Controlled Delivery of Pan-PAD-Inhibitor Cl-Amidine Using Poly(3-Hydroxybutyrate) Microspheres

This study deals with the process of optimization and synthesis of Poly(3-hydroxybutyrate) microspheres with encapsulated Cl-amidine. Cl-amidine is an inhibitor of peptidylarginine deiminases (PADs), a group of calcium-dependent enzymes, which play critical roles in a number of pathologies, including autoimmune and neurodegenerative diseases, as well as cancer. While Cl-amidine application has been assessed in a number of in vitro and in vivo models; methods of controlled release delivery remain to be investigated. P(3HB) microspheres have proven to be an effective delivery system for several compounds applied in antimicrobial, wound healing, cancer, and cardiovascular and regenerative disease models. In the current study, P(3HB) microspheres with encapsulated Cl-amidine were produced in a size ranging from ~4–5 µm and characterized for surface morphology, porosity, hydrophobicity and protein adsorption, in comparison with empty P(3HB) microspheres. Cl-amidine encapsulation in P(3HB) microspheres was optimized, and these were found to be less hydrophobic, compared with the empty microspheres, and subsequently adsorbed a lower amount of protein on their surface. The release kinetics of Cl-amidine from the microspheres were assessed in vitro and expressed as a function of encapsulation efficiency. There was a burst release of ~50% Cl-amidine in the first 24 h and a zero order release from that point up to 16 days, at which time point ~93% of the drug had been released. As Cl-amidine has been associated with anti-cancer effects, the Cl-amidine encapsulated microspheres were assessed for the inhibition of vascular endothelial growth factor (VEGF) expression in the mammalian breast cancer cell line SK-BR-3, including in the presence of the anti-proliferative drug rapamycin. The cytotoxicity of the combinatorial effect of rapamycin with Cl-amidine encapsulated P(3HB) microspheres was found to be 3.5% more effective within a 24 h period. The cells treated with Cl-amidine encapsulated microspheres alone, were found to have 36.5% reduction in VEGF expression when compared with untreated SK-BR-3 cells. This indicates that controlled release of Cl-amidine from P(3HB) microspheres may be effective in anti-cancer treatment, including in synergy with chemotherapeutic agents. Using controlled drug-delivery of Cl-amidine encapsulated in Poly(3-hydroxybutyrate) microspheres may be a promising novel strategy for application in PAD-associated pathologies.     

Liquid flow texture analysis in trickle bed reactors using high-resolution gamma ray tomography

Trickle bed reactor performance and safety may suffer from radial and axial liquid maldistribution and thus from non-uniform utilization of the catalyst packing. Therefore, experimental analysis and fluid dynamic simulation of liquid–gas flow in trickle bed reactors is an important topic in chemical engineering. In the present study for the first time a truly high-resolution gamma ray tomography technique was applied to the quantitative analysis of the liquid flow texture in a laboratory cold flow trickle bed reactor of 90 mm diameter. The objective of this study was to present the comparative analysis of the liquid flow dynamics for two different initial liquid distributions and two different types of reactor configurations. Thus, the hydrodynamic behavior of a glass bead packing was compared to a porous Al₂O₃ catalyst particle packing using inlet flow from a commercial spray nozzle (uniform initial liquid distribution) and inlet flow from a central point source (strongly non-uniform initial liquid distribution), respectively. The column was operated in downflow mode at a gas flow rate of 180 L h⁻¹ and at liquid flow rates of 15 and 25 L h⁻¹.     

Influence of the glycosidic linkage on the solution conformation of glucans

In order to gain a better understanding of the influence of β-glycosidic linkages on the solution conformation of glucans, a comparison was made between the carboxymethyl derivatives of cellulose (CMC, 100% 1,4-), barley glucan (CMGG, 30 : 70 1,3 : 1,4-) and curdlan (CMCd, 100% 1,3-glycosidic), each with an average degree of substitution of DS = 1.0–1.5 and molar masses of 144 000–720 000 g mol^–1. For this purpose curdlan and barley glucan were chemically modified, whereas carboxymethylcellulose was available as a commercial sample. Via congo red analysis it was proved for the microbial β-1,3-glucans curdlan (unsubstituted) and scleroglucan (one β-1,6-linked glucose side group on every third monomer unit) that substituents in glucan derivatives weaken an existing helical structure but that reduction of the molar mass with ultrasound has no influence on the helices. The molecular parameters M_w, M_n, R_G, L_P and [η] were determined by means of SEC/MALLS measurements and viscometry and the chain mobility was quantified using the ¹³C NMR relaxation times, T₁, of the different polymers. From this it was possible to derive [η]-M_w relationships. For all samples, the exponent ν of the R_G-M_W relationship lay in the range 0.54–0.59, from which it is possible to deduce a coiled solution structure. However, β-1,3-glucans occupy 25% less volume than β-1,4-glucans and exhibit less chain mobility. Hence β-1,4-glucans should be considerably more viscous than β-1,3-glucans, as was indeed demonstrated by rheological flow curves of 6% solutions of the carboxymethylglucan derivatives. The zero-shear viscosity, η₀, decreases by 3 decades in the order of CMC > CMGG > CMCd.     

