bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Model-Based Analysis of the Emergence of Bacterial Cross-Feeding through Extensive Gene Loss
Authors: McNally Colin P , Borenstein Elhanan
Published: August 2017

Metabolic dependencies between microbial species are common and have a significant impact on the assembly and resilience of microbial communities. However, the origins of such metabolic dependencies, the evolutionary forces that drive metabolic cross-feeding, and the impact of metabolic and genomic architecture on their emergence are not clear. To address these questions, we developed a novel simulation-based framework coupling a model of reductive evolution with a multi-species genome-scale model of microbial metabolism. We used this framework to model the evolution of a two-species microbial community, simulating thousands of independent evolutionary trajectories and investigating the link between genome reductive evolution and the emergence of metabolic interactions. Surprisingly, even though our model does not impose explicit selection for cooperation, metabolic dependencies emerged in nearly half of all evolutionary runs. Evolved dependencies involved cross-feeding of a diverse set of metabolites at varying frequencies, reflecting various constraints imposed by the metabolic network architecture. We additionally found metabolic ‘missed opportunities’, wherein species failed to capitalize on metabolites made available by their partners. When cross-feeding did evolve, it generally emerged immediately after a metabolite became available, but a complete dependence on such cross-fed metabolites often evolved relatively slowly. Examining the genes deleted and retained in each evolutionary trajectory and the timing of gene deletion events along these trajectories, we were further able to identify both genome-wide properties and specific gene retentions that were associated with metabolic phenotypes. Our findings provide insight into the evolution of cooperative metabolic interaction among microbial species, offering a unique view into the way such relationships could emerge in natural settings.
FGFR2 amplification in colorectal adenocarcinoma
Authors: Carter Jamal H. , Cottrell Catherine E. , McNulty Samantha N. , Vigh-Conrad Katinka A. , Lamp Stephen , Heusel Jonathan W. , Duncavage Eric J.
Published: August 2017

FGFR2 is recurrently amplified in 5% of gastric cancers and 1%–4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.
Schooling health: the critical contribution of curriculum in the 1980s
Authors: Leahy Deana , Penney Dawn , Welch Rosie
Published: August 2017

Purpose

Public health authorities have long regarded schools as important sites for improving children and young people’s health. In Australia, and elsewhere, lessons on health have been an integral component of public health’s strategy mix. Historical accounts of schools’ involvement in public health lack discussion of the role of health education curriculum. The purpose of this paper is to redress this silence and illustrate the ways health education functioned as a key governmental apparatus in Victoria in the 1980s.

Design/methodology/approach

The paper draws on governmentality studies to consider the explicit governmental role of official health education curriculum in the 1980s in Victoria, Australia. The authors conduct a discourse analysis of the three official curriculum texts that were released during this period to consider the main governmental rationalities and techniques that were assembled together by curriculum writers.

Findings

School health education functions as a key governmental apparatus of governmentality. One of its major functions is to provide opportunities to responsibilise young people with an aim to ensure that that they can perform their duty to be well. The authors demonstrate the central role of policy events in the 1970s and how they contributed to conditions of possibility that shaped versions of health education throughout the 1980s and beyond. Despite challenges posed by the critical turn in health education in the late 1980s, the governmental forces that shape health education are strong and have remained difficult to displace.

Originality/value

Many public health and schooling histories fail to take into account insights from the history of education and curriculum studies. The authors argue that in order to grasp the complexities of school health education, we need to consider insights afforded by curriculum histories. Historical insights can provide us with an understanding of the changing approaches to governing health in schools.
School medical inspection and the “healthy” child in the Netherlands, 1904-1970
Authors: Bakker Nelleke
Published: August 2017

Purpose

The purpose of this paper is to explore the meaning of child health as applied by school doctors in the Netherlands and the way it was adapted to the rapidly improving standard of living and the increasing importance of mental health after the Second World War. The extension of the concept beyond physical health into emotional and social well-being is particularly interesting as the school medical inspection was the only public child-hygienic service in a country where religious groups opposed the extension of public hygienic care into parenting and the family.

Design/methodology/approach

On the basis of secondary literature, the paper discusses the early development of Dutch school medical inspection from a comparative perspective. Changes in the national authority’s and the school doctors’ concepts of what a “healthy” child was between the 1930s and 1970 are examined using a variety of primary sources. These concern both the national discourse and sources that shed light on the daily practice of school medical inspection from the single province for which these are available.

Findings

Although they adopted a new and more inclusive concept of health in theory, school doctors in the Netherlands were reluctant to actually take up issues of mental health in their daily practice. This reluctance was inspired by the fear of losing their pivotal role in child hygiene and their status as public servants.

