bluuebunny/crossref_metadata_2025 huggingface dataset:
Traceable GISAXS measurements for pitch determination of a 25 nm self-assembled polymer grating
Authors: Wernecke Jan , Krumrey Michael , Hoell Armin , Kline R. Joseph , Liu Hung-Kung , Wu Wen-Li
Published: November 2014

The feature sizes of only a few nanometres in modern nanotechnology and next-generation microelectronics continually increase the demand for suitable nanometrology tools. Grazing-incidence small-angle X-ray scattering (GISAXS) is a versatile technique to measure lateral and vertical sizes in the nanometre range, but the traceability of the obtained parameters, which is a prerequisite for any metrological measurement, has not been demonstrated so far. In this work, the first traceable GISAXS measurements, demonstrated with a self-assembled block copolymer grating structure with a nominal pitch of 25 nm, are reported. The different uncertainty contributions to the obtained pitch value of 24.83 (9) nm are discussed individually. The main uncertainty contribution results from the sample–detector distance and the pixel size measurement, whereas the intrinsic asymmetry of the scattering features is of minor relevance for the investigated grating structure. The uncertainty analysis provides a basis for the evaluation of the uncertainty of GISAXS data in a more general context, for example in numerical data modeling.
A scattering function of star polymers including excluded volume effects
Authors: Li Xin , Do Changwoo , Liu Yun , Sánchez-Diáz Luis , Smith Gregory , Chen Wei-Ren
Published: November 2014

This work presents a new model for the form factor of a star polymer consisting of self-avoiding branches. This new model incorporates excluded volume effects and is derived from the two-point correlation function for a star polymer. This model is compared with small-angle neutron scattering measurements from polystyrene stars immersed in a good solvent, tetrahydrofuran. It is shown that this model provides a good description of the scattering signature originating from the excluded volume effect, and it explicitly elucidates the connection between the global conformation of a star polymer and the local stiffness of its constituent branch.
A concept of walking robot for humanitarian demining
Authors: Doroftei Ioan , Baudoin Yvan
Published: November 2014

Purpose

At present, more than 100 million undetonated landmines left over from wars remain buried worldwide. These mines kill or injure approximately 3,000 individuals each year (80 persons per day), most of them civilians. They represent a particularly acute problem in developing countries and nations already economically hard hit by war. The problem of unexploded mines has become a serious international issue, with many people striving to find a solution. The purpose of this paper is to examine the requirements of the robotic systems for humanitarian demining purposes. It will discuss a hexapod walking robot developed at the Royal Military Academy of Brussels in collaboration with the Free University of Brussels, Belgium, in the framework of the Humanitarian Demining Project (HUDEM).

Design/methodology/approach

Considerations for the design of the walking robot according to the humanitarian demining requirements are discussed in detail.

Findings

A successful walking robot design for demining purposes must consider functional requirements relevant to this difficult application. The principal requirements are mentioned in this paper.

Originality/value

This paper is the result of the research of the HUDEM project team and it is of value to engineers and researchers developing robotic systems for humanitarian demining purposes.
Complete coverage path planning of mobile robots for humanitarian demining
Authors: Đakulovic Marija , Petrovic Ivan
Published: November 2014

Purpose

The purpose of this paper is to present a path planning algorithm for a non‐circular shaped mobile robot to autonomously navigate in an unknown area for humanitarian demining. For that purpose the path planning problem comes down to planning a path from some starting location to a final location in an area so that the robot covers all the reachable positions in the area while following the planned path.

Design/methodology/approach

The proposed algorithm uses occupancy grid map representation of the area. Every free cell in the grid map represents a node in the graph being searched to find the complete coverage path. The complete coverage path is followed by the dynamic window algorithm, which includes robot's kinematic and dynamic constraints.

Findings

The proposed algorithm finds the complete coverage path in the graph accounting for the dimensions of the mobile robot, where non‐circular shaped robots can be easily included. The algorithms are implemented under the ROS (robot operating system) and tested in the stage 3D simulator for mobile robots with a randomly generated simulation map of an unknown area.

Research limitations/implications

Some parts of the area close to obstacles are hard to cover due to complex non‐circular shaped robot and non‐perfect path following. The future work should include better path following algorithm.

Practical implications

The proposed algorithm has shown itself as effective and could meet the working demands of humanitarian demining.

Originality/value

The algorithm proposed in the paper enables complete coverage path planning of non‐circular shaped robots in unknown areas.
Designing parallel manipulators: from specifications to a real prototype
Authors: Hernández Alfonso , Altuzarra Oscar , Salgado Oscar , Pinto Charles , Petuya Víctor
Published: November 2014

Purpose

The purpose of this paper is to present a step‐by‐step methodology for the design of parallel kinematic machines (PKMs), from the initial stages of the conceptual definition of a new machine to an optimum design fulfilling the complete set of design requirements.

Design/methodology/approach

The methodology includes consideration of the kinematic, static and dynamic features required for the manipulator, which must all be assessed in complete industrial design. It is applied to a 4‐degrees‐of‐freedom (DOF) Schönflies motion generator for pick & place operations by way of example.

