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\"Taking place nearly a century before the events of A Game of Thrones, [this book] compiles the first three official prequel novellas to George R.R. Martin's ongoing masterwork, A Song of Ice and Fire. These never-before-collected [but previously published] adventures recount an age when the Targaryen line still holds the Iron Throne, and the memory of the last dragon has not yet passed from living consciousness\"--Dust jacket flap.

Key Points Nuclear factor of activated T cells (NFAT) transcription factors are activated by cell surface receptors that are coupled to Ca 2+ mobilization, which induce the activation of calmodulin and calcineurin. Calcineurin dephosphorylates multiple phosphoserines in the regulatory domain, leading to the nuclear translocation of NFAT. In the nucleus, NFAT cooperates with multiple transcriptional partners to initiate and maintain specific gene expression programmes, which vary with cell type and stimulation conditions. The activity of NFAT transcription factors is regulated by a complex network that includes stromal interaction molecule (STIM)–ORAI signalling pathways, regulators of Ca 2+ homeostasis, calcineurin, calcineurin regulators, NFAT kinases and post-translational modifications (including sumoylation, ubiquitylation and ADP-ribosylation). NFAT transcription factors are of primary importance during T cell activation and differentiation. Recent studies have revealed that they also have an important role in other immune cell types, including dendritic cells, mast cells, B cells, natural killer T (NKT) cells and megakaryocytes. NFAT proteins are also involved in various developmental programmes, including those of the heart, skeletal muscle, smooth muscle, vasculature, neurons, bone, pancreas and skin. The last few years have provided important new insights into the role of NFAT proteins in T cell tolerance. NFAT proteins are of key importance for the induction of anergy-inducing genes such as gene related to anergy in lymphocytes ( GRAIL ), itchy homolog E3 ubiquitin protein ligase ( ITCH ), Casitas B-lineage lymphoma B ( CBL-B ), caspase 3, deltex and numerous others. NFAT proteins also regulate forkhead box P3 ( FOXP3 ) expression in induced regulatory T cells, and have been shown to cooperate with FOXP3 to regulate the expression of interleukin-2 (IL-2), CD25 and cytotoxic T lymphocyte antigen 4 (CTLA4). NFAT transcription factors control tumour cell proliferation and homeostasis by modulating the expression of cyclin-dependent kinase 4 (CDK4) and cyclin A2, and by regulating apoptosis. They also have an important role in regulating tumour cell migration and angiogenesis. Dysregulation of the Ca 2+ –NFAT signalling pathway has been reported in many different types of cancer, including haematological malignancies, breast cancer and pancreatic adenocarcinomas. NFAT transcription factors are expressed by most immune cells and have critical roles in regulating immune responses. This Review describes recent insights into the NFAT-mediated regulation of distinct immune cells and details our increasing understanding of the importance of the NFAT family during tumorigenesis. Nuclear factor of activated T cells (NFAT) was first identified more than two decades ago as a major stimulation-responsive DNA-binding factor and transcriptional regulator in T cells. It is now clear that NFAT proteins have important functions in other cells of the immune system and regulate numerous developmental programmes in vertebrates. Dysregulation of these programmes can lead to malignant growth and cancer. This Review focuses on recent advances in our understanding of the transcriptional functions of NFAT proteins in the immune system and provides new insights into their potential roles in cancer development.

\"After the alien virus struck humanity in the wake of World War II, a handful of the survivors found they possessed superhuman powers. The Wild Cards shared-world volumes tell their story. Here in book two, we trace these heroes and villains through the tumultuous 1980s, in stories from SF and fantasy giants such as George R. R. Martin, Roger Zelazny, Pat Cadigan, Lewis Shiner, Walter Jon Williams, and others\"-- Provided by publisher.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic therapies in patients with type 2 diabetes mellitus and are associated with improved glycaemic control as well as with reductions in body mass and blood pressure. In large cardiovascular outcome trials in patients with diabetes, SGLT2 inhibitors improve cardiovascular and renal outcomes, including hospitalization for heart failure, with this benefit extending to patients without diabetes who have heart failure with reduced ejection fraction. The possible mechanisms of benefit are being extensively investigated because they are unlikely to be related to improved glycaemic control. Early natriuresis with a reduction in plasma volume, a consequent rise in haematocrit, improved vascular function, a reduction in blood pressure and changes in tissue sodium handling are all likely to have a role. Additional mechanisms of SGLT2 inhibitors that might be beneficial include a reduction in adipose tissue-mediated inflammation and pro-inflammatory cytokine production, a shift towards ketone bodies as the metabolic substrate for the heart and kidneys, reduced oxidative stress, lowered serum uric acid level, reduced glomerular hyperfiltration and albuminuria, and suppression of advanced glycation end-product signalling. Further outcome trials and mechanistic studies, including in patients with heart failure with preserved ejection fraction or non-diabetic kidney disease, might identify other possible mechanisms of benefit of SGLT2-inhibitor therapy.SGLT2 inhibitors improve cardiovascular and renal outcomes even in patients without diabetes mellitus. In this Review, Cowie and Fisher describe the additional mechanisms of benefit of SGLT2 inhibitors, unrelated to improved glycaemic control.

