Biotechnology and Bioengineering

Cover image for Vol. 114 Issue 1

Early View (Online Version of Record published before inclusion in an issue)

Edited By: Douglas S. Clark

Impact Factor: 4.243

ISI Journal Citation Reports © Ranking: 2015: 24/161 (Biotechnology & Applied Microbiology)

Online ISSN: 1097-0290


  1. 1 - 69
  1. Communications to the Editor

    1. Noninvasive assessment of tissue-engineered graft viability by oxygen-17 magnetic resonance spectroscopy

      Samuel A. Einstein, Bradley P. Weegman, Jennifer P. Kitzmann, Klearchos K. Papas and Michael Garwood

      Version of Record online: 29 NOV 2016 | DOI: 10.1002/bit.26227

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      Techniques to measure tissue-engineered graft (TEG) viability are limited, but a 17O-MRS technique is proposed to quantify the viability of macroencapsulated cells. Cells metabolized 17O2 gas into H217O water and this oxygen consumption rate (OCR) was measured with 17O-MRS. The 17O-MRS measurements agreed well with those of a stirred microchamber, a well-established technique, and it was found that 17O-MRS offers a reliable, accurate, and noninvasive approach to TEG viability assessment.

  2. Articles

    1. Tissue Engineering and Delivery Systems

      Enhancement of human neural stem cell self-renewal in 3D hypoxic culture

      Sasan Sharee Ghourichaee, Elizabeth M. Powell and Jennie B. Leach

      Version of Record online: 29 NOV 2016 | DOI: 10.1002/bit.26224

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      Human neural stem cells exhibit synergistic responses to culture dimensionality and hypoxic oxygen concentration in the presence of growth factors to enhance the proliferation of viable, undifferentiated hNSCs. In the absence of growth factors, dimensionality and hypoxia synergistically promote differentiation.

    2. Integration of parallel 13C-labeling experiments and in silico pathway analysis for enhanced production of ascomycin

      Haishan Qi, Mengmeng Lv, Kejing Song and Jianping Wen

      Version of Record online: 29 NOV 2016 | DOI: 10.1002/bit.26223

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      A novel strategy combining 13C-labeling experiments and elementary flux modes analysis for efficient strain improvement was developed in this study, which provides potential applications in balancing and increasing the flux through engineering target genes in a target organism to achieve higher yield and productivity. Based on this strategy, an industrial Streptomyces hygroscopicus var. ascomyceticus strain TD-ΔPyc-fkbO capable of efficiently producing ascomycin was obtained.

    3. Omega-3 production by fermentation of Yarrowia lipolytica: From fed-batch to continuous

      Dongming Xie, Edward Miller, Pamela Sharpe, Ethel Jackson and Quinn Zhu

      Version of Record online: 29 NOV 2016 | DOI: 10.1002/bit.26216

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      With the help of an established mathematical model, a two-stage continuous fermentation process was developed for the production of omega-3 EPA (eicosapentaenoic acid, C20:5) by recombinant strains of Y. lipolytica. The two stage continuous experiment, which was equipped with a 2 L growth fermentor and a 5 L production fermentor, successfully improved the overall EPA productivity by 80% and EPA concentration by 40% while achieving comparable EPA content in biomass (22∼25% DCW) and similar conversion yield from glucose as compared to the standard fed-batch fermentation process.

    4. An expression tag toolbox for microbial production of membrane bound plant cytochromes P450

      Dario Vazquez-Albacete, Ana Mafalda Cavaleiro, Ulla Christensen, Susanna Seppälä, Birger Lindberg Møller and Morten H. H. Nørholm

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26203

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      In this study a library of N-terminal fusion tags has been constructed to improve expression and membrane targeting of cytochrome P450 enzymes (P450s). A high-throughput C-terminal GFP platform allows for fast identification of highly expressed P450 chimeras. The approach has been successfully applied in a plant multigene pathway leading to the production of a natural compound. Using this platform, new N-terminal tags can be rapidly assessed in order to accelerate the design of new cell factories.

    5. In vitro suppression of two different stop codons

      Eden Ozer, Yonatan Chemla, Orr Schlesinger, Haim Yuval Aviram, Inbal Riven, Gilad Haran and Lital Alfonta

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26226

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      A protein containing two different unnatural amino acids, incorporated in response to two different stop-codons, was generated through a combination of two different cell-free extracts. Each extract contained a different tRNA-synthetase/tRNA pair prior to lysis, thus resulting in two lysates with the ability to incorporate a different unnatural amino acid. The authors were able to produce a protein containing two biorthogonal chemical-handles, which were tethered to fluorophores, and susequently was used for FRET.

  3. Communication to the Editors

    1. Enhanced itaconic acid production by self-assembly of two biosynthetic enzymes in Escherichia coli

      Zhongwei Yang, Xin Gao, Hui Xie, Fengqing Wang, Yuhong Ren and Dongzhi Wei

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26081

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      A novel strategy for the production of itaconic acid by self-assembly of two key enzymes via the interactional force of protein–peptide was developed in this study, which provides remarkable potentials for the further improvement of itaconate production by improving the local concentration of metabolic intermediate.

  4. Articles

    1. Identification of mineral-binding peptides that discriminate between chalcopyrite and enargite

      Susan Curtis, Franziska L. Lederer, W. Scott Dunbar and Ross T.A. MacGillivray

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26218

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      Significant economic and environmental costs are associated with processing copper concentrates containing arsenic in the production of pure copper. Curtis and co-workers utilized phage display to identify peptides that discriminate between two copper-containing ores that occur naturally together; the arsenic-containing enargite and the arsenic-free chalcopyrite. Mineral-binding selectivity was demonstrated by binding studies, zeta potential determination and immunochemistry. Peptides that discriminate between enargite and chalcopyrite would provide a greener option for the separation of arsenic containing contaminants from copper concentrates.

    2. Overexpression of OLE1 enhances stress tolerance and constitutively activates the MAPK HOG pathway in Saccharomyces cerevisiae

      Olviyani Nasution, Young Mi Lee, Eunjung Kim, Yeji Lee, Wankee Kim and Wonja Choi

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26093

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      OLE1 of Saccharomyces cerevisiae encodes the sole and essential Δ-9 desaturase catalyzing the conversion of saturated to unsaturated fatty acids. Ectopic overexpression of OLE1 in S. cerevisiae enhances tolerance to various types of stress with significant increases in the membrane oleic acid content.

