@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{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{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{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{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{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{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{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} } @book{WagemannTippkoetter2019, author = {Wagemann, Kurt and Tippk{\"o}tter, Nils}, title = {Biorefineries / Kurt Wagemann, Nils Tippk{\"o}tter (editors)}, series = {Advances in biochemical engineering/biotechnology book series (ABE)}, journal = {Advances in biochemical engineering/biotechnology book series (ABE)}, publisher = {Springer}, address = {Cham (Switzerland)}, isbn = {978-3-319-97117-9}, doi = {10.1007/978-3-319-97119-3}, pages = {VI, 549 Seiten}, year = {2019}, 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{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{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{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{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{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{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{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{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} } @inproceedings{KazukiKobayashiHirabayashietal.2019, author = {Kazuki, Yasuhiro and Kobayashi, Kaoru and Hirabayashi, Masumi and Abe, Satoshi and Kajitani, Naoyo and Kazuki, Kanoko and Takehara, Shoko and Takiguchi, Masato and Satoh, Daisuke and Kuze, Jiro and Sakuma, Tetsushi and Kaneko, Takehito and Mashimo, Tomoji and Osamura, Minori and Hashimoto, Mari and Wakatsuki, Riko and Hirashima, Rika and Fujiwara, Ryoichi and Deguchi, Tsuneo and Kurihara, Atsushi and Tsukazaki, Yasuko and Senda, Naoto and Yamamoto, Takashi and Scheer, Nico and Oshimura, Mitsuo}, title = {Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism}, series = {PNAS Proceedings of the National Academy of Sciences of the United States of America}, volume = {116}, booktitle = {PNAS Proceedings of the National Academy of Sciences of the United States of America}, number = {8}, issn = {1091-6490}, doi = {10.1073/pnas.1808255116}, pages = {3072 -- 3081}, year = {2019}, 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{EngelHoltmannUlberetal.2018, author = {Engel, Mareike and Holtmann, Dirk and Ulber, Roland and Tippk{\"o}tter, Nils}, title = {Increased Biobutanol Production by Mediator-Less Electro-Fermentation}, series = {Biotechnology Journal}, journal = {Biotechnology Journal}, number = {Volume 14, Issue 4}, publisher = {Wiley-VCH}, issn = {1860-7314}, doi = {10.1002/biot.201800514}, pages = {Artikel 1800514}, year = {2018}, abstract = {A future bio-economy should not only be based on renewable raw materials but also in the raise of carbon yields of existing production routes. Microbial electrochemical technologies are gaining increased attention for this purpose. In this study, the electro-fermentative production of biobutanol with C. acetobutylicum without the use of exogenous mediators is investigated regarding the medium composition and the reactor design. It is shown that the use of an optimized synthetic culture medium allows higher product concentrations, increased biofilm formation, and higher conductivities compared to a synthetic medium supplemented with yeast extract. Moreover, the optimization of the reactor system results in a doubling of the maximum product concentrations for fermentation products. When a working electrode is polarized at -600 mV vs. Ag/AgCl, a shift from butyrate to acetone and butanol production is induced. This leads to an increased final solvent yield of Yᴀᴃᴇ = 0.202 gg⁻¹ (control 0.103 gg⁻¹), which is also reflected in a higher carbon efficiency of 37.6\% compared to 23.3\% (control) as well as a fourfold decrease in simplified E-factor to 0.43. The results are promising for further development of biobutanol production in bioelectrochemical systems in order to fulfil the principles of Green Chemistry.}, language = {en} } @article{RoehlenPilasDahmenetal.2018, author = {R{\"o}hlen, Desiree and Pilas, Johanna and Dahmen, Markus and Keusgen, Michael and Selmer, Thorsten and Sch{\"o}ning, Michael Josef}, title = {Toward a Hybrid Biosensor System for Analysis of Organic and Volatile Fatty Acids in Fermentation Processes}, series = {Frontiers in Chemistry}, journal = {Frontiers in Chemistry}, number = {6}, publisher = {Frontiers}, address = {Lausanne}, doi = {10.3389/fchem.2018.00284}, pages = {Artikel 284}, year = {2018}, abstract = {Monitoring of organic acids (OA) and volatile fatty acids (VFA) is crucial for the control of anaerobic digestion. In case of unstable process conditions, an accumulation of these intermediates occurs. In the present work, two different enzyme-based biosensor arrays are combined and presented for facile electrochemical determination of several process-relevant analytes. Each biosensor utilizes a platinum sensor chip (14 × 14 mm²) with five individual working electrodes. The OA biosensor enables simultaneous measurement of ethanol, formate, d- and l-lactate, based on a bi-enzymatic detection principle. The second VFA biosensor provides an amperometric platform for quantification of acetate and propionate, mediated by oxidation of hydrogen peroxide. The cross-sensitivity of both biosensors toward potential interferents, typically present in fermentation samples, was investigated. The potential for practical application in complex media was successfully demonstrated in spiked sludge samples collected from three different biogas plants. Thereby, the results obtained by both of the biosensors were in good agreement to the applied reference measurements by photometry and gas chromatography, respectively. The proposed hybrid biosensor system was also used for long-term monitoring of a lab-scale biogas reactor (0.01 m³) for a period of 2 months. In combination with typically monitored parameters, such as gas quality, pH and FOS/TAC (volatile organic acids/total anorganic carbonate), the amperometric measurements of OA and VFA concentration could enhance the understanding of ongoing fermentation processes.