Modelling dynamic programming-based global constraints in constraint programming

Dynamic Programming (DP) can solve many complex problems in polynomial or pseudo-polynomial time, and it is widely used in Constraint Programming (CP) to implement powerful global constraints. Implementing such constraints is a nontrivial task beyond the capability of most CP users, who must rely on their CP solver to provide an appropriate global constraint library. This also limits the usefulness of generic CP languages, some or all of whose solvers might not provide the required constraints. A technique was recently introduced for directly modelling DP in CP, which provides a way around this problem. However, no comparison of the technique with other approaches was made, and it was missing a clear formalisation. In this paper we formalise the approach and compare it with existing techniques on MiniZinc benchmark problems, including the flow formulation of DP in Integer Programming. We further show how it can be improved by state reduction methods

Stochastic dynamic programming heuristic for the (R, s, S) policy parameters computation

The (R, s, S) is a stochastic inventory control policy widely used by practitioners. In an inventory system managed according to this policy, the inventory is reviewed at instant R; if the observed inventory position is lower than the reorder level s an order is placed. The order's quantity is set to raise the inventory position to the order-up-to-level S. This paper introduces a new stochastic dynamic program (SDP) based heuristic to compute the (R, s, S) policy parameters for the non-stationary stochastic lot-sizing problem with backlogging of the excessive demand, fixed order and review costs, and linear holding and penalty costs. In a recent work, Visentin et al. (2021) present an approach to compute optimal policy parameters under these assumptions. Our model combines a greedy relaxation of the problem with a modified version of Scarf's (s, S) SDP. A simple implementation of the model requires a prohibitive computational effort to compute the parameters. However, we can speed up the computations by using K-convexity property and memorisation techniques. The resulting algorithm is considerably faster than the state-of-the-art, extending its adoptability by practitioners. An extensive computational study compares our approach with the algorithms available in the literature

Accuracy of a CGM Sensor in Pediatric Subjects With Type 1 Diabetes. Comparison of Three Insertion Sites: Arm, Abdomen, and Gluteus

Patients with diabetes, especially pediatric ones, sometimes use continuous glucose monitoring (CGM) sensor in different positions from the approved ones. Here we compare the accuracy of Dexcom\uae G5 CGM sensor in three different sites: abdomen, gluteus (both approved) and arm (off-label)

Modeling Doxorubicin Pharmacokinetics in Multiple Myeloma Suggests Mechanism of Drug Resistance

Objective: Multiple myeloma (MM) is a plasma cell malignancy often treated with chemotherapy drugs. Among these, doxorubicin (DOXO) is commonly employed, sometimes in combined-drug therapies, but it has to be optimally administered in order to maximize its efficacy and reduce possible side effects. To support DOXO studies and treatment optimization, here we propose an experimental/modeling approach to establish a model describing DOXO pharmacokinetics (PK) in MM cells. Methods: A series of in vitro experiments were performed in MM1R and MOLP-2 cells. DOXO was administered at two dosages (200 nM, 450 nM) at [Formula: see text]=0 and removed at [Formula: see text]=3 hrs. Intracellular DOXO concentration was measured via fluorescence microscopy during both drug uptake ([Formula: see text]=0-3 hrs) and release phases ([Formula: see text]=3-8 hrs). Four PK candidate models were identified, and were compared and selected based on their ability to describe DOXO data and numerical parameter identification. Results: The most parsimonious model consists of three compartments describing DOXO distribution between the extracellular space, the cell cytoplasm and the nucleus, and defines the intracellular DOXO efflux rate through a Hill function, simulating a threshold/saturation drug resistance mechanism. This model predicted DOXO data well in all the experiments and provided precise parameter estimates (mean ± standard deviation coefficient of variation: 15.8±12.2%). Conclusions: A reliable PK model describing DOXO uptake and release in MM cells has been successfully developed. Significance: The proposed PK model, once integrated with DOXO pharmacodynamics, has the potential of allowing the study and the optimization of DOXO treatment strategies in MM

Combined Treatment of Cancer Cells Using Allyl Palladium Complexes Bearing Purine-Based NHC Ligands and Molecules Targeting MicroRNAs miR-221-3p and miR-222-3p: Synergistic Effects on Apoptosis

Combined treatments employing lower concentrations of different drugs are used and studied to develop new and more effective anticancer therapeutic approaches. The combination therapy could be of great interest in the controlling of cancer. Regarding this, our research group has recently shown that peptide nucleic acids (PNAs) that target miR-221 are very effective and functional in inducing apoptosis of many tumor cells, including glioblastoma and colon cancer cells. Moreover, in a recent paper, we described a series of new palladium allyl complexes showing a strong antiproliferative activity on different tumor cell lines. The present study was aimed to analyze and validate the biological effects of the most active compounds tested, in combination with antagomiRNA molecules targeting two miRNAs, miR-221-3p and miR-222-3p. The obtained results show that a “combination therapy”, produced by combining the antagomiRNAs targeting miR-221-3p, miR-222-3p and the palladium allyl complex 4d, is very effective in inducing apoptosis, supporting the concept that the combination treatment of cancer cells with antagomiRNAs targeting a specific upregulated oncomiRNAs (in this study miR-221-3p and miR-222-3p) and metal-based compounds represents a promising therapeutic strategy to increase the efficacy of the antitumor protocol, reducing side effects at the same time

Soil, humipedon, forest life and management

In recent years, three sections (Humipedon, Copedon and Lithopedon) were recognized in the soil profile. It was then possible to link the first and most biologically active section to the characteristics of the environment and soil genesis. In particular, it is now possible to distinguish organic horizons, mainly produced by arthropods and enchytraeids in cold and acidic or dry and arid environments, from organo-mineral horizons produced by earthworms in more temperate and mesotrophic environments. Each set of horizons can be associated with a humus system or form, with important implications for forestry. Anecic/endogeic earthworms and Mull or Amphi systems are more abundant in the early and late stages of sylvogenesis; by completely recycling litter, earthworms accelerate the availability of organic and inorganic soil nutrients to roots and pedofauna. On the other hand, arthropods and Moder or Tangel systems characterize the intermediate stages of sylvogenesis, where thickening in the organic horizons and the parallel impoverishment/reduction in the underlying organo-mineral horizons are observed. Recognizing the humus system at the right spatial and temporal scale is crucial for the biological management of a forest. This article includes a data review, new data from a doctoral thesis, and recent comparisons of Italian and French investigation

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg$^{−1}$) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10$^{−6}$ M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10$^{−6}$ M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO