bluuebunny/crossref_metadata_2025 huggingface dataset:
New Possibilities for Project Management Theory: A Critical Engagement
Authors: Cicmil Svetlana , Hodgson Damian
Published: July 2018

This paper provides avenues for a broader engagement with the conceptual considerations of projects and project management with the aim of creating new possibilities for thinking about, researching, and developing our understanding of the field as practiced. Attention is drawn to the legacy of conventional but deeply rooted mainstream approaches to studying projects and project management, and implications of the specific underpinning intellectual tradition for recommendations proposed to organisational members as best practice project management. The identified concerns and limitations are discussed in the context of project management evolution where taken-for-granted advantages of project management as a disciplined effective methodology and its popularity are reexamined. The paper sheds light on a variety of voices from both scholarly and practitioner communities that have attempted to respond to this paradox and move the field forward. Taking issue with conventional labels of project success or failure, and drawing attention to alternative theoretical and methodological propositions, the argument turns toward critical management studies, outlining the implications of this intellectual tradition for studies of projects, project management, project performance, and individual skills and competencies to cope with social arrangements labelled “projects.”
Managing Project Risks as Knowledge Gaps
Authors: Regev Sary , Shtub Avraham , Ben-Haim Yakov
Published: July 2018

The development of new technologies and the implementation of such technologies in new applications is a continuous effort to close technological and logistical knowledge gaps. Although knowledge gapscan be closed by accident—like the case of Archimedes who closed an important knowledge gap about the laws of nature while bathing—in most cases, knowledge gaps are closed by a consistent, organized effort, namely by projects.

Project management methodologies attempt to manage the risk generated by the one-time nature of projects. This risk is generated by the lack of knowledge and its resulting uncertainty. Tools for managing project risks and their consequences, including risk identification, risk quantification, risk elimination, risk reduction, risk sharing, and risk control, were developed and are implemented to some degree in many technological projects. However, most of these tools are based on statistical theory (e.g., the central limit theorem). Unfortunately, statistical theory may not be applicable to technological projects where there is very little or no relevant previous experience at all. The question is: what can we do when past data is not an appropriate basis for future decisions?

In this paper we describe a new approach for dealing with technological projects—an approach based on the analysis of knowledge gaps (i.e., the gap between what we should know in order to succeed in the project and what we really know).
The Changing Bias of Project Management Research: A Consideration of the Literatures and an Application of Extant Theory
Authors: Leybourne Stephen A.
Published: July 2018

This paper addresses two important current trends in project management research: the first relating to the changing emphasis of project-based research output, and the second relating to the development of a theory of project management. The first aspect is driven by evidence of a move from process-based research toward the interactions between people and projects. The second involves the alignment of certain aspects of the management of projects with more established theoretical domains. This paper applies a theoretical lens to some elements of the management of project-based work, in order to embed it within more robust theoretical imperatives.
Soft Skills Quantification (SSQ) Foi Project Manager Competencies
Authors: Muzio Edward , Fisher Deborah J. , Thomas Erv R. , Peters Valerie
Published: July 2018

“Soft” skills, also referred to as “micro-social” skills, are universally recognized as being critical to successful project management. Methods of measuring those skills, however, are to date largely subjective and nonsystematic. This paper examines multiple approaches to the problem, as well as the next evolution in soft skill assessment: a model that allows soft skill quantification (SSQ), and its utility in predicting performance. The results of an SSQ assessment were compared to formal employee performance results and individual program manager observations. Using a small initial sample, the SSQ model provided statistically verifiable alignment with professional project management employee performance. Moreover, the assessment identified specific strengths and weaknesses beyond what the manager was able to deduce from observation, and it highlighted the importance of skill areas that were not initially thought to be important by the manager.
An Existential Hermeneutic Philosophical Approach to Project Management
Authors: Rolfe Bradley , Segal Steven , Cicmil Svetlana
Published: July 2018

The philosophies of Martin Heidegger and Richard Rorty are used to redescribe the fundamental assumptions underpinning project management. Rather than viewing project management as merely a science, the significance and value of philosophy for project management are developed. The philosophical practice of redescription as a way of responding to existential disruptions of the lived experience of managing projects is seen as vital not only to being a project manager but also to describing project management.
Let's Discuss Aesthetics for Projects
Authors: van der Hoorn Bronte , Whitty Jon
Published: July 2018