Originality/value

Studies in the history of school medical services have focussed mainly on their establishment and development as an institution. They seldom extend into the post-war era and do not discuss the extension of the inspection into mental health.
Competitive advantage through Six Sigma at plastic injection molded parts manufacturing unit
Authors: Desai Darshak , Prajapati Bhavikkumar Nileshbhai
Published: August 2017

Purpose

The purpose of this paper is to illustrate the successful application of Six Sigma at a small and medium scale plastic parts manufacturing unit. Overall operational excellence is one of the foundations of global competiveness. Indian industries are also keeping up with achieving and maintaining operational excellence through different improvement tools and methodologies. Plastic parts manufacturing industries in India are also on the move to increase their overall quality, productivity and profitability. However, it appears from the available literature that application of Six Sigma, one of the most effective breakthrough improvement strategies having direct impact on bottom line of the organization, is not being explored to its full potential, especially at plastic parts manufacturing industries in India. This study was thus undertaken at plastic products manufacturing plant to introduce Six Sigma to them by applying the same to their chronic problems and drawing improvements in quality, productivity and profitability.

Design/methodology/approach

This paper illustrates the real-life case study of improving quality and productivity of injection molding process by phase wiz application of define, measure, analyze, improve and control, the process improvement methodology of Six Sigma.

Findings

The critical defects, such as short molding, contamination, injection point and flash are reduced from the process leading to annual savings of INR 10.80 lacs. This is a considerable amount for a small concern in question.

Research limitations/implications

Because this was the pilot project and the firm was of small and medium size, data collection was the major issue, which consequently took considerable time and efforts at define and measure phases. Injection molding is a very salient process for plastic products manufacturing. Almost one-third of plastic products are made by this process. Thus, improving quality of products made out of injection molding process is of paramount importance. The paper is an attempt to exhibit how a small-scale plastic injection molded parts manufacturing unit can put fruitful efforts to achieve competitive advantage through Six Sigma.

Originality/value

From the review of literature, it appears that application of Six Sigma among plastic parts manufacturing units, especially small and medium, is very rare, not in India but across the globe. This case study has opened up the direction to small- and medium-scale plastic parts manufacturing units to implement Six Sigma and to move a step forward toward achieving competitive advantage.
Lean thinking: planning and implementation in the public sector
Authors: de Almeida Juliana Pascualote Lemos , Galina Simone Vasconcelos Ribeiro , Grande Marcia Mazzeo , Brum Daiane Gressler
Published: August 2017

Purpose

The purpose of this paper is to analyse how Lean office planning and implementation take place in a Brazilian regulatory agency and to investigate the adjustments needed for its implementation.

Design/methodology/approach

A longitudinal case study was conducted. Interview was the main source of evidence. Between September and October 2012, data about the planning phase were collected; between April and May 2015, Lean office implementation was investigated. Altogether, five employees of the agency were interviewed.

Findings

The agency assumed its mission as value for the user, establishing control process, evaluating and improving processes to achieve perfection and recognising its weakness in a continuous improvement culture. Planning and implementation of Lean office in the regulatory agency followed the main recommendations in the literature. However, adjustments were necessary in accordance with the particularities of the public institution.

Research limitations/implications

Owing to the nature of this study, no generalisation was possible. Moreover, interviews with managers were about both Lean planning, which has taken place in the past, and Lean implementing, which is still running; thus, some information may be abstruse.

Practical implications

It was possible to list the main adjustments needed for planning and implementing the Lean office in the public agency and some are applicable for other public administration bodies.

Originality/value

Lean office studies are mainly related to private organizations, but this paper demonstrates that their fundamentals are preserved in public service, and thus it proved that Lean thinking may be applied to the public administration. It also raised a series of questions for future studies.
Investing in work: exclusionary inclusion in Austria, Belgium and Norway
Authors: Gubrium Erika K. , Leibetseder Bettina , Dierckx Danielle , Raeymaeckers Peter
Published: August 2017

Purpose

The purpose of this paper is to compare the impact of two social investment strategies (labour activation and governance coordination) targeted to social assistance clients within three different welfare-system coordination cases, with focus on social and economic inclusion.

Design/methodology/approach

The authors focus on the impact of reform at micro (individually experienced impact), meso (impact across settings) and macro (socio-structural impact) levels.

