Insulin-degrading enzyme (IDE) is a 110 kDa chambered zinc metalloendopeptidase that degrades insulin, amyloid β, and other intermediate-sized aggregation prone peptides that adopt β-structures. ...Structural studies of IDE in complex with multiple physiological substrates have suggested a role for hydrophobic and aromatic residues of the IDE active site in substrate binding and catalysis. Here, we examine functional requirements for conserved hydrophobic and aromatic IDE active site residues that are positioned within 4.5 Å of IDE-bound insulin B chain and amyloid β peptides in the reported crystal structures for the respective enzyme–substrate complexes. Charge, size, hydrophobicity, aromaticity, and other functional group requirements for substrate binding IDE active site residues were examined through mutational analysis of the recombinant human enzyme and enzyme kinetic studies conducted using native and fluorogenic derivatives of human insulin and amyloid β peptides. A functional requirement for IDE active site residues F115, A140, F141, Y150, W199, F202, F820, and Y831 was established, and specific contributions of residue charge, size, and hydrophobicity to substrate binding, specificity, and proteolysis were demonstrated. IDE mutant alleles that exhibited enhanced or diminished proteolytic activity toward insulin or amyloid β peptides and derivative substrates were identified.
Abstract In recent years, several advanced technologies, such as Artificial Intelligence (AI) techniques, have been developed to automate inspections and monitoring processes of existing bridges. In ...this context, the efficiency of computational models is crucial in model updating for monitoring systems and training neural networks. Although the nonlinear structural response of the bridges can be efficiently analysed through two-dimensional and three-dimensional finite element (FE) models, these commonly require high computational efforts. This work adopts a high-performance beam finite element based on a damage-plasticity model, implemented in the OpenSees framework, for prestressed reinforced concrete girders. The beam FE relies on a force-based (FB) formulation which is more efficient than the classical displacement-based approach. The constitutive law of the concrete fibers is based on a plastic-damage model, which considers two different damage parameters for the compression and tensile behaviour to take into account the re-closure of the tensile cracks. Dynamic responses in both linear and nonlinear regime are simulated under white noise excitation. ANNs are trained in a subset of the predicted responses in the linear range and the trained network is used to simulate the high amplitude response in which nonlinear behaviour is experienced. Interesting results are acquired useful for further investigations.
Abstract Background Polypharmacy in the elderly is a matter of concern, especially regarding adverse events and drug–drug interactions. Little is known about real world drug use in the elderly in ...Italy. The present study aimed at describing drug use in the elderly with respect to individual characteristics, performing a cross-sectional population study in Lazio, Italy. Methods From the regional health care assistance file, residents aged 65 years and older (mean age = 75.9 years, SD = 7.4) and alive at the end of 2010 were enrolled. Drug consumption was linked from the drug claims registry for 2010, and hospital admissions were retrieved from the hospital admission registry during 2009–2010. Enrolees were characterised for socio-demographic variables, presence of chronic diseases, and drug consumption, considering large groups, and specific sub-groups. Polypharmacy was defined as use of 6+ drugs (ATC 4th level). Results Of the 1,122,864 elderly residents, 57.9% were women, and 48.8% aged 75+. In the previous two years, 28.3% had been admitted to hospital; most common causes were cerebro- and cardiovascular diseases, diabetes and tumours; 78.9% of the elderly population of the city of Rome lived in low-level socio-economic areas. Only 6.8% had not been prescribed drugs in the 12-months observation period, and 58.8% were exposed to polypharmacy. With respect to the overall population, polypharmacy users were more often females (59.7%), older (54.5% aged 75 + ), had poorer health conditions (37.2% hospitalised), and more often lived in poorer areas (19.9%). Conclusion In Lazio, polypharmacy is an important phenomenon in the elderly population. Female gender, older ages and presence of chronic diseases are related to multiple drug use. The present results offer a useful tool for future initiatives aiming at reducing inappropriate polypharmacy and target interventions to subpopulations at higher risk of being exposed to polypharmacy.
IntroductionClinical guidelines recommend treatment with evidence-based (EB) drug therapy (antiplatelets, β-blockers, agents acting on the renin-angiotensin system, statins) for patients with acute ...myocardial infarction (AMI). Results on long term outcomes from observational population studies are scarce.ObjectivesAnalysing the association between EB drug therapy and 2 years mortality in AMI patients.MethodsTwothousand-twohundred-and-four AMI patients, discharged in 2006 and resident in Rome were selected from the Hospital Information System, excluding deaths during the first month after discharge. Exposure information was collected from the drug claims data considering EB drug prescriptions at discharge and during the first month; exposure was defined as at least one prescription, comparing different composite treatments (1, 2, 3 or 4 EB drug groups). The association between exposure to EB drug therapy and all-cause mortality during a 24 months follow-up was analysed through logistic regression, adjusting for gender, age and co-morbidities.ResultsMost patients were treated with EB drug combinations (0: 9.5%, 1: 4.6%, 2: 14.7%, 3: 30.1%, 4: 41.1%); 7.4% of the patients died during follow-up. Mortality risk decreased with increasing number of prescribed EB drugs; combinations of 3 or 4 EB drugs were associated with a significant protective effect vs no EB drugs (4 vs 0 EB drugs: ORadj=0.46; 95% CI 0.27 to 0.78; 3 vs 0 EB drugs: ORadj=0.50; 95% CI 0.29 to 0.86; 2 vs 0 EB drugs: ORadj=0.69; 95% CI 0.39 to 1.23; 1 vs 0 EB drugs: ORadj=0.49; 95% CI 0.21 to 1.13).ConclusionsIn Rome, most patients are treated with EB drugs after AMI; first-month poly-drug therapy is associated with reduction in 2 years mortality.
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