bluuebunny/crossref_metadata_2025 huggingface dataset:
Lessons from self-assessments within urban climate resilience programs
Authors: Henceroth Justin , Friend Richard M. , Thinphanga Pakamas , Tran Phong Van Gai , Nghiem Tuyen Phuong
Published: February 2015

Purpose

– This paper aims to review and develop lessons learned from the United Nations Office of Disaster Risk Reduction Local Government Self Assessment Tool (LGSAT) experience in four cities. The capacity to understand, learn from and respond to or reorganize in the face of change is at the core of urban resilience to disasters, climate change and major shocks. Self assessments, like the LGSAT, can be used to engage city stakeholders in critically assessing and understanding their capacity according to a set of standards of resilience.

Design/methodology/approach

– City stakeholders in four cities, Hat Yai and Udon Thani, Thailand and Hue and Lao Cai, Vietnam, completed the LGSAT in an open multi-stakeholder process as part of urban climate resilience programs.

Findings

– Completing the LGSAT provided important and valuable information about institutional capacity that is important for disaster risk reduction and climate change efforts. Multi-stakeholder processes allowed for greater and more sustained dialogue among groups that may not have a chance to interact regularly and helped build trust and relationships that contribute to climate resilience and disaster risk reduction efforts.

Originality/value

– Further, the inclusion of multiple viewpoints allowed for more nuanced and novel consideration of issues and in multiple cities led to new projects that focused on building institutional and agent capacity. The LGSAT process relied on facilitation that was able to guide discussion, ensure safe spaces for dialogue and address stakeholder questions. Finally, while the tool was applied to questions of climate change in this process, there is still room to improve the tool to more adequately and directly address issues of climate change risk.
CARL Libraries – a Canadian resource-sharing experience
Authors: de Jong C J , Frederiksen Linda J
Published: February 2015

Purpose

– This study aims to map the current resource-sharing environment in Canada through the lens of its research libraries in general and the University of Alberta in particular. The findings present an interesting view of changing resource sharing patterns and trends.

Design/methodology/approach

– Interlibrary loan (ILL) transaction data were compiled from annual data reported to the Canadian Association of Research Libraries (CARL) and a case study of the University of Alberta is presented.

Findings

– The current trend shows declines in both borrowing and lending transactions.

Research limitations/implications

– Validity of the CARL ILL transactional data is subject to consistency in institutional reporting and accuracy of the data. The trends portrayed in the data are deemed realistic of the Canadian experience.

Originality/value

– This is an original study of CARL ILL transactional data, providing an aggregated view of 13 years of annual data, and an analysis of this data. It updates previous research and benchmarks current ILL patterns at CARL institutions.
Reform of UK copyright law and its benefits for libraries
Authors: Cornish Graham Peter
Published: February 2015

Purpose

– The purpose of this paper is to provide an overview of copyright law changes in the UK, especially as they affect interlibrary loan.

Design/methodology/approach

– Analysis of new legislation were tested against interlibrary needs.

Findings

– The new laws bring major benefits to libraries and their users by expanding the types of material available and simplifying the management procedures required for document delivery.

Practical implications

– Libraries and other institutions can now offer a much wider range of services.

Social implications

– There are considerable benefits to individual users, including those with disabilities, as access is granted to a wider range of materials.

Originality/value

– New research and analysis relating to laws passed in October 2014.
Understanding the roles of cultural differences and socio-economic status in social media continuance intention
Authors: Hsu Meng-Hsiang , Tien Shih-Wei , Lin Hsien-Cheng , Chang Chun-Ming
Published: February 2015

Purpose

– Drawing upon the literature of Uses and Gratifications (U
&
G) Theory, the purpose of this paper is to propose that entertainment, information seeking, socialization, and self-presentation are the motivational factors affecting continuance intention of social media. This paper further investigates the moderating effects of cultural difference and socio-economic status on the link between these motivational factors and continuance intention.

Design/methodology/approach

– Data collected from the 493 active users of Facebook in five countries (Australia, Austria, Japan, Taiwan, and the USA) were used to test the proposed model. Partial least squares method was used to assess the relationships in the model and the subgroup analysis method was employed as well to examine the moderating roles of cultural difference and socio-economic status.

Findings

– Information seeking exerts stronger effect on continuance intention for users from individualistic cultures, while socialization, and self-presentation has stronger influence on continuance intention for users from collective cultures. Entertainment has stronger influence on continuance for high educated users, whereas self-presentation has stronger influence on continuance intention for users with lower level of education. Finally, the effect of entertainment, information seeking on continuance intention is stronger for users with higher level of income, while self-presentation has stronger influence on continuance intention for users with lower level of income.

Originality/value

– This study is one of first studies to extend the research context of U
&
G Theory from adoption of social media to continuance intention of social media. This study is also the first to investigate the moderating roles of cultural difference and socio-economic statuses in social media usage behavior simultaneously.
Do cultural dimensions differentiate ERP acceptance? A study in the context of Saudi Arabia
Authors: Alhirz Hisham , Sajeev A. S. M.
Published: February 2015

Purpose

– The purpose of this paper is to examine the influence of espoused national cultural values of individuals on user acceptance of enterprise resource planning (ERP) systems. Such an influence is mediated by perceived user resistance, involvement and satisfaction with ERP. Education level, organisational size and ERP user level, on the other hand, are considered as moderating factors.

Design/methodology/approach

– Survey instruments were constructed for relevant variables with items mostly sourced from the literature. In total, 230 ERP users from various organisations in Saudi Arabia participated in the survey. The data were analysed using SPSS and AMOS statistical packages to test the hypotheses.

Findings

– The structural equation model did not show evidence for power distance and individualism influencing perceived user resistance and involvement with ERP, whereas uncertainty avoidance has a significant influence over perceived user involvement and user resistance with ERP. Perceived user involvement positively influences perceived user satisfaction with ERP, and education level moderates the influence. Perceived user satisfaction with ERP positively impacts on user acceptance of ERP; however, moderator variables did not show significant influence on this relationship. Finally, perceived user resistance negatively influences user acceptance of ERP, and the influence varies across education level of the ERP users.

Research limitations/implications

– The results may only generalise to Saudi Arabia and other countries with a similar culture. The sample was identified as users of ERP without taking into account users of individual modules of ERP software.

Practical implications

– Findings of this paper contribute to the existing knowledge of ERP studies from cultural and social perspectives; such a contribution is to broaden the scope of IS research about the implementation and behavioural adoption and acceptance of ERP in middle eastern countries. It will also assist ERP implementers in deciding what cultural factors to consider in preparing an ERP implementation strategy in such countries.

Originality/value

– Prior studies that analysed individual variations in the national cultural values were conducted in the context of general IT acceptance. The authors, instead, study them in an ERP implementation context; this is important because, unlike general IT acceptance, ERP implementations have an all-encompassing mandatory nature and has the potential to change organisational culture. Furthermore, prior studies on ERP usage in Saudi Arabia are mostly qualitative case studies with associated limitations on generalisability. This quantitative study, on the contrary, addresses the influence of individual’s espoused national cultural values on ERP acceptance.
Managing work-life boundaries with mobile technologies
Authors: Cousins Karlene , Robey Daniel
Published: February 2015

Purpose

– The purpose of this paper is to explore the role that mobile technologies play in mobile workers’ efforts to manage the boundaries between work and non-work domains. Previous theories of work-life boundary management frame boundary management strategies as a range between the segmentation and integration of work-life domains, but fail to provide a satisfactory account of technology’s role.

Design/methodology/approach

– The authors apply the concept of affordances, defined as the relationship between users’ abilities and features of mobile technology, in two field studies of a total of 25 mobile workers who used a variety of mobile devices and services.

Findings

– The results demonstrate that the material features of mobile technologies offer five specific affordances that mobile workers use in managing work-life boundaries: mobility, connectedness, interoperability, identifiability and personalization. These affordances persist in their influence across time, despite their connection to different technology features.

Originality/value

– The author found that mobile workers’ boundary management strategies do not fit comfortably along a linear segmentation-integration continuum. Rather, mobile workers establish a variety of personalized boundary management practices to match their particular situations. The authors speculate that mobile technology has core material properties that endure over time. The authors surmise that these material properties provide opportunities for users to interact with them in a manner to make the five affordances possible. Therefore, in the future, actors interacting with mobile devices to manage their work-life boundaries may experience affordances similar to those the authors observed because of the presence of the core material properties.
Same but different? Mobile technology adoption in China
Authors: Song Jinzhu , Sawang Sukanlaya , Drennan Judy , Andrews Lynda
Published: February 2015

Purpose

– The purpose of this paper is to answer two research questions which are “What are key factors which influence Chinese to adopt mobile technology?” and “Do these key factors differ from factors which are identified from western context?”.

Design/methodology/approach

– The findings from a pilot study with 45 in-depth interviews are used to develop questionnaires and test across 800 residents from the three research cities. The data were analyzed by structural equation modeling together with multi-group analysis.

Findings

– The data suggest eight important concepts, i.e. utilitarian expectation, hedonic expectation, status gains, status loss avoidance, normative influence, external influence, cost, and quality concern, are influential factors affecting users’ intentions to adopt 3G mobile technology. Differences are found between the samples in the three research cities in the effect of hedonic expectation, status gains, status loss avoidance, and normative influence on mobile technology adoption intention.