Aesthetics is concerned with the knowledge and affects related to sensory experience and corporeality (the body). While there has been an increase in the literature based on non-positivist foundations and focusing on the “lived experience” of projects, there remains a need to recognize aesthetic factors—for example: dress, office layout, and body language—in the project experience. Aesthetics enable us to access facets of the project experience that are beyond the rational and analytic. This article uses Heideggerian concepts to explore this “missing mass” in project management and proposes the need for further research and education in this area.
Why Distinctions Matter: What Does Philosophical Analysis Have to Do with Project Management?
Authors: Idler José
Published: July 2018

This article explores the conceptual nature of project management and argues that making distinctions, as seen in the analytic philosophical method, is a powerful tool for optimizing project outcomes. Project management relies on conceptual analysis, and further understanding this form of analysis can help project managers gain a clearer understanding of what an expected project outcome is and how to judge whether the outcome has been achieved.
The Metaphysical Questions Every Project Practitioner Should Ask
Authors: Ika Lavagnon A. , Bredillet Christophe N.
Published: July 2018

Project practitioners become so familiar with the word project that they think about it more in terms of how it is used, and less in terms of what it really is. But is there such a thing as the project being managed? What's most real in the project? What's a project? We raise these questions to contribute a subtler understanding of project management, and to help project practitioners see that their metaphysical stance informs their project management style: A thing-based understanding leads to a planned project management style, and a process-based understanding leads to an emergent management style.
The Open Secret of Values: The Roles of Values and Axiology in Project Research
Authors: Biedenbach Thomas , Jacobsson Mattias
Published: July 2018

The purpose of this article is to explore the roles and potential benefits of axiology and value theory in project research. This is done through (1) an exploration of the essentials of axiology and value theory; (2) a review focused on how values have been used in project research; and (3) a reflection based on the historical–logical development of—and paradigmatic influences on—projects and their management. It is concluded that project research would benefit from a more encompassing philosophical treatment of axiology beyond merely acknowledging values as a thematic concept or as part of a project management methodology.
Governance and Ethics in Temporary Organizations: The Mediating Role of Corporate Governance
Authors: Müller Ralf , Turner J. Rodney , Andersen Erling S. , Shao Jingting , Kvalnes Øyvind
Published: July 2018

The impact of multilevel level governance on the frequency of ethical issues in temporary organizations (TOs) is investigated. A structural equation model, based on a global survey, showed that behavior control, as a governance mechanism at the temporary organization (TO) level, reduces the frequency of ethical issues. This relationship is partly mediated through corporate governance, which controls ethical issues by following good governance principles. Using institutional and agency theory, we identify a substitution effect, where micro level (TO) governance substitutes for ‘holes’ in the macro level (corporate) governance. Situational contingencies for the synchronization of governance efforts across macro and micro levels are discussed.
Sustainability and Success Variables in the Project Management Context: An Expert Panel
Authors: Martens Mauro Luiz , Carvalho Marly M.
Published: July 2018

This research identifies the key variables of sustainability in project management and explores the impact of these variables on project success. The methodological approach combined a literature review and an expert panel. The expert panel was conducted in two phases: interviews were conducted with five experts to validate the content of the identified variables, and a forum was held with 11 experts from 10 universities in 6 different countries. Research data were analyzed using content analysis, descriptive statistics, and analytic hierarchy process. Through systematic expert reviews, this research shows a succinct and relevant list of variables and their classification, reflecting the experts’ consensus, which can help practitioners and scholars introduce sustainability into project management. Similarly, the key variables for project success are identified and classified. Finally, the article explores the experts’ perspectives on the impact of sustainability in project success.
Profiling Project Complexity: Insights from Complexity Science and Project Management Literature
Authors: Kiridena Senevi , Sense Andrew
Published: July 2018

The current understanding of project complexity is limited in that there is neither a widely recognized conceptualization of project complexity nor a convergent view on how to deal with its effects. Drawing on the extant literature concerning project complexity and complexity science, this article develops a coherent and holistic profile of project complexity and provides reflections on its implications for project management theory and practice. This profile serves as a touchstone for practitioners to better understand, assess, and address complexity in their projects and as an aid to researchers in framing their research efforts.
Risk Identification in Megaprojects as a Crucial Phase of Risk Management: A Literature Review
Authors: Sanchez-Cazorla Alvaro , Alfalla-Luque Rafaela , Irimia-Dieguez Ana Isabel
Published: July 2018