}, language = {en} } @article{MuellerBeckersMussmannetal.2018, author = {M{\"u}ller, Janina and Beckers, Mario and Mußmann, Nina and Bongaerts, Johannes and B{\"u}chs, Jochen}, title = {Elucidation of auxotrophic deficiencies of Bacillus pumilus DSM 18097 to develop a defined minimal medium}, series = {Microbial Cell Factories}, volume = {17}, journal = {Microbial Cell Factories}, number = {1}, publisher = {BioMed Central}, issn = {1475-2859}, doi = {10.1186/s12934-018-0956-1}, pages = {Article No. 106}, year = {2018}, abstract = {Background Culture media containing complex compounds like yeast extract or peptone show numerous disadvantages. The chemical composition of the complex compounds is prone to significant variations from batch to batch and quality control is difficult. Therefore, the use of chemically defined media receives more and more attention in commercial fermentations. This concept results in better reproducibility, it simplifies downstream processing of secreted products and enable rapid scale-up. Culturing bacteria with unknown auxotrophies in chemically defined media is challenging and often not possible without an extensive trial-and-error approach. In this study, a respiration activity monitoring system for shake flasks and its recent version for microtiter plates were used to clarify unknown auxotrophic deficiencies in the model organism Bacillus pumilus DSM 18097. Results Bacillus pumilus DSM 18097 was unable to grow in a mineral medium without the addition of complex compounds. Therefore, a rich chemically defined minimal medium was tested containing basically all vitamins, amino acids and nucleobases, which are essential ingredients of complex components. The strain was successfully cultivated in this medium. By monitoring of the respiration activity, nutrients were supplemented to and omitted from the rich chemically defined medium in a rational way, thus enabling a systematic and fast determination of the auxotrophic deficiencies. Experiments have shown that the investigated strain requires amino acids, especially cysteine or histidine and the vitamin biotin for growth. Conclusions The introduced method allows an efficient and rapid identification of unknown auxotrophic deficiencies and can be used to develop a simple chemically defined tailor-made medium. B. pumilus DSM 18097 was chosen as a model organism to demonstrate the method. However, the method is generally suitable for a wide range of microorganisms. By combining a systematic combinatorial approach based on monitoring the respiration activity with cultivation in microtiter plates, high throughput experiments with high information content can be conducted. This approach facilitates media development, strain characterization and cultivation of fastidious microorganisms in chemically defined minimal media while simultaneously reducing the experimental effort.}, language = {en} } @article{EckertRudolphGuoetal.2018, author = {Eckert, Alexander and Rudolph, Tobias and Guo, Jiaqi and Mang, Thomas and Walther, Andreas}, title = {Exceptionally Ductile and Tough Biomimetic Artificial Nacre with Gas Barrier Function}, series = {Advanced Materials}, volume = {30}, journal = {Advanced Materials}, number = {32}, publisher = {Wiley-VCH}, doi = {10.1002/adma.201802477}, pages = {Article number 1802477}, year = {2018}, abstract = {Synthetic mimics of natural high-performance structural materials have shown great and partly unforeseen opportunities for the design of multifunctional materials. For nacre-mimetic nanocomposites, it has remained extraordinarily challenging to make ductile materials with high stretchability at high fractions of reinforcements, which is however of crucial importance for flexible barrier materials. Here, highly ductile and tough nacre-mimetic nanocomposites are presented, by implementing weak, but many hydrogen bonds in a ternary nacre-mimetic system consisting of two polymers (poly(vinyl amine) and poly(vinyl alcohol)) and natural nanoclay (montmorillonite) to provide efficient energy dissipation and slippage at high nanoclay content (50 wt\%). Tailored interactions enable exceptional combinations of ductility (close to 50\% strain) and toughness (up to 27.5 MJ m⁻³). Extensive stress whitening, a clear sign of high internal dynamics at high internal cohesion, can be observed during mechanical deformation, and the materials can be folded like paper into origami planes without fracture. Overall, the new levels of ductility and toughness are unprecedented in highly reinforced bioinspired nanocomposites and are of critical importance to future applications, e.g., as barrier materials needed for encapsulation and as a printing substrate for flexible organic electronics.}, language = {en} } @techreport{Tippkoetter2018, author = {Tippk{\"o}tter, Nils}, title = {Lokale Vorbehandlung nachwachsender Rohstoffe f{\"u}r Bioraffinerien (BioSats) : Schlussbericht zum Vorhaben : Laufzeit: 01.03.2012 bis 30.04.2017}, organization = {Technische Universit{\"a}t Kaiserslautern}, doi = {10.2314/GBV:1024204243}, pages = {191 Seiten}, year = {2018}, language = {de} } @incollection{DuweTippkoetterUlber2018, author = {Duwe, A. and Tippk{\"o}tter, Nils and Ulber, R.}, title = {Lignocellulose-Biorefinery: Ethanol-Focused}, series = {Biorefineries}, booktitle = {Biorefineries}, publisher = {Springer}, address = {Cham}, doi = {10.1007/10_2016_72}, pages = {177 -- 215}, year = {2018}, abstract = {The development prospects of the world markets for petroleum and other liquid fuels are diverse and partly contradictory. However, comprehensive changes for the energy supply of the future are essential. Notwithstanding the fact that there are still very large deposits of energy resources from a geological point of view, the finite nature of conventional oil reserves is indisputable. To reduce our dependence on oil, the EU, the USA, and other major economic zones rely on energy diversification. For this purpose, alternative materials and technologies are being sought, and is most obvious in the transport sector. The objective is to progressively replace fossil fuels with renewable and more sustainable fuels. In this respect, biofuels have a pre-eminent position in terms of their capability of blending with fossil fuels and being usable in existing cars without substantial modification. Ethanol can be considered as the primary renewable liquid fuel. In this chapter enzymes, micro-organisms, and processes for ethanol production based on renewable resources are described.}, language = {en} } @incollection{TippkoetterMoehringRothetal.2019, author = {Tippk{\"o}tter, Nils and M{\"o}hring, Sophie and Roth, Jasmine and Wulfhorst, Helene}, title = {Logistics of lignocellulosic feedstocks: preprocessing as a preferable option}, series = {Biorefineries}, booktitle = {Biorefineries}, publisher = {Springer}, address = {Cham}, isbn = {978-3-319-97117-9}, doi = {10.1007/10_2017_58}, pages = {43 -- 68}, year = {2019}, abstract = {In comparison to crude oil, biorefinery raw materials are challenging in concerns of transport and storage. The plant raw materials are more voluminous, so that shredding and compacting usually are necessary before transport. These mechanical processes can have a negative influence on the subsequent biotechnological processing and shelf life of the raw materials. Various approaches and their effects on renewable raw materials are shown. In addition, aspects of decentralized pretreatment steps are discussed. Another important aspect of pretreatment is the varying composition of the raw materials depending on the growth conditions. This problem can be solved with advanced on-site spectrometric analysis of the material.