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      Reuß, M.; Jefferis, Raymond P.; Lehmann, J.; Gesellschaft für Biotechnologische Forschung (GBF) (1976)
      The application of the method of quasilinearization to fermentation modelling is discussed. The text includes a tutorial explanation of the method. Examples include parameter identification in a growth model and both parameter and state estimation in a column reactor. The latter example was performed by an on-line system of coupled process and time-sharing computers.

      Yoshida, T.; Taguchi, H.; Department of Fermentation Technology Faculty of Engineering, Osaka University Yamada-kami, Suita-shi, Osaka 565, Japan (1976)
      Recently there has been a strong interest in the direct digital control of fermentation processes. More effort on identification or modeling of the processes is indispensable to accomplish this highly sophisticated control. This paper was written to present a fundamental view on model construction, process identification, parameter estimation, analysis of model and examples of uses of model. Models in the papers surveyed in the last five years are presented classifying them into three categories: subculture, subcellular and submolecular models. Assessment of model by means of sensitivity analysis and several approaches to modify models for process control are discussed.

      Blachère, Henri T.; Peringer, Paul; Corrieu, Georges V.; Station de Génie Microbiologique, 7 rue Sully, Dijon,France (1976)
      Techniques for estimation of investment and manufacturing costs in fermentation are discussed. A method for optimization of fermentation Plants as whole is described. 5 It necessitates knowledge of a model of the biosynthesis and equations correlating investment and manufacturing costs to the size of equipment. The Minimization of the non-linear objective function in a non-convex field is obtained by a two step method. Optimization in fermentation industry may have numerous aspects. One may envision improving the growth rate, the production rate or the yield in compound biosynthesis. In this case, the main control parameters are : substrate concentrations, temperature, pH, aeration and agitation etc... Since a mathematical model of microbial cell-growth has been formulated by Monod (1), the kinetic pattern of various fermentation systems has been intensively studied. The number of publications in this field is strongly increasing (2,3,4,5,6). The problem concerning the reduction of manufacturing costs such as those of steam, energy of agitation and aeration, consumption of air, water and raw materials belong to another category of optimization. Okabe and Aiba have recently presented solutions to these problems (7,8,9,10,11). The purpose of this paper concerns the approach of a global optimization of a new plan supposing that the annual production of a fermentation product is given, then the optimization consists in determining the size of the fermentor, power of agitation and aeration system, size of heat exchangers, pumps, filters, centrifuges etc... the required condition for temperature, pH, dissolved oxygen, substrate concentration etc... so that the investment capital and annual expenditure for the production be minimized. Since the same control variables and equipment are used in most fermentation industries, we consider that the method proposed, as regards yeast production, will also apply to various other production.

      Jefferis, Raymond P.; Winter, H.; Vogelmann, H.; Gesellschaft für Biotechnologische Forschung (GBF) (1976)
      The application of digital filtering techniques to the data from automatic fermentation process analyzers is discussed. An example illustrates the application of these methods to cell density and growth rate (productivity) estimation from periodic measurements of fermentation broth turbidity. The method of recursive least squares filtering was found best for the cell density estimates. A hybrid technique which combines this method with a model for culture oxygen uptake rate was found to have more rapid response for the cell productivity estimation. The results of on-line use of these digital filtering techniques are included.

      Ribot, D.; Laboratoire d'Automatique et d'Analyse des Systémes du C.N.R.S. Institut National des Sciences Appliquées - TOULOUSE - France (1976)
      The measure of the state variables of a fermentation (biomass and substrate concentration) is always liable to error. It is possible to reconstitute well enough the rates of their variations during a transient state, by a polynomial smoothing. By calculation of the derivative polynomial, the values of the growth rate HM and the global conversion rate R. at each moment can be deduced. The fermentation parameters are then identified through 2 linear smoothings. The method is tested with data obtained by simulation and given purposely noisy (known parameters). It is applied in order to determine the growth parameters of a continuous fermentation. The advantage of this direct method upon the usual sequential techniques is its rapidity and its small occupation of the central memory of the computer. It can be applied to continuous or discontinuous fermentation.
    • Foreword and Contents

      Jefferis, R. P.; Gesellschaft für Biotechnologische Forschung (GBF) (1976)

      Selva, G.; Zerbetto, P.; TEMA S.p.A., Bologna — ITALY — (1976)
      The paper emphasizes the importance of a methodology in programming, on the opi— nion that we are in the proper times to develop a "new deal" in EDP. The methodology is defined as a habit of systematic reasoning which faces problem complexity by a proper interpretation of structured design and by "egoless" programming. The development of this habit of thought is based upon the choice of a proper programming language and upon a new team organization: the adaptive team. The result and the use of these ideas, in the design and implementation of production planning has been very successful in reducing the time required to test and debug large software systems.

