@article{MichalakNacerddinePietersenetal.2013, author = {Michalak, Ewa Malgorzata and Nacerddine, Karim and Pietersen, Alexandra and Beuger, Vincent and Pawlitzky, Inka and Cornelissen-Steijger, Paulien and Wientjens, Ellen and Tanger, Ellen and Seibler, Jost and Lohuizen, Maarten van and Jonkers, Jos}, title = {Polycomb group gene Ezh2 regulates mammary gland morphogenesis and maintains the luminal progenitor pool}, series = {Stem Cells}, volume = {Vol 31}, journal = {Stem Cells}, number = {9}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1549-4918}, doi = {10.1002/stem.1437}, pages = {1910 -- 1920}, year = {2013}, language = {en} } @article{GebeshuberKornauthDongetal.2013, author = {Gebeshuber, Christoph A. and Kornauth, Christoph and Dong, Lihua and Sierig, Ralph and Seibler, Jost and Reiss, Martina and Tauber, Stefanie and Bilban, Martin and Wang, Shijun and Kain, Renate and B{\"o}hmig, Georg A. and Moeller, Marcus J. and Gr{\"o}ne, Hermann-Josef and Englert, Christoph and Martinez, Javier and Kerjaschki, Dontscho}, title = {Focal segmental glomerulosclerosis is induced by microRNA-193a and its downregulation of WT1}, series = {Nature Medicine}, volume = {19}, journal = {Nature Medicine}, number = {4}, issn = {1078-8956}, doi = {10.1038/nm.3142}, pages = {481 -- 487}, year = {2013}, language = {en} } @article{KornfeldBaitzelKoenneretal.2013, author = {Kornfeld, Jan-Wilhelm and Baitzel, Catherina and K{\"o}nner, A. Christine and Nicholls, Hayley T. and Vogt, Merly C. and Herrmanns, Karolin and Scheja, Ludger and Haumaitre, C{\´e}cile and Wolf, Anna M. and Knippschild, Uwe and Seibler, Jost and Cereghini, Silvia and Heeren, Joerg and Stoffel, Markus and Br{\"u}ning, Jens C.}, title = {Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b}, series = {Nature}, volume = {494}, journal = {Nature}, number = {7435}, publisher = {Springer Nature}, address = {Cham}, isbn = {0028-0836}, doi = {10.1038/nature11793}, pages = {111 -- 115}, year = {2013}, language = {en} } @article{BreuerRaueStrobeletal.2016, author = {Breuer, Lars and Raue, Markus and Strobel, M. and Mang, Thomas and Sch{\"o}ning, Michael Josef and Thoelen, R. and Wagner, Torsten}, title = {Hydrogels with incorporated graphene oxide as light-addressable actuator materials for cell culture environments in lab-on-chip systems}, series = {Physica status solidi (a)}, volume = {213}, journal = {Physica status solidi (a)}, number = {6}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1862-6300}, doi = {10.1002/pssa.201533056}, pages = {1520 -- 1525}, year = {2016}, abstract = {Abstractauthoren Graphene oxide (GO) nanoparticles were incorporated in temperature-sensitive Poly(N-isopropylacrylamide) (PNIPAAm) hydrogels. The nanoparticles increase the light absorption and convert light energy into heat efficiently. Thus, the hydrogels with GO can be stimulated spatially resolved by illumination as it was demonstrated by IR thermography. The temporal progression of the temperature maximum was detected for different concentrations of GO within the polymer network. Furthermore, the compatibility of PNIPAAm hydrogels with GO and cell cultures was investigated. For this purpose, culture medium was incubated with hydrogels containing GO and the viability and morphology of chinese hamster ovary (CHO) cells was examined after several days of culturing in presence of this medium.}, language = {en} } @article{HeinzeMangPopescuetal.2016, author = {Heinze, D. and Mang, Thomas and Popescu, C. and Weichold, O.}, title = {Effect of side chain length and degree of polymerization on the decomposition and crystallization behaviour of chlorinated poly(vinyl ester) oligomers}, series = {Thermochimica Acta}, volume = {637}, journal = {Thermochimica Acta}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0040-6031 (electronic)}, doi = {10.1016/j.tca.2016.05.015}, pages = {143 -- 153}, year = {2016}, abstract = {Four members of a homologous series of chlorinated poly(vinyl ester) oligomers CCl₃-(CH₂CH (OCO(CH₂)ₘCH₃))ₙ-Cl with degrees of polymerization of 10 and 20 were prepared by telomerisation using carbon tetrachloride. The number of side chain carbon atoms ranges from 2 (poly(vinyl acetate) to 18 (poly(vinyl stearate)). The effect of the n-alkyl side chain length and of the degree of polymerization on the thermal stability and crystallization behaviour of the synthesized compounds was investigated. All oligomers degrade in two major steps by first losing HCl and side chains with subsequent breakdown of the backbone. The members with short side chains, up to poly(vinyl octanoate), are amorphous and show internal plasticization, whereas those with high number of side chain carbon atoms are semi-crystalline due to side-chain crystallization. A better packing for poly(vinyl stearate) is also noticeable. The glass transition and melting temperatures as well as the onset temperature of decomposition are influenced to a larger extent by the side chain length than by the degree of polymerization. Thermal stability is improved if both the size and number of side chains increase, but only a long side chain causes a significant increase of the resistance to degradation. This results in a stabilization of PVAc so that oligomers from poly(vinyl octanoate) on are stable under atmospheric conditions. Thus, the way to design stable, chlorinated PVEs oligomers is to use a long n-alkyl side chain.}, language = {en} } @article{PinkenburgSchiffelsSelmer2016, author = {Pinkenburg, Olaf and Schiffels, Johannes and Selmer, Thorsten}, title = {Das CoLibry-Konzept - ein Werkzeugkasten f{\"u}r die Synthetische Biologie: Bioproduktion}, series = {BIOspektrum}, volume = {22}, journal = {BIOspektrum}, number = {6}, publisher = {Springer}, address = {Berlin}, doi = {10.1007/s12268-016-0734-8}, pages = {593 -- 595}, year = {2016}, abstract = {Regardless of size or destination, synthetic biology starts with com-parably small information units, which need to be combined and properly arranged in order to achieve a certain goal. This may be the de novo synthesis of individual genes from oligonucleotides, a shuffling of protein domains in order to create novel biocatalysts, the assembly of multiple enzyme encoding genes in metabolic pathway design, or strain development at the production stage. The CoLibry concept has been designed in order to close the gap between recombinant production of individual genes and genome editing.}, language = {de} } @article{MolinnusSorichBartzetal.2016, author = {Molinnus, Denise and Sorich, Maren and Bartz, Alexander and Siegert, Petra and Willenberg, Holger S. and Lisdat, Fred and Poghossian, Arshak and Keusgen, Michael and Sch{\"o}ning, Michael Josef}, title = {Towards an adrenaline biosensor based on substrate recycling amplification in combination with an enzyme logic gate}, series = {Sensors and Actuators B: Chemical}, volume = {237}, journal = {Sensors and Actuators B: Chemical}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0925-4005}, doi = {10.1016/j.snb.2016.06.064}, pages = {190 -- 195}, year = {2016}, abstract = {An amperometric biosensor using a substrate recycling principle was realized for the detection of low adrenaline concentrations (1 nM) by measurements in phosphate buffer and Ringer's solution at pH 6.5 and pH 7.4, respectively. In proof-of-concept experiments, a Boolean logic-gate principle has been applied to develop a digital adrenaline biosensor based on an enzyme AND logic gate. The obtained results demonstrate that the developed digital biosensor is capable for a rapid qualitative determination of the presence/absence of adrenaline in a YES/NO statement. Such digital biosensor could be used in clinical diagnostics for the control of a correct insertion of a catheter in the adrenal veins during adrenal venous-sampling procedure.}, language = {en} } @article{GhoschBaierSchuetzetal.2016, author = {Ghosch, S. and Baier, M. and Sch{\"u}tz, J. and Schneider, Felix and Scherer, Ulrich W.}, title = {Analysis of electronic autoradiographs by mathematical post-processing}, series = {Radiation Effects and Defects in Solids: Incorporating plasma science and plasma technology}, volume = {171}, journal = {Radiation Effects and Defects in Solids: Incorporating plasma science and plasma technology}, number = {1-2}, publisher = {Taylor \& Francis}, address = {London}, issn = {1029-4953}, doi = {10.1080/10420150.2016.1155587}, pages = {161 -- 172}, year = {2016}, abstract = {Autoradiography is a well-established method of nuclear imaging. When different radionuclides are present simultaneously, additional processing is needed to distinguish distributions of radionuclides. In this work, a method is presented where aluminium absorbers of different thickness are used to produce images with different cut-off energies. By subtracting images pixel-by-pixel one can generate images representing certain ranges of β-particle energies. The method is applied to the measurement of irradiated reactor graphite samples containing several radionuclides to determine the spatial distribution of these radionuclides within pre-defined energy windows. The process was repeated under fixed parameters after thermal treatment of the samples. The greyscale images of the distribution after treatment were subtracted from the corresponding pre-treatment images. Significant changes in the intensity and distribution of radionuclides could be observed in some samples. Due to the thermal treatment parameters the most significant differences were observed in the ³H and ¹⁴C inventory and distribution.}, language = {en} } @article{TeumerCapitainRossJonesetal.2018, author = {Teumer, T. and Capitain, C. and Ross-Jones, J. and Tippk{\"o}tter, Nils and R{\"a}dle, M. and Methner, F.-J.}, title = {In-line Haze Monitoring Using a Spectrally Resolved Back Scattering Sensor}, series = {BrewingScience}, volume = {71}, journal = {BrewingScience}, number = {5/6}, publisher = {Fachverlag Hans Carl}, address = {N{\"u}rnberg}, issn = {1613-2041}, pages = {49 -- 55}, year = {2018}, abstract = {In the present work an optical sensor in combination with a spectrally resolved detection device for in-line particle-size-monitoring for quality control in beer production is presented. The principle relies on the size and wavelength dependent backscatter of growing particles in fluids. Measured interference structures of backscattered light are compared with calculated theoretical values, based on Mie-Theory, and fitted with a linear least square method to obtain particle size distributions. For this purpose, a broadband light source in combination with a process-CCD-spectrometer (charge ? coupled device spectrometer) and process adapted fiber optics are used. The goal is the development of an easy and flexible measurement device for in-line-monitoring of particle size. The presented device can be directly installed in product fill tubes or vessels, follows CIP- (cleaning in place) and removes the need of sample taking. A proof of concept and preliminary results, measuring protein precipitation, are presented.}, language = {en} } @article{AboulnagaZouSelmeretal.2018, author = {Aboulnaga, E. A. and Zou, H. and Selmer, Thorsten and Xian, M.}, title = {Development of a plasmid-based, tunable, tolC-derived expression system for application in Cupriavidus necator H16}, series = {Journal of Biotechnology}, volume = {274}, journal = {Journal of Biotechnology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-1656}, doi = {10.1016/j.jbiotec.2018.03.007}, pages = {15 -- 27}, year = {2018}, abstract = {Cupriavidus necator H16 gains increasing attention in microbial research and biotechnological application due to its diverse metabolic features. Here we present a tightly controlled gene expression system for C. necator including the pBBR1-vector that contains hybrid promoters originating from C. necator native tolC-promoter in combination with a synthetic tetO-operator. The expression of the reporter gene from these plasmids relies on the addition of the exogenous inducer doxycycline (dc). The novel expression system offers a combination of advantageous features as; (i) high and dose-dependent recombinant protein production, (ii) tight control with a high dynamic range (On/Off ratio), which makes it applicable for harmful pathways or for toxic protein production, (iii) comparable cheap inducer (doxycycline, dc), (iv) effective at low inducer concentration, that makes it useful for large scale application, (v) rapid, diffusion controlled induction, and (vi) the inducer does not interfere within the cell metabolism. As applications of the expression system in C. necator H16, the growth ability on glycerol was enhanced by constitutively expressing the E. coli glpk gene-encoding for glycerol kinase. Likewise, we used the system to overcome the expression toxicity of mevalonate pathway in C. necator H16. With this system, the mevalonate-genes were successfully introduced in the host and the recombinant strains could produce about 200 mg/l mevalonate.}, language = {en} } @article{DruckenmuellerGuentherElbers2018, author = {Druckenm{\"u}ller, Katharina and G{\"u}nther, Klaus and Elbers, Gereon}, title = {Near-infrared spectroscopy (NIRS) as a tool to monitor exhaust air from poultry operations}, series = {Science of the Total Environment}, volume = {630}, journal = {Science of the Total Environment}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0048-9697}, doi = {10.1016/j.scitotenv.2018.02.072}, pages = {536 -- 543}, year = {2018}, abstract = {Intensive poultry operation systems emit a considerable volume of inorganic and organic matter in the surrounding environment. Monitoring cleaning properties of exhaust air cleaning systems and to detect small but significant changes in emission characteristics during a fattening cycle is important for both emission and fattening process control. In the present study, we evaluated the potential of near-infrared spectroscopy (NIRS) combined with chemometric techniques as a monitoring tool of exhaust air from poultry operation systems. To generate a high-quality data set for evaluation, the exhaust air of two poultry houses was sampled by applying state-of-the-art filter sampling protocols. The two stables were identical except for one crucial difference, the presence or absence of an exhaust air cleaning system. In total, twenty-one exhaust air samples were collected at the two sites to monitor spectral differences caused by the cleaning device, and to follow changes in exhaust air characteristics during a fattening period. The total dust load was analyzed by gravimetric determination and included as a response variable in multivariate data analysis. The filter samples were directly measured with NIR spectroscopy. Principal component analysis (PCA), linear discriminant analysis (LDA), and factor analysis (FA) were effective in classifying the NIR exhaust air spectra according to fattening day and origin. The results indicate that the dust load and the composition of exhaust air (inorganic or organic matter) substantially influence the NIR spectral patterns. In conclusion, NIR spectroscopy as a tool is a promising and very rapid way to detect differences between exhaust air samples based on still not clearly defined circumstances triggered during a fattening period and the availability of an exhaust air cleaning system.