The role of lipid metabolism in the immunopathogenesis of juvenile-onset systemic lupus erythematosus

Juvenile-onset systemic lupus erythematosus (JSLE) is a complex autoimmune disorder characterised by chronic inflammation, multiple organ damage and increased risk of cardiovascular disease (CVD). Disease onset in JSLE is more common during puberty and the female to male ratio is 4.5:1, suggesting a hormonal importance in disease pathogenesis. Work by the Jury lab in adult-onset SLE links immune cell dysregulation with defects in plasma membrane lipids rafts; signalling platforms that facilitate immune cell activation and effector function. However, in patients with JSLE, the immune system is still developing and very little is known about disease pathogenesis, whether it is the same as adult disease and whether the same treatments available to the adults are relevant for this younger group of patients. My hypothesis is that altered lipid metabolism leads to changes in immune cell function; differences in lipid metabolism exist between males and females and defects in these pathways contribute to JSLE pathogenesis. My aims were to 1) investigate sex differences in immune and metabolic phenotype in healthy individuals and JSLE patients, 2) assess the relationship between immune cells and serum lipids and 3) identify predictive biomarkers for CVD risk in JSLE. Using in depth immunophenotyping by flow cytometry and metabolomic analysis, this study has identified fundamental differences between healthy adolescent males and females. Males had increased regulatory T-cell (Treg) frequencies, altered lipid raft profiles and functional differences including an increased IL-4 production and suppressive capacity compared to females. These Treg phenotypic differences were associated with the very low density lipoprotein (VLDL) signature connected with males. In a chronic inflammatory setting (JSLE), these differences were lost between males and females. I also found that JSLE patients could be stratified according to their serum lipoprotein profile allowing potential identification of patients with increased CVD risk. This work provides evidence that a combination of pubertal development, immune cell defects and dyslipidemia may contribute to JSLE pathogenesis. Patient stratification has identified a unique group of patients that could benefit from lipid modification therapy, reducing both CVD risk and immune cell activity

The Role of Immunometabolism in the Pathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder in which pathogenic abnormalities within both the innate and adaptive immune response have been described. In order to activated, proliferate and maintain this immunological response a drastic upregulation in energy metabolism is required. Recently, a greater understanding of these changes in cellular bioenergetics have provided new insight into the links between immune response and the pathogenesis of a number of diseases, ranging from cancer to diabetes and multiple sclerosis. In this review, we highlight the latest understanding of the role of immunometabolism in SLE with particular focus on the role of abnormal mitochondrial function, lipid metabolism, and mTOR signaling in the immunological phenomenon observed in the SLE. We also consider what implications this has for future therapeutic options in the management of the disease in future

Forecasting substantial data revisions in the presence of model uncertainty

A recent revision to the preliminary measurement of GDP(E) growth for 2003Q2 caused considerable press attention, provoked a public enquiry and prompted a number of reforms to UK statistical reporting procedures. In this article, we compute the probability of 'substantial revisions' that are greater (in absolute value) than the controversial 2003 revision. The predictive densities are derived from Bayesian model averaging over a wide set of forecasting models including linear, structural break and regime-switching models with and without heteroscedasticity. Ignoring the nonlinearities and model uncertainty yields misleading predictives and obscures recent improvements in the quality of preliminary UK macroeconomic measurements

DNA Damage–Induced Bcl-x(L) Deamidation Is Mediated by NHE-1 Antiport Regulated Intracellular pH

The pro-survival protein Bcl-x(L) is critical for the resistance of tumour cells to DNA damage. We have previously demonstrated, using a mouse cancer model, that oncogenic tyrosine kinase inhibition of DNA damage–induced Bcl-x(L) deamidation tightly correlates with T cell transformation in vivo, although the pathway to Bcl-x(L) deamidation remains unknown and its functional consequences unclear. We show here that rBcl-x(L) deamidation generates an iso-Asp(52)/iso-Asp(66) species that is unable to sequester pro-apoptotic BH3-only proteins such as Bim and Puma. DNA damage in thymocytes results in increased expression of the NHE-1 Na/H antiport, an event both necessary and sufficient for subsequent intracellular alkalinisation, Bcl-x(L) deamidation, and apoptosis. In murine thymocytes and tumour cells expressing an oncogenic tyrosine kinase, this DNA damage–induced cascade is blocked. Enforced intracellular alkalinisation mimics the effects of DNA damage in murine tumour cells and human B-lineage chronic lymphocytic leukaemia cells, thereby causing Bcl-x(L) deamidation and increased apoptosis. Our results define a signalling pathway leading from DNA damage to up-regulation of the NHE-1 antiport, to intracellular alkalanisation to Bcl-x(L) deamidation, to apoptosis, representing the first example, to our knowledge, of how deamidation of internal asparagine residues can be regulated in a protein in vivo. Our findings also suggest novel approaches to cancer therapy

