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Publikation Predictive computational models for assessing the impact of co-milling on drug dissolution(Elsevier, 07/2024) Pätzmann, Nicolas; O'Dwyer, Patrick J.; Beránek, Josef; Kuentz, Martin; Griffin, Brendan T.Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Modulating the electronic structure of Mn promotes singlet oxygen generation from electrochemical oxidation of H₂O via O-O coupling(Elsevier, 12/2024) Chen, Hao; Hou, Zhiang; Yue, Jinzhu; Wang, Jinnan; Wang, Yi; Li, Aimin; Corvini, PhilippeSelectively catalytic conversion H₂O into singlet oxygen (¹O₂) without additional oxidants is considered as an economic-efficient method for organic pollutants degradation. However, H₂O are more consistent with the spin state of ¹O₂ than common oxygen (O₂), retarding the kinetics of spin transition-induced reaction between O₂ and ¹O₂. Herein, we report an unprecedented ¹O₂ mediated electrocatalytic oxidation process, which allows O–O coupling for ¹O₂ evolution from H₂O over CrMn@C anode. The electron occupancy (eg) of CrMn@C (0.89) is very close to the optimal eg (0.95) of manganese-based materials reported in the literature, which facilitates the activation of H₂O on surface. Mn(Mn0.193Cr1.808)O₄-Mn in CrMn@C electrode significantly promotes the activation of H₂O to produce *O, followed by coupling of *O at adjacent sites to produce *OO, which further spontaneously forms ¹O₂. And H₂¹⁸O isotope experiments provide direct evidence for the production of ¹O₂ directly from H₂O. Consequently, the production of ¹O₂ is enhanced with the yield of 785.6 μmol·L⁻¹. Such ¹O₂-dominated electrocatalytic oxidation system can achieve efficient removal of electron-rich pollutant (bisphenol A) and improve the biodegradability of pharmaceutical wastewater (from 0.17 to 0.39).01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Comparison of protein-like model particles fabricated by micro 3D printing to established standard particles(Elsevier, 08/2024) Amara, Ilias; Germershaus, Oliver; Lentes, Christopher; Sass, Steffen; Youmto, Stephany Mamdjo; Stracke, Jan Olaf; Clemens-Hemmelmann, Mirjam; Assfalg, AnaceliaInnovative analytical instruments and development of new methods has provided a better understanding of protein particle formation in biopharmaceuticals but have also challenged the ability to obtain reproducible and reliable measurements. The need for protein-like particle standards mimicking the irregular shape, translucent nature and near-to-neutral buoyancy of protein particles remained one of the hot topics in the field of particle detection and characterization in biopharmaceutical formulations. An innovative protein-like particle model has been developed using two photo polymerization (2PP) printing allowing to fabricate irregularly shaped particles with similar properties as protein particles at precise size of 50 µm and 150 µm, representative of subvisible particles and visible particles, respectively. A study was conducted to compare the morphological, physical, and optical properties of artificially generated protein particles, polystyrene spheres, ETFE, and SU-8 particle standards, along with newly developed protein-like model particles manufactured using 2PP printing. Our results suggest that 2PP printing can be used to produce protein-like particle standards that might facilitate harmonization and standardization of subvisible and visible protein particle characterization across laboratories and organizations.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Technical note: development of a simulation framework, enabling the investigation of locally tuned single energy proton radiography(IOP Publishing, 07.02.2024) Lundberg, Måns; Meijers, Arturs; Souris, Kevin; Deffet, Sylvain; Weber, Damien C; Lomax, Antony; Knopf, AntjeRange uncertainties remain a limitation for the confined dose distribution that proton therapy can offer. The uncertainty stems from the ambiguity when translating CT Hounsfield Units (HU) into proton stopping powers. Proton Radiography (PR) can be used to verify the proton range. Specifically, PR can be used as a quality-control tool for CBCT-based synthetic CTs. An essential part of the work illustrating the potential of PR has been conducted using multi-layer ionization chamber (MLIC) detectors and mono-energetic PR. Due to the dimensions of commercially available MLICs, clinical adoption is cumbersome. Here, we present a simulation framework exploring locally-tuned single energy (LTSE) proton radiography and corresponding potential compact PR detector designs. Based on a planning CT data set, the presented framework models the water equivalent thickness. Subsequently, it analyses the proton energies required to pass through the geometry within a defined ROI. In the final step, an LTSE PR is simulated using the MCsquare Monte Carlo code. In an anatomical head phantom, we illustrate that LTSE PR allows for a significantly shorter longitudinal dimension of MLICs. We compared PR simulations for two exemplary 30 × 30 mm2proton fields passing the phantom at a 90° angle at an anterior and a posterior location in an iso-centric setup. The longitudinal distance over which all spots per field range out is significantly reduced for LTSE PR compared to mono-energetic PR. In addition, we illustrate the difference in shape of integral depth dose (IDD) when using constrained PR energies. Finally, we demonstrate the accordance of simulated and experimentally acquired IDDs for an LTSE PR acquisition. As the next steps, the framework will be used to investigate the sensitivity of LTSE PR to various sources of errors. Furthermore, we will use the framework to systematically explore the dimensions of an optimized MLIC design for daily clinical use.