The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.

Dissidents with an innovation cause? Non-institutionalized actors’ online social knowledge sharing, solution-finding tensions and technology management innovation

Purpose – Traditionally, most studies focus on institutionalized management-driven actors to understand technology management innovation. The purpose of this paper is to argue that there is a need for research to study the nature and role of dissident non-institutionalized actors’ (i.e. outsourced web designers and rapid application software developers). The authors propose that through online social knowledge sharing, non-institutionalized actors’ solution-finding tensions enable technology management innovation. Design/methodology/approach – A synthesis of the literature and an analysis of the data (21 interviews) provided insights in three areas of solution-finding tensions enabling management innovation. The authors frame the analysis on the peripherally deviant work and the nature of the ways that dissident non-institutionalized actors deviate from their clients (understood as the firm) original contracted objectives. Findings – The findings provide insights into the productive role of solution-finding tensions in enabling opportunities for management service innovation. Furthermore, deviant practices that leverage non-institutionalized actors’ online social knowledge to fulfill customers’ requirements are not interpreted negatively, but as a positive willingness to proactively explore alternative paths. Research limitations/implications – The findings demonstrate the importance of dissident non-institutionalized actors in technology management innovation. However, this work is based on a single country (USA) and additional research is needed to validate and generalize the findings in other cultural and institutional settings. Originality/value – This paper provides new insights into the perceptions of dissident non-institutionalized actors in the practice of IT managerial decision making. The work departs from, but also extends, the previous literature, demonstrating that peripherally deviant work in solution-finding practice creates tensions, enabling management innovation between IT providers and users.

Challenges of Teaching Written Communication in the Cloud

Report published in the Proceedings of the National Conference on "Education and Research in the Information Society", Plovdiv, May, 2014

Guest editors' introduction : diversity and inclusion in different work settings:emerging patterns, challenges, and research agenda

The purpose of this article is to analyze and highlight the developments in the current scholarship on managing diversity and inclusion (D&I) and provide insights for future research. While doing so, the article advances our understanding of “what matters” in this field, through the integration of different literature concerning the dimensions of D&I. It also provides a neo-institutionalist framework, which locates different themes in the D&I scholarship to assist in further development of the field. It argues for a consideration of inquiry in D&I from a neo-institutionalist perspective to encourage interdisciplinarity and align with broader social science research in human resource management (HRM) and development, highlighting the complexity involved in the theorizing of D&I management in organizations. Specifically, we argue for the need to engage with a variety of stakeholders concerned with the management of D&I, to enable cross-fertilization of theories and mixing methods for future research designs. The article also introduces the manuscripts included in this special issue and build on them as well to develop the future research agenda. © 2015 Wiley Periodicals, Inc.

An investigation into the factors affecting e-commerce adoption decisions by SMEs:a study in Saudi Arabia

Electronic commerce (e-commerce) has become an increasingly important initiative among Small and Medium Enterprises (SMEs) as both a great opportunity and as a source of competition. The factors affecting adoption decisions of e-commerce by SMEs have been well documented, but there is a paucity of empirical studies that examine the adoption of e-commerce in the Arab world. The aim of this chapter is to provide insights into the salient e-commerce adoption issues by focusing on Saudi Arabian businesses. This chapter investigates the state of e-commerce adoption and analyses the factors that determine the extent to which SMEs in Saudi Arabia are inclined towards deploying e-commerce technologies. This research was designed using a qualitative approach through exploratory case studies selected from firms in Saudi Arabia. The findings contribute towards a better conceptual and practical understanding of the main factors driving SMEs to adopt e-commerce. The study has found that the level of e-commerce implementation has yet to mature and customer readiness for Internet shopping has to improve before e-commerce reaches the levels of maturity seen in other regions of the world. This study highlights several directions for future inquiry and implications for policymakers and managers who are involved in efforts to introduce complex innovations such as e-commerce into their organisations or are interested in expanding their e-commerce applications and generating more revenue.

An investigation into the adoption of electronic commerce among Saudi Arabian SMEs

Despite the proliferation of e-commerce adoption by SMEs and the world-wide growth of e-commerce, in general there is a paucity of empirical studies that examine the adoption of e-commerce by SMEs in the Middle East. In this paper, the authors provide insights into the salient e-commerce adoption issues by focusing on Saudi Arabian SMEs. This research was designed using a qualitative approach through in-depth case studies selected from firms in Saudi Arabia. The findings contribute toward a better conceptual and practical understanding of the main factors driving SMEs to adopt e-commerce. The authors find that the level of e-commerce implementation has yet to mature and customer readiness for Internet shopping must improve before e-commerce reaches the levels of maturity seen in other regions of the world. This study highlights directions for future inquiry and implications for information and technology managers and policymakers in developing Arab nations.

