Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery

The copolymerization in bulk and solution of trimethylene carbonate (TMC) with adipic anhydride (AA) as well as the blending of homopolymers are described. We show experimentally that the components are not copolymerizable but partially miscible, forming a microscopic dispersion without any visible signs of phase separation. Poly(adipic anhydride) (PAA) functions as a plasticizer, permitting an increase in the erosion rate by increasing the porosity and hydration. Drug delivery from the blends was evaluated. A statistical factorial model was designed to explore the influence of three important blend parameters and their interactions, making it possible to predict the erosion and drug‐release behavior of the blend matrices. The PAA:poly(trimethylene carbonate) (PTMC) ratio and molecular weight of the polycarbonate component significantly influence the drug‐release performance, mass loss, and degree of plasticization. The interaction among these factors also influences the blend properties. Plasticization of PTMC enhances the drug release to an extent that is dependent on the amount of PAA used. We demonstrate that blending offers a convenient alternative to copolymerization for the preparation of polymer matrices with predictable drug delivery. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 227–239, 1999     

Index Criteria for Differential Algebraic Equations Arising from Linear-Quadratic Optimal Control Problems

The index of DAE systems arising from linear quadratic optimal control problems is considered. Necessary and sufficient conditions ensuring regularity with tractability index one are proved. Then, it is shown that if the control problem DAE is regular with index one and if the leading term of the DAE to be controlled is given by one full-column-rank and one full-row-rank matrix, then it has a Hamiltonian inherent explicit ODE. For problems with regular index zero or index one DAEs to be controlled, the DAE of the control problem is shown to be regular with tractability index one or three, depending on whether the control coefficient R is singular. 2000 Mathematics Subject Classification. 49N10, 49J15, 34A09. Supported by the DFG research center MATHEON in Berlin. This work was partially supported by the Russian Fundamental Research Foundation Project Nos. 02-01-00351 and 06-01-00296.     

Effect of Microstructure and Hydrogen Pores on the Mechanical Behavior of an Al7%Si0.3%Mg Alloy Studied by a Combined Phase‐Field and Micromechanical Approach

A combination of the phase‐field method for the simulation of the microstructure evolution during solidification with subsequent finite element simulation of fracture appearance in the final solidification structure is proposed for the prediction of the mechanical behavior of Al? Si based casting alloys, including the effect of solidification porosity caused by hydrogen. Metallographic investigations and computer tomographic observations of the as cast microstructure of an Al7%Si0.3%Mg alloy together with the data obtained from mechanical tensile testing are used to compare and validate the simulation results to demonstrate the capabilities as well as current limitations in micromechanical modeling of void containing materials. In micromechanical simulations with the element elimination technique (EET) it is shown that porosity influences the crack path as well as crack propagation by connecting the pores. In the eutectic microstructure without porosity, failure starts to develop in silicon lamellae and proceeds in the ductile matrix. However, in the presence of pores fracture also initiates in silicon, and in the later stages of loading, porosity affects the path of the crack and results in additional crack nucleation, and thus, these pores also influence crack propagation in the matrix.     

CYP51: A Major Drug Target in the Cytochrome P450 Superfamily

The cytochrome P540 (CYP) superfamily currently includes about 9000 proteins forming more than 800 families. The enzymes catalyze monooxygenation of a vast array of compounds and play essentially two roles. They provide biodefense (detoxification of xenobiotics, antibiotic production) and participate in biosynthesis of important endogenous molecules, particularly steroids. Based on these two roles, sterol 14/*alpha*/-demethylases (CYP51) belong to the second group of P450s. The CYP51 family, however, is very special as its members preserve strict functional conservation in enzyme activity in all biological kingdoms. At amino acid identity across the kingdoms as low as 25-30%, they all catalyze essentially the same three-step reaction of oxidative removal of the 14/*alpha*/-methyl group from the lanostane frame. This reaction is the required step in sterol biosynthesis of pathogenic microbes. We have shown that specific inhibition of protozoan CYP51 can potentially provide treatment for human trypanosomiases. Three sets of CYP51 inhibitors tested in vitro and in trypanosomal cells in this study include azoles [best results being 50% cell growth inhibition at <1 and at 1.3 muM for Trypanosoma cruzi (TC) and Trypanosoma brucei (TB), respectively], non-azole compounds (50% TC cell growth inhibition at 5 microM) and substrate analogs of the 14/*alpha*/-demethylase reaction. 32-Methylene cyclopropyl lanost-7-enol exhibited selectivity toward TC with 50% cell growth inhibition at 3 microM.     

