Project sigma: the temporality of activism

This chapter focuses on sigma, a network of cultural practitioners that was active roughly between 1963–1965. This highly ambitious project involved a network of writers, artists, scientists and psychiatrists, including William Burroughs, Jeff Nuttall and R.D. Laing. Its successes were modest: the most tangible outcome of the project was the sigma portfolio, an expanding, self-published collection of texts (Trocchi, 1964), ‘part manifesto, part manual’ for art activism (Wark, 2011 : 126). Its initiator and convener was Alexander Trocchi, the Scottish novelist, poet, Situationist and drug addict. The intention of the text is to present a close reading of sigma essays to explore the unfolding of an art activist logic within the programmatic texts of the portfolio

Genetically proxied growth-differentiation factor 15 levels and body mass index.

Growth-differentiation factor 15 (GDF15) is an inflammatory cytokine involved in energy homeostasis that is being pursued as a drug target for obesity. Its circulating levels are acutely increased by the type 2 diabetes medication metformin, resulting in reduced appetite and weight loss. We identified a genetic variant at the GDF15 gene to proxy a small, lifelong increase in circulating GDF15 levels, and leveraged it in colocalization and Mendelian randomization analyses to investigate the effects of chronically elevated GDF15 levels on body mass index (BMI) and type 2 diabetes liability. The results provide human genetic evidence supporting that chronically elevated GDF15 levels increase BMI. There was no genetic evidence to support bi-directional effects, or that chronically elevated GDF15 levels directly affect liability to type 2 diabetes. Our results contrast the BMI-lowering effects of an acute increase in GDF15 levels observed after metformin use. These findings have direct implications for informing pharmacological strategies aimed at targeting GDF15 levels for weight loss

Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study

Background: C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework. Methods Instrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome. Results: Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer genetic variants being identified to instrument this target. Conclusions: This genetic analysis supports the cardioprotective effects of pharmacologically inhibiting NPR3 receptor function, which is only partly mediated by an effect on blood pressure. There was unlikely sufficient statistical power to investigate the cardioprotective effects of NPR2 signalling

Inhibition of interleukin 6 signalling and renal function: a Mendelian randomization study.

Inhibition of interleukin 6 (IL-6) signalling has been proposed as a potential cardioprotective strategy for patients with chronic kidney disease (CKD), but the direct effects of IL-6 inhibition on renal function are not known. A Mendelian randomization (MR) study was performed to investigate the association of genetically proxied inhibition of IL-6 signalling with estimated glomerular filtration rate (eGFR), CKD and blood urea nitrogen (BUN). Inverse-variance weighted MR was used as the main analysis, with sensitivity analyses performed using simple median, weighted median and MR-Egger methods. There was no evidence for an association of genetically proxied inhibition of IL-6 signalling (scaled per standard deviation unit decrease in C-reactive protein) with log eGFR (0.001, 95% confidence interval -0.004 - 0.007), BUN (0.009, 95% confidence interval -0.003 - 0.021) and CKD (odds ratio 0.948, 95% confidence interval 0.822 - 1.094). These findings do not raise concerns for IL-6 signalling having large adverse effects on renal function

Cardiometabolic traits mediating the effect of education on osteoarthritis risk: a Mendelian randomization study.

OBJECTIVE: To investigate which cardiometabolic factors underlie clustering of osteoarthritis (OA) with cardiovascular disease, and the extent to which these mediate an effect of education. DESIGN: Genome-wide association study (GWAS) of OA was performed in UK Biobank (60,800 cases and 328,251 controls) to obtain genetic association estimates for OA risk. Genetic instruments and association estimates for body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP), smoking and education were obtained from existing GWAS summary data (sample sizes 188,577-866,834 individuals). Two-sample Mendelian randomization (MR) analyses were performed to investigate the effects of exposure traits on OA risk. MR mediation analyses were undertaken to investigate whether the cardiometabolic traits mediate any effect of education on OA risk. RESULTS: MR analyses identified protective effects of higher genetically predicted education (main MR analysis odds ratio (OR) per standard deviation increase 0.59, 95% confidence interval (CI) 0.54-0.64) and LDL-C levels (OR 0.94, 95%CI 0.91-0.98) on OA risk, and unfavourable effects of higher genetically predicted BMI (OR 1.82, 95%CI 1.73-1.92) and smoking (OR 2.23, 95%CI 1.85-2.68). There was no strong evidence of an effect of genetically predicted SBP on OA risk (OR 0.98, 95% CI 0.90-1.06). The proportion of the effect of genetically predicted education mediated through genetically predicted BMI and smoking was 35% (95%CI 13-57%). CONCLUSIONS: These findings highlight education, obesity and smoking as common mechanisms underlying OA and cardiovascular disease. These risk factors represent clinical and public health targets for reducing multi-morbidity related to the burden these common conditions

