Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells

Damaged, aged or unwanted cells are removed from the body by an active process known as apoptosis. This highly orchestrated programme results in cell disassembly and the exposure of ‘flags’ at the dying cell surface that permit recognition and removal by viable cells (phagocytes). Efficient phagocytic removal of dying cells is essential to prevent inflammatory and autoimmune disorders. Relatively little is known of the molecular mechanisms underlying changes at the apoptotic cell surface. We have previously shown that ICAM-3 (a heavily glycosylated, leukocyte-restricted Immunoglobulin Super-Family member) undergoes a change of function as cells die so that it acts as a molecular ‘flag’ to mediate corpse removal. Our work seeks to characterise apoptosis-associated changes in ICAM-3 and define their role in ICAM-3’s novel function in apoptotic cell clearance. Here we extend earlier studies to show that apoptotic cell-associated ICAM-3 functions, at least minimally, to tether apoptotic leukocytes to macrophages via an undefined receptor. Whilst CD14 has been suggested as a possible innate immune receptor for apoptotic cell-associated ICAM-3, we demonstrate ICAM-3 functions for apoptotic cell clearance in the absence of CD14. Our data additionally indicate, that during apoptosis, leukocytes display early changes in cell surface glycosylation and a marked reduction in ICAM-3, a change that correlates with a reduction in cell volume. This reduction in ICAM-3 is explained by cell surface shedding of microparticles (‘apoptotic bodies’) that contain ICAM-3. Such microparticles, released from apoptotic leukocytes, are strongly chemoattractive for macrophages. In addition, microparticles from ICAM-3-deficient leukocytes are significantly less chemoattractive than microparticles from their ICAM-3-replete counterparts. Taken together these data support the hypothesis that ICAM-3 acts as an apoptotic cell-associated ligand to tether dying cells to phagocytes in a CD14-independent manner. Furthermore our data suggest that released ICAM-3 may promote the recruitment of phagocytes to sites of leukocyte apoptosis.

War crimes, conditionality and EU integration in the Western Balkans

The baleful legacy of the wars of the 1990s continues to dog the states and societies of the former Yugoslavia and has overshadowed the disappointingly slow and hesitant trajectory of the region towards the EU. At the start of the new millennium, with the removal of key wartime leaders from the political scene in both Croatia and Serbia, it was widely hoped that the region would prove able to ‘leave the past behind’ and rapidly move on to the hopeful new agenda of EU integration. The EU’s Copenhagen criteria, which in 1993 first explicitly set out the basic political conditions expected of aspirant EU Member States, proved effective in the case of the new democracies of Central and Eastern Europe in supporting the entrenchment of democratic norms and practices, and stimulating reconciliation and good neighbourly relations among countries with turbulent histories. Building on this experience, the Stabilisation and Association Process, launched for the countries of the Western Balkans in 1999, included both full cooperation with the International Criminal Tribunal for the former Yugoslavia (ICTY) and regional reconciliation among the political conditions set for advancing these countries on the path to EU integration. EU political conditionality was intended to support the efforts of new political leaders to redefine national goals away from the nationalist enmities of the past and focus firmly on forging a path to a better future. This Chaillot Paper examines the extent to which this strategy has worked, especially in the light of the difficulties it has encountered in the face of strong resistance to cooperation among sections of the former Yugoslav population, many of whom have not yet fully acknowledged the crimes committed during the 1990s. Key chapters in the volume raise the vital questions of leadership and political will. EU political conditionality does not work unless the EU has a partner ready and willing to ‘play the game’, which presupposes that EU integration has become the overriding priority on the national political agenda.