Research limitations/implications

– As the stability of intentions may change over time, only measuring intentions might be inadequate in predicting actual adoption behaviors. However, the focus on potential users is thought to be appropriate, given that the development of 3G is still in its infancy in China.

Originality/value

– Previous research into information technology adoption among Chinese users has not paid attention to regional diversity. Some research considered China as a large single market and some was conducted in only one province or one city. Culturally, China is a heterogeneous country.
Managing BYOD: how do organizations incorporate user-driven IT innovations?
Authors: Leclercq - Vandelannoitte Aurélie
Published: February 2015

Purpose

– In reference to increasing consumerization, this article investigates how organizations react to employees’ adoption and use of personal devices at work, such as by incorporating innovative, individual, IT-driven changes into their corporate practices. The paper aims to discuss these issues.

Design/methodology/approach

– Four in-depth, longitudinal case studies, conducted between 2006 and 2010, feature 92 interviews and observations to ensure triangulation.

Findings

– We identify three types of organizational reactions (induction, normalization, and regulation) that depend on specific dimensions and affect the nature of subsequent IT-based organizational change.

Research limitations/implications

– Continued research into the consumerization of IT can explore how it affects organizations today and whether different effects might arise in other contexts and with different kinds of organizations.

Practical implications

– Reversed IT adoption logics have deep consequences for organizations; companies could achieve great gains from them, if carefully considered and managed.

Originality/value

– This article addresses a topic that has been analyzed only scarcely and rarely, namely, the consumerization of IT and the tactics organizations use to incorporate user-driven IT innovation. Although this article presents only a few cases, it constitutes an initial attempt to explore this research area theoretically and investigate the ways organizations can harness employees’ personal IT adoption logics to promote creative, IT-driven change in firms.
A web-based DSS for fuzzy distribution network optimization
Authors: Ustundag Alp , Budak Aysenur
Published: February 2015

Purpose

– Distribution network design (DND) has become an important strategic decision for supply chain managers with increasing competitive nature of the industry nowadays. The purpose of this paper is to propose a web-based decision support system (DSS) for fuzzy distribution network optimization. For this purpose, a web-based DSS using fuzzy linear programming model is proposed to solve DND problem under uncertainty and a framework is created to optimize a distribution network.

Design/methodology/approach

– In this study, the fuzziness in distribution network optimization is addressed. Fuzzy linear programming is used in a DSS to consider the uncertain and imprecise data. A web-based DSS architecture is presented. Furthermore, as an application, distribution network optimization is conducted for a company in the ceramics industry.

Findings

– By using this DSS, the optimal transshipment amounts in the distribution network and the required facility and distribution centers can be determined for different fuzziness levels. In fact, for different uncertainty levels of input parameters, the planner can understand the range of optimum network planning costs. Based on the results of this study, planners will be able to decide how to develop the distribution network under uncertain demand.

Originality/value

– Reviewing previous research in the related literature revealed that there are no studies presenting a web-based DSS using fuzzy linear programming model to solve this type of problems under uncertainty.
Service capabilities within open innovation
Authors: Carroll Noel , Helfert Markus
Published: February 2015

Purpose

– Open innovation is an emerging paradigm which exposes organisations to networked capabilities and competencies though collaboration relationships. The traditional view of the organisational environment raises concerns regarding the mismatch in the methods used to assess business value and understanding service process maturity. The purpose of this paper is to address this gap.

Design/methodology/approach

– This paper employs a systematic literature review to present a state-of-the-art literature review with particular focus on the applicability of capability maturity models (CMM) within an open innovation context.

Findings

– The authors present a conceptual account of our research developments and build on the state-of-the-art which bridges open innovation and CMM. The authors provide a comprehensive discussion on the literature and challenge the applicability of individual organisations evolving through maturity stages. The authors identify a significant gap in the emergence of open innovation and CMM and present a service capability sourcing model (SCSM) to bridge these two research areas.

Practical implications

– Unpacking the nature of service capabilities allows us to understand the primary components of value co-creation and their contribution towards service maturity within an open service innovation environment. The authors verify the explanation model using a cloud computing scenario within an open service innovation environment.

Originality/value

– The contribution of this paper is an explanation model of an open service innovation environment through our SCSM. Though an open innovation perspective, the authors examine the nature of service capabilities and the suitability of traditional CMM in a modern service context.
Can GPs coordinate “whole person care”?
Authors: Hudson Bob
Published: February 2015

Purpose

– As the notion of “integrated care” has received ever greater policy traction, so the idea that a named individual should take responsibility for coordinating the various elements of care for service users has also gained ground. The purpose of this paper is to look at the proposal to hand this role to GPs, examine the policy expectations and explore some of the implementation dilemmas.