The purpose of this study is to perform a literature review of risk management in megaprojects and systematize the risks studied in the literature. A systematic search of the main databases has been performed. The contributions include: (1) a bibliometric analysis of articles; (2) the systematization and classification into nine categories of the risks found in a content analysis of the articles; and (3) the identification of possible areas of interest for research and practice. Risks are comprehensively categorized to assist practitioners during the identification phase, while potential areas for future lines of research are presented for academics.
The Impact of Project Managers’ Personality on Project Success in NGOs: The Mediating Role of Transformational Leadership
Authors: Hassan Muhammad Mubbashar , Bashir Sajid , Abbas Syed Moqaddas
Published: July 2018

This study examined the extent to which project managers’ personality determines project success through the mediating mechanism of transformational leadership. The context of the study was nongovernmental projects that focused on education and health. Data were collected from 170 project managers who were engaged in 10 different programs in various areas of Pakistan. Based on the post-positivism approach and a specific deductive design, the results of the study indicated that Extraversion, Agreeableness, and Openness to Experience were direct positive predictors of project success, whereas transformational leadership acted as a mediator of these relations. One of the personality dimensions (i.e., Conscientiousness) had only an indirect effect on project success through transformational leadership. No relation was found between Neuroticism and project success. The theoretical and practical implications for project management are also discussed.
Toward a Systemic View to Cost Overrun Causation in Infrastructure Projects: A Review and Implications for Research
Authors: Ahiaga-Dagbui Dominic D. , Love Peter E. D. , Smith Simon D. , Ackermann Fran
Published: July 2018

Infrastructure cost overruns receive a significant amount of attention in the academic literature as well as the popular press. The methodological weaknesses in the dominant approaches adopted to explain cost overrun causation on infrastructure projects are explored in this article. A considerable amount of cost overrun research is superficial, replicative, and thus has stagnated the development of a robust theory to mitigate and contain the problem. Future research should move from single-cause identification and the traditional net-effect correlational analysis to a search for causal recipes through systems thinking and retrospective sensemaking to address the high-level interactions between multiple factors.
Customer Participation and Project Performance: A Moderated-Mediation Examination
Authors: Yu Ming-Chuan
Published: July 2018

This article proposes a theoretical model to understanding how and why customer participation can promote project performance. The research model was empirically examined by collecting data from 245 software development projects. The research found that knowledge integration mediates the positive relationship between customer participation and project performance. Additionally, project complexity strengthens the main effect of customer participation and an indirect effect of knowledge integration was found. Theoretical and managerial implications for project management and research limitations are also discussed.
Comparative Analysis of the Success Criteria for Public–Private Partnership Projects in Ghana and Hong Kong
Authors: Osei-Kyei Robert , Chan Albert P. C.
Published: July 2018

The criteria for measuring the success of public–private partnership (PPP) projects have become very topical because of the global interest in PPP project success. This article empirically investigates the differences and similarities of PPP project success criteria in developing and developed economies, represented by Ghana and Hong Kong, respectively. Results reveal profitability, meeting output specifications, and adherence to budget as the top three success criteria in Ghana, whereas adherence to budget, adherence to time, and effective risk management are considered more important in Hong Kong. The findings inform practitioners of the success measures considered in PPP in developing and developed countries.
The Influence of Critical Success Factors on Value for Money Viability Analysis in Public–Private Partnership Projects
Authors: Almarri Khalid , Boussabaine Halim
Published: July 2018

Governments are increasingly entering partnerships with the private sector through the public–private partnership (PPP) model for the development of public projects. Value for money analysis is used to assess the viability of these ventures. This research aims to investigate the contribution of the PPP critical success factors to value for money viability analysis. Relevant data were collected through a questionnaire to establish the PPP critical success factors and value for money success criteria. Data were collected from 92 participants. The data obtained were analyzed using mean score, t-test, and regression analysis. The research found that government guarantees, macroeconomic conditions, shared authority between the public and private sectors, social support, and transparent procurement process contributed positively to value for money viability analysis. The results imply that practitioners should consider these key indicators for improving the value for money viability of PPP projects.
Mechanisms of Isomorphism in Project-Based Organizations
Authors: Miterev Maxim , Engwall Mats , Jerbrant Anna
Published: July 2018

This article challenges the dominant assumption of goal rationality behind temporary organizations’ design in project-based organizations (PBOs). While extant literature posits that organizations strive to select the most appropriate project arrangements to fit particular task requirements at hand, findings from an in-depth ethnography-inspired case study suggest that projects in PBOs tend to imitate each other's structures, strategies, and practices with little consideration of the potential performance effects. Building upon the new institutionalism, this article conceptualizes the PBO as an organizational field of temporary and permanent organizations embedded in wider organizational and institutional fields and explicates isomorphic processes among temporary organizations in PBOs.
Achieving Sustainability in Railway Projects: Major Stakeholder Concerns
Authors: Yuan Hongping
Published: July 2018