Findings

While social investment reform has given some clients new opportunities, in no study case were clients fully able to use the incentive-driven strategies. Reforms have led to a “Matthew effect”: the better resourced reap the largest benefit from new services on offer while the less resourced have their marginal socioeconomic position reinforced. Clients may internalise their relative activation success. Intimate connections between macro- and micro-impacts may have heightened the sense of social and economic exclusion, stigma and shame experienced by those who are most vulnerable.

Social implications

Social investment reform (labour activation) may not be a model that reduces social and economic exclusion and it may, instead, reify socioeconomic marginalisation, enhancing sense of stigma and shame and reducing self-efficacy.

Originality/value

Scholars have assessed social investment according to its economic performance, but there has been a lack of research considering impact of reform on socioeconomic inclusion.
Making sense of contemporary disasters: a liquid development perspective
Authors: Perkiss Stephanie , Handley Karen
Published: August 2017

Purpose

The purpose of this paper is to explore economic conditions of contemporary society to provide insight into the ways in which the consequences of disaster, including environmental migration, are accentuated.

Design/methodology/approach

This research draws on Zygmunt Bauman’s theory of liquid modernity and notions of development to analyse disaster. From the analysis, a new concept, liquid development, is proposed and critiqued as a contributing factor leading to severe contemporary disaster.

Findings

Liquid development provides a new way of making sense of the conditions and consequences of economic growth and a business as usual attitude. It further provides a framework to explore the potential disaster of environmental migration in the Pacific Islands arising from liquid development driven climate change-induced sea level rise.

Research limitations/implications

Analysing these conditions provides greater understanding of the resulting impact of disaster, creating awareness and informing the need for accountability and social policy. This study aims to contribute to further practical and research enquiry that will challenge liquid developers to reconsider their impact and to accept responsibility for vulnerable members of society as part of their business as usual structure.

Originality/value

This paper adds to Bauman’s understanding of the consequences of globalisation through the construct of liquid development. It also continues his debate by giving awareness to the global issue of environmental migration.
Female knowledge workers and the illusion of working-time autonomy
Authors: Tammelin Mia , Koivunen Tuija , Saari Tiina
Published: August 2017

Purpose

The purpose of this paper is to ask: what are the temporal realities of female knowledge workers? It especially focusses on women’s possibilities of using working-time autonomy, and the work and non-work practices that shape their possibility to use work-hour autonomy. In knowledge work, working-time autonomy is usually high, but exercising autonomy is not always possible. The study was carried out in Finland, where full-time work is common also among women, even if they have small children.

Design/methodology/approach

The data include 19 semi-structured interviews of women who have knowledge-intensive work. The method of analysis is problem-driven content analysis.

Findings

Female knowledge workers intertwine several temporal realities. The utilisation of working-time autonomy is restricted by unpredictability, continuous interruptions, hurriedness and ineffective work practices. The temporal realities of family life, such as taking children to the daycare or school, other everyday routines and a spouse’s working-time autonomy have an effect on women’s possibilities to use working-time autonomy. The line between work and non-work blurs.

Originality/value

This study sheds light on working-time autonomy among female knowledge workers. It adds an understanding to the temporal realities of work and outside work that influence the use of work-hour autonomy. This information is needed to understand time demands arising from work, which play a role in work-family research in particular.
Changing concerns of beginning Dutch university teachers
Authors: van den Bos Paul
Published: August 2017

Purpose

The purpose of this paper is to address the concerns of beginning university teachers about learning to teach in the context of an induction programme.

Design/methodology/approach

The author asked 162 beginning teachers at Dutch universities of applied sciences to express their concerns about teaching. Of those, the author first asked 44 teachers to write down their concerns freely. These open statements were categorised and translated to a 20-item questionnaire, which was completed by the remaining 118 teachers before and after the induction programme.

Findings

Statistical analysis identified three main concerns: activating students, being an effective teacher in general, and being sufficiently facilitated and supported in the teaching context. While concerns about activating students and being an effective teacher were reduced after the programme, concerns about the supportiveness of the teaching context remained unchanged.

Research limitations/implications

The study was conducted in the context of a specific induction programme with a specific pedagogical design; thus, generalisation of the results should be done carefully. Additionally, while the instrument that was developed in this study must be improved, this study indicates a relevant problem: the results of induction programmes might be less sustainable without a proper supportive organisational context.

Originality/value

The study adds insight into the concerns of beginning university teachers and highlights some consequences at the organisational level.
Doctoral student support programs in diverse national contexts
Authors: Caliskan Omer , Holley Karri
Published: August 2017

Purpose

The growing demand for doctoral education and the role of the doctoral degree to advance nations socially, economically, and culturally forces countries and individual institutions to respond to concerns stemming from the doctoral process. Numerous initiatives to support doctoral students have been adopted with varying features across countries. The purpose of this paper is to examine doctoral student support programs in two countries: the USA and Turkey. These countries offer higher education systems at different stages of maturity and stability.

