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

Crowdsourcing Linked Data on listening experiences through reuse and enhancement of library data

Research has approached the practice of musical reception in a multitude of ways, such as the analysis of professional critique, sales figures and psychological processes activated by the act of listening. Studies in the Humanities, on the other hand, have been hindered by the lack of structured evidence of actual experiences of listening as reported by the listeners themselves, a concern that was voiced since the early Web era. It was however assumed that such evidence existed, albeit in pure textual form, but could not be leveraged until it was digitised and aggregated. The Listening Experience Database (LED) responds to this research need by providing a centralised hub for evidence of listening in the literature. Not only does LED support search and reuse across nearly 10,000 records, but it also provides machine-readable structured data of the knowledge around the contexts of listening. To take advantage of the mass of formal knowledge that already exists on the Web concerning these contexts, the entire framework adopts Linked Data principles and technologies. This also allows LED to directly reuse open data from the British Library for the source documentation that is already published. Reused data are re-published as open data with enhancements obtained by expanding over the model of the original data, such as the partitioning of published books and collections into individual stand-alone documents. The database was populated through crowdsourcing and seamlessly incorporates data reuse from the very early data entry phases. As the sources of the evidence often contain vague, fragmentary of uncertain information, facilities were put in place to generate structured data out of such fuzziness. Alongside elaborating on these functionalities, this article provides insights into the most recent features of the latest instalment of the dataset and portal, such as the interlinking with the MusicBrainz database, the relaxation of geographical input constraints through text mining, and the plotting of key locations in an interactive geographical browser

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

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

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

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)

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

General relativity as an effective field theory: The leading quantum corrections

I describe the treatment of gravity as a quantum effective field theory. This allows a natural separation of the (known) low energy quantum effects from the (unknown) high energy contributions. Within this framework, gravity is a well behaved quantum field theory at ordinary energies. In studying the class of quantum corrections at low energy, the dominant effects at large distance can be isolated, as these are due to the propagation of the massless particles (including gravitons) of the theory and are manifested in the nonlocal/nonanalytic contributions to vertex functions and propagators. These leading quantum corrections are parameter-free and represent necessary consequences of quantum gravity. The methodology is illustrated by a calculation of the leading quantum corrections to the gravitational interaction of two heavy masses.Comment: 34 pages, Latex, UMHEP-40

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