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It is well settled that the amyloidogenic properties of the plasma protein transporter transthyretin (TTR) can be modulated by compounds that stabilize its native tetrameric conformation. TTR is also present in cerebrospinal fluid where it can bind to Aβ-peptides and prevent Aβ aggregation. We have previously shown that treatment of Alzheimer's Disease (AD) model mice with iododiflunisal (IDIF), a TTR tetramer stabilizing compound, prevents AD pathologies. This evidence positioned IDIF as a new lead drug for AD. In dissecting the mechanism of action of IDIF, we disclose here different labeling strategies for the preparation of 131I-labeled IDIF and 131I- and 124I-labeled TTR, which have been further used for the preparation of IDIF-TTR complexes labeled either on the compound or the protein. The biodistribution of all labeled species after intravenous administration has been investigated in mice using ex vivo and in vivo techniques. Our results confirm the capacity of TTR to cross the blood brain barrier (BBB) and suggest that the formation of TTR-IDIF complexes enhances BBB permeability of both IDIF and TTR. The increased TTR and IDIF brain concentrations may result in higher Aβ-peptide sequestration capacity with the subsequent inhibition of AD symptoms as we have previously observed in mice.
Pubmed ID: 31541162
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Solvers, or optimizers, are software tools that help users find the best way to allocate scarce resources. The resources may be raw materials, machine time or people time, money, or anything else in limited supply. The best or optimal solution may mean maximizing profits, minimizing costs, or achieving the best possible quality. An almost infinite variety of problems can be tackled this way, but here are some typical examples: Finance and Investment Working capital management involves allocating cash to different purposes (accounts receivable, inventory, etc.) across multiple time periods, to maximize interest earnings. Capital budgeting involves allocating funds to projects that initially consume cash but later generate cash, to maximize a firm''s return on capital. Portfolio optimization -- creating efficient portfolios -- involves allocating funds to stocks or bonds to maximize return for a given level of risk, or to minimize risk for a target rate of return. Manufacturing Job shop scheduling involves allocating time for work orders on different types of production equipment, to minimize delivery time or maximize equipment utilization. Blending (of petroleum products, ores, animal feed, etc.) involves allocating and combining raw materials of different types and grades, to meet demand while minimizing costs. Cutting stock (for lumber, paper, etc.) involves allocating space on large sheets or timbers to be cut into smaller pieces, to meet demand while minimizing waste. Distribution and Networks Routing (of goods, natural gas, electricity, digital data, etc.) involves allocating something to different paths through which it can move to various destinations, to minimize costs or maximize throughput. Loading (of trucks, rail cars, etc.) involves allocating space in vehicles to items of different sizes so as to minimize wasted or unused space. Scheduling of everything from workers to vehicles and meeting rooms involves allocating capacity to various tasks in order to meet demand while minimizing overall costs.
View all literature mentionsAmerican chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.
View all literature mentionsSoftware application with data analysis tools and spreadsheet templates to track and visualize data. It is used to manage and process data.
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