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.
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.
The profound effects of the bisphosphonates on calcium metabolism were discovered over 30 years ago, and they are now well established as the major drugs used for the treatment of bone diseases ...associated with excessive resorption. Their principal uses are for Paget disease of bone, myeloma, bone metastases, and osteoporosis in adults, but there has been increasing and successful application in pediatric bone diseases, notably osteogenesis imperfecta. Bisphosphonates are structural analogues of inorganic pyrophosphate but are resistant to enzymatic and chemical breakdown. Bisphosphonates inhibit bone resorption by selective adsorption to mineral surfaces and subsequent internalization by bone-resorbing osteoclasts where they interfere with various biochemical processes. The simpler, non-nitrogen-containing bisphosphonates (eg, clodronate and etidronate) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendronate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl pyrophosphate synthase, in the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small guanosine triphosphate (GTP)-binding proteins (which are also GTPases) such as Rab, Rho, and Rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explains the loss of osteoclast activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to explain differences in potency, onset and duration of action, and clinical effectiveness.
On the MSSM Higgsino mass and fine tuning Ross, Graham G.; Schmidt-Hoberg, Kai; Staub, Florian
Physics letters. B,
08/2016, Letnik:
759, Številka:
C
Journal Article
Recenzirano
Odprti dostop
It is often argued that low fine tuning in the MSSM necessarily requires a rather light Higgsino. In this note we show that this need not be the case when a more complete set of soft SUSY breaking ...mass terms are included. In particular an Higgsino mass term, that correlates the μ-term contribution with the soft SUSY-breaking Higgsino masses, significantly reduces the fine tuning even for Higgsinos in the TeV mass range where its relic abundance means it can make up all the dark matter.
Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and
) account for some familial aggregation of colorectal cancer, their population prevalence and the ...causes of the remaining familial aggregation are not known.
We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and
We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.
We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (
= 1 in 1,946,
= 1 in 2,841,
= 1 in 758,
= 1 in 714), 1 in 45 carry mutations in
, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).
Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.
Our findings could aid gene discovery and development of better colorectal cancer risk prediction models.
.
The Glasgow Norms are a set of normative ratings for 5,553 English words on nine psycholinguistic dimensions: arousal, valence, dominance, concreteness, imageability, familiarity, age of acquisition, ...semantic size, and gender association. The Glasgow Norms are unique in several respects. First, the corpus itself is relatively large, while simultaneously providing norms across a substantial number of lexical dimensions. Second, for any given subset of words, the same participants provided ratings across all nine dimensions (33 participants/word, on average). Third, two novel dimensions—semantic size and gender association—are included. Finally, the corpus contains a set of 379 ambiguous words that are presented either alone (e.g.,
toast
) or with information that selects an alternative sense (e.g.,
toast (bread)
,
toast (speech)
). The relationships between the dimensions of the Glasgow Norms were initially investigated by assessing their correlations. In addition, a principal component analysis revealed four main factors, accounting for 82% of the variance (Visualization, Emotion, Salience, and Exposure). The validity of the Glasgow Norms was established via comparisons of our ratings to 18 different sets of current psycholinguistic norms. The dimension of size was tested with megastudy data, confirming findings from past studies that have explicitly examined this variable. Alternative senses of ambiguous words (i.e., disambiguated forms), when discordant on a given dimension, seemingly led to appropriately distinct ratings. Informal comparisons between the ratings of ambiguous words and of their alternative senses showed different patterns that likely depended on several factors (the number of senses, their relative strengths, and the rating scales themselves). Overall, the Glasgow Norms provide a valuable resource—in particular, for researchers investigating the role of word recognition in language comprehension.
We discuss models involving two scalar fields coupled to classical gravity that satisfy the general criteria: (i) the theory has no mass input parameters, (ii) classical scale symmetry is broken only ...through −112ςϕ2R couplings where ς departs from the special conformal value of 1; (iii) the Planck mass is dynamically generated by the vacuum expectations values (VEVs) of the scalars (iv) there is a stage of viable inflation associated with slow roll in the two-scalar potential; (v) the final vacuum has a small to vanishing cosmological constant and an hierarchically small ratio of the VEVs and the ratio of the scalar masses to the Planck scale. This assumes the paradigm of classical scale symmetry as a custodial symmetry of large hierarchies.
Alcoholic beverages are produced following the fermentation of sugars by yeasts, mainly (but not exclusively) strains of the species, Saccharomyces cerevisiae. The sugary starting materials may ...emanate from cereal starches (which require enzymatic pre-hydrolysis) in the case of beers and whiskies, sucrose-rich plants (molasses or sugar juice from sugarcane) in the case of rums, or from fruits (which do not require pre-hydrolysis) in the case of wines and brandies. In the presence of sugars, together with other essential nutrients such as amino acids, minerals and vitamins, S. cerevisiae will conduct fermentative metabolism to ethanol and carbon dioxide (as the primary fermentation metabolites) as the cells strive to make energy and regenerate the coenzyme NAD+ under anaerobic conditions. Yeasts will also produce numerous secondary metabolites which act as important beverage flavour congeners, including higher alcohols, esters, carbonyls and sulphur compounds. These are very important in dictating the final flavour and aroma characteristics of beverages such as beer and wine, but also in distilled beverages such as whisky, rum and brandy. Therefore, yeasts are of vital importance in providing the alcohol content and the sensory profiles of such beverages. This Introductory Chapter reviews, in general, the growth, physiology and metabolism of S. cerevisiae in alcoholic beverage fermentations.
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