Design/methodology/approach

– Review of policy documents and relevant literature.

Findings

– That the role of “care coordinator” has rarely succeeded in the past and that there are specific difficulties in expecting GPs to take on the task.

Research limitations/implications

– Review of existing literature linked to emergent policy – no original research.

Originality/value

– This is a new application of an enduring policy concept. Currently the literature is thin.
It was people that brought down the Berlin Wall – not process
Authors: Thomas Jim
Published: February 2015

Purpose

– Integrating services does not necessarily lead to improved outcomes for people with care and support needs and fails to address the need for workforce integration. Workforce integration requires different professional groups to give up personal power, put the people they are supporting ahead of entrenched professional rivalries and be versatile not flexible in how they work. Integration is not important to people with care and support needs, unless it makes a difference to their ability to lead an independent life. The paper aims to discuss these issues.

Design/methodology/approach

– A personal opinion piece based on learning from the development of principles for workforce integration with social care and health employers.

Findings

– Integration takes time and there is no quick fix or magic solution, but it can happen. People's behaviour and motivations are complex, confusing and often inconsistent, and mandating service integration will not change the way workers behave. Perhaps it is now time to stop using service integration as a way of avoiding making tough decisions about the more challenging issue of workforce integration and what this means for those with power and control over people's lives.

Originality/value

– The paper separates integration into service and workforce integration and argues that too much focus is given to the former rather the latter.
Organizational justice and employee mental health’s moderating roles in organizational identification
Authors: Rai Sumita
Published: February 2015

Purpose

– The purpose of this paper is to test the impact of organizational justice on employees’ mental health. This paper is also an attempt to understand the moderating role of organizational identification on organizational justice and employee mental health.

Design/methodology/approach

– Standard questionnaires were used to collect data. A survey study was conducted in two multinational companies located in northern and southern part of India. The sample size of the study was 321.

Findings

– The result of hierarchical regression highlights that distributive and interactional justice were significantly correlated with employee mental health with positive interaction effect in the case of strong identification. Moderating effect of organizational identification on mental health and organizational justice was also found significant.

Research limitations/implications

– The theoretical development from this paper will contribute to organizational justice research presenting its impact on employee mental health. The moderating effect of organizational identification will bring a new dimension to understand the relationship of organizational justice and mental health.

Practical implications

– This study will provide insight to practicing manager to reinforce organizational justice practices at workplace. This will also help manager and leader to understand the identification level of employee with organization, and its impact on mental health.

Originality/value

– This paper explores all the three forms of organizational justice as antecedents. It also studied employee mental health as consequence and the role of organizational identification as moderator on justice and mental health.
A grounded theory study on family-to-work enrichment
Authors: Mishra Pavitra
Published: February 2015

Purpose

– The purpose of this paper is to demonstrate systematic application of grounded theory to understand antecedents, moderators and consequences of family-to-work enrichment in India. The paper throws light on the key tenets of grounded theory research and explains its use as a rigorous method for management research.

Design/methodology/approach

– “Paradigm model” of grounded theory was used for data analysis. Data were collected through in-depth interviews of 24, middle managers in India. Interviewees were from various industries like IT, software, insurance, banking, telecom, media, consulting and fast moving consumer goods.

Findings

– This study identifies family resources as an antecedent of family-to-work enrichment. Community resources and work-role salience facilitate positive relation between family resources and family-to-work enrichment. Further, psychological capital has been identified as a consequence. Strategies adopted by the professionals to enhance their family-to-work enrichment have also been explored.

Research limitations/implications

– This study provides a holistic understanding of family-to-work enrichment, an under researched phenomenon by exploring relation between work, family and community resources.

Practical implications

– The integration of three domains, i.e. work, family and community provide insights to managers and policy makers about the importance of family and community in the organizations.

Originality/value

– This study fulfills the need to explore positive side of work-family interface especially, in emerging economies like India. Moreover, it is the first attempt to study the work-family-community interface from a grounded theory approach in the Indian context and probably one of the first few in the literature.
Strategic integration of HRM for organizational performance: Nepalese reality
Authors: Gautam Dhruba Kumar
Published: February 2015

Purpose

– The purpose of this paper is to explore the extent of strategic integration between business strategy and human resource (HR) policies and their impact on organizational performance of public listed companies in Nepal.

Design/methodology/approach

– Exploratory cum descriptive research design is followed with structured questionnaire distributed to 105 publicly listed individual organizations as a unit of analysis and secondary source of information used to verify the performance result of perceptual measurement.

Findings

– Formulation of explicit mission and business strategies indicate that around half of the organizations are doing business without business strategy and just one-fourth organizations formulate explicit HR strategy in order to support business strategies. Among the respondent organizations, few organizations meet the requirement of high strategic integrating organizations that were performing better than organizations that were low integrating.