      Jefferis, Raymond P.; Gesellschaft für Biotechnologische Forschung (GBF) (1976)
      Software and file structures are discussed which were successfully used to couple six fermentation vessels to a process computer in a research pilot plant. Computer program functions are described which performed the data processing, process operator service, and communications in this installation. Also discussed are extensions to the FORTRAN language which were used for process operator graphics and for communication between the process computer and a time-sharing computer.

      Nyiri, L. K.; Toth, G. M.; Krishnaswami, C. S.; Parmenter, D. V.; FERMENTATION DESIGN, INC. Division of New Brunswick Scientific Co., Inc. Bethlehem, PA 18015 USA (1976)
      This paper gives a brief account on the results using mini-computer for on-line, real-time followup and control of fermentation processes. Data indicate that the status of a microbiol culture can be characterized if the available direct sensor signals are further analyzed. Such an analysis gives insight into the physico-chemical, physiological and biochemical conditions of the culture. In particular, the gas exchange conditions (oxygen uptake, CO? release rates and especially respiratory quotient (RQ)) were found sensitive indicators of the culture's status. Using the process status analysis capability of the computer optimum environmental conditions were searched by means of perturbation testing of the culture. For example, a C/N ratio was found in C. utilis culture which resulted in near perfect oxidation (RQ close to 1.0) which coincided with enhanced cell growth rate and suppressed ethyl alcohol formation. During these tests interactions between the environmental factors and the cellular metabolism were also detected. Analysis of these interactions is a prerequisite to develop control techniques for microbiological processes. Information on the interactions between the cells and environment as well as on the process status made it possible to establish a culture milieu in which the C. utilis cells metabolism was shifted in the direction of protein synthesis with simultaneous decrease in ETOH production. This operation was implemented using a double control loop strategy in which the setpoints of the individual controlled variables (composite of which creates the environment) were adjusted according to the physiological state of the culture.

      Hampel, W.; Bach, H. P.; Röhr, M.; Institute of Biochemical Technology and Microbiology University of Technology, Vienna, Austria (1976)
      A low cost version for the interfacing of a programmable desk calculator to a well instrumented fermentation system is described providing the possibilities of data acquisition and on-line as well as off-line data analysis with high efficiency and flexibility, which enables also smaller research units to perform advanced fermentation research on the laboratory or pilot-plant scale. Further advantages of the present configuration are the ease of programming and the versatility of almost every part of the system.

      Zabriskie, D. W.; Arminger, W. B.; Humphrey, A. E.; University of Pennsylvania Department of Chemical and Biochemical Engineering Philadelphia, Pennsylvania 19174 U.S.A. (1976)
      The true advantage to the interfacing of computers to fermentation processes is the dynamic optimization of the fermentation using model reference control techniques. This has not been realized and is due in part to the absence of accurate realtime process variable data such a biomass concentration and growth rate.Real-time techniques employing an on-line computer were evaluated to estimate biomass concentration and growth rate data by material balancing oxygen using the yield and maintenance model. The results of this analysis were satisfactory for 2 metabolically simple fermentations. However, in order to obtain estimates of equivalent accuracy for a metabolically complex fermentation (aerobic growth of Baker's yeast), it was necessary to correct values of Y. and My for metabolic variations by introducing a x/0 metabolic correction function, B Z/X which is a function of respiratory quotient.

      Meskanen, Arto; Rintekno Oy (1976)
      Three interfaces are identified in an industrial process computer system: the process/ instrumentation-computer interface, the power interface, and the man-machine interface. The man-machine interface is further divided into three sub-interfaces: The plant operatorprocess interface, the control room operator-automation system interface, and the process engineer interface. The problems in designing man-machine interfaces and the results from research work and practical experiments in human engineering are briefly discussed. In chapters 4 and 5, the design of the man-machine interface is visualized by a short introduction of the concepts realized in the pilot fermentor control system (PFCS), developed by Rintekno Oy.
    • Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters

      Kiefer, Alexander F.; Bousis, Spyridon; Hamed, Mostafa M.; Diamanti, Eleonora; Haupenthal, Jörg; Hirsch, Anna K.H.; a Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Campus E8.1, Saarbrücken, 66123, Germany b Department of Pharmacy, Saarland University, Campus E8.1, Saarbrücken, 66123, Germany c Helmholtz International Lab for Anti-Infectives, Campus E8.1, Saarbrücken, 66123, Germany (ACS/ American Chemical Society, 2022-07-14)
      Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target that is not addressed by any antibiotic in the market. Since the ECF module is crucial for the vitamin transport mechanism, the prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects. © 2022 American Chemical Society.
    • POTATO: Automated pipeline for batch analysis of optical tweezers data

