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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.
Linoleic acid hydroperoxides are versatile intermediates for the production of green note aroma compounds and bifunctional ω-oxo-acids. An enzyme cascade consisting of lipoxygenase, lipase and catalase was developed for one-pot synthesis of 13-hydroperoxyoctadecadienoic acid starting from safflower oil. Reaction conditions were optimized for hydroperoxidation using lipoxygenase 1 from Glycine max (LOX-1) in a solvent-free system. The addition of green surfactant Triton CG-110 improved the reaction more than two-fold and yields of >50% were obtained at linoleic acid concentrations up to 100 mM. To combine hydroperoxidation and oil hydrolysis, 12 lipases were screened for safflower oil hydrolysis under the reaction conditions optimized for LOX-1. Lipases from Candida rugosa and Pseudomonas fluorescens were able to hydrolyze safflower oil to >75% within 5 h at a pH of 8.0. In contrast to C. rugosa lipase, the enzyme from P. fluorescens did not exhibit a lag phase. Combination of P. fluorescens lipase and LOX-1 worked well upon LOX-1 dosage and a synergistic effect was observed leading to >80% of hydroperoxides. Catalase from Micrococcus lysodeikticus was used for in-situ oxygen production with continuous H2O2 dosage in the LOX-1/lipase reaction system. Foam generation was significantly reduced in the 3-enzyme cascade in comparison to the aerated reaction system. Safflower oil concentration was increased up to 300 mM linoleic acid equivalent and 13-hydroperoxides could be produced in a yield of 70 g/L and a regioselectivity of 90% within 7 h.
Abstract
(−)‐Menthol is one of the most popular aroma compounds worldwide. While in the past mostly extracted from mint plants, today (−)‐menthol synthesis from other raw materials is becoming more relevant. Common starting materials for menthol synthesis are m‐cresol, citral and myrcene, but also substrates like menthone, mono‐ and bicyclic terpenes and terpenoids have been used for this purpose in the past. As for many applications (−)‐menthol of high purity is required, asymmetric syntheses and enantiomeric resolution of obtained raw products are applied for menthol production. This review gives an overview on the most important synthetic menthol production processes of the companies Symrise, Takasago and BASF and relevant literature in the field of menthol synthesis with a focus on the last 20 years.
Porous polymer membranes substantially contribute to an acceleration of sustainability transformation based on the energy efficient separation of liquid and gaseous mixtures. This rapid shift toward sustainable industrial processes leads to an increased demand for specifically tailored membranes. In order to predict membrane performance factors like permeability, selectivity and durability, the membrane formation process by film casting and phase inversion needs to be understood further. In recent years, computational models of the membrane formation process have been studied intensely. Their high spatial and temporal resolution allows a detailed quantitative description of phase inversion phenomena. New experimental techniques complement this development, as they provide quantitative data, e.g., on compositional changes of the polymer solution during membrane formation as well as the kinetic progression of the phase separation process. This state-of-the-art review compiles computational and experimental approaches that characterize the phase inversion process. We discuss how this methodological pluralism is necessary for improving the tailoring of membrane parameters, but that it is unlikely to be the way to the ultimate goal of a complete description of the evolution of the membrane structure from the initial demixing to the final solidification. Alternatively, we formulate an approach that includes a database of standardized and harmonized membrane performance data based on previously publicized data, as well as the application of artificial neural networks as a new powerful tool to link membrane production parameters to membrane performance.
Due to reasons of sustainability and conservation of resources, polyurethane (PU)-based systems with preferably neutral carbon footprints are in increased focus of research and development. The proper design and development of bio-based polyols are of particular interest since such polyols may have special property profiles that allow the novel products to enter new applications. Sophorolipids (SL) represent a bio-based toolbox for polyol building blocks to yield diverse chemical products. For a reasonable evaluation of the potential for PU chemistry, however, further investigations in terms of synthesis, derivatization, reproducibility, and reactivity towards isocyanates are required. It was demonstrated that SL can act as crosslinker or as plasticizer in PU systems depending on employed stoichiometry. (ω-1)-hydroxyl fatty acids can be derived from SL and converted successively to polyester polyols and PU. Additionally, (ω-1)-hydroxyl fatty acid azides can be prepared indirectly from SL and converted to A/B type PU by Curtius rearrangement.
The oxidation of cumene and following cleavage of cumene hydroperoxide (CHP) with sulfuric acid (Hock rearrangement) is still, by far, the dominant synthetic route to produce phenol. In 2020, the global phenol market reached a value of 23.3 billion US$ with a projected compound annual growth rate of 3.4% for 2020–2025. From ecological and economical viewpoints, the key step of this process is the cleavage of CHP. One sought-after way to likewise reduce energy consumption and waste production of the process is to substitute sulfuric acid with heterogeneous catalysts. Different types of zeolites, silicon-based clays, heteropoly acids, and ion exchange resins have been investigated and tested in various studies. For every type of these solid acid catalysts, several materials were found that show high yield and selectivity to phenol. In this mini-review, first a brief introduction and overview on the Hock process is given. Next, the mechanism, kinetics, and safety aspects are summarized and discussed. Following, the different types of heterogeneous catalysts and their performance as catalyst in the Hock process are illustrated. Finally, the different approaches to substitute sulfuric acid in the synthetic route to produce phenol are briefly concluded and a short outlook is given.