Findings

The authors specify the key stages of a detailed design procedure for parallel manipulators.

Originality/value

There are many publications on the development of specific robots and parallel manipulators based on their particular characteristics. However, it is relatively rare to find a paper on the general procedure with a step‐by‐step methodology applicable to any parallel manipulator.
Challenges for young management scholars in Iberia and Latin America
Authors: Vieira da Cunha João
Published: November 2014

Purpose

The purpose of this paper is to offer the author's view about some of the challenges young Iberoamerican scholars face in order to build a successful research record.

Design/methodology/approach

This is an individual account of some of the most common barriers Iberoamerican scholars face when starting their academic career.

Findings

The paper presents some of the difficulties encountered by young scholars, such as motivation, lack of feedback, teaching load, and lack of resources and addresses these challenges in an almost intimate fashion.

Originality/value

The paper uses an idiosyncratic approach to the practical career obstacles faced by a young scholar outside the mainstream academic environment.
Predominant strategies of legitimacy in environmental and social disclosures
Authors: Beuren Ilse Maria , Lucia Boff Marines
Published: November 2014

Purpose

The purpose of this study is to identify which of Lindblom's strategies of organizational legitimacy predominate in environmental and social disclosures in administration reports of publicly traded family companies under Brazilian shareholder control during the period 1997‐2006.

Design/methodology/approach

Descriptive research from a universe of 500 large companies from the ranking made in Exame magazine – “best and biggest”, 2006 edition. From these, 21 publicly traded family companies under Brazilian shareholder control were identified, but the longitudinal study was made with the 16 that published their administration reports in the last ten years. The sentence was considered as the unit of analysis, with application of the content analysis technique to messages contained in the administration reports that were related to environmental and social disclosures.

Findings

Research results show that the companies researched used the four strategies of organizational legitimacy proposed by Lindblom, either together or separately.

Research limitations/implications

The second and third strategies predominated in the environmental and social disclosures from administration reports made from 1997 to 2006.

Originality/value

The value of the study is in its advancement of research made in the UK by Gray et al., Parsa and Kouhy, and in Brazil by Silva.
Earthquake risk in urban street network: an example from region 6 of Tehran, Iran
Authors: Shieh Esmaeil , Habibi Kyoumars , Torabi Kamal , E. Masoumi Houshmand
Published: November 2014

Purpose

– Zone 6 of Tehran, with a populations of 220,000 people (3.6 per cent of the city population) and 20 km2 area (3 per cent of the city area), is one of the main municipal zones of Tehran. Major land-uses, like ministries, embassies, universities, general hospitals and medical centers, big financial firms, and so on, manifest the high importance of this region on a local and national scale. Thus, it is necessary to pay close attention to issues concerning crisis management in this area.

Design/methodology/approach

– In this paper, by using indexes such as access to medical centers, street inclusion, building and population density, land-use, peak ground acceleration and building quality, vulnerability degree of street networks in zone 6 against the earthquake is calculated through overlaying maps and data in combination with inversion hierarchical weight process method and geographic information systems.

Findings

– This article concludes that buildings alongside the streets with high population and building density, low building quality, far to rescue centers and high level of inclusion represent high rate of vulnerability, compared with other buildings. Also, by moving from north to south of the zone, the vulnerability increases. Likewise, highways and streets with substantial width and low building and population density hold little values of vulnerability. Thus, streets with high level of inclusion, building and population density present further vulnerability.

Originality/value

– It is expected that the results of this paper be used by the urban decision-makers. Due to high vulnerability of most parts of the urban textures of Tehran, similar researches will have importance for preparation for the future possible earthquakes.
The academy-profession nexus in CFA partner programs
Authors: Akimov Alexandr , J. Bianchi Robert , E. Drew Michael
Published: November 2014

Purpose

– The purpose of this paper is to comprehensively review one example of academic-industry cooperation, namely, the partnership arrangements between the CFA Institute and universities around the globe. There is a scarcity of literature relating to academic-industry cooperation between the finance discipline and business.

Design/methodology/approach

– Relevant data were hand-collected and a comprehensive analysis of individual CFA partner programs was undertaken, including the geographical distribution of the programs and program characteristics and ranking of partners programs; the motivation for and approaches of universities toward the CFA Institute partnership and program design are identified. The general findings are validated with a detailed analysis of the CFA partner postgraduate programs offered in Australian universities.

Findings

– The research finds that the primary focus of cooperation between the CFA Institute and universities is the adoption of practitioner-relevant academic curriculum in universities, which should assist in setting industry educational standards. The authors observed a great diversity of partner institutions and programs around the globe, their rankings and their approach to cooperation with the CFA Institute thanks to the flexibility of their partnership arrangements. This explains the rapid growth of universities seeking formal cooperation with the CFA Institute. However, this growth has created challenges for the CFA Institute in managing and delivering value in their partnership arrangements.

Research limitations/implications

– Due to data limitations, the research does not provide an empirical analysis of factors driving enrollments in Australian postgraduate finance programs.