Achieving sustainability is becoming increasingly critical for measuring the overall success of infrastructure projects. Given the complexity of such projects, the successful management of sustainability-related targets requires joint efforts from the major stakeholders involved, including project clients, contractors, suppliers, and the general public. Nevertheless, these stakeholders often have different, and sometimes even conflicting, concerns regarding the achievement of project sustainability. Confrontations and disputes can arise unless these concerns are carefully analyzed and addressed. However, we know little specifically about how major stakeholders perceive infrastructure sustainability and how their concerns differ in the three dimensions of project sustainability: economic, environmental, and social sustainability. This study investigated the major concerns of stakeholders in achieving sustainability in a typical infrastructure project (i.e., railway projects). A triangulated methodology was adopted, including a literature review, a questionnaire survey, and interviews to obtain data from project stakeholders. Based on the results, there was a significant divergence of views among stakeholder groups, and conflicts arose when there was a mismatch between stakeholders’ perceptions. A list of major concerns from each individual stakeholder group was ranked and discussed. Some measures for promoting the consensus on achieving project sustainability among different stakeholder groups were also provided. The study not only provides insights into understanding differences in the concerns of major stakeholder groups in achieving railway project sustainability, it also helps develop quantitative approaches for measuring the degree of consensus and conflict among major stakeholder groups so as to minimize their concern differences.
Competitive Precinct Projects: The Five Consistent Criticisms of “Global” Mixed-Use Megaprojects
Authors: Harris Mike
Published: July 2018

Mixed-use megaprojects on state-owned land have been increasingly occurring around the world over the past few decades. This article reviews the body of literature that has emerged on these projects during this period and investigates a number of projects more deeply by reviewing original planning documents and undertaking interviews with government officials, consultants, and other insiders. Project motives, delivery methods, and built outcomes have been examined in order to contextualize their emergence and proliferation, leading to a typological understanding, defined in this article as competitive precinct projects. A content analysis of 30 reviews covering 42 mixed-use megaprojects in 20 countries reveals remarkable global consistency in thematic criticisms. Framed in this article as the “five consistent criticisms of ‘global’ mixed-use megaprojects,” they pose a significant barrier to addressing increasingly complex urban challenges as well as to their successful management from inception to delivery. While the consistent criticisms represent patterns that have endured within a globally active urban development type for over three decades, this research shows that rather than being a neoliberal hegemony, there are mixed political and ideological aims and outcomes across projects and sometimes within the same project. A typological understanding allows patterns to be examined and understood, variances and hybridity to be evaluated, and more sophisticated future directions to be mapped out in the pursuit of broader based and city-scale project outcomes.
Evolutionary Governance for Mega-Event Projects (Meps): A Case Study of the World Expo 2010 in China
Authors: Li Yongkui , Lu Yujie , Ma Liang , Kwak Young Hoon
Published: July 2018

A mega-event is an open socioeconomic system characterized by massive budget demands and multiple types of subprojects and their complex interrelationships. Although a mega-event is an opportunity for a country to show its international reputation, management capacity, and societal strength, it demands a long preparation time; an enormous amount of investment; and massive resource mobilization, with far-reaching effects on both the economic and social development of a country. Mega-event projects (MEPs) face remarkable challenges in terms of overrun costs, delayed schedules, and political issues, indicating that the research on such mega-events is still insufficient and that there is a lack of effective theories to support the management and governance of MEPs. Existing studies have also ignored the dynamic evolution and adaptation of governance in a changing environment, particularly in relation to the success of MEPs. To fill this research gap, this study aims to examine the dynamic governance of MEPs on the basis of a new theory—evolutionary governance theory (EGT)—which combines institutional economics, systems theory, and project governance. The study was conducted in three main steps: (1) studying the case of the evolutionary governance of the World Expo 2010 in China during its life cycle stage, including planning, construction, operation, and post-event development; (2) discussing the impact of the hierarchical and cross-functional governance structure of the Expo; and (3) summarizing the theories and best practices of dynamic governance mechanisms for MEPs. The result of the study can deepen understanding of the multi-level governance of mega-events during the life cycle process and can also support the evolution of governance transition over the different stages.
Converting Remote Distribution Centers to a Frame Relay Based Wide Area Network
Authors: Levins Jess W.
Published: July 2018