Design/methodology/approach

The data for this study came from a comparative case study analysis of doctoral student experiences in support programs at two research universities, one in the USA and one in Turkey. Ten American doctoral students and eight Turkish doctoral students were interviewed, for a total of 18 interviews. The study utilized the conceptual framework specified by the PhD Completion Project initiated by the US Council of Graduate Schools.

Findings

The two national systems featured in this study are at different points of their development. These developmental starting points influence the rationale and construction of a student support program, particularly one focused on advanced degrees, research activity, and knowledge production. The Turkish higher education system faces the challenge of building its infrastructure to be responsive to national needs in future decades, including producing qualified faculty as teachers and researchers. The American model of doctoral student support concentrates on increasing diversity within the academy. By focusing on first-generation students, students of color, and women in STEM disciplines, efforts are directed toward not just improving the quantity of graduates, but also the diversity of those graduates.

Originality/value

While doctoral student support programs are increasingly common in multiple national contexts, analyses of these programs are rare, and comparative analyses even more so. The emergence of new academic disciplines, the trend toward interdisciplinary research, and the prevalence of neo-liberal policies has made the doctoral experience increasingly complex. The data presented here reveal that while doctoral education is influenced by country-specific contexts, doctoral students from multiple countries share many of the same experiences.
Social skills as a moderator between R&D personnel’s knowledge sharing and job performance
Authors: Yun Yang-Joong , Lee Kyoung-Joo
Published: August 2017

Purpose

Research and development (R&D) personnel are an organization’s ultimate source of creative knowledge. Thus, their job performance ensures an organization’s innovative capability. Focusing on the process nature of creativity and innovation in organizations, the purpose of this paper is to analyze the influence of R&D personnel’s active knowledge sharing on their job performance and highlight the significance of social skills by examining their moderation effect.

Design/methodology/approach

This study conducted a survey of 252 R&D personnel in 60 R&D organizations in large South Korean firms. Data reliability and validity were confirmed, and regression analysis was performed to test the hypotheses.

Findings

The authors found that R&D personnel’s knowledge sharing has a significant effect on their job performance. Furthermore, social skills significantly moderate the relationship between knowledge sharing and job performance.

Originality/value

This study addresses the existing literature’s limited understanding of the process nature of creativity and innovation by examining knowledge sharing as a personal engagement in the innovation process, which has a positive effect on job performance. The study also casts new light on the importance of social skills in fortifying personal engagement in the innovation process. The overall results will prove valuable in the selection of effective R&D personnel and the design of competency development programs for R&D organizations.
Firms’ money demand and monetary policy
Authors: Bafile Romina , Piergallini Alessandro
Published: August 2017

Standard New Keynesian models for monetary policy analysis are ‘cashless’. When the nominal interest rate is the central bank's operating instrument, the LM equation is endogenous and, it is argued, can be ignored. The modern theoretical and quantitative debate on the importance of money for monetary policy conduct, however, overlooks firms’ money demand. Working in an otherwise canonical New Keynesian setup, we show that macroeconomic dynamics are critically affected by the firms’ money demand choice. Under the conventional Taylor‐rule framework, we prove that equilibrium determinacy may require either an active interest rate policy, overreacting to inflation, or a passive interest rate policy, underreacting to inflation, depending on the elasticity of production with respect to cash balances. We then develop a numerical analysis to evaluate our theoretical results. We find that macroeconomic stability is more likely to occur under an active, but not overly aggressive, monetary policy stance. We also examine the dynamic effects of forward‐looking feedback rules. We show that, in this policy regime, indeterminacy is likely to be induced by both active and passive rules, even for relatively low productivity effects of money.
Promoting equity in water access: the limits of fairness of a rural water programme in semi‐arid Mozambique
Authors: Ducrot Raphaëlle , Bourblanc Magalie
Published: August 2017

Bridging the water infrastructure gap has become a major policy concern. In rural areas of Africa, access to water is as much constrained by territorial coverage as it is by the poor conditions of water points due to the difficulty in mobilizing communities for repairs. This paper examines the equity considerations of a rural water and sanitation programme in a district of Mozambique, and their impacts on the achievement of the programme's objectives. Our analysis underlines the contradictions in the conceptualization of equity in the design, planning and implementation of the programme. Even an explicitly pro‐poor strategy can fall short of delivering equity. Our findings stress the fact that overlooking local perception of equity can have a direct impact on the ability of a community to ensure the maintenance of their water points. They call for a careful definition of equity in the design of water programmes, as well as closer attention to this criterion as a precondition to achieving the long‐term objective of the programme.
Welfare‐at‐Risk and Extreme Dependency of Regional Wheat Yields: Implications of a Stochastic CGE Model
Authors: Erhan Ünal Gözde , Karapinar Baris , Tanaka Tetsuji
Published: August 2017