Political strategies of external support for democratization

Political strategies of external support to democratization are contrasted and critically examined in respect of the United States and European Union. The analysis begins by defining its terms of reference and addresses the question of what it means to have a strategy. The account briefly notes the goals lying behind democratization support and their relationship with the wider foreign policy process, before considering what a successful strategy would look like and how that relates to the selection of candidates. The literature's attempts to identify strategy and its recommendations for better strategies are compared and assessed. Overall, the article argues that the question of political strategies of external support for democratization raises several distinct but related issues including the who?, what?, why?, and how? On one level, strategic choices can be expected to echo the comparative advantage of the "supporter." On a different level, the strategies cannot be divorced from the larger foreign policy framework. While it is correct to say that any sound strategy for support should be grounded in a theoretical understanding of democratization, the literature on strategies reveals something even more fundamental: divergent views about the nature of politics itself. The recommendations there certainly pinpoint weaknesses in the actual strategies of the United States and Europe but they have their own limitations too. In particular, in a world of increasing multi-level governance strategies for supporting democratization should go beyond preoccupation with just an "outside-in" approach

First radial velocity results from the MINiature Exoplanet Radial Velocity Array (MINERVA)

The MINiature Exoplanet Radial Velocity Array (MINERVA) is a dedicated observatory of four 0.7m robotic telescopes fiber-fed to a KiwiSpec spectrograph. The MINERVA mission is to discover super-Earths in the habitable zones of nearby stars. This can be accomplished with MINERVA's unique combination of high precision and high cadence over long time periods. In this work, we detail changes to the MINERVA facility that have occurred since our previous paper. We then describe MINERVA's robotic control software, the process by which we perform 1D spectral extraction, and our forward modeling Doppler pipeline. In the process of improving our forward modeling procedure, we found that our spectrograph's intrinsic instrumental profile is stable for at least nine months. Because of that, we characterized our instrumental profile with a time-independent, cubic spline function based on the profile in the cross dispersion direction, with which we achieved a radial velocity precision similar to using a conventional "sum-of-Gaussians" instrumental profile: 1.8 m s$^{-1}$ over 1.5 months on the RV standard star HD 122064. Therefore, we conclude that the instrumental profile need not be perfectly accurate as long as it is stable. In addition, we observed 51 Peg and our results are consistent with the literature, confirming our spectrograph and Doppler pipeline are producing accurate and precise radial velocities.Comment: 22 pages, 9 figures, submitted to PASP, Peer-Reviewed and Accepte

Unfinished Decolonisation and Globalisation

This article locates John Darwin’s work on decolonisation within an Oxbridge tradition which portrays a British world system, of which formal empire was but one part, emerging to increasing global dominance from the early nineteenth century. In this mental universe, decolonisation was the mirror image of that expanding global power. According to this point of view, it was not the sloughing off of individual territories, but rather the shrinking away of the system and of the international norms that supported it, until only its ghost remained by the end of the 1960s. The article then asks, echoing the title of Darwin’s Unfinished Empire, whether the decolonisation project is all but complete, or still ongoing. In addition, what is the responsibility of the imperial historian to engage with, inform, or indeed refrain from, contemporary debates that relate to some of these issues? The answer is twofold. On the one hand, the toolkit that the Oxbridge tradition and Darwin provide remains relevant, and also useful in thinking about contemporary issues such as China’s move towards being a global power, the United States’ declining hegemony, and some states and groups desires to rearticulate their relationship with the global. On the other hand, the decline of world systems of power needs to be recognised as just one of several types of, and approaches to, analysing ‘decolonisation’. One which cannot be allowed to ignore or marginalise the study of others, such as experience, first nations issues, the shaping of the postcolonial state, and empire legacies. The article concludes by placing the Oxbridge tradition into a broader typology of types and methodologies of decolonisation, and by asking what a new historiography of decolonisation might look like. It suggests that it would address the Oxbridge concern with the lifecycles of systems of power and their relationship to global changes, but also place them alongside, and in dialogue with, a much broader set of perspectives and analytical approaches