The innate immune system and the clearance of apoptotic cells

Apoptosis, programmed cell death, is used by multicellular organisms to remove cells that are in excess, damaged or diseased. Activation of the apoptosis programme generates "eat me" signals on the surface of the apoptotic cell that mediate recognition and clearance by the innate immune system. CD14, a pattern recognition receptor expressed on macrophages, is widely known for its ability to recognise the pathogen-associated molecular pattern lipopolysaccharide (LPS) and promote inflammation. However, CD14 has also been shown to mediate binding and removal of apoptotic cells in a process that is anti-inflammatory suggesting CD14 is capable of producing two distinct, ligand-dependent macrophage responses. Whilst the molecular basis for this dichotomy has yet to be defined it is clear that CD14 defines a point of interest on the macrophage surface where we may study ligand-specific responses of macrophages. Our work seeks to define the molecular mechanisms underlying the involvement of CD14 in the non-inflammatory clearance of apoptotic cells. Here we used three different differentiation strategies to generate macrophages from the monocytic cell line THP-1. The resultant macrophage models were characterised to assess the expression and function of CD14 within each model system. Whilst each macrophage model shows increased levels of surface CD14 expression, our results demonstrate significant differences in the various models’ abilities to respond to LPS and clear apoptotic cells in a CD14-dependent manner. TLR4 levels correlated positively with LPS responsiveness but not CD14-dependent apoptotic cell clearance or anti-inflammatory responses to apoptotic cells. These observations suggest CD14-dependent apoptotic cell clearance is not dependent on TLR4. Taken together our data support the notion that the CD14 ligand-dependent responses to LPS and apoptotic cells derive from changes at the macrophage surface. The nature and composition of the CD14-co-receptor complex for LPS and apoptotic cell binding and responses is the subject of further study.

CD14 and innate immune clearance of apoptotic cells

Rapid elimination of cells undergoing programmed cell death (apoptosis) is vital to maintain tissue homeostasis. The phagocytic removal of apoptotic cells (AC) is mediated by innate immune molecules, professional phagocytes and amateur phagocytes that recognise "eat me" signals on the surface of the AC. CD14, a pattern recognition receptor expressed on macrophages, is widely known for its ability to recognise the pathogen-associated molecular pattern lipopolysaccharide (LPS) and promote inflammation. CD14 also mediates the binding and removal of AC, a process that is considered to be anti-inflammatory therefore suggesting CD14 is capable of producing two distinct ligand-dependent responses. Our work seeks to define the molecular mechanisms underlying the involvement of CD14 in the non-inflammatory clearance of AC. Here we describe three different differentiation strategies used to generate macrophages from the monocytic cell line THP-1. Whilst CD14 expression was increased in each macrophage model we demonstrate significant differences in the various macrophage models' abilities to respond to LPS and clear AC. We show that CD14 expression correlates with CD14-dependent AC clearance and anti-inflammatory responses to AC. However LPS responsiveness correlates, as expected, with TLR4 but not CD14 expression. These observations suggest CD14-dependent AC clearance is not dependent on TLR4. Taken together our data support the notion that CD14 ligand-dependent responses to LPS and AC are derived from changes at the macrophage surface. The nature and composition of the CD14-co-receptor complex for LPS and AC binding and consequent responses is the subject of further study.

Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells

Damaged, aged or unwanted cells are removed from the body by an active process known as apoptosis. This highly orchestrated programme results in cell disassembly and the exposure of ‘flags’ at the dying cell surface that permit recognition and removal by viable cells (phagocytes). Efficient phagocytic removal of dying cells is essential to prevent inflammatory and autoimmune disorders. Relatively little is known of the molecular mechanisms underlying changes at the apoptotic cell surface. We have previously shown that ICAM-3 (a heavily glycosylated, leukocyte-restricted Immunoglobulin Super-Family member) undergoes a change of function as cells die so that it acts as a molecular ‘flag’ to mediate corpse removal. Our work seeks to characterise apoptosis-associated changes in ICAM-3 and define their role in ICAM-3’s novel function in apoptotic cell clearance. Here we extend earlier studies to show that apoptotic cell-associated ICAM-3 functions, at least minimally, to tether apoptotic leukocytes to macrophages via an undefined receptor. Whilst CD14 has been suggested as a possible innate immune receptor for apoptotic cell-associated ICAM-3, we demonstrate ICAM-3 functions for apoptotic cell clearance in the absence of CD14. Our data additionally indicate, that during apoptosis, leukocytes display early changes in cell surface glycosylation and a marked reduction in ICAM-3, a change that correlates with a reduction in cell volume. This reduction in ICAM-3 is explained by cell surface shedding of microparticles (‘apoptotic bodies’) that contain ICAM-3. Such microparticles, released from apoptotic leukocytes, are strongly chemoattractive for macrophages. In addition, microparticles from ICAM-3-deficient leukocytes are significantly less chemoattractive than microparticles from their ICAM-3-replete counterparts. Taken together these data support the hypothesis that ICAM-3 acts as an apoptotic cell-associated ligand to tether dying cells to phagocytes in a CD14-independent manner. Furthermore our data suggest that released ICAM-3 may promote the recruitment of phagocytes to sites of leukocyte apoptosis.