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Computational support to explore ternary solid dispersions of challenging drugs using coformer and hydroxypropyl cellulose(American Chemical Society, 10.10.2024) Niederquell, Andreas; Herzig, Susanne; Schönenberger, Monica; Stoyanov, Edmont; Kuentz, MartinA majority of drugs marketed in amorphous formulations have a good glass-forming ability, while compounds less stable in the amorphous state still pose a formulation challenge. This work explores ternary solid dispersions of two model drugs with a polymer (i.e., hydroxypropyl cellulose) and a coformer as stabilizing excipients. The aim was to introduce a computational approach by preselecting additives using solubility parameter intervals (i.e., overlap range of solubility parameter, ORSP) followed by more advanced COSMO-RS theory modeling. Thus, a mapping of calculated mixing enthalpy and melting points is proposed for in silico evaluation prior to hot melt extrusion. Following experimental testing of process feasibility, the selected formulations were tested for their physical stability using conventional bulk analytics and by confocal laser scanning and atomic force microscopy imaging. In line with the in silico screening, dl-malic and l-tartaric acid (20%, w/w) in HPC formulations showed no signs of early drug crystallization after 3 months. However, l-tartaric acid formulations displayed few crystals on the surface, which was likely a humidity-induced surface phenomenon. Although more research is needed, the conclusion is that the proposed computational small-scale extrusion approach of ternary solid dispersion has great potential in the formulation development of challenging drugs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Insecticide exposure alters flight-dependent gene-expression in honey bees, Apis mellifera(Elsevier, 12/2024) Christen, Verena; Jeker, Lukas; Lim, Ka S.; Menz, Myles H.M.; Straub, LarsThe increased reports of wild bee declines and annual losses of managed bees pose a significant threat to biodiversity and agricultural productivity. While these losses and declines are likely driven by various factors, the exposure of bees to agrochemicals has raised significant concern due to their ubiquitous use and potential adverse effects. Despite numerous studies suggesting neonicotinoids can negatively affect bees at the behavioral and molecular level, data linking these two factors remains sparse. Here we provide data on the impact of an acute dose of the neonicotinoid thiamethoxam on the flight performance and molecular transcription profiles of foraging honey bees (Apis mellifera). Using a controlled experimental design with tethered flight mills, we measured flight distance, duration, and speed, alongside the expression of genes involved in energy metabolism, hormone regulation, and biosynthesis. Acute thiamethoxam exposure resulted in hyperactive flight behavior but led to significant dysregulation of genes associated with oxidative phosphorylation, indicating potential disruptions in cellular energy production. These molecular changes were particularly evident when bees engaged in flight activities, suggesting that the combined stress of pesticide exposure and physical exertion exacerbates negative outcomes. Our study provides new insights into the molecular mechanisms underlying neonicotinoid-induced impairments in bee physiology that can help understand the potential long-term consequences of xenobiotic exposure on the foraging abilities of bees and ultimately fitness.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Definition of the binding specificity of the T7 bacteriophage primase by analysis of a protein binding microarray using a thermodynamic model(Oxford University Press, 10.04.2024) Lipps, GeorgProtein binding microarrays (PBM), SELEX, RNAcompete and chromatin-immunoprecipitation have been intensively used to determine the specificity of nucleic acid binding proteins. While the specificity of proteins with pronounced sequence specificity is straightforward, the determination of the sequence specificity of proteins of modest sequence specificity is more difficult. In this work, an explorative data analysis workflow for nucleic acid binding data was developed that can be used by scientists that want to analyse their binding data. The workflow is based on a regressor realized in scikit-learn, the major machine learning module for the scripting language Python. The regressor is built on a thermodynamic model of nucleic acid binding and describes the sequence specificity with base- and position-specific energies. The regressor was used to determine the binding specificity of the T7 primase. For this, we reanalysed the binding data of the T7 primase obtained with a custom PBM. The binding specificity of the T7 primase agrees with the priming specificity (5′-GTC) and the template (5′-GGGTC) for the preferentially synthesized tetraribonucleotide primer (5′-pppACCC) but is more relaxed. The dominant contribution of two positions in the motif can be explained by the involvement of the initiating and elongating nucleotides for template binding.