Shape forming alumina slurries via Colloidal IsoPressing

The relative density, deformation behavior, and dynamic rheology of bodies consolidated from aqueous alumina slurries, formulated at pH 4 and containing NH₄Cl, were studied as a function of the salt concentration (0.1–0.75 M). The smallest salt concentration produced the highest relative density (0.596), which was independent of consolidation pressure. Nearly identical relative densities were obtained for the other salt concentrations, ranging from 0.57 to 0.59 for consolidation pressures of 5–100 MPa, respectively. The consolidated bodies exhibited either a plastic or an elastic behavior when tested in compression. It was observed that the transition from a plastic to an elastic behavior occurred at a critical consolidation pressure. This critical consolidation pressure was directly dependent on the salt concentration. The storage (elastic) modulus for the fluidized, plastic bodies increased with salt concentration. The storage modulus was also observed to be dependent on the time the bodies were allowed to rest after they were subjected to a high shear rate. A pre-consolidated and fluidized slurry formulated to contain 0.5 NH₄Cl was extruded into a rubber mold cavity and further consolidated by isopressing at 200 MPa for 2 min. The body not only increased its relative density (0.58–0.62), but it also became elastic to enable its removal from the rubber cavity without shape distortion. No linear shrinkage was detected after the isopressed bodies were dried. Because of the lack of shrinkage, rapid drying was possible. For example, bar specimens (6.4 mm × 12.7 mm × 60 mm) would survive a 34 °C/min heating rate to 300 °C; the specimen was completely dried within 20 min. Because shrinkage does not occur during drying, bodies could be placed directly into a furnace and heated to 1500 °C for 0.5 h to achieve a relative density of >0.99 and an average grain size of 1.6 μm.     

Coupling Interrupted Fischer and Multicomponent Joullié-Ugi to Chase Chemical Diversity: from Batch to Sustainable Flow Synthesis of Peptidomimetics

The generation of peptidomimetic substructures for medicinal chemistry purposes requires effective and divergent synthetic methods. We present in this work an efficient flow process that allows quick modulation of reagents for Joullié-Ugi multicomponent reaction, using spiroindolenines as core motifs. This sterically hindered imine equivalent could successfully be diversified using various isocyanides and amino acids in generally good space-time yields. A telescoped flow process combining interrupted Fischer reaction for spiroindolenine synthesis and subsequent Joullié-Ugi-type modification resulted in product formation in very good overall yield in less than 2 hours compared to 48 hours required in batch mode. The developed protocol can be seen as a general tool for rapid and facile generation of peptidomimetic compounds. We also showcase preliminary biological assessments for the prepared compounds.     

Mediator-Related Symptoms and Anaphylaxis in Children with Mastocytosis

Mastocytosis is characterized by the pathological accumulation of mast cells (MC) in various organs. In these patients, MC may degranulate and thereby contribute to clinical symptoms, especially when a concomitant allergy is present. However, MC activation can not only be induced by high-affinity receptors for IgE, but also by anaphylatoxins, neuropeptides, IgG immune complexes, complement-components, drugs, products of bacteria or parasites, as well as physical factors such as heat, cold, vibration, stress, sun, or physical effort. Symptoms due to mediators released by activated MC may develop in adults suffering from systemic mastocytosis, but also evolve in children who usually have cutaneous mastocytosis (CM). Clinically, CM is otherwise characterized by typical brown, maculopapular skin lesions or mastocytoma associated with a positive Darier’s sign. Pruritus and flushing are common and blistering may also be recorded, especially in diffuse CM (DCM). Pediatric patients with mastocytosis may also have gastrointestinal, respiratory, and neurologic complaints. Although anaphylaxis is not a typical finding, pediatric patients with massive skin involvement and high tryptase levels have a relatively high risk to develop anaphylaxis. This paper reviews MC mediator-related symptoms and anaphylaxis in children with mastocytosis, with special emphasis on risk factors, triggers, and management.     

Where the wind blows

The power systems in Denmark, Spain, Ireland, and New Zealand have some of the highest wind penetrations in the world (see Table 1). The management of the different power systems to date, with increasing amounts of wind energy, has been successful. There have been no incidents in which the wind has directly or indirectly been a major factor causing operational problems for the system. However, there are a number of parameters that are being monitored that indicate the need for active management in the near future (and in some cases already today). In this article, we briefly describe the situations in these four countries, giving special emphasis to the market integration of wind power, the use of wind forecasting, and curtailment experience. The final section provides an overview of the main wind forecasting methodologies and challenges.