but not limited to, citations, editor ships, professional leadership positions and other measures of professional esteem.

Research limitations/implications

– The implications of the 2013 AACSB accreditation standards for deans are potentially less positive. The new standards codify one of the deans’ major duties – that of ensuring that the faculty have resources adequate to support the school’s mission.

Originality/value

– This paper represents a starting point for understanding the implications of the 2013 AACSB accreditation standards, and that as the standards are operationalized over the subsequent years that these standards, like the previous changes in AACSB standards, will stimulate additional research on business school accreditation. The implications for both faculty and deans are speculative, but are grounded both by the literature and experience of the authors. The paper uses a set of tables to illustrate the impact of the new AACSB standards with examples for each guiding principle and standard.
Health LEADS Australia and implications for medical leadership
Authors: Sebastian Andi , Fulop Liz , Dadich Ann , Fitzgerald Anneke , Kippist Louise , Smyth Anne
Published: November 2014

Purpose

– The purpose of this paper is to call for strong medical co-leadership in transforming the Australian health system. The paper discusses how Health LEADS Australia, the Australian health leadership framework, offers an opportunity to engage medical clinicians and doctors in the leadership of health services.

Design/methodology/approach

– The paper first discusses the nature of medical leadership and its associated challenges. The paper argues that medical leaders have a key role in the design, implementation and evaluation of healthcare reforms, and in translating these reforms for their colleagues. Second, this paper describes the origins and nature of Health LEADS Australia. Third, this paper discusses the importance of the goal of Health LEADS Australia and suggests the evidence-base underpinning the five foci in shaping medical leadership education and professional development. This paper concludes with suggestions on how Health LEADS Australia might be evaluated.

Findings

– For the well-being of the Australian health system, doctors need to play an important role in the kind of leadership that makes measurable differences in the retention of clinical professions; improves organisational cultures; enhances the engagement of consumers and their careers; is associated with better patient and public health outcomes; effectively addresses health inequalities; balances cost effectiveness with improved quality and safety; and is sustainable.

Originality/value

– This is the first article addressing Health LEADS Australia and medical leadership. Australia is actively engaging in a national approach to health leadership. Discussions about the mechanisms and intentions of this are valuable in both national and global health leadership discourses.
Embedding physician leadership development within health organizations
Authors: Snell Anita Joanne , Eagle Chris , Van Aerde John Emile
Published: November 2014

Purpose

– The purpose of this conceptual paper is to provide strategies on how to embed physician leadership development efforts within health organizations.

Design/methodology/approach

– Findings from our previous research, which include an extensive literature review and analysis of 53 interviews with representatives from healthcare organizations across the globe, are integrated within the context of the Influencer© framework to provide a useful and grounded tool for physician leadership development strategies.

Findings

– Physician leadership development strategies are identified for each of the six domains within the Influencer© framework.

Practical implications

– A number of physician leadership development strategies are provided. They can be used in combination or used independently.

Originality/value

– Integrating the knowledge gained from practices in health organizations and from the literature within the Influencer© framework is a unique approach and strengthens the usefulness of the identified physician leadership development strategies.
Numerical estimation of carbonate rock properties using multiscale images
Authors: Jouini Mohamed Soufiane , Vega Sandra , Al‐Ratrout Ahmed
Published: November 2014

Characterizing the pore space of rock samples using three‐dimensional (3D) X‐ray computed tomography images is a crucial step in digital rock physics. Indeed, the quality of the pore network extracted has a high impact on the prediction of rock properties such as porosity, permeability and elastic moduli. In carbonate rocks, it is usually very difficult to find a single image resolution which fully captures the sample pore network because of the heterogeneities existing at different scales. Hence, to overcome this limitation a multiscale analysis of the pore space may be needed. In this paper, we present a method to estimate porosity and elastic properties of clean carbonate (without clay content) samples from 3D X‐ray microtomography images at multiple resolutions. We perform a three‐phase segmentation to separate grains, pores and unresolved porous phase using 19 μm resolution images of each core plug. Then, we use images with higher resolution (between 0.3 and 2 μm) of microplugs extracted from the core plug samples. These subsets of images are assumed to be representative of the unresolved phase. We estimate the porosity and elastic properties of each sample by extrapolating the microplug properties to the whole unresolved phase. In addition, we compute the absolute permeability using the lattice Boltzmann method on the microplug images due to the low resolution of the core plug images.