In der vorliegenden Arbeit wurde eine HPLC-Methode mit der dazugehörigen Probenvorbereitung entwickelt, welche es ermöglicht Essigsäure und Acrylsäure in komplexen Matrizes wie Deponiesickerwasser zu bestimmen. Hauptaugenmerk lag dabei auf der Matrixreduzierung, die bei 96 % lag. Die Wiederfindung der Analyten Essigsäure und Acrylsäure liegt bei der beschriebenen Methode bei ca. 100 %.
In the last decade, the utilization of waste by-product apple pomace has been extensively researched (due to its difficult disposal) and currently finds beneficial usage in various industries; as substrate for microbial growth or recovery of pectin, xyloglucan and polyphenols. In this research apple juice was produced at pilot scale. Furthermore, apple pomace was employed as substrate for the production of pectin, biofuel (pellets) and concentrated apple pomace extract. Extensive mass and heat balances were conducted to evaluate the feasibility of this approach on industrial scale. The produced pellets had very similar characteristics to wood pellets (net calorific value of 20.3 MJ/kg). Dried apple pomace contained 11.9% of pectin. Fed-batch cultivation of baker´s yeast with apple pomace extract demonstrated a potential for partial substitution of molasses in industrial bioprocesses. This concept shows how a zero discharge biorefinery process converts waste from apple juice production into three valuable products enabling connections between different industries.
Pseudozyma antarctica Lipase B catalyzed esterification and transesterification in deep eutectic solvents (DES) was investigated in reaction systems with alcohols of different polarity. Coconut oil and crude biodiesel were deacidified successfully with non-immobilized CALBL and final acid values of 1.2 for biodiesel and 0.5 for coconut oil were obtained, while no esterification with ethanol was observed without DES. Water depletion of the lipid phase in the presence of water adsorbing DES causes this difference. Analysis of water contents revealed a 10 fold lower water content of the lipid phase in the presence of a second DES phase than in trials without utilization of DES. In contrast reactions of hydrophilic polyols are suppressed in the presence of DES. While the esterification of fructose and the transesterification with glycerol worked well in the polar solvent 2-methyl-2-butanol, almost no fructose esterification and a decreased transesterification with glycerol were observed in the presence of DES. Analysis of logP values of the substrates explains the substrate dependent differences in reactivity. The polar alcohols are probably bound strongly in the hydrogen-bonding network of the DES phase and are thus not available for lipase catalyzed reactions.
Despite great efforts to develop a vaccine against human immunodeficiency virus (HIV), which causes AIDS if untreated, no approved HIV vaccine is available to date. A promising class of vaccines are virus-like particles (VLPs), which were shown to be very effective for the prevention of other diseases. In this study, production of HI-VLPs using different 293F cell lines, followed by a three-step purification of HI-VLPs, was conducted. The quality-by-design-based process development was supported by process analytical technology (PAT). The HI-VLP concentration increased 12.5-fold while >80% purity was achieved. This article reports on the first general process development and optimization up to purification. Further research will focus on process development for polishing and formulation up to lyophilization. In addition, process analytical technology and process modeling for process automation and optimization by digital twins in the context of quality-by-design framework will be developed.
The internal armed conflict in Colombia has been closely linked to the illegal exploitation of natural resources and the appropriation of territories, including the planting of illicit coca crops. This activity has led to deforestation and the degradation of natural ecosystems, aggravating the problems associated with violence and drug trafficking. Regions with little state presence, such as Catatumbo, were particularly affected.
Following the signing of the peace agreement with the Revolutionary Armed Forces of Colombia (FARC) in 2016, a post-agreement scenario emerged that highlighted the need to address complex socio-environmental conflicts in affected regions. This research aims to identify the potential of environmental governance to contribute to peacebuilding and the reduction of deforestation associated with illicit coca cultivation.
A qualitative methodological approach was used in this study, which seeks to integrate research methods and techniques such as: documentary review, participant observation, semi-structured and in-depth interviews, and mapping of the current reality through the Theory U 3D mapping tool.
The results include the socio-environmental context of the territory of analysis, describing the origins of the conflict of deforestation for illicit crops, where the growing dynamics of transformation of the sowing of illicit crops are related, as well as the dynamics of deforestation in the territory of analysis. Tthe identification and analysis of the most relevant actors that have historically participated in the processes of deforestation for illicit crops, their characterization according to the relations of power, interest and legitimisation legitimization. The forms of participation and conflict resolution in the management of natural resources.
Considering as a contextual axis two important processes at a socio-political level in Colombia and the territory under analysis, which correspond to the consolidation of the Comprehensive Rural Reform after the peace agreement and the post-agreement context. Several intervention proposals were proposed from the perspective of environmental governance related to the reconstruction of the social fabric, the reconversion of productive systems, and the resignification of new dynamics of natural resource management. In this sense, the potential of environmental governance is discussed as a useful framework for establishing new relationships based on horizontality in which the actors possess sovereignty over the territory, participation and representativeness in the management of natural resources.
Key words: Deforestation, illicit coca crops, environmental governance, forest management, peacebuilding.