PI3K beta Plays a Critical Role in Neutrophil Activation by Immune Complexes

Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (Fc gamma Rs). Here, we used genetic and pharmacological approaches to define a selective role for the beta isoform of phosphoinositide 3-kinase (PI3K beta) in Fc gamma R-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3K beta alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3K beta and PI3K delta, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3K beta by immune complexes involved cooperation between Fc gamma Rs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B-4. Coincident activation by a tyrosine kinase-coupled receptor (Fc gamma R) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the beta isoform of PI3K. PI3K beta-deficient mice were highly protected in an Fc gamma R-dependent model of autoantibody-induced skin blistering and were partially protected in an Fc gamma R-dependent model of inflammatory arthritis, whereas combined deficiency of PI3K beta and PI3K delta resulted in near-complete protection in the latter case. These results define PI3K beta as a potential therapeutic target in inflammatory disease.

Protocolised versus non-protocolised weaning from mechanical ventilation in adult critical care.

Contribution: I co-authored this paper. This paper is primarily aimed at informing clinically based health professionals.

Confined Site Construction: A qualitative investigation of critical issues affecting management of Health and Safety

The construction industry is inherently risky, with a significant number of accidents and disasters occurring, particularly on confined construction sites. This research investigates and identifies the various issues affecting successful management of health and safety in confined construction sites. The rationale is that identifying the issues would assist the management of health and safety particularly in inner city centres which are mostly confined sites. Using empiricism epistemology, the methodology was based on qualitative research approach by means of multiple case studies in three different geographical locations of Ireland, UK and USA. Data on each case study were collected through individual interviews and focus group discussion with project participants. The findings suggest that three core issues are the underlying factors affecting management of health and safety on confined construction sites. It include, (i) lack of space, (ii) problem of co-ordination and management of site personnel, and (iii) overcrowding of workplace. The implication of this is that project teams and their organisations should see project processes from a holistic point of view, as a unified single system, where quick intervention in solving a particular issue should be the norm, so as not to adversely affect interrelated sequence of events in project operations. Proactive strategies should be devised to mitigate these issues and may include detail project programming, space management, effective constructability review and efficient co-ordination of personnel, plant and materials among others. The value of this research is to aid management and operation of brownfield sites by identifying issues impacting on health and safety management in project process.

Struggles against Injustice:: Contemporary Critical Theory and Political Violence

This article investigates a significant problem in contemporary critical theory, namely its failure to address effectively the possibility that a campaign of political violence may be a legitimate means of fighting grave injustice. Having offered a working definition of ‘political violence’, I argue that critical theory should be focused on experiences of injustice rather than on ideals of justice. I then explore the reasons as to why, save for some intriguing remarks on retrospective legitimation, Jürgen Habermas has not addressed this issue directly. While Axel Honneth's recognition theory may have greater potential here, the absence of explicit consideration of the matter by him leaves considerable work to do. I introduce five questions in the concluding section that provide a starting point in setting out an appropriately stringent, normative test for claims that support violent action against injustice.

Langerin(+) Dermal Dendritic Cells Are Critical for CD8(+) T Cell Activation and IgH gamma-1 Class Switching in Response to Gene Gun Vaccines

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin(+) dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin(+) DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin(+) DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin(+) cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin(+) DC abrogated the activation of IFN-gamma producing and cytolytic CD8(+) T cells after gene gun vaccination. Moreover, we identified migratory langerin(+) dermal DC as the subset that directly activated CD8(+) T cells in lymph nodes. Langerin(+) DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4(+) T helper cells by langerin(+) or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin(+) DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation. The Journal of Immunology, 2011, 186: 1377-1383.

Securing the human in critical security studies: the insecurity of a secure ethics

This article argues that Critical Security Studies (CSS), exemplified by Ken Booth’s Theory of World Security, has outlined an ethics of security as emancipation of the ‘human’, but also a highly problematic security of ethics. After drawing out how the ethics of CSS operates, we examine the security of this ethics by examining it against a hard case, that of the 199899 Kosovo crisis. Confronting this concrete situation, we draw out three possibilities for action used at the time to secure the human: ‘humanitarian containment’, military intervention and hospitality. Assessing each against Booth’s requirements for ethical security action, we counter that, in fact, no option was without risks, pitfalls and ambiguities. Ultimately, if any action to promote the security and the emancipation of the human is possible, it must embrace and prioritise the fundamental insecurity of ethics, or else find itself paralysed through a fear of making situations worse.

The Critical Reading of the Images Associated with Science-Related News Reports: Establishing a knowledge, skills, and attitudes framework

For the majority of adults, the media constitute their main source of information about science and science-related matters impacting on society. To help prepare young people to engage with science in the media, teachers are being exhorted to equip their students with the knowledge, skills, and attitudes to respond critically to science-related news reports. Typically, such reports comprise not only text, but also visual elements. These images are not simply adjuncts to the written word; they are integral to meaning-making. Though science teachers make considerable use of newspaper images, they tend to view these representations unproblematically, underestimating their potential ambiguity, complexity, and role in framing media messages. They rarely aim to develop students’ ability to ‘read’, critically, such graphics. Moreover, research into how this might be achieved is limited and, consequently, research-informed guidance which could support this instruction is lacking. This paper describes a study designed to formulate a framework for such teaching. Science communication scholars, science journalists and media educators with acknowledged relevant expertise were surveyed to ascertain what knowledge, skills, and attitudes they deemed useful to engagement with science related news images. Their proposals were recast as learning intentions (instructional objectives), and science and English teachers collaborated to suggest which could be addressed with secondary school students and the age group best suited to their introduction. The outcome is an inventory of learning intentions on which teachers could draw to support their planning of instructional sequences aimed at developing students’ criticality in respect of the totality of science news reports.