In order to validate the results of the numerical simulations, we compare our results with available laboratory measurements at the core plug scale. Porosity average simulations for the eight samples agree within 13%. Permeability numerical predictions provide realistic values in the range of experimental data but with a higher relative error. Finally, elastic moduli show the highest disagreements, with simulation error values exceeding 150% for three samples.
From Regulation to Behaviour Change: Giving Nudge the Third Degree
Authors: Baldwin Robert
Published: November 2014

Behaviour change strategies such as ‘nudge’ have become hugely popular with administrations on both sides of the Atlantic. The practice of nudging, however, raises conceptual and controversial issues which must be addressed in examining the conditions under which nudging can be used effectively and acceptably. A key to a clear conceptual understanding of nudge‐related issues is to distinguish between three degrees of nudge. These three degrees raise different, and identifiable, concerns and it is possible to assess the extent to which these can be responded to in positive terms. The compatibility of nudging with other control devices cannot be assumed and, when contemplating nudging, it is essential to be transparent about its philosophical basis, as well as to be aware that different modes of intervention may operate with clashes of logic that threaten not only effectiveness but also the serving of representative and ethical ends.
The Localism Act 2011: The Hollow Housing Law Revolution
Authors: Bevan Chris
Published: November 2014

In November 2011, the Localism Act was passed and, on one view, reflects the widest‐ranging reforms to housing law for over a half century. Ambitious in its stated aims, the legislation was trailed as representing a broad shift in power from central Whitehall to local communities and individuals. The article critically examines the central changes introduced by the 2011 Act as they pertain specifically to housing law in England, namely the new flexible tenancy regime, the changes to homelessness duties under Part VII of the Housing Act 1996 and the reforms concerning the allocation of social housing. The article interrogates the extent to which the reforms realise the stated localist agenda and highlights areas of difficulty in interpretation and application. It concludes that rather than bestowing greater power on local communities, the reforms to housing law will instead effect a perceptible reduction of power in the hands of local people.
Unjust Enrichment and Contract
Authors: Jaffey Peter
Published: November 2014

Benedetti v Sawiris was concerned with the measure of a quantum meruit, and in particular whether a ‘subjective’ or ‘objective’ measure should be preferred. The Supreme Court addressed the issue broadly in line with the approach in the mainstream academic literature on unjust enrichment, according to which this is a problem of how to measure benefit. The article argues that this unjust enrichment approach is misguided because it obscures the role of agreement and conflates transfer and exchange, and that a contractual analysis of the case would make the issues clearer and easier to resolve.
What does it mean to suffer loss? Haxton v Philips Electronics
Authors: Burin Achas K.
Published: November 2014

In Haxton v Philips Electronics the Court of Appeal considered whether a widow could recover the diminution in value of her dependency claim following the defendant's tortious reduction of her life expectancy. The note outlines the development of the common law, demonstrating that Haxton is novel but not unorthodox, and tests whether Haxton's principles can provide a sound foundation for future cases. Positing three hypothetical scenarios, it argues that the disparity in outcome, rather than indicating a lack of unifying principle, as was suggested in Jobling v Associated Dairies, may be explained by combining Austin's division between primary and secondary rights with Gardner and Stevens' contributions as to how they are protected. Restitutio in integrum requires consideration of the reasons and values underlying the right in question and these are discernible in the jurisprudence. The note also considers whether Haxton could have been decided on the basis that a defendant should not profit from its own wrongdoing.
The effect of inulin as a fat replacer on the quality of low‐fat ice cream
Authors: Tiwari Anurag , Sharma Harish Kumar , Kumar Navneet , Kaur Mandeep
Published: November 2014