    3. Dynamic changes of substrate reactivity and enzyme adsorption on partially hydrolyzed cellulose

      Jian Shi, Dong Wu, Libing Zhang, Blake A. Simmons, Seema Singh, Bin Yang and Charles E. Wyman

      Version of Record online: 28 NOV 2016 | DOI: 10.1002/bit.26180

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      Dynamic changes of substrate reactivity and enzyme adsorption on partially hydrolyzed cellulose.

    4. Shuttle-mediated nanoparticle transport across an in vitro brain endothelium under flow conditions

      Andrea P. Falanga, Gabriele Pitingolo, Maurizio Celentano, Armando Cosentino, Pietro Melone, Raffaele Vecchione, Daniela Guarnieri and Paolo A. Netti

      Version of Record online: 24 NOV 2016 | DOI: 10.1002/bit.26221

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      A microfluidic system was designed in order to study the effect of flow conditions in controlling the interaction of functionalized nanoparticles with a blood brain barrier (BBB) model in vitro. Endothelial barrier formation in this system and the enhancement of BBB crossing in flow conditions upon nanoparticle functionalization with gH625 peptides were successfully obtained. This study confirms the efficacy of gH625-based delivery platform and highlights the potentiality of the fabricated microfluidic system in transport studies across the BBB.

    5. Maximization of cell viability rather than biocatalyst activity improves whole-cell ω-oxyfunctionalization performance

      Marvin Kadisch, Mattijs K. Julsing, Manfred Schrewe, Nico Jehmlich, Benjamin Scheer, Martin von Bergen, Andreas Schmid and Bruno Bühler

      Version of Record online: 24 NOV 2016 | DOI: 10.1002/bit.26213

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      Whole-cell biotransformations of fatty acid methyl esters (FAMEs) to oxyfunctionalized products (Ox-FAMEs) benefit from fine-tuned gene expression. Balancing the expression of the hydrophobic membrane porin AlkL and the monooxygenase AlkBGT conciliates between stability and activity of respective whole-cell biocatalysts. By this strategy, the highest product titers published to date for E. coli-based oxyfunctionalization processes have been achieved.

    6. You have full text access to this OnlineOpen article
      Segmented linear modeling of CHO fed-batch culture and its application to large scale production

      Bassem Ben Yahia, Boris Gourevitch, Laetitia Malphettes and Elmar Heinzle

      Version of Record online: 21 NOV 2016 | DOI: 10.1002/bit.26214

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      A systematic approach based on segmented linear modelling to predict CHO metabolism during biopharmaceutical production across a wide range of cell culture conditions is presented. Using the model structure and parameter values from a small scale cell culture training dataset, it was possible to predict metabolic rates of new fed-batch cultures just using the experimental specific growth rates. Such prediction was successful both at the laboratory scale with 2 L bioreactors and at the production scale of 2000 L.

    7. Online measurement of viscosity for biological systems in stirred tank bioreactors

      Maximilian Schelden, William Lima, Eric Will Doerr, Martin Wunderlich, Lars Rehmann, Jochen Büchs and Lars Regestein

      Version of Record online: 21 NOV 2016 | DOI: 10.1002/bit.26219

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      This study demonstrates a method for the online determination of the viscosity inside a stirred tank reactor. The presented method is based on online measurement of heat transfer capacity from the bulk medium to the jacket of the reactor. To prove the feasibility of the method, fermentations with the xanthan producing bacterium Xanthomonas campestris pv. campestris B100 as model system were performed. The developed tool should be applicable to any other process with formation of biopolymers and filamentous growth.

    8. Anaerobic reduction of 2,6-dinitrotoluene by Shewanella oneidensis MR-1: Roles of Mtr respiratory pathway and NfnB

      Dong-Feng Liu, Di Min, Lei Cheng, Feng Zhang, Dao-Bo Li, Xiang Xiao, Guo-Ping Sheng and Han-Qing Yu

      Version of Record online: 21 NOV 2016 | DOI: 10.1002/bit.26212

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      The anaerobic reduction mechanism of 2,6-dinitrotoluene (2,6-DNT) by Shewanella oneidensis MR-1, a typical EAB, was investigated. Liu and coworkers have found that S. oneidensis MR-1 was able to obtain energy for growth through the anaerobic respiration on 2,6-DNT. Both intracellular and extracellular reductions contributed to such a rapid bioreduction.

  5. Communication to the Editors

    1. Novel technique for high throughput measurement of active monooxygenase concentration

      Tim Welters, Thomas Horn, Anna Joelle Ruff, Ulrich Schwaneberg and Jochen Büchs

      Version of Record online: 21 NOV 2016 | DOI: 10.1002/bit.26215

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      The authors provide a novel method for high throughput screening of P450 monooxygenase concentrations in 96-well MTPs. Based on scattered light measurements of reflective particles in monooxygenase solutions concentrations of P450 BM3 are determined online.

  6. Articles

    1. Establishing very long-chain fatty alcohol and wax ester biosynthesis in Saccharomyces cerevisiae

      Leonie Wenning, Tao Yu, Florian David, Jens Nielsen and Verena Siewers

      Version of Record online: 21 NOV 2016 | DOI: 10.1002/bit.26220

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      In this study a new synthesis route for very long-chain fatty alcohols (C18–C22) and very long-chain wax esters (C30–C42) in the yeast Saccharomyces cerevisiae was established. This was achieved by expression of heterologous genes, including the fatty acyl-CoA reductases (FAR) from Apis mellifera (AmFAR) and Marinobacter aquaeolei VT8 (MaFAldhR = Maqu_2220) as well as the wax ester synthase (WS) from Simmondsia chinensis (SciWS) in a S. cerevisiae background strain containing a deletion of the ELO3 gene and a constitutive active ACC1 gene (ACC1**).

  7. Communication to the Editors

    1. Cholestyramine as a promising, strong anion exchange resin for direct capture of genetic biomarkers from raw pancreatic fluids

      Andrew J. Hilmer, R. Brooke Jeffrey, Walter G. Park and Chaitan Khosla

      Version of Record online: 17 NOV 2016 | DOI: 10.1002/bit.26207

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      A FDA-approved anion exchange resin is re-purposed for direct DNA capture from raw pancreatic fluids. Such resins hold promise for incorporation into smart capsules for in vivo DNA biomarker sequestration to aid in enhanced diagnosis of gastrointestinal diseases.