Practical implications

– This study provides sufficient evidences to Nepalese decision makers and academics that integration of business and HR strategies will have better impact on organizational performance. The result of this study motivates decision makers and academics, particularly South Asian, to understand the importance of investing in HR to raise organizational performance.

Originality/value

– Examining strategic integration for organizational performance is perhaps the first study which certainly contributes to the overall assessment HRM and its impact on organizational performance to the developing countries of South Asia, like Nepal and add values to the process of theoretical development as well as HR management.
Working towards successful retirement: older workers and retirees speaking about ageing, change and later life
Authors: Gewolb Sheila J.
Published: February 2015

Purpose

– The purpose of this paper is to demonstrate how older workers and people who have already retired speak about ageing and change and their experience of retirement.

Design/methodology/approach

– A qualitative study is described in which focus groups with older workers and semi-structured interviews with retired people were carried out. The recorded data were analysed using a linguistic approach (Discourse Analysis), which investigates in detail how people express their views and opinions and how their discourse might relate to societal attitudes towards ageing and retirement.

Findings

– Many older people who were still at work were concerned that they would decline and become senile once they retired unless they could remain active in some way. This was confirmed by people who had already retired and who spoke about how keeping busy and active had resulted in successful retirement and ageing.

Research limitations/implications

– Participants from four focus groups and five interview respondents represent only a small sample of older people who are still working or who are retired. This means that the results of this study cannot be extended to include all older workers and retired people.

Social implications

– This study will help to raise awareness of the concerns of older workers who may be nearing retirement, and how keeping busy and active after leaving work is considered by retirees to be part of successful retirement and helping to combat decline.

Originality/value

– A study of this nature which examines how older workers express their views about retirement using Discourse Analysis is original and may be used as a method for future research into other aspects of being older at work.
Have older generations overplayed their hands?
Authors: Emerson Liz , Hanton Angus
Published: February 2015

Purpose

– The purpose of this paper is to expand upon the Intergenerational Foundation (IF) presentation given at the “Portraying of Ageing” conference, which was organised by the British Library and held in London in April 2014.

Design/methodology/approach

– Changing demographics, wealth distribution, government debt and voting patterns are examined in order to question whether current government policy should continue to protect older generations at the expense of younger and future generations.

Findings

– IF provides statistically robust evidence that, in spite of increasing wealth, older generations continue to be protected by government policy while younger generations are targeted for cuts from liabilities built up, but not paid for, by previous generations.

Social implications

– Government policy may have tipped too far in favour of older wealthier cohorts, many of whom receive automatic benefits based on reaching a certain age. Governments should consider replacing age as a proxy for need with means-testing in order to rebalance benefits more fairly across the generations.

Originality/value

– There have been limited research studies comparing the incidence of wealth amongst older generations and the scale of liabilities being passed on to younger and future generations. This paper will be of value to policy-makers interested in rebalancing the interests of all generations more equitably.
Portraying ageing: its contradictions and paradoxes
Authors: Segal Lynne
Published: February 2015

Purpose

– The purpose of this paper is to highlight the stigma surrounding old age, which in many ways has increased rather than decreased with the ageing of the population.

Design/methodology/approach

– The approach of this paper is to introduce the reader to recent writing and research surrounding talk of a “demograhic time bomb”, with the ageing of populations world wide. It also looks back on the work on “ageing studies” over the last two decades, revealing the prevailing disavowals of old age among the old themselves, as well as the contrasting gendered dynamics of the ways in which we are, as Margaret Gullette writes, “aged by culture”.

Findings

–The author introduces the conceptual notion of “temporal vertigo” to the complicated effects of the multiplicity of continuities and discontinuities older people experience when reflecting upon who they are over a lifetime. Ageing is of interest for those who have always been sceptical about any notion of the “true self”, allowing us to puzzle over how the account the old give of themselves will rely upon their ability to incorporate differing versions of the self, woven into the volatilities of memory and fantasy.

Originality/value

– The paper's exploration of the radical ambiguities in the representation and discussions surrounding old age in these times.
Autophagy in Helicobacter pylori Infection and Related Gastric Cancer
Authors: Castaño‐Rodríguez Natalia , Kaakoush Nadeem O. , Goh Khean‐Lee , Fock Kwong Ming , Mitchell Hazel M.
Published: February 2015

Background

Autophagy, a degradation pathway in which cytoplasmic content is engulfed and degraded by lysosomal hydrolases, plays a pivotal role in infection and inflammation. Given that defects in autophagy lead to increased susceptibility to infection, we investigated the role of autophagy in Helicobacter pylori‐related gastric cancer (GC).

