A new lot sizing and scheduling heuristic for multi-site biopharmaceutical production

Biopharmaceutical manufacturing requires high investments and long-term production planning. For large biopharmaceutical companies, planning typically involves multiple products and several production facilities. Production is usually done in batches with a substantial set-up cost and time for switching between products. The goal is to satisfy demand while minimising manufacturing, set-up and inventory costs. The resulting production planning problem is thus a variant of the capacitated lot-sizing and scheduling problem, and a complex combinatorial optimisation problem. Inspired by genetic algorithm approaches to job shop scheduling, this paper proposes a tailored construction heuristic that schedules demands of multiple products sequentially across several facilities to build a multi-year production plan (solution). The sequence in which the construction heuristic schedules the different demands is optimised by a genetic algorithm. We demonstrate the effectiveness of the approach on a biopharmaceutical lot sizing problem and compare it with a mathematical programming model from the literature. We show that the genetic algorithm can outperform the mathematical programming model for certain scenarios because the discretisation of time in mathematical programming artificially restricts the solution space.     

Generation of Haploid Spermatids on Silk Fibroin-Alginate-Laminin-Based Porous 3D Scaffolds

In vitro production of sperm is a desirable idea for fertility preservation in azoospermic men and prepubertal boys suffering from cancer. In this study, a biocompatible porous scaffold based on a triad mixture of silk fibroin (SF), alginate (Alg), and laminin (LM) is developed to facilitate the differentiation of mouse spermatogonia stem cells (SSCs). Following SF extraction, the content is analyzed by SDS-PAGE and stable porous 3D scaffolds are successfully prepared by merely Alg, SF, and a combination of Alg-SF, or Alg-SF-LM through freeze-drying. Then, the biomimetic scaffolds are characterized regarding the structural and biological properties, water absorption capacity, biocompatibility, biodegradability, and mechanical behavior. Neonatal mice testicular cells are seeded on three-dimensional scaffolds and their differentiation efficiency is evaluated using real-time PCR, flow cytometry, immunohistochemistry. Blend matrices showed uniform porous microstructures with interconnected networks, which maintained long-term stability and mechanical properties better than homogenous structures. Molecular analysis of the cells after 21 days of culture showed that the expression of differentiation-related proteins in cells that are developed in composite scaffolds is significantly higher than in other groups. The application of a composite system can lead to the differentiation of SSCs, paving the way for a novel infertility treatment landscape in the future.     

Targeted Delivery of Anticancer Drug Loaded Charged PLGA Polymeric Nanoparticles Using Electrostatic Field

Pure positive electrostatic charges (PPECs) show suppressive effect on the proliferation and metabolism of invasive cancer cells without affecting normal tissues. PPECs are used for the delivery of drug-loaded polymeric nanoparticles (DLNs) capped with negatively charged poly(lactide-co-glycolide) (PLGA) and Poly(vinyl-alcohol) PVA into the tumor site of mouse models. The charged patch is installed on top of the skin in the mouse models' tumor region, and the controlled selective release of the drug is assayed by biochemical, radiological, and histological experiments on both tumorized models and normal rats' livers. It is found that DLNs synthesized by PLGA show great attraction to PPECs due to their stable negative charges, which would not degrade immediately in blood. The burst and drug release after less than 48h of this synthesized DLNs are 10% and 50%, respectively. These compounds can deliver the loaded-drug into the tumor site with the assistance of PPECs, and the targeted-retarded release will take place. Hence, local therapy can be achieved with much lower drug concentration (conventional chemotherapy [2 mg kg⁻¹] versus DLNs-based chemotherapy [0.75 mg kg⁻¹]) with negligible side effects in non-targeted organs. PPECs have many potential clinical applications for advanced-targeted chemotherapy with the lowest discernible side effects.     

Preyssler heteropolyacid supported on silica coated NiFe2O4 nanoparticles for the catalytic synthesis of bis(dihydropyrimidinone)benzene and 3,4-dihydropyrimidin-2(1H)-ones

A novel magnetic acidic catalyst comprising Preyssler (H14[NaP5W30O110]) heteropoly acid support‐ed on silica coated nickel ferrite nanoparticles (NiFe2O4@SiO2) was prepared. The catalyst was character...     

Performance of hydrodynamic journal bearing under the combined influence of textured surface and journal misalignment: A numerical survey

A wisely chosen geometry of micro textures with the favorable relative motion of lubricated surfaces in contacts can enhance tribological characteristics. In this paper, a computational investigation related to the combined influence of bearing surface texturing and journal misalignment on the performances of hydrodynamic journal bearings is reported. To this end, a numerical analysis is performed to test three texture shapes: square “SQ”, cylindrical “CY”, and triangular “TR”, and shaft misalignment variation in angle and degree. The Reynolds equation of a thin viscous film is solved using a finite differences scheme and a mass conservation algorithm (JFO boundary conditions), taking into account the presence of textures on both full film and cavitation regions. Preliminary results are compared with benchmark data and are consistent with a positive enhancement in misaligned bearing performances (load carrying capacity and friction). The results suggest that the micro-step bearing mechanism is a key parameter, where the micro-pressure recovery action present in dimples located at the second angular part of the bearing (from 180° to 360°) can compensate for the loss on performances caused by shaft misalignment, while the micro-pressure drop effect at the full film region causes poor performances. Considering the right arrangement of textures on the contact surface, their contours geometries can have a significant impact on the performance of misaligned journal bearings, particularly at high eccentricity ratios, high misalignment degrees and when the misalignment angle α approaches to $0\mathrm{°}$ or $180\mathrm{°}$.     

A Simple and Convenient Synthesis of Glycosyl Azides

Treatment of glycosyl halides with NaN₃ in aqueous acetone or acetonitrile is a convenient method for the stereoselective synthesis of 1,2-trans-per-O-acetyl-glycosyl azides.     

THE PREPARATION AND SOME REACTIONS OF 3-THIETANONES

Abstract

3-Thietanones have been prepared by treating certain ketones with thionyl chloride or sulphur dichloride. In the case of ketones containing a tertiary alpha proton the initial product obtained on treatment with thionyl chloride is the sulphinyl chloride which then cyclises to the thietanone.     

IDSite: An accurate approach to predict P450-mediated drug metabolism

Accurate prediction of drug metabolism is crucial for drug design. Since a large majority of drugs metabolism involves P450 enzymes, we herein describe a computational approach, IDSite, to predict P450-mediated drug metabolism. To model induced-fit effects, IDSite samples the conformational space with flexible docking in Glide followed by two refinement stages using the Protein Local Optimization Program (PLOP). Sites of metabolism (SOMs) are predicted according to a physical-based score that evaluates the potential of atoms to react with the catalytic iron center. As a preliminary test, we present in this paper the prediction of hydroxylation and O-dealkylation sites mediated by CYP2D6 using two different models: a physical-based simulation model, and a modification of this model in which a small number of parameters are fit to a training set. Without fitting any parameters to experimental data, the Physical IDSite scoring recovers 83% of the experimental observations for 56 compounds with a very low false positive rate. With only 4 fitted parameters, the Fitted IDSite was trained with the subset of 36 compounds and successfully applied to the other 20 compounds, recovering 94% of the experimental observations with high sensitivity and specificity for both sets.