  8. Articles

    1. You have full text access to this OnlineOpen article
      Oxygen mapping: Probing a novel seeding strategy for bone tissue engineering

      Ines Westphal, Claudia Jedelhauser, Gregor Liebsch, Arnd Wilhelmi, Attila Aszodi and Matthias Schieker

      Version of Record online: 17 NOV 2016 | DOI: 10.1002/bit.26202

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      Oxygen mapping was introduced in bone tissue engineering (BTE) in order to analyze a novel cell-seeding strategy. To study the influence of cell density at the time of harvest, oxygen consumption was analyzed in 3D-scaffolds seeded with MSCs harvested at low (30–40%) and high confluence (70–80%). Oxygen maps revealed that scaffolds, seeded with cells harvested at low density, exhibited rapidly exponential oxygen consumption. In contrast, harvesting cells at higher density resulted in very slow, almost linear oxygen decrease. Authors have shown that not only the final seeding density but also the cell density at the time of harvest is important for BTE.

    2. Metabolic engineering of Methanosarcina acetivorans for lactate production from methane

      Michael J. McAnulty, Venkata Giridhar Poosarla, Jine Li, Valerie W. C. Soo, Fayin Zhu and Thomas K. Wood

      Version of Record online: 11 NOV 2016 | DOI: 10.1002/bit.26208

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      The authors previously reversed methanogenesis for the first time to grow anaerobically on methane by producing active methyl-coenzyme M reductase from an unculturable organism in the Black Sea in the methanogen Methanosarcina acetivorans. Here, further metabolic engineering by adding production of 3-hydroxybutyryl-CoA dehydrogenase from Clostridium acetobutylicum led to the production of optically pure L-lactate from methane with a higher yield than that of aerobic processes.

    3. Evaluation of eco-friendly zwitterionic detergents for enveloped virus inactivation

      Lynn Conley, Yinying Tao, Alexis Henry, Edward Koepf, Douglas Cecchini, John Pieracci and Sanchayita Ghose

      Version of Record online: 9 NOV 2016 | DOI: 10.1002/bit.26209

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      To ensure the safety of cell culture derived biotherapeutics, manufacturing processes of such molecules need to incorporate steps capable of inactivating or removing viruses. In this study we identified and tested several eco-friendly, zwitterionic, detergents for their ability to inactivate enveloped viruses, and discovered that lauryldimethylamine N-oxide provided very potent inactivation. Studies investigating the robustness of this step revealed that only very low detergent concentrations negatively impacted inactivation.

    4. Optimizing carbon dioxide utilization for microalgae biofilm cultivation

      Ward Blanken, Stefan Schaap, Sophie Theobald, Arjen Rinzema, René H. Wijffels and Marcel Janssen

      Version of Record online: 9 NOV 2016 | DOI: 10.1002/bit.26199

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      The loss of carbon dioxide (CO2) to the environment during microalgae cultivation is undesirable for both environmental and economic reasons. In this study, a phototrophic biofilm growth model was developed and validated with the objective to maximize both CO2 utilization efficiency and production of microalgae in biofilms. Employing this model Blanken and coworkers identified that concentrated CO2 streams and plug flow behavior of the gaseous phase over the biofilm surface are essential for high productivity and CO2 utilization efficiency.

    5. Collagen and collagen-chondroitin sulfate scaffolds with uniaxially aligned pores for the biomimetic, three dimensional culture of trabecular meshwork cells

      Matthew Osmond, Sarah M. Bernier, Mina B. Pantcheva and Melissa D. Krebs

      Version of Record online: 7 NOV 2016 | DOI: 10.1002/bit.26206

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      Using a uniaxial freezing technique, scaffolds are fabricated with unaxially aligned pores. The morphologies of these scaffolds are analyzed by scanning electron microscopy and the mechanical properties determined by dynamic mechanical analysis. Trabecular meshwork cells isolated from porcine eyes are cultured on the porous scaffolds and cell growth is characterized via proliferation assay, qPCR, and confocal microscopy.

  9. Communications to the Editor

    1. Integrated process design for biocatalytic synthesis by a Leloir Glycosyltransferase: UDP-glucose production with sucrose synthase

      Katharina Schmölzer, Martin Lemmerer, Alexander Gutmann and Bernd Nidetzky

      Version of Record online: 7 NOV 2016 | DOI: 10.1002/bit.26204

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      In this study of UDP-glucose production by the Leloir glycosyltransferase (GT) sucrose synthase (SuSy), typical efficiency targets of industrial biotransformation processes were reached. We demonstrate that a holistic process design, involving coordinated development of biocatalyst production, biotransformation, and downstream processing (DSP), was vital for target achievement at 30 gram scale synthesis. Overall, the process would allow production of ∼0.7 kg of isolated product/L E. coli bioreactor culture, thus demonstrating how integrated process design promotes the practical use of a GT conversion.

  10. Articles

    1. Improved fermentative production of gamma-aminobutyric acid via the putrescine route: Systems metabolic engineering for production from glucose, amino sugars, and xylose

      João M. P. Jorge, Anh Q. D. Nguyen, Fernando Pérez-García, Stefanie Kind and Volker F. Wendisch

      Version of Record online: 7 NOV 2016 | DOI: 10.1002/bit.26211

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      In this study, putrescine-based GABA production by recombinant Corynebacterium glutamicum was increased by transport engineering to abolish the export of the intermediates l-glutamate and putrescine and by improving precursor supply by reduction of the 2-oxoglutarate dehydrogenase activity. The final strain was able to produce 59.7 g L−1 of GABA by fed-batch fermentation with a volumetric productivity of 1.34 g L−1 h−1. In addition, strains to enable GABA production from carbon sources alternative to glucose were constructed.

    2. Insights into cellulase-lignin non-specific binding revealed by computational redesign of the surface of green fluorescent protein

      Carolyn N. Haarmeyer, Matthew D. Smith, Shishir P. S Chundawat, Deanne Sammond and Timothy A. Whitehead

      Version of Record online: 7 NOV 2016 | DOI: 10.1002/bit.26201

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      Haarmeyer et al. systematically modify the surface of a model protein using computational protein design in order to determine the effect of protein surface potential on lignin binding. Binding assays with experimentally characterized designs reveal that net charge is the strongest predictor of low protein–lignin binding.