Person-oriented and process-oriented teachers : an investigation of the links between ESOL teachers' personal belief systems and approaches to teaching

This thesis looks to two traditions in research into language teaching, teacher beliefs and classroom interaction, in order to investigate the question: Do teachers of ESOL have an identifiable and coherent system of beliefs about teaching and learning that may account for different approaches to teaching? A qualitative approach to research is taken, following a case study tradition, in order to carry out an in-depth study into the beliefs of six ESOL teachers. Five teachers participated in an initial pilot study and two subsequently became the main case studies for the research. The beliefs of a sixth teacher were then investigated to verify the findings. Semi-structured interviews and classroom observations were carried out with all the teachers. The teachers in the study were found to have personal belief systems that cohere around two orientations to teaching and learning - a person orientation and a process orientation. Moreover, the findings suggest that underlying the orientations is the perception that teachers have of their teacher identity, in terms of whether this is seen as a separate identity or as part of their personality. It is suggested that the two orientations may offer a powerful tool for teacher education as it is increasingly recognised that, in order to be effective, teacher educators must take into account the beliefs that teachers bring with them to training and development programmes. An initial investigations into the teachers’ classroom behaviour suggests that while their methodologies approach may be very similar there are fundamental differences in their interactions patterns and these differences may be a result of their own orientation. However, while teachers’ personal belief systems undoubtedly underlie their approach to teaching, further research is needed to establish the extent and the nature of the relationship between orientation and classroom interaction.

Computer aided process planning (CAPP) for flat rolling of copper alloys

The manufacture of copper alloy flat rolled metals involves hot and cold rolling operations, together with annealing and other secondary processes, to transform castings (mainly slabs and cakes) into such shapes as strip, plate, sheet, etc. Production is mainly to customer orders in a wide range of specifications for dimensions and properties. However, order quantities are often small and so process planning plays an important role in this industry. Much research work has been done in the past in relation to the technology of flat rolling and the details of the operations, however, there is little or no evidence of any research in the planning of processes for this type of manufacture. Practical observation in a number of rolling mills has established the type of manual process planning traditionally used in this industry. This manual approach, however, has inherent drawbacks, being particularly dependent on the individual planners who gain their knowledge over a long span of practical experience. The introduction of the retrieval CAPP approach to this industry was a first step to reduce these problems. But this could not provide a long-term answer because of the need for an experienced planner to supervise generation of any plan. It also fails to take account of the dynamic nature of the parameters involved in the planning, such as the availability of resources, operation conditions and variations in the costs. The other alternative is the use of a generative approach to planning in the rolling mill context. In this thesis, generative methods are developed for the selection of optimal routes for single orders and then for batches of orders, bearing in mind equipment restrictions, production costs and material yield. The batch order process planning involves the use of a special cluster analysis algorithm for optimal grouping of the orders. This research concentrates on cold-rolling operations. A prototype model of the proposed CAPP system, including both single order and batch order planning options, has been developed and tested on real order data in the industry. The results were satisfactory and compared very favourably with the existing manual and retrieval methods.

The pro-reform movement led by Avenir de la Francaise:a point of leverage in the French political process?

