Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

How much risk ought we to take? Exploring the possibilities of risk-sensitive consequentialism in the context of climate engineering

When it comes to assessing the deontic status of acts and policies in the context of risk and uncertainty, moral theories are often at a loss. In this paper we hope to show that employing a multi-dimensional consequentialist framework provides ethical guidance for decision-making in complex situations. The paper starts by briefly rehearsing consequentialist responses to the issue of risk, as well as their shortcomings. We then go on to present our own proposal based on three dimensions: wellbeing, fairness and probability. In the last section we apply our approach to a comparison of different climate policy options, including stratospheric solar-radiation management.

STAT3 regulated ARF expression suppresses prostate cancer metastasis

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

Optimising element choice for nanoparticle radiosensitisers

There is considerable interest in the use of heavy atom nanoparticles as theranostic contrast agents due to their high radiation cross-section compared to soft tissue. However, published studies have primarily focused on applications of gold nanoparticles. This study applies Monte Carlo radiation transport modelling using Geant4 to evaluate the macro- and micro-scale radiation dose enhancement following X-ray irradiation with both imaging and therapeutic energies on nanoparticles consisting of stable elements heavier than silicon. An approach based on the Local Effect Model was also used to assess potential biological impacts. While macroscopic dose enhancement is well predicted by simple absorption cross-sections, nanoscale dose deposition has a much more complex dependency on atomic number, with local maxima around germanium (Z = 32) and gadolinium (Z = 64), driven by variations in secondary Auger electron spectra, which translate into significant variations in biological effectiveness. These differences may provide a valuable tool for predicting and elucidating fundamental mechanisms of these agents as they move towards clinical application.

The time-course of lexical activation in Japanese morphographic word recognition: Evidence for a character-driven processing model

This lexical decision study with eye tracking of Japanese two-kanji-character words investigated the order in which a whole two-character word and its morphographic constituents are activated in the course of lexical access, the relative contributions of the left and the right characters in lexical decision, the depth to which semantic radicals are processed, and how nonlinguistic factors affect lexical processes. Mixed-effects regression analyses of response times and subgaze durations (i.e., first-pass fixation time spent on each of the two characters) revealed joint contributions of morphographic units at all levels of the linguistic structure with the magnitude and the direction of the lexical effects modulated by readers’ locus of attention in a left-to-right preferred processing path. During the early time frame, character effects were larger in magnitude and more robust than radical and whole-word effects, regardless of the font size and the type of nonwords. Extending previous radical-based and character-based models, we propose a task/decision-sensitive character-driven processing model with a level-skipping assumption: Connections from the feature level bypass the lower radical level and link up directly to the higher character level.

La moral : ensayo sobre los principios teóricos y su aplicación a las circunstancias particulares de la vida

UANL