    3. Engineering three dimensional micro nerve tissue using postnatal stem cells from human dental apical papilla

      Byung-Chul Kim, Sung-Min Jun, So Yeon Kim, Yong-Dae Kwon, Sung Chul Choe, Eun-Chul Kim, Jae-Hyung Lee, Jinseok Kim, Jun-Kyo Francis Suh and Yu-Shik Hwang

      Version of Record online: 2 NOV 2016 | DOI: 10.1002/bit.26205

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      Kim and colleagues develop an integrated bioprocess for 3D organotypic culture of postnatal stem cells. Stem cells with neural crest-derived ectomesenchymal origin can be isolated from dental apical papilla, expanded, differentiated to neural cells, and form 3D micro nerve tissue in vitro using the integrated bioprocess. The culture strategy is useful for efficient 3D cell-based nerve tissue formation.

    4. Specific growth rate and multiplicity of infection affect high-cell-density fermentation with bacteriophage M13 for ssDNA production

      Benjamin Kick, Samantha Hensler, Florian Praetorius, Hendrik Dietz and Dirk Weuster-Botz

      Version of Record online: 26 OCT 2016 | DOI: 10.1002/bit.26200

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      DNA origami, a bottom-up method in the field of DNA nanotechnology, requires ssDNA in good quality and high quantities. Therefore, a high-cell-density fermentation of Escherichia coli infected with bacteriophage M13 is investigated to produce scaffold ssDNA in a gram scale. Kick and coworkers show that specific cell growth rate (µ) and multiplicity of infection (MOI) are the crucial state variables influencing phage amplification rate and ssDNA concentration.

  11. Communication to the Editors

    1. A droplet-merging platform for comparative functional analysis of m1 and m2 macrophages in response to e. coli-induced stimuli

      Evangelia Hondroulis, Alexandru Movila, Pooja Sabhachandani, Saheli Sarkar, Noa Cohen, Toshihisa Kawai and Tania Konry

      Version of Record online: 24 OCT 2016 | DOI: 10.1002/bit.26196

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      The platform developed by Konry and coworkers present a simple and effective method for the co-encapsulation of cells and assay reagents using a passive merging design in an integrated droplet docking microfluidic device. For proof-of-concept studies, they co-encapsulated polarized M1 and M2 macrophages with Escherichia coli (E. coli) by passive merging. This approach facilitated live cell profiling of effector immune functions in situ and quantitative functional analysis of macrophage heterogeneity.

  12. Articles

    1. Metabolic engineering of Escherichia coli for microbial production of L-methionine

      Jian-Feng Huang, Zhi-Qiang Liu, Li-Qun Jin, Xiao-Ling Tang, Zhen-Yang Shen, Huan-Huan Yin and Yu-Guo Zheng

      Version of Record online: 21 OCT 2016 | DOI: 10.1002/bit.26198

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      Methionine is an essential sulfur containing amino acid which is wildly used in feed stock industry and for medical purpose. The authors engineered Escherichia coli W3110 to produce L-methionine from glucose. The main strategies include disruption of metJ, overexpression of homoserine O-transsuccinylase (metA) together with methionine exporter (yjeH), partial disruption of methionine transporter MetD and deletion of lysA to block the competitive pathway. The fed-batch fermentation of the final strain resulted in 9.75 g/L of L-methionine after optimization.

    2. In situ enhancement of surfactin biosynthesis in Bacillus subtilis using novel artificial inducible promoters

      Song Jiao, Xu Li, Huimin Yu, Huan Yang, Xue Li and Zhongyao Shen

      Version of Record online: 21 OCT 2016 | DOI: 10.1002/bit.26197

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      Novel artificial inducible promoters used for enhanced surfactin biosynthesis in B. subtilis was developed in this study. A super-strong promoter Pg3 integrating the core promoter region of PgroE screened from the B. subtilis THY-7 genome, E. coli lacI-lacO operon and B. subtilis sigma factor 70(σA) −35 and −10 consensus motifs was constructed. By substituting the wild PsrfA with Pg3, the engineered strain produced 9.74 g/L surfactin in a 5-L fermentor, 17.7 folds of that of the wild strain.

    3. Metabolic engineering of Escherichia coli W3110 to produce L-malate

      Xiaoxiang Dong, Xiulai Chen, Yuanyuan Qian, Yuancai Wang, Li Wang, Weihua Qiao and Liming Liu

      Version of Record online: 17 OCT 2016 | DOI: 10.1002/bit.26190

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      To improve L-malate production, four strategies have been adopted: (i) the branch of pyruvate metabolism was knocked out to increase pyruvate production; (ii) the heterologous malic enzyme was overexpressed and engineered to enhance catalytic efficiency; (iii) the branch of L-malate metabolism was deleted to reduce L-malate consumption; (iv) cofactor regeneration system was constructed to achieve cofactor balance. These approaches in this study open up new venues for pathway optimization and efficient production of natural products.

    4. Comprehensive reconstruction and in silico analysis of Aspergillus niger genome-scale metabolic network model that accounts for 1210 ORFs

      Hongzhong Lu, Weiqiang Cao, Liming Ouyang, Jianye Xia, Mingzhi Huang, Ju Chu, Yingping Zhuang, Siliang Zhang and Henk Noorman

      Version of Record online: 17 OCT 2016 | DOI: 10.1002/bit.26195

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      Based on the latest genome annotations, the A. niger genome-scale metabolic network model was systematically reconstructed. The new model iHL1210 contains 1,764 reactions and 1,210 unique ORFs. The existence of most reactions could be verified by latest RNA-seq. The average correlation coefficients between the predicted fluxes and estimated fluxes from 13C-labeling data were sufficiently high. The new A. niger GSMM was obviously improved in metabolic coverage and prediction performance, which paves the way for systematic metabolic engineering of A. niger.

