This book covers adaptive mesh generation and moving mesh methods for solving time-dependent PDEs. It gives a general description of the components of moving mesh methods as well as examples of their ...application for a number of nontrivial physical problems.
Abstract The first full publications on the biological effects of the diphosphonates, later renamed bisphosphonates, appeared in 1969, so it is timely after 40 years to review the history of their ...development and their impact on clinical medicine. This special issue of BONE contains a series of review articles covering the basic science and clinical aspects of these drugs, written by some of many scientists who have participated in the advances made in this field. The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and is a paradigm of a successful journey from ‘bench to bedside’. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate (PPi), and it was studies on the role of PPi as the body's natural ‘water softener’ in the control of soft tissue and skeletal mineralisation that led to the need to find inhibitors of calcification that would resist hydrolysis by alkaline phosphatase. The observation that PPi and BPs could not only retard the growth but also the dissolution of hydroxyapatite crystals prompted studies on their ability to inhibit bone resorption. Although PPi was unable to do this, BPs turned out to be remarkably effective inhibitors of bone resorption, both in vitro and in vivo experimental systems, and eventually in humans. As ever more potent BPs were synthesised and studied, it became apparent that physico-chemical effects were insufficient to explain their biological effects, and that cellular actions must be involved. Despite many attempts, it was not until the 1990s that their biochemical actions were elucidated. It is now clear that bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen containing bisphosphonates (such as etidronate and clodronate) can be metabolically incorporated into non-hydrolysable analogues of ATP, which interfere with ATP-dependent intracellular pathways. The more potent, nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate and zoledronate) are not metabolised in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway. The major enzyme target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS), and the crystal structure elucidated for this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. Inhibition of FPPS prevents the biosynthesis of isoprenoid compounds (notably farnesol and geranylgeraniol) that are required for the post-translational prenylation of small GTP-binding proteins (which are also GTPases) such as rab, rho and rac, which are essential for intracellular signalling events within osteoclasts. The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. As reviewed elsewhere in this issue, bisphosphonates are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, the skeletal complications of malignancy, and osteoporosis. Several of the leading BPs have achieved ‘block-buster’ status with annual sales in excess of a billion dollars. As a class, BPs share properties in common. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile in terms of mineral binding and cellular effects that may help to explain potential clinical differences among the BPs. Even though many of the well-established BPs have come or are coming to the end of their patent life, their use as cheaper generic drugs is likely to continue for many years to come. Furthermore in many areas, e.g. in cancer therapy, the way they are used is not yet optimised. New ‘designer’ BPs continue to be made, and there are several interesting potential applications in other areas of medicine, with unmet medical needs still to be fulfilled. The adventure that began in Davos more than 40 years ago is not yet over. This article is part of a Special Issue entitled Bisphosphonates.
The fungus
Ganoderma produces many bioactive compounds which have a wide-range of the most important biomedical activities. These are predominantly terpenoids and polysaccharides. Effects range from ...anti-cancer to anti-HIV. Metabolites are being produced increasingly in artificial culture which may assist in discovering effective medical treatments.
Ganoderma is a basidiomycete white rot fungus which has been used for medicinal purposes for centuries particularly in China, Japan and Korea. A great deal of work has been carried out on
Ganoderma lucidum. The common names for preparations include Lingzhi, Munnertake, Sachitake, Reishi and Youngzhi. This review collates the publications detailing activities and compounds by representative species whilst considering the most valid claims of effectiveness. The biological activities reported of preparations from
Ganoderma are remarkable and given most emphasis herein as distinct from structure/activity information. The metabolites consist of mainly polysaccharides and terpenoids. Many are activities against the major diseases of our time and so the present review is of great importance. The list of effects is huge ranging from anti-cancer to relieving blockages of the bladder. However, the reports have not all been tested scientifically with the convincing evidence is reserved for assays of pure compounds. It is a prime example of an ancient remedy being of great relevance to the modern era. There does appear to be an assumption that the therapeutic effects attributed to the fungus have been proven. The next step is to produce some effective medicines which may be hampered by problems of mass production.
Summary
Bisphosphonates (BPs) are well established as the leading drugs for the treatment of osteoporosis. There is new knowledge about how they work. The differences that exist among individual BPs ...in terms of mineral binding and biochemical actions may explain differences in their clinical behavior and effectiveness.
Introduction
The classical pharmacological effects of bisphosphonates (BPs) appear to be the result of two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts.
Discussion
There is new information about both properties. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The antiresorptive effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) appear to result from their inhibition of the enzyme farnesyl pyrophosphate synthase (FPPS) in osteoclasts. FPPS is a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. BPs share several common properties as a drug class. However, as with other families of drugs, there are obvious chemical, biochemical, and pharmacological differences among the individual BPs. Each BP has a unique profile that may help to explain potential clinical differences among them, in terms of their speed and duration of action, and effects on fracture reduction.
Abstract To treat systemic bone loss as in osteoporosis and/or focal osteolysis as in rheumatoid arthritis or periodontal disease, most approaches target the osteoclasts, the cells that resorb bone. ...Bisphosphonates are currently the most widely used antiresorptive therapies. They act by binding the mineral component of bone and interfere with the action of osteoclasts. The nitrogen-containing bisphosphonates, such as alendronate, act as inhibitors of farnesyl-pyrophosphate synthase, which leads to inhibition of the prenylation of many intracellular signaling proteins. The discovery of RANKL and the essential role of RANK signaling in osteoclast differentiation, activity and survival have led to the development of denosumab, a fully human monoclonal antibody. Denosumab acts by binding to and inhibiting RANKL, leading to the loss of osteoclasts from bone surfaces. In phase 3 clinical studies, denosumab was shown to significantly reduce vertebral, nonvertebral and hip fractures compared with placebo and increase areal BMD compared with alendronate. In this review, we suggest that the key pharmacological differences between denosumab and the bisphosphonates reside in the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This may explain differences in the degree and rapidity of reduction of bone resorption, their potential differential effects on trabecular and cortical bone, and the reversibility of their actions.