This case study reviews a project that involved the selection and installation of a new information system for unifying four auto parts distribution centers within an overall corporate system. The system consists of local area networks joined together in a wide area network utilizing Fractional T1s and frame relay technology. The project included the implementation of a warehouse management system with radio frequency bar code scanners integrated with inventory, operating and other software for enhancing overall warehouse management.
Project Leadership: A Question of Timing
Authors: Thoms Peg , Pinto Jeffrey K.
Published: July 2018

Project managers face a profession coupled with a number of unique challenges. Tasked with the successful implementation of their project, these leaders are given a mandate to operate their project teams as de facto profit centers for the organization as a whole. One key skill that successful project leaders need to master is the ability to attune their temporal skills to the nature of the work they are called upon to perform. Different aspects of their duties require appropriate and varying time orientations. This paper discusses the development of a model of time orientation, which argues that project leaders must possess or develop a number of temporal skills that match the various tasks and situations they are called upon to address. Finally, we posit some roles that project leaders must undertake and the desirable temporal alignment likely to enhance their chances for success.
A Quality Management Case Study: Defects in Spacecraft Electronics Components
Authors: Kuprenas John A. , Kendall Randolph L. , Madjidi Farzin
Published: July 2018

Production of spacecraft components presents a management challenge in that the systems are complex, costly to build and launch, and once a spacecraft is launched, it is extremely difficult and expensive to repair. For these reasons, strict standards for quality and reliability are essential. This paper presents a project quality management case study for the production of spacecraft electronics components as part of an overall spacecraft project. Printed circuit board data is examined by project managers using a Pareto analysis of different defect types to reveal process problems. Corrective actions to the production process that were implemented by project managers are explained, and ideas to improve future quality management studies, regardless of the industry, are discussed.
Critical Chain Project Management Improves Project Performance
Authors: Leach Larry P.
Published: July 2018

This paper describes the theory and practice of critical chain project management (CCPM). CCPM provides a substantial step in the ongoing improvement to the Project Management Body of Knowledge. The critical chain differs from the critical path by including resource dependencies and never changing. CCPM improves the project plan by ensuring that it is feasible and immune from reasonable common cause variation (uncertainty or statistical fluctuations). It does this by aggregating uncertainty into buffers at the end of activity paths (or chains). The project buffer protects the overall project completion on the critical chain path, and feeding buffers protect the critical chain from path merging. Buffer management enhances measurement and decision-making for project control. CCPM implements required changes in resource behavior, including elimination of date-driven activity performance and multitasking. Most of all, CCPM improves the focus of the project manager and performers. Projects that use CCPM have a greatly improved record of schedule, cost, and scope performance. Experience with CCPM projects demonstrates completion in less than one half the time of projects using previous planning and control methods.
Fuzzy Operations and Petri Nets: Techniques for Resource Substitution in Projects
Authors: Kumar V.K. Ashok , Ganesh L.S.
Published: July 2018

This paper discusses the linguistic labels that an expert would use to describe the effects of different types of resource substitutions and shows how a simple fuzzy aggregation method can be used to assess the net effect of the substitutions. A Petri net model, which can accommodate multiple resources and dynamically generate activity schedules taking into consideration resource availability and substitution, is used for illustration. The simple example presented brings out the usefulness of fuzzy operations and Petri net techniques for real-time project activity scheduling by monitoring quantity and quality of multiple resources in a resource-constrained project environment. The methodology can be equally effectively extended to incorporate other external factors such as weather conditions, changes in work specifications, changed conditions in contracts and cash flow.
An Assessment of Post-Project Reviews
Authors: Busby J.S.
Published: July 2018

A detailed analysis of post-project reviews was conducted to assess whether such reviews should be conducted, and, if so, how they should be conducted. It was found that post-project reviews are effective in disseminating knowledge about good practices, correcting errors in individuals’ knowledge (especially their knowledge about other functions within the organization), and predicting how well alternative practices would have turned out. At the same time these reviews demonstrated several limitations. The diagnosis that took place in reviews tended to be shallow, remedies were planned only at a very superficial level, and explanations of events tended to be overly specific. Participants also made potentially misleading assumptions: for example, that unimportant problems implied unimportant causes. Nonetheless, post-project reviews are important learning mechanisms and their value seems to be underestimated by individuals who do not appreciate the need to disseminate insights throughout the organization.
Requirements for an Effective Project Risk Management Process
Authors: Ward Stephen
Published: July 2018

