Pharmacokinetic Parameters of HIV-1 Protease Inhibitors

Since the beginning of the HIV epidemic, research has been carried out to control the virus. Understanding the mechanisms of replication has given access to the various classes of drugs that over time have transformed AIDS into a manageable chronic disease. The class of protease inhibitors (PIs) gained notice in anti-retroviral therapy, once it was found that peptidomimetic molecules act by blocking the active catalytic center of the aspartic protease, which is directly related to HIV maturation. However, mutations in enzymatic internal residues are the biggest issue for these drugs, because a small change in biochemical interaction can generate resistance. Low plasma concentrations of PIs favor viral natural selection; high concentrations can inhibit even partially resistant enzymes. Food-drug/drug-drug interactions can decrease the bioavailability of PIs and are related to many side effects. Therefore, this review summarizes the pharmacokinetic properties of current PIs, the changes when pharmacological boosters are used and also lists the major mutations to help understanding of how long the continuous treatment can ensure a low viral load in patients.     

Self-Assembly and Neurotoxicity of β-Amyloid (21–40) Peptide Fragment: The Regulatory Role of GxxxG Motifs

The three GxxxG repeating motifs from the C-terminal region of β-amyloid (Aβ) peptide play a significant role in regulating the aggregation kinetics of the peptide. Mutation of these glycine residues to leucine greatly accelerates the fibrillation process but generates a varied toxicity profile. Using an array of biophysical techniques, we demonstrated the uniqueness of the composite glycine residues in these structural repeats. We used solvent relaxation NMR spectroscopy to investigate the role played by the surrounding water molecules in determining the corresponding aggregation pathway. Notably, the conformational changes induced by Gly³³ and Gly³⁷ mutations result in significantly decreased toxicity in a neuronal cell line. Our results indicate that G³³xxxG³⁷ is the primary motif responsible for Aβ neurotoxicity, hence providing a direct structure–function correlation. Targeting this motif, therefore, can be a promising strategy to prevent neuronal cell death associated with Alzheimer's and other related diseases, such as type II diabetes and Parkinson's.     

Rolling Kanban: a new visual tool to schedule family batch manufacturing processes with kanban

Rolling Kanban is the name of a kanban management methodology for batch processes manufacturing environment. Proposed in the early 2000s by FESTO Consulting, for two decades we have lost knowledge both from operative and scientific point of view. Basically, Rolling Kanban means a visual planning methodology based on the production of product-families and variants where: (i) set-up times are reduced between the products of the same family, and (ii) relevant times (dozens of minutes if not even hours) must be considered for changeover between products of different families. In addition, the cyclic production sequence between different product families cannot be maintained. Considering that very few technical information and documents are available about this approach, the main objective of this paper is to retrieve and present, for the first time to the scientific community, the Rolling Kanban methodology. Besides, a real industrial implementation concerning a manufacturer of domestic fittings is discussed as a case study. More specifically, two novel versions of the original Rolling Kanban technique are fully presented to effectively overcome certain limits and criticalities found during its operative use, such as the difficulty to realise a pull production, considering increased set-up time for changeover between products of different families.     

Maximizing Convergence Speed for Second Order Consensus in Leaderless Multi-Agent Systems

The paper deals with the consensus problem in a leaderless network of agents that have to reach a common velocity while forming a uniformly spaced string. Moreover, the final common velocity (reference velocity) is determined by the agents in a distributed and leaderless way. Then, the consensus protocol parameters are optimized for networks characterized by a communication topology described by a class of directed graphs having a directed spanning tree, in order to maximize the convergence rate and avoid oscillations. The advantages of the optimized consensus protocol are enlightened by some simulation results and comparison with a protocol proposed in the related literature. The presented protocol can be applied to coordinate agents such as mobile robots, automated guided vehicles (AGVs) and autonomous vehicles that have to move with the same velocity and a common inter-space gap.      

Mercury contamination in fish from gold mining areas in Indonesia and human health risk assessment

This study investigates the effects on fish and assesses human health hazards from mercury released in two gold mining areas in Indonesia: Tatelu (North Sulawesi Province) and Galangan (Katingan District, Central Kalimatan Province). In Tatelu, 154 fish specimens of 10 freshwater species were collected, as well as five marine species from the fish market. The mean concentration of total mercury in muscles of freshwater fish from this area was 0.58+/-0.44 microg/g, with more than 45% of fish having Hg levels above the WHO guideline for human consumption of 0.5 microg/g. In Galangan, where 263 fish specimens of 25 species were collected, the total mercury in muscles averaged 0.25+/-0.69 microg/g. Excluding data from flooded open pits in sub-area P4, mean Hg levels in fish from Galangan were 2 to 4 times lower than 0.5 microg/g, while fewer than 10% of fish from Galangan exceeded WHO guidelines. The Hazard Quotient (HQ) was applied to both areas to determine the threat of MeHg exposure for communities in both areas. The HQ is a risk assessment indicator which defines the ratio of exposure level to a single substance in relation to a reference dose. Samples from Tatelu (excluding marine species) had an HQ above one, while those from Galangan resulted in values of 2.4 for the whole area and 9.9 for sub-area P4, pointing to potentially harmful fish consumption for the local population. By using the single-compartment model to estimate mercury levels in blood and hair from daily intake dose, sub-area P4 showed the highest levels, higher than the upper limit guideline for pregnant women, but still lower than threshold levels associated with observed clinical effects.     

Thermoelectric Properties of TiNiSn Half Heusler Alloy Obtained by Rapid Solidification and Sintering

Thermoelectric TiNiSn-based half Heusler compound reveals high Seebeck coefficient and electrical conductivity, leading to high power factor. As a consequence of the solidification path, TiNiSn single phase cannot be obtained directly from the liquid phase. Thus, a long annealing step is needed to homogenize the alloy. In this work, we present a new processing route for half Heusler compound formation, combining arc melting of pure elements, rapid solidification of the molten alloy and sintering. Rapid solidification of the molten alloy allows to obtain almost single TiNiSn phase, limiting the formation of the primary TiNi₂Sn phase as a consequence of the deep undercooling of the liquid. The rapidly solidified alloy was ground to powder and sintered by open die pressing. As-sintered samples show a density around 95% of the theoretical value. Thermal cycling of the sintered samples shows evolution of the phases, suggesting that after sintering the sample is not in equilibrium yet. After the second thermal cycle thermoelectric properties become reproducible, indicating the attainment of the equilibrium. In conclusion, the proposed processing route allows to obtain dense TiNiSn in bulk form avoiding the time-consuming annealing step, typically used to homogenize this alloy after solidification.