The study examines factors influencing language planning decisions in contemporary France. It focuses upon the period 1992-1994, which witnessed the introduction of two major language policy measures, the first an amendment to the French Constitution, in 1992, proclaiming the language of the Republic as French, the second, in 1994, legislation to extend the ambit of the loi Bas-Lauriol, governing the use of the French language in France. The thesis posits a significant role for the pro-reform movement led by the French language association Avenir de la Langue Francaise (ALF) in the introduction and formulation of the policy measures concerned. The movement is depicted as continuing the traditional pattern of intellectual involvement in language planning, whilst also marking the beginning of a highly proactive, and increasingly political approach. Detailed examination of the movement's activities reveals that contextual factors and strategic strength combined to facilitate access to the levers of power, and enabled those involved to exert an impact on policy initiation, formulation, and ultimately implementation. However, ALF's decision to pursue the legislative route led to the expansion of the network of actors involved in language policymaking, and the development of counter-pressure from sectoral groups. It is suggested that this more interventionist approach destabilised the traditionally consensual language policy community, and called into question the quasi-monopoly of the intelligentsia in respect of language policymaking. It raised broader questions relating to freedom of expression and the permissible limits of language regulation in a democracy such as France. It also exposed ongoing ambiguities and inconsistencies in the interpretation of the tenets of language planning.

The innate immune system and the clearance of apoptotic cells

Removal of unwanted, effete, or damaged cells through apoptosis, an active cell death culminating in phagocytic removal of cell corpses, is an important process throughout the immune system in development, control, and homeostasis. For example, neutrophil apoptosis is central to the resolution of acute inflammation, whereas autoreactive and virus-infected cells are similarly deleted. The AC removal process functions not only to remove cell corpses but further, to control inappropriate immune responses so that ACs are removed in an anti-inflammatory manner. Such "silent" clearance is mediated by the innate immune system via polarized monocyte/macrophage populations that use a range of PRRs and soluble molecules to promote binding and phagocytosis of ACs. Additionally, attractive signals are released from dying cells to recruit phagocytes to sites of death. Here, we review the molecular mechanisms associated with innate immune removal of and responses to ACs and outline how these may impact on tissue homeostasis and age-associated pathology (e.g., cardiovascular disease). Furthermore, we discuss how an aging innate immune system may contribute to the inflammatory consequences of aging and why the study of an aging immune system may be a useful path to advance characterization of mechanisms mediating effective AC clearance. © Society for Leukocyte Biology.

Developing and evaluating a methodology for business process improvement

Purpose – There appears to be an ever-insatiable demand from markets for organisations to improve their products and services. To meet this, there is a need to provide business process improvement (BPI) methodologies that are holistic, structured and procedural. Therefore, this paper describes research that has formed and tested a generic and practical methodology termed model-based and integrated process improvement (MIPI) to support the implementation of BPI; and to validate its effectiveness in organisations. This methodology has been created as an aid for practitioners within organisations. Design/methodology/approach – The research objectives were achieved by: reviewing and analysing current methodologies, and selecting a few frameworks against key performance indicators. Using a refined Delphi approach and semi-structured interview with the “experts” in the field. Intervention, case study and process research approach to evaluating a methodology. Findings – The BPI methodology was successfully formed and applied by the researcher and directly by the companies involved against the criteria of feasibility, usability and usefulness. Research limitations/implications – The paper has demonstrated a new knowledge on how to systematically assess a BPI methodology in practice. Practical implications – Model-based and integrated process improvement methodology (MIPI) methodology offers the practitioner (experienced and novice) a set of step-by-step aids necessary to make informed, consistent and efficient changes to business processes. Originality/value – The novelty of this research work is the creation of a holistic workbook-based methodology with relevant tools and techniques. It extends the capabilities of existing methodologies.