}, 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} } @incollection{WagemannTippkoetter2019, author = {Wagemann, Kurt and Tippk{\"o}tter, Nils}, title = {Biorefineries: a short introduction}, series = {Biorefineries}, booktitle = {Biorefineries}, publisher = {Springer}, address = {Cham}, isbn = {978-3-319-97117-9}, doi = {10.1007/10_2017_4}, pages = {1 -- 11}, year = {2019}, abstract = {The terms bioeconomy and biorefineries are used for a variety of processes and developments. This short introduction is intended to provide a delimitation and clarification of the terminology as well as a classification of current biorefinery concepts. The basic process diagrams of the most important biorefinery types are shown.}, 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{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} } @book{ArtmannTemizArtmannZhubanovaetal.2018, author = {Artmann, Gerhard and Temiz Artmann, Ayseg{\"u}l and Zhubanova, Azhar A. and Digel, Ilya}, title = {Biological, physical and technical basics of cell engineering}, editor = {Artmann, Gerhard and Temiz Artmann, Ayseg{\"u}l and Zhubanova, Azhar A. and Digel, Ilya}, publisher = {Springer}, address = {Singapore}, isbn = {978-981-10-7903-0}, pages = {xxiv, 481 Seiten ; Illustrationen, Diagramme}, year = {2018}, language = {en} } @phdthesis{TemizArtmann2001, author = {Temiz Artmann, Ayseg{\"u}l}, title = {Sicanlarda egzersiz sonrasi oksidatif hasar ve eritrosit membran degisikliklerinin hemoreolojik etkileri}, year = {2001}, language = {mul} } @phdthesis{TemizArtmann1996, author = {Temiz Artmann, Ayseg{\"u}l}, title = {Sicanlarda, akut egzersiz sonucu gelisen oksidan stresin l{\"o}kosit aktivasyon degisiklikleri ile ile olan iliskisi ve eritrosit deformabilitesine etkisi}, year = {1996}, language = {mul} } @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{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} } @incollection{DuongSeifarthTemizArtmannetal.2018, author = {Duong, Minh Tuan and Seifarth, Volker and Temiz Artmann, Ayseg{\"u}l and Artmann, Gerhard and Staat, Manfred}, title = {Growth Modelling Promoting Mechanical Stimulation of Smooth Muscle Cells of Porcine Tubular Organs in a Fibrin-PVDF Scaffold}, series = {Biological, Physical and Technical Basics of Cell Engineering}, booktitle = {Biological, Physical and Technical Basics of Cell Engineering}, editor = {Artmann, Gerhard and Temiz Artmann, Ayseg{\"u}l and Zhubanova, Azhar A. and Digel, Ilya}, publisher = {Springer}, address = {Singapore}, isbn = {978-981-10-7904-7}, doi = {10.1007/978-981-10-7904-7_9}, pages = {209 -- 232}, year = {2018}, abstract = {Reconstructive surgery and tissue replacements like ureters or bladders reconstruction have been recently studied, taking into account growth and remodelling of cells since living cells are capable of growing, adapting, remodelling or degrading and restoring in order to deform and respond to stimuli. Hence, shapes of ureters or bladders and their microstructure change during growth and these changes strongly depend on external stimuli such as training. We present the mechanical stimulation of smooth muscle cells in a tubular fibrin-PVDFA scaffold and the modelling of the growth of tissue by stimuli. To this end, mechanotransduction was performed with a kyphoplasty balloon catheter that was guided through the lumen of the tubular structure. The bursting pressure was examined to compare the stability of the incubated tissue constructs. The results showed the significant changes on tissues with training by increasing the burst pressure as a characteristic mechanical property and the smooth muscle cells were more oriented with uniformly higher density. Besides, the computational growth models also exhibited the accurate tendencies of growth of the cells under different external stimuli. Such models may lead to design standards for the better layered tissue structure in reconstructing of tubular organs characterized as composite materials such as intestines, ureters and arteries.}, language = {en} } @incollection{ArtmannMeruvuKizildagetal.2018, author = {Artmann, Gerhard and Meruvu, Haritha and Kizildag, Sefa and Temiz Artmann, Ayseg{\"u}l}, title = {Functional Toxicology and Pharmacology Test of Cell Induced Mechanical Tensile Stress in 2D and 3D Tissue Cultures}, series = {Biological, Physical and Technical Basics of Cell Engineering}, booktitle = {Biological, Physical and Technical Basics of Cell Engineering}, editor = {Artmann, Gerhard and Temiz Artmann, Ayseg{\"u}l and Zhubanova, Azhar A. and Digel, Ilya}, publisher = {Springer}, address = {Singapore}, isbn = {978-981-10-7904-7}, doi = {10.1007/978-981-10-7904-7_7}, pages = {157 -- 192}, year = {2018}, abstract = {Mechanical forces/tensile stresses are critical determinants of cellular growth, differentiation and migration patterns in health and disease. The innovative "CellDrum technology" was designed for measuring mechanical tensile stress of cultured cell monolayers/thin tissue constructs routinely. These are cultivated on very thin silicone membranes in the so-called CellDrum. The cell layers adhere firmly to the membrane and thus transmit the cell forces generated. A CellDrum consists of a cylinder which is sealed from below with a 4 μm thick, biocompatible, functionalized silicone membrane. The weight of cell culture medium bulbs the membrane out downwards. Membrane indentation is measured. When cells contract due to drug action, membrane, cells and medium are lifted upwards. The induced indentation changes allow for lateral drug induced mechanical tension quantification of the micro-tissues. With hiPS-induced (human) Cardiomyocytes (CM) the CellDrum opens new perspectives of individualized cardiac drug testing. Here, monolayers of self-beating hiPS-CMs were grown in CellDrums. Rhythmic contractions of the hiPS-cells induce membrane up-and-down deflections. The recorded cycles allow for single beat amplitude, single beat duration, integration of the single beat amplitude over the beat time and frequency analysis. Dose effects of agonists and antagonists acting on Ca2+ channels were sensitively and highly reproducibly observed. Data were consistent with published reference data as far as they were available. The combination of the CellDrum technology with hiPS-Cardiomyocytes offers a fast, facile and precise system for pharmacological and toxicological studies. It allows new preclinical basic as well as applied research in pharmacolgy and toxicology.