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James Wyatt (1746-1813) : architect to George III
\"James Wyatt (1746-1813) is widely recognized as the most celebrated and prolific English architect of the 18th century. At the start of his lengthy career, Wyatt worked on designs for the Oxford Street Pantheon's neo-Classical interior as well as Dodington, the Graeco-Roman house that served as the model for the Regency country house. Wyatt was the first truly eclectic and historicist architect, employing several versions of Classical and Gothic styles with great facility while also experimenting in Egyptian, Tudor, Turkish, and Saxon modes. His pioneering Modern Gothic marked him as an innovator, and his unique neo-Classical designs were influenced by his links with the Midlands Industrial Revolution and his Grand Tour education.This groundbreaking book sheds new light on modern architectural and design history by interweaving studies of Wyatt's most famous works with his fascinating life narrative. This masterly presentation covers the complex connections formed by his web of wealthy patrons and his influence on both his contemporaries and successors\"-- Provided by publisher.
Book
Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges
Multiple nanotherapeutics have been approved for patients with cancer, but their effects on survival have been modest and, in some examples, less than those of other approved therapies. At the same time, the clinical successes achieved with immunotherapy have revolutionized the treatment of multiple advanced-stage malignancies. However, the majority of patients do not benefit from the currently available immunotherapies and many develop immune-related adverse events. By contrast, nanomedicines can reduce — but do not eliminate — the risk of certain life-threatening toxicities. Thus, the combination of these therapeutic classes is of intense research interest. The tumour microenvironment (TME) is a major cause of the failure of both nanomedicines and immunotherapies that not only limits delivery, but also can compromise efficacy, even when agents accumulate in the TME. Coincidentally, the same TME features that impair nanomedicine delivery can also cause immunosuppression. In this Perspective, we describe TME normalization strategies that have the potential to simultaneously promote the delivery of nanomedicines and reduce immunosuppression in the TME. Then, we discuss the potential of a combined nanomedicine-based TME normalization and immunotherapeutic strategy designed to overcome each step of the cancer-immunity cycle and propose a broadly applicable ‘minimal combination’ of therapies designed to increase the number of patients with cancer who are able to benefit from immunotherapy.An immunosuppressive tumour microenvironment is one of the main reasons why patients with solid tumours fail to respond to immune-checkpoint inhibition. In this Perspective, the authors describe the potential of nanomedicines to normalize the tumour microenvironment, thus overcoming this immunosuppressive barrier and enabling greater numbers of patients to respond to immune-checkpoint inhibition.
Journal Article
FGF23 induces left ventricular hypertrophy
Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.
Journal Article
Financial modeling with Crystal Ball and Excel
\"Updated look at financial modeling and Monte Carlo simulation with software by Oracle Crystal BallThis revised and updated edition of the bestselling book on financial modeling provides the tools and techniques needed to perform spreadsheet simulation. It answers the essential question of why risk analysis is vital to the decision-making process, for any problem posed in finance and investment. This reliable resource reviews the basics and covers how to define and refine probability distributions in financial modeling, and explores the concepts driving the simulation modeling process. It also discusses simulation controls and analysis of simulation results.The second edition of Financial Modeling with Crystal Ball and Excel contains instructions, theory, and practical example models to help apply risk analysis to such areas as derivative pricing, cost estimation, portfolio allocation and optimization, credit risk, and cash flow analysis. It includes the resources needed to develop essential skills in the areas of valuation, pricing, hedging, trading, risk management, project evaluation, credit risk, and portfolio management. Offers an updated edition of the bestselling book covering the newest version of Oracle Crystal Ball Contains valuable insights on Monte Carlo simulation--an essential skill applied by many corporate finance and investment professionals Written by John Charnes, the former finance department chair at the University of Kansas and senior vice president of global portfolio strategies at Bank of America, who is currently President and Chief Data Scientist at Syntelli Solutions, Inc. Risk Analytics and Predictive Intelligence Division (Syntelli RAPID) Engaging and informative, this book is a vital resource designed to help you become more adept at financial modeling and simulation\"-- Provided by publisher.
Book
Additive manufacturing of polymer-derived ceramics
The extremely high melting point of many ceramics adds challenges to additive manufacturing as compared with metals and polymers. Because ceramics cannot be cast or machined easily, three-dimensional (3D) printing enables a big leap in geometrical flexibility. We report preceramic monomers that are cured with ultraviolet light in a stereolithography 3D printer or through a patterned mask, forming 3D polymer structures that can have complex shape and cellular architecture. These polymer structures can be pyrolyzed to a ceramic with uniform shrinkage and virtually no porosity. Silicon oxycarbide microlattice and honeycomb cellular materials fabricated with this approach exhibit higher strength than ceramic foams of similar density. Additive manufacturing of such materials is of interest for propulsion components, thermal protection systems, porous burners, microelectromechanical systems, and electronic device packaging.
Journal Article
Osteoclast-Derived Coupling Factors in Bone Remodeling
In the bone remodeling process that takes place throughout the skeleton at bone multicellular units, intercellular communication processes are crucial. The osteoblast lineage has long been known to program osteoclast formation and hence resorption, but the preservation of bone mass and integrity requires tight control of remodeling. This needs local controls that ensure availability of mesenchymal precursors and the provision of local signals that promote differentiation through the osteoblast lineage. Some signals can come from growth factors released from resorbed bone matrix, and there is increasing evidence that the osteoclast lineage itself produces factors that can either enhance or inhibit osteoblast differentiation and hence bone formation. A number of such factors have been identified from predominantly in vitro experiments. The coupling of bone formation to resorption is increasingly recognized as a complex, dynamic process that results from the input of many local factors of cell and matrix origin that can either promote or inhibit bone formation.
Journal Article
The fluorspar mines of Newfoundland : their history and the epidemic of radiation lung cancer
John Martin tells the history of Newfoundland's fluorspar mines from their founding to the last shipment of fluorspar in 1990 and declaration of bankruptcy a year later. He focuses on the health hazards experienced by the miners, and how the mining companies, workers, governments, and health services came to terms with the unfolding human tragedy. He also covers such matters as the improvement of methods for dust quantification and radiation surveillance in the mines, battles for compensation, and the influence of the St Lawrence case on the development of labour law in the province.
Book
Patient cases with malignant otitis externa at the university clinic of Ludwig Maximilians University Munich from 2009 until 2020
Malignant otitis externa (MOE) is a rare, potentially life-threatening disease. It involves inflammation of the external auditory canal with concomitant osteomyelitis of the temporal bone, usually with evidence of
Pseudomonas aeruginosa
. The patient population is often immunocompromised, mostly due to inadequately treated type 2 diabetes mellitus or the use of immunosuppressants. Erosion of the temporal bone is common and can lead to complications such as peripheral facial nerve paralysis, meningitis, and/or cochlear and vestibular damage. The treatment of choice is usually several weeks of antibiogram-controlled intravenous antimicrobial therapy and possibly surgical treatment. Furthermore, if available, optimization of antidiabetic therapy is essential. A retrospective, descriptive, single-center study was performed to characterize consecutive real-life patients with MOE at the University Hospital Munich, Ludwig-Maximilians University, Germany. Thirteen patients with MOE were included in this study. Patient data concerning age, sex, comorbidities, pathogen spectrum, radiological imaging, antibiotic and surgical treatment and other variables were analyzed. In this study, we present a detailed description of a cohort of patients with MOE and propose a therapeutic algorithm that focuses on a combination of antibiotic therapy and surgical debridement of the affected tissue.
Journal Article