}, language = {en} } @article{MolinnusMuschallikGonzalezetal.2018, author = {Molinnus, Denise and Muschallik, Lukas and Gonzalez, Laura Osorio and Bongaerts, Johannes and Wagner, Torsten and Selmer, Thorsten and Siegert, Petra and Keusgen, Michael and Sch{\"o}ning, Michael Josef}, title = {Development and characterization of a field-effect biosensor for the detection of acetoin}, series = {Biosensors and Bioelectronics}, volume = {115}, journal = {Biosensors and Bioelectronics}, publisher = {Elsevier}, address = {Amsterdam}, doi = {10.1016/j.bios.2018.05.023}, pages = {1 -- 6}, year = {2018}, abstract = {A capacitive electrolyte-insulator-semiconductor (EIS) field-effect biosensor for acetoin detection has been presented for the first time. The EIS sensor consists of a layer structure of Al/p-Si/SiO₂/Ta₂O₅/enzyme acetoin reductase. The enzyme, also referred to as butane-2,3-diol dehydrogenase from B. clausii DSM 8716T, has been recently characterized. The enzyme catalyzes the (R)-specific reduction of racemic acetoin to (R,R)- and meso-butane-2,3-diol, respectively. Two different enzyme immobilization strategies (cross-linking by using glutaraldehyde and adsorption) have been studied. Typical biosensor parameters such as optimal pH working range, sensitivity, hysteresis, linear concentration range and long-term stability have been examined by means of constant-capacitance (ConCap) mode measurements. Furthermore, preliminary experiments have been successfully carried out for the detection of acetoin in diluted white wine samples.}, language = {en} } @article{PilasYaziciSelmeretal.2018, author = {Pilas, Johanna and Yazici, Y. and Selmer, Thorsten and Keusgen, M. and Sch{\"o}ning, Michael Josef}, title = {Application of a portable multi-analyte biosensor for organic acid determination in silage}, series = {Sensors}, volume = {18}, journal = {Sensors}, number = {5}, publisher = {MDPI}, address = {Basel}, issn = {1424-8220}, doi = {10.3390/s18051470}, pages = {12 Seiten}, year = {2018}, abstract = {Multi-analyte biosensors may offer the opportunity to perform cost-effective and rapid analysis with reduced sample volume, as compared to electrochemical biosensing of each analyte individually. This work describes the development of an enzyme-based biosensor system for multi-parametric determination of four different organic acids. The biosensor array comprises five working electrodes for simultaneous sensing of ethanol, formate, d-lactate, and l-lactate, and an integrated counter electrode. Storage stability of the biosensor was evaluated under different conditions (stored at +4 °C in buffer solution and dry at -21 °C, +4 °C, and room temperature) over a period of 140 days. After repeated and regular application, the individual sensing electrodes exhibited the best stability when stored at -21 °C. Furthermore, measurements in silage samples (maize and sugarcane silage) were conducted with the portable biosensor system. Comparison with a conventional photometric technique demonstrated successful employment for rapid monitoring of complex media.}, language = {en} } @article{WilsonDickieSchreiteretal.2018, author = {Wilson, C. E. and Dickie, A. P. and Schreiter, K. and Wehr, R. and Wilson, E. M. and Bial, J. and Scheer, Nico and Wilson, I. D. and Riley, R. J.}, title = {The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice}, series = {Archives of Toxicology}, volume = {92}, journal = {Archives of Toxicology}, number = {6}, publisher = {Springer}, issn = {1432-0738}, doi = {10.1007/s00204-018-2212-1}, pages = {1953 -- 1967}, year = {2018}, abstract = {The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUCinf of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.}, language = {en} } @article{WilsonWilsonScheeretal.2017, author = {Wilson, Ian D. and Wilson, Claire E. and Scheer, Nico and Dickie, A.P. and Schreiter, K. and Wilson, E. M. and Riley, R. J. and Wehr, R. and Bial, J.}, title = {The Pharmacokinetics and Metabolism of Lumiracoxib in Chimeric Humanized and Murinized FRG Mice}, series = {Biochemical pharmacology}, volume = {Volume 135}, journal = {Biochemical pharmacology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1873-2968}, doi = {10.1016/j.bcp.2017.03.015}, pages = {139 -- 150}, year = {2017}, language = {en} } @article{ZhangHeimbachScheeretal.2016, author = {Zhang, Jin and Heimbach, Tycho and Scheer, Nico and Barve, Avantika and Li, Wenkui and Lin, Wen and He, Handan}, title = {Clinical Exposure Boost Predictions by Integrating Cytochrome P450 3A4-Humanized Mouse Studies With PBPK Modeling}, series = {Journal of Pharmaceutical Sciences}, volume = {Volume 105}, journal = {Journal of Pharmaceutical Sciences}, number = {Issue 4}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0022-3549}, doi = {doi.org/10.1016/j.xphs.2016.01.021}, pages = {1398 -- 1404}, year = {2016}, abstract = {NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 (ƒₘCYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate ƒₘCYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human ƒₘCYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir.}, language = {en} } @article{ScheerMclaughlinRodeetal.2014, author = {Scheer, Nico and Mclaughlin, Lesley A. and Rode, Anja and MacLeod, Alastair Kenneth and Henderson, Colin J. and Wolf, Roland C.}, title = {Deletion of thirty murine cytochrome P450 genes results in viable mice with compromised drug metabolism}, series = {Drug Metabolism and Disposition}, volume = {42}, journal = {Drug Metabolism and Disposition}, number = {6}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-009X}, doi = {10.1124/dmd.114.057885}, pages = {1022 -- 1030}, year = {2014}, abstract = {In humans, 75\% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80\% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15\%) and larger livers (20\%). Changes in hepatic morphology and a decreased blood glucose (30\%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.}, language = {en} } @article{ScheerBalimaneHaywardetal.2012, author = {Scheer, Nico and Balimane, Praveen and Hayward, Michael D. and Buechel, Sandra and Kauselmann, Gunther and Wolf, C. Roland}, title = {Generation and Characterization of a Novel Multidrug Resistance Protein 2 Humanized Mouse Line}, series = {Drug Metabolism and Disposition}, volume = {40}, journal = {Drug Metabolism and Disposition}, number = {11}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/dmd.112.047605}, pages = {2212 -- 2218}, year = {2012}, abstract = {The multidrug resistance protein (MRP) 2 is predominantly expressed in liver, intestine, and kidney, where it plays an important role in the excretion of a range of drugs and their metabolites or endogenous compounds into bile, feces, and urine. Mrp knockout [Mrp2(-/-)] mice have been used recently to study the role of MRP2 in drug disposition. Here, we describe the first generation and initial characterization of a mouse line humanized for MRP2 (huMRP2), which is nulled for the mouse Mrp2 gene and expresses the human transporter in the organs and cell types where MRP2 is normally expressed. Analysis of the mRNA expression for selected cytochrome P450 and transporter genes revealed no major changes in huMRP2 mice compared with wild-type controls. We show that human MRP2 is able to compensate functionally for the loss of the mouse transporter as demonstrated by comparable bilirubin levels in the humanized mice and wild-type controls, in contrast to the hyperbilirubinemia phenotype that is observed in MRP2(-/-) mice. The huMRP2 mouse provides a model to study the role of the human transporter in drug disposition and in assessing the in vivo consequences of inhibiting this transporter by compounds interacting with human MRP2.}, language = {en} } @article{ScheerKapelyukhRodeetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and Rode, Anja and Buechel, Sandra and Wolf, C. Roland}, title = {Generation and characterization of novel cytochrome P450 Cyp2c gene cluster knockout and CYP2C9 humanized mouse lines}, series = {Molecular Pharmacology}, volume = {82}, journal = {Molecular Pharmacology}, number = {6}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.112.080036}, pages = {1022 -- 1029}, year = {2012}, abstract = {Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction.}, language = {en} } @article{KapelyukhHendersonScheeretal.2019, author = {Kapelyukh, Yury and Henderson, Colin James and Scheer, Nico and Rode, Anja and Wolf, Charles Roland}, title = {Defining the contribution of CYP1A1 and CYP1A2 to drug metabolism using humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 KO mice}, series = {Drug Metabolism and Disposition}, journal = {Drug Metabolism and Disposition}, number = {Early view}, doi = {10.1124/dmd.119.087718}, pages = {43 Seiten}, year = {2019}, language = {en} } @article{LempiaeinenCouttetBolognanietal.2012, author = {Lempi{\"a}inen, Harri and Couttet, Philippe and Bolognani, Federico and M{\"u}ller, Arne and Dubost, Val{\´e}rie and Luisier, Rapha{\"e}lle and Rio-Espinola, Alberto del and Vitry, Veronique and Unterberger, Elif B. and Thomson, John P. and Treindl, Fridolin and Metzger, Ute and Wrzodek, Clemens and Hahne, Florian and Zollinger, Tulipan and Brasa, Sarah and Kalteis, Magdalena and Marcellin, Magali and Giudicelli, Fanny and Braeuning, Albert and Morawiec, Laurent and Zamurovic, Natasa and L{\"a}ngle, Ulrich and Scheer, Nico and Sch{\"u}beler, Dirk and Goodman, Jay and Chibout, Salah-Dine and Marlowe, Jennifer and Theil, Dietlinde and Heard, David J. and Grenet, Olivier and Zell, Andreas and Templin, Markus F. and Meehan, Richard R. and Wolf, Roland C. and Elcombe, Clifford R. and Schwarz, Michael and Moulin, Pierre and Terranova, R{\´e}mi and Moggs, Jonathan G.}, title = {Identification of Dlk1-Dio3 imprinted gene cluster non-coding RNAs as novel candidate biomarkers for liver tumor promotion}, series = {Toxicological Sciences}, volume = {131}, journal = {Toxicological Sciences}, number = {2}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1094-2025}, doi = {10.1093/toxsci/kfs303}, pages = {375 -- 386}, year = {2012}, abstract = {The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.}, language = {en} } @article{RossPlummerRodeetal.2010, author = {Ross, Jillian and Plummer, Simon M. and Rode, Anja and Scheer, Nico and Bower, Conrad C. and Vogel, Ortwin and Henderson, Colin J. and Wolf, C. Roland and Elcombe, Clifford R.}, title = {Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo}, series = {Toxicological Sciences}, volume = {116}, journal = {Toxicological Sciences}, number = {2}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1096-0929}, doi = {10.1093/toxsci/kfq118}, pages = {452 -- 466}, year = {2010}, abstract = {Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear. The xenoreceptors, constitutive androstane receptors (CARs), and pregnane X receptor (PXR) play key roles in these processes. Novel "humanized" and knockout models for both receptors were developed to investigate potential species differences in hepatomegaly. The effects of PB (80 mg/kg/4 days) and chlordane (10 mg/kg/4 days) were investigated in double humanized PXR and CAR (huPXR/huCAR), double knockout PXR and CAR (PXRKO/CARKO), and wild-type (WT) C57BL/6J mice. In WT mice, both compounds caused increased liver weight, hepatocellular hypertrophy, and cell proliferation. Both compounds caused alterations to a number of cell cycle genes consistent with induction of cell proliferation in WT mice. However, these gene expression changes did not occur in PXRKO/CARKO or huPXR/huCAR mice. Liver hypertrophy without hyperplasia was demonstrated in the huPXR/huCAR animals in response to both compounds. Induction of the CAR and PXR target genes, Cyp2b10 and Cyp3a11, was observed in both WT and huPXR/huCAR mouse lines following treatment with PB or chlordane. In the PXRKO/CARKO mice, neither liver growth nor induction of Cyp2b10 and Cyp3a11 was seen following PB or chlordane treatment, indicating that these effects are CAR/PXR dependent. These data suggest that the human receptors are able to support the chemically induced hypertrophic responses but not the hyperplastic (cell proliferation) responses. At this time, we cannot be certain that hCAR and hPXR when expressed in the mouse can function exactly as the genes do when they are expressed in human cells. However, all parameters investigated to date suggest that much of their functionality is maintained.}, language = {en} } @article{ScheerRossKapelyukhetal.2010, author = {Scheer, Nico and Ross, Jillian and Kapelyukh, Yury and Rode, Anja and Wolf, C. Roland}, title = {In vivo responses of the human and murine pregnane X receptor to dexamethasone in mice}, series = {Drug Metabolism and Disposition}, volume = {38}, journal = {Drug Metabolism and Disposition}, number = {7}, publisher = {ASPET}, address = {Bethesda}, issn = {1521-009X}, doi = {10.1124/dmd.109.031872}, pages = {1046 -- 1053}, year = {2010}, abstract = {Dexamethasone (DEX) is a potent and widely used anti-inflammatory and immunosuppressant glucocorticoid. It can bind and activate the pregnane X receptor (PXR), which plays a critical role as xenobiotic sensor in mammals to induce the expression of many enzymes, including cytochromes P450 in the CYP3A family. This induction results in its own metabolism. We have used a series of transgenic mouse lines, including a novel, improved humanized PXR line, to compare the induction profile of PXR-regulated drug-metabolizing enzymes after DEX administration, as well as looking at hepatic responses to rifampicin (RIF). The new humanized PXR model has uncovered further intriguing differences between the human and mouse receptors in that RIF only induced Cyp2b10 in the new humanized model. DEX was found to be a much more potent inducer of Cyp3a proteins in wild-type mice than in mice humanized for PXR. To assess whether PXR is involved in the detoxification of DEX in the liver, we analyzed the consequences of high doses of the glucocorticoid on hepatotoxicity on different PXR genetic backgrounds. We also studied these effects in an additional mouse model in which functional mouse Cyp3a genes have been deleted. These strains exhibited different sensitivities to DEX, indicating a protective role of the PXR and CYP3A proteins against the hepatotoxicity of this compound.}, language = {en} } @article{ScheerRossRodeetal.2008, author = {Scheer, Nico and Ross, Jillian and Rode, Anja and Zevnik, Branko and Niehaves, Sandra and Faust, Nicole and Wolf, C. Roland}, title = {A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response}, series = {Journal of Clinical Investigation}, volume = {118}, journal = {Journal of Clinical Investigation}, number = {9}, issn = {1558-8238}, doi = {https://doi.org/10.1172/JCI35483}, pages = {3228 -- 3239}, year = {2008}, language = {en} } @article{ScheerKapelyukhMcEwanetal.2012, author = {Scheer, Nico and Kapelyukh, Yury and McEwan, Jillian and Beuger, Vincent and Stanley, Lesley A. and Rode, Anja and Wolf, C. Roland}, title = {Modeling Human Cytochrome P450 2D6 Metabolism and Drug-drug Interaction by a Novel Panel of Knockout and Humanized Mouse Lines}, series = {Molecular Pharmacology}, volume = {81}, journal = {Molecular Pharmacology}, number = {1}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.111.075192}, pages = {63 -- 72}, year = {2012}, abstract = {The highly polymorphic human cytochrome P450 2D6 enzyme is involved in the metabolism of up to 25\% of all marketed drugs and accounts for significant individual differences in response to CYP2D6 substrates. Because of the differences in the multiplicity and substrate specificity of CYP2D family members among species, it is difficult to predict pathways of human CYP2D6-dependent drug metabolism on the basis of animal studies. To create animal models that reflect the human situation more closely and that allow an in vivo assessment of the consequences of differential CYP2D6 drug metabolism, we have developed a novel straightforward approach to delete the entire murine Cyp2d gene cluster and replace it with allelic variants of human CYP2D6. By using this approach, we have generated mouse lines expressing the two frequent human protein isoforms CYP2D6.1 and CYP2D6.2 and an as yet undescribed variant of this enzyme, as well as a Cyp2d cluster knockout mouse. We demonstrate that the various transgenic mouse lines cover a wide spectrum of different human CYP2D6 metabolizer phenotypes. The novel humanization strategy described here provides a robust approach for the expression of different CYP2D6 allelic variants in transgenic mice and thus can help to evaluate potential CYP2D6-dependent interindividual differences in drug response in the context of personalized medicine.