Requirements for an effective risk management process carried out by a project participant are associated with the project context and characteristics of the participant. Project context can be characterized by the nature of the project, the immediate working environment, the identity and actions of other participants, and the progress of the project to date. Characteristics related to a particular project participant include motivation, capability, and perceived responsibilities in undertaking risk management. This paper discusses how these factors influence the manner in which project risk management processes should be undertaken.
Compass: An Assessment Tool for Improving Project Team Communications
Authors: Thomas Stephen R. , Tucker Richard L. , Kelly William R.
Published: July 2018

Research from the Construction Industry Institute (CII) confirms the importance of effective communications to project success. As part of its research into the potential for enhanced project success through improvement in team communications, a CII research team developed “Compass,” the Communications Project Assessment Tool. Compass is a Windows-compatible software application designed for project manager use in assessing team communications during the design and construction phases of engineering, procurement, and construction projects. The tool collects and analyzes team member responses, assesses the effectiveness of team communications, and provides benchmark results from 72 CII projects for comparison.
Natural clay from Cuba for environmental remediation
Authors: Martín S. A. , Valdés L. , Mérida F. , de Ménorval L. C. , Velázquez M. , Rivera A.
Published: July 2018

The use of natural clays for the removal of dyes from wastewater, an important part of environmental remediation, is desirable due, not least, to their low cost. Palygorskite (PAL), a rigid-structure clay, is a good candidate for use in the elimination of industrial effluents, based on its exceptional adsorptive properties. Recently, a new palygorskite deposit has been discovered in Cuba and its use in the adsorption of dyes has not yet been explored in detail. In the present study, the use of unmodified natural Cuban palygorskite as a host for dyes was evaluated. Congo red (CR) and methylene blue (MB) were the anionic and cationic dyes tested, respectively, because of their wide use and toxicity to the environment. Several physical-chemical parameters were studied in order to establish the best experimental conditions under which to achieve the greatest dye load per gram of clay. Natural mixtures with different percentages of montmorillonite were also tested to evaluate their effect on the adsorption of the dyes. The results indicated that at pH values of ~7–9 and an initial dye concentration of 0.1 mg mL–1, the process was efficient. X-ray diffraction (XRD) analysis proved the surface adsorption of both dyes on the clays. The main interactions involved in the clay-dye system were electrostatic forces and H-bonds. Adsorption of CR seemed to be controlled fundamentally by the palygorskite phase. Such results support the use of this natural clay as an efficient host for the removal of MB and CR from wastewater.
Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease
Authors: Branford Susan , Wang Paul , Yeung David T. , Thomson Daniel , Purins Adrian , Wadham Carol , Shahrin Nur Hezrin , Marum Justine E. , Nataren Nathalie , Parker Wendy T. , Geoghegan Joel , Feng Jinghua , Shanmuganathan Naranie , Mueller Martin C. , Dietz Christian , Stangl Doris , Donaldson Zoe , Altamura Haley , Georgievski Jasmina , Braley Jodi , Brown Anna , Hahn Christopher , Walker Ieuan , Kim Soo-Hyun , Choi Soo-Young , Park Sa-Hee , Kim Dong-Wook , White Deborah L. , Yong Agnes S. M. , Ross David M. , Scott Hamish S. , Schreiber Andreas W. , Hughes Timothy P.
Published: July 2018

Key Points

Next-generation sequencing revealed variants in cancer-associated genes at diagnosis of CML more frequently in patients with poor outcomes. All patients at BC had mutated cancer genes, including fusions, that predated BCR-ABL1 kinase domain mutations in a majority.
Modelling out-of-area admissions
Authors: Paton Lewis W. , Tiffin Paul A.
Published: July 2018

Out-of-area (OOA) placements occur when patients cannot be admitted to local facilities, which can be extremely stressful for patients and families. Thus, the Department of Health aims to eliminate the need for OOA admissions. Using data from a UK mental health trust we developed a ‘virtual mental health ward’ to evaluate the potential impact of referral rates and length of stay (LOS) on OOA rates. The results indicated OOA rates were equally sensitive to LOS and referral rate. This suggests that investment in community services that reduce both LOS and referral rates are required to meaningfully reduce OOA admission rates.