}, language = {en} } @incollection{UlberMufflerTippkoetteretal.2011, author = {Ulber, Roland and Muffler, Kai and Tippk{\"o}tter, Nils and Hirth, Thomas and Sell, Dieter}, title = {Introduction to Renewable Resources in the Chemical Industry}, series = {Renewable raw materials : new feedstocks for the chemical industry}, booktitle = {Renewable raw materials : new feedstocks for the chemical industry}, editor = {Ulber, Roland and Sell, Dieter and Hirth, Thomas}, edition = {1. Auflage}, publisher = {Wiley-VCH-Verlag}, address = {Weinheim}, isbn = {978-3-527-32548-1}, pages = {1 -- 6}, year = {2011}, language = {de} } @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{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{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{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{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{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{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{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{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{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{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{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{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{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{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} } @inproceedings{Tippkoetter2013, author = {Tippk{\"o}tter, Nils}, title = {Biotechnologische Gewinnung von Wertstoffen aus Molke : BiobasedWorld - Innovation in food}, series = {Biotechnica 2013 : European biotechnology science \& industry news}, volume = {12}, booktitle = {Biotechnica 2013 : European biotechnology science \& industry news}, number = {9, special}, pages = {33 -- 50}, year = {2013}, language = {de} } @inproceedings{TippkoetterMoehringMaureretal.2013, author = {Tippk{\"o}tter, Nils and M{\"o}hring, S. and Maurer, S. and Roth, J.}, title = {Dezentrale Vorbehandlung und Verarbeitung pflanzlicher Reststoffe f{\"u}r Bioraffinerien}, series = {Kurzfassungen der Vortr{\"a}ge nach Sessions : Fr{\"u}hjahrstagung der Biotechnologen 2013, 4. - 5. M{\"a}rz 2013, Dechema-Haus, Frankfurt am Main}, booktitle = {Kurzfassungen der Vortr{\"a}ge nach Sessions : Fr{\"u}hjahrstagung der Biotechnologen 2013, 4. - 5. M{\"a}rz 2013, Dechema-Haus, Frankfurt am Main}, address = {Frankfurt am Main}, pages = {5}, year = {2013}, language = {de} } @inproceedings{TippkoetterRoikaewUlber2008, author = {Tippk{\"o}tter, Nils and Roikaew, W. and Ulber, R.}, title = {An automated pilot plant for the bioengineering processing of concentrated whey}, series = {European BioPerspectives : in cooperation with BIOTECHNICA 2008 : 7 - 9 October 2008 Hannover, Germany ; book of abstracts ; abstracts, poster programme}, booktitle = {European BioPerspectives : in cooperation with BIOTECHNICA 2008 : 7 - 9 October 2008 Hannover, Germany ; book of abstracts ; abstracts, poster programme}, publisher = {Dechema}, address = {Frankfurt am Main}, pages = {98}, year = {2008}, language = {en} } @inproceedings{TippkoetterStueckmannWinkelmannetal.2007, author = {Tippk{\"o}tter, Nils and St{\"u}ckmann, H. and Winkelmann, G. and Noack, U. and Beutel, S. and Scheper, T. and Ulber, R.}, title = {Optimisation of antibody-labelling of gold colloids for their application in an immunchromatographic assay for microcystin-LR}, series = {European BioPerspectives : celebrating the 25th DECHEMA annual convention of biotechnologists ; 30 May - 1 June 2007, Cologne, Germany ; book of abstracts ; abstracts, poster programme}, booktitle = {European BioPerspectives : celebrating the 25th DECHEMA annual convention of biotechnologists ; 30 May - 1 June 2007, Cologne, Germany ; book of abstracts ; abstracts, poster programme}, publisher = {Dechema}, address = {Frankfurt am Main}, pages = {126}, year = {2007}, language = {en} } @inproceedings{AlKaidyUlberTippkoetter2014, author = {Al-Kaidy, H. and Ulber, R. and Tippk{\"o}tter, Nils}, title = {A platform technology for the automated reaction control in magnetizable micro-fluidic droplets}, series = {Biomaterials - made in bioreactors : book of abstracts, May 26 - 28, 2014, Radisson Blu Park Hotel and Conference Dentre, Radebeul, Germany}, booktitle = {Biomaterials - made in bioreactors : book of abstracts, May 26 - 28, 2014, Radisson Blu Park Hotel and Conference Dentre, Radebeul, Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {21 -- 22}, year = {2014}, language = {en} } @inproceedings{TippkoetterSchuenemannChristmannetal.2008, author = {Tippk{\"o}tter, Nils and Sch{\"u}nemann, V. and Christmann, R. and Pasteur, A. and Schweizer, J. and Ulber, R.}, title = {Bioaffinity Layering magnetisierbarer Mikro- und Nanopartikel}, series = {Technische Systeme f{\"u}r die Lebenswissenschaften : 14. Heiligenst{\"a}dter Kolloquium, Heilbad Heiligenstadt, 22.09. - 24.09.2008}, booktitle = {Technische Systeme f{\"u}r die Lebenswissenschaften : 14. Heiligenst{\"a}dter Kolloquium, Heilbad Heiligenstadt, 22.09. - 24.09.2008}, editor = {Beckmann, Dieter}, address = {Heiligenstadt}, isbn = {978-3-00-025695-0}, pages = {97 -- 98}, year = {2008}, language = {de} } @inproceedings{DeterdingTippkoetterUlber2006, author = {Deterding, A. and Tippk{\"o}tter, Nils and Ulber, R.}, title = {Online-Essigs{\"a}ureanalytik in Fermentationsbr{\"u}hen mittels Fließdiffusionstechnik (FDT)}, series = {Technische Systeme f{\"u}r Biotechnologie und Umwelt : 13. Heiligenst{\"a}dter Kolloquium, Heilbad Heiligenstadt, 25.09. - 27.09.2006}, booktitle = {Technische Systeme f{\"u}r Biotechnologie und Umwelt : 13. Heiligenst{\"a}dter Kolloquium, Heilbad Heiligenstadt, 25.09. - 27.09.2006}, editor = {Beckmann, Dieter}, address = {Heiligenstadt}, organization = {Institut f{\"u}r Bioprozeß- und Analysenmeßtechnik}, isbn = {978-3-00-018621-9}, pages = {273 -- 280}, year = {2006}, language = {de} } @article{WerkhausenAlbrachtCroninetal.2017, author = {Werkhausen, Amelie and Albracht, Kirsten and Cronin, Neil J. and Meier, Rahel and Mojsen-Moeller, Jens and Seynnes, Olivier R.