The influence of different levels of inulin as fat replacer on the quality of ice cream was investigated. Inulin was added at 2, 4 and 6% to replace milk fat and the experimental ice creams were compared to a control with 10% milk fat. The chemical composition, overrun, water activity, viscosity, melting rate, hardness and colour value were determined. Sensory properties of the ice cream samples were evaluated during storage. The overall acceptability of ice creams prepared with 2 and 4% substitution were similar to the control.
Albumin Leakage in Online Hemodiafiltration, More Convective Transport, More Losses?
Authors: Vega Almudena , Quiroga Borja , Abad Soraya , Aragoncillo Inés , Arroyo David , Panizo Nayara , López‐Gómez Juan M.
Published: November 2014

Online hemodiafiltration (OL‐HDF) has now demonstrated some benefits in reducing mortality. It seems that rising convective volumes improve the outcomes, but the risks of it, such as albumin leakage, are not well defined yet. The aim of the present study was to evaluate the albumin leakage using two different filters with 20 and 30 L of post‐dilution OL‐HDF. In this cross‐sectional study, 20 prevalent patients receiving post‐dilution OL‐HDL were included. We analyzed two dialyzers: FX1000, FMC and Polyflux 210H, Gambro. During four consecutive dialysis sessions, monitors were programmed using control‐volume to obtain 20 or 30 L with both dialyzers. We collected albumin samples of the effluent at 5, 15, 30, 45 and 60 min and performed area under the curve (AUC) determinations for evaluating the losses. Mean patient age was 60 ± 9 years, and 70% were men. Albumin leakage was significant higher with Polyflux 210H when compared to FX 1000 FMC. A convective volume of 30 L produced greater albumin leakage than 20 L with both filters, though only with the FX 1000 FMC was it significant (minimum albumin leakage during first hour with FX 1000 FMC 20 L: 79.2 [0.0–175.7] mg; 30 liters: 403.3 [63.5–960.7] mg; with PF 210 Gambro 20 L: 869.1 [420.0–3214.7] mg; 30 L: 1841.7 [443.8–3417.5] mg). During OL‐HDF, convective transport causes albumin leakage at least during the first hour. The albumin concentration in the effluent differs according to the type of filter used and the convective volume.
Effect of nutrient application and water turbidity on submergence tolerance of rice (Oryza sativa)
Authors: Gautam P. , Lal B. , Raja R. , Baig M.J. , Mohanty S. , Tripathi R. , Shahid M. , Bhattacharyya P. , Nayak A.K.
Published: November 2014

Flooding imposes severe selection pressure on plants, principally because excess water in their surroundings deprives the plants from certain basic resources such as oxygen, carbon dioxide and light for photosynthesis. Here, the effects of nitrogen and phosphorus application and their application time, on four Indica rice cultivars and their tolerance to submergence under turbid and clear flood water was studied. Submergence tolerance on metabolic changes, photosynthetic (Pn) rate and ethylene accumulation were evaluated. Submergence substantially reduced survival, chlorophyll, soluble sugars, Pn rate across cultivars with drastic reduction in IR‐20. Sub1 cultivars showed greater Pn rate as compared to sensitive cultivar under submergence because of better protection of chlorophyll, more stomatal conductance leading to higher survival. Turbid water resulted in lower under‐water photosynthesis because of poor light transmission, chlorophyll retention and silt deposition and ultimately poor survival. Foliar spray of N after desubmergence along with basal P improved the chlorophyll, soluble sugars and Pn rate and extenuated ethylene accumulation and shoot elongation resulting in significantly higher survival. To the best of our knowledge, this is the first time that such a study has been performed. Crop establishment could therefore be enhanced in areas where untimely flooding is anticipated by applying basal P and foliar spray of post‐submergence N.
Scandinavian clinical practice guideline on choice of fluid in resuscitation of critically ill patients with acute circulatory failure
Authors: PERNER A. , JUNTTILA E. , HANEY M. , HREINSSON K. , KVÅLE R. , VANDVIK P. O. , MØLLER M. H.
Published: November 2014

Background

The task force on Acute Circulatory Failure of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine produced this guideline with recommendations concerning the use of crystalloid vs. colloid solutions in adult critically ill patients with acute circulatory failure.