}, language = {en} } @article{ReugelsBoggettiScheeretal.2006, author = {Reugels, Alexander M. and Boggetti, Barbara and Scheer, Nico and Campos-Ortega, Jos{\´e} A.}, title = {Asymmetric localization of Numb:EGFP in dividing neuroepithelial cells during neurulation in Danio rerio}, series = {Developmental Dynamics}, volume = {235}, journal = {Developmental Dynamics}, number = {4}, issn = {1097-0177}, doi = {10.1002/dvdy.20699}, pages = {934 -- 948}, year = {2006}, language = {en} } @article{HansScheerRiedletal.2004, author = {Hans, Stefan and Scheer, Nico and Riedl, Iris and Weiz{\"a}cker, Elisabeth von and Blader, Patrick and Campos-Ortega, Jos{\´e} A.}, title = {her3, a zebrafish member of the hairy-E(spl) family, is repressed by Notch signalling}, series = {Development}, volume = {131}, journal = {Development}, number = {12}, issn = {1477-9129}, doi = {10.1242/dev.01167}, pages = {2957 -- 2969}, year = {2004}, language = {en} } @article{ScheerRiedlWarrenetal.2002, author = {Scheer, Nico and Riedl, Iris and Warren, J.T. and Kuwada, John Y. and Campos-Ortega, Jos{\´e} A.}, title = {A quantitative analysis of the kinetics of Gal4 activator and effector gene expression in the zebrafish}, series = {Mechanism of Development}, volume = {112}, journal = {Mechanism of Development}, number = {1-2}, issn = {0925-4773}, doi = {10.1016/S0925-4773(01)00621-9}, pages = {9 -- 14}, year = {2002}, language = {en} } @article{LawsonScheerPhametal.2001, author = {Lawson, Nathan D. and Scheer, Nico and Pham, Van N. and Kim, Ceol-Hee and Chitnis, Ajay B. and Campos-Ortega, Jos{\´e} A. and Weinstein, Brant M.}, title = {Notch signaling is required for arterial-venous differentiation during embryonic vascular development}, series = {Development}, volume = {128}, journal = {Development}, number = {19}, issn = {1477-9129}, pages = {3675 -- 3683}, year = {2001}, language = {en} } @article{ScheerGrothHansetal.2001, author = {Scheer, Nico and Groth, Anne and Hans, Stefan and Campos-Ortega, Jos{\´e} A.}, title = {An instructive function for Notch in promoting gliogenesis in the zebrafish retina}, series = {Development}, volume = {128}, journal = {Development}, number = {7}, issn = {0950-1991}, pages = {1099 -- 1107}, year = {2001}, language = {en} } @article{DallasSalphatiGomezZepedaetal.2016, author = {Dallas, Shannon and Salphati, Laurent and Gomez-Zepeda, David and Wanek, Thomas and Chen, Liangfu and Chu, Xiaoyan and Kunta, Jeevan and Mezler, Mario and Menet, Marie-Claude and Chasseigneaux, Stephanie and Decl{\`e}ves, Xavier and Langer, Oliver and Pierre, Esaie and DiLoreto, Karen and Hoft, Carolin and Laplanche, Loic and Pang, Jodie and Pereira, Tony and Andonian, Clara and Simic, Damir and Rode, Anja and Yabut, Jocelyn and Zhang, Xiaolin and Scheer, Nico}, title = {Generation and Characterization of a Breast Cancer Resistance Protein Humanized Mouse Model}, series = {Molecular Pharmacology}, volume = {89}, journal = {Molecular Pharmacology}, number = {5}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-0111}, doi = {10.1124/mol.115.102079}, pages = {492 -- 504}, year = {2016}, abstract = {Breast cancer resistance protein (BCRP) is expressed in various tissues, such as the gut, liver, kidney and blood brain barrier (BBB), where it mediates the unidirectional transport of substrates to the apical/luminal side of polarized cells. Thereby BCRP acts as an efflux pump, mediating the elimination or restricting the entry of endogenous compounds or xenobiotics into tissues and it plays important roles in drug disposition, efficacy and safety. Bcrp knockout mice (Bcrp-/-) have been used widely to study the role of this transporter in limiting intestinal absorption and brain penetration of substrate compounds. Here we describe the first generation and characterization of a mouse line humanized for BCRP (hBCRP), in which the mouse coding sequence from the start to stop codon was replaced with the corresponding human genomic region, such that the human transporter is expressed under control of the murine Bcrp promoter. We demonstrate robust human and loss of mouse BCRP/Bcrp mRNA and protein expression in the hBCRP mice and the absence of major compensatory changes in the expression of other genes involved in drug metabolism and disposition. Pharmacokinetic and brain distribution studies with several BCRP probe substrates confirmed the functional activity of the human transporter in these mice. Furthermore, we provide practical examples for the use of hBCRP mice to study drug-drug interactions (DDIs). The hBCRP mouse is a promising model to study the in vivo role of human BCRP in limiting absorption and BBB penetration of substrate compounds and to investigate clinically relevant DDIs involving BCRP.}, language = {en} } @article{ScheerKapelyukhRodeetal.2015, author = {Scheer, Nico and Kapelyukh, Yury and Rode, Anja and Oswald, Stefan and Busch, Diana and Mclaughlin, Lesley A. and Lin, De and Henderson, Colin J. and Wolf, C. Roland}, title = {Defining Human Pathways of Drug Metabolism In Vivo through the Development of a Multiple Humanized Mouse Model}, series = {Drug Metabolism and Disposition}, volume = {43}, journal = {Drug Metabolism and Disposition}, number = {11}, publisher = {ASPET}, address = {Bethesda}, issn = {1521-009x}, doi = {10.1124/dmd.115.065656}, pages = {1679 -- 1690}, year = {2015}, language = {en} } @article{HoughNalwalkDingetal.2015, author = {Hough, Lindsay B. and Nalwalk, Julia W. and Ding, Xinxin and Scheer, Nico}, title = {Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms}, series = {Drug Metabolism and Disposition}, volume = {43}, journal = {Drug Metabolism and Disposition}, number = {9}, issn = {1521-009x}, doi = {10.1124/dmd.115.065490}, pages = {1326 -- 1330}, year = {2015}, language = {en} } @article{HendersonMclaughlinScheeretal.2015, author = {Henderson, Colin J. and Mclaughlin, Lesley A. and Scheer, Nico and Stanley, Lesley A. and Wolf, C. Roland}, title = {Cytochrome b5 Is a Major Determinant of Human Cytochrome P450 CYP2D6 and CYP3A4 Activity In Vivo s}, series = {Molecular Pharmacology}, volume = {87}, journal = {Molecular Pharmacology}, number = {4}, publisher = {ASPET}, address = {Bethesda}, issn = {1521-0111}, doi = {10.1124/mol.114.097394}, pages = {733 -- 739}, year = {2015}, language = {en} } @article{LuisierLempiaeinenScherbichleretal.2014, author = {Luisier, Rapha{\"e}lle and Lempi{\"a}inen, Harri and Scherbichler, Nina and Braeuning, Albert and Geissler, Miriam and Dubost, Valerie and M{\"u}ller, Arne and Scheer, Nico and Chibout, Salah-Dine and Hara, Hisanori and Picard, Frank and Theil, Diethilde and Couttet, Philippe and Vitobello, Antonio and Grenet, Olivier and Grasl-Kraupp, Bettina and Ellinger-Ziegelbauer, Heidrung and Thomson, John P. and Meehan, Richard R. and Elcombe, Clifford R. and Henderson, Colin J. and Wolf, C. Roland and Schwarz, Michael and Moulin, Pierre and Terranova, Remi and Moggs, Jonathan G.}, title = {Phenobarbital Induces Cell Cycle Transcriptional Responses in Mouse Liver Humanized for Constitutive Androstane and Pregnane X Receptors}, series = {Toxicological Sciences}, volume = {139}, journal = {Toxicological Sciences}, number = {2}, publisher = {Oxford University Press}, address = {Oxford}, issn = {1094-2025}, doi = {https://doi.org/10.1093/toxsci/kfu038}, pages = {501 -- 511}, year = {2014}, abstract = {The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcinogenesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARᴷᴼ-PXRᴷᴼ), double humanized CAR and PXR (CARʰ-PXRʰ), and wild-type C57BL/6 mice. Wild-type and CARʰ-PXRʰ mouse livers exhibited temporally and quantitatively similar transcriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were observed with peak expression occurring between 1 and 7 days PB exposure. All these transcriptional responses were absent in CARᴷᴼ-PXRᴷᴼ mouse livers and largely reversible in wild-type and CARʰ-PXRʰ mouse livers following 91 days of PB exposure and a subsequent 4-week recovery period. Furthermore, PB-mediated upregulation of the noncoding RNA Meg3, which has recently been associated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARʰ-PXRʰ mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB.}, language = {en} } @article{SalpatiChuChenetal.2014, author = {Salpati, Laurent and Chu, Xiaoyan and Chen, Liangfu and Prasad, Bhagwat and Dallas, Shannon and Evers, Raymond and Mamaril-Fishman, Donna and Geier, Ethan G. and Kehler, Jonathan and Kunta, Jeevan and Mezler, Mario and Laplanche, Loic and Pang, Jodie and Soars, Matthew G. and Unadkat, Jashvant D. and van Waterschoot, Robert A.B. and Yabut, Jocelyn and Schinkel, Alfred H. and Scheer, Nico and Rode, Anja}, title = {Evaluation of organic anion transporting polypeptide 1B1 and 1B3 humanized mice as a translational model to study the pharmacokinetics of statins}, series = {Drug Metabolism and Disposition}, volume = {42}, journal = {Drug Metabolism and Disposition}, number = {8}, publisher = {ASPET}, address = {Bethesda, Md.}, issn = {1521-009X}, doi = {10.1124/dmd.114.057976}, pages = {1301 -- 1313}, year = {2014}, abstract = {Organic anion transporting polypeptide (Oatp) 1a/1b knockout and OATP1B1 and -1B3 humanized mouse models are promising tools for studying the roles of these transporters in drug disposition. Detailed characterization of these models will help to better understand their utility for predicting clinical outcomes. To advance this approach, we carried out a comprehensive analysis of these mouse lines by evaluating the compensatory changes in mRNA expression, quantifying the amounts of OATP1B1 and -1B3 protein by liquid chromatography-tandem mass spectrometry, and studying the active uptake in isolated hepatocytes and the pharmacokinetics of some prototypical substrates including statins. Major outcomes from these studies were 1) mostly moderate compensatory changes in only a few genes involved in drug metabolism and disposition, 2) a robust hepatic expression of OATP1B1 and -1B3 proteins in the respective humanized mouse models, and 3) functional activities of the human transporters in hepatocytes isolated from the humanized models with several substrates tested in vitro and with pravastatin in vivo. However, the expression of OATP1B1 and -1B3 in the humanized models did not significantly alter liver or plasma concentrations of rosuvastatin and pitavastatin compared with Oatp1a/1b knockout controls under the conditions used in our studies. Hence, although the humanized OATP1B1 and -1B3 mice showed in vitro and/or in vivo functional activity with some statins, further characterization of these models is required to define their potential use and limitations in the prediction of drug disposition and drug-drug interactions in humans.}, language = {en} } @article{ScheerHendersonKapelyukhetal.2019, author = {Scheer, Nico and Henderson, Colin James and Kapelyukh, Yury and Rode, Anja and Mclaren, Aileen W. and MacLeod, Alastair Kenneth and Lin, De and Wright, Jayne and Stanley, Lesley and Wolf, C. Roland}, title = {An extensively humanised mouse model to predict pathways of drug disposition, drug/drug interactions, and to facilitate the design of clinical trials}, series = {Drug Metabolism and Disposition}, journal = {Drug Metabolism and Disposition}, number = {Early view}, doi = {10.1124/dmd.119.086397}, pages = {69 Seiten}, year = {2019}, language = {en} } @article{HalbachScheer2000, author = {Halbach, Thorsten and Scheer, Nico}, title = {Transcriptional activation by the PHD finger is inhibited through an adjacent leucine zipper that binds 14-3-3 proteins}, series = {Nucleic Acids Research}, volume = {28}, journal = {Nucleic Acids Research}, number = {18}, issn = {1362-4962}, doi = {10.1093/nar/28.18.3542}, pages = {3542 -- 3550}, year = {2000}, language = {en} } @article{ScheerCamposOrtega1999, author = {Scheer, Nico and Campos-Ortega, Jos{\´e} A.}, title = {Use of the Gal4-UAS technique for targeted gene expression in the zebrafish}, series = {Mechanism of Development}, volume = {80}, journal = {Mechanism of Development}, number = {2}, issn = {0925-4773}, doi = {10.1016/S0925-4773(98)00209-3}, pages = {153 -- 158}, year = {1999}, language = {en} } @article{ScheerWilson2016, author = {Scheer, Nico and Wilson, Ian D.}, title = {A comparison between genetically humanized and chimeric liver humanized mouse models for studies in drug metabolism and toxicity}, series = {Drug Discovery Today}, volume = {21}, journal = {Drug Discovery Today}, number = {2}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1359-6446}, doi = {10.1016/j.drudis.2015.09.002}, pages = {250 -- 263}, year = {2016}, abstract = {Mice that have been genetically humanized for proteins involved in drug metabolism and toxicity and mice engrafted with human hepatocytes are emerging and promising in vivo models for an improved prediction of the pharmacokinetic, drug-drug interaction and safety characteristics of compounds in humans. The specific advantages and disadvantages of these models should be carefully considered when using them for studies in drug discovery and development. Here, an overview on the corresponding genetically humanized and chimeric liver humanized mouse models described to date is provided and illustrated with examples of their utility in drug metabolism and toxicity studies. We compare the strength and weaknesses of the two different approaches, give guidance for the selection of the appropriate model for various applications and discuss future trends and perspectives.}, language = {en} } @article{ScheerWolf2014, author = {Scheer, Nico and Wolf, C. Roland}, title = {Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications}, series = {Xenobiotica}, volume = {44}, journal = {Xenobiotica}, number = {2}, publisher = {Taylor \& Francis}, address = {Abingdon}, issn = {1366-5928}, doi = {10.3109/00498254.2013.815831}, pages = {96 -- 108}, year = {2014}, abstract = {1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug-drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described. 2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created. 3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug-drug interactions as well as in human metabolite testing and risk assessment. 4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.