Design of novel FN3 domains with high stability by a consensus sequence approach

The use of consensus design to produce stable proteins has been applied to numerous structures and classes of proteins. Here, we describe the engineering of novel FN3 domains from two different proteins, namely human fibronectin and human tenascin-C, as potential alternative scaffold biotherapeutics. The resulting FN3 domains were found to be robustly expressed in Escherichia coli, soluble and highly stable, with melting temperatures of 89 and 78°C, respectively. X-ray crystallography was used to confirm that the consensus approach led to a structure consistent with the FN3 design despite having only low-sequence identity to natural FN3 domains. The ability of the Tenascin consensus domain to withstand mutations in the loop regions connecting the β-strands was investigated using alanine scanning mutagenesis demonstrating the potential for randomization in these regions. Finally, rational design was used to produce point mutations that significantly increase the stability of one of the consensus domains. Together our data suggest that consensus FN3 domains have potential utility as alternative scaffold therapeutics.     

The Kiss-and-Run Model of Intra-Golgi Transport

The Golgi apparatus (GA) is the main station along the secretory pathway. Mechanisms of intra-Golgi transport remain unresolved. Three models compete with each other for the right to be defined as the paradigm. The vesicular model cannot explain the following: (1) lipid droplets and aggregates of procollagen that are larger than coatomer I (COPI)-dependent vesicles are transported across the GA; and (2) most anterograde cargoes are depleted in COPI vesicles. The compartment progression/maturation model has the following problems: (1) most Golgi-resident proteins are depleted in COPI vesicles; (2) there are no COPI vesicles for the recycling of the resident proteins in the trans-most-Golgi cisterna; and (3) different proteins have different rates of intra-Golgi transport. The diffusion model based on permanent inter-cisternal connections cannot explain the existence of lipid, ionic and protein gradients across the Golgi stacks. In contrast, the kiss-and-run model has the potential to explain most of the experimental observations. The kiss-and-run model can be symmetric when fusion and then fission occurs in the same place, and asymmetric when fusion takes place in one location, whereas fission takes place in another. The asymmetric kiss-and-run model resembles the carrier maturation mechanism, and it can be used to explain the transport of large cargo aggregates.     

Prehydrolysis in softwood pulping produces a valuable biorefinery fraction for material utilization

A scaled-up prehydrolysis process was elaborated to demonstrate an industrially feasible operation step in a pulping process that generates a valuable side product in addition to the cellulose pulp. The valuable side product is aqueous process liquor, a softwood hydrolysate (SWH) herein produced in 60 L batches, and its components were recovered and utilized as materials. The process parameters were shown to influence the yield, composition, and quality of the obtained hydrolysates. Furthermore, the process conditions were shown to influence the ability of SWHs to form free-standing, foldable films in blends with either microfibrillated cellulose (MFC) or carboxymethyl cellulose (CMC). Films with oxygen permeabilities (OP) as low as 0.35 cm(3) μm day(-1) m(-2) kPa(-1) at 50% relative humidity, were produced from aqueous solutions providing a viable and green alternative to petroleum-based packaging barriers. The OPs were very low regardless of SWH film composition and upgrading conditions, whereas the films' tensile performance was directly controlled by the ratio of SWH to cocomponent.