Methods

Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to grade the quality of evidence and to determine the strengths of the recommendations. As efficacy and harm may vary in different subpopulations of patients with acute circulatory failure, we produced recommendations for general intensive care unit (ICU) patients and those with sepsis, trauma and burn injury.

Results

For general ICU patients and those with sepsis, we recommend using crystalloids for resuscitation rather than hydroxyethyl starch and we suggest using crystalloids rather than gelatin and albumin. For patients with trauma we recommend to use crystalloids for resuscitation rather than colloid solutions. For patients with burn injury we provide no recommendations as there are very limited data from randomised trials on fluid resuscitation in this patient population.

Conclusions

We recommend using crystalloid solutions rather than colloid solutions for resuscitation in the majority of critically ill patients with acute circulatory failure.
Localization of sunitinib, its metabolites and its target receptors in tumour‐bearing mice: a MALDI‐MS imaging study
Authors: Torok S , Vegvari A , Rezeli M , Fehniger T E , Tovari J , Paku S , Laszlo V , Hegedus B , Rozsas A , Dome B , Marko‐Varga G
Published: November 2014

Background and Purpose

The clinical effects of anti‐angiogenic agents remain controversial. Therefore, elucidating the pharmacological properties of these compounds is a pivotal issue.

Experimental Approach

The effects of treatment with sunitinib on tumour and normal tissues of mice bearing C‐26 adenocarcinoma cells were analysed by matrix‐assisted laser desorption ionization MS imaging (MALDI‐MSI). Expression of the key targets of sunitinib – angiogenic receptors – was studied by immunofluorescent labelling.

Key Results

MALDI‐MS assays showed that sunitinib and its fragment ions were present throughout tumour and normal tissues. Major metabolites were identified in blood and solid tissues, while minor drug metabolites were detectable only in blood. Tumour growth and intratumour VEGF receptor‐2 expressions were significantly reduced in sunitinib‐treated mice, while the expression of the other targeted receptors, PDGF receptor ‐α or ‐β and fibroblast growth factor receptor‐1, remained unaffected. Within tumour tissue, the close proximity of sunitinib metabolites to the precursor ion suggested in situ metabolism of the administered drug. There were intratumour areas where the signal intensity of sunitinib correlated with expression of VEGF receptor‐2.

Conclusions and Implications

This is the first study that demonstrates MALDI‐MSI is a versatile platform to study the intratumour localization of an unlabelled anti‐angiogenic drug. The combination of MALDI‐MSI and immunofluorescence analysis can provide further insights into the molecular interaction of drug compounds and their targets within tumour tissue.
Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice
Authors: Cheng Wen‐Lin , Wang Pi‐Xiao , Wang Tao , Zhang Yan , Du Cheng , Li Hongliang , Ji Yong
Published: November 2014

Background and Purpose

Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.

Experimental Approach

RGS5−/− apolipoprotein E (ApoE)−/− and ApoE−/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.

Key Results

Atherosclerotic phenotypes were significantly accelerated in RGS5−/−ApoE−/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.

Conclusions and Implications

RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
FM19G11 reverses endothelial dysfunction in rat and human arteries through stimulation of the PI3K/Akt/eNOS pathway, independently of mTOR/HIF‐1α activation
Authors: El Assar M , Sánchez‐Puelles J M , Royo I , López‐Hernández E , Sánchez‐Ferrer A , Aceña J L , Rodríguez‐Mañas L , Angulo J
Published: November 2014

Background and Purpose

FM19G11 up‐regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor‐1α (HIF‐1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved.

Experimental Approach

Effects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin‐resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated‐endothelial NOS (p‐eNOS), phosphorylated‐Akt (p‐Akt) and HIF‐1α was determined by immunodetection and cGMP by elisa.

Key Results

Chronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium‐dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p‐eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p‐Akt and p‐eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11‐induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF‐1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients.

Conclusions and Implications

Stimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO‐mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF‐1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED.
AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation
Authors: Feuerbach Dominik , Pezous Nicole , Weiss Markus , Shakeri‐Nejad Kasra , Lingenhoehl Kurt , Hoyer Daniel , Hurth Konstanze , Bilbe Graeme , Pryce Christopher R , McAllister Kevin , Chaperon Frederique , Kucher Klaus , Johns Donald , Blaettler Thomas , Lopez Lopez Cristina
Published: November 2014

Background and Purpose

Activation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7‐nACh receptor agonist AQW051 as a promising drug candidate for this indication.