}, language = {en} } @article{ScheerWolf2013, author = {Scheer, Nico and Wolf, C. Roland}, title = {Xenobiotic receptor humanized mice and their utility}, series = {Drug Metabolism Reviews}, journal = {Drug Metabolism Reviews}, number = {1}, publisher = {Taylor \& Francis}, address = {London}, issn = {1097-9883}, doi = {10.3109/03602532.2012.738687}, pages = {110 -- 121}, year = {2013}, language = {en} } @article{HendersonScheerWolf2009, author = {Henderson, Colin J. and Scheer, Nico and Wolf, C. Roland}, title = {Advances in the generation of mouse models to elucidate the pathways of drug metabolism in rodents and man}, series = {Expert Review of Clinical Pharmacology}, volume = {2}, journal = {Expert Review of Clinical Pharmacology}, number = {2}, publisher = {Taylor \& Francis}, address = {London}, issn = {1751-2441}, doi = {10.1586/17512433.2.2.105}, pages = {105 -- 109}, year = {2009}, language = {en} } @article{StanleyHorsburghRossetal.2009, author = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland}, title = {Drug transporters: Gatekeepers controlling access of xenobiotics to the cellular interior}, series = {Drug Metabolism Reviews}, volume = {41}, journal = {Drug Metabolism Reviews}, number = {1}, publisher = {Taylor \& Francis}, address = {London}, issn = {1097-9883}, doi = {10.1080/03602530802605040}, pages = {27 -- 65}, year = {2009}, language = {en} } @article{StanleyHorsburghRossetal.2006, author = {Stanley, Lesley A. and Horsburgh, Brian C. and Ross, Jillian and Scheer, Nico and Wolf, C. Roland}, title = {Nuclear Receptors which play a pivotal role in drug disposition and chemical toxicity}, series = {Drug Metabolism Reviews}, volume = {38}, journal = {Drug Metabolism Reviews}, number = {3}, issn = {1097-9883}, doi = {10.1080/03602530600786232}, pages = {515 -- 597}, year = {2006}, language = {en} } @article{EngelGemuendeHoltmannetal.2019, author = {Engel, Mareike and Gem{\"u}nde, Andre and Holtmann, Dirk and M{\"u}ller-Renno, Christine and Ziegler, Christiane and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Clostridium acetobutylicum's connecting world: cell appendage formation in bioelectrochemical systems}, series = {ChemElectroChem}, volume = {7}, journal = {ChemElectroChem}, number = {2}, publisher = {Wiley}, address = {Weinheim}, issn = {2196-0216}, doi = {10.1002/celc.201901656}, pages = {414 -- 420}, year = {2019}, abstract = {Bacterial cell appendix formation supports cell-cell interaction, cell adhesion and cell movement. Additionally, in bioelectrochemical systems (BES), cell appendages have been shown to participate in extracellular electron transfer. In this work, the cell appendix formation of Clostridium acetobutylicum in biofilms of a BES are imaged and compared with conventional biofilms. Under all observed conditions, the cells possess filamentous appendages with a higher number and density in the BES. Differences in the amount of extracellular polymeric substance in the biofilms of the electrodes lead to the conclusion that the cathode can be used as electron donor and the anode as electron acceptor by C. acetobutylicum. When using conductive atomic force microscopy, a current response of about 15 nA is found for the cell appendages from the BES. This is the first report of conductivity for clostridial cell appendices and represents the basis for further studies on their role for biofilm formation and electron transfer.}, language = {en} } @article{ThielMufflerTippkoetteretal.2015, author = {Thiel, Alexander and Muffler, Kai and Tippk{\"o}tter, Nils and Suck, Kirstin and Sohling, Ulrich and Hruschka, Steffen M. and Ulber, Roland}, title = {A novel integrated downstream processing approach to recover sinapic acid, phytic acid and proteins from rapeseed meal}, series = {Journal of Chemical Technology and Biotechnology}, volume = {90}, journal = {Journal of Chemical Technology and Biotechnology}, number = {11}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/jctb.4664}, pages = {1999 -- 2006}, year = {2015}, abstract = {BACKGROUND Currently, several techniques exist for the downstream processing of protein, phytic acid and sinapic acid from rapeseed and rapeseed meal, but no technique has been developed to separate all of the components in one process. In this work, two new downstream processing strategies focusing on recovering sinapic acid, phytic acid and protein from rapeseed meal were established. RESULTS The sinapic acid content was enhanced by a factor of 4.5 with one method and 5.1 with the other. The isolation of sinapic acid was accomplished using a zeolite-based adsorbent with high adsorptive and optimal desorption characteristics. Phytic acid was isolated using the anion-exchange resin Purolite A200®. In addition, the processes resulted in two separated protein fractions. The ratios of globulin and albumin ratio to the total protein were 59.2\% and 40.1\%, respectively. The steps were then combined in two different ways: (a) a 'sequential process' using the zeolite and A200 in batch processes; and (b) a 'parallel process' using only A200 in a chromatographic system to separate all of the compounds. CONCLUSIONS It can be concluded that isolation of all three components was possible in both processes. These could enhance the added value of current processes using rapeseed meal as a protein source. © 2015 Society of Chemical Industry}, language = {en} } @article{SchumannRoginSchneideretal.2015, author = {Schumann, Christiane and Rogin, Sabine and Schneider, Horst and Tippk{\"o}tter, Nils and Oster, J{\"u}rgen and Kampeis, Percy}, title = {Simultane Atline-Quantifizierung von Magnetpartikeln und Mikroorganismen bei einer HGMS-Filtration}, series = {Chemie Ingenieur Technik}, volume = {87}, journal = {Chemie Ingenieur Technik}, number = {1-2}, doi = {10.1002/cite.201300158}, pages = {137 -- 149}, year = {2015}, abstract = {Es wird eine neue Atline-Messmethode vorgestellt, mit der w{\"a}hrend einer Hochgradienten-Magnetseparation (HGMS)-Filtration eine simultane Quantifizierung von Magnetpartikeln und Mikroorganismen im Filtrat vorgenommen werden kann. Dabei gelingt die Quantifizierung signifikant besser als mit bisher verwendeten Messmethoden. Mit dieser Methode ist es m{\"o}glich, die Trennleistung einer HGMS-Filtration zu bestimmen und einen Filterdurchbruch durch Konzentrationsanstiege im Bereich einiger µg L-1 von Magnetpartikeln im Filtrat fr{\"u}hzeitig zu detektieren, ohne dass nennenswerte Partikelmengen verloren gehen.}, language = {de} } @article{ThielMufflerTippkoetteretal.2015, author = {Thiel, Alexander and Muffler, Kai and Tippk{\"o}tter, Nils and Suck, Kirstin and Sohling, Ulrich and Ruf, Friedrich and Ulber, Roland}, title = {Aufarbeitung von Polyphenolen aus Weizen mittels Zeolithen am Beispiel der Ferulas{\"a}ure}, series = {Chemie IngenieurTechnik}, volume = {87}, journal = {Chemie IngenieurTechnik}, number = {1-2}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/cite.201400031}, pages = {128 -- 136}, year = {2015}, abstract = {Aufarbeitung von Polyphenolen aus Weizenmittels Zeolithen am Beispiel der Ferulasa¨ ureAlexander Thiel1, Kai Muffler1, Nils Tippko¨ tter1, Kirstin Suck2, Ulrich Sohling2, Friedrich Ruf3und Roland Ulber1,*DOI: 10.1002/cite.201400031Bei der Ferulasa¨ure handelt es sich um einen Wertstoff, der aus Weizen gewonnen und in der Lebensmittel- und Pharma-industrie eingesetzt werden kann. Der Einsatz von Weizen als nachwachsende Rohstoffquelle ist allerdings nur dann wirt-schaftlich durchfu¨hrbar, wenn eine Prozessintegration in die bestehenden industriellen Verfahren gewa¨hrleistet oder einedirekte Konkurrenz zur Mehl- und Sta¨rkeindustrie vermieden werden kann. In diesem Artikel wird ein Verfahren aufge-zeigt, welches hohe Ausbeuten ermo¨glicht und eine Konkurrenz zu bestehenden Verwertungspfaden vermeidet.}, language = {de} } @article{PasteurTippkoetterKampeisetal.2014, author = {Pasteur, Aline and Tippk{\"o}tter, Nils and Kampeis, Percy and Ulber, Roland}, title = {Optimization of high gradient magnetic separation filter units for the purification of fermentation products}, series = {IEEE TRANSACTIONS ON MAGNETICS}, volume = {50}, journal = {IEEE TRANSACTIONS ON MAGNETICS}, number = {10}, publisher = {IEEE}, address = {New York, NY}, issn = {0018-9464}, doi = {10.1109/TMAG.2014.2325535}, pages = {Artikel 5000607}, year = {2014}, abstract = {High gradient magnetic separation (HGMS) has been established since the early 1970s. A more recent application of these systems is the use in bioprocesses. To integrate the HGMS in a fermentation process, it is necessary to optimize the separation matrix with regard to the magnetic separation characteristics and permeability of the non-magnetizable components of the fermentation broth. As part of the work presented here, a combined fluidic and magnetic force finite element model simulation was created using the software COMSOL Multiphysics and compared with separation experiments. Finally, as optimal lattice orientation of the separation matrix, a transversal rhombohedral arrangement was defined. The high suitability of the new filter matrix has been verified by separation experiments.}, language = {en} } @article{TippkoetterWollnySucketal.2014, author = {Tippk{\"o}tter, Nils and Wollny, Steffen and Suck, Kirstin and Sohling, Ulrich and Ruf, Friedrich and Ulber, Roland}, title = {Recycling of spent oil bleaching earth as source of glycerol for the anaerobic production of acetone, butanol, and ethanol with Clostridium diolis and lipolytic Clostridium lundense}, series = {Engineering in Life Sciences}, volume = {14}, journal = {Engineering in Life Sciences}, number = {4}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1618-2863}, doi = {10.1002/elsc.201300113}, pages = {425 -- 432}, year = {2014}, abstract = {A major part of edible oil is subjected to bleaching procedures, primarily with minerals applied as adsorbers. Their recycling is currently done either by regaining the oil via organic solvent extraction or by using the spent bleaching earth (SBE) as additive for animal feed, etc. As a new method, the reutilization of the by-product SBE for the microbiologic formation of acetone, butanol, and ethanol (ABE) is presented as proof-of-concept. The SBE was taken from a palm oil cleaning process. The recycling concept is based on the application of lipolytic clostridia strains. Due to considerably long fermentation times, co-fermentation with Candida rugosa and enzymatic hydrolyses of the bound oil with a subsequent clostridia fermentation are shown as alternative routes. Anaerobic fermentations under comparison of different clostridia strains were performed with glycerol media, enzymatically hydrolyzed palm oil and SBE. Solutes, side product compositions and productivities were quantified via HPLC. A successful production of ABE solutes from SBE has been done with a yield of 0.15 g butanol per gram of bound glycerol. Thus, the biotechnological recycling of the waste stream is possible in principle. Inhibition of the substrate suspension has been observed. A chromatographic ion-exchange of substrates increased the biomass concentration.}, language = {en} } @article{AlKaidyDuweHusteretal.2014, author = {Al-Kaidy, Huschyar and Duwe, Anna and Huster, Manuel and Muffler, Kai and Schlegel, Christin and Sieker, Tim and Stadtm{\"u}ller, Ralf and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Biotechnologie und Bioverfahrenstechnik - Vom ersten Ullmanns Artikel bis hin zu aktuellen Forschungsthemen}, series = {Chemie Ingenieur Technik}, volume = {86}, journal = {Chemie Ingenieur Technik}, number = {12}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {0009-286X}, doi = {10.1002/cite.201400083}, pages = {2215 -- 2225}, year = {2014}, abstract = {Biotechnologie und die mit ihr verbundenen technischen Prozesse pr{\"a}gen seit Jahrtausenden die Entwicklung der Menschheit. Ausgehend von empirischen Verfahren, insbesondere zur Herstellung von Lebensmitteln und t{\"a}glichen Gebrauchsg{\"u}tern, haben sich diese Disziplinen zu einem der innovativsten Zukunftsfelder entwickelt. Durch das immer detailliertere Verst{\"a}ndnis zellul{\"a}rer Vorg{\"a}nge k{\"o}nnen mittlerweile Produktionsst{\"a}mme gezielt optimiert werden. Im Zusammenspiel mit moderner Prozesstechnik k{\"o}nnen so eine Vielzahl von Bulk- und Feinchemikalien sowie Pharmazeutika effizient hergestellt werden. In diesem Artikel werden exemplarisch einige der aktuellen Trends vorgestellt.}, language = {de} } @article{WiesenTippkoetterMuffleretal.2014, author = {Wiesen, Sebastian and Tippk{\"o}tter, Nils and Muffler, Kai and Suck, Kirstin and Sohling, Ulrich and Ruf, Nils and Ulber, Roland}, title = {Adsorptive Vorbehandlung von Rohglycerin f{\"u}r die 1,3-Propandiol Fermentation mit Clostridium diolis}, series = {Chemie Ingenieur Technik}, volume = {86}, journal = {Chemie Ingenieur Technik}, number = {1-2}, publisher = {Wiley-VCH}, address = {Weinheim}, doi = {10.1002/cite.201300080}, pages = {129 -- 135}, year = {2014}, abstract = {Bei der Gewinnung von Fetts{\"a}uren aus Pflanzen{\"o}len, z. B. zur Herstellung von Biopolymeren, oder bei der Biodiesel- und Seifenproduktion, f{\"a}llt Glycerin als Nebenprodukt an. Bei der Biokonversion dieses Rohstoffes zu 1,3-Propandiol wird der Produktionsorganismus Clostridium diolis durch Verunreinigungen im Rohglycerin gehemmt. Als inhibierende Substanzen konnten freie Fetts{\"a}uren identifiziert werden. Mithilfe eines adsorptiven Aufarbeitungsverfahrens ist es gelungen, die Fetts{\"a}uren zu entfernen und die Konversionseffizienz zu 1,3-Propandiol zu erh{\"o}hen.}, language = {de} } @article{ThielTippkoetterSucketal.2013, author = {Thiel, Alexander and Tippk{\"o}tter, Nils and Suck, Kirstin and Sohling, Ulrich and Ruf, Friedrich and Ulber, Roland}, title = {New zeolite adsorbents for downstream processing of polyphenols from renewable resources}, series = {Engineering in Life Sciences}, volume = {13}, journal = {Engineering in Life Sciences}, number = {3}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/elsc.201200188}, pages = {239 -- 246}, year = {2013}, abstract = {Commercial materials with polyvinylpolypyrrolidone and polymeric amberlites (XAD7HP, XAD16) are commonly used for the adsorptive downstream processing of polyphenols from renewable resources. In this study, beta-zeolite-based adsorbent systems were examined, and their properties were compared to organic resins. Batch adsorption experiments were conducted with synthetic solutions of major polyphenols. Adsorption isotherms and desorption characteristics of individual adsorbent were determined based on these results. Maximum adsorption capacities were calculated using the Langmuir model. For example, the zeolites had capacities up to 203.2 mg/g for ferulic acid. To extend these results to a complex system, additional experiments were performed on rapeseed meal and wheat seed extracts as representative renewable resources. HPLC analysis showed that with 7.5\% w/v, which is regarded as the optimum amount of zeolites, zeolites A and B could bind 100\% of the major polyphenols as well as release polyphenols at high yields. Additionally, regeneration experiments were performed with isopropyl alcohol at 99°C to evaluate how zeolites regenerate under mild conditions. The results showed only a negligible loss of adsorption capacity and no loss of desorption capacity. In summary, it was concluded that beta-zeolites were promising adsorbents for developing new processes to isolate polyphenols from renewable resources.