The N-terminus of CD14 acts to bind apoptotic cells and confers rapid-tethering capabilities on non-myeloid cells:CD14 and rapid tethering of apoptotic cells

Cell death and removal of cell corpses in a timely manner is a key event in both physiological and pathological situations including tissue homeostasis and the resolution of inflammation. Phagocytic clearance of cells dying by apoptosis is a complex sequential process comprising attraction, recognition, tethering, signalling and ultimately phagocytosis and degradation of cell corpses. A wide range of molecules acting as apoptotic cell-associated ligands, phagocyte-associated receptors or soluble bridging molecules have been implicated within this process. The role of myeloid cell CD14 in mediating apoptotic cell interactions with macrophages has long been known though key molecules and residues involved have not been defined. Here we sought to further dissect the function of CD14 in apoptotic cell clearance. A novel panel of THP-1 cell-derived phagocytes was employed to demonstrate that CD14 mediates effective apoptotic cell interactions with macrophages in the absence of detectable TLR4 whilst binding and responsiveness to LPS requires TLR4. Using a targeted series of CD14 point mutants expressed in non-myeloid cells we reveal CD14 residue 11 as key in the binding of apoptotic cells whilst other residues are reported as key for LPS binding. Importantly we note that expression of CD14 in non-myeloid cells confers the ability to bind rapidly to apoptotic cells. Analysis of a panel of epithelial cells reveals that a number naturally express CD14 and that this is competent to mediate apoptotic cell clearance. Taken together these data suggest that CD14 relies on residue 11 for apoptotic cell tethering and it may be an important tethering molecule on so called 'non-professional' phagocytes thus contributing to apoptotic cell clearance in a non-myeloid setting. Furthermore these data establish CD14 as a rapid-acting tethering molecule, expressed in monocytes, which may thus confer responsiveness of circulating monocytes to apoptotic cell derived material. © 2013 Thomas et al.

Is more capability always beneficial for firm performance? Market orientation, core business process capabilities, and business environment

This study examines the role of capabilities in core marketing-related business processes–product development management (PDM), supply chain management (SCM) and customer relationship management (CRM)–in translating a firm’s market orientation (MO) into firm performance. The study is the first to examine the interplay of all three business process capabilities simultaneously, while investigating how environmental conditions moderate their performance effects. A moderated mediation analysis of 468 product-focused firms finds that PDM and CRM process capabilities play important mediating roles, whereas SCM process capability does not mediate the relationship between MO and performance. However, the relative importance of the capabilities as mediators varies along the degree of environmental turbulence, and under certain conditions, an increase in the level of business process capability may even turn detrimental.

A szervezeti identitás meghatározása, elemei és menedzselése (Defining of organizational identity and its components and management)

Jelen cikk a szervezeti identitás különböző tudományos értelmezéseit, elemeit mutatja be és kapcsolja össze a gyakorlattal. A szerzők értelmezése szerint a szervezeti identitás nem azonos a köznyelvben elterjedt arculattal (sem image-zsal), hanem egy holisztikus, menedzsment-szakirodalmakon átívelő fogalomként értelmezhető, mely a külső tényezők hatására a szervezeti kultúra és a szervezeti stratégia alapján alakítható ki. A szervezeti identitás három alkotóelem-csoportból áll (nevezhetjük ezt identitásmixnek is): a munkáltatói márkázásból, az integrált marketingkommunikációból és a vizuális identitásból. Mivel a változó környezet szükségessé teszi, a szervezeti identitás menedzselése egy véget nem érő „spirálfolyamat”, mely a felmérés, a meghatározás, a bevezetés és értékelés szakaszok ismétléséből áll addig, amíg az ideális identitás ki nem alakul. Melyet talán soha nem ér el a vállalat. _____ In this article the different scientific interpretations and elements of organizational identity are presented and combined with practice. According to the authors’ interpretation the organizational identity is not the same as the corporate image, but it can be interpreted as a holistic management literatures panning notion which can be formed by the effect of external factors on basis of the organizational culture and organizational strategy. The organizational identity consists of three component-groups (also called this identity mix) the employer branding, integrated marketingcommunications and visual identity. Due to the changing environment makes it necessary the management of organizational identity is a never-ending ”spiral process”, which consists of repetitions of the survey, the definition, the introduction and the assessment phases until the ideal identity will be formed. Which may be never achieved by the corporate.