(a) The Yin and Yang symbol: The philosophical basis of some of the assumed properties and research on
Cordyceps (see text)? (b)
Cordyceps spp. parasitizing a dead
Campanotus insect and (c) ...cordyheptapeptide A, a natural product from the fungus.
Traditional Chinese medicines (TCM) are growing in popularity. However, are they effective?
Cordyceps is not studied as systematically for bioactivity as another TCM,
Ganoderma.
Cordyceps is fascinating per se, especially because of the pathogenic lifestyle on Lepidopteron insects. The combination of the fungus and dead insect has been used as a TCM for centuries. However, the natural fungus has been harvested to the extent that it is an endangered species. The effectiveness has been attributed to the Chinese philosophical concept of Yin and Yang and can this be compatible with scientific philosophy? A vast literature exists, some of which is scientific, although others are popular myth, and even hype.
Cordyceps sinensis is the most explored species followed by
Cordyceps militaris. However, taxonomic concepts were confused until a recent revision, with undefined material being used that cannot be verified. Holomorphism is relevant and contamination might account for some of the activity. The role of the insect has been ignored. Some of the analytical methodologies are poor. Data on the “old” compound cordycepin are still being published: ergosterol and related compounds are reported despite being universal to fungi. There is too much work on crude extracts rather than pure compounds with water and methanol solvents being over-represented in this respect (although methanol is an effective solvent). Excessive speculation exists as to the curative properties. However, there are some excellent pharmacological data and relating to apoptosis. For example, some preparations are active against cancers or diabetes which should be fully investigated. Polysaccharides and secondary metabolites are of particular interest. The use of genuine anamorphic forms in bioreactors is encouraged.
Ozone (O3) is an important trace and greenhouse gas in the atmosphere, posing a threat to the ecological environment and human health at the ground level. Large-scale and long-term studies of O3 ...pollution in China are few due to highly limited direct ground and satellite measurements. This study offers a new perspective to estimate ground-level O3 from solar radiation intensity and surface temperature by employing an extended ensemble learning of the space-time extremely randomized trees (STET) model, together with ground-based observations, remote sensing products, atmospheric reanalysis, and an emission inventory. A full-coverage (100%), high-resolution (10 km) and high-quality daily maximum 8-h average (MDA8) ground-level O3 dataset covering China (called ChinaHighO3) from 2013 to 2020 was generated. Our MDA8 O3 estimates (predictions) are reliable, with an average out-of-sample (out-of-station) coefficient of determination of 0.87 (0.80) and root-mean-square error of 17.10 (21.10) μg/m3 in China. The unique advantage of the full coverage of our dataset allowed us to accurately capture a short-term severe O3 pollution exposure event that took place from 23 April to 8 May in 2020. Also, a rapid increase and recovery of O3 concentrations associated with variations in anthropogenic emissions were seen during and after the COVID-19 lockdown, respectively. Trends in O3 concentration showed an average growth rate of 2.49 μg/m3/yr (p < 0.001) from 2013 to 2020, along with the continuous expansion of polluted areas exceeding the daily O3 standard (i.e., MDA8 O3 = 160 μg/m3). Summertime O3 concentrations and the probability of occurrence of daily O3 pollution have significantly increased since 2015, especially in the North China Plain and the main air pollution transmission belt (i.e., the “2 + 26” cities). However, a decline in both was seen in 2020, mainly due to the coordinated control of air pollution and ongoing COVID-19 effects. This carefully vetted and smoothed dataset is valuable for studies on air pollution and environmental health in China.
•A full-coverage of daily MDA8 O3 dataset (10 km) from 2013 to 2020 in China is generated.•The ChinaHighO3 dataset yields a high-quality information (CV-R2 = 0.87, RMSE = 17.10 μg/m3).•Ground-level O3 showed a significant increasing trend of 2.49 μg/m3/yr (p < 0.001) during 2013–2020.•Rapid O3 increase and recovery were observed during and after the COVID-19 lockdown.
On modeling pollution-generating technologies Murty, Sushama; Robert Russell, R.; Levkoff, Steven B.
Journal of environmental economics and management,
07/2012, Letnik:
64, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We argue analytically that many commonly used models of pollution-generating technologies, which treat pollution as a freely disposable input or as a weakly disposable and null-joint output, may ...generate unacceptable implications for the trade-offs among inputs, outputs, and pollution. We show that the correct trade-offs in production are best captured if a pollution-generating technology is modeled as an intersection of an intended-production technology of the firm and nature's residual-generation set. The former satisfies standard disposability properties, while the latter violates free (strong) disposability of pollution and pollution-causing inputs. As a result, the intersection—which we call a by-production technology—violates standard free disposability of pollution and pollution-causing inputs. Employing data envelopment analysis on an electric-power-plant database, we illustrate shortcomings, under by-production, of two popular efficiency indexes: the hyperbolic and directional-distance-function indexes. We propose and implement an alternative index with superior properties. Under by-production, most efficiency indexes decompose very naturally into intended-production and environmental efficiency indexes. This decomposition is difficult to find under alternative specifications of pollution-generating technologies.
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