Entropy Encoding, Hilbert Space and Karhunen-Loeve Transforms

By introducing Hilbert space and operators, we show how probabilities, approximations and entropy encoding from signal and image processing allow precise formulas and quantitative estimates. Our main results yield orthogonal bases which optimize distinct measures of data encoding.Comment: 25 pages, 1 figur

Genetically Predicted Midlife Blood Pressure and Coronary Artery Disease Risk: Mendelian Randomization Analysis.

Background Elevated blood pressure is a major cause of cardiovascular morbidity and mortality. However, it is not known whether midlife blood pressure affects later life cardiovascular risk independent of later life blood pressure. Methods and Results Using genetic association estimates from the UK Biobank and CARDIoGRAMplusC4D consortium, univariable mendelian randomization was performed to investigate the total effect of genetically predicted mean arterial pressure (MAP) at age ≤55 years on coronary artery disease (CAD) risk, and multivariable mendelian randomization was performed to investigate the effect of genetically predicted MAP on CAD risk after adjusting for genetically predicted MAP at age >55 years. In both univariable and multivariable mendelian randomization analyses, there was consistent evidence of higher genetically predicted MAP at age ≤55 years increasing CAD risk. This association persisted after adjusting for genetically predicted MAP at age >55 years, when considering nonoverlapping populations for the derivation of MAP and CAD risk genetic association estimates, when investigating only incident CAD events after age >55 years, and when restricting the analysis to variants with most heterogeneity in their associations with MAP ≤55 and >55 years. For a 10-mm Hg increase in genetically predicted MAP at age ≤55 years, the odds ratio of later life CAD was 1.43 (95% CI, 1.16-1.77; P=0.001) after adjusting for genetically predicted MAP at age >55 years. Conclusions These mendelian randomization findings support a cumulative lifetime effect of elevated blood pressure on increasing CAD risk. Clinical and public health efforts toward cardiovascular disease reduction should optimize blood pressure control throughout life

Experimental distinction of the molecularly induced Balmer emission contribution and its application for inferring molecular divertor density with 2D filtered camera measurements during detachment in JET L-mode plasmas

A previously presented model for generating 2D estimates of the divertor plasma conditions at JET from deuterium Balmer line intensity ratios, obtained from tomographic reconstructions of divertor camera images, was amended to consider also the Balmer emission arising from molecular processes. Utilizing the AMJUEL and H2VIBR atomic and molecular databases of EIRENE enabled also inference of the molecular divertor density from the distinguished molecularly induced emission. Analysis of a JET L-mode density scan suggests the molecularly induced emission accounting for up to 60%-70% and 10%-20% of the Balmer D-alpha and D-gamma intensities, respectively, at the onset of detachment, while electron-ion recombination becomes increasingly dominant with deepening detachment. Similar observations were made by post-processing EDGE2D-EIRENE simulations, which indicated significant roles of molecular D-2(+) ions and vibrational excitation of the D-2 molecules as precursors for the molecularly induced emission. The experimentally inferred molecular density at the outer strike point was found to increase monotonously with decreasing strike point temperature, reaching approximately 30%-50% of the local electron density at n(mol,osp) = 1-2 x10(20) m(-3) at T-e,T-osp approximate to 0.7 eV. A further steep increase by a factor of 3-5 was observed with decrease of T-e,T-osp to 0.5 eV. The observations are in qualitative and reasonable quantitative agreement with EDGE2D-EIRENE predictions of n(mol,osp) within the uncertainties of the experimental data.Peer reviewe