Receptor activity-modifying proteins; multifunctional G protein-coupled receptor accessory proteins

Receptor activity-modifying proteins (RAMPs) are single pass membrane proteins initially identified by their ability to determine the pharmacology of the calcitonin receptor-like receptor (CLR), a family B G protein-coupled receptor (GPCR). It is now known that RAMPs can interact with a much wider range of GPCRs. This review considers recent developments on the structure of the complexes formed between the extracellular domains (ECDs) of CLR and RAMP1 or RAMP2 as these provide insights as to how the RAMPs direct ligand binding. The range of RAMP interactions is also considered; RAMPs can interact with numerous family B GPCRs as well as examples of family A and family C GPCRs. They influence receptor expression at the cell surface, trafficking, ligand binding and G protein coupling. The GPCR-RAMP interface offers opportunities for drug targeting, illustrated by examples of drugs developed for migraine.

Fejezetek a nemzetközi üzleti gazdaságtanból 4. = Chapters in International Business. Reviews on Selected Papers on International Business 4.

A kötet azzal a céllal készült, hogy a Nemzetközi vállalatgazdaságtant tanulmányozók számára további támpontokat és ismeretbővítési lehetőségeket adjon magyar nyelven. A műhelytanulmány a nemzetközi üzleti gazdaságtan (international business) öt témaköréről ad áttekintést: az internalizációs elmélet, az intézményi megközelítés, a külpiacra lépés kisvállalati nézőpontból, a leányvállalatok lehetséges szerepei, és végül módszertani megfontolások. A korábbi kötetekhez hasonlóan, a műhelytanulmány fejezeteit a BCE Gazdálkodástani Doktori Iskola PhD hallgatói készítették. ----- The aim of the working paper is to provide insights on selected areas in international business. It is a supplement for the Hungarian language IB textbook. Five fields are covered in the working paper: internalization theory and its extensions, forming institutions in host countries, challenges of foreign market entry for small businesses, roles of subsidiaries in the multinational corporations, and methodological issues in IB. The chapters in the working paper were prepared by the PhD students of the Business and Management PhD School at Corvinus University of Budapest.

Examining the process of regime change in the North Atlantic Treaty Organization: The divide between rhetoric and reality

The North Atlantic Treaty Organization (NATO) is a product of the Cold War through which its members organized their military forces for the purpose of collective defense against the common threat of Soviet-backed aggression. Employing the terminology of regime theory, the creation of NATO can be viewed as the introduction of an international security regime. Throughout the Cold War, NATO member states preserved their commitment to mutual defense while increasingly engaging in activities aimed at overcoming the division of Europe and promoting regional stability. The end of the Cold War has served as the catalyst for a new period of regime change as the Alliance introduced elements of a collective security regime by expanding its mandate to address new security challenges and reorganizing both its political and military organizational structures. ^ This research involves an interpretive analysis of NATO's evolution applying ideal theoretical constructs associated with distinct approaches to regime analysis. The process of regime change is investigated over several periods throughout the history of the Alliance in an effort to understand the Alliance's changing commitment to collective security. This research involves a review of regime theory literature, consisting of an examination of primary source documentation, including official documents and treaties, as well as a review of numerous secondary sources. This review is organized around a typology of power-based, organization-based, and norm-based approaches to regime analysis. This dissertation argues that the process of regime change within NATO is best understood by examining factors associated with multiple theoretical constructs. Relevant factors provide insights into the practice of collective security among NATO member states within Europe, while accounting for the inability of the NATO allies to build on the experience gained within Europe to play a more central role in operations outside of this region. This research contributes to a greater understanding of the nature of international regimes and the process of regime change, while offering recommendations aimed at increasing NATO's viability as a source of greater security and more meaningful international cooperation.^

Examining argumentative coherence in essays by undergraduate students of English as a foreign language in Mainland China and their English speaking peers in the United States