}, title = {Modulation of muscle-tendon interaction in the human triceps surae during an energy dissipation task}, series = {Journal of Experimental Biology}, volume = {220}, journal = {Journal of Experimental Biology}, number = {22}, issn = {0022-0949}, doi = {10.1242/jeb.164111}, pages = {4141 -- 4149}, year = {2017}, language = {en} } @article{DemmerChowdhurySelmeretal.2017, author = {Demmer, Julius K. and Chowdhury, Nilanjan Pal and Selmer, Thorsten and Ermler, Ulrich and Buckel, Wolfgang}, title = {The semiquinone swing in the bifurcating electron transferring flavoprotein/butyryl-CoA dehydrogenase complex from Clostridium difficile}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, number = {1}, issn = {2041-1723}, doi = {10.1038/s41467-017-01746-3}, pages = {1 -- 10}, year = {2017}, language = {en} } @article{BreuerMangSchoeningetal.2017, author = {Breuer, Lars and Mang, Thomas and Sch{\"o}ning, Michael Josef and Thoelen, Ronald and Wagner, Torsten}, title = {Investigation of the spatial resolution of a laser-based stimulation process for light-addressable hydrogels with incorporated graphene oxide by means of IR thermography}, series = {Sensors and Actuators A: Physical}, volume = {268}, journal = {Sensors and Actuators A: Physical}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0924-4247}, doi = {10.1016/j.sna.2017.11.031}, pages = {126 -- 132}, year = {2017}, language = {en} } @article{UlberTippkoetter2009, author = {Ulber, Roland and Tippk{\"o}tter, Nils}, title = {Nitratfreie Molke}, series = {Rundschau f{\"u}r Fleischhygiene und Lebensmittel{\"u}berwachung}, journal = {Rundschau f{\"u}r Fleischhygiene und Lebensmittel{\"u}berwachung}, number = {4}, pages = {150 -- 152}, year = {2009}, language = {de} } @article{TippkoetterStueckmannKrolletal.2009, author = {Tippk{\"o}tter, Nils and St{\"u}ckmann, Henning and Kroll, Stephen and Winkelmann, Gunda and Noack, Udo and Scheper, Thomas and Ulber, Roland}, title = {A semi-quantitative dipstick assay for microcystin}, series = {Analytical and Bioanalytical Chemistry}, volume = {394}, journal = {Analytical and Bioanalytical Chemistry}, number = {3}, publisher = {springer}, address = {Berlin}, issn = {1618-2650}, doi = {10.1007/s00216-009-2750-8}, pages = {863 -- 869}, year = {2009}, abstract = {An immunochromatographic lateral flow dipstick assay for the fast detection of microcystin-LR was developed. Colloid gold particles with diameters of 40 nm were used as red-colored antibody labels for the visual detection of the antigen. The new dipstick sensor is capable of detecting down to 5 µg·l-1 (ppb; total inversion of the color signal) or 1 ppb (observation of color grading) of microcystin-LR. The course of the labeling reaction was observed via spectrometric wave shifts caused by the change of particle size during the binding of antibodies. Different stabilizing reagents showed that especially bovine serum albumin (BSA) and casein increase the assays sensitivity and the conjugate stability. Performance of the dipsticks was quantified by pattern processing of capture zone CCD images. Storage stability of dipsticks and conjugate suspensions over 115 days under different conditions were monitored. The ready-to-use dipsticks were successfully tested with microcystin-LR-spiked samples of outdoor drinking- and salt water and applied to the tissue of microcystin-fed mussels.}, language = {en} } @article{UlberTippkoetterBuchholzetal.2008, author = {Ulber, R. and Tippk{\"o}tter, Nils and Buchholz, H. and Demmer, W. and Scheper, T.}, title = {Innovative Verfahren in der Molkeaufarbeitung zur Gewinnung neuer Produkte}, series = {Deutsche Milchwirtschaft}, volume = {59}, journal = {Deutsche Milchwirtschaft}, number = {19}, issn = {0012-0480}, pages = {704 -- 706}, year = {2008}, language = {de} } @article{TippkoetterRoikaewUlber2008, author = {Tippk{\"o}tter, Nils and Roikaew, W. and Ulber, R.}, title = {Nitrate removal from whey concentrate with biotechnological regeneration of the waste water}, series = {European dairy magazine : EDM}, journal = {European dairy magazine : EDM}, number = {1}, isbn = {0936-6318}, pages = {30 -- 32}, year = {2008}, language = {en} } @article{TippkoetterRoikaewUlber2007, author = {Tippk{\"o}tter, Nils and Roikaew, N. and Ulber, R.}, title = {Nitratentfernung aus Molkekonzentrat mit biotechnologischer Regeneration der Abw{\"a}sser}, series = {Deutsche Milchwirtschaft}, volume = {58}, journal = {Deutsche Milchwirtschaft}, number = {15}, issn = {0012-0480}, pages = {540 -- 542}, year = {2007}, language = {de} } @misc{StadtmuellerTippkoetterUlber2013, author = {Stadtm{\"u}ller, Ralf and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {A method for production of single-stranded nucleic acids [Europ{\"a}ische Patentanmeldung]}, publisher = {Europ{\"a}isches Patentamt}, address = {Den Hague}, pages = {14 Seiten}, year = {2013}, language = {en} } @misc{AlKaidyTippkoetterUlber2013, author = {Al-Kaidy, Huschyar and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {A system and a method for the implementation of chemical, biological or physical reactions [Europ{\"a}ische Patentanmeldung]}, publisher = {Europ{\"a}isches Patentamt}, address = {Den Hague}, pages = {16 Seiten}, year = {2013}, abstract = {The invention relates to a system for the implementation of chemical, biological or physical reactions, consisting of - one or more magnetic micro-reactors, each comprising a shell made of hydrophobic magnetic nanoparticles encapsulating an aqueous core, - a plane platform comprising a surface to receive the micro-reactors, - a source that generates a magnetic field above or underneath the platform for manipulating the one or more hydrophobic magnetic micro-reactors, or for moving them along the surface of the platform from one position to another position, characterized in that the aqueous core of the one or more magnetic micro-reactors contains a reaction solution or buffer, and wherein the magnetic field generated by the source correlates to a defined position on the surface of the platform.}, language = {en} } @misc{AlKaidyTippkoetterUlber2014, author = {Al-Kaidy, Huschyar and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Vorrichtung und Verfahren zur Bestimmung des Kontaktwinkels eines fl{\"u}ssigen oder mit Fl{\"u}ssigkeit gef{\"u}llten K{\"o}rpers [Offenlegungsschrift]}, publisher = {Deutsches Patent- und Markenamt}, address = {M{\"u}nchen}, pages = {13 Seiten}, year = {2014}, abstract = {Die vorliegende Erfindung betrifft eine Vorrichtung und ein Verfahren zur Bestimmung des Kontaktwinkels eines fl{\"u}ssigen oder mit Fl{\"u}ssigkeit gef{\"u}llten K{\"o}rpers. Dieser besteht aus einem Tr{\"a}ger (1) und einer damit verbundenen, in einem Winkelbereich von mehr als 0° bis maximal 90° neigbaren Ebene (8) mit einer darin ausgebildeten Abrollbahn (9) f{\"u}r den fl{\"u}ssigen oder mit Fl{\"u}ssigkeit gef{\"u}llten K{\"o}rper. An der Ebene (8) sind mehrere Sensoren (11, 12) zur Erfassung der Rolldauer des K{\"o}rpers entlang der Rollstrecke angeordnet. Erfindungsgem{\"a}ß ist vorgesehen, dass die Einstellung des Neigungswinkels der Ebene (8) {\"u}ber ein Winkelmessger{\"a}t (10) erfolgt, wodurch ein Abrollwinkel erfassbar ist, bei dem der K{\"o}rper in Bewegung ger{\"a}t. Aus der Rolldauer, der Rollstrecke und dem Abrollwinkel wird der Kontaktwinkel des K{\"o}rpers ermittelt.