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We study a warehouse management problem in which the schedule of incoming supplies and customer orders for a wide variety of products is known over a number of periods. In addition to storage at the warehouse, products can be kept in the shipping trailers (rolling inventory) parked in the warehouse yard, avoiding material handling costs but incurring trailer handling and opportunity costs. Our objective is to determine the amount of product (if any) to leave in each of the incoming trailers, so that it does not have to be stored and then reloaded for an outgoing delivery, in order to minimize overall warehousing costs. We propose three possible implementation policies and show that the search for optimal solutions can be restricted to these three basic policies without loss of generality. Using this result, we formulate the problem as an integer program, in which incoming trailers are assigned to outgoing deliveries. Under one of the proposed policies incoming trailers can only be stored in the yard directly upon arrival, with their original contents. In this case, we show that our formulation possesses the integrality property and thus the optimal solution can be easily obtained. When the three policies are considered jointly, however, this is no longer the case. Nevertheless, computational tests show that the linear programming bound is very strong and commercial integer programming solvers generate an optimal solution very quickly. In most cases, no branch-and-bound nodes are required. Finally, we perform a computational study based on realistic data provided by our industry partner to evaluate the benefits of rolling inventory, the effectiveness of the different implementation policies and the viability of our proposed solution approaches., 1. Introduction The concept of rolling inventory was introduced to us by a team from Kimberly-Clark and Schneider Logistics as a warehouse management strategy aimed at saving handling costs and [...]

Numerous studies have highlighted the implications of the glycogen synthase kinase 3 (GSK-3) in several processes associated with Alzheimer's disease (AD). Therefore, GSK-3 has become a crucial therapeutic target for the treatment of this neurodegenerative disorder. Hereby, we report the design and multistep synthesis of ethyl 4-oxo-pyrazolo[4,3-d][1–3]triazine-7-carboxylates and their biological evaluation as GSK-3 inhibitors. Molecular modelling studies allow us to develop this new scaffold optimising the chemical structure. Potential binding mode determination in the enzyme and the analysis of the key features in the catalytic site are also described. Furthermore, the ability of pyrazolotriazinones to cross the blood–brain barrier (BBB) was evaluated by passive diffusion and those who showed great GSK-3 inhibition and permeation to the central nervous system (CNS) showed neuroprotective properties against tau hyperphosphorylation in a cell-based model. These new brain permeable pyrazolotriazinones may be used for key in vivo studies and may be considered as new leads for further optimisation for the treatment of AD. [ABSTRACT FROM AUTHOR]