I conducted this study to provide insights toward deepening understanding of association between culture and writing by building, assessing, and refining a conceptual model of second language writing. To do this, I examined culture and coherence as well as the relationship between them through a mixed methods research design. Coherence has been an important and complex concept in ESL/EFL writing. I intended to study the concept of coherence in the research context of contrastive rhetoric, comparing the coherence quality in argumentative essays written by undergraduates in Mainland China and their U.S. peers. In order to analyze the complex concept of coherence, I synthesized five linguistic theories of coherence: Halliday and Hasan's cohesion theory, Carroll's theory of coherence, Enkvist's theory of coherence, Topical Structure Analysis, and Toulmin's Model. Based upon the synthesis, 16 variables were generated. Across these 16 variables, Hotelling t-test statistical analysis was conducted to predict differences in argumentative coherence between essays written by two groups of participants. In order to complement the statistical analysis, I conducted 30 interviews of the writers in the studies. Participants' responses were analyzed with open and axial coding. By analyzing the empirical data, I refined the conceptual model by adding more categories and establishing associations among them. The study found that U.S. students made use of more pronominal reference. Chinese students adopted more lexical devices of reiteration and extended paralleling progression. The interview data implied that the difference may be associated with the difference in linguistic features and rhetorical conventions in Chinese and English. As far as Toulmin's Model is concerned, Chinese students scored higher on data than their U.S. peers. According to the interview data, this may be due to the fact that Toulmin's Model, modified as three elements of arguments, have been widely and long taught in Chinese writing instruction while U.S. interview participants said that they were not taught to write essays according to Toulmin's Model. Implications were generated from the process of textual data analysis and the formulation of structural model defining coherence. These implications were aimed at informing writing instruction, assessment, peer-review, and self-revision.

COERC 2002: Proceedings of the Annual College of Education Research Conference

This conference was designed to offer a view to novice scholars of what scholarship is and provide insights on how to share knowledge with others.

Mechanisms governing the eyewall replacement cycle in numerical simulations of tropical cyclones

Eyewall replacement cycle (ERC) is frequently observed during the evolution of intensifying Tropical Cyclones (TCs). Although intensely studied in recent years, the underlying mechanisms of ERC are still poorly understood, and the forecast of ERC remains a great challenge. To advance our understanding of ERC and provide insights in improvement of numerical forecast of ERC, a series of numerical simulations is performed to investigate ERCs in TC-like vortices on a f-plane. The simulated ERCs possess key features similar to those observed in real TCs including the formation of a secondary tangential wind maximum associated with the outer eyewall. The Sawyer-Eliassen equation and tangential momentum budget analyses are performed to diagnose the mechanisms underlying the secondary eyewall formation (SEF) and ERC. Our diagnoses reveal crucial roles of outer rainband heating in governing the formation and development of the secondary tangential wind maximum and demonstrate that the outer rainband convection must reach a critical strength relative to the eyewall before SEF and the subsequent ERC can occur. A positive feedback among low-level convection, acceleration of tangential winds in the boundary layer, and surface evaporation that leads to the development of ERC and a mechanism for the demise of inner eyewall that involves interaction between the transverse circulations induced by eyewall and outer rainband convection are proposed. The tangential momentum budget indicates that the net tendency of tangential wind is a small residual resultant from a large cancellation between tendencies induced by the resolved and sub-grid scale (SGS) processes. The large SGS contribution to the tangential wind budget explains different characteristics of ERC shown in previous numerical studies and poses a great challenge for a timely correct forecast of ERC. The sensitivity experiments show that ERCs are strongly subjected to model physics, vortex radial structure and background wind. The impact of model physics on ERC can be well understood with the interaction among eyewall/outer rainband heating, radilal inflow in the boundary layer, surface layer turbulent processes, and shallow convection in the moat. However, further investigations are needed to fully understand the exhibited sensitivities of ERC to vortex radial structure and background wind.

Theoretical Investigation of Intra- and Inter-cellular Spatiotemporal Calcium Patterns in Microcirculation

Microcirculatory vessels are lined by endothelial cells (ECs) which are surrounded by a single or multiple layer of smooth muscle cells (SMCs). Spontaneous and agonist induced spatiotemporal calcium (Ca2+) events are generated in ECs and SMCs, and regulated by complex bi-directional signaling between the two layers which ultimately determines the vessel tone. The contractile state of microcirculatory vessels is an important factor in the determination of vascular resistance, blood flow and blood pressure. This dissertation presents theoretical insights into some of the important and currently unresolved phenomena in microvascular tone regulation. Compartmental and continuum models of isolated EC and SMC, coupled EC-SMC and a multi-cellular vessel segment with deterministic and stochastic descriptions of the cellular components were developed, and the intra- and inter-cellular spatiotemporal Ca2+ mobilization was examined. Coupled EC-SMC model simulations captured the experimentally observed localized subcellular EC Ca2+ events arising from the opening of EC transient receptor vanilloid 4 (TRPV4) channels and inositol triphosphate receptors (IP3Rs). These localized EC Ca2+ events result in endothelium-derived hyperpolarization (EDH) and Nitric Oxide (NO) production which transmit to the adjacent SMCs to ultimately result in vasodilation. The model examined the effect of heterogeneous distribution of cellular components and channel gating kinetics in determination of the amplitude and spread of the Ca2+ events. The simulations suggested the necessity of co-localization of certain cellular components for modulation of EDH and NO responses. Isolated EC and SMC models captured intracellular Ca2+ wave like activity and predicted the necessity of non-uniform distribution of cellular components for the generation of Ca2+ waves. The simulations also suggested the role of membrane potential dynamics in regulating Ca2+ wave velocity. The multi-cellular vessel segment model examined the underlying mechanisms for the intercellular synchronization of spontaneous oscillatory Ca2+ waves in individual SMC. From local subcellular events to integrated macro-scale behavior at the vessel level, the developed multi-scale models captured basic features of vascular Ca2+ signaling and provide insights for their physiological relevance. The models provide a theoretical framework for assisting investigations on the regulation of vascular tone in health and disease.

The Immunomodulatory Role of Alcohol on HIV-Infected Monocyte-Derived Dendritic Cells

Alcohol is known to induce inflammation in the presence of the human immunodeficiency virus (HIV). In our previous studies, we revealed that alcohol induces cannabinoid receptors which play a role in the regulation of inflammatory cytokine production in monocyte-derived dendritic cells (MDDC). However, the ability of alcohol to alter MDDC function during HIV infection has not been clearly elucidated yet. To study the potential impact of alcohol on HIV-infected MDDC (confirmed by p24 ELISA), monocytes were isolated from commercially available buffy coats and cultured for 7 days with GM-CSF and IL-4. MDDC were infected with HIV- 1Ba-L and treated with different concentrations of alcohol (0.1% band 0.2%) for 4-7 days. MDDC phenotype, endocytosis, cytokine production, and ability to transmit HIV to T cells were analyzed. Uninfected CD4+ T cells were co-cultured for 7 days with either infected/treated MDDC or the supernatants from infected/treated MDDC. Inflammatory cytokine arrays were performed using supernatants from HIV-infected MDDC treated with alcohol. Results showed that HIV positive MDDC treated with alcohol had higher levels of infection compared to untreated HIV positive controls. CD4+ T cells exposed to HIV-infected MDDC acquired 100-fold higher levels of p24 compared to CD4+ T cells exposed to only supernatants. CD4+ T cells exposed to HIV-infected and alcohol-treated MDDC had higher levels of infection compared to controls. Cytokine array data show dysregulation of cytokine production by alcohol. In addition, MDDC phenotype and endocytic capacity were altered in the alcohol treated MDDC. Our results indicate a crucial role of MDDC in HIV transmission to T cells and provide insights into the inflammatory role alcohol exerts on dendritic cell function in the context of HIV infection. Supported by the National Institute on Alcohol Abuse and Alcoholism award R00AA021264, the National Institute on Drug Abuse award R01DA034547, and the Institute on NeuroImmune Pharmacology at FIU.

An experimental geochemical characterization analysis of archaeological iron from the contact period of Newfoundland and Labrador

This research uses scanning electron microscopy-energy dispersive X-ray spectrometry (SEM-EDX) and inductively coupled plasma-mass spectrometry (ICP-MS) on cross-sections of iron artifacts sectioned from along shafts to determine the elemental constituents of a collection of Inuit and European artifacts from along the coast of Labrador. Hand-wrought iron nails from early historic period (16th – 18th centuries CE) Inuit sites in Labrador were originally manufactured by and acquired from early whalers and fishers of various European nationalities. The purpose of this research was to assess if the elements in different samples are sufficiently homogeneous to be viable for a provenience analysis to discern which Inuit nails were originally derived from which European groups; the Basque, English or French. The consistent relationships between the geochemical signatures of iron nails found in Inuit sites and historic nails derived from specific European groups could provide insights into the prevalence, activity and the nature of indigenous interactions of different European nationalities in the region over time. The results show that the methods applied to evaluate the geochemistry of the nails was not sufficient to detect meaningful patterns because the nails did not demonstrate the necessary degree of chemical uniformity among different samples in the same artifacts.