}, language = {de} } @inproceedings{SiekerDuwePothetal.2012, author = {Sieker, T. and Duwe, A. and Poth, S. and Tippk{\"o}tter, Nils and Ulber, R.}, title = {Herstellung von Itacons{\"a}ure aus Buchenholzhydrolysaten}, series = {Kurzfassungsband / GVC-DECHEMA Vortrags- und Diskussionstagung Biopharmazeutische Produktion : 14. - 16. Mai 2012. Konzerthaus Freibung}, booktitle = {Kurzfassungsband / GVC-DECHEMA Vortrags- und Diskussionstagung Biopharmazeutische Produktion : 14. - 16. Mai 2012. Konzerthaus Freibung}, publisher = {DECHEMA}, address = {Frankfurt, M.}, pages = {57}, year = {2012}, language = {de} } @inproceedings{WulfhorstDuweMoehringetal.2016, author = {Wulfhorst, H. and Duwe, A. and M{\"o}hring, S. and Jurca, O. and Tippk{\"o}tter, Nils}, title = {Analysis of pretreated biomass by differential scanning 132 calorimetry and multivariate data analysis}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {132}, year = {2016}, language = {en} } @inproceedings{CapitainHeringTippkoetteretal.2016, author = {Capitain, C. and Hering, T. and Tippk{\"o}tter, Nils and Ulber, R.}, title = {Enzymatic polymerization of lignin model compounds and solubilized lignin in an aqueous ethanol extract}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {151 -- 152}, year = {2016}, language = {en} } @inproceedings{MoehringWulfhorstRothetal.2016, author = {M{\"o}hring, S. and Wulfhorst, H. and Roth, J. and Tippk{\"o}tter, Nils}, title = {Pretreatment strategies for lignocellulosic biomass}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {131}, year = {2016}, language = {en} } @inproceedings{RothMoehringTippkoetter2016, author = {Roth, J. and M{\"o}hring, S. and Tippk{\"o}tter, Nils}, title = {Characterization and evaluation of lignocellulosic biomass 130 hydrolysates for ABE fermentation}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {130}, year = {2016}, language = {en} } @inproceedings{HeringUlberTippkoetter2016, author = {Hering, T. and Ulber, Roland and Tippk{\"o}tter, Nils}, title = {Development of a screening system for antimicrobial surfaces}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {129}, year = {2016}, language = {en} } @inproceedings{EngelThieringerTippkoetter2016, author = {Engel, M. and Thieringer, J. and Tippk{\"o}tter, Nils}, title = {Microbial electrosynthesis for sustainable biobutanol production}, series = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, booktitle = {New frontiers of biotech-processes (Himmelfahrtstagung) : 02-04 May 2016, Rhein-Mosel-Halle, Koblenz/Germany}, publisher = {DECHEMA}, address = {Frankfurt am Main}, pages = {77 -- 78}, year = {2016}, language = {en} } @article{SeifarthGrosseGrossmannetal.2017, author = {Seifarth, Volker and Grosse, Joachim O. and Grossmann, Matthias and Janke, Heinz Peter and Arndt, Patrick and Koch, Sabine and Epple, Matthias and Artmann, Gerhard and Temiz Artmann, Ayseg{\"u}l}, title = {Mechanical induction of bi-directional orientation of primary porcine bladder smooth muscle cells in tubular fibrin-poly(vinylidene fluoride) scaffolds for ureteral and urethral repair using cyclic and focal balloon catheter stimulation}, series = {Journal of Biomaterials Applications}, volume = {32}, journal = {Journal of Biomaterials Applications}, number = {3}, publisher = {Sage}, address = {London}, issn = {1530-8022}, doi = {10.1177/0885328217723178}, pages = {321 -- 330}, year = {2017}, language = {en} } @article{PilasYaziciSelmeretal.2017, author = {Pilas, Johanna and Yazici, Yasemen and Selmer, Thorsten and Keusgen, Michael and Sch{\"o}ning, Michael Josef}, title = {Optimization of an amperometric biosensor array for simultaneous measurement of ethanol, formate, d- and l-lactate}, series = {Electrochimica Acta}, volume = {251}, journal = {Electrochimica Acta}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0013-4686}, doi = {10.1016/j.electacta.2017.07.119}, pages = {256 -- 262}, year = {2017}, abstract = {The immobilization of NAD+-dependent dehydrogenases, in combination with a diaphorase, enables the facile development of multiparametric sensing devices. In this work, an amperometric biosensor array for simultaneous determination of ethanol, formate, d- and l-lactate is presented. Enzyme immobilization on platinum thin-film electrodes was realized by chemical cross-linking with glutaraldehyde. The optimization of the sensor performance was investigated with regard to enzyme loading, glutaraldehyde concentration, pH, cofactor concentration and temperature. Under optimal working conditions (potassium phosphate buffer with pH 7.5, 2.5 mmol L-1 NAD+, 2.0 mmol L-1 ferricyanide, 25 °C and 0.4\% glutaraldehyde) the linear working range and sensitivity of the four sensor elements was improved. Simultaneous and cross-talk free measurements of four different metabolic parameters were performed successfully. The reliable analytical performance of the biosensor array was demonstrated by application in a clarified sample of inoculum sludge. Thereby, a promising approach for on-site monitoring of fermentation processes is provided.}, language = {en} } @article{RoehlenPilasSchoeningetal.2017, author = {R{\"o}hlen, Desiree and Pilas, Johanna and Sch{\"o}ning, Michael Josef and Selmer, Thorsten}, title = {Development of an amperometric biosensor platform for the combined determination of l-Malic, Fumaric, and l-Aspartic acid}, series = {Applied Biochemistry and Biotechnology}, volume = {183}, journal = {Applied Biochemistry and Biotechnology}, publisher = {Springer}, address = {Berlin}, issn = {1559-0291}, doi = {10.1007/s12010-017-2578-1}, pages = {566 -- 581}, year = {2017}, abstract = {Three amperometric biosensors have been developed for the detection of L-malic acid, fumaric acid, and L -aspartic acid, all based on the combination of a malate-specific dehydrogenase (MDH, EC 1.1.1.37) and diaphorase (DIA, EC 1.8.1.4). The stepwise expansion of the malate platform with the enzymes fumarate hydratase (FH, EC 4.2.1.2) and aspartate ammonia-lyase (ASPA, EC 4.3.1.1) resulted in multi-enzyme reaction cascades and, thus, augmentation of the substrate spectrum of the sensors. Electrochemical measurements were carried out in presence of the cofactor β-nicotinamide adenine dinucleotide (NAD+) and the redox mediator hexacyanoferrate (III) (HCFIII). The amperometric detection is mediated by oxidation of hexacyanoferrate (II) (HCFII) at an applied potential of + 0.3 V vs. Ag/AgCl. For each biosensor, optimum working conditions were defined by adjustment of cofactor concentrations, buffer pH, and immobilization procedure. Under these improved conditions, amperometric responses were linear up to 3.0 mM for L-malate and fumarate, respectively, with a corresponding sensitivity of 0.7 μA mM-1 (L-malate biosensor) and 0.4 μA mM-1 (fumarate biosensor). The L-aspartate detection system displayed a linear range of 1.0-10.0 mM with a sensitivity of 0.09 μA mM-1. The sensor characteristics suggest that the developed platform provides a promising method for the detection and differentiation of the three substrates.