Practical implications

– The paper serves as a guide to universities interested in engaging in cooperation with the CFA Institute. This study is also useful for the professional bodies that evaluate various models of cooperation with educational institutions.

Originality/value

– The paper is the first, to the authors' knowledge, to examine the practical aspects of cooperation between universities and a professional body in the finance discipline. Moreover, it is the first to evaluate perceived benefits and problems universities may experience by entering into a popular CFA Institute Partner Program.
Enhancing first year student engagement: collaborative practice in a core business unit
Authors: Fleming Tina , Stanway Alicia
Published: November 2014

Purpose

– The purpose of this paper, informed by an action research framework, was to evaluate how a collaborative approach between unit facilitators and learning advisors in a first-year core business unit contributes to an environment where students are actively engaged in their learning. Student engagement in their learning is a key priority for university faculties, particularly in first year, as it is a key factor in student performance and persistence in their studies.

Design/methodology/approach

– Using the Australasian Survey of Student Engagement as a benchmark, a mixed-methods approach was adopted using an online survey (n = 171) and focus groups (n = 17).

Findings

– Findings indicate that specific cohorts of students benefit from this collaborative learning model, as it encourages students to actively engage in their learning, provides them with early feedback on their performance, encourages self-reflection and provides transferable skills that form the foundation of their future learning.

Research/implications

– The current study contributes to student engagement literature pertaining to the factors affecting student engagement in higher education.

Originality/value

– The key lesson learnt is that the future success of embedded learning support relies heavily on building strong relationships between academic and professional staff.
Unique benefits of physician leadership – an American perspective
Authors: Angood Peter , Shannon Diane
Published: November 2014

Purpose

– This paper aims to present the argument that effective physician leadership is needed to improve the quality and efficiency of healthcare delivery in the USA and around the world.

Design/methodology/approach

– This paper is based on an in-depth literature review, interviews with physician leaders and a study of the competencies required for physicians to successfully lead healthcare organizations.

Findings

– The paper finds that a clear need exists for training to improve specific leadership competencies among physicians, regardless of their career stage or career path.

Research limitations/implications

– Limited research has been conducted on the value of physician leadership and its impact on quality outcomes and patient safety.

Practical implications

– This paper establishes the need for physician leadership in healthcare organizations.

Social implications

– This paper will influence public attitudes within the healthcare sphere on the value that physician leaders can bring to healthcare.

Originality/value

– This paper fulfils a need for more study on the impact that physician leadership brings to quality and patient care, and establishes the need for physician leaders to obtain specific leadership competencies.
Leadership styles used by senior medical leaders
Authors: Chapman Ann LN , Johnson David , Kilner Karen
Published: November 2014

Purpose

– The purpose of this study was to determine the predominant leadership styles used by medical leaders and factors influencing leadership style use. Clinician leadership is important in healthcare delivery and service development. The use of different leadership styles in different contexts can influence individual and organisational effectiveness.

Design/methodology/approach

– A mixed methods approach was used, combining a questionnaire distributed electronically to 224 medical leaders in acute hospital trusts with in-depth “critical incident” interviews with six medical leaders. Questionnaire responses were analysed quantitatively to determine, first, the overall frequency of use of six predefined leadership styles and, second, individual leadership style based on a consultative/decision-making paradigm. Interviews were analysed thematically using both a confirmatory approach with predefined leadership styles as themes, and also an inductive grounded theory approach exploring influencing factors.

Findings

– Leaders used a range of styles, the predominant styles being democratic, affiliative and authoritative. Although leaders varied in their decision-making authority and consultative tendency, virtually all leaders showed evidence of active leadership. Organisational culture, context, individual propensity and “style history” emerged during the inductive analysis as important factors in determining use of leadership styles by medical leaders.

Practical implications

– The outcomes of this evaluation are useful for leadership development at the level of the individual, organisation and wider National Health Service (NHS).

Originality/value

– This study adds to the very limited evidence base on patterns of leadership style use in medical leadership and reports a novel conceptual framework of factors influencing leadership style use by medical leaders.
Skin sloughing rate increases with chytrid fungus infection load in a susceptible amphibian
Authors: Ohmer Michel E.B. , Cramp Rebecca L. , White Craig R. , Franklin Craig E.
Published: November 2014

Amphibian chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd), is responsible for the greatest disease‐driven loss of vertebrate biodiversity in recorded history. Understanding drivers of host susceptibility to this cutaneous disease is hindered by gaps in our knowledge of the host–pathogen relationship. One such overlooked aspect of susceptibility is variation in skin maintenance processes, particularly skin turnover via routine sloughing. It has been suggested that sloughing plays a role in immune defence, by removing skin‐associated microbes. Thus, skin sloughing may play an important role in the pathogenesis of chytridiomycosis.

To determine the relationship between skin sloughing and disease progression, we exposed adult Australian green tree frogs (Litoria caerulea) to a local Bd strain and monitored sloughing rates and individual infection loads on a naturalistic cycling temperature regime (15–23 °C).

We determined sloughing rates in real‐time by using an array of infrared video cameras to film frog behaviour and monitored infection load before and after sloughing by swabbing and analysis with quantitative PCR.

