Dissecting interferon-induced transcriptional programs in human peripheral blood cells

Interferons are key modulators of the immune system, and are central to the control of many diseases. The response of immune cells to stimuli in complex populations is the product of direct and indirect effects, and of homotypic and heterotypic cell interactions. Dissecting the global transcriptional profiles of immune cell populations may provide insights into this regulatory interplay. The host transcriptional response may also be useful in discriminating between disease states, and in understanding pathophysiology. The transcriptional programs of cell populations in health therefore provide a paradigm for deconvoluting disease-associated gene expression profiles.We used human cDNA microarrays to (1) compare the gene expression programs in human peripheral blood mononuclear cells (PBMCs) elicited by 6 major mediators of the immune response: interferons alpha, beta, omega and gamma, IL12 and TNFalpha; and (2) characterize the transcriptional responses of purified immune cell populations (CD4+ and CD8+ T cells, B cells, NK cells and monocytes) to IFNgamma stimulation. We defined a highly stereotyped response to type I interferons, while responses to IFNgamma and IL12 were largely restricted to a subset of type I interferon-inducible genes. TNFalpha stimulation resulted in a distinct pattern of gene expression. Cell type-specific transcriptional programs were identified, highlighting the pronounced response of monocytes to IFNgamma, and emergent properties associated with IFN-mediated activation of mixed cell populations. This information provides a detailed view of cellular activation by immune mediators, and contributes an interpretive framework for the definition of host immune responses in a variety of disease settings

Trust, regulatory processes and NICE decision-making: Appraising cost-effectiveness models through appraising people and systems.

This article presents an ethnographic study of regulatory decision-making regarding the cost-effectiveness of expensive medicines at the National Institute for Health and Care Excellence (NICE) in England. We explored trust as one important mechanism by which problems of complexity and uncertainty were resolved. Existing studies note the salience of trust for regulatory decisions, by which the appraisal of people becomes a proxy for appraising technologies themselves. Although such (dis)trust in manufacturers was one important influence, we describe a more intricate web of (dis)trust relations also involving various expert advisors, fellow committee members and committee Chairs. Within these complex chains of relations, we found examples of both more blind-acquiescent and more critical-investigative forms of trust as well as, at times, pronounced distrust. Difficulties in overcoming uncertainty through other means obliged trust in some contexts, although not in others. (Dis)trust was constructed through inferences involving abstract systems alongside actors’ oral and written presentations-of-self. Systemic features and ‘forced options’ to trust indicate potential insidious processes of regulatory capture

On the Mean-Field Limit of Bosons with Coulomb Two-Body Interaction

In the mean-field limit the dynamics of a quantum Bose gas is described by a Hartree equation. We present a simple method for proving the convergence of the microscopic quantum dynamics to the Hartree dynamics when the number of particles becomes large and the strength of the two-body potential tends to 0 like the inverse of the particle number. Our method is applicable for a class of singular interaction potentials including the Coulomb potential. We prove and state our main result for the Heisenberg-picture dynamics of "observables", thus avoiding the use of coherent states. Our formulation shows that the mean-field limit is a "semi-classical" limit.Comment: Corrected typos and included an elementary proof of the Kato smoothing estimate (Lemma 6.1

Iwasawa Effects in Multi-layer Optics

There are many two-by-two matrices in layer optics. It is shown that they can be formulated in terms of a three-parameter group whose algebraic property is the same as the group of Lorentz transformations in a space with two space-like and one time-like dimensions, or the $Sp(2)$ group which is a standard theoretical tool in optics. Among the interesting mathematical properties of this group, the Iwasawa decomposition drastically simplifies the matrix algebra under certain conditions, and leads to a concise expression for the S-matrix for transmitted and reflected rays. It is shown that the Iwasawa effect can be observed in multi-layer optics, and a sample calculation of the S-matrix is given.Comment: RevTex 10 pages including 1 psfi

Changes in lipid composition during sexual development of the malaria parasite Plasmodium falciparum