}, language = {en} } @article{MuschallikMolinnusBongaertsetal.2017, author = {Muschallik, Lukas and Molinnus, Denise and Bongaerts, Johannes and Pohl, Martina and Wagner, Torsten and Sch{\"o}ning, Michael Josef and Siegert, Petra and Selmer, Thorsten}, title = {(R,R)-Butane-2,3-diol Dehydrogenase from Bacillus clausii DSM 8716T: Cloning and Expression of the bdhA-Gene, and Initial Characterization of Enzyme}, series = {Journal of Biotechnology}, volume = {258}, journal = {Journal of Biotechnology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0168-1656}, doi = {10.1016/j.jbiotec.2017.07.020}, pages = {41 -- 50}, year = {2017}, abstract = {The gene encoding a putative (R,R)-butane-2,3-diol dehydrogenase (bdhA) from Bacillus clausii DSM 8716T was isolated, sequenced and expressed in Escherichia coli. The amino acid sequence of the encoded protein is only distantly related to previously studied enzymes (identity 33-43\%) and exhibited some uncharted peculiarities. An N-terminally StrepII-tagged enzyme variant was purified and initially characterized. The isolated enzyme catalyzed the (R)-specific oxidation of (R,R)- and meso-butane-2,3-diol to (R)- and (S)-acetoin with specific activities of 12 U/mg and 23 U/mg, respectively. Likewise, racemic acetoin was reduced with a specific activity of up to 115 U/mg yielding a mixture of (R,R)- and meso-butane-2,3-diol, while the enzyme reduced butane-2,3-dione (Vmax 74 U/mg) solely to (R,R)-butane-2,3-diol via (R)-acetoin. For these reactions only activity with the co-substrates NADH/NAD+ was observed. The enzyme accepted a selection of vicinal diketones, α-hydroxy ketones and vicinal diols as alternative substrates. Although the physiological function of the enzyme in B. clausii remains elusive, the data presented herein clearly demonstrates that the encoded enzyme is a genuine (R,R)-butane-2,3-diol dehydrogenase with potential for applications in biocatalysis and sensor development.}, language = {en} } @article{TippkoetterDuweWiesenetal.2014, author = {Tippk{\"o}tter, Nils and Duwe, Anna-Maria and Wiesen, Sebastian and Sieker, Tim and Ulber, Roland}, title = {Enzymatic hydrolysis of beech wood lignocellulose at high solid contents and its utilization as substrate for the production of biobutanol and dicarboxylic acids}, series = {Bioresource Technology}, volume = {167}, journal = {Bioresource Technology}, publisher = {Elsevier}, address = {Amsterdam}, doi = {10.1016/j.biortech.2014.06.052}, pages = {447 -- 455}, year = {2014}, abstract = {The development of a cost-effective hydrolysis for crude cellulose is an essential part of biorefinery developments. To establish such high solid hydrolysis, a new solid state reactor with static mixing is used. However, concentrations >10\% (w/w) cause a rate and yield reduction of enzymatic hydrolysis. By optimizing the synergetic activity of cellulolytic enzymes at solid concentrations of 9\%, 17\% and 23\% (w/w) of crude Organosolv cellulose, glucose concentrations of 57, 113 and 152 g L⁻¹ are reached. However, the glucose yield decreases from 0.81 to 0.72gg⁻¹ at 17\% (w/w). Optimal conditions for hydrolysis scale-up under minimal enzyme addition are identified. As result, at 23\% (w/w) crude cellulose the glucose yield increases from 0.29 to 0.49gg⁻¹. As proof of its applicability, biobutanol, succinic and itaconic acid are produced with the crude hydrolysate. The potential of the substrate is proven e.g. by a high butanol yield of 0.33gg⁻¹.}, language = {en} } @article{WiesenTippkoetterMuffleretal.2015, author = {Wiesen, Sebastian and Tippk{\"o}tter, Nils and Muffler, Kai and Suck, Kirstin and Sohling, Ulrich and Ruf, Friedrich and Ulber, Roland}, title = {Adsorption of fatty acids to layered double hydroxides in aqueous systems}, series = {Adsorption}, volume = {21}, journal = {Adsorption}, number = {6-7}, publisher = {Springer}, address = {Berlin}, pages = {459 -- 466}, year = {2015}, abstract = {Due to their anion exchange characteristics, layered double hydroxides (LDHs) are suitable for the detoxification of aqueous, fatty acid containing fermentation substrates. The aim of this study is to examine the adsorption mechanism, using crude glycerol from plant oil esterification as a model system. Changes in the intercalation structure in relation to the amount of fatty acids adsorbed are monitored by X-ray diffraction and infra-red spectroscopy. Additionally, calcination of LDH is investigated in order to increase the binding capacity for fatty acids. Our data propose that, at ambient temperature, fatty acids can be bound to the hydrotalcite by adsorption or in addition by intercalation, depending on fatty acid concentration. The adsorption of fatty acids from crude glycerol shows a BET-like behavior. Above a fatty acid concentration of 3.5 g L-1, intercalation of fatty acids can be shown by the appearance of an increased interlayer spacing. This observation suggests a two phase adsorption process. Calcination of LDHs allows increasing the binding capacity for fatty acids by more than six times, mainly by reduction of structural CO32-.}, language = {en} } @article{WulfhorstDuweMerseburgetal.2016, author = {Wulfhorst, Helene and Duwe, Anna-Maria and Merseburg, Johannes and Tippk{\"o}tter, Nils}, title = {Compositional analysis of pretreated (beech) wood using differential scanning calorimetry and multivariate data analysis}, series = {Tetrahedron}, volume = {72}, journal = {Tetrahedron}, number = {46}, publisher = {Elsevier}, address = {Amsterdam}, doi = {10.1016/j.tet.2016.04.029}, pages = {7329 -- 7334}, year = {2016}, abstract = {The composition of plant biomass varies depending on the feedstock and pre-treatment conditions and influences its processing in biorefineries. In order to ensure optimal process conditions, the quantitative proportion of the main polymeric components of the pre-treated biomass has to be determined. Current standard procedures for biomass compositional analysis are complex, the measurements are afflicted with errors and therefore often not comparable. Hence, new powerful analytical methods are urgently required to characterize biomass. In this contribution, Differential Scanning Calorimetry (DSC) was applied in combination with multivariate data analysis (MVA) to detect the cellulose content of the plant biomass pretreated by Liquid Hot Water (LHW) and Organosolv processes under various conditions. Unlike conventional techniques, the developed analytic method enables the accurate quantification of monosaccharide content of the plant biomass without any previous sample preparation. It is easy to handle and avoids errors in sample preparation.