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"Clark, M"
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MicroRNA-Based Diagnosis and Therapy
MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.
Journal Article
Time and power : visions of history in German politics, from the Thirty Years' War to the Third Reich
Inspired by the insights of Reinhart Koselleck and Franًcois Hartog, two pioneers of the \"temporal turn\" in historiography, Clark shows how Friedrich Wilhelm rejected the notion of continuity with the past, believing instead that a sovereign must liberate the state from the entanglements of tradition to choose freely among different possible futures. He demonstrates how Frederick the Great abandoned this paradigm for a neoclassical vision of history in which sovereign and state transcend time altogether, and how Bismarck believed that the statesman's duty was to preserve the timeless permanence of the state amid the torrent of historical change. Clark describes how Hitler did not seek to revolutionize history like Stalin and Mussolini, but instead sought to evade history altogether, emphasizing timeless racial archetypes and a prophetically foretold future.
Book
Age-Dependent Changes in Temperature Regulation – A Mini Review
It is now well recognized that the body temperature of older men and women is lower than that of younger people and that their tolerance of thermal extremes is more limited. The regulation of body temperature does not depend on a single organ, but rather involves almost all the systems of the body, i.e. systems not exclusively dedicated to thermoregulatory functions such as the cardiovascular and respiratory systems. Since these deteriorate naturally with advancing age, the decrement in their functions resonates throughout all the bodily processes, including those that control body temperature. To the extent that the age-related changes in some of these, e.g. in the musculoskeletal system, can be slowed, or even prevented, by certain measures, e.g. fitness training, so can the decrements in thermoregulatory functions. Some deficits, however, are unavoidable, e.g. structural skin changes and metabolic alterations. These impact directly on the ability of the elderly to maintain thermal homeostasis, particularly when challenged by ambient thermal extremes. Since the maintenance of a relatively stable, optimal core temperature is one of the body’s most important activities, its very survival can be threatened by these disorders. The present article describes the principal, age-associated changes in physiological functions that could affect the ability of seniors to maintain their body temperature when exposed to hot or cold environments.
Journal Article
Exploiting machine learning for end-to-end drug discovery and development
A variety of machine learning methods such as naive Bayesian, support vector machines and more recently deep neural networks are demonstrating their utility for drug discovery and development. These leverage the generally bigger datasets created from high-throughput screening data and allow prediction of bioactivities for targets and molecular properties with increased levels of accuracy. We have only just begun to exploit the potential of these techniques but they may already be fundamentally changing the research process for identifying new molecules and/or repurposing old drugs. The integrated application of such machine learning models for end-to-end (E2E) application is broadly relevant and has considerable implications for developing future therapies and their targeting.This Perspective describes the application of machine learning models in the design, synthesis and characterisation of molecules at different stages in the drug discovery and development process.
Journal Article
Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial
The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.
We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.
Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 2·2, 95% CI 1·4 to 3·3; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.
Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.
National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.
Journal Article
Understanding architecture : its elements, history, and meaning
\"This bestselling, illustrated survey of Western architecture is now fully revised throughout, explaining the structure, function, history, and meaning of architecture in a way that is both accessible and engaging. The long-awaited third edition includes increased global coverage with new mini chapters on Africa, Japan, China, India, and Islamic Architecture; a new chapter covering the future of architecture in the twenty-first century; updated coverage of sustainability and green architecture and its impact on design; an update to the historical survey; and over fifty images in full color. Understanding Architecture continues to be the only text in the field to examine architecture as a cultural phenomenon as well as an artistic and technological achievement with its straightforward, two-part structure: (1) The Elements of Architecture and (2) The History and Meaning of Architecture. Comprehensive and clearly written, Understanding Architecture is a classic survey of Western architecture. \"-- Provided by publisher.
Book
Exploring the impact of forcing error characteristics on physically based snow simulations within a global sensitivity analysis framework
Physically based models provide insights into key hydrologic processes but are associated with uncertainties due to deficiencies in forcing data, model parameters, and model structure. Forcing uncertainty is enhanced in snow-affected catchments, where weather stations are scarce and prone to measurement errors, and meteorological variables exhibit high variability. Hence, there is limited understanding of how forcing error characteristics affect simulations of cold region hydrology and which error characteristics are most important. Here we employ global sensitivity analysis to explore how (1) different error types (i.e., bias, random errors), (2) different error probability distributions, and (3) different error magnitudes influence physically based simulations of four snow variables (snow water equivalent, ablation rates, snow disappearance, and sublimation). We use the Sobol' global sensitivity analysis, which is typically used for model parameters but adapted here for testing model sensitivity to coexisting errors in all forcings. We quantify the Utah Energy Balance model's sensitivity to forcing errors with 1 840 000 Monte Carlo simulations across four sites and five different scenarios. Model outputs were (1) consistently more sensitive to forcing biases than random errors, (2) generally less sensitive to forcing error distributions, and (3) critically sensitive to different forcings depending on the relative magnitude of errors. For typical error magnitudes found in areas with drifting snow, precipitation bias was the most important factor for snow water equivalent, ablation rates, and snow disappearance timing, but other forcings had a more dominant impact when precipitation uncertainty was due solely to gauge undercatch. Additionally, the relative importance of forcing errors depended on the model output of interest. Sensitivity analysis can reveal which forcing error characteristics matter most for hydrologic modeling.
Journal Article