Declaration of interest

P.A.T. holds an honorary consultant contract with the Tees, Esk and Wear Valleys NHS Foundation Trust.
SP8 and SP9 coordinately promote D2-type medium spiny neuron production by activating Six3 expression
Authors: Xu Zhejun , Liang Qifei , Song Xiaolei , Zhang Zhuangzhi , Lindtner Susan , Li Zhenmeiyu , Wen Yan , Liu Guoping , Guo Teng , Qi Dashi , Wang Min , Wang Chunyang , Li Hao , You Yan , Wang Xin , Chen Bin , Feng Hua , Rubenstein John L. , Yang Zhengang
Published: July 2018

Dopamine receptor DRD1-expressing medium spiny neurons (D1 MSNs) and dopamine receptor DRD2-expressing medium spiny neurons (D2 MSNs) are the principal projection neurons in the striatum, which is divided into dorsal striatum (caudate nucleus and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle). Progenitors of these neurons arise in the lateral ganglionic eminence (LGE). Using conditional deletion, we show that mice lacking the transcription factor genes Sp8 and Sp9 lose virtually all D2 MSNs as a result of reduced neurogenesis in the LGE, whereas D1 MSNs are largely unaffected. SP8 and SP9 together drive expression of the transcription factor Six3 in a spatially restricted domain of the LGE subventricular zone. Conditional deletion of Six3 also prevents the formation of most D2 MSNs, phenocopying the Sp8/9 mutants. Finally, ChIP-Seq reveals that SP9 directly binds to the promoter and a putative enhancer of Six3. Thus, this study defines components of a transcription pathway in a regionally restricted LGE progenitor domain that selectively drives the generation of D2 MSNs.
A carcinogenic trigger to study the function of tumor suppressor genes in Schmidtea mediterranea
Authors: Van Roten Andromeda , Barakat Amal Zohir Abo-Zeid , Wouters Annelies , Tran Thao Anh , Mouton Stijn , Noben Jean-Paul , Gentile Luca , Smeets Karen
Published: July 2018

Planarians have been long known for their regenerative ability, which hinges on pluripotency. Recently, however, the planarian model has been successfully established for routine toxicological screens aimed to assess overproliferation, mutagenicity and tumorigenesis. In this study, we focused on planarian tumor suppressor genes (TSGs) and their role during chemically induced carcinogenic stress in Schmidtea mediterranea. Combining in silico and proteomic screens with exposure to human carcinogen type 1A agent cadmium (Cd), we showed that many TSGs have a function in stem cells and that, in general, exposure to Cd accelerated the onset and increased the severity of the observed phenotype. This suggested that the interaction between environmental and genetic factors plays an important role in tumor development in S. mediterranea. Therefore, we further focused on the synergistic effects of Cd exposure and p53 knockdown (KD) at the cellular and molecular levels. Cd also produced a specific proteomic landscape in homeostatic animals, with 172 proteins differentially expressed, 43 of which were downregulated. Several of these proteins have tumor suppressor function in human and other animals, namely Wilms Tumor 1 Associated Protein (WT1), Heat Shock Protein 90 (HSP90), Glioma Pathogenesis-Related Protein 1 (GLIPR1) and Matrix Metalloproteinase B (Smed-MMPB). Both Glipr1 and MmpB KD produced large outgrowths, epidermal lesions and epidermal blisters. The epidermal blisters that formed as a consequence of Smed-MmpB KD were populated by smedwi1+ cells, many of which were actively proliferating, while large outgrowths contained ectopically differentiated structures, such as photoreceptors, nervous tissue and a small pharynx. In conclusion, Smed-MmpB is a planarian TSG that prevents stem cell proliferation and differentiation outside the proper milieu.
HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice
Authors: Kim Young-Eun , Lee Minji , Gu Hyejung , Kim Jeongwoo , Jeong Seongju , Yeo Sujin , Lee You Jeong , Im Sin-Hyeog , Sung Young-Chul , Kim Hak Jae , Weissman Irving L. , Ahn G-One
Published: July 2018

Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.
Switch-like PKA responses in the nucleus of striatal neurons
Authors: Yapo Cédric , Nair Anu G. , Hellgren Kotaleski Jeanette , Vincent Pierre , Castro Liliana R. V.
Published: July 2018

Although it is known that protein kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast all-or-none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus. Our numerical model suggests that a positive feed-forward mechanism inhibiting nuclear phosphatase activity – possibly mediated by DARPP-32 (also known as PPP1R1B) – could be responsible for this non-linear pattern of nuclear PKA response, allowing for a better detection of the transient dopamine signals that are often associated with reward-mediated learning.
Lipid-dependence of target membrane stability during influenza viral fusion
Authors: Haldar Sourav , Mekhedov Elena , McCormick Chad D. , Blank Paul S. , Zimmerberg Joshua
Published: July 2018

