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Stable recombinant mammalian cells are of growing importance in pharmaceutical biotechnology production scenarios for biologics such as monoclonal antibodies, growth and blood factors, cytokines and subunit vaccines. However, the establishment of recombinant producer cells using classical stable transfection of plasmid DNA is hampered by low stable gene transfer efficiencies. Consequently, subsequent selection of transgenic cells and the screening of clonal cell populations are time- and thus cost-intensive. To overcome these limitations, expression cassettes were embedded into transposon-derived donor vectors. Upon the co-transfection with transposase-encoding constructs, elevated vector copy numbers stably integrated into the genomes of the host cells are readily achieved facilitating under stringent selection pressure the establishment of cell pools characterized by sustained and high-yield recombinant protein production. Here, we discuss some aspects of transposon vector technologies, which render these vectors promising candidates for their further utilization in the production of biologics.
Despite intensive research over the last three decades, it has not yet been possible to bring an effective vaccine against human immunodeficiency virus (HIV) and the resulting acquired immunodeficiency syndrome (AIDS) to market. Virus-like particles (VLP) are a promising approach for efficient and effective vaccination and could play an important role in the fight against HIV. For example, HEK293 (human embryo kidney) cells can be used to produce virus-like particles. In this context, given the quality-by-design (QbD) concept for manufacturing, a digital twin is of great importance for the production of HIV-Gag-formed VLPs. In this work, a dynamic metabolic model for the production of HIV-Gag VLPs was developed and validated. The model can represent the VLP production as well as the consumption or formation of all important substrates and metabolites. Thus, in combination with already described process analytical technology (PAT) methods, the final step towards the implementation of a digital twin for process development and design, as well as process automation, was completed.
Abstract
Due to their pronounced bioactivity and limited availability from natural resources, metabolites of the soft coral Pseudopterogorgia elisabethae, such as erogorgiaene and the pseudopterosines, represent important target molecules for chemical synthesis. We have now developed a particularly short and efficient route towards these marine diterpenes exploiting an operationally convenient enantioselective cobalt‐catalyzed hydrovinylation as the chirogenic step. Other noteworthy C−C bond forming transformations include diastereoselective Lewis acid‐mediated cyclizations, a Suzuki coupling and a carbonyl ene reaction. Starting from 4‐methyl‐styrene the anti‐tubercular agent (+)‐erogorgiaene (>98 % ee) was prepared in only 7 steps with 46 % overall yield. In addition, the synthesis of the pseudopterosin A aglycone was achieved in 12 steps with 30 % overall yield and, surprisingly, was found to exhibit a similar anti‐inflammatory activity (inhibition of LPS‐induced NF‐κB activation) as a natural mixture of pseudopterosins A−D or iso‐pseudopterosin A, prepared by β‐D‐xylosylation of the synthetic aglycone.
Aerobic microbial cultivations are industrially important group of processes and pose challenges for the reactor design. In particular, estimation of industrial scale conditions is difficult from laboratory and pilot scale data. Due to complex interaction of gas/liquid phase hydrodynamics, mass transfer parameters and microbial metabolism, both improvement of modelling tools and reactor design are desired. We present an approach to estimate growth conditions in industrial scale reactor by combining black-box metabolic models with CFD-model.
The reactor type used here is Outotec OKTOP9000®, which is used in the industrial hydrometallurgical processes at 900 m3 scale. It is adopted to a laboratory setting and compared to stirred tank reactor (STR) in gas dispersion, mass transfer and yeast cultivation experiments. In addition, a kinetic model for the yeast growth is developed based on literature sources and validated by the laboratory scale batch cultivations. This kinetic model is used along with CFD-model that is developed to describe the flow and mass transfer conditions in the industrial scale reactor.
The laboratory scale experiments show the feasibility of OKTOP9000® reactor when compared to STR, particularly with improved gas handling capacity. The modelling approach shows qualitatively similar behavior in the large scale simulations when compared to laboratory scale cultivations.
Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of β-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively.
In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target.
AbstractThis paper discusses the comparison of two methods to achieve thermal comfort utilising air conditioning (AC) system in a small indoor space – adaptive control and fuzzy control. Thermal comfort indoors is performed to provide comfortability individually or for a group of people. Due to the small indoor space which usually a bit cramped, crowded and less airy, the ambience can be very uncomfortable either for doing sedentary or active work, thus the AC system can be very useful to provide thermal comfort. Both methods can be utilised depending on how thermal comfort is viewed and how the level of thermal comfort is decided. Every method has its own advantage and limitations, and will be covered in this paper as well.