We found that sloughing rate increased with Bd infection load in infected frogs, but sloughing itself did not affect Bd load on the ventral skin surface. Furthermore, Bd infection did not affect the duration of characteristic sloughing behaviour, and sloughing retained rhythmicity even at high infection loads.

Although an increased sloughing rate might be considered advantageous for Bd‐infected animals, it does not appear to curb the progression of disease and may actually contribute to the loss of physiological homoeostasis seen in terminally ill frogs by further inhibiting water and electrolyte transport across the skin.

By measuring sloughing rates directly for the first time, our results shed light on how Bd interacts with the physiological processes of the skin and indicate that variation in skin sloughing frequency may play a role in the observed inter‐ and intraspecific variation in susceptibility to disease.
Implementation aspects of eigendecomposition‐based high‐resolution velocity spectra
Authors: Barros Tiago , Lopes Renato , Tygel Martin
Published: November 2014

In this paper, we discuss high‐resolution coherence functions for the estimation of the stacking parameters in seismic signal processing. We focus on the Multiple Signal Classification which uses the eigendecomposition of the seismic data to measure the coherence along stacking curves. This algorithm can outperform the traditional semblance in cases of close or interfering reflections, generating a sharper velocity spectrum. Our main contribution is to propose complexity‐reducing strategies for its implementation to make it a feasible alternative to semblance. First, we show how to compute the multiple signal classification spectrum based on the eigendecomposition of the temporal correlation matrix of the seismic data. This matrix has a lower order than the spatial correlation used by other methods, so computing its eigendecomposition is simpler. Then we show how to compute its coherence measure in terms of the signal subspace of seismic data. This further reduces the computational cost as we now have to compute fewer eigenvectors than those required by the noise subspace currently used in the literature. Furthermore, we show how these eigenvectors can be computed with the low‐complexity power method. As a result of these simplifications, we show that the complexity of computing the multiple signal classification velocity spectrum is only about three times greater than semblance. Also, we propose a new normalization function to deal with the high dynamic range of the velocity spectrum. Numerical examples with synthetic and real seismic data indicate that the proposed approach provides stacking parameters with better resolution than conventional semblance, at an affordable computational cost.
The Ten Commandments of Applied Regional Integration Analysis: The African Case
Authors: Charaf‐Eddine Naym , Strauss Ilan
Published: November 2014

This paper offers ten guidelines for researchers to improve their analysis of regional integration and their approach to regional integration. By way of analysis, regional integration statistics are often misunderstood or poorly constructed. In one way or another this leads to an oversimplification of their meaning. With respect to the approach taken by policymakers to regional integration, the goals of Africa's regional integration have not been seriously interrogated; nor have the necessary national and regional preconditions for achieving even a minimal form of regional integration that is sustainable.
The Will to Integrate: South Africa's Responses to Regional Migration from the SADC Region
Authors: Nshimbi Christopher Changwe , Fioramonti Lorenzo
Published: November 2014

This paper surveys frameworks of labour migration in southern Africa and determines South Africa's policy responses to inflows of migrants from seven neighbouring countries. Legislations, policy reports and scientific publications on migration were thoroughly reviewed and interviews and correspondence with key policymakers were conducted. Statistical analyses of data on foreign worker recruitments and permits issued by South Africa's Department of Home Affairs were also performed. The absence of a migration protocol in southern Africa suggests SADC Members have not implemented the African Union's migration policy basic guidelines. Two systems coexist in southern Africa that complicate migration governance: a South Africa‐managed bilateral migration policy, and aspirations for a formal SADC‐managed migration policy. Bilateral agreements between South Africa and neighbours have established a labour migration system that dims prospects for a regional migration policy. SACU Members could establish a two‐tier policy to achieve free movement while maintaining managed migration policy outside SACU. An official multilateral migration governance mechanism would serve SADC better than the current ad‐hoc measures.
Public Rewards and Innovation Policy: Lessons from the Eighteenth and Early Nineteenth Centuries
Authors: Burrell Robert , Kelly Catherine
Published: November 2014

There has been renewed interest in recent years in using prizes and rewards to promote innovation. History has played a central role in public debates in the UK about the merits of such interventions, with the Longitude Prize 2014 being self‐consciously modelled on its eighteenth century precursor. Similarly, historical case studies have been used extensively in the scholarly literature in this area. However, it is striking that there has been little engagement with parliament's role generally in rewarding inventors in the eighteenth and early nineteenth centuries and how this formed part of a broader system of rewards. The article explores how this system operated and demonstrates that it formed an established part of the legal landscape for many decades. It considers the extent to which a more complete understanding of the historical use of prizes and rewards during the key period of Britain's industrialisation might inform current debates.
Factors Behind Dialysis Patient Satisfaction: Exploring Their Effects on Overall Satisfaction
Authors: Gu Xiuzhu , Itoh Kenji
Published: November 2014