    5. The productive cellulase binding capacity of cellulosic substrates

      Nardrapee Karuna and Tina Jeoh

      Version of Record online: 13 OCT 2016 | DOI: 10.1002/bit.26193

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      Productive binding sites on cellulose are sites at which cellulases bind and hydrolyze glycosidic bonds. The productive binding capacity of cellulosic substrates is thus the total moles of productive binding sites per mass of the insoluble substrate. We present a method to measure the productive cellulase binding capacity of cellulose based on a mechanistic model relating the initial productive cellulase binding concentrations to enzyme loadings. Processing histories and source are shown to impact the productive cellulase binding capacities of cellulose.

    6. Bioprocess Engineering and Supporting Technologies

      Genetic engineering of CHO cells for viral resistance to minute virus of mice

      Joaquina X. Mascarenhas, Nikolay Korokhov, Lisa Burger, Ademola Kassim, Jason Tuter, Daniel Miller, Trissa Borgschulte, Henry J. George, Audrey Chang, David J. Pintel, David Onions and Kevin J. Kayser

      Version of Record online: 12 OCT 2016 | DOI: 10.1002/bit.26186

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      Cell engineering to reduce cell surface sialic acid by affecting major glycosylation pathways. Complete absence of cell surface sialic acid in the Slc35a1 knockout cell line leads to absolute resistance to MVM infection. Our data demonstrate that resistance against MVM virus can be incorporated into CHO production cell lines, adding another level of defense against the devastating financial consequences of this virus infection while maintaining optimum recombinant protein yield and quality.

    7. Development of in situ product removal strategies in biocatalysis applying scaled-down unit operations

      Søren Heintz, Tim Börner, Rolf H. Ringborg, Gustav Rehn, Carl Grey, Mathias Nordblad, Ulrich Krühne, Krist V. Gernaey, Patrick Adlercreutz and John M. Woodley

      Version of Record online: 12 OCT 2016 | DOI: 10.1002/bit.26191

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      Application of scaled-down unit operations combined in a plug-and-play manner for easy and flexible development and testing of advanced biocatalytic process options, such as in situ product removal (ISPR) process strategies.

    8. Enhanced cellulase recovery without β-glucosidase supplementation for cellulosic ethanol production using an engineered strain and surfactant

      Renliang Huang, Hong Guo, Rongxin Su, Wei Qi and Zhimin He

      Version of Record online: 10 OCT 2016 | DOI: 10.1002/bit.26194

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      A simple and practical method for recycling cellulases was developed: cellulase absorption onto substrates was combined with the use of an engineered S. cerevisiae strain and surfactants. This method did not require β-glucosidase supplementation and was demonstrated to provide excellent ethanol production in the three successive high solid SSF processes with high ethanol concentrations, recovery efficiency, and enzyme productivity. This method is better than other known cellulase recovery methods and has great potential for industrial application.

    9. Identification of key genes involved in polysaccharide bioflocculant synthesis in Bacillus licheniformis

      Zhen Chen, Peize Liu, Zhipeng Li, Wencheng Yu, Zhi Wang, Haosheng Yao, Yuanpeng Wang, Qingbiao Li, Xu Deng and Ning He

      Version of Record online: 6 OCT 2016 | DOI: 10.1002/bit.26189

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      This paper identified key genes involved in polysaccharide bioflocculant production in Bacillus licheniformis CGMCC2876 and proposed a pathway for this production. The identification of the genetic information will provide new tools to engineer B.licheniformis for bioflocculant industrial production.

  13. Reviews

    1. Management of knee osteoarthritis. Current status and future trends

      Marta Ondrésik, Fatima R. Azevedo Maia, Alain da Silva Morais, Ana C. Gertrudes, Ana H. Dias Bacelar, Cristina Correia, Cristiana Gonçalves, Hajer Radhouani, Rui Amandi Sousa, Joaquim M. Oliveira and Rui L. Reis

      Version of Record online: 5 OCT 2016 | DOI: 10.1002/bit.26182

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      The aim of the authors in this work was to summarize the current management of osteoarthritis, and discuss the potential of advanced therapies for future applications. After a brief introduction of the disease, the authors list and describe a set of biomaterials, as well as cells from various sources for combined cartilage regeneration. Gene therapy is also the subject of this review paper as a promising approach to resolve osteoarthritis.

  14. Articles

    1. FX knockout CHO hosts can express desired ratios of fucosylated or afucosylated antibodies with high titers and comparable product quality

      Salina Louie, Benjamin Haley, Brett Marshall, Amy Heidersbach, Mandy Yim, Martina Brozynski, Danming Tang, Cynthia Lam, Bronislawa Petryniak, David Shaw, Jeongsup Shim, Aaron Miller, John B. Lowe, Brad Snedecor and Shahram Misaghi

      Version of Record online: 4 OCT 2016 | DOI: 10.1002/bit.26188

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      FX knock out CHO host cell lines enable expression of fucosylated or afucosylated antibodies, or even desired ratios of antibodies with such glycan modifications simply by titrating fucose into the media. Since the same cell line can express both versions of the antibody, titer and product quality attributes remain comparable. This feature may be helpful in tuning the ADCC response by either natural killer and/or polymorphonuclear cells.

    2. Metabolic profile of 1,5-diaminopentane producing Corynebacterium glutamicum under scale-down conditions: Blueprint for robustness to bioreactor inhomogeneities

      Michael H. Limberg, Julia Schulte, Tita Aryani, Regina Mahr, Meike Baumgart, Michael Bott, Wolfgang Wiechert and Marco Oldiges

      Version of Record online: 3 OCT 2016 | DOI: 10.1002/bit.26184

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      Performance losses during scale-up are still one of the major obstacles for industrial bioprocess development. Consequently, robustness to short-term environmental changes is an important quality of industrial production organisms. This study focuses on the identification of metabolic key mechanisms for the robustness of Corynebacterium glutamicum, by combining scale down technology and multi omics based analytical methods, to get a deeper insight and provide future targets for process orientated strain development.