Experimental Approach

AQW051 was functionally characterized in vitro and cognitive effects evaluated in rodent behavioural models. Pharmacokinetics and tolerability were evaluated in three phase I placebo‐controlled studies in 180 healthy subjects.

Key Results

In vitro, AQW051 bound with high affinity to α7‐nACh receptors and stimulated calcium influx in cells recombinantly expressing the human α7‐nACh receptor. In vivo, AQW051 demonstrated good oral bioavailability and rapid penetration into the rodent brain. AQW051 administered over a broad dose range facilitated learning/memory performance in the object recognition and social recognition test in mice and the water maze model in aged rats. Clinically, AQW051 was well tolerated in healthy young and elderly subjects, with an adverse event (AE) profile comparable with placebo. No serious AEs were reported and all AEs were either mild or moderate in severity at single oral doses up to 200 mg and multiple daily doses up to 75 mg. Once‐daily oral administration of AQW051 resulted in continuous exposure and a two‐ to threefold accumulation compared with steady state was achieved by 1 week.

Conclusions and Implications

These data support further development of AQW051 as a cognitive‐enhancing agent, as a therapeutic, for example, in Alzheimer's disease or schizophrenia.
Genistein alleviates pressure overload‐induced cardiac dysfunction and interstitial fibrosis in mice
Authors: Qin Wei , Du Ning , Zhang Longyin , Wu Xianxian , Hu Yingying , Li Xiaoguang , Shen Nannan , Li Yang , Yang Baofeng , Xu Chaoqian , Fang Zhiwei , Lu Yanjie , Zhang Yong , Du Zhimin
Published: November 2014

Background and Purpose

Pressure overload‐induced cardiac interstitial fibrosis is viewed as a major cause of heart failure in patients with hypertension or aorta atherosclerosis. The purpose of this study was to investigate the effects and the underlying mechanisms of genistein, a natural phytoestrogen found in soy bean extract, on pressure overload‐induced cardiac fibrosis.

Experimental Approach

Genisten was administered to mice with pressure overload induced by transverse aortic constriction. Eight weeks later, its effects on cardiac dysfunction, hypertrophy and fibrosis were determined. Its effects on proliferation, collagen production and myofibroblast transformation of cardiac fibroblasts (CFs) and the signalling pathways were also assessed in vitro.

Key Results

Pressure overload‐induced cardiac dysfunction, hypertrophy and fibrosis were markedly attenuated by genistein. In cultured CFs, genistein inhibited TGFβ1‐induced proliferation, collagen production and myofibroblast transformation. Genistein suppressed TGFβ‐activated kinase 1 (TAK1) expression and produced anti‐fibrotic effects by blocking the TAK1/MKK4/JNK pathway. Further analysis indicated that it up‐regulated oestrogen‐dependent expression of metastasis‐associated gene 3 (MTA3), which was found to be a negative regulator of TAK1. Silencing MTA3 by siRNA, or inhibiting the activity of the MTA3‐NuRD complex with trichostatin A, abolished genistein's anti‐fibrotic effects.

Conclusions and Implications

Genistein improved cardiac function and inhibited cardiac fibrosis in response to pressure overload. The underlying mechanism may involve regulation of the MTA3/TAK1/MKK4/JNK signalling pathway. Genistein may have potential as a novel agent for prevention and therapy of cardiac disorders associated with fibrosis.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
CAD/CAM fabrication accuracy of long‐ vs. short‐span implant‐supported FDPs
Authors: Katsoulis Joannis , Müller Philipp , Mericske‐Stern Regina , Blatz Markus B.
Published: November 2014

Objective

To compare the precision of fit of long‐span vs. short‐span implant‐supported screw‐retained fixed dental prostheses (FDPs) made from computer‐aided‐design/computer‐aided‐manufactured (CAD/CAM) titanium and veneered with ceramic. The null hypothesis was that there is no difference in the vertical microgap between long‐span and short‐span FDPs.

