1,721,051 research outputs found
La religiosità dopo la secolarizzazione
No full textIl contributo discute i risultati della quinta rilevazione sui "Valori degli europei e degli italiani", a quarant'anni dalla prima rilevazione del 1981, a proposito degli atteggiamenti degli italiani nei confronti della religiosita
Ligand-binding studies: old beliefs and new strategies
No full textLigand-binding studies remain a very popular technique among many experimentalists. As far as equilibrium experiments are concerned, saturation and displacement curves are commonly performed for simplicity, convenience or for the sake of tradition. However, alternative protocols, such as 'mixed'-type protocols or multiligand experiments, are also possible. Indeed, there are cases where kinetic experiments, usually considered a 'second-choice' experiment, might have a superior resolving power compared to equilibrium ones. A combination of equilibrium and kinetic experiments might be a powerful solution to overcome limits and shortcomings of each specific technique and is discussed in this issue by G. Enrico Rovati. Thus, a careful choice of the design, a protocol optimization and a computerized analysis of the data can yield a dramatic improvement in the precision of the parameter estimation over more conventional approaches
A VERSATILE IMPLEMENTATION OF THE GAUSS-NEWTON MINIMIZATION ALGORITHM USING MATLAB FOR MACINTOSH MICROCOMPUTERS
No full textThe present report describes a weighted nonlinear least-squares minimization routine for fitting a wide variety of functions nonlinear in the parameters. The minimization routine is implemented in MacMATLAB, the Macintosh microcomputer version of MATLAB, an interactive program for scientific numeric calculations. Our algorithm makes use of a subroutine that estimates the required derivatives numerically, avoiding the need to differentiate the function under study analytically. We have also implemented two specific subroutines to integrate ordinary differential equations numerically. Therefore, in principle, any kind of nonlinear function can be fitted to a given set of data. The program only requires that the user writes the appropriate equation in a specific subroutine, thus relieving one from knowing and using any 'low-level' code. Other features of the program are: (a) the possibility of using weights to correct for nonuniformity of variance by flexible specification of the error structure; (b) the possibility of checking the parameter values and the residual variance at each iteration; and (c) by the use of the graphic capabilities of MacMATLAB, the possibility of following the improvement of the fitting graphically. One example of nonlinear functions and one example of linear differential equation together with their respective 'function file' and illustrative data are presented to demonstrate the flexibility of our approach and the power of the method used
Cross-talk Between Cysteinyl-Leukotriene and Purinergic Receptors
No full textCysteinyl-LTs (cysteinyl-LTs), LTC4, LTD4 and LTE4, are potent inflammatory mediators and bronchoconstrictors known to play an important role in asthma and allergic rhinitis. Until now, two receptor subtypes for cysteinyl-LTs have been cloned, namely CysLT1 and CysLT2, both belonging to the rhodopsin family of the G-protein-coupled receptors (GPCRs) superfamily and, in particular, to the purine receptor cluster.
P2Y receptors are GPCRs responsive to both adenine (ATP, ADP) and uracil (UTP, UDP) nucleotides, or to sugar nucleotides (UDP-glucose and UDP-galactose) and eight P2Y subtypes are currently recognized, i.e. P2Y1-14. These receptors are widely distributed in human tissues, and important pathophysiological roles also in respiratory functions have been suggested.
Since both mediators accumulate at sites of inflammation, and inflammatory cells express both classes of receptors, their responses are likely to be cross-regulated. We have demonstrated that activation of P2Y receptors with ATP, UDP or UTP induced CysLT1 receptor heterologous desensitization. Conversely, LTD4-induced CysLT1 receptor activation had no effect on P2Y receptor responses, suggesting that the latter have a hierarchy in producing desensitizing signals.
Interestingly, montelukast, pranlukast and zafirlukast, orally-active leukotriene antagonists (LTRAs) selective for the CysLT1 receptor subtype, inhibited both UDP- and UTP-induced activation of phospholipase C and intracellular Ca2+ mobilization in a non-competitive manner, as well as UDP-induced IL-8 production.
Furthermore, administration of LTE4 to the airways of sensitized mice has been demonstrated to potentiate eosinophilia, goblet cell metaplasia, and expression of IL-13 in response to low-dose aerosolized allergen, an effect abrogated by P2Y12 knock-down or platelet depletion.
All together these data not only point to a cross-talk between the CysLT and the P2Y recepor systems, but also suggest that it might be some common molecular target mediating nucleotide- and cysteinyl-LT-induced signaling, something that may have a profound physiological implication in the regulation of responses at the sites of inflammation.
In addition, these data also demonstrate non-CysLT1-mediated antiinflammatory effect of clinically used antiasthmatic drugs, suggesting activities potentially relevant for interpatient variability in response to treatment. Higher doses of currently known LTRAs or new compounds derived from this class of drugs may represent a new strategy for finding more efficient therapy for bronchial asthma
LOWER EFFICACY - INTERACTION WITH AN INHIBITORY RECEPTOR OR PARTIAL AGONISM
No full textIt is very common in practice to find that some concentration-response curves are 'bell shaped', and this phenomenon also applies to partial agonist curves. On the basis of these considerations, a mathematical model has been developed for the interaction of a ligand with two different receptors that mediate opposite effects (one stimulatory and one inhibitory), and is discussed in this article by Enrico Rovati and Simonetta Nicosia. This model can account for both an apparent reduction in efficacy and the curvature of the upper plateau of some concentration-response curves. Therefore, under certain conditions, an agonist that also interacts with an inhibitory receptor might be mistaken for a partial agonist, unless the concentration-response curves are performed over the widest possible range of concentrations
Leukotriene receptor antagonists in the treatment of allergic rhinitis
No full textLeukotriene receptor antagonists (LTRAs) have been long used in the therapy of some forms of asthma. Indeed, cysteinyl-leukotrienes (cysteinyl-LTs), potent lipid mediators derived from the oxidative metabolism of the arachidonic acid, are synthesized in response to different immune and inflammatory stimuli, and are deeply involved in the pathophysiology of asthma. A number of molecular and clinical studies substantiate a role for cysteinyl-LTs and their receptors also in allergic rhinitis,
indicating that they contribute to nasal allergy increasing
blood flow and nasal airway resistance, nasal mucous secretion and congestion. Considering that cysteynil-LTs play a critical role in the pathogenesis of both these diseases, a common therapeutic approach would seem logical. The LTRA therapeutic potential in allergic rhinitis has been, therefore, evaluated in a number of clinical trials that have demonstrated their safety and efficacy. LTRAs, thus, can provide an effective treatment option for patients with allergic rhinitis, and are generally used as an adjunct in the treatment of a patient who does not have an adequate response to antihistamines, a nasal corticosteroid, or both. In addition, LTRAs are beneficial for large proportion of patients suffering also from asthma. However, despite encouraging results, their place in the therapy of allergic rhinitis is not completely defined, and, as today, topical nasal steroid still should be considered the first-line therapy. It is likely that future developments in the pharmacogenetic will allow a more effective use of these drugs as, at present it is largely recognized that different genetic phenotypes reflect different responses to LTRAs. Today, unfortunately, it is not yet possible to identify patients with an LT-“dependent” disease and to predict responders or non-responders other than by use of a trial of therap
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