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation In situ minimally invasive 3D printing for bone and cartilage regeneration - a scoping review(De Gruyter, 14.09.2024) Maintz, Michaela; Tomooka, Yukiko; Eugster, Manuela; Gerig, Nicolas; Sharma, Neha; Thieringer, Florian M.; Rauter, GeorgAdvancements in personalized medicine, three-dimensional (3D) printing, miniaturization, and robot-assistedsurgery are driving innovation in tissue engineering. A novelapproach, known asin situprinting, focuses on the direct depo-sition of materials at the surgical site. Using thein situprintingapproach, bone and/or cartilage defects can be addressed withhigh precision. Furthermore, highly customized 3D printed tis-sue constructs or implants can be deposited directly insidethe body. Currently, most applications ofin situprinting arelimited to areas near the skin or open surgeries. Even thougha minimally invasive approach would bring clinical benefits,only a few research groups have focused on this field. In thisscoping review, we provide an overview of the current stateofin situminimally invasive 3D printing technology for boneand cartilage regeneration and discuss its advantages and cur-rent challenges.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Host cell protein networks as a novel co‐elution mechanism during protein. A chromatography(Wiley, 07.03.2024) Panikulam, Sherin; Hanke, Alexander; Kroener, Frieder; Karle, Anette; Anderka, Oliver; Villiger, Thomas; Lebesgue, NicolasHost cell proteins (HCPs) are process-related impurities of therapeutic proteins produced in for example, Chinese hamster ovary (CHO) cells. Protein A affinity chromatography is the initial capture step to purify monoclonal antibodies or Fc-based proteins and is most effective for HCP removal. Previously proposed mechanisms that contribute to co-purification of HCPs with the therapeutic protein are either HCP-drug association or leaching from chromatin heteroaggregates. In this study, we analyzed protein A eluates of 23 Fc-based proteins by LC-MS/MS to determine their HCP content. The analysis revealed a high degree of heterogeneity in the number of HCPs identified in the different protein A eluates. Among all identified HCPs, the majority co-eluted with less than three Fc-based proteins indicating a drug-specific co-purification for most HCPs. Only ten HCPs co-purified with over 50% of the 23 Fc-based proteins. A correlation analysis of HCPs identified across multiple protein A eluates revealed their co-elution as HCP groups. Functional annotation and protein interaction analysis confirmed that some HCP groups are associated with protein-protein interaction networks. Here, we propose an additional mechanism for HCP co-elution involving protein-protein interactions within functional networks. Our findings may help to guide cell line development and to refine downstream purification strategies.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Bi atom sharing Co-Bi₂O₂CO₃/BiOI S-scheme induced singlet oxygen-dominated photocatalytic oxidation system(Elsevier, 12/2024) Hou, Zhiang; Yue, Jinzhu; Chen, Hao; Wang, Jinnan; Li, Aimin; Corvini, PhilippeEndocrine disrupting chemicals (EDCs) interfere with the normal secretion, transport and metabolism of human hormones, thus affecting neurological, reproductive and immune functions. Photocatalysis is regarded as a facile organic degradation technique. The construction of heterojunctions can modulate the reactive oxygen species and enhance the photocatalytic performance of semiconductors. However, poor contact interfaces still severely limit carrier separation and transfer. Herein, we have doped Co to modulate the band structure of Bi₂O₂CO₃ while facilitating the in situ growth of BiOI on its surface via shared Bi atoms. This approach led to the development of a 2D/2D Co-Bi₂O₂CO₃/BiOI (Co-BOC/BiOI) S-scheme heterojunction characterized by atomically close contact interfaces. Furthermore, the photo-electrochemical characterization results indicate that the light adsorption capacity, carrier separation and transport efficiency of the optimized Co-BOC/BiOI-3 are greatly improved. This system demonstrates almost 100% removal rate for three typical EDCs within 60 min. The degradation kinetic constants show an improvement by an order of magnitude compared to single BiOI and Bi₂O₂CO₃. More importantly, O₂•﹣, which is produced from O₂ reduction on high negative conduction band, can be subsequently oxidized into 1O2 by photogenerated hole. Electron paramagnetic resonance and quenching experiments indicate that the organics degradation process is dominated by 1O2. This work offers new insights into the construction of high-quality S-scheme heterojunction interfaces for modulation of reactive oxygen species.01A - Beitrag in wissenschaftlicher Zeitschrift