Materials and methods

CAD/CAM titanium frameworks for an implant‐supported maxillary FDP on implants with a flat platform were fabricated on one single master cast. Group A consisted of six 10‐unit FDPs connected to six implants (FDI positions 15, 13, 11, 21, 23, 25) and group B of six 5‐unit FDPs (three implants, FDI positions 21, 23, 25). The CAD/CAM system from Biodenta Swiss AG (Berneck, Switzerland) was used for digitizing (laser scanner) the master cast and anatomical CAD of each framework separately. The frameworks were milled (CAM) from a titanium grade V monobloc and veneered with porcelain. Median vertical distance between implant and FDP platforms from the non‐tightened implants (one‐screw test on implant 25) was calculated from mesial, buccal, and distal scanning electron microscope measurements.

Results

All measurements showed values <40 μm. Total median vertical microgaps were 23 μm (range 2–38 μm) for group A and 7 μm (4–24 μm) for group B. The difference between the groups was statistically significant at implant 21 (P = 0.002; 97.5% CI −27.3 to −4.9) and insignificant at implant 23 (P = 0.093; −3.9 to 1.0).

Conclusions

CAD/CAM fabrication including laboratory scanning and porcelain firing was highly precise and reproducible for all long‐ and short‐span FDPs. While all FDPs showed clinically acceptable values, the short‐span FDPs were statistically more precise at the 5‐unit span distance.
Stability of cognitive performance in children with mild intellectual disability
Authors: Jenni Oskar G , Fintelmann Sylvia , Caflisch Jon , Latal Beatrice , Rousson Valentin , Chaouch Aziz
Published: November 2014

Aim

Longitudinal studies that have examined cognitive performance in children with intellectual disability more than twice over the course of their development are scarce. We assessed population and individual stability of cognitive performance in a clinical sample of children with borderline to mild non‐syndromic intellectual disability.

Method

Thirty‐six children (28 males, eight females; age range 3–19y) with borderline to mild intellectual disability (Full‐scale IQ [FSIQ] 50–85) of unknown origin were examined in a retrospective clinical case series using linear mixed models including at least three assessments with standardized intelligence tests.

Results

Average cognitive performance remained remarkably stable over time (high population stability, drop of only 0.38 IQ points per year, standard error=0.39, p=0.325) whereas individual stability was at best moderate (intraclass correlation of 0.58), indicating that about 60% of the residual variation in FSIQ scores can be attributed to between‐child variability. Neither sex nor socio‐economic status had a statistically significant impact on FSIQ.

Interpretation

Although intellectual disability during childhood is a relatively stable phenomenon, individual stability of IQ is only moderate, likely to be caused by test‐to‐test reliability (e.g. level of child's cooperation, motivation, and attention). Therefore, clinical decisions and predictions should not rely on single IQ assessments, but should also consider adaptive functioning and previous developmental history.
Common European birds are declining rapidly while less abundant species' numbers are rising
Authors: Inger Richard , Gregory Richard , Duffy James P. , Stott Iain , Voříšek Petr , Gaston Kevin J.
Published: November 2014

Biodiversity is undergoing unprecedented global decline. Efforts to slow this rate have focused foremost on rarer species, which are at most risk of extinction. Less interest has been paid to more common species, despite their greater importance in terms of ecosystem function and service provision. How rates of decline are partitioned between common and less abundant species remains unclear. Using a 30‐year data set of 144 bird species, we examined Europe‐wide trends in avian abundance and biomass. Overall, avian abundance and biomass are both declining with most of this decline being attributed to more common species, while less abundant species showed an overall increase in both abundance and biomass. If overall avian declines are mainly due to reductions in a small number of common species, conservation efforts targeted at rarer species must be better matched with efforts to increase overall bird numbers, if ecological impacts of birds are to be maintained.
“Subtotal” hemispherectomy in children with intractable focal epilepsy
Authors: Chugani Harry T. , Asano Eishi , Juhász Csaba , Kumar Ajay , Kupsky William J. , Sood Sandeep
Published: November 2014

Objective

Cortical resections in epilepsy surgery tend to be larger in children, compared to adults, partly due to underlying pathology. Some children show unilateral multifocal seizure onsets involving much of the hemisphere. If there were a significant hemiparesis present, hemispherectomy would be the procedure of choice. Otherwise, it is preferable to spare the primary sensorimotor cortex. We report the results of “subtotal” hemispherectomy in 23 children.