}, language = {en} } @article{TippkoetterAlKaidyWollnyetal.2013, author = {Tippk{\"o}tter, Nils and Al-Kaidy, Huschyar and Wollny, Steffen and Ulber, Roland}, title = {Functionalized magnetizable particles for downstream processing in single-use systems}, series = {Chemie Ingenieur Technik}, volume = {85}, journal = {Chemie Ingenieur Technik}, number = {1-2: Special Issue: Single-Use Technology}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/cite.201200130}, pages = {76 -- 86}, year = {2013}, abstract = {Biotechnological downstream processing is usually an elaborate procedure, requiring a multitude of unit operations to isolate the target component. Besides the disadvantageous space-time yield, the risks of cross-contaminations and product loss grow fast with the complexity of the isolation procedure. A significant reduction of unit operations can be achieved by application of magnetic particles, especially if these are functionalized with affinity ligands. As magnetic susceptible materials are highly uncommon in biotechnological processes, target binding and selective separation of such particles from fermentation or reactions broths can be done in a single step. Since the magnetizable particles can be produced from iron salts and low priced polymers, a single-use implementation of these systems is highly conceivable. In this article, the principles of magnetizable particles, their synthesis and functionalization are explained. Furthermore, applications in the area of reaction engineering, microfluidics and downstream processing are discussed focusing on established single-use technologies and development potential.}, language = {en} } @article{SiekerNeunerDimitrovaetal.2011, author = {Sieker, Tim and Neuner, Andreas and Dimitrova, Darina and Tippk{\"o}tter, Nils and Muffler, Kai and Bart, Hans-J{\"o}rg and Heinzle, Elmar and Ulber, Roland}, title = {Ethanol production from grass silage by simultaneous pretreatment, saccharification and fermentation: First steps in the process development}, series = {Engineering in Life Sciences}, volume = {11}, journal = {Engineering in Life Sciences}, number = {4}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/elsc.201000160}, pages = {436 -- 442}, year = {2011}, abstract = {Grass silage provides a great potential as renewable feedstock. Two fractions of the grass silage, a press juice and the fiber fraction, were evaluated for their possible use for bioethanol production. Direct production of ethanol from press juice is not possible due to high concentrations of organic acids. For the fiber fraction, alkaline peroxide or enzymatic pretreatment was used, which removes the phenolic acids in the cell wall. In this study, we demonstrate the possibility to integrate the enzymatic pretreatment with a simultaneous saccharification and fermentation to achieve ethanol production from grass silage in a one-process step. Achieved yields were about 53 g ethanol per kg silage with the alkaline peroxide pretreatment and 91 g/kg with the enzymatic pretreatment at concentrations of 8.5 and 14.6 g/L, respectively. Furthermore, it was shown that additional supplementation of the fermentation medium with vitamins, trace elements and nutrient salts is not necessary when the press juice is directly used in the fermentation step.}, language = {en} } @article{PothMonzonTippkoetteretal.2011, author = {Poth, Sebastian and Monzon, Magaly and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Lignocellulosic biorefinery: Process integration of hydrolysis and fermentation (SSF process)}, series = {Holzforschung}, volume = {65}, journal = {Holzforschung}, number = {5}, publisher = {De Gruyter}, address = {Berlin}, pages = {633 -- 637}, year = {2011}, abstract = {The aim of the present work is the process integration and the optimization of the enzymatic hydrolysis of wood and the following fermentation of the products to ethanol. The substrate is a fiber fraction obtained by organosolv pre-treatment of beech wood. For the ethanol production, a co-fermentation by two different yeasts (Saccharomyces cerevisiae and Pachysolen tannophilus) was carried out to convert glucose as well as xylose. Two approaches has been followed: 1. A two step process, in which the hydrolysis of the fiber fraction and the fermentation to product are separated from each other. 2. A process, in which the hydrolysis and the fermentation are carried out in one single process step as simultaneous saccharification and fermentation (SSF). Following the first approach, a yield of about 0.15 g ethanol per gram substrate can be reached. Based on the SSF, one process step can be saved, and additionally, the gained yield can be raised up to 0.3 g ethanol per gram substrate.}, language = {en} } @article{TippkoetterRoikaewUlberetal.2010, author = {Tippk{\"o}tter, Nils and Roikaew, Wipa and Ulber, Roland and Hoffmann, Alexander and Denzler, Hans-J{\"o}rg and Buchholz, Heinrich}, title = {Paracoccus denitrificans for the effluent recycling during continuous denitrification of liquid food}, series = {Biotechnology Progress}, volume = {26}, journal = {Biotechnology Progress}, number = {3}, publisher = {Wiley}, address = {Hoboken, NJ}, issn = {8756-7938}, doi = {10.1002/btpr.384}, pages = {756 -- 762}, year = {2010}, abstract = {Nitrate is an undesirable component of several foods. A typical case of contamination with high nitrate contents is whey concentrate, containing nitrate in concentrations up to 25 l. The microbiological removal of nitrate by Paracoccus denitrificans under formation of harmless nitrogen in combination with a cell retention reactor is described here. Focus lies on the resource-conserving design of a microbal denitrification process. Two methods are compared. The application of polyvinyl alcohol-immobilized cells, which can be applied several times in whey feed, is compared with the implementation of a two step denitrification system. First, the whey concentrate's nitrate is removed by ion exchange and subsequently the eluent regenerated by microorganisms under their retention by crossflow filtration. Nitrite and nitrate concentrations were determined by reflectometric color measurement with a commercially available Reflectoquant® device. Correction factors for these media had to be determined. During the pilot development, bioreactors from 4 to 250 mg·L-1 and crossflow units with membrane areas from 0.02 to 0.80 m2 were examined. Based on the results of the pilot plants, a scaling for the exemplary process of denitrifying 1,000 tons per day is discussed.}, language = {en} } @article{SiekerNeunerDimitrovaetal.2010, author = {Sieker, Tim and Neuner, Andreas and Dimitrova, Darina and Tippk{\"o}tter, Nils and Bart, Hans-J{\"o}rg and Heinzle, Elmar and Ulber, Roland}, title = {Grassilage als Rohstoff f{\"u}r die chemische Industrie}, series = {Chemie Ingenieur Technik}, volume = {82}, journal = {Chemie Ingenieur Technik}, number = {8, Special Issue: Industrielle Nutzung nachwachsender Rohstoffe}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1522-2640}, doi = {10.1002/cite.201000088}, pages = {1153 -- 1159}, year = {2010}, abstract = {Grassilage stellt einen nachwachsenden Rohstoff mit großem Potenzial dar. Neben Cellulose und Hemicellulose enth{\"a}lt sie auch organische S{\"a}uren, insbesondere Milchs{\"a}ure. In einem Bioraffinerie-Projekt wird die Milchs{\"a}ure aus der Silage isoliert und mit gentechnisch optimierten St{\"a}mmen zu L-Lysin weiterverarbeitet. Die Lignocellulose wird hydrolysiert und zu Ethanol fermentiert. Ein besonderes Augenmerk liegt auf der Integration der unterschiedlichen Prozesse sowie der einzelnen Prozessschritte zu einem Gesamtprozess, der s{\"a}mtliche Inhaltsstoffe der Silage verwertet.}, language = {de} } @article{UlberPothMonzonetal.2010, author = {Ulber, Roland and Poth, Sebastian and Monzon, Magaly and Tippk{\"o}tter, Nils}, title = {Prozessintegration von Hydrolyse und Fermentation von Cellulose- Faserstoff}, series = {Chemie Ingenieur Technik}, volume = {82}, journal = {Chemie Ingenieur Technik}, number = {1-2}, issn = {1522-2640}, doi = {10.1002/cite.200900103}, pages = {135 -- 139}, year = {2010}, abstract = {Ein viel versprechender erneuerbarer Rohstoff f{\"u}r die Produktion von Chemikalien und Treibstoffen ist Lignocellulose aus pflanzlicher Biomasse. Die darin enthaltenen Zucker k{\"o}nnen mittels enzymatischer Hydrolyse freigesetzt und fermentativ zu Ethanol umgesetzt werden. Ein interessanter Ansatz ist dabei die simultane Verzuckerung und Fermentation. Hefen und Enzyme haben mit 30 °C bzw. 50 °C zwar unterschiedliche Temperaturoptima, es konnte aber gezeigt werden, dass auch bei den niedrigeren Temperaturen eine Umsetzung der Cellulose zu Glucose erfolgt, wenn auch langsamer als bei optimalen Bedingungen. Außerdem konnte in Vorversuchen gezeigt werden, dass Ethanol in den zu erwartenden Konzentrationen keinen Einfluss auf die enzymatische Umsetzung hat.}, language = {de} } @article{TippkoetterDeterdingUlber2008, author = {Tippk{\"o}tter, Nils and Deterding, A. and Ulber, Roland}, title = {Determination of acetic acid in fermentation broth by gas-diffusion technique}, series = {Engineering in Life Sciences}, volume = {8}, journal = {Engineering in Life Sciences}, number = {1, Special Issue: Technical Systems for the Use in Life Sciences}, doi = {10.1002/elsc.200820227}, pages = {62 -- 67}, year = {2008}, abstract = {Due to the interfering effects of acetic acid in many fermentation processes, a gas-diffusion technique was developed for the online determination of acetic acid. The measurements were accomplished with a flow diffusion analysis (FDA) unit from the TRACE Analytics GmbH, Braunschweig, Germany. The diffusion analysis is based on the UV-absorbance of acetic acid at 205 nm. The measurement was achieved by the separation of an acceptor and a carrier stream (acidified fermentation broth) using a gas permeable polytetrafluoroethylene (PTFE) membrane, whereby broth constituents that would otherwise disturb the UV-measurement of acetic acid, are held back efficiently. Merely, the fermentation by-products, e.g. formic acid, is capable of diffusing through the membrane. While formic acid can disturb the measurement, carbon dioxide does not absorb at 205 nm. The method operates with time-dependent sample enrichment. During the analysis, a small volume of the acceptor stream is stopped for a defined time interval in the acceptor chamber. During this period, the gaseous acetic acid diffuses through the membrane and is enriched in the acceptor chamber. Subsequently after the enrichment, the acceptor stream flows through a UV-detector. The intensity of the signal is proportional to the acetic acid concentration. Online measurements in bioreactors via a sterile filtration probe have been accomplished. A linear calibration in the range of 0.5-5.0 g/L acetic acid with a relative standard deviation of <5 \% was obtained. A sampling rate of 8 samples per hour was possible. The system was applied for the determination of acetic acid in E. coli fermentation broth. The instrument is easy to clean, very user-friendly and does not require any toxic or expensive reagents.}, language = {en} } @article{KapplerTanudyayaSchmittTippkoetteretal.2007, author = {Kappler-Tanudyaya, Nathalie and Schmitt, Heike and Tippk{\"o}tter, Nils and Meyer, Lina and Lenzen, Sigurd and Ulber, Roland}, title = {Combination of biotransformation and chromatography for the isolation and purification of mannoheptulose}, series = {Biotechnology Journal}, volume = {2}, journal = {Biotechnology Journal}, number = {6}, issn = {1860-7314}, doi = {10.1002/biot.200700004}, pages = {692 -- 699}, year = {2007}, abstract = {Mannoheptulose is a seven-carbon sugar. It is an inhibitor of glucose-induced insulin secretion due to its ability to selectively inhibit the enzyme glucokinase. An improved procedure for mannoheptulose isolation from avocados is described in this study (based upon the original method by La Forge). The study focuses on the combination of biotransformation and downstream processing (preparative chromatography) as an efficient method to produce a pure extract of mannoheptulose. The experiments were divided into two major phases. In the first phase, several methods and parameters were compared to optimize the mannoheptulose extraction with respect to efficiency and purity. In the second phase, a mass balance of mannoheptulose over the whole extraction process was undertaken to estimate the yield and efficiency of the total extraction process. The combination of biotransformation and preparative chromatography allowed the production of a pure mannoheptulose extract. In a biological test, the sugar inhibited the glucokinase enzyme activity efficiently.}, language = {en} } @article{RoeschKratzHeringetal.2016, author = {R{\"o}sch, C. and Kratz, F. and Hering, T. and Trautmann, S. and Umanskaya, N. and Tippk{\"o}tter, Nils and M{\"u}ller-Renno, C.M. and Ulber, Roland and Hannig, M. and Ziegler, C.}, title = {Albumin-lysozyme interactions: cooperative adsorption on titanium and enzymatic activity}, series = {Colloids and Surfaces B: Biointerfaces}, volume = {149}, journal = {Colloids and Surfaces B: Biointerfaces}, number = {1}, publisher = {Elsevier}, address = {Amsterdam}, doi = {10.1016/j.colsurfb.2016.09.048}, pages = {115 -- 121}, year = {2016}, abstract = {The interplay of albumin (BSA) and lysozyme (LYZ) adsorbed simultaneously on titanium was analyzed by gel electrophoresis and BCA assay. It was found that BSA and lysozyme adsorb cooperatively. Additionally, the isoelectric point of the respective protein influences the adsorption. Also, the enzymatic activity of lysozyme and amylase (AMY) in mixtures with BSA was considered with respect to a possible influence of protein-protein interaction on enzyme activity. Indeed, an increase of lysozyme activity in the presence of BSA could be observed. In contrast, BSA does not influence the activity of amylase.}, language = {en} } @article{RothTippkoetter2016, author = {Roth, Jasmine and Tippk{\"o}tter, Nils}, title = {Evaluation of lignocellulosic material for butanol production using enzymatic hydrolysate medium}, series = {Cellulose Chemistry and Technology}, volume = {50}, journal = {Cellulose Chemistry and Technology}, number = {3-4}, publisher = {Editura Academiei Romane}, address = {Bukarest}, pages = {405 -- 410}, year = {2016}, abstract = {Butanol is a promising gasoline additive and platform chemical that can be readily produced via acetone-butanolethanol (ABE) fermentation from pretreated lignocellulosic materials. This article examines lignocellulosic material from beech wood for ABE fermentation, using Clostridium acetobutylicum. First, the utilization of both C₅₋ (xylose) and C₆₋ (glucose) sugars as sole carbon source was investigated in static cultivation, using serum bottles and synthetic medium. The utilization of pentose sugar resulted in a solvent yield of 0.231 g·g_sugar⁻¹, compared to 0.262 g·g_sugar⁻¹ using hexose. Then, the Organosolv pretreated crude cellulose fibers (CF) were enzymatically decomposed, and the resulting hydrolysate medium was analyzed for inhibiting compounds (furans, organic acids, phenolics) and treated with ionexchangers for detoxification. Batch fermentation in a bioreactor using CF hydrolysate medium resulted in a total solvent yield of 0.20 gABE·g_sugar⁻¹.