Instrumentation and control of anaerobic digestion processes: a review and some research challenges

The final publication is available at Springer via http://dx.doi.org/10.1007/s11157-015-9382-6[EN] To enhance energy production from methane or resource recovery from digestate, anaerobic digestion processes require advanced instrumentation and control tools. Over the years, research on these topics has evolved and followed the main fields of application of anaerobic digestion processes: from municipal sewage sludge to liquid mainly industrial then municipal organic fraction of solid waste and agricultural residues. Time constants of the processes have also changed with respect to the treated waste from minutes or hours to weeks or months. Since fast closed loop control is needed for short time constant processes, human operator is now included in the loop when taking decisions to optimize anaerobic digestion plants dealing with complex solid waste over a long retention time. Control objectives have also moved from the regulation of key variables measured online to the prediction of overall process perfor- mance based on global off-line measurements to optimize the feeding of the processes. Additionally, the need for more accurate prediction of methane production and organic matter biodegradation has impacted the complexity of instrumentation and should include a more detailed characterization of the waste (e.g., biochemical fractions like proteins, lipids and carbohydrates)andtheirbioaccessibility andbiodegradability characteristics. However, even if in the literature several methodologies have been developed to determine biodegradability based on organic matter characterization, only a few papers deal with bioaccessibility assessment. In this review, we emphasize the high potential of some promising techniques, such as spectral analysis, and we discuss issues that could appear in the near future concerning control of AD processes.The authors acknowledge the financial support of INRA (the French National Institute for Agricultural Research), the French National Research Agency (ANR) for the "Phycover" project (project ANR-14-CE04-0011) and ADEME for Inter-laboratory assay financial support.Jimenez, J.; Latrille, E.; Harmand, J.; Robles Martínez, Á.; Ferrer Polo, J.; Gaida, D.; Wolf, C.... (2015). Instrumentation and control of anaerobic digestion processes: a review and some research challenges. Reviews in Environmental Science and Biotechnology. 14(4):615-648. doi:10.1007/s11157-015-9382-6S615648144Aceves-Lara CA, Latrille E, Steyer JP (2010) Optimal control of hydrogen production in a continuous anaerobic fermentation bioreactor. Int J Hydrogen Energ 35:10710–10718Aguado D, Montoya T, Ferrer J, Seco A (2006) Relating ions concentration variations to conductivity variations in a sequencing batch reactor operated for enhanced biological phosphorus removal. Environ Modell Softw 21:845–851Aguilar-Garnica E, Dochain D, Alcaraz-González V, González-Álvarez V (2009) A multivariable control scheme in a two-stage anaerobic digestion system described by partial differential equations. J Process Contr 19:1324–1332Ahring BK, Angelidaki I, Johansen K (1992) Anaerobic treatment of manure together with industrial waste. Water Sci Technol 25:311–318Ajeej A, Thanikal JV, Narayanan CM, Senthil Kumar R (2015) An overview of bio augmentation of methane by anaerobic co-digestion of municipal sludge along with microalgae and waste paper. Renew Sustain Energy Rev 50:270–276Alcaraz-González V, González-Álvarez V (2007) Selected topics in dynamics and control of chemical and biological processes. Springer, BerlinAlcaraz-González V, Harmand J, Rapaport A, Steyer JP, González-Álvarez V, Pelayo-Ortiz C (2005a) Robust interval-based regulation for anaerobic digestion processes. Water Sci Technol 52:449–456Alcaraz-González V, Salazar-Peña R, González-Alvarez V, Gouzé JL, Steyer JP (2005b) A tunable multivariable nonlinear robust observer for biological systems. C R Biol 328:317–325Alferes J, Irizar I (2010) Combination of extremum-seeking algorithms with effective hydraulic handling of equalization tanks to control anaerobic digesters. Water Sci Technol 61:2825–2834Alferes J, García-Heras JL, Roca E, García C, Irizar I (2008) Integration of equalisation tanks within control strategies for anaerobic reactors. Validation based on ADM1 simulations. Water Sci Technol 57:747–752Alimahmoodi M, Mulligan CN (2008) Anaerobic bioconversion of carbon dioxide to biogas in an upflow anaerobic sludge blanket reactor. J Air Waste Manage Assoc 58:95–103Alvarez JA, Otero L, Lema JM (2010) A methodology for optimising feed composition for anaerobic co-digestion of agro-industrial wastes. Bioresour Technol 101:1153–1158Alvarez-Ramirez J, Meraz M, Monroy O, Velasco A (2002) Feedback control design for an anaerobic digestion process. J Chem Technol Biotechnol 77:725–734Anderson GK, Yang G (1992) Determination of bicarbonate and total volatile acid concentration in anaerobic digesters using a simple titration. Water Environ Res 64:53–59Andrews JF, Graef SP (1971) Dynamic modelling and simulation of the AD process. Advances in chemistry series no. 105, Anaerobic Biological Treatment Processes. American Chemical Society, Washington, DC, p 126Andrews JF, Pearson EA (1965) Kinetics and characteristics of volatile acid production in anaerobic fermentation processes. Air Water Pollut 9:439–461Angelidaki I, Sanders W (2004) Assessment of the anaerobic biodegradability of macropllutants. Rev Environ Sci Biotechnol 3:117–129Antila J, Tuohiniemi M, Rissanen A, Kantojärvi U, Lahti M, Viherkanto K, Kaarre M, Malinen J (2014) MEMS- and MOEMS-based near-infrared spectrometers. Encycl Anal Chem 1–36. doi: 10.1002/9780470027318.a9376Antoniades CD, Christofides P (2001) Integrating nonlinear output feedback control and optimal actuator/sensor placement for transport-reaction processes. Chem Eng Sci 56:4517–4535APHA (2005) American Public Health Association/American Water Works Association/Water Environmental Federation, Standard methods for the Examination of Water and Wastewater, 21st edn. Washington, DC, USAAppels L, Baeyens J, Degrève J, Dewil R (2008) Principles and potential of the anaerobic digestion of waste-activated sludge. Prog Energ Combust 34:755–781Appels L, Lauwers J, Gins G, Degreve J, Van Impe J, Dewil R (2011) Parameter identification and modeling of the biochemical methane potential of waste activated sludge. Environ Sci Technol 45:4173–4178Aquino SF, Chernicharo CAL, Soares H, Takemoto SY, Vazoller RF (2008) Methodologies for determining the bioavailability and biodegradability of sludges. Environ Technol 29:855–862Astals S, Esteban-Gutiérrez M, Fernández-Arévalo T, Aymerich E, García-Heras JL, Mata-Alvarez J (2013a) Anaerobic digestion of seven different sewage sludges: a biodegradability and modelling study. Water Res 47:6033–6043Astals S, Nolla-Ardèvol V, Mata-Alvarez J (2013b) Thermophilic co-digestion of pig manure and crude glycerol: process performance and digestate stability. J Biotechnol 166:97–104Babary JP, Julien S, Nihtilä MT et al (1999) New boundary conditions and adaptive control of fixed-bed bioreactors. Chem Eng Process Process Intensif 38:35–44Barat R, Serralta J, Ruano MV, Jiménez E, Ribes J, Seco A, Ferrer J (2012) Biological nutrient removal model No 2 (BNRM2): a general model for wastewater treatment plants. Water Sci Technol 67:1481–1489Bastin G, Dochain D (1990) On-line estimation and adaptive control of bioreactors. Elsevier Science, AmsterdamBatstone DJ (2013) Modelling and control in anaerobic digestion: achievements and challenges. 13th IWA World Congress on Anaerobic Digestion (AD 13), pp 1–6Batstone DJ, Keller J, Angelidaki I et al (2002) Anaerobic digestion model No. 1. (ADM1). IWA Scientific and Technical Report No. 13. IWABatstone DJ, Tait S, Starrenburg D (2009) Estimation of hydrolysis parameters in full-scale anaerobic digesters. Biotechnol Bioeng 102:1513–1520Batstone DJ, Amerlinck Y, Ekama G et al (2012) Towards a generalized physicochemical framework. Water Sci Technol 66:1147–1161Baumann WT, Rugh WJ (1986) Feedback control of nonlinear systems by extended linearization. IEEE Trans Automat Contr AC-31:40–46Benyahia B, Campillo F, Cherki B, Harmand J (2012) Particle filtring for the chemostat. In: MED’12, Barcelone, SpainBernard O (2011) Hurdles and challenges for modelling and control of microalgae for CO2 mitigation and biofuel production. J Process Control 21:1378–1389Bernard O, Gouzé JL (2004