    3. You have full text access to this OnlineOpen article
      MAR-Mediated transgene integration into permissive chromatin and increased expression by recombination pathway engineering

      Kaja Kostyrko, Samuel Neuenschwander, Thomas Junier, Alexandre Regamey, Christian Iseli, Emanuel Schmid-Siegert, Sandra Bosshard, Stefano Majocchi, Valérie Le Fourn, Pierre-Alain Girod, Ioannis Xenarios and Nicolas Mermod

      Version of Record online: 3 OCT 2016 | DOI: 10.1002/bit.26086

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      Main mammalian DNA repair pathways, i.e., non-homologous end-joining and homologous recombination, are not prominently used for transgene integration in CHO cell genome. Instead, this process may be mediated by DNA synthesis-dependent microhomology-mediated end-joining. Inhibition of specific components of homologous recombination, and the use of DNA elements termed Matrix Attachment Region (MAR), enhances transgene integration and expression. These findings help uncover some of the mechanisms mediating DNA recombination, and they provide an approach for cell engineering to improve recombinant protein expression.

    4. Glucose oxidase stabilization against thermal inactivation using high hydrostatic pressure and hydrophobic modification

      Ali Halalipour, Michael R. Duff Jr, Elizabeth E. Howell and José I. Reyes-De-Corcuera

      Version of Record online: 27 SEP 2016 | DOI: 10.1002/bit.26185

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      High hydrostatic pressure and aniline modification stabilized glucose oxidase. At 240 MPa, high hydrostatic pressure increased the stability of glucose oxidase by 50-fold against thermal inactivation compared to atmospheric pressure at 74.5 ºC. Thermograms for the thermal stability of the enzyme examined by DSC indicated aniline modification thermally stabilized glucose oxidase by 8 ºC, while benzoate modification destabilized the enzyme.

    5. Biogas-based denitrification in a biotrickling filter: Influence of nitrate concentration and hydrogen sulfide

      Juan C. López, Estefanía Porca, Gavin Collins, Rebeca Pérez, Alberto Rodríguez-Alija, Raúl Muñoz and Guillermo Quijano

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26092

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      A novel strategy for nitrogen removal combining simultaneously anoxic CH4 and H2S oxidations with denitrification by DAMO and NR-SOB, respectively, was developed in this study. Here, the authors have confirmed not only the potential use of biogas for this purpose, but also the urgent need to control N2O production by adjusting NO3− concentration along the process.

    6. Enhanced noradrenergic axon regeneration into schwann cell-filled PVDF-TrFE conduits after complete spinal cord transection

      Yee-Shuan Lee, Siliang Wu, Treena Livingston Arinzeh and Mary Bartlett Bunge

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26088

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      A novel strategy combining random or aligned fibrous piezoelectric conduits with Schwann cells (SCs) was evaluated for axon regeneration in completely transected rat spinal cord. SCs adhered and proliferated when seeded onto the scaffolds in vitro. Both types of conduits led to a permissive interface between the host cord and the SC transplant in vivo. The use of aligned conduits with SCs promoted noradrenergic axon regeneration further into the transplant and more sensory axons were present at the caudal interface.

    7. A synthetic microbial consortium of Shewanella and Bacillus for enhanced generation of bioelectricity

      Ting Liu, Yang-Yang Yu, Tao Chen and Wei Ning Chen

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26094

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      A synthetic microbial consortium, in which exoelectrongen Shewanella oneidensis MR-1 can efficiently utilize the high concentration of riboflavin produced by Bacillus subtilis RH33 to largely enhance bioelectricity generation, was rationally designed and successfully constructed. The maximum power density of microbial fuel cells with this synthetic consortium was 277.4 mW/m2, which was 4.9 times of that with MR-1 (56.9 mW/m2) and 40.2 times of RH33 (6.9 mW/m2).

    8. The role of host cell physiology in the productivity of the baculovirus-insect cell system: Fluxome analysis of Trichoplusia ni and Spodoptera frugiperda cell lines

      Francisca Monteiro, Vicente Bernal and Paula M. Alves

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26089

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      Metabolism overview of High Five and Sf9 cells during growth. (A) Fluxome distribution of High Five and Sf9 cells at exponential phase. Numbers indicate normalized metabolic fluxes by the specific glucose uptake rate and standard deviation of independent replicates in brackets. Arrow thickness is representative of the net flow of each reaction. (B) Contribution of glucose and amino acids carbon skeletons for incorporation and oxidation at the TCA cycle. (C) Relative contribution of the different amino acids for oxidation at the TCA cycle.

    9. Application of a mechanistic model as a tool for on-line monitoring of pilot scale filamentous fungal fermentation processes—The importance of evaporation effects

      Lisa Mears, Stuart M. Stocks, Mads O. Albaek, Gürkan Sin and Krist V. Gernaey

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26187

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      A mechanistic model-based soft sensor is developed and validated for 550L filamentous fungus fermentations operated at Novozymes A/S. The soft sensor is comprised of a parameter estimation block based on a stoichiometric balance, coupled to a dynamic process model. State estimation at this scale requires a robust mass model including evaporation.

    10. Discriminating typical and atypical cystic fibrosis-related bacteria by multiplex PNA-FISH

      Susana P. Lopes, Daniel T. Carvalho, Maria O. Pereira and Nuno F. Azevedo

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26085

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      This study highlights the successful adaptation of a multiplex PNA-FISH assay to detect polymicrobial communities encompassing CF-typical and atypical bacteria. The method is therefore suitable to further describe species-dependent prevention strategies and deliver more effective target control therapeutics in cystic fibrosis disease.

  15. Reviews

    1. The future of protein scaffolds as affinity reagents for purification

      Ana M.G.C. Dias and Ana C.A. Roque

      Version of Record online: 26 SEP 2016 | DOI: 10.1002/bit.26090

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      In this review we highlight the developments of small protein scaffolds as reagents in affinity purification. We discuss the biophysical properties, protein evolution, and engineering strategies of non-immunoglobulin scaffolds; as well as, their targets, immobilization methodologies, solid supports, and purification conditions. We emphasize the strengths and weaknesses of the scaffolds versus current affinity reagents. Finally, we explore the challenges and future opportunities for these scaffolds to be implemented as affinity ligands in research and industrial applications.

  16. Communications to the Editor

    1. Fam60A plays a role for production stabilities of recombinant CHO cell lines

      Anett Ritter, Sandro Nuciforo, Axel Schulze, Mevion Oertli, Tatjana Rauschert, Bernd Voedisch, Sabine Geisse, Thomas Jostock and Holger Laux

      Version of Record online: 22 SEP 2016 | DOI: 10.1002/bit.26181

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      Ritter and coauthors provide primary evidence that the FAM60A protein plays a key role in production stability of CHO cell lines. Knock-out of the gene Fam60A, which is located within the telomeric region of the small chromosome 8 in CHO-K1a cells, increases the percentage of stable clones after long-term cultivation. This highlights that Fam60a is a relevant gene for cell line engineering approaches to increase production stability in recombinant cell lines.