We would establish a construct of dialysis patients' satisfaction and identify their contribution to overall satisfaction. We also seek to identify present satisfaction levels of Japanese dialysis patients and some important characteristics of their satisfaction/dissatisfaction. A self‐administered questionnaire for measuring dialysis patient satisfaction was developed, which comprised 32 closed‐ended satisfaction question items that were facet‐specific, three items on overall satisfaction, four items on respondent's health status and quality of life as well as demographic information. Reliability and validity of the questionnaire was verified. A questionnaire‐based survey was conducted between July and September 2013. A total of 807 valid responses (63% of response rate) were collected from dialysis patients in 22 facilities located in most regions of Japan. Seven satisfaction factors were derived with 65% of cumulative variance accounted for by applying principal component analysis to responses to facet‐specific satisfaction items. More than 80% of patients expressed positive overall satisfaction and that they wished to continue dialysis therapy in the current facility (they can change dialysis facilities if they wish to). Dialysis patients' overall satisfaction was formulated significantly by five out of seven satisfaction factors by regression analysis. Japanese dialysis patients expressed their high satisfaction with and strong loyalty to the facility where they currently receive dialysis therapy (i.e., patient loyalty). The more satisfied dialysis patients were with the facility, the stronger loyalty they would like to maintain. The overall satisfaction was critically determined by their satisfaction with clinical environment, equipment, treatment and therapy. In addition, patients' quality of life was highly associated with their overall satisfaction.
Effects of Elevated Temperature Postharvest on Color Aspect, Physiochemical Characteristics, and Aroma Components of Pineapple Fruits
Authors: Liu Chuanhe , Liu Yan
Published: November 2014

In this work, 2 separate experiments were performed to describe the influence of elevated temperature treatments postharvest on the color, physiochemical characteristics and aroma components of pineapple fruits during low‐temperature seasons. The L* (lightness) values of the skin and pulp of pineapple fruits were decreased. The a* (greenness‐redness) and b* (blueness‐yellowness) values of the skin and pulp were all markedly increased. The elevated temperature significantly increased the contents of total soluble solids (TSS) and slightly affected contents of vitamin C (nonsignificant). Titratable acidity (TA) of pineapple fruits were notably decreased, whereas the values of TSS/TA of pineapple fruits were significantly increased. The firmness of the pineapple fruits decreased and more esters and alkenes were identified. The total relative contents of esters were increased, and the total relative contents of alkenes were decreased.
Histamine H4 receptors in the gastrointestinal tract
Authors: Deiteren A , De Man J G , Pelckmans P A , De Winter B Y
Published: November 2014

Histamine is a well‐established mediator involved in a variety of physiological and pathophysiological mechanisms and exerts its effect through activation of four histamine receptors (H1–H4). The histamine H4 receptor is the newest member of this histamine receptor family, and is expressed throughout the gastrointestinal tract as well as in the liver, pancreas and bile ducts. Functional studies using a combination of selective and non‐selective H4 receptor ligands have rapidly increased our knowledge of H4 receptor involvement in gastrointestinal processes both under physiological conditions and in models of disease. Strong evidence points towards a role for H4 receptors in the modulation of immune‐mediated responses in gut inflammation such as in colitis, ischaemia/reperfusion injury, radiation‐induced enteropathy and allergic gut reactions. In addition, data have emerged implicating H4 receptors in gastrointestinal cancerogenesis, sensory signalling, and visceral pain as well as in gastric ulceration. These studies highlight the potential of H4 receptor targeted therapy in the treatment of various gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and cancer.
Synthesis and SAR studies of novel 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives for anticancer activity
Authors: Chen Yi‐Fong , Lin Yi‐Chien , Morris‐Natschke Susan L , Wei Chen‐Fang , Shen Ting‐Chen , Lin Hui‐Yi , Hsu Mei‐Hua , Chou Li‐Chen , Zhao Yu , Kuo Sheng‐Chu , Lee Kuo‐Hsiung , Huang Li‐Jiau
Published: November 2014

Background and Purpose

4‐Phenylquinolin‐2(1H)‐one (4‐PQ) derivatives can induce cancer cell apoptosis. Additional new 4‐PQ analogs were investigated as more effective, less toxic antitumour agents.

Experimental Approach

Forty‐five 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives were synthesized. Antiproliferative activities were evaluated using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliun bromide assay and structure–activity relationship correlations were established. Compounds 9b, 9c, 9e and 11e were also evaluated against the National Cancer Institute‐60 human cancer cell line panel. Hoechst 33258 and Annexin V‐FITC/PI staining assays were used to detect apoptosis, while inhibition of microtubule polymerization was assayed by fluorescence microscopy. Effects on the cell cycle were assessed by flow cytometry and on apoptosis‐related proteins (active caspase‐3, ‐8 and ‐9, procaspase‐3, ‐8, ‐9, PARP, Bid, Bcl‐xL and Bcl‐2) by Western blotting.

