1,354,444 research outputs found
A thermodynamic assay to test pharmacological chaperones for Fabry disease.
No full textBackground The majority of the disease-causing mutations affect protein stability, but not functional sites and are amenable, in principle, to be treated with pharmacological chaperones. These drugs enhance the thermodynamic stability of their targets. Fabry disease, a disorder caused by mutations in the gene encoding lysosomal alpha-galactosidase, represents an excellent model system to develop experimental protocols to test the efficiency of such drugs. Methods The stability of lysosomal alpha-galactosidase under different conditions was studied by urea-induced unfolding followed by limited proteolysis and Western blotting. Results We measured the concentration of urea needed to obtain half-maximal unfolding because this parameter represents an objective indicator of protein stability. Conclusions Urea-induced unfolding is a versatile technique that can be adapted to cell extracts containing tiny amounts of wild-type or mutant proteins. It allows testing of protein stability as a function of pH, in the presence or in the absence of drugs. Results are not influenced by the method used to express the protein in transfected cells. General significance Scarce and dispersed populations pose a problem for the clinical trial of drugs for rare diseases. This is particularly true for pharmacological chaperones that must be tested on each mutation associated with a given disease. Diverse in vitro tests are needed. We used a method based on chemically induced unfolding as a tool to assess whether a particular Fabry mutation is responsive to pharmacological chaperones, but, by no means is our protocol limited to this disease
L'operatività dei Centri di prima accoglienza nel nuovo processo penale minorile. L'esperienza di Trieste
No full textIl conglomerate discount nelle aziende diversificate
No full textL'articolo afferma che la diversificazione comporta uno sconto sul valore per le aziende multibusiness (conglomerate discount) ma che, in periodi di turbolenza economica, tale strategia può essere comunque efficace per una migliore gestione interna delle risorse finanziarie
In-situ Spectroscopic Analysis for Pulsed Laser Deposition of Superconductive Y-Ba-Cu-O Thin Films
No full text
Missense mutations in the Fas gene resulting in autoimmune lymphoproliferative syndrome: a molecular and immunological analysis
No full textProgrammed cell death (or apoptosis) is a physiological process essential to the normal development and homeostatic maintenance of the immune system. The Fas/Apo-1 receptor plays a crucial role in the regulation of apoptosis, as demonstrated by lymphoproliferation in MRL-lpr/lpr mice and by the recently described autoimmune lymphoproliferative syndrome (ALPS) in humans, both of which are due to mutations in the Fas gene. We describe a novel family with ALPS in which three affected siblings carry two distinct missense mutations on both the Fas gene alleles and show lack of Fas-induced apoptosis. The children share common clinical features including splenomegaly and lymphadenopathy, but only one developed severe autoimmune manifestations. In all three siblings, we demonstrated the presence of anergic CD3+CD4-CD8- (double negative, [DN]) T cells; moreover, a chronic lymphocyte activation was found, as demonstrated by the presence of high levels of HLA-DR expression on peripheral CD3+ cells and by the presence of high levels of serum activation markers such as soluble interleukin-2 receptor (slL-2R) and soluble CD30 (sCD30)
Water and salt imbalance: Diagnostic and therapeutic approach.
No full textDehydration is a medical condition that occurs when the water balance, which is the amount of water taken under the water lost, is negative. In case of a dehydrated child, the paediatrician should be able not only to quantify but also to recognize the quality of dehydration in order to prescribe the most appropriate therapy. The paediatrician should decide the optimal therapeutic intervention between oral therapy at home and intravenously rehydration at hospital
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