Although influenza kills about a half million people each year, even after excluding pandemics, there is only one set of antiviral drugs: neuraminidase inhibitors. By using a new approach utilizing giant unilamellar vesicles and infectious X-31 influenza virus, and testing for the newly identified pore intermediate of membrane fusion, we observed ∼30–87% poration, depending upon lipid composition. Testing the hypothesis that spontaneous curvature (SC) of the lipid monolayer controls membrane poration, our Poisson model and Boltzmann energetic considerations suggest a transition from a leaky to a non-leaky fusion pathway depending on the SC of the target membrane. When the target membrane SC is below approximately −0.20 nm−1 fusion between influenza virus and target membrane is predominantly non-leaky while above that fusion is predominantly leaky, suggesting that influenza hemagglutinin (HA)-catalyzed topological conversion of target membranes during fusion is associated with a loss of membrane integrity.
Why do models of insect respiratory patterns fail?
Authors: Terblanche John S. , Woods H. Arthur
Published: July 2018

Insects exchange respiratory gases using an astonishing diversity of patterns. Of these, discontinuous gas exchange cycles (DGCs) have received the most study, but there are many other patterns exhibited intraspecifically and interspecifically. Moreover, some individual insects transition between patterns based on poorly understood combinations of internal and external factors. Why have biologists failed, so far, to develop a framework capable of explaining this diversity? Here, we propose two answers. The first is that the framework will have to be simultaneously general and highly detailed. It should describe, in a universal way, the physical and chemical processes that any insect uses to exchange gases through the respiratory system (i.e. tracheal tubes and spiracles) while simultaneously containing enough morphological, physiological and neural detail that it captures the specifics of patterns exhibited by any species or individual. The second difficulty is that the framework will have to provide ultimate, evolutionary explanations for why patterns vary within and among insects as well as proximate physiological explanations for how different parts of the respiratory system are modified to produce that diversity. Although biologists have made significant progress on all of these problems individually, there has been little integration among approaches. We propose that renewed efforts be undertaken to integrate across levels and approaches with the goal of developing a new class of general, flexible models capable of explaining a greater fraction of the observed diversity of respiratory patterns.
Upper thermal limits of growth in brook trout and their relationship to stress physiology
Authors: Chadwick Joseph G. , McCormick Stephen D.
Published: July 2018

Despite the threat of climate change, the physiological mechanisms responsible for reduced performance at high temperatures remain unclear for most species. Elevated but sublethal temperatures may act via endocrine and cellular stress responses to limit performance in important life-history traits such as growth. Here, brook trout (Salvelinus fontinalis) subjected to chronically elevated or daily oscillating temperatures were monitored for growth and physiological stress responses. Growth rate decreased at temperatures above 16°C and was negative at 24°C, with an estimated upper limit for positive growth of 23.4°C. Plasma cortisol increased with temperature and was 12- and 18-fold higher at 22 and 24°C, respectively, than at 16°C, whereas plasma glucose was unaffected by temperature. Abundance of heat shock protein 70 (HSP70) in the gill increased with temperature and was 11- and 56-fold higher at 22°C and 24°C, respectively, than at 16°C. There was no relationship between temperature and plasma Cl−, but there was a 53% and 80% decrease in gill Na+/K+-ATPase activity and abundance at 24°C in comparison with 16°C. Daily temperature oscillations of 4°C or 8°C (19–23°C or 17–25°C) were compared with 21°C controls. Growth rate decreased with temperature and was 43% and 35% lower by length and mass, respectively, in the 8°C daily oscillation treatment than in the controls. There was no effect of temperature oscillation on plasma cortisol or glucose levels. In contrast, gill HSP70 abundance increased with increasing daily oscillation and was 40- and 700-fold greater at 4°C and 8°C daily oscillation, respectively, than in the constant temperature controls. In individuals exposed to 17–25°C diel oscillations for 4 days and then allowed to recover at 21°C, gill HSP70 abundance was still elevated after 4 days recovery, but not after 10 days. Our results demonstrate that elevated temperatures induce cellular and endocrine stress responses and provide a possible mechanism by which growth is limited at elevated temperatures. Temperature limitations on growth may play a role in driving brook trout distributions in the wild.