Key Results

Nine 6,7,8‐substituted 4‐substituted benzyloxyquinolin‐2(1H)‐one derivatives (7e, 8e, 9b, 9c, 9e, 10c, 10e, 11c and 11e) displayed high potency against HL‐60, Hep3B, H460, and COLO 205 cancer cells (IC50 < 1 μM) without affecting Detroit 551 normal human cells (IC50 > 50 μM). Particularly, compound 11e exhibited nanomolar potency against COLO 205 cancer cells. Mechanistic studies indicated that compound 11e disrupted microtubule assembly and induced G2/M arrest, polyploidy and apoptosis via the intrinsic and extrinsic signalling pathways. Activation of JNK could play a role in TRAIL‐induced COLO 205 apoptosis.

Conclusion and Implications

New quinolone derivatives were identified as potential pro‐apoptotic agents. Compound 11e could be a promising lead compound for future antitumour agent development.
Protective effect of 23‐hydroxybetulinic acid on doxorubicin‐induced cardiotoxicity: a correlation with the inhibition of carbonyl reductase‐mediated metabolism
Authors: Zhou Fang , Hao Gang , Zhang Jingwei , Zheng Yuanting , Wu Xiaolan , Hao Kun , Niu Fang , Luo Dan , Sun Yuan , Wu Liang , Ye Wencai , Wang Guangji
Published: November 2014

Background and Purpose

The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. 23‐Hydroxybetulinic acid (23‐HBA), isolated from Pulsatilla chinensis, enhances the anticancer effect of doxorubicin while simultaneously reducing its cardiac toxicity, but does not affect the concentration of doxorubicin in the plasma and heart. As the metabolite doxorubicinol is more potent than doxorubicin at inducing cardiac toxicity, in the present study we aimed to clarify the role of doxorubicinol in the protective effect of 23‐HBA.

Experimental Approach

Doxorubicin was administered to mice for two weeks in the presence or absence of 23‐HBA. The heart pathology, function, myocardial enzymes and accumulation of doxorubicin and doxorubicinol were then analysed. A cellular pharmacokinetic study of doxorubicin and doxorubicinol, carbonyl reductase 1 (CBR1) interference and molecular docking was performed in vitro.

Key Results

23‐HBA alleviated the doxorubicin‐induced cardiotoxicity in mice, and this was accompanied by inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts. In H9c2 cells, the protective effect of 23‐HBA was shown to be closely associated with a decreased rate and extent of accumulation of doxorubicinol in mitochondria and nuclei. siRNA and docking analysis demonstrated that CBR1 has a crucial role in doxorubicin‐mediated cardiotoxicity and 23‐HBA inhibits this metabolic pathway.

Conclusions and Implications

Inhibition of CBR‐mediated doxorubicin metabolism might be one of the protective mechanisms of 23‐HBA against doxorubicin‐induced cardiotoxicity. The present study provides a new research strategy guided by pharmacokinetic theory to elucidate the mechanism of drugs with unknown targets.

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
MLN4924 sensitizes monocytes and maturing dendritic cells for TNF‐dependent and ‐independent necroptosis
Authors: El‐Mesery Mohamed , Seher Axel , Stühmer Thorsten , Siegmund Daniela , Wajant Harald
Published: November 2014

Background and Purpose

MLN4924 prevents the formation of active cullin‐RING ubiquitin ligase complexes and thus inhibits NF‐κB signalling. Here, we evaluated the effects of this compound on monocytes and dendritic cells (DCs).

Experimental Approach

Monocytes and DCs were challenged with TNF or LPS in the presence and absence of MLN4924. The effects of MLN4924 on cellular viability, pro‐inflammatory gene induction and DC maturation were investigated using the MTT assay, elisa and FACS analysis. Mechanisms of cell death induction were evaluated by using inhibitors of caspases, RIPK1 and MLKL.

Key Results

MLN4924 inhibited NF‐κB activation and sensitized monocytes and immature DCs (iDCs) for TNFR1‐induced cell death. Neither the caspase inhibitor zVAD‐fmk, the RIPK1 inhibitor necrostatin‐1 (nec‐1) nor the MLKL inhibitor necrosulfonamide (NSA) alone prevented TNF‐induced cell death. A combination of zVAD‐fmk and nec‐1 or NSA, however, rescued monocytes and iDCs from MLN4924/TNF‐induced cell death indicating that MLN4924 affects anti‐apoptotic and anti‐necrotic activities in TNFR1 signalling. MLN4924 also converted the response of iDCs to LPS from maturation to cell death. LPS‐induced cell death in MLN4924‐treated iDCs was again only effectively blocked by cotreatment with zVAD‐fmk and nec‐1 or NSA. Noteworthy, MLN4924/LPS‐induced cell death was almost completely independent of endogenous TNF. MLN4924 also strongly inhibited maturation and activation of iDCs that were rescued from cell death by zVAD‐fmk and nec‐1.