Intelligent algorithms are already well on their way to making white collar jobs obsolete: travel agents, data-analysts, and paralegals are currently in the firing line. In the near future, doctors, taxi-drivers and ironically even computer programmers are poised to be replaced by 'robots'. Without a radical reassessment of our economic and political structures, we risk the very implosion of the capitalist economy itself ... In The Rise of the Robots, technology expert Martin Ford systematically outlines the achievements of artificial intelligence and uses a wealth of economic data to illustrate the terrifying societal implications. From health and education to finance and technology, his warning is stark-all jobs that are on some level routine are likely to eventually be automated, resulting in the death of traditional careers and a hollowed-out middle class. The robots are coming and we have to decide-now-whether the future will bring prosperity or catastrophe.

Key Points The vitamin D receptor (VDR) and enzymes for vitamin D metabolism are expressed throughout the cardiovascular system VDR and 1α-hydroxylase knockout mice have hypertension with myocardial hypertrophy and increased activity of the renin–angiotensin–aldosterone system The molecular effects of VDR activation indicate various antiatherosclerotic and protective effects on the heart and on common cardiovascular risk factors Observational studies have shown that low 25-hydroxyvitamin D levels are associated with an adverse cardiovascular risk profile and significantly increased risk of cardiovascular events Mendelian randomization studies and randomized clinical trials have not shown significant effects of vitamin D on cardiovascular events, but these trials were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals Vitamin D supplementation is currently not indicated for the purpose of cardiovascular disease prevention, but treatment of vitamin D deficiency is critical for skeletal health This Review summarizes the existing knowledge on the effects of vitamin D on cardiovascular diseases and the associated risk factors. Pilz and colleagues provide an update on clinical studies on vitamin D and cardiovascular risk, discuss ongoing vitamin D research, and consider the management of vitamin D deficiency from the perspective of cardiovascular health. Vitamin D is a precursor of the steroid hormone calcitriol that is crucial for bone and mineral metabolism. Both the high prevalence of vitamin D deficiency in the general population and the identification of the vitamin D receptor in the heart and blood vessels raised interest in the potential cardiovascular effects of vitamin D. Experimental studies have demonstrated various cardiovascular protective actions of vitamin D, but vitamin D intoxication in animals is known to induce vascular calcification. In meta-analyses of epidemiological studies, vitamin D deficiency is associated with an increased cardiovascular risk. Findings from Mendelian randomization studies and randomized, controlled trials (RCTs) do not indicate significant effects of a general vitamin D supplementation on cardiovascular outcomes. Previous RCTs, however, were not adequately designed to address extraskeletal events, and did not focus on vitamin D-deficient individuals. Therefore, currently available evidence does not support cardiovascular benefits or harms of vitamin D supplementation with the commonly used doses, and whether vitamin D has cardiovascular effects in individuals with overt vitamin D deficiency remains to be evaluated. Here, we provide an update on clinical studies on vitamin D and cardiovascular risk, discuss ongoing vitamin D research, and consider the management of vitamin D deficiency from a cardiovascular health perspective.

\"If you have a smartphone, you have AI in your pocket. It's everywhere online. And it has already changed how doctors diagnose disease as well as how you interact with friends or read the news. But In Rule of the Robots, Silicon Valley tech entrepreneur Martin Ford argues that true disruption is yet to come, as AI ceases to be a tool applied to specific problems, and becomes a utility: the industrial foundation upon which practically all activity-personal, economic, and political-is based. Ford calls it an \"electricity of intelligence.\" Not so long ago, running a machine required animals, or access to water, and was completely unportable. Electricity turned power into a utility-something cheap and omnipresent. The change enabled us to do work wherever we wanted, and it radically altered every aspect of life, from our diets to our jobs to our entertainment. In Rule of the Robots, Ford shows how AI-heretofore as specialized as a water mill was 200 years ago-is breaking free from its bonds, becoming as ubiquitous and simple to use as a power jack and an extension cord. No one would begin any enterprise, no matter how minor, without power or running water. Ford argues the same will go for AI in the future: the police will rely on it as they surveil us; our business partners as they decide how to work with us and their own customers; schools as they weigh how to teach our children; and probably even you, as you try to juggle the tasks of work and home. This is no mere tech tour of today. Ford has already proven incredibly prescient about the future of AI and work in Rise of the Robots. Thanks to his connections in the AI community, Ford isn't simply reporting on tools, like deep neural networks, that already exist: he is able to map out the course of the technology's future as well; who's full of hot air and who might delivery on what they've promised. That access enables him to see what is likely to change in the near term, and what will take longer, giving us time to implement the necessary political and social measures to ensure that society shapes its own future, rather than simply being driven by the consequences of our technology. Those consequences will be profound. Running water eradicated a great many diseases from our midst, and electricity banished darkness. Ubiquitous AI promises empowerment, but it also threatens to infantilize us. In the right hands, as Ford shows, AI should help us best coronavirus and escape the worst consequences of climate change. In the wrong ones, it will empower totalitarianism and put us all out of work. We are in the midst of the ultimate disruption. Rule of the Robots is the essential guide to not just whether we thrive in it, but even if we just manage to survive\"-- Provided by publisher.

Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.