Abstract Background The development of differentiated sexual stages (gametocytes) within human red blood cells is essential for the propagation of the malaria parasite, since only mature gametocytes will survive in the mosquito’s midgut. Hence gametocytogenesis is a pre-requisite for transmission of the disease. Physiological changes involved in sexual differentiation are still enigmatic. In particular the lipid metabolism—despite being central to cellular regulation and development—is not well explored. Methods Here the lipid profiles of red blood cells infected with the five different sexual stages of Plasmodium falciparum were analysed by mass spectrometry and compared to those from uninfected and asexual trophozoite infected erythrocytes. Results Fundamental differences between erythrocytes infected with the different parasite stages were revealed. In mature gametocytes many lipids that decrease in the trophozoite and early gametocyte infected red blood cells are regained. In particular, regulators of membrane fluidity, cholesterol and sphingomyelin, increased significantly during gametocyte maturation. Neutral lipids (serving mainly as caloriometric reserves) increased from 3 % of total lipids in uninfected to 27 % in stage V gametocyte infected red blood cells. The major membrane lipid class (phospholipids) decreased during gametocyte development. Conclusions The lipid profiles of infected erythrocytes are characteristic for the particular parasite life cycle and maturity stages of gametocytes. The obtained lipid profiles are crucial in revealing the lipid metabolism of malaria parasites and identifying targets to interfere with this deadly disease.We are grateful to the Australian Red Cross for providing human RBCs and serum. Support of the Australian Research Council is acknowledged. TWM is an Australian Research Council Future Fellow (FT110100249)

Statistical challenges in assessing potential efficacy of complex interventions in pilot or feasibility studies

Early phase trials of complex interventions currently focus on assessing the feasibility of a large RCT and on conducting pilot work. Assessing the efficacy of the proposed intervention is generally discouraged, due to concerns of underpowered hypothesis testing. In contrast, early assessment of efficacy is common for drug therapies, where phase II trials are often used as a screening mechanism to identify promising treatments. In this paper we outline the challenges encountered in extending ideas developed in the phase II drug trial literature to the complex intervention setting. The prevalence of multiple endpoints and clustering of outcome data are identified as important considerations, having implications for timely and robust determination of optimal trial design parameters. The potential for Bayesian methods to help to identify robust trial designs and optimal decision rules is also explored

Retelling racialized violence, remaking white innocence: the politics of interlocking oppressions in transgender day of remembrance

Transgender Day of Remembrance has become a significant political event among those resisting violence against gender-variant persons. Commemorated in more than 250 locations worldwide, this day honors individuals who were killed due to anti-transgender hatred or prejudice. However, by focusing on transphobia as the definitive cause of violence, this ritual potentially obscures the ways in which hierarchies of race, class, and sexuality constitute such acts. Taking the Transgender Day of Remembrance/Remembering Our Dead project as a case study for considering the politics of memorialization, as well as tracing the narrative history of the Fred F. C. Martinez murder case in Colorado, the author argues that deracialized accounts of violence produce seemingly innocent White witnesses who can consume these spectacles of domination without confronting their own complicity in such acts. The author suggests that remembrance practices require critical rethinking if we are to confront violence in more effective ways. Description from publisher's site: http://caliber.ucpress.net/doi/abs/10.1525/srsp.2008.5.1.2

Selection of workers and firm heterogeneity

A model based on differences between workers regarding their preferences for wage and leisure drives the heterogeneity of firms result. The more industrious workers are driven to small firms due to free riding in large firms. An industry consisting of small and large firms turns out to produce more output than an industry consisting of only large firms. Some comparative statics results are derived with respect to the size of large firms, the productivity difference between firms, and monitoring capabilities

Wittgenstein's Thought Experiments and Relativity Theory

In this paper, I discuss the similarity between Wittgenstein’s use of thought experiments and Relativity Theory. I begin with introducing Wittgenstein’s idea of “thought experiments” and a tentative classification of different kinds of thought experiments in Wittgenstein’s work. Then, after presenting a short recap of some remarks on the analogy between Wittgenstein’s point of view and Einstein’s, I suggest three analogies between the status of Wittgenstein’s mental experiments and Relativity theory: the topics of time dilation, the search for invariants, and the role of measuring tools in Special Relativity. This last point will help to better define Wittgenstein’s idea of description as the core of his philosophical enterprise

The impact of marketisation on postgraduate career preparedness in a high skills economy

This study focuses on the consequences for high skills development of the erosion of the once clear demarcation between higher education and business. It contributes to the broader debate about the relevance of higher education for thewell-being of the society of the future. The research explores the effects of marketisation on the postgraduate curriculum and students’ preparedness for careers in public relations and marketing communications. Interviews with lecturers and students in two universities in the UK and Australia indicate that a tension exists between academic rigour and corporate relevancy. The consequences are a diminution of academic attachment to critique and wider social/cultural engagement, with a resulting impoverishment of students’ creative abilities and critical consciences. Subsequently, graduates of public relations and marketing communications, and to some extent those from other profession-related disciplines, are insufficiently prepared for careers as knowledge workers in a future high-skills economy