Methods

All children (ages 1 year and 4 months to 14 years and 2 months) were operated on between 2001 and 2013 at Children's Hospital of Michigan (Detroit). Patients were evaluated with scalp video–electroencephalography (EEG), magnetic resonance imaging (MRI), 18F‐fluorodeoxyglucose–positron emission tomography (FDG‐PET) scans, and neuropsychological assessments when applicable. Subsequently, each case was discussed in a multidisciplinary epilepsy surgery conference, and a consensus was reached pertaining to candidacy for surgery and optimum surgical approach. The actual extent of resection was based on the results from subdural electrocorticography (ECoG) monitoring. The surgical outcome is based on International League Against Epilepsy (ILAE) classification (class 1–6).

Results

Among the 23 patients, 11 had epileptic spasms as their major seizure type; these were associated with focal seizures in 3 children. MRI showed focal abnormalities in 12 children. FDG‐PET was abnormal in all but one subject. All except two children underwent chronic subdural ECoG. Multiple subpial transections were performed over the sensorimotor cortex in three subjects. On histopathology, various malformations were seen in 9 subjects; the remainder showed gliosis alone (n = 12), porencephaly (n = 1), and gliosis with microglial activation (n = 1). Follow‐up ranged from 13 to 157 months (mean = 65 months). Outcomes consisted of class 1 (n = 17, 74%), class 2 (n = 2), class 3 (n = 1), class 4 (n = 1), and class 5 (n = 2).

Significance

Extensive unilateral resections sparing only sensorimotor cortex can be performed with excellent results in seizure control. Even with the presence of widespread unilateral epileptogenicity or anatomic/functional imaging abnormalities, complete hemispherectomy can often be avoided, particularly when there is little hemiparesis.
Coping as mediator of the relationship between stress and itch in patients with atopic dermatitis: a regression and mediation analysis
Authors: Schut Christina , Weik Ulrike , Tews Natalia , Gieler Uwe , Deinzer Renate , Kupfer Jörg
Published: November 2014

Even though it has been shown that stress and itch are associated in patients with atopic dermatitis (AD), it remains unclear whether this relationship occurs due to certain coping strategies being activated under stress. Therefore, this study investigates the role of coping as possible mediating factor between stress and itch in 31 patients with AD. Coping and itch were assessed by self‐reported measures, while stress was measured both by a validated questionnaire and by a physiological stress marker, the postawakening cortisol. Using a regression and a mediation analysis, this study showed a relationship between perceived stress and itch (corrected R2 = 0.21), which was fully mediated by negative itch‐related cognitions. 62.3% of the variance of itch intensity could be explained by negative itch‐related cognitions. This finding helps to explain the positive effects of cognitive restructuring in the treatment of chronic itch.
A tiered aquatic life unit bioassessment model for Gulf of Mexico coastal streams
Authors: Daniel W. M. , Brown K. M. , Kaller M. D.
Published: November 2014

The tiered aquatic life unit (TALU) model allows quick and efficient bioassessment with goals that are based on practical, systematic sampling of commonly measured stream variables. A six‐tier hybrid TALU model was developed as a proof of concept study for streams in six level IV ecoregions in the north‐central Gulf of Mexico coastal plain. The model used in‐stream habitat variables, land use, surveys of the unionid mussels, number of intolerant fish species and fish diversity in streams varying from 2nd through 6th order. The model classification identified sites considered a priori either as impaired or best available and minimised Type I (mistakenly concluding impairment) and Type II (failing to detect impairment) errors. The model also detected transitional sites, thereby illustrating incremental degradation or recovery, in contrast to previous monitoring tools focused on pass/fail approaches. Because the model classifies transitional sites and is easily modified to fit other ecoregions, it offers a useful foundation for resource managers to monitor the health of coastal plain rivers.