The Exploration Ethic: Its Historical-Intellectual Basis. Outlook for Space (1980 - 2000)

Principle components of the exploration ethic are discussed. Attempts were made to justify both the historical and intellectual aspects of the concept. It was noted that intellectual justification is strongly grounded on: (1) the complementarity of objective and normative inquiry as to method, and (2) interdisciplinary alliance of ethics of adaptive systems with contemporary decision sciences, as a theoretical basis. Historical exploration justification was associated with: (1) periods of civilization transition, (2) changes in the process of exploration which cause change in types of rationals used, sponsors involved, and explorers interest, and (3) the incorrectness of proven prior cost/benefit calculations

New approaches to object classification in synoptic sky surveys

Digital synoptic sky surveys pose several new object classification challenges. In surveys where real-time detection and classification of transient events is a science driver, there is a need for an effective elimination of instrument-related artifacts which can masquerade as transient sources in the detection pipeline, e.g., unremoved large cosmic rays, saturation trails, reflections, crosstalk artifacts, etc. We have implemented such an Artifact Filter, using a supervised neural network, for the real-time processing pipeline in the Palomar-Quest (PQ) survey. After the training phase, for each object it takes as input a set of measured morphological parameters and returns the probability of it being a real object. Despite the relatively low number of training cases for many kinds of artifacts, the overall artifact classification rate is around 90%, with no genuine transients misclassified during our real-time scans. Another question is how to assign an optimal star-galaxy classification in a multi-pass survey, where seeing and other conditions change between different epochs, potentially producing inconsistent classifications for the same object. We have implemented a star/galaxy multipass classifier that makes use of external and a priori knowledge to find the optimal classification from the individually derived ones. Both these techniques can be applied to other, similar surveys and data sets

Phosphodiesterase 5 Inhibition Improves β-Cell Function in Metabolic Syndrome

OBJECTIVE: This study tested the hypothesis that phosphodiesterase 5 inhibition alone or in combination with ACE inhibition improves glucose homeostasis and fibrinolysis in individuals with metabolic syndrome. RESEARCH DESIGN AND METHODS: Insulin sensitivity, beta-cell function, and fibrinolytic parameters were measured in 18 adults with metabolic syndrome on 4 separate days after a randomized, crossover, double-blind, 3-week treatment with placebo, ramipril (10 mg/day), tadalafil (10 mg o.d.), and ramipril plus tadalafil. RESULTS: Ramipril decreased systolic and diastolic blood pressure, ACE activity, and angiotensin II and increased plasma renin activity. Ramipril did not affect insulin sensitivity or beta-cell function. In contrast, tadalafil improved beta-cell function (P = 0.01). This effect was observed in women (331.9 +/- 209.3 vs. 154.4 +/- 48.0 32 micro x mmol(-1) x l(-1), respectively, for tadalafil treatment vs. placebo; P = 0.01) but not in men. There was no effect of any treatment on fibrinolysis. CONCLUSIONS Phosphodiesterase 5 inhibition may represent a novel strategy for improving beta-cell function in metabolic syndrome

Photoluminescence of exchange-coupled Mo3+ pairs in CsMgCl3

The high-resolution luminescence spectra of CsMgCl3 doped with Mo3+ contain bands that are very temperature-sensitive between 5 K and 2 K and that can be assigned to exchange-coupled Mo3+-V-Mo3+ pair centres (V=divalent vacancy). When the host lattice is doped with both Mo3+ and Li+ it is found that pair formation is inhibited and the spectra are principally those of the single Mo3+ cation. Well-resolved multi-line luminescence spectra have been obtained from exchange-coupled Mo3+ pairs in the far red and near infrared. The spectra correlate well with the reported ground-state energy levels of the pairs as calculated from EPR measurements.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48867/2/cm920221.pd

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption

Background: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. Results: We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. Conclusion: A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat

Hepatic steatosis risk is partly driven by increased de novo lipogenesis following carbohydrate consumption.