Team diversity and leadership: Tests of model of process and direct effects

A model was tested to examine relationships among leadership behaviors, team diversity, and team process measures with team performance and satisfaction at both the team and leader-member levels of analysis. Relationships between leadership behavior and team demographic and cognitive diversity were hypothesized to have both direct effects on organizational outcomes as well as indirect effects through team processes. Leader member differences were investigated to determine the effects of leader-member diversity leader-member exchange quality, individual effectiveness and satisfaction.^ Leadership had little direct effect on team performance, but several strong positive indirect effects through team processes. Demographic Diversity had no impact on team processes, directly impacted only one performance measure, and moderated the leadership to team process relationship.^ Cognitive Diversity had a number of direct and indirect effects on team performance, the net effects uniformly positive, and did not moderate the leadership to team process relationship.^ In sum, the team model suggests a complex combination of leadership behaviors positively impacting team processes, demographic diversity having little impact on team process or performance, cognitive diversity having a positive net impact impact, and team processes having mixed effects on team outcomes.^ At the leader-member level, leadership behaviors were a strong predictor of Leader-Member Exchange (LMX) quality. Leader-member demographic and cognitive dissimilarity were each predictors of LMX quality, but failed to moderate the leader behavior to LMX quality relationship. LMX quality was strongly and positively related to self reported effectiveness and satisfaction.^ The study makes several contributions to the literature. First, it explicitly links leadership and team diversity. Second, demographic and cognitive diversity are conceptualized as distinct and multi-faceted constructs. Third, a methodology for creating an index of categorical demographic and interval cognitive measures is provided so that diversity can be measured in a holistic conjoint fashion. Fourth, the study simultaneously investigates the impact of diversity at the team and leader-member levels of analyses. Fifth, insights into the moderating impact of different forms of team diversity on the leadership to team process relationship are provided. Sixth, this study incorporates a wide range of objective and independent measures to provide a 360$\sp\circ$ assessment of team performance. ^

Experimental analysis of soil and dust stabilizers for controlling displacement of contaminated soils by wind tunnel experiments

During the remediation of burial grounds at the US Department of Energy's (DOE's) Hanford Site in Washington State, the dispersion of contaminated soil particles and dust is an issue that is faced by site workers on a daily basis. This contamination problem is even more of a concern when one takes into account the semi-arid characteristics of the region where the site is located. To mitigate this problem, workers at the site use a variety of engineered methods to minimize the dispersion of contaminated soil and dust (i.e. use of water and/or suppression agents that stabilizes the soil prior to soil excavation, segregation, and removal activities). A primary contributor to the dispersion of contaminated soil and dust is wind soil erosion. The erosion process occurs when the wind speed exceeds a certain threshold value which depends on a number of factors including wind force loading, particle size, surface soil moisture, and the geometry of the soil. Thus under these circumstances, the mobility of contaminated soil and generation and dispersion of particulate matter are significantly influenced by these parameters. This dependence of soil and dust movement on threshold shear velocity, fixative dilution and/or application rates, soil moisture content, and soil geometry were studied for Hanford's sandy soil through a series of wind tunnel experiments, laboratory experiments and theoretical analysis. In addition, the behavior of plutonium (Pu) powder contamination in the soil was studied by introducing a Pu simulant (cerium oxide). The results showed that soil dispersion and PM10 concentrations decreased with increasing soil moisture. Also, it was shown that the mobility of the soil was affected by increasing wind velocity. It was demonstrated that the use of fixative products greatly decreased the amount of soil and PM10 concentrations when exposed to varying wind conditions. In addition, it was shown that geometry of the soil sample affected the velocity profile and calculation of roughness surface coefficient when comparing round and flat soil samples. Finally, threshold shear velocities were calculated for soil with flat surface and their dependency on surface soil moisture was demonstrated. A theoretical framework was developed to explain these dependencies.