      Buck, Stefan; Pekarek, Lukas; Caliskan, Neva; Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, GermanyMedical Faculty, Julius-Maximilians University Würzburg, Würzburg, Germany (Elsevier, 2022-08-02)
      Optical tweezers are a single-molecule technique that allows probing of intra- and intermolecular interactions that govern complex biological processes involving molecular motors, protein-nucleic acid interactions, and protein/RNA folding. Recent developments in instrumentation eased and accelerated optical tweezers data acquisition, but analysis of the data remains challenging. Here, to enable high-throughput data analysis, we developed an automated python-based analysis pipeline called POTATO (practical optical tweezers analysis tool). POTATO automatically processes the high-frequency raw data generated by force-ramp experiments and identifies (un)folding events using predefined parameters. After segmentation of the force-distance trajectories at the identified (un)folding events, sections of the curve can be fitted independently to a worm-like chain and freely jointed chain models, and the work applied on the molecule can be calculated by numerical integration. Furthermore, the tool allows plotting of constant force data and fitting of the Gaussian distance distribution over time. All these features are wrapped in a user-friendly graphical interface, which allows researchers without programming knowledge to perform sophisticated data analysis. -(c) 2022 Biophysical Society
    • Bacteria as genetically programmable producers of bioactive natural products

      Hug, Joachim J.; Krug, Daniel; Müller, Rolf (2020-04-01)
    • Repositories for Taxonomic Data: Where We Are and What is Missing.

      Miralles, Aurélien; Bruy, Teddy; Wolcott, Katherine; Scherz, Mark D; Begerow, Dominik; Beszteri, Bank; Bonkowski, Michael; Felden, Janine; Gemeinholzer, Birgit; Glaw, Frank; et al. (2020-11-01)
    • A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals.

      Demetriou, Philippos; Abu-Shah, Enas; Valvo, Salvatore; McCuaig, Sarah; Mayya, Viveka; Kvalvaag, Audun; Starkey, Thomas; Korobchevskaya, Kseniya; Lee, Lennard Y W; Friedrich, Matthias; et al. (2020-09-14)
      The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a 'CD2 corolla'. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.
    • Cell-substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime.

      Singh, Shashi Prakash; Thomason, Peter A; Lilla, Sergio; Schaks, Matthias; Tang, Qing; Goode, Bruce L; Machesky, Laura M; Rottner, Klemens; Insall, Robert H (2020-08-03)
    • Absence of cGAS-mediated type I IFN responses in HIV-1-infected T cells.

      Elsner, Carina; Ponnurangam, Aparna; Kazmierski, Julia; Zillinger, Thomas; Jansen, Jenny; Todt, Daniel; Döhner, Katinka; Xu, Shuting; Ducroux, Aurélie; Kriedemann, Nils; et al. (2020-07-24)
      The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4+ T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression of IFIT1 and MX2 was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4+ T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1ΔUL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4+ T cells, plasmid challenge or HSV-1ΔUL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1ΔUL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.
    • Planctopirus ephydatiae, a novel Planctomycete isolated from a freshwater sponge.

      Kohn, T; Wiegand, S; Boedeker, C; Rast, P; Heuer, A; Jetten, M S M; Schüler, M; Becker, S; Rohde, C; Müller, R-W; et al. (2019-10-11)
      The microbiome of freshwater sponges is rarely studied, and not a single novel bacterial species has been isolated and subsequently characterized from a freshwater sponge to date. A previous study showed that 14.4% of the microbiome from Ephydatia fluviatilis belong to the phylum Planctomycetes. Therefore, we sampled an Ephydatia sponge from a freshwater lake and employed enrichment techniques targeting bacteria from the phylum Planctomycetes. The obtained strain spb1T was subject to genomic and phenomic characterization and found to represent a novel planctomycetal species proposed as Planctopirus ephydatiae sp. nov. (DSM 106606 = CECT 9866). In the process of differentiating spb1T from its next relative Planctopirus limnophila DSM 3776T, we identified and characterized the first phage - Planctopirus phage vB_PlimS_J1 - infecting planctomycetes that was only mentioned anecdotally before. Interestingly, classical chemotaxonomic methods would have failed to distinguish Planctopirus ephydatiae strain spb1T from Planctopirus limnophila DSM 3776T. Our findings demonstrate and underpin the need for whole genome-based taxonomy to detect and differentiate planctomycetal species.