  17. Articles

    1. Non-chromatographic bioprocess engineering of a recombinant mineralizing protein for the synthesis of silica nanocapsules

      David Wibowo, Guang-Ze Yang, Anton P.J. Middelberg and Chun-Xia Zhao

      Version of Record online: 21 SEP 2016 | DOI: 10.1002/bit.26079

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      A chromatography-free and high-yield recovery of mineralizing protein, D4S2, from recombinant Escherichia coli for making silica nanocapsules was developed based on selective thermochemical precipitation method: (i) DNA removal using poly(ethyleneimine); (ii) protein-contaminant precipitation using 1 M Na2SO4 (90°C, 5 min) in which D4S2 protein remained soluble; and (iii) D4S2-protein isolation using 1.8 M Na2SO4 (30°C, 60 min). The final yield of D4S2 protein was ∼29 mg per 800 mL cells (OD600 ∼2) which accounts for ∼79% of D4S2-protein recovery.

  18. Reviews

    1. Stem cells for spinal cord injury: Strategies to inform differentiation and transplantation

      Nisha R. Iyer, Thomas S. Wilems and Shelly E. Sakiyama-Elbert

      Version of Record online: 21 SEP 2016 | DOI: 10.1002/bit.26074

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      Advances in stem cell technologies have enabled their ethical and efficacious use in the context of spinal cord injury treatment. This review describes strategies to optimize the differentiation of stem cells into discrete spinal cell types, including culture formats, induction methodologies, and the directed differentiation of somatic cells. In addition to outcomes post-transplantation, the authors discuss potential combinatorial strategies with biomaterial scaffolds and controlled drug delivery systems to improve stem cell therapies for clinical use.

  19. Articles

    1. You have full text access to this OnlineOpen article
      Real-time monitoring and control of the load phase of a protein A capture step

      Matthias Rüdt, Nina Brestrich, Laura Rolinger and Jürgen Hubbuch

      Version of Record online: 21 SEP 2016 | DOI: 10.1002/bit.26078

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      Protein A capture steps are central to the preparative purification of mAbs. However, capture steps are only partly controlled in realtime. In this study, partial least squares regression on UV/Vis absorption spectra was applied to quantify mAb in the effluent of a protein A capture step during the load phase.

    2. Cellobiose dehydrogenase and chitosan-based lysozyme responsive materials for antimicrobial wound treatment

      Christoph Öhlknecht, Gregor Tegl, Bianca Beer, Christoph Sygmund, Roland Ludwig and Georg M. Guebitz

      Version of Record online: 21 SEP 2016 | DOI: 10.1002/bit.26070

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      General scheme of the mode of action of the intelligent antimicrobial system. NAc-CTS is hydrolyzed to COS in the presence of lysozyme. The produced COSs act as substrate for CDH that generates the antimicrobial agent H2O2.

    3. Continuous multistep synthesis of perillic acid from limonene by catalytic biofilms under segmented flow

      Christian Willrodt, Babu Halan, Lisa Karthaus, Jessica Rehdorf, Mattijs K. Julsing, Katja Buehler and Andreas Schmid

      Version of Record online: 21 SEP 2016 | DOI: 10.1002/bit.26071

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      Catalytic biofilms in segmented flow capillary micro-reactors enabled successful multi-step oxyfunctionalization of (R)-(+)-limonene to (R)-(+)-perillic acid with a high productivity of 34 g Ltube−1 d−1. We demonstrated the lab-scale production of a highly toxic chemical from a volatile substrate with a wild type Pseudomonas putida GS1 and as well a recombinant Pseudomonas taiwanensis VLB120 harboring p-cymene monooxygenase. The technical applicability of the concept was extended by purifying the product. The conceptual design can be transferred to other equally challenging biotransformations.

    4. A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic–pharmacodynamic (PK–PD) model

      Hyuna Lee, Dae Shik Kim, Sang Keun Ha, Inwook Choi, Jong Min Lee and Jong Hwan Sung

      Version of Record online: 14 SEP 2016 | DOI: 10.1002/bit.26087

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      Multi-organ-on-a-chip recapitulates simultaneous metabolism and cell-killing effect of drugs, and its action inside the chip is simulated with a PK–PD model, providing insight into the action of the drug.

    5. LPMOs in cellulase mixtures affect fermentation strategies for lactic acid production from lignocellulosic biomass

      Gerdt Müller, Dayanand Chandrahas Kalyani and Svein Jarle Horn

      Version of Record online: 9 SEP 2016 | DOI: 10.1002/bit.26091

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      Bioconversion of birch wood to lactic acid by means of SHF and SSF using an LPMO-containing cellulase cocktail combined with either a mesophilic or thermophilic fermenting microbe.

  20. Communication to the Editors

    1. Application of an oxygen-inducible nar promoter system in metabolic engineering for production of biochemicals in Escherichia coli

      Hee J. Hwang, Jin W. Kim, Si Y. Ju, Jin H. Park and Pyung C. Lee

      Version of Record online: 7 SEP 2016 | DOI: 10.1002/bit.26082

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      A dissolved oxygen-dependent nar promoter has been utilized as an alternative to commonly-used promoters for engineering biochemical pathways because of its relatively simple and cost-effective induction mechanism. The three engineered biosynthetic pathways in which the expression of genes was controlled by the nar promoter showed reasonable performances [113.12 ± 2.37 g/L d-lactate, 48.0 ± 8.48 g/L (R, R)-2,3-butandiol, and 15.8 ± 0.62 g/L 1, 3-propandiol].

  21. Reviews

    1. Modulation of human mesenchymal and pluripotent stem cell behavior using biophysical and biochemical cues: A review

      Sheryl Ding, Peter Kingshott, Helmut Thissen, Martin Pera and Peng-Yuan Wang

      Version of Record online: 2 SEP 2016 | DOI: 10.1002/bit.26075

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      The ability to manipulate human stem cells in vitro is vital in regenerative medicine and cellular therapies. While biochemical cues have been the focus of this area for some time, biophysical cues are emerging as a major factor in stem cell control. In this review, the authors summarize how different forms of biophysical stimulation influence stem cell behavior, and compare their effects to those of conventional culture methods.