Conclusions and Implications

Our data reveal a strong dual suppressive effect of MLN4924 on DC activity. The targeting of NAE by MLN4924 could be a new way to treat inflammatory diseases.
Novel Nrf2 activators from microbial transformation products inhibit blood–retinal barrier permeability in rabbits
Authors: Nakagami Yasuhiro , Masuda Kayoko , Hatano Emiko , Inoue Tatsuya , Matsuyama Takuya , Iizuka Mayumi , Ono Yasunori , Ohnuki Takashi , Murakami Yoko , Iwasaki Masaru , Yoshida Kazuhiro , Kasuya Yuji , Komoriya Satoshi
Published: November 2014

Background and Purpose

Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a redox‐sensitive transcription factor that binds to antioxidant response elements located in the promoter region of genes encoding many antioxidant enzymes and phase II detoxifying enzymes. Activation of the Nrf2 pathway seems protective for many organs, and although a well‐known Nrf2 activator, bardoxolone methyl, was evaluated clinically for treating chronic kidney disease, it was found to induce adverse events. Many bardoxolone methyl derivatives, mostly derived by chemical modifications, have already been studied. However, we adopted a biotransformation technique to obtain a novel Nrf2 activator.

Experimental Approach

The potent novel Nrf2 activator, RS9, was obtained from microbial transformation products. Its Nrf2 activity was evaluated by determining NADPH:quinone oxidoreductase‐1 induction activity in Hepa1c1c7 cells. We also investigated the effects of RS9 on oxygen‐induced retinopathy in rats and glycated albumin‐induced blood–retinal barrier permeability in rabbits because many ocular diseases are associated with oxidative stress and inflammation.

Key Results

Bardoxolone methyl doubled the specific activity of Nrf2 in Hepa1c1c7 cells at a much higher concentration than RS9. Moreover, the induction of Nrf2‐targeted genes was observed at a one‐tenth lower concentration of RS9. Interestingly, the cytotoxicity of RS9 was substantially reduced compared with bardoxolone methyl. Oral and intravitreal administration of RS9 ameliorated the pathological scores and leakage in the models of retinopathy in rats and ocular inflammation in rabbits respectively.

Conclusion and Implications

Nrf2 activators are applicable for treating ocular diseases and novel Nrf2 activators have potential as a unique method for prevention and treatment of retinovascular disease.
The phytocannabinoid, Δ9‐tetrahydrocannabivarin, can act through 5‐HT1A receptors to produce antipsychotic effects
Authors: Cascio Maria Grazia , Zamberletti Erica , Marini Pietro , Parolaro Daniela , Pertwee Roger G
Published: November 2014

Background and Purpose

This study aimed to address the questions of whether Δ9‐tetrahydrocannabivarin (THCV) can (i) enhance activation of 5‐HT1A receptors in vitro and (ii) induce any apparent 5‐HT1A receptor‐mediated antipsychotic effects in vivo.

Experimental Approach

In vitro studies investigated the effect of THCV on targeting by 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) of 5‐HT1A receptors in membranes obtained from rat brainstem or human 5‐HT1A CHO cells, using [35S]‐GTPγS and 8‐[3H]‐OH‐DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5‐HT1A receptor‐mediated antipsychotic effects in rats.

Key Results

THCV (i) potently, albeit partially, displaced 8‐[3H]‐OH‐DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8‐OH‐DPAT‐induced activation of receptors in these membranes; (iii) produced concentration‐related increases in 8‐[3H]‐OH‐DPAT binding to specific sites in membranes of human 5‐HT1A receptor‐transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8‐OH‐DPAT‐induced activation of these human 5‐HT1A receptors. In phencyclidine‐treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5‐HT1A receptor antagonist, WAY100635, or could be reproduced by the CB1 antagonist, AM251.

Conclusions and Implications

Our findings suggest that THCV can enhance 5‐HT1A receptor activation, and that some of its apparent antipsychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia.
Inhibition of L‐carnitine biosynthesis and transport by methyl‐γ‐butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction
Authors: Liepinsh E , Makrecka‐Kuka M , Kuka J , Vilskersts R , Makarova E , Cirule H , Loza E , Lola D , Grinberga S , Pugovics O , Kalvins I , Dambrova M
Published: November 2014

Background and Purpose

The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long‐chain acylcarnitines in the case of acute ischaemia‐reperfusion. The aim of this study is to test whether decreasing the L‐carnitine content represents an effective strategy to decrease accumulation of long‐chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia–reperfusion injury.

Key Results

In this study, we used a novel compound, 4‐[ethyl(dimethyl)ammonio]butanoate (Methyl‐GBB), which inhibits γ‐butyrobetaine dioxygenase (IC50 3 μM) and organic cation transporter 2 (OCTN2, IC50 3 μM), and, in turn, decreases levels of L‐carnitine and acylcarnitines in heart tissue. Methyl‐GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl‐GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl‐GBB (5 or 20 mg·kg−1) decreased the infarct size by 45–48%. In vivo pretreatment with Methyl‐GBB (20 mg·kg−1) attenuated the infarct size by 45% and improved 24 h survival of rats by 20–30%.

Conclusions and Implications

Reduction of L‐carnitine and long‐chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia–reperfusion‐induced damage. Methyl‐GBB treatment exerted cardioprotective effects and increased survival by limiting long‐chain fatty acid oxidation and facilitating glucose metabolism.
Left Atrial Function Assessed by Left Atrial Strain in Patients with Left Circumflex Branch Culprit Acute Myocardial Infarction
Authors: Lee Dong Hyun , Park Tae‐Ho , Lee Jung Eun , Cho Young‐Rak , Park Kyungil , Park Jong Sung , Kim Moo‐Hyun , Kim Young‐Dae
Published: November 2014

Introduction

Although left atrium (LA) has played an important role in diastole, ischemic insult of atrium in acute myocardial infarction (AMI) has not been clearly evaluated.