Stochastic computable general equilibrium (CGE) models have ignored regional correlations in agricultural yields, assuming random shocks to be independent between regions. This could lead to misinterpretation of simulation outputs which ignore extreme positive or negative harvests at the global scale. We develop a multi‐regional CGE model which allows for five types of interregional correlation between wheat yields to analyse the vulnerability of countries against fluctuating international markets, focusing on Value at Risk (VaR) and extreme dependency. We find that global welfare risks could be underestimated by up to 33% if significant interregional correlations in yield shocks are not taken into account. Egypt, Kazakhstan, Ukraine, the former Soviet Union and Northern Africa are particularly vulnerable to global volatilities in terms of economic welfare.
The time paradox of emergency medicine: Another inverted U curve
Authors: Fatovich Daniel M
Published: August 2017

Time is integral to emergency medicine, but the importance of time is over‐rated. Media promotes a focus on time over suffering. Terms such as the ‘golden hour’ and ‘time is muscle’ are embedded into our language, but is language that corrupts thought. Time‐based metrics for ED quality measures focus on speed over accuracy, reflecting another inverted U curve in our system of care. We often fail to understand the importance of heterogeneity, and the heterogeneity of treatment effect, for example, sicker patients are more likely to benefit from the intervention, whereas less sick patients do not benefit but are more likely to be harmed. This highlights the importance of nuanced judgements. We need to get into the Goldilocks zone of the ‘just right’ balance between speed and accuracy. This essay challenges us to focus more on the suffering human subject, rather than on time‐based metrics that reflect our hope bias.
Rollout Strategy to Implement Interoperable Traceability in the Seafood Industry
Authors: Gooch Martin , Dent Benjamin , Sylvia Gilbert , Cusack Christopher
Published: August 2017

Verifying the accuracy and rigor of data exchanged within and between businesses for the purposes of traceability rests on the existence of effective and efficient interoperable information systems that meet users’ needs. Interoperability, particularly given the complexities intrinsic to the seafood industry, requires that the systems used by businesses operating along the supply chain share a common technology architecture that is robust, resilient, and evolves as industry needs change. Technology architectures are developed through engaging industry stakeholders in understanding why an architecture is required, the benefits provided to the industry and individual businesses and supply chains, and how the architecture will translate into practical results. This article begins by reiterating the benefits that the global seafood industry can capture by implementing interoperable chain‐length traceability and the reason for basing the architecture on a peer‐to‐peer networked database concept versus more traditional centralized or linear approaches. A summary of capabilities that already exist within the seafood industry that the proposed architecture uses is discussed; and a strategy for implementing the architecture is presented. The 6‐step strategy is presented in the form of a critical path.
Enrichment and Cytotoxic Activity of Curcuminoids from Turmeric Using Macroporous Resins
Authors: Chen Cheng , Jin Shuna , Xiang Xingliang , Wang Xuanyuan , Shi Qingxin , Yang Min , Ji Simin , Huang Rongzeng , Song Chengwu
Published: August 2017

Curcuminoids are functional secondary metabolites abundant in turmeric. In the present study, a simple and efficient method for enrichment of curcuminoids from turmeric was developed using macroporous resin. Eight different types of macroporous resins were examined by static adsorption/desorption properties and the type of XDA‐7 was selected as the optimum one. Under the optimized conditions, the final contents of refined extract excluded 84.2% of impurities, by comparison with crude extract in a scale‐up experiment. Meanwhile, 8 representative curcuminoids including 4 dihydro‐ and tetrahydro‐curcuminoids were enriched, isolated, and identified by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS) and nuclear magnetic resonance (NMR) data. In addition, the individual curcuminoids were prepared to evaluate their cytotoxic activity toward HeLa tumor cell lines. All compounds, especially the trace amount of curcuminoids, demonstrated notable cytotoxic activity. The results supported that those trace amount of curcuminoids can be good candidates for drug development as anticancer agents. The purification process was simple and efficient, which could afford a potential method to enrich and concentrate not only the major curcuminoids, but also the trace amount of ones from turmeric raw materials for industrial applications.
Imperial Expansion and Local Agency: A Case Study of Labor Organization Under Inca Rule
Authors: Garrido Francisco , Salazar Diego
Published: August 2017