}, language = {en} } @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{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{TippkoetterWollnyKampeisetal.2011, author = {Tippk{\"o}tter, Nils and Wollny, S. and Kampeis, P. and Oster, J. and Schneider, H. and Ulber, R.}, 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} } @inproceedings{PothMonzonTippkoetteretal.2010, author = {Poth, Sebastian and Monzon, Magaly and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Lignocellulosic biorefinery : process integration of hydrolysis and fermentation}, series = {Proceedings / 11th European Workshop on Lignocellulosics and Pulp : August 16 - 19, 2010, Hamburg, Germany}, booktitle = {Proceedings / 11th European Workshop on Lignocellulosics and Pulp : August 16 - 19, 2010, Hamburg, Germany}, publisher = {vTi}, address = {Hamburg}, pages = {65 -- 68}, year = {2010}, language = {en} } @book{Tippkoetter2010, author = {Tippk{\"o}tter, Nils}, title = {Reaktionssysteme zur Aufarbeitung und Umsetzung nachwachsender Rohstoffe : Einsatz chromatographischer Verfahren sowie Membran- und Festbettreaktoren zur Verarbeitung von Molke, St{\"a}rke und Cellulose}, publisher = {Logos-Verlag}, address = {Berlin}, isbn = {978-3-8325-2717-4}, pages = {III, 269 Seiten}, year = {2010}, language = {de} } @incollection{MufflerTippkoetterUlber2010, author = {Muffler, Kai and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Chemical feedstocks and fine chemicals from other substrates}, series = {Handbook of hydrocarbon and lipid microbiology. Volume 4: Consequences of microbial interactions with hydrocarbons, oils and lipids. - (Springer reference)}, booktitle = {Handbook of hydrocarbon and lipid microbiology. Volume 4: Consequences of microbial interactions with hydrocarbons, oils and lipids. - (Springer reference)}, editor = {Timmis, Kenneth N.}, publisher = {Springer}, address = {Berlin [u.a.]}, isbn = {978-3-540-77588-1}, doi = {10.1007\%2F978-3-540-77587-4_214}, pages = {2891 -- 2902}, year = {2010}, language = {en} } @incollection{MufflerPothSiekeretal.2011, author = {Muffler, Kai and Poth, Sabastian and Sieker, Tim and Tippk{\"o}tter, Nils and Ulber, Roland and Sell, Dieter}, title = {Bio-feedstocks}, series = {Comprehensive biotechnology : principles and practices in industry, agcriculture, medicine and the environment. Volume 2: Engineering fundamentals of biotechnology}, booktitle = {Comprehensive biotechnology : principles and practices in industry, agcriculture, medicine and the environment. Volume 2: Engineering fundamentals of biotechnology}, editor = {Moo-Young, Murray}, edition = {2. edition}, publisher = {Elsevier}, address = {Amsterdam}, isbn = {978-0-444-53352-4}, doi = {10.1016/B978-0-08-088504-9.00088-X}, pages = {93 -- 101}, year = {2011}, language = {en} } @incollection{HahnKellyMuffleretal.2011, author = {Hahn, Thomas and Kelly, Svenja and Muffler, Kai and Tippk{\"o}tter, Nils and Ulber, Roland}, title = {Extraction of lignocellulose and algae for the production of bulk and fine chemicals}, series = {Industrial scale natural products extraction}, booktitle = {Industrial scale natural products extraction}, editor = {Hans-J{\"o}rg, Bart and Pilz, Stephan}, publisher = {Wiley-VCH}, address = {Weinheim}, isbn = {978-3-527-32504-7 (Print)}, doi = {10.1002/9783527635122}, pages = {221 -- 245}, year = {2011}, language = {en} } @incollection{Tippkoetter2016, author = {Tippk{\"o}tter, Nils}, title = {Grundlagen der bio-chemischen Umwandlung}, series = {Energie aus Biomasse : Grundlagen, Techniken und Verfahren}, booktitle = {Energie aus Biomasse : Grundlagen, Techniken und Verfahren}, editor = {Kaltschmidt, Martin}, edition = {3., aktualisierte, erweiterte Auflage}, publisher = {Springer Vieweg}, address = {Berlin ; Heidelberg}, isbn = {978-3-662-47437-2 (Print)}, doi = {10.1007/978-3-662-47438-9}, pages = {1447 -- 1500}, year = {2016}, language = {de} } @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{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{GrafSteinhofLotzetal.2009, author = {Graf, Alain-Michel and Steinhof, Rafael and Lotz, Martin and Tippk{\"o}tter, Nils and Kasper, Cornelia and Beutel, Sascha and Ulber, Roland}, title = {Downstream-Processing mit Membranadsorbern zur Isolierung nativer Proteinfraktionen aus Kartoffelfruchtwasser}, series = {Chemie Ingenieur Technik}, volume = {81}, journal = {Chemie Ingenieur Technik}, number = {3}, publisher = {Wiley}, address = {Weinheim}, doi = {10.1002/cite.200800139}, pages = {267 -- 274}, year = {2009}, abstract = {Bei der St{\"a}rkeproduktion entstehendes Kartoffelfruchtwasser besitzt mit 2 - 3 \% einen hohen Anteil an ern{\"a}hrungsphysiologisch interessanten Proteinen. Die industrielle Gewinnung dieser Proteinfracht liefert jedoch lediglich ein minderwertiges, denaturiertes Produkt. Mit Hilfe der Membranadsorber-Technologie lassen sich aus Kartoffelfruchtwasser unter milden Reaktionsbedingungen native bioaktive Proteinfraktionen gewinnen. Geeignete Trennbedingungen wurden im Labormaßstab entwickelt und in den Technikumsmaßstab {\"u}bertragen. An Anionenaustauscher-Membranadsorbern mit einer Membranfl{\"a}che von 10 000 cm2 wurde eine Patatinhaltige Fraktion (44 kDa) mit Bindungskapazit{\"a}ten von 0,37 mg/cm2 isoliert. Eine niedermolekulare Proteinfraktion mit Protease-Inhibitoren konnte durch Kationenaustauscher-Membranadsorber mit Bindungskapazit{\"a}ten von 1,00 mg/cm2 gewonnen werden. Sie ist f{\"u}r verschiedenste Applikationen in der pharmazeutischen, kosmetischen und der Nahrungsmittelindustrie interessant z. B. f{\"u}r Appetitz{\"u}gler oder muskelaufbauende Proteinpr{\"a}parate. Der Aufreinigung der nativen Proteinfraktionen durch Ultra-/Diafiltration schließt sich die Konfektionierung durch Spr{\"u}htrocknung an. Die bioanalytische Charakterisierung der Produkte belegt die Reinheit und die enzymatische Aktivit{\"a}t sowie die Abreicherung von St{\"o}rkomponenten wie Glykoalkaloide und Polyphenoloxidasen.}, 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{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} }