Materials and Methods

Gene expression of 84 molecules was examined through quantitative real‐time PCR in gastric epithelial cells (AGS) and macrophages (THP‐1) upon exposure to H. pylori GC026 (GC) and 26695 (gastritis). Further, ATG16L1 rs2241880, IRGM rs13361189, and IRGM rs4958847, polymorphisms that have been investigated in relation to H. pylori infection or GC in Caucasians, were detected by MALDI‐TOF mass spectrometry in 304 ethnic Chinese (86 noncardia GC cases/218 functional dyspepsia controls).

Results

Gene expression analyses showed twenty‐eight molecules involved in vesicle nucleation, elongation, and maturation to be significantly down‐regulated in H. pylori GC026‐challenged AGS cells. Further, core autophagy proteins and autophagy regulators were differentially expressed in H. pylori‐challenged THP‐1‐derived macrophages. Analyses of the selected polymorphisms showed that ATG16L1 rs2241880 increased the risk of GC (OR: 2.38, 95% CI: 1.34–4.24) and H. pylori infection (OR: 1.49, 95% CI: 1.02–2.16) while IRGM rs4958847 decreased GC risk (OR: 0.26, 95% CI: 0.09–0.74) in ethnic Chinese, these effect sizes being especially strong in H. pylori‐infected individuals (ATG16L1 rs2241880 and IRGM rs13361189).

Conclusions

Our findings indicate that highly virulent H. pylori strains markedly modulate autophagy in the host cell. Further, for the first time, autophagy polymorphisms were associated with GC in Chinese, a high GC‐risk population.
Power‐free values of polynomials
Authors: Reuss T.
Published: February 2015

Let be an irreducible polynomial of degree with no fixed th power prime divisor. We derive an asymptotic formula for the number of primes such that is ‐free.
Trafficking through the Late Endosome Significantly Impacts Candida albicans Tolerance of the Azole Antifungals
Authors: Luna-Tapia Arturo , Kerns Morgan E. , Eberle Karen E. , Jursic Branko S. , Palmer Glen E.
Published: February 2015

The azole antifungals block ergosterol biosynthesis by inhibiting lanosterol demethylase (Erg11p). The resulting depletion of cellular ergosterol and the accumulation of “toxic” sterol intermediates are both thought to compromise plasma membrane function. However, the effects of ergosterol depletion upon the function of intracellular membranes and organelles are not well described. The purpose of this study was to characterize the effects of azole treatment upon the integrity of the
Candida albicans
vacuole and to determine whether, in turn, vacuolar trafficking influences azole susceptibility. Profound fragmentation of the
C. albicans
vacuole can be observed as an early consequence of azole treatment, and it precedes significant growth inhibition. In addition, a
C. albicans
vps21
Δ/Δ mutant, blocked in membrane trafficking through the late endosomal prevacuolar compartment (PVC), is able to grow significantly more than the wild type in the presence of several azole antifungals under standard susceptibility testing conditions. Furthermore, the
vps21
Δ/Δ mutant is able to grow despite the depletion of cellular ergosterol. This phenotype resembles an exaggerated form of “trailing growth” that has been described for some clinical isolates. In contrast, the
vps21
Δ/Δ mutant is hypersensitive to drugs that block alternate steps in ergosterol biosynthesis. On the basis of these results, we propose that endosomal trafficking defects may lead to the cellular “redistribution” of the sterol intermediates that accumulate following inhibition of ergosterol biosynthesis. Furthermore, the destination of these intermediates, or the precise cellular compartments in which they accumulate, may be an important determinant of their toxicity and thus ultimately antifungal efficacy.
Variants of β-Lactamase KPC-2 That Are Resistant to Inhibition by Avibactam
Authors: Papp-Wallace Krisztina M. , Winkler Marisa L. , Taracila Magdalena A. , Bonomo Robert A.
Published: February 2015