Imperial expansion can produce broad economic intensification throughout the provinces to provide key economic resources for the state. However, not all such economic intensification is the direct result of the imposition of an imperial political economy over subject populations. This article presents evidence for some cases where intensification occurred due to bottom‐up responses of small groups that were able to profit from imperial conquest. In the case of the Incas, although the imposition of a labor‐tax system, or mit'a, was an important economic device for their imperial expansion, we question its universality. This article addresses the economic changes that local communities experienced within the Tawantinsuyu by comparing the coexistence of attached and independent modes of production in two cases of mining production in the Atacama Desert, in northern Chile. This contributes to finding and elaborating on explicit archaeological indicators that enable us to contrast both modes of engagement with the political economy of the Inca Empire and to identify, archaeologically, alternative and independent local responses to imperial expansion. Our study thus energizes debates on how and to what extent local populations, under conditions of empire, can negotiate spaces and activities outside of state control. [mit'a, prehistoric mining, bottom‐up dynamics, imperial expansion, Inca Empire]
Premature ventricular contraction‐induced concealed retrograde penetration: Electrocardiographic manifestations on anterograde ventricular preexcitation
Authors: Longo Damián , Baranchuk Adrian
Published: August 2017

In patients with manifest anterograde ventricular preexcitation, the electrocardiographic manifestation of the anomalous conduction through the simultaneous conduction over the atrioventricular (AV) node and the accessory pathway (“delta wave”); depends on several factors, the most representative being the conduction velocity over one or another connection. Occasionally, ventricular ectopic beats may present with retrograde penetration over one or both conduction pathways (AV node and/or accessory pathway), impacting on the morphology of the next immediate anterogradely conducted QRS. We present a case of a young patient with WPW syndrome and ectopic ventricular beats with different manifestations on the postectopic QRS due to concealed penetration of different conduction pathways.
Distinct in vivo target occupancy by bivalent‐ and induced‐fit‐like binding drugs
Authors: Vauquelin Georges
Published: August 2017

Background and Purpose

Optimal drug therapy often requires long‐lasting target occupancy While this attribute was usually linked to the drug's pharmacokinetic properties, the dissociation rate is now increasingly recognized to contribute as well. Nearly all the earlier pharmacokinetic‐pharmacodynamic (PK‐PD) simulations encompassed single‐step binding drugs and focused on koff. However, ‘micro’‐PK mechanisms and more complex binding mechanisms like bivalent‐ and induced‐fit binding may contribute as well. Corresponding binding models are presently explored.

Experimental Approach

We compared the 24 h in vivo occupancy over time profiles of prototype bivalent‐ and induced‐fit‐like binding drugs (A and B) after one or repeated daily dosings, both without and with rebinding. Special attention was focused on the effect of each of the microscopic rate constants on the occupancy profiles and on the metrics to represent those profiles.

Key Results

Although both models can be represented by the same mathematical formulation, drugs A and B display quite different occupancy profiles, even though they have the same potency. These differences can be attributed to the different effects of their microscopic rate constants on their composite koff and also on their susceptibility to experience rebinding. This also affects how the occupancy profiles of bivalent‐ and induced‐fit‐like binders progress when repeating the dosings and by changing the dosage.

Conclusions and Implications

Closer attention should be paid to more complex binding models in PK‐PD simulations. This may help pharmacologists and medicinal chemists to improve the translation of in vitro kinetic measurements from preclinical screening programmes into clinical efficiency.
Aphid specialism as an example of ecological–evolutionary divergence
Authors: Loxdale Hugh D. , Balog Adalbert
Published: August 2017

Debate still continues around the definition of generalism and specialism in nature. To some, generalism is equated solely with polyphagy, but this cannot be readily divorced from other essential biological factors, such as morphology, behaviour, genetics, biochemistry, chemistry and ecology, including chemical ecology. Viewed in this light, and accepting that when living organisms evolve to fill new ecological–evolutionary niches, this is the primal act of specialisation, then perhaps all living organisms are specialist in the broadest sense. To illustrate the levels of specialisation that may be found in a group of animals, we here provide an overview of those displayed by a subfamily of hemipteran insects, the Aphididae, which comprises some 1600 species/subspecies in Europe alone and whose members are specialised in a variety of lifestyle traits. These include life cycle, host adaptation, dispersal and migration, associations with bacterial symbionts (in turn related to host adaptation and resistance to hymenopterous wasp parasitoids), mutualisms with ants, and resistance to insecticides. As with polyphagy, these traits cannot easily be separated from one another, but rather, are interconnected, often highly so, which makes the Aphididae a fascinating animal group to study, providing an informative, perhaps unique, model to illustrate the complexities of defining generalism versus specialism.
Drought, post‐dispersal seed predation, and the establishment of epiphytic bromeliads (Tillandsia spp.)
Authors: Chilpa‐Galván Nahlleli , Zotz Gerhard , Sánchez‐Fuente Guillermo J. , Espadas‐Manrique Celene , Andrade José L. , Reyes‐García Casandra
Published: August 2017