  22. Articles

    1. Mixing and mass transfer in a pilot scale U-loop bioreactor

      Leander A.H. Petersen, John Villadsen, Sten B. Jørgensen and Krist V. Gernaey

      Version of Record online: 2 SEP 2016 | DOI: 10.1002/bit.26084

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      Mixing time and mass transfer coefficients considerably higher than those obtainable in an STR and previous tubular loop reactors were determined in a forced flow U-loop fermenter of a novel construction. The system also proved capable of handling a large volumetric gas fraction, which was shown to have only minor effect on the power drawn from the pump impeller.

    2. You have free access to this content
      Efficient gene knockdown in Clostridium acetobutylicum by synthetic small regulatory RNAs

      Changhee Cho and Sang Yup Lee

      Version of Record online: 30 AUG 2016 | DOI: 10.1002/bit.26077

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      Clostridium acetobutylicum is an industrially important bacterium, that has been known to be extremely difficult to genetically manipulate. Here we report development of synthetic sRNA-based gene knockdown system that allows efficient knockdown of inherent and heterologous genes in C. acetobutylicum. By knocking down the pta gene in buk-negative mutant C. acetobutylicum strain, butanol production could be enhanced both in batch culture and fed-batch culture coupled with in situ recovery.

    3. Boosted structured additive regression for Escherichia coli fed-batch fermentation modeling

      Michael Melcher, Theresa Scharl, Markus Luchner, Gerald Striedner and Friedrich Leisch

      Version of Record online: 30 AUG 2016 | DOI: 10.1002/bit.26073

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      In this study, the potential of boosted structured additive regression (STAR) models for monitoring key process parameters such as the cell dry mass or protein concentration in Escherichia coli fed-batch fermentations is investigated. Besides promising results—the responses can be predicted with an accuracy between 3% and 16%—boosted STAR models are more interpretable and facilitate the assessment of predictor importance.

    4. Model-supported phototrophic growth studies with Scenedesmus obtusiusculus in a flat-plate photobioreactor

      Anja Pia Koller, Hannes Löwe, Verena Schmid, Sabine Mundt and Dirk Weuster-Botz

      Version of Record online: 30 AUG 2016 | DOI: 10.1002/bit.26072

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      In this work, the light dependent growth of a novel microalgae isolate, Scenedesmus obtusiusculus, in flat-plate photobioreactor was investigated, leading to an improved batch cultivation process. The kinetic parameters were identified and the light penetration within the reactor was characterized on the basis of an enhanced modeling approach that considers a change of biomass during exponential growth. Using the model, a lighting profile was successfully developed, which resulted in a further accelerated cultivation process for S. obtusiusculus.

    5. Development of a Rhodobacter capsulatus self-reporting model system for optimizing light-dependent, [FeFe]-hydrogenase-driven H2 production

      Matt S.A. Wecker, Stephen E. Beaton, Robert A. Chado and Maria L. Ghirardi

      Version of Record online: 23 AUG 2016 | DOI: 10.1002/bit.26076

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      The authors have created a self-reporting bacterial system for the detection and selection of improved H2-production characteristics. They describe photosynthetic, hydrogenase-based H2 production in Rhodobacter capsulatus in the absence nitrogenase activity. The system has potential use in the directed evolution of hydrogenases, hydrogenase assembly proteins, and hydrogenase fusion proteins; in the selection and modeling of increased H2 metabolism in bacteria; and in optimizing photosynthetic production of H2.

    6. Process performance and product quality in an integrated continuous antibody production process

      Daniel J. Karst, Fabian Steinebach, Miroslav Soos and Massimo Morbidelli

      Version of Record online: 17 AUG 2016 | DOI: 10.1002/bit.26069

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      The authors show a detailed analysis of process performance and product quality of an integrated continuous monoclonal antibody production process at a variety of stable operating points. The application of deterministic mathematical models for the optimization of process performance is shown.

    7. Integrated molecular and bioprocess engineering for bacterially produced immunogenic modular virus-like particle vaccine displaying 18 kDa rotavirus antigen

      Alemu Tekewe, Yuanyuan Fan, Emilyn Tan, Anton P.J. Middelberg and Linda H.L. Lua

      Version of Record online: 17 AUG 2016 | DOI: 10.1002/bit.26068

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      A multipronged approach for simplified production of highly immunogenic modular virus-like particles displaying 18 kDa rotavirus antigens. Integrating Escherichia coli protein co-expression, non-chromatography purification and cell-free in vitro virus-like particle assembly resulted in a highly stable bacterial-based modular virus-like particles displaying conformational rotavirus VP8* antigenic modules. These modular virus-like particles induced high titres of VP8* antigen-specific antibodies in mice.

  23. Communication to the Editors

    1. Enhancing fatty acid production in Escherichia coli by Vitreoscilla hemoglobin overexpression

      Di Liu, Ni Wan, Fuzhong Zhang, Yinjie J. Tang and Stephen G. Wu

      Version of Record online: 17 AUG 2016 | DOI: 10.1002/bit.26067

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      Energy metabolism is a rate-limiting factor for fatty acid overproduction in E. coli strains. Vitreoscilla hemoglobin overexpression promotes oxygen supply and increases free fatty acid production under micro-aerobic conditions. The “Push-Pull-Block-Power” strategy and metabolic burden analysis may offer rational design of synthetic biology strains.

  24. Articles

    1. Regeneration and control of human fibroblast cell density by intermittently delivered pulsed electric fields

      Alexander Golberg, Marianna Bei, Robert L. Sheridan and Martin L. Yarmush

      Version of Record online: 22 FEB 2013 | DOI: 10.1002/bit.24832

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      Intermittently delivered pulsed electric fields for cell density control. The top line shows the timing for pulses delivery. The line on the bottom shows the respective cell concentration in the culture. E0- Electric field in applied on the cells population between the treatments, Eep- Electric field applied on cell population during the treatment, Tp- Time interval between the treatment, Tep- Total time of the delivery of electric field, Chigh- Higher threshold of cell density, Clow- Lower threshold for cell density.


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