KPC-2 is the most prevalent class A carbapenemase in the world. Previously, KPC-2 was shown to hydrolyze the β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam. In addition, substitutions at amino acid position R220 in the KPC-2 β-lactamase increased resistance to clavulanic acid. A novel bridged diazabicyclooctane (DBO) non-β-lactam β-lactamase inhibitor, avibactam, was shown to inactivate the KPC-2 β-lactamase. To better understand the mechanistic basis for inhibition of KPC-2 by avibactam, we tested the potency of ampicillin-avibactam and ceftazidime-avibactam against engineered variants of the KPC-2 β-lactamase that possessed single amino acid substitutions at important sites (i.e., Ambler positions 69, 130, 234, 220, and 276) that were previously shown to confer inhibitor resistance in TEM and SHV β-lactamases. To this end, we performed susceptibility testing, biochemical assays, and molecular modeling.
Escherichia coli
DH10B carrying KPC-2 β-lactamase variants with the substitutions S130G, K234R, and R220M demonstrated elevated MICs for only the ampicillin-avibactam combinations (e.g., 512, 64, and 32 mg/liter, respectively, versus the MICs for wild-type KPC-2 at 2 to 8 mg/liter). Steady-state kinetics revealed that the S130G variant of KPC-2 resisted inactivation by avibactam; the
k
2
/
K
ratio was significantly lowered 4 logs for the S130G variant from the ratio for the wild-type enzyme (21,580 M
−1
s
−1
to 1.2 M
−1
s
−1
). Molecular modeling and molecular dynamics simulations suggested that the mobility of K73 and its ability to activate S70 (i.e., function as a general base) may be impaired in the S130G variant of KPC-2, thereby explaining the slowed acylation. Moreover, we also advance the idea that the protonation of the sulfate nitrogen of avibactam may be slowed in the S130G variant, as S130 is the likely proton donor and another residue, possibly K234, must compensate. Our findings show that residues S130 as well as K234 and R220 contribute significantly to the mechanism of avibactam inactivation of KPC-2. Fortunately, the emergence of S130G, K234R, and R220M variants of KPC in the clinic should not result in failure of ceftazidime-avibactam, as the ceftazidime partner is potent against
E. coli
DH10B strains possessing all of these variants.
Moxifloxacin Pharmacokinetic Profile and Efficacy Evaluation in Empiric Treatment of Community-Acquired Pneumonia
Authors: Öbrink-Hansen Kristina , Hardlei Tore Forsingdal , Brock Birgitte , Jensen-Fangel Søren , Kragh Thomsen Marianne , Petersen Eskild , Kreilgaard Mads
Published: February 2015

When antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (
C
max
) and area under the free drug concentration-time curve from 0 to 24 h (
f
AUC
0–24
) values predicted for each patient were evaluated against epidemiological cutoff MIC values for
Streptococcus pneumoniae
,
Haemophilus influenzae
, and
Legionella pneumophila
. PK-PD targets adopted were a
C
max
/MIC of ≥12.2 for all pathogens, an
f
AUC
0–24
/MIC of >34 for
S. pneumoniae
, and an
f
AUC
0–24
/MIC of >75 for
H. influenzae
and
L. pneumophila
. Individual predicted estimates for
C
max
/MIC and
f
AUC
0–24
/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for
S. pneumoniae
and
H. influenzae
but not for
L. pneumophila
. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused by
L. pneumophila
. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.)
Cyclophilin and NS5A Inhibitors, but Not Other Anti-Hepatitis C Virus (HCV) Agents, Preclude HCV-Mediated Formation of Double-Membrane-Vesicle Viral Factories
Authors: Chatterji Udayan , Bobardt Michael , Tai Andrew , Wood Malcolm , Gallay Philippe A.
Published: February 2015

Although the mechanisms of action (MoA) of nonstructural protein 3 inhibitors (NS3i) and NS5B inhibitors (NS5Bi) are well understood, the MoA of cyclophilin inhibitors (CypI) and NS5A inhibitors (NS5Ai) are not fully defined. In this study, we examined whether CypI and NS5Ai interfere with hepatitis C virus (HCV) RNA synthesis of replication complexes (RCs) or with an earlier step of HCV RNA replication, the creation of double-membrane vesicles (DMVs) essential for HCV RNA replication. In contrast to NS5Bi, both CypI and NS5Ai do not block HCV RNA synthesis by way of RCs, suggesting that they exert their antiviral activity prior to the establishment of enzymatically active RCs. We found that viral replication is not a precondition for DMV formation, since the NS3-NS5B polyprotein or NS5A suffices to create DMVs. Importantly, only CypI and NS5Ai, but not NS5Bi, mir-122, or phosphatidylinositol-4 kinase IIIα (PI4KIIIα) inhibitors, prevent NS3-NS5B-mediated DMV formation. NS3-NS5B was unable to create DMVs in cyclophilin A (CypA) knockdown (KD) cells. We also found that the isomerase activity of CypA is absolutely required for DMV formation. This not only suggests that NS5A and CypA act in concert to build membranous viral factories but that CypI and NS5Ai mediate their early anti-HCV effects by preventing the formation of organelles, where HCV replication is normally initiated. This is the first investigation to examine the effect of a large panel of anti-HCV agents on DMV formation, and the results reveal that CypI and NS5Ai act at the same membranous web biogenesis step of HCV RNA replication, thus indicating a new therapeutic target of chronic hepatitis C.
Combination of the R263K and M184I/V Resistance Substitutions against Dolutegravir and Lamivudine Decreases HIV Replicative Capacity
Authors: Singhroy Diane N. , Wainberg Mark A. , Mesplède Thibault
Published: February 2015