Post‐dispersal, epiphyte seed predation is poorly documented. Our study on the in situ germination of two Tillandsia species in a deciduous forest in Yucatan, Mexico showed an average post‐dispersal seed predation rate by the Yucatan deer mouse (Peromyscus yucatanicus) of 90%. Post‐dispersal predation was thus more limiting than drought.
Recurrent fruit harvesting reduces seedling density but increases the frequency of clonal reproduction in a tropical tree
Authors: Gaoue Orou G. , Gado Choukouratou , Natta Armand K. , Kouagou M'Mouyohoun
Published: August 2017

Studies on the ecological impacts of non‐timber forest products (NTFP) harvest reveal that plants are often more resilient to fruit and seed harvest than to bark and root harvest. Several studies indicate that sustainable fruit harvesting limits can be set very high (>80% fruit harvesting intensity). For species with clonal and sexual reproduction, understanding how fruit harvest affects clonal reproduction can shed light on the genetic risks and sustainability of NTFP harvest. We studied 18 populations of a gallery forest tree, Pentadesma butyracea (Clusiaceae), to test the impact of fruits harvest, climate and habitat size (gallery forest width) on the frequency of sexual or clonal recruitment in Benin, West Africa. We sampled populations in two ecological regions (Sudanian and Sudano‐Guinean) and in each region, we selected sites with low, moderate and high fruit harvesting intensities. These populations were selected in gallery forests with varying width to sample the natural variation in P. butyracea habitat size. Heavily harvested populations produced significantly less seedlings but had the highest density and proportion of clonal offspring. Our study suggests that for plant species with dual reproductive strategy (via seeds and clonal), fruit harvesting and associated disturbances that come with it can lead to an increase in the proportion of clonal offspring. This raises the issue that excessive fruit harvest by increasing the proportion of clonal offspring to the detriment of seed originated offspring may lead to a reduction in genetic diversity with consequence on harvested species capability to withstand environmental stochasticity.
Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer
Authors: Nishio Shin , Takekuma Munetaka , Takeuchi Satoshi , Kawano Kouichirou , Tsuda Naotake , Tasaki Kazuto , Takahashi Nobutaka , Abe Masakazu , Tanaka Aki , Nagasawa Takayuki , Shoji Tadahiro , Xiong Hao , Nuthalapati Silpa , Leahy Terri , Hashiba Hideyuki , Kiriyama Tsukasa , Komarnitsky Philip , Hirashima Yasuyuki , Ushijima Kimio
Published: August 2017

This phase 1, open‐label, dose‐escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21‐day cycles. Dose escalation followed a 3 + 3 design to determine dose‐limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose‐limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.
Chromobox homolog 8 is a predictor of muscle invasive bladder cancer and promotes cell proliferation by repressing the p53 pathway
Authors: Yuan Gang‐jun , Chen Xin , Lu Jun , Feng Zi‐hao , Chen Si‐liang , Chen Ri‐xin , Wei Wen‐su , Zhou Fang‐jian , Xie Dan
Published: August 2017