}, language = {en} } @article{AlKaidyTippkoetter2016, author = {Al-Kaidy, Huschyar and Tippk{\"o}tter, Nils}, title = {Superparamagnetic hydrophobic particles as shell material for digital microfluidic droplets and proof-of-principle reaction assessments with immobilized laccase}, series = {Engineering in Life Sciences}, volume = {16}, journal = {Engineering in Life Sciences}, number = {3}, publisher = {Wiley-VCH}, address = {Weinheim}, doi = {10.1002/elsc.201400124}, pages = {222 -- 230}, year = {2016}, abstract = {In the field of biotechnology and molecular biology, the use of small liquid volumes has significant advantages. In particular, screening and optimization runs with acceptable amounts of expensive and hardly available catalysts, reagents, or biomolecules are feasible with microfluidic technologies. The presented new microfluidic system is based on the inclusion of small liquid volumes by a protective shell of magnetizable microparticles. Hereby, discrete aqueous microreactor drops with volumes of 1-30 μL can be formed on a simple planar surface. A digital movement and manipulation of the microreactor is performed by overlapping magnetic forces. The magnetic forces are generated by an electrical coil matrix positioned below a glass plate. With the new platform technology, several discrete reaction compartments can be moved simultaneously on one surface. Due to the magnetic fields, the reactors can even be merged to initiate reactions by mixing or positioned above surface-immobilized catalysts and then opened by magnetic force. Comparative synthesis routes of the magnetizable shell particles and superhydrophobic glass slides including their performance and stability with the reaction platform are described. The influence of diffusive mass transport during the catalyzed reaction is discussed by evaluation finite element model of the microreactor. Furthermore, a first model dye reaction of the enzyme laccase has been established.}, language = {en} } @article{AlKaidyDuweHusteretal.2015, author = {Al-Kaidy, Huschyar and Duwe, Anna and Huster, Manuel and Muffler, Kai and Schlegel, Christin and Tim, Sieker and Stadtm{\"u}ller, Ralf and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Biotechnology and bioprocess engineering - from the first ullmann's article to recent trends}, series = {ChemBioEng Reviews}, volume = {2}, journal = {ChemBioEng Reviews}, number = {3}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/cben.201500008}, pages = {175 -- 184}, year = {2015}, abstract = {For several thousand years, biotechnology and its associated technical processes have had a great impact on the development of mankind. Based on empirical methods, in particular for the production of foodstuffs and daily commodities, these disciplines have become one of the most innovative future issues. Due to the increasing detailed understanding of cellular processes, production strains can now be optimized. In combination with modern bioprocesses, a variety of bulk and fine chemicals as well as pharmaceuticals can be produced efficiently. In this article, some of the current trends in biotechnology are discussed.}, language = {en} } @article{TippkoetterWollnyKampeisetal.2011, author = {Tippk{\"o}tter, Nils and Wollny, S. and Kampeis, P. and Oster, J. and Schneider, H. and Ulber, Roland}, title = {Magnetseparation von Proteinen : Separation von Zielmolek{\"u}len durch hochselektive Aptamere}, series = {GIT Labor-Fachzeitschrift}, volume = {55}, journal = {GIT Labor-Fachzeitschrift}, number = {10}, publisher = {Wiley}, address = {Weinheim}, pages = {666}, year = {2011}, abstract = {Durch die Kombination von Oligonukleotid-Liganden (Aptameren) hoher Bindungsaffinit{\"a}ten mit hochselektiv abtrennbaren magnetisierbaren Mikropartikeln wird eine einstufige Separation von Zielmolek{\"u}len aus mikrobiologischen Produktionsans{\"a}tzen m{\"o}glich. Die Aptamere werden hierf{\"u}r reversibel auf den Partikeloberfl{\"a}chen gebunden und f{\"u}r die spezifische Isolierung von Bioprodukten eingesetzt. Die Abtrennung der beladenen Partikel erfolgt durch einen neuen Rotor-Stator-Separator mit Hochgradient-Magnetfeld.}, language = {de} } @article{SiekerUlberDimitrovaetal.2009, author = {Sieker, Tim and Ulber, Roland and Dimitrova, Darina and Bart, Hans-J{\"o}rg and Neuner, Andreas and Heinzle, Elmar and Tippk{\"o}tter, Nils}, title = {Silage : Fermentationsrohstoff f{\"u}r die chemische Industrie?}, series = {labor\&more}, journal = {labor\&more}, number = {2}, pages = {44 -- 45}, year = {2009}, abstract = {In Anbetracht des zu erwartenden R{\"u}ckgangs der Verf{\"u}gbarkeit fossiler Rohstoffe m{\"u}ssen nicht nur f{\"u}r den Energiesektor, sondern auch f{\"u}r die Herstellung industrieller Produkte alternative Rohstoffe gefunden werden. Ein Beispiel f{\"u}r einen nicht in Nahrungsmittelkonkurrenz stehenden nachwachsenden Rohstoff ist gr{\"u}ne Biomasse wie Gras und Klee. Diese lassen sich in Deutschland auf großen Fl{\"a}chen anbauen und enthalten eine Vielzahl potenzieller Substrate f{\"u}r Fermentationen.}, language = {de} } @article{AlKaidyKuthanHeringetal.2016, author = {Al-Kaidy, Huschyar and Kuthan, Kai and Hering, Thomas and Tippk{\"o}tter, Nils}, title = {Aqueous droplets used as enzymatic microreactors and their electromagnetic actuation}, series = {Journal of Visualized Experiments}, journal = {Journal of Visualized Experiments}, number = {Issue 126}, issn = {1940-087X}, doi = {10.3791/54643}, year = {2016}, abstract = {For the successful implementation of microfluidic reaction systems, such as PCR and electrophoresis, the movement of small liquid volumes is essential. In conventional lab-on-a-chip-platforms, solvents and samples are passed through defined microfluidic channels with complex flow control installations. The droplet actuation platform presented here is a promising alternative. With it, it is possible to move a liquid drop (microreactor) on a planar surface of a reaction platform (lab-in-a-drop). The actuation of microreactors on the hydrophobic surface of the platform is based on the use of magnetic forces acting on the outer shell of the liquid drops which is made of a thin layer of superhydrophobic magnetite particles. The hydrophobic surface of the platform is needed to avoid any contact between the liquid core and the surface to allow a smooth movement of the microreactor. On the platform, one or more microreactors with volumes of 10 µL can be positioned and moved simultaneously. The platform itself consists of a 3 x 3 matrix of electrical double coils which accommodate either neodymium or iron cores. The magnetic field gradients are automatically controlled. By variation of the magnetic field gradients, the microreactors' magnetic hydrophobic shell can be manipulated automatically to move the microreactor or open the shell reversibly. Reactions of substrates and corresponding enzymes can be initiated by merging the microreactors or bringing them into contact with surface immobilized catalysts.}, language = {en} } @article{BrabandPaulssenAbram2006, author = {Braband, Henrik and Paulßen, Elisabeth and Abram, Ulrich}, title = {Nitridorhenium(V) Complexes with 1,3-Dialkyl-4,5-dimethylimidazole-2-ylidenes}, series = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, volume = {632}, journal = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, number = {6}, issn = {1521-3749}, doi = {10.1002/zaac.200600002}, pages = {1051 -- 1056}, year = {2006}, language = {en} } @article{PaulssenSchweighoeferAbram2010, author = {Paulßen, Elisabeth and Schweigh{\"o}fer, Philip V. and Abram, Ulrich}, title = {Reactions of [ReOX3(PPh3)2] Complexes (X = Cl, Br) with Phenylacetylene and the Structures of the Products}, series = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, volume = {636}, journal = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, number = {5}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1521-3749}, doi = {10.1002/zaac.200900478}, pages = {779 -- 783}, year = {2010}, abstract = {Oxorhenium(V) complexes [ReOX3(PPh3)2] (X = Cl, Br) react with phenylacetylene under formation of complexes with ylide-type ligands. Compounds of the compositions [ReOCl3(PPh3){C(Ph)C(H)(PPh3)}] (1), [ReOBr3(OPPh3){C(Ph)C(H)(PPh3)}] (2), and [ReOBr3(OPPh3){C(H)C(Ph)(PPh3)}] (3) were isolated and characterized by X-ray diffraction. They contain a ligand, which was formed by a nucleophilic attack of released PPh3 at coordinated phenylacetylene. The structures of the products show that there is no preferable position for this attack. Cleavage of the Re-C bond in 3 and dimerization of the organic ligand resulted in the formation of the [{(PPh3)(H)CC(Ph)}2]2+ cation, which crystallized as its [(ReOBr4)(OReO3)]2- salt.}, language = {en} } @article{PaulssenKueckmannAbram2007, author = {Paulßen, Elisabeth and K{\"u}ckmann, Theresa and Abram, Ulrich}, title = {Silver(I) Complexes of 1,3-Dialkyl-4,5-dimethylimidazol-2-ylidenes and their Use as Precursors for the Synthesis of Rhenium(V) NHC Complexes}, series = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, volume = {633}, journal = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, number = {5-6}, issn = {1521-3749}, doi = {10.1002/zaac.200700021}, pages = {830 -- 834}, year = {2007}, language = {en} } @article{BrabandYegenPaulssenetal.2005, author = {Braband, Henrik and Yegen, Eda and Paulßen, Elisabeth and Abram, Ulrich}, title = {[{ReN(PMe2Ph)3}{ReO3N}]2 - Structural Evidence for the Nitridotrioxorhenate(VII) Anion, [ReO3N]2-}, series = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, volume = {631}, journal = {Zeitschrift f{\"u}r anorganische und allgemeine Chemie : ZAAC = Journal of inorganic and general chemistry}, number = {12}, issn = {1521-3749}, doi = {10.1002/zaac.200500240}, pages = {2408 -- 2410}, year = {2005}, language = {en} } @article{PaulssenAlbertoAbram2010, author = {Paulßen, Elisabeth and Alberto, Roger and Abram, Ulrich}, title = {Synthesis, Characterization, and Structures of R3EOTcO3 Complexes (E = C, Si, Ge, Sn, Pb) and Related Compounds}, series = {Inorganic Chemistry}, volume = {49}, journal = {Inorganic Chemistry}, number = {7}, publisher = {American Chemical Society}, address = {Washington}, issn = {1520-510X}, doi = {10.1021/ic1001094}, pages = {3525 -- 3530}, year = {2010}, abstract = {AgTcO4 reacts with R3ECl compounds (E = C, Si, Ge, Sn, Pb; R = Me, iPr, tBu, Ph), tBu2SnCl2, or PhMgCl under formation of novel trioxotechnetium(VII) derivatives. The carbon and silicon derivatives readily undergo decomposition, which was proven by 99Tc NMR spectroscopy and the isolation of decomposition products such as [TcOCl3(THF)(OH2)]. Compounds [Ph3GeOTcO3], [(THF)Ph3SnOTcO3], [(O3TcO)SntBu2(OH)]2, and [(THF)4Mg(OTcO3)2] are more stable and were isolated in crystalline form and characterized by X-ray diffraction.}, language = {en} } @article{PaulssenKongArciszewskietal.2012, author = {Paulßen, Elisabeth and Kong, Shushu and Arciszewski, Pawel and Wielbalck, Swantje and Abram, Ulrich}, title = {Aryl and NHC Compounds of Technetium and Rhenium}, series = {Journal of the American Chemical Society}, volume = {134}, journal = {Journal of the American Chemical Society}, number = {22}, publisher = {ACS Publications}, address = {Washington, DC}, issn = {1520-5126}, doi = {10.1021/ja3033718}, pages = {9118 -- 9121}, year = {2012}, abstract = {Air- and water-stable phenyl complexes with nitridotechnetium(V) cores can be prepared by straightforward procedures. [TcNPh2(PPh3)2] is formed by the reaction of [TcNCl2(PPh3)2] with PhLi. The analogous N-heterocyclic carbene (NHC) compound [TcNPh2(HLPh)2], where HLPh is 1,3,4-triphenyl-1,2,4-triazol-5-ylidene, is available from (NBu4)[TcNCl4] and HLPh or its methoxo-protected form. The latter compound allows the comparison of different Tc-C bonds within one compound. Surprisingly, the Tc chemistry with such NHCs does not resemble that of corresponding Re complexes, where CH activation and orthometalation dominate.}, language = {en} } @article{BarbazanHagenbachPaulssenetal.2010, author = {Barbaz{\´a}n, Paula and Hagenbach, Adelheid and Paulßen, Elisabeth and Abram, Ulrich and Carballo, Rosa and Rodriguez-Hermida, Sabina and V{\´a}zquez-L{\´o}pez, Ezequiel M.}, title = {Tricarbonyl Rhenium(I) and Technetium(I) Complexes with Hydrazones Derived from 4,5-Diazafluoren-9-one and 1,10-Phenanthroline-5,6-dione}, series = {European Journal of Inorganic Chemistry}, journal = {European Journal of Inorganic Chemistry}, number = {29}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1099-0682}, doi = {10.1002/ejic.201000522}, pages = {4622 -- 4630}, year = {2010}, abstract = {Tricarbonylrhenium(I) and -technetium(I) halide (halide = Cl and Br) complexes of ligands derived from 4,5-diazafluoren-9-one (df) and 1,10-phenanthroline-5,6-dione (phen) derivatives of benzoic and 2-hydroxybenzoic acid hydrazides have been prepared. The complexes have been characterized by elemental analysis, MS, IR, 1H NMR and absorption and emission UV/Vis spectroscopic methods. The metal centres (ReI and TcI) are coordinated through the nitrogen imine atoms and establish five-membered chelate rings, whereas the hydrazone groups stand uncoordinated. The 1H NMR spectra suggest the same behaviour in solution on the basis of only marginal variations in the chemical shifts of the hydrazine protons.}, language = {en} } @article{PaulssenNgyugenKahlckeetal.2012, author = {Paulßen, Elisabeth and Ngyugen, Hung Huy and Kahlcke, Nils and Deflon, Victor M. and Abram, Ulrich}, title = {Tricarbonyltechnetium(I) and -rhenium(I) complexes with N′-thiocarbamoylpicolylbenzamidines}, series = {Polyhedron}, volume = {40}, journal = {Polyhedron}, number = {1}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0277-5387}, doi = {10.1016/j.poly.2012.04.008}, pages = {153 -- 158}, year = {2012}, abstract = {N,N-Dialkylamino(thiocarbonyl)-N′-picolylbenzamidines react with (NEt4)2[M(CO)3X3] (M = Re, X = Br; M = Tc, X = Cl) under formation of neutral [M(CO)3L] complexes in high yields. The monoanionic NNS ligands bind in a facial coordination mode and can readily be modified at the (CS)NR1R2 moiety. The complexes [99Tc(CO)3(LPyMor)] and [Re(CO)3(L)] (L = LPyMor, LPyEt) were characterized by X-ray diffraction. Reactions of [99mTc(CO)3(H2O)3]+ with the N′-thiocarbamoylpicolylbenzamidines give the corresponding 99mTc complexes. The ester group in HLPyCOOEt allows linkage between biomolecules and the metal core.