BACKGROUND: Diet is a major contributor to metabolic disease risk, but there is controversy as to whether increased incidences of diseases such as non-alcoholic fatty liver disease arise from consumption of saturated fats or free sugars. Here, we investigate whether a sub-set of triacylglycerols (TAGs) were associated with hepatic steatosis and whether they arise from de novo lipogenesis (DNL) from the consumption of carbohydrates. RESULTS: We conduct direct infusion mass spectrometry of lipids in plasma to study the association between specific TAGs and hepatic steatosis assessed by ultrasound and fatty liver index in volunteers from the UK-based Fenland Study and evaluate clustering of TAGs in the National Survey of Health and Development UK cohort. We find that TAGs containing saturated and monounsaturated fatty acids with 16-18 carbons are specifically associated with hepatic steatosis. These TAGs are additionally associated with higher consumption of carbohydrate and saturated fat, hepatic steatosis, and variations in the gene for protein phosphatase 1, regulatory subunit 3b (PPP1R3B), which in part regulates glycogen synthesis. DNL is measured in hyperphagic ob/ob mice, mice on a western diet (high in fat and free sugar) and in healthy humans using stable isotope techniques following high carbohydrate meals, demonstrating the rate of DNL correlates with increased synthesis of this cluster of TAGs. Furthermore, these TAGs are increased in plasma from patients with biopsy-confirmed steatosis. CONCLUSION: A subset of TAGs is associated with hepatic steatosis, even when correcting for common confounding factors. We suggest that hepatic steatosis risk in western populations is in part driven by increased DNL following carbohydrate rich meals in addition to the consumption of saturated fat

GPs’ mindlines on deprescribing antihypertensives in older patients with multimorbidity: a qualitative study in English general practice

Background:  Optimal management of hypertension in older patients with multimorbidity is a cornerstone of primary care practice. Despite emphasis on personalised approaches to treatment in older patients, there is little guidance on how to achieve medication reduction when GPs are concerned that possible risks outweigh potential benefits of treatment. Mindlines — tacit, internalised guidelines developed over time from multiple sources — may be of particular importance in such situations. Aim:  To explore GPs’ decision-making on deprescribing antihypertensives in patients with multimorbidity aged ≥80 years, drawing on the concept of mindlines. Design and setting: Qualitative interview study set in English general practice. Method Thematic analysis of face-to-face interviews with a sample of 15 GPs from seven practices in the East of England, using a chart-stimulated recall approach to explore approaches to treatment for older patients with multimorbidity with hypertension. Results:  GPs are typically confident making decisions to deprescribe antihypertensive medication in older patients with multimorbidity when prompted by a trigger, such as a fall or adverse drug event. GPs are less confident to attempt deprescribing in response to generalised concerns about polypharmacy, and work hard to make sense of multiple sources (including available evidence, shared experiential knowledge, and non-clinical factors) to guide decision-making. Conclusion:  In the absence of a clear evidence base on when and how to attempt medication reduction in response to concerns about polypharmacy, GPs develop ‘mindlines’ over time through practicebased experience. These tacit approaches to making complex decisions are critical to developing confidence to attempt deprescribing and may be strengthened through reflective practice

Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis

$\textbf{BACKGROUND}$: Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. $\textbf{METHODS AND FINDINGS}$: Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10-8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10-25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26-1.65, p = 9.5 × 10-8) for isoleucine, 1.85 (95% CI 1.41-2.42, p = 7.3 × 10-6) for leucine, and 1.54 (95% CI 1.28-1.84, p = 4.2 × 10-6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. $\textbf{CONCLUSIONS}$: Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes.MRC Epidemiology Unit, Fenland study, EPIC-InterAct study, EPIC-Norfolk case-cohort study funding: this study was funded by the United Kingdom’s Medical Research Council through grants MC_UU_12015/1, MC_UU_12015/5, MC_PC_13046, MC_PC_13048 and MR/L00002/1. We acknowledge support from the National Institute for Health Research Biomedical Research Centre. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement number 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. EPIC-InterAct Study funding: funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). MRC Human Nutrition Research funding: This research was supported by the Medical Research Council (MC_UP_A090_1006) and Cambridge Lipidomics Biomarker Research Initiative (G0800783). The SABRE study was funded at baseline by the UK Medical Research Council, Diabetes UK and the British Heart Foundation and at follow-up by a programme grant from the Wellcome Trust (WT082464) and British Heart Foundation (SP/07/001/23603); Diabetes UK funded the metabolomics analyses (13/0004774). RJOS, EN, JRZ and AK received funding from the Swedish Research Council, Stockholm County Council, Novo Nordisk Foundation and Diabetes Wellness. DBS is supported by the Wellcome Trust grant number 107064. MIM is a Wellcome Trust Senior Investigator and is supported by the following grants from the Wellcome Trust: 090532 and 098381. IB is supported by the Wellcome Trust grant WT098051