Chromobox homolog 8 (CBX8), also known as human polycomb 8, is a repressor that maintains the transcriptionally repressive state in various cellular genes, and has been reported to promote tumorigenesis. In the present study, we examined CBX8 expression in eight pairs of muscle invasive bladder cancer tissues and adjacent non‐tumor tissues, and found that CBX8 was frequently upregulated in muscle invasive bladder cancer tissues when compared to adjacent non‐tumor tissues. Analysis showed that high expression of CBX8 in 152 muscle invasive bladder cancer specimens was associated with progression of the T, N, and M stages (P = 0.004, 0.005, <0.001, respectively). Furthermore, Kaplan–Meier survival analysis and log–rank test showed that muscle invasive bladder cancer patients with high CBX8 expression had a poor rate of overall survival (P < 0.001) and 5‐year recurrence‐free survival (P < 0.001) compared to patients with low CBX8 expression. High CBX8 expression predicted poor overall survival and 5‐year recurrence‐free survival in T and N stages of muscle invasive bladder cancer patients. Moreover, knockdown of CBX8 inhibited cell proliferation of urothelial carcinoma of the bladder both in vitro and in vivo. In addition, CBX8 depletion resulted in cell cycle delay of urothelial carcinoma cells of the bladder at the G2/M phase by the p53 pathway. The data suggest that high expression of CBX8 plays a critical oncogenic role in aggressiveness of urothelial carcinoma cells of the bladder through promoting cancer cell proliferation by repressing the p53 pathway, and CBX8 could be used as a novel predictor for muscle invasive bladder cancer patients.
Elevated expression of JAM‐A promotes neoplastic properties of lung adenocarcinoma
Authors: Magara Kazufumi , Takasawa Akira , Osanai Makoto , Ota Misaki , Tagami Yohei , Ono Yusuke , Takasawa Kumi , Murata Masaki , Hirohashi Yoshihiko , Miyajima Masahiro , Yamada Gen , Hasegawa Tadashi , Sawada Norimasa
Published: August 2017

A cell–cell adhesion protein, junctional adhesion molecule‐A (JAM‐A), has been shown to be involved in neoplasia of various organs. However, the fundamental role of JAM‐A in tumorigenesis is still under debate because dysregulated expression of this protein has distinct effects, playing opposite roles in carcinogenesis depending on the target tissues. In the present study, we found elevated levels of JAM‐A expression in lung adenocarcinoma and its preinvasive lesions, including atypical adenomatous hyperplasia and adenocarcinoma in situ by immunohistochemistry. We also showed that suppression of constitutive JAM‐A expression conferred target cells with increased susceptibility to apoptosis in lung adenocarcinoma cells. Consequently, inhibition of JAM‐A activity decreased colony‐forming capability in vitro and tumorigenicity in vivo. The transformed phenotype following suppression of JAM‐A expression was sufficient to reduce motile and invasive capacities. Importantly, knockout of JAM‐A had striking effects on cells. Our observations suggest that increased expression of JAM‐A promotes neoplasia of lung adenocarcinoma. In addition, an anti‐JAM‐A antibody efficiently reduced cell proliferation and provoked apoptosis, indicating the potential feasibility of JAM‐A‐inhibitory cancer therapy.
Smart Conformists: Children and Adolescents Associate Conformity With Intelligence Across Cultures
Authors: Wen Nicole J. , Clegg Jennifer M. , Legare Cristine H.
Published: August 2017

The current study used a novel methodology based on multivocal ethnography to assess the relations between conformity and evaluations of intelligence and good behavior among Western (U.S.) and non‐Western (Ni‐Vanuatu) children (6‐ to 11‐year‐olds) and adolescents (13‐ to 17‐year‐olds; N = 256). Previous research has shown that U.S. adults were less likely to endorse high‐conformity children as intelligent than Ni‐Vanuatu adults. The current data demonstrate that in contrast to prior studies documenting cultural differences between adults' evaluations of conformity, children and adolescents in the United States and Vanuatu have a conformity bias when evaluating peers' intelligence and behavior. Conformity bias for good behavior increases with age. The results have implications for understanding the interplay of conformity bias and trait psychology across cultures and development.
Effect of vitamin D on blood–brain barrier function in multiple sclerosis
Authors: Suzumura Akio
Published: August 2017

Vitamin D deficiency might be a risk factor for multiple sclerosis (MS). The active form of vitamin D has some protective effects on MS. The study by Takahashi et al. in this issue addressed the question of how vitamin D works on MS pathology. Using a human brain microvascular endothelial cell line, they showed that vitamin D attenuated the damage of barrier function of the cell line after exposure to either MS sera or tumor necrosis factor‐α. The study along with their previous study suggests that vitamin D might protect blood–brain barrier function, and could give us a rationale for the use of vitamin D in MS patients.
‘A Pest to Society’: The Charity Organisation Society's Domiciliary Assessments into the Circumstances of Poor Families and Children
Authors: Skinner Annie , Thomas Nigel
Published: August 2017

This article examines the work of the Charity Organisation Society (COS) in assessing applications for children's admission to care in the late nineteenth‐century. It is based on an archive study of records kept by the ‘Waifs and Strays’ Society in England and Wales between 1882 and 1899, in particular 270 family assessments conducted by the COS. The focus was on parental behaviour rather than children's needs, with a strong narrative of taking children away to relieve parents of a burden. The research illuminates contested assumptions about childhood in the period, with resonance for current issues in policy and practice.