Methods

We hypothesized that LA function would be further decreased in AMI patients with a culprit lesion in the left circumflex branch (LCX). This was an observational cohort study in a single university hospital. Echocardiography was performed to evaluate left ventricular diastolic function, LA volume, and LA function. Systolic (LAS) and late diastolic (LAA) LA strain were measured using speckle tracking echocardiography.

Results

Sixty‐eight AMI patients treated with emergent or urgent percutaneous coronary intervention were enrolled. Global LAS strain was significantly lower in patients with a culprit lesion in the LCX than culprit lesions in other vessels (left anterior descending, 27.3 ± 6.8%; left circumflex, 20.1 ± 8.9%; right coronary artery, 23.3 ± 6.5%; P = 0.007). LA volume index did not differ significantly (P = 0.093). Other clinical and conventional echocardiographic parameters, including Doppler measurements, did not differ significantly.

Conclusions

Global LAS strain was lower in AMI patients with a culprit lesion in the LCX than those with culprit lesions in other vessels, without any significant difference in LA volume index. The lower global LAS strain might suggest decreased LA function resulting from ischemic insult by AMI with culprit lesions in the LCX.
The Biplane Modified Simpson's Method Accurately Estimates Pericardial Effusion Volume: A Comparison with Pericardiocentesis
Authors: Khosraviani Khashayar , Goldberg Ythan , Salari Behzad , Nezami Nariman , Peng Chang‐Fu , Taub Cynthia C.
Published: November 2014

Background

Pericardial effusion (PE) volume is often assessed semiqualitatively by echocardiography and categorized into minimal, small, moderate, or large. Several methods of echocardiographic quantification have been proposed, but their application is limited either by complexity or inaccuracy. We evaluated the accuracy of PE volume quantification by two‐dimensional transthoracic echocardiogram (2DTTE) and commercially available volume quantification software in patients undergoing pericardiocentesis.

Methods

In a retrospective case series, immediate preprocedure echocardiograms of 33 patients for pericardiocentesis were analyzed. 2DTTE using the Simpson's method was adopted for volume measurement in the apical two‐ and four‐chamber views. Pericardial fluid volume was calculated by taking the difference between volumes obtained by tracing the epicardial border of the heart and the pericardium. Postprocedure echocardiograms were performed to verify adequate pericardiocentesis.

Results

The mean pericardiocentesis fluid volume was 725.1 ± 299.5 mL (range, 250–1420 mL). The average volume estimated echocardiographically by the Simpson's method was 657.5 ± 276.9 mL (range, 205.7–1193.2 mL). There was strong direct linear correlation between echocardiographic and pericardiocentesis‐derived volumes (P < 0.001, r = +0.823). Echocardiography underestimated PE volume by a mean of 9.3%.

Conclusion

Two‐dimensional transthoracic echocardiography using biplane Simpson's method of disks can simply and accurately estimate PE volume.
Improvement in Tricuspid Annular Plane Systolic Excursion with Pulmonary Hypertension Therapy in Pediatric Patients
Authors: Bano Maria , Kanaan Usama B. , Ehrlich Alexandra C. , McCracken Courtney , Morrow Gemma , Oster Matthew E. , Sachdeva Ritu
Published: November 2014

Background

Tricuspid annular plane systolic excursion (TAPSE) has emerged as a novel and reliable measure of right ventricular (RV) function. The purpose of this study was to determine the effect of pulmonary hypertension (PH) therapy on TAPSE in pediatric patients and compare TAPSE to other quantitative measures of RV function.

Methods

A retrospective review of medical records and echocardiograms of patients in the PH clinic from January 2011 to August 2013 was done. Echocardiograms were analyzed prior to initiation or addition of a PH drug and at least 8 weeks later. Following quantitative measures of RV function were compared: TAPSE, TAPSE age‐based z‐score, RV fractional area change (RVFAC), tricuspid annular S′, tricuspid inflow E/tricuspid annular E′ velocity (TV E/E′), and RV myocardial performance index (RVMPI).

Results

Of the 37 patients included in this study (median age 0.6 years), 23 (62.2%) were treatment naive and others had a new PH drug added to their regimen at the time of the baseline echocardiogram. The median duration between the baseline and follow‐up echocardiogram was 8 (2–25) months. There was a significant improvement in TAPSE and TAPSE age‐based z‐score on the follow‐up echocardiogram. RVFAC, tricuspid S′, TV E/E′, and RVMPI did not show a statistically significant change.

Conclusion

In contrast to the other echocardiographic markers of RV function, TAPSE, and TAPSE age‐based z‐score significantly improve after initiation or addition of PH therapy and can be used for serial noninvasive monitoring of RV function in pediatric PH patients.