}, language = {en} } @article{PellegriniHowellShepherdetal.2013, author = {Pellegrini, Paul A. and Howell, Nicholas R. and Shepherd, Rachael K. and Lengkeek, Nigel A. and Paulßen, Elisabeth and Katsifis, Andrew G. and Greguric, Ivan}, title = {Synthesis and Radiolabelling of DOTA-Linked Glutamine Analogues with 67,68Ga as Markers for Increased Glutamine Metabolism in Tumour Cells}, series = {Molecules}, volume = {18}, journal = {Molecules}, number = {6}, publisher = {MDPI}, address = {Basel}, issn = {1420-3049}, doi = {10.3390/molecules18067160}, pages = {7160 -- 7178}, year = {2013}, language = {en} } @article{PaulssenLeLengkeeketal.2013, author = {Paulßen, Elisabeth and Le, Van So and Lengkeek, Nigel and Pellegrini, Paul and Jackson, Tim and Greguric, Ivan and Weiner, Ron}, title = {Influence of Metal Ions on the 68Ga-labeling of DOTATATE}, series = {Applied Radiation and Isotopes}, volume = {82}, journal = {Applied Radiation and Isotopes}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1872-9800}, doi = {10.1016/j.apradiso.2013.08.010}, pages = {232 -- 238}, year = {2013}, language = {en} } @article{PaulssenLengkeekLeetal.2016, author = {Paulßen, Elisabeth and Lengkeek, Nigel A. and Le, Van So and Pellegrini, Paul A. and Greguric, Ivan and Weiner, Ron}, title = {The role of additives in moderating the influence of Fe(III) and Cu(II) on the radiochemical yield of [⁶⁸Ga(DOTATATE)]}, series = {Applied Radiation and Isotopes}, volume = {107}, journal = {Applied Radiation and Isotopes}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1872-9800}, doi = {10.1016/j.apradiso.2015.09.008}, pages = {13 -- 16}, year = {2016}, abstract = {[⁶⁸Ga(DOTATATE)] has demonstrated its clinical usefulness. Both Fe³⁺ and Cu²⁺, potential contaminants in Gallium-68 generator eluent, substantially reduce the radiochemical (RC) yield of [⁶⁸Ga(DOTATATE)] if the metal/ligand ratio of 1:1 is exceeded. A variety of compounds were examined for their potential ability to reduce this effect. Most had no effect on RC yield. However, addition of phosphate diminished the influence of Fe³⁺ by likely forming an insoluble iron salt. Addition of ascorbic acid reduced Cu²⁺ and Fe³⁺ to Cu⁺ and Fe²⁺ respectively, both of which have limited impact on RC yields. At low ligand amounts (5 nmol DOTATATE), the addition of 30 nmol phosphate (0.19 mM) increased the tolerance of Fe3⁺ from 4 nmol to 10 nmol (0.06 mM), while the addition of ascorbic acid allowed high RC yields (>95\%) in the presence of 40 nmol Fe³⁺ (0.25 mM) and 100 nmol Cu²⁺ (0.63 mM). The effect of ascorbic acid was highly pH-dependant, and gave optimal results at pH 3.}, language = {en} } @article{PaulssenHoehrHouetal.2015, author = {Paulßen, Elisabeth and Hoehr, Cornelia and Hou, Xinchi and Hanemaayer, Victoire and Zeisler, Stefan and Adam, Michael J. and Ruth, Thomas J. and Celler, Anna and Buckley, Ken and Benard, Francois and Schaffer, Paul}, title = {Production of Y-86 and other radiometals for research purposes using a solution target system}, series = {Nuclear medicine and biology}, volume = {42}, journal = {Nuclear medicine and biology}, number = {11}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1872-9614}, doi = {10.1016/j.nucmedbio.2015.06.005}, pages = {842 -- 849}, year = {2015}, language = {en} } @article{HoehrPaulssenBenardetal.2014, author = {Hoehr, Cornelia and Paulßen, Elisabeth and Benard, Francois and Lee, Chris Jaeil and Hou, Xinchi and Badesso, Brian and Ferguson, Simon and Miao, Qing and Yang, Hua and Buckley, Ken and Hanemaayer, Victoire and Zeisler, Stefan and Ruth, Thomas and Celler, Anna and Schaffer, Paul}, title = {⁴⁴ᶢSc production using a water target on a 13 MeV cyclotron}, series = {Nuclear medicine and biology}, volume = {41}, journal = {Nuclear medicine and biology}, number = {5}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1872-9614}, doi = {10.1016/j.nucmedbio.2013.12.016}, pages = {401 -- 406}, year = {2014}, abstract = {Access to promising radiometals as isotopes for novel molecular imaging agents requires that they are routinely available and inexpensive to obtain. Proximity to a cyclotron center outfitted with solid target hardware, or to an isotope generator for the metal of interest is necessary, both of which can introduce significant hurdles in development of less common isotopes. Herein, we describe the production of ⁴⁴Sc (t₁⸝₂ = 3.97 h, Eavg,β⁺ = 1.47 MeV, branching ratio = 94.27\%) in a solution target and an automated loading system which allows a quick turn-around between different radiometallic isotopes and therefore greatly improves their availability for tracer development. Experimental yields are compared to theoretical calculations.}, language = {en} } @article{InfantinoPaulssenMostaccietal.2016, author = {Infantino, Angelo and Paulßen, Elisabeth and Mostacci, Domiziano and Schaffer, Paul and Trinczek, Michael and Hoehr, Cornelia}, title = {Assessment of the production of medical isotopes using the Monte Carlo code FLUKA: Simulations against experimental measurements}, series = {Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms}, volume = {366}, journal = {Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms}, publisher = {Elsevier}, address = {Amsterdam}, issn = {1872-9584}, doi = {10.1016/j.nimb.2015.10.067}, pages = {117 -- 123}, year = {2016}, abstract = {The Monte Carlo code FLUKA is used to simulate the production of a number of positron emitting radionuclides, ¹⁸F, ¹³N, ⁹⁴Tc, ⁴⁴Sc, ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr, ⁵²Mn, ⁶¹Cu and ⁵⁵Co, on a small medical cyclotron with a proton beam energy of 13 MeV. Experimental data collected at the TR13 cyclotron at TRIUMF agree within a factor of 0.6 ± 0.4 with the directly simulated data, except for the production of ⁵⁵Co, where the simulation underestimates the experiment by a factor of 3.4 ± 0.4. The experimental data also agree within a factor of 0.8 ± 0.6 with the convolution of simulated proton fluence and cross sections from literature. Overall, this confirms the applicability of FLUKA to simulate radionuclide production at 13 MeV proton beam energy.}, language = {en} } @article{LiuSchaapBallemansetal.2017, author = {Liu, Z. and Schaap, K. S. and Ballemans, L. and de Blois, E. and Rohde, M. and Paulßen, Elisabeth}, title = {Measurement of reaction kinetics of [177Lu]Lu-DOTA-TATE using a microfluidic system}, series = {Dalton Transactions}, volume = {46}, journal = {Dalton Transactions}, number = {42}, issn = {1477-9234}, doi = {10.1039/C7DT01830D}, pages = {14669 -- 14676}, year = {2017}, language = {en} } @article{RauppSchmittWalzetal.2018, author = {Raupp, Sebastian M. and Schmitt, Marcel and Walz, Anna-Lena and Diehm, Ralf and Hummel, Helga and Scharfer, Philip and Schabel, Wilhelm}, title = {Slot die stripe coating of low viscous fluids}, series = {Journal of Coatings Technology and Research}, volume = {15}, journal = {Journal of Coatings Technology and Research}, number = {5}, publisher = {Springer}, issn = {1935-3804}, doi = {10.1007/s11998-017-0039-y}, pages = {899 -- 911}, year = {2018}, abstract = {Slot die coating is applied to deposit thin and homogenous films in roll-to-roll and sheet-to-sheet applications. The critical step in operation is to choose suitable process parameters within the process window. In this work, we investigate an upper limit for stripe coatings. This maximum film thickness is characterized by stripe merging which needs to be avoided in a stable process. It is shown that the upper limit reduces the process window for stripe coatings to a major extent. As a result, stripe coatings at large coating gaps and low viscosities are only possible for relatively thick films. Explaining the upper limit, a theory of balancing the side pressure in the gap region in the cross-web direction has been developed.}, language = {en} } @article{Delaittre2019, author = {Delaittre, Guillaume}, title = {Telechelic Poly(2-Oxazoline)s}, series = {European Polymer Journal}, journal = {European Polymer Journal}, number = {In Press, Journal Pre-proof, 109281}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0014-3057}, doi = {10.1016/j.eurpolymj.2019.109281}, year = {2019}, language = {en} } @article{SchmidtTurgutLeetal.2020, author = {Schmidt, Aaron C. and Turgut, Hatice and Le, Dao and Beloqui, Ana and Delaittre, Guillaume}, title = {Making the best of it: nitroxide-mediated polymerization of methacrylates via the copolymerization approach with functional styrenics}, series = {Polymer Chemistry}, volume = {11}, journal = {Polymer Chemistry}, number = {2}, publisher = {Royal Society of Chemistry (RSC)}, address = {Cambridge}, doi = {10.1039/C9PY01458F}, pages = {593 -- 604}, year = {2020}, abstract = {The SG1-mediated solution polymerization of methyl methacrylate (MMA) and oligo(ethylene glycol) methacrylate (OEGMA, Mₙ = 300 g mol⁻¹) in the presence of a small amount of functional/reactive styrenic comonomer is investigated. Moieties such as pentafluorophenyl ester, triphenylphosphine, azide, pentafluorophenyl, halide, and pyridine are considered. A comonomer fraction as low as 5 mol\% typically results in a controlled/living behavior, at least up to 50\% conversion. Chain extensions with styrene for both systems were successfully performed. Variation of physical properties such as refractive index (for MMA) and phase transition temperature (for OEGMA) were evaluated by comparing to 100\% pure homopolymers. The introduction of an activated ester styrene derivative in the polymerization of OEGMA allows for the synthesis of reactive and hydrophilic polymer brushes with defined thickness. Finally, using the example of pentafluorostyrene as controlling comonomer, it is demonstrated that functional PMMA-b-PS are able to maintain a phase separation ability, as evidenced by the formation of nanostructured thin films.}, language = {en} } @article{MuschallikMolinnusJablonskietal.2020, author = {Muschallik, Lukas and Molinnus, Denise and Jablonski, Melanie and Kipp, Carina Ronja and Bongaerts, Johannes and Pohl, Martina and Wagner, Torsten and Sch{\"o}ning, Michael Josef and Selmer, Thorsten and Siegert, Petra}, title = {Synthesis of α-hydroxy ketones and vicinal (R, R)-diols by Bacillus clausii DSM 8716ᵀ butanediol dehydrogenase}, series = {RSC Advances}, volume = {10}, journal = {RSC Advances}, publisher = {Royal Society of Chemistry (RSC)}, address = {Cambridge}, issn = {2046-2069}, doi = {10.1039/D0RA02066D}, pages = {12206 -- 12216}, year = {2020}, abstract = {α-hydroxy ketones (HK) and 1,2-diols are important building blocks for fine chemical synthesis. Here, we describe the R-selective 2,3-butanediol dehydrogenase from B. clausii DSM 8716ᵀ (BcBDH) that belongs to the metal-dependent medium chain dehydrogenases/reductases family (MDR) and catalyzes the selective asymmetric reduction of prochiral 1,2-diketones to the corresponding HK and, in some cases, the reduction of the same to the corresponding 1,2-diols. Aliphatic diketones, like 2,3-pentanedione, 2,3-hexanedione, 5-methyl-2,3-hexanedione, 3,4-hexanedione and 2,3-heptanedione are well transformed. In addition, surprisingly alkyl phenyl dicarbonyls, like 2-hydroxy-1-phenylpropan-1-one and phenylglyoxal are accepted, whereas their derivatives with two phenyl groups are not substrates. Supplementation of Mn²⁺ (1 mM) increases BcBDH's activity in biotransformations. Furthermore, the biocatalytic reduction of 5-methyl-2,3-hexanedione to mainly 5-methyl-3-hydroxy-2-hexanone with only small amounts of 5-methyl-2-hydroxy-3-hexanone within an enzyme membrane reactor is demonstrated.}, language = {en} } @article{CapitainRossJonesMoehringetal.2020, author = {Capitain, Charlotte and Ross-Jones, Jesse and M{\"o}hring, Sophie and Tippk{\"o}tter, Nils}, title = {Differential scanning calorimetry for quantification of polymer biodegradability in compost}, series = {International Biodeterioration \& Biodegradation}, volume = {149}, journal = {International Biodeterioration \& Biodegradation}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0964-8305}, doi = {10.1016/j.ibiod.2020.104914}, pages = {In Press, Article number 104914}, year = {2020}, abstract = {The objective of this study is the establishment of a differential scanning calorimetry (DSC) based method for online analysis of the biodegradation of polymers in complex environments. Structural changes during biodegradation, such as an increase in brittleness or crystallinity, can be detected by carefully observing characteristic changes in DSC profiles. Until now, DSC profiles have not been used to draw quantitative conclusions about biodegradation. A new method is presented for quantifying the biodegradation using DSC data, whereby the results were validated using two reference methods. The proposed method is applied to evaluate the biodegradation of three polymeric biomaterials: polyhydroxybutyrate (PHB), cellulose acetate (CA) and Organosolv lignin. The method is suitable for the precise quantification of the biodegradability of PHB. For CA and lignin, conclusions regarding their biodegradation can be drawn with lower resolutions. The proposed method is also able to quantify the biodegradation of blends or composite materials, which differentiates it from commonly used degradation detection methods.}, language = {en} } @article{WardoyoNoorElbersetal.2020, author = {Wardoyo, Arinto Y.P. and Noor, Johan A.E. and Elbers, Gereon and Schmitz, Sandra and Flaig, Sascha T. and Budianto, Arif}, title = {Characterizing volcanic ash elements from the 2015 eruptions of bromo and raung volcanoes, Indonesia}, series = {Polish Journal of Environmental Studies}, volume = {29}, journal = {Polish Journal of Environmental Studies}, number = {2}, publisher = {HARD}, address = {Olsztyn}, issn = {2083-5906}, doi = {10.15244/pjoes/99101}, pages = {1899 -- 1907}, year = {2020}, abstract = {The volcanic eruptions of Mt. Bromo and Mt. Raung in East Java, Indonesia, in 2015 perturbed volcanic materials and affected surface-layer air quality at surrounding locations. During the episodes, the volcanic ash from the eruptions influenced visibility, traffic accidents, flight schedules, and human health. In this research, the volcanic ash particles were collected and characterized by relying on the detail of physical observation. We performed an assessment of the volcanic ash elements to characterize the volcanic ash using two different methods which are aqua regia extracts followed by MP-AES and XRF laboratory test of bulk samples. The analysis results showed that the volcanic ash was mixed of many materials, such as Al, Si, P, K, Ca, Ti, V, Cr, Mn, Fe, Ni, and others. Fe, Si, Ca, and Al were found as the major elements, while the others were the trace elements Ba, Cr, Cu, Mn, P, Mn, Ni, Zn, Sb, Sr, and V with the minor concentrations. XRF analyses showed that Fe dominated the elements of the volcanic ash. The XRF analysis showed that Fe was at 35.40\% in Bromo and 43.00\% in Raung of the detected elements in bulk material. The results of aqua regia extracts analyzed by MP-AES were 1.80\% and 1.70\% of Fe element for Bromo and Raung volcanoes, respectively.}, language = {en} } @article{MonakhovaDiehl2022, author = {Monakhova, Yulia and Diehl, Bernd W.K.}, title = {Nuclear magnetic resonance spectroscopy as an elegant tool for a complete quality control of crude heparin material}, series = {Journal of Pharmaceutical and Biomedical Analysis}, volume = {219}, journal = {Journal of Pharmaceutical and Biomedical Analysis}, number = {Article number: 114915}, publisher = {Elsevier}, address = {New York, NY}, issn = {0731-7085}, doi = {10.1016/j.jpba.2022.114915}, year = {2022}, abstract = {Nuclear magnetic resonance (NMR) spectrometric methods for the quantitative analysis of pure heparin in crude heparin is proposed. For quantification, a two-step routine was developed using a USP heparin reference sample for calibration and benzoic acid as an internal standard. The method was successfully validated for its accuracy, reproducibility, and precision. The methodology was used to analyze 20 authentic porcine heparinoid samples having heparin content between 4.25 w/w \% and 64.4 w/w \%. The characterization of crude heparin products was further extended to a simultaneous analysis of these common ions: sodium, calcium, acetate and chloride. A significant, linear dependence was found between anticoagulant activity and assayed heparin content for thirteen heparinoids samples, for which reference data were available. A Diffused-ordered NMR experiment (DOSY) can be used for qualitative analysis of specific glycosaminoglycans (GAGs) in heparinoid matrices and, potentially, for quantitative prediction of molecular weight of GAGs. NMR spectrometry therefore represents a unique analytical method suitable for the simultaneous quantitative control of organic and inorganic composition of crude heparin samples (especially heparin content) as well as an estimation of other physical and quality parameters (molecular weight, animal origin and activity).