The Production of Isophorone
(2023)
Isophorone is a technically important compound used as a high-boiling-point solvent for coatings, adhesives, etc., and it is used as a starting material for various valuable compounds, including isophorone diisocyanate, a precursor for polyurethanes. For over 80 years, isophorone has been synthesized via base-catalyzed self-condensation of acetone. This reaction has a complex reaction mechanism with numerous possible reaction steps including the formation of isophorone, triacetone dialcohol, and ketonic resins. This review provides an overview of the different production processes of isophorone in liquid- and vapor-phase and reviews the literature-reported selectivity toward isophorone achieved using different reaction parameters and catalysts.
In this work, supported cellulose acetate (CA) mixed matrix membranes (MMMs) were prepared and studied concerning their gas separation behaviors. The dispersion of carbon nanotube fillers were studied as a factor of polymer and filler concentrations using the mixing methods of the rotor–stator system (RS) and the three-roll-mill system (TRM). Compared to the dispersion quality achieved by RS, samples prepared using the TRM seem to have slightly bigger, but fewer and more homogenously distributed, agglomerates. The green γ-butyrolactone (GBL) was chosen as a polyimide (PI) polymer-solvent, whereas diacetone alcohol (DAA) was used for preparing the CA solutions. The coating of the thin CA separation layer was applied using a spin coater. For coating on the PP carriers, a short parameter study was conducted regarding the plasma treatment to affect the wettability, the coating speed, and the volume of dispersion that was applied to the carrier. As predicted by the parameter study, the amount of dispersion that remained on the carriers decreased with an increasing rotational speed during the spin coating process. The dry separation layer thickness was varied between about 1.4 and 4.7 μm. Electrically conductive additives in a non-conductive matrix showed a steeply increasing electrical conductivity after passing the so-called percolation threshold. This was used to evaluate the agglomeration behavior in suspension and in the applied layer. Gas permeation tests were performed using a constant volume apparatus at feed pressures of 5, 10, and 15 bar. The highest calculated CO2/N2 selectivity (ideal), 21, was achieved for the CA membrane and corresponded to a CO2 permeability of 49.6 Barrer.
This study explores the potential of robust, strongly basic type I ion exchange resins—specifically, Amberlyst® A26 OH and Lewatit® K 6465—as catalysts for the aldol condensation of citral and acetone, yielding pseudoionone. Emphasis is placed on their long-term stability and commendable performance in continuous operational settings. The aldol reaction, which traditionally is carried out using aqueous sodium hydroxide as the catalyst, holds the potential for enhanced sustainability and reduced waste production through the use of basic ion exchange resins in heterogeneous catalysis. Density Functional Theory (DFT) calculations are employed to investigate catalyst deactivation mechanisms. The result of these calculations indicates that the active sites of Amberlyst® A26 OH are cleaved more easily than the active sites of Lewatit® K 6465. However, the experimental data show a gradual decline in catalytic activity for both resins. Batch experiments reveal Amberlyst® A26 OH’s active sites diminishing, while Lewatit® K 6465 maintains relative consistency. This points to distinct deactivation processes for each catalyst. The constant count of basic sites in Lewatit® K 6465 during the reaction suggests additional factors due to its unique polymer structure. This intriguing observation also highlights an exceptional temperature stability for Lewatit® K 6465 compared to Amberlyst® A26 OH, effectively surmounting one of the prominent challenges associated with the utilization of ion exchange resins in catalytic applications.
Due to the worldwide shortage of petrochemical based resources, the usage of renewable bio-based raw materials for established and novel products becomes increasingly important.[1] Such bio-based resources are already used for the fabrication of a variety of products, e. g. paper, lubricants, detergents or cosmetics. In the future they are expected to emerge in many more applications in industry and household.[1]
A very promising approach relies on the use of glycolipids as a source of hydroxy-oleic acid.[2] Microbial glycolipids are produced for instance via fermentation from natural resources such as plant oils and sugar.[3] After fermentation complex product mixtures are obtained with the composition depending on the microorganism, substrate and fermentation time.[3] The successful use of microbial glycolipids and hydroxy-oleic acid (HOA) derived therefrom as bio-based intermediates requires reliable analytical methods as well as robust manufacturing processes for the synthesis and cleavage of bio-based molecules. In order to obtain hydroxy-oleic acids as bio-based intermediates, the acidic cleavage of microbial derived sophorolipid was investigated. In addition the implementation of HOA in polyurethane (PU) systems was explored.