We investigated the effect of combining the dolutegravir-specific R263K integrase resistance substitution with either M184I or M184V, two reverse transcriptase drug resistance substitutions that are frequently detected in individuals failing therapeutic regimens containing either lamivudine or emtricitabine. The presence of R263K and M184I/V in a single virus resulted in substantial further decreases in the viral replicative capacity compared to that in the presence of single substitutions alone.
Dermatophytes Activate Skin Keratinocytes via Mitogen-Activated Protein Kinase Signaling and Induce Immune Responses
Authors: Achterman Rebecca R. , Moyes David L. , Thavaraj Selvam , Smith Adam R. , Blair Kris M. , White Theodore C. , Naglik Julian R.
Published: February 2015

Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte,
Trichophyton equinum
. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with
Microsporum gypseum
inducing the greatest level of damage and cytokine release. Using
T. equinum
as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected.
T. equinum
also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of
T. equinum
to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation.
Role of Copper Efflux in Pneumococcal Pathogenesis and Resistance to Macrophage-Mediated Immune Clearance
Authors: Johnson Michael D. L. , Kehl-Fie Thomas E. , Klein Roger , Kelly Jacqueline , Burnham Corinna , Mann Beth , Rosch Jason W.
Published: February 2015

In bacteria, the intracellular levels of metals are mediated by tightly controlled acquisition and efflux systems. This is particularly true of copper, a trace element that is universally toxic in excess. During infection, the toxic properties of copper are exploited by the mammalian host to facilitate bacterial clearance. To better understand the role of copper during infection, we characterized the contribution of the
cop
operon to copper homeostasis and virulence in
Streptococcus pneumoniae
. Deletion of either the exporter, encoded by
copA
, or the chaperone, encoded by
cupA
, led to hypersensitivity to copper stress. We further demonstrated that loss of the copper exporter encoded by
copA
led to decreased virulence in pulmonary, intraperitoneal, and intravenous models of infection. Deletion of
copA
resulted in enhanced macrophage-mediated bacterial clearance
in vitro
. The attenuation phenotype of the
copA
mutant in the lung was found to be dependent on pulmonary macrophages, underscoring the importance of copper efflux in evading immune defenses. Overall, these data provide insight into the role of the
cop
operon in pneumococcal pathogenesis.
Two-Tiered Histidine Kinase Pathway Involved in Heat Shock and Salt Sensing in the General Stress Response of Sphingomonas melonis Fr1
Authors: Kaczmarczyk Andreas , Hochstrasser Ramon , Vorholt Julia A. , Francez-Charlot Anne
Published: February 2015

The general stress response (GSR) allows bacteria to monitor and defend against a broad set of unrelated, adverse environmental conditions. In
Alphaproteobacteria
, the key step in GSR activation is phosphorylation of the response regulator PhyR. In
Sphingomonas melonis
Fr1, seven PhyR-activating kinases (Paks), PakA to PakG, are thought to directly phosphorylate PhyR under different stress conditions, but the nature of the activating signals remains obscure. PakF, a major sensor of NaCl and heat shock, lacks a putative sensor domain but instead harbors a single receiver (REC) domain (PakF
REC
) N-terminal to its kinase catalytic core. Such kinases are called “hybrid response regulators” (HRRs). How HRRs are able to perceive signals in the absence of a true sensor domain has remained largely unexplored. In the present work, we show that stresses are actually sensed by another kinase, KipF (kinase of PakF), which phosphorylates PakF
REC
and thereby activates PakF. KipF is a predicted transmembrane kinase, harboring a periplasmic CHASE3 domain flanked by two transmembrane helices in addition to its cytoplasmic kinase catalytic core. We demonstrate that KipF senses different salts through its CHASE3 domain but is not a sensor of general osmotic stress. While salt sensing depends on the CHASE3 domain, heat shock sensing does not, suggesting that these stresses are perceived by different mechanisms. In summary, our results establish a two-tiered histidine kinase pathway involved in activation of the GSR in
S. melonis
Fr1 and provide the first experimental evidence for the so far uncharacterized CHASE3 domain as a salt sensor.

IMPORTANCE
Hybrid response regulators (HRRs) represent a particular class of histidine kinases harboring an N-terminal receiver (REC) domain instead of a true sensor domain. This suggests that the actual input for HRRs may be phosphorylation of the REC domain. In the present study, we addressed this question by using the HRR PakF. Our results suggest that PakF is activated through phosphorylation of its REC domain and that this is achieved by another kinase, KipF. KipF senses heat shock and salt stress, with the latter requiring the periplasmic CHASE3 domain. This work not only suggests that HRRs work in two-tiered histidine kinase pathways but also provides the first experimental evidence for a role of the so far uncharacterized CHASE3 domain in salt sensing.