}, language = {en} } @article{LindnerBurgerRutledgeetal.2022, author = {Lindner, Simon and Burger, Ren{\´e} and Rutledge, Douglas N. and Do, Xuan Tung and Rumpf, Jessica and Diehl, Bernd W. K. and Schulze, Margit and Monakhova, Yulia}, title = {Is the calibration transfer of multivariate calibration models between high- and low-field NMR instruments possible? A case study of lignin molecular weight}, series = {Analytical chemistry}, volume = {94}, journal = {Analytical chemistry}, number = {9}, publisher = {ACS Publications}, address = {Washington, DC}, isbn = {1520-6882}, doi = {10.1021/acs.analchem.1c05125}, pages = {3997 -- 4004}, year = {2022}, abstract = {Although several successful applications of benchtop nuclear magnetic resonance (NMR) spectroscopy in quantitative mixture analysis exist, the possibility of calibration transfer remains mostly unexplored, especially between high- and low-field NMR. This study investigates for the first time the calibration transfer of partial least squares regressions [weight average molecular weight (Mw) of lignin] between high-field (600 MHz) NMR and benchtop NMR devices (43 and 60 MHz). For the transfer, piecewise direct standardization, calibration transfer based on canonical correlation analysis, and transfer via the extreme learning machine auto-encoder method are employed. Despite the immense resolution difference between high-field and low-field NMR instruments, the results demonstrate that the calibration transfer from high- to low-field is feasible in the case of a physical property, namely, the molecular weight, achieving validation errors close to the original calibration (down to only 1.2 times higher root mean square errors). These results introduce new perspectives for applications of benchtop NMR, in which existing calibrations from expensive high-field instruments can be transferred to cheaper benchtop instruments to economize.}, language = {en} } @article{MonakhovaDiehl2022, author = {Monakhova, Yulia and Diehl, Bernd W.K.}, title = {Multinuclear NMR screening of pharmaceuticals using standardization by 2H integral of a deuterated solvent}, series = {Journal of Pharmaceutical and Biomedical Analysis}, volume = {209}, journal = {Journal of Pharmaceutical and Biomedical Analysis}, number = {Article number: 114530}, publisher = {Elsevier}, isbn = {0731-7085}, doi = {10.1016/j.jpba.2021.114530}, year = {2022}, abstract = {NMR standardization approach that uses the 2H integral of deuterated solvent for quantitative multinuclear analysis of pharmaceuticals is described. As a proof of principle, the existing NMR procedure for the analysis of heparin products according to US Pharmacopeia monograph is extended to the determination of Na+ and Cl- content in this matrix. Quantification is performed based on the ratio of a 23Na (35Cl) NMR integral and 2H NMR signal of deuterated solvent, D2O, acquired using the specific spectrometer hardware. As an alternative, the possibility of 133Cs standardization using the addition of Cs2CO3 stock solution is shown. Validation characteristics (linearity, repeatability, sensitivity) are evaluated. A holistic NMR profiling of heparin products can now also be used for the quantitative determination of inorganic compounds in a single analytical run using a single sample. In general, the new standardization methodology provides an appealing alternative for the NMR screening of inorganic and organic components in pharmaceutical products.}, language = {en} } @article{BurgerLindnerRumpfetal.2022, author = {Burger, Ren{\´e} and Lindner, Simon and Rumpf, Jessica and Do, Xuan Tung and Diehl, Bernd W.K. and Rehahn, Matthias and Monakhova, Yulia and Schulze, Margit}, title = {Benchtop versus high field NMR: Comparable performance found for the molecular weight determination of lignin}, series = {Journal of Pharmaceutical and Biomedical Analysis}, volume = {212}, journal = {Journal of Pharmaceutical and Biomedical Analysis}, number = {Article number: 114649}, publisher = {Elsevier}, address = {New York, NY}, isbn = {0731-7085}, doi = {10.1016/j.jpba.2022.114649}, year = {2022}, abstract = {Lignin is a promising renewable biopolymer being investigated worldwide as an environmentally benign substitute of fossil-based aromatic compounds, e.g. for the use as an excipient with antioxidant and antimicrobial properties in drug delivery or even as active compound. For its successful implementation into process streams, a quick, easy, and reliable method is needed for its molecular weight determination. Here we present a method using 1H spectra of benchtop as well as conventional NMR systems in combination with multivariate data analysis, to determine lignin's molecular weight (Mw and Mn) and polydispersity index (PDI). A set of 36 organosolv lignin samples (from Miscanthus x giganteus, Paulownia tomentosa and Silphium perfoliatum) was used for the calibration and cross validation, and 17 samples were used as external validation set. Validation errors between 5.6\% and 12.9\% were achieved for all parameters on all NMR devices (43, 60, 500 and 600 MHz). Surprisingly, no significant difference in the performance of the benchtop and high-field devices was found. This facilitates the application of this method for determining lignin's molecular weight in an industrial environment because of the low maintenance expenditure, small footprint, ruggedness, and low cost of permanent magnet benchtop NMR systems.}, language = {en} } @article{MonakhovaSobolevaFedotovaetal.2022, author = {Monakhova, Yulia and Soboleva, Polina M. and Fedotova, Elena S. and Musina, Kristina T. and Burmistrova, Natalia A.}, title = {Quantum chemical calculations of IR spectra of heparin disaccharide subunits}, series = {Computational and Theoretical Chemistry}, volume = {1217}, journal = {Computational and Theoretical Chemistry}, number = {Article number: 113891}, publisher = {Elsevier}, address = {New York, NY}, isbn = {2210-271X}, doi = {10.1016/j.comptc.2022.113891}, year = {2022}, abstract = {Heparin is a natural polysaccharide, which plays essential role in many biological processes. Alterations in building blocks can modify biological roles of commercial heparin products, due to significant changes in the conformation of the polymer chain. The variability structure of heparin leads to difficulty in quality control using different analytical methods, including infrared (IR) spectroscopy. In this paper molecular modelling of heparin disaccharide subunits was performed using quantum chemistry. The structural and spectral parameters of these disaccharides have been calculated using RHF/6-311G. In addition, over-sulphated chondroitin sulphate disaccharide was studied as one of the most widespread contaminants of heparin. Calculated IR spectra were analyzed with respect to specific structure parameters. IR spectroscopic fingerprint was found to be sensitive to substitution pattern of disaccharide subunits. Vibrational assignments of calculated spectra were correlated with experimental IR spectral bands of native heparin. Chemometrics was used to perform multivariate analysis of simulated spectral data.}, language = {en} } @article{MonakhovaDiehl2021, author = {Monakhova, Yulia and Diehl, Bernd W.K.}, title = {Novel approach of qNMR workflow by standardization using 2H integral: Application to any intrinsic calibration standard}, series = {Talanta}, volume = {222}, journal = {Talanta}, number = {Article number: 121504}, publisher = {Elsevier}, isbn = {0039-9140}, doi = {10.1016/j.talanta.2020.121504}, year = {2021}, abstract = {Quantitative nuclear magnetic resonance (qNMR) is routinely performed by the internal or external standardization. The manuscript describes a simple alternative to these common workflows by using NMR signal of another active nuclei of calibration compound. For example, for any arbitrary compound quantification by NMR can be based on the use of an indirect concentration referencing that relies on a solvent having both 1H and 2H signals. To perform high-quality quantification, the deuteration level of the utilized deuterated solvent has to be estimated. In this contribution the new method was applied to the determination of deuteration levels in different deuterated solvents (MeOD, ACN, CDCl3, acetone, benzene, DMSO-d6). Isopropanol-d6, which contains a defined number of deuterons and protons, was used for standardization. Validation characteristics (precision, accuracy, robustness) were calculated and the results showed that the method can be used in routine practice. Uncertainty budget was also evaluated. In general, this novel approach, using standardization by 2H integral, benefits from reduced sample preparation steps and uncertainties, and can be applied in different application areas (purity determination, forensics, pharmaceutical analysis, etc.).}, language = {en} } @article{BurmistrovaSobolevaMonakhova2021, author = {Burmistrova, Natalia A. and Soboleva, Polina M. and Monakhova, Yulia}, title = {Is infrared spectroscopy combined with multivariate analysis a promising tool for heparin authentication?}, series = {Journal of Pharmaceutical and Biomedical Analysis}, volume = {194}, journal = {Journal of Pharmaceutical and Biomedical Analysis}, number = {Article number: 113811}, publisher = {Elsevier}, address = {Amsterdam}, isbn = {0731-7085}, doi = {10.1016/j.jpba.2020.113811}, year = {2021}, abstract = {The investigation of the possibility to determine various characteristics of powder heparin (n = 115) was carried out with infrared spectroscopy. The evaluation of heparin samples included several parameters such as purity grade, distributing company, animal source as well as heparin species (i.e. Na-heparin, Ca-heparin, and heparinoids). Multivariate analysis using principal component analysis (PCA), soft independent modelling of class analogy (SIMCA), and partial least squares - discriminant analysis (PLS-DA) were applied for the modelling of spectral data. Different pre-processing methods were applied to IR spectral data; multiplicative scatter correction (MSC) was chosen as the most relevant. Obtained results were confirmed by nuclear magnetic resonance (NMR) spectroscopy. Good predictive ability of this approach demonstrates the potential of IR spectroscopy and chemometrics for screening of heparin quality. This approach, however, is designed as a screening tool and is not considered as a replacement for either of the methods required by USP and FDA.}, language = {en} } @article{MonakhovaDiehl2021, author = {Monakhova, Yulia and Diehl, Bernd W. K.}, title = {Simplification of NMR Workflows by Standardization Using 2H Integral of Deuterated Solvent as Applied to Aloe vera Preparations}, series = {Applied Magnetic Resonance}, volume = {52}, journal = {Applied Magnetic Resonance}, number = {11}, publisher = {Springer}, address = {Cham}, issn = {1613-7507}, doi = {10.1007/s00723-021-01393-4}, pages = {1591 -- 1600}, year = {2021}, abstract = {In this study, a recently proposed NMR standardization approach by 2H integral of deuterated solvent for quantitative multicomponent analysis of complex mixtures is presented. As a proof of principle, the existing NMR routine for the analysis of Aloe vera products was modified. Instead of using absolute integrals of targeted compounds and internal standard (nicotinamide) from 1H-NMR spectra, quantification was performed based on the ratio of a particular 1H-NMR compound integral and 2H-NMR signal of deuterated solvent D2O. Validation characteristics (linearity, repeatability, accuracy) were evaluated and the results showed that the method has the same precision as internal standardization in case of multicomponent screening. Moreover, a dehydration process by freeze drying is not necessary for the new routine. Now, our NMR profiling of A. vera products needs only limited sample preparation and data processing. The new standardization methodology provides an appealing alternative for multicomponent NMR screening. In general, this novel approach, using standardization by 2H integral, benefits from reduced sample preparation steps and uncertainties, and is recommended in different application areas (purity determination, forensics, pharmaceutical analysis, etc.).}, language = {en} } @article{BurgerRumpfDoetal.2021, author = {Burger, Ren{\´e} and Rumpf, Jessica and Do, Xuan Tung and Monakhova, Yulia and Diehl, Bernd W. K. and Rehahn, Matthias and Schulze, Margit}, title = {Is NMR combined with multivariate regression applicable for the molecular weight determination of randomly cross-linked polymers such as lignin?}, series = {ACS Omega}, volume = {6}, journal = {ACS Omega}, number = {44}, publisher = {ACS Publications}, address = {Washington, DC}, issn = {2470-1343}, doi = {10.1021/acsomega.1c03574}, pages = {29516 -- 29524}, year = {2021}, abstract = {The molecular weight properties of lignins are one of the key elements that need to be analyzed for a successful industrial application of these promising biopolymers. In this study, the use of 1H NMR as well as diffusion-ordered spectroscopy (DOSY NMR), combined with multivariate regression methods, was investigated for the determination of the molecular weight (Mw and Mn) and the polydispersity of organosolv lignins (n = 53, Miscanthus x giganteus, Paulownia tomentosa, and Silphium perfoliatum). The suitability of the models was demonstrated by cross validation (CV) as well as by an independent validation set of samples from different biomass origins (beech wood and wheat straw). CV errors of ca. 7-9 and 14-16\% were achieved for all parameters with the models from the 1H NMR spectra and the DOSY NMR data, respectively. The prediction errors for the validation samples were in a similar range for the partial least squares model from the 1H NMR data and for a multiple linear regression using the DOSY NMR data. The results indicate the usefulness of NMR measurements combined with multivariate regression methods as a potential alternative to more time-consuming methods such as gel permeation chromatography.}, language = {en} } @article{NiedermeyerZhouDursunetal.2016, author = {Niedermeyer, Angela and Zhou, Bei and Dursun, G{\"o}zde and Temiz Artmann, Ayseg{\"u}l and Markert, Bernd}, title = {An examination of tissue engineered scaffolds in a bioreactor}, series = {Proceedings in Applied Mathematics and Mechanics PAMM}, volume = {16}, journal = {Proceedings in Applied Mathematics and Mechanics PAMM}, number = {1}, publisher = {Wiley-VCH}, address = {Weinheim}, issn = {1617-7061}, doi = {10.1002/pamm.201610038}, pages = {99 -- 100}, year = {2016}, abstract = {Replacement tissues, designed to fill in articular cartilage defects, should exhibit the same properties as the native material. The aim of this study is to foster the understanding of, firstly, the mechanical behavior of the material itself and, secondly, the influence of cultivation parameters on cell seeded implants as well as on cell migration into acellular implants. In this study, acellular cartilage replacement material is theoretically, numerically and experimentally investigated regarding its viscoelastic properties, where a phenomenological model for practical applications is developed. Furthermore, remodeling and cell migration are investigated.}, language = {en} }