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41.
The binding thermodynamics of the HIV-1 protease inhibitor acetyl pepstatin and the substrate Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln, corresponding to one of the cleavage sites in the gag, gag-pol polyproteins, have been measured by direct microcalorimetric analysis. The results indicate that the binding of the peptide substrate or peptide inhibitor is entropically driven; i.e., it is characterized by an unfavorable enthalpy and a favorable entropy change, in agreement with a structure-based thermodynamic analysis based upon an empirical parameterization of the energetics. Dissection of the binding enthalpy indicates that the intrinsic interactions are favorable and that the unfavorable enthalpy originates from the energy cost of rearranging the flap region in the protease molecule. In addition, the binding is coupled to a negative heat capacity change. The dominant binding force is the increase in solvent entropy that accompanies the burial of a significant hydrophobic surface. Comparison of the binding energetics obtained for the substrate with that obtained for synthetic nonpeptide inhibitors indicates that the major difference is in the magnitude of the conformational entropy change. In solution, the peptide substrate has a higher flexibility than the synthetic inhibitors and therefore suffers a higher conformational entropy loss upon binding. This higher entropy loss accounts for the lower binding affinity of the substrate. On the other hand, due to its higher flexibility, the peptide substrate is more amenable to adapt to backbone rearrangements or subtle conformational changes induced by mutations in the protease. The synthetic inhibitors are less flexible, and their capacity to adapt is more restricted. The expected result is a more pronounced effect of mutations on the binding affinity of the synthetic inhibitors. On the basis of the thermodynamic differences in the mode of binding of substrate and synthetic inhibitors, it appears that a key factor to understanding resistance is given by the relative balance of the different forces that contribute to the binding free energy and, in particular, the balance between conformational and solvation entropy. 相似文献
42.
MJ Mulet Pons MT Sarrión Ferre A Barea Montoro N Marín Rueda JJ Blanquer Grégori MA Melchor Penella 《Canadian Metallurgical Quarterly》1995,16(7):423-427
OBJECTIVE: To find the reasons which determine failures to comply with anti-flu vaccinations, so that these can be corrected and the coverage of this preventive action be increased. DESIGN: Observational crossover study, done by means of a telephone survey of people over 65. A questionnaire with closed questions, composed after a pilot study and validated by Cronbach's alpha. SETTING: Primary Care Centre (PCC). PATIENTS: We calculated a population sample for qualitative variables (_ = 0.05; p = 0.60; e = 0.05) of 294 people over 65, chosen from the PCC records, by means of random sampling (K = 4) stratified for age and discounting the telephone selection bias. MEASUREMENTS AND RESULTS: The proportion of vaccinated patients (60.9%) obtained in our study did not significantly differ from that in the general population. The percentage of patients included in the programme for the first time was 14%. Level of satisfaction among those vaccinated was 89.4%, with 8.9% of problems detected being light. Main causes of non-vaccination were: thinking that they didn't need it (63.5%), ignorance of the campaign (35.7%), fear of the reaction (24.3%), forgetting (10.4%). The main form of access to the campaign information was from the PCC, both through individuals and posters. Lack of information was statistically significant (p < 0.00001) as a determinant of non-vaccination, without other factors (age, sex, associated pathologies...) explaining these differences. CONCLUSIONS: Individualised and on-going health education by the PCC is fundamental. This would enable the identification of the group not vaccinated due to their express refusal and the recovery of non-vaccinated patients. 相似文献
43.
MJ Glantz PC Burger AH Friedman RA Radtke EW Massey SC Schold 《Canadian Metallurgical Quarterly》1994,44(11):2020-2027
When radiation is used to treat nervous system cancer, exposure of adjacent normal nervous system tissue is unavoidable, and radiation-induced injury may occur. Acute injury is usually mild and transient, but late forms of radiation-induced nervous system injury are usually progressive and debilitating. Treatment with corticosteroids, surgery, and antioxidants is often ineffective. We treated 11 patients with late radiation-induced nervous system injuries (eight with cerebral radionecrosis, one with a myelopathy, and two with plexopathies, all unresponsive to dexamethasone and prednisone) with full anticoagulation. Some recovery of function occurred in five of the eight patients with cerebral radionecrosis, and all the patients with myelopathy or plexopathy. Anticoagulation was continued for 3 to 6 months. In one patient with cerebral radionecrosis, symptoms recurred after discontinuation of anticoagulation and disappeared again after reinstitution of treatment. We hypothesize that anticoagulation may arrest and reverse small-vessel endothelial injury--the fundamental lesion of radiation necrosis--and produce clinical improvement in some patients. 相似文献
44.
Aard J. Groen Petra C. De WeerdNederhof Inge C. Kerssensvan Drongelen Rob A.J. Badoux Gerard P.H. Olthuis 《Creativity & Innovation Management》2002,11(1):2-16
In this paper we describe a framework for analysing the creation and justification of Research & Development. The 4S framework is developed for analysing the scope, scale, skills and social network aspects of Research & Development value. The framework is based on social system theory, a process contingency model, and recent Research & Development metrics. We present a first empirical assessment based on a workshop using the 4S framework for leveraging Research & Development. Results that assist in the assessment of value creation utilising R & D within networks are very relevant in high tech industries. The multi–dimensional process approach of this framework seems promising for understanding and managing R&D value creation, but needs further operationalisation. Case studies are described and a Dutch network on leveraging R&D has been initiated. 相似文献
45.
PO Livingston MJ Calves F Helling WD Zollinger MS Blake GH Lowell 《Canadian Metallurgical Quarterly》1993,11(12):1199-1204
The gangliosides of melanoma and other tumours of neuroectodermal origin are suitable targets for immune intervention with tumour vaccines. The optimal vaccines in current use contain ganglioside plus bacillus Calmette-Guérin and induce considerable morbidity. We have screened a variety of new adjuvants in the mouse, and describe one antigen-delivery system, proteosomes, which is especially effective. Highly hydrophobic Neisserial outer membrane proteins (OMP) form multimolecular liposome-like vesicular structures termed proteosomes which can readily incorporate amphiphilic molecules such as GD3 ganglioside. The optimal GD3/proteosome vaccine formulation for induction of GD3 antibodies in the mouse is determined. Interestingly, the use of potent immunological adjuvants in addition to proteosomes augments the IgM and IgG antibody titres against OMP in these vaccines but GD3 antibody titres are unaffected. The application of proteosomes to enhance the immune response to GD3 extends the concept of the proteosome immunopotentiating system from lipopeptides to amphipathic carbohydrate epitopes such as cell-surface gangliosides. The demonstrated safety of meningococcal OMP in humans and the data in mice presented here suggest that proteosome vaccines have potential for augmenting the immunogenicity of amphipathic tumour antigens in humans. 相似文献
46.
J Santafe J Segarra M Garrido V Pablo MJ Martinez de Ibarreta 《Canadian Metallurgical Quarterly》1993,24(2):471-478
1. Interaction between topical isoprenaline and timolol on intraocular pressure was studied in conscious rabbits through changes of the dose-response curves. 2. Both drugs caused a dose-dependent fall of intraocular pressure mainly by reducing the aqueous humour formation. 3. When combined, timolol increased the response to submaximal concentrations of isoprenaline as well as EC50 (from 2.06 x 10(-3) M to 3.63 x 10(-3) M) and slope (from 1.21 to 1.89), but peak response to isoprenaline remained unchanged. 4. Discordance between experimental and theoretical additive curves as well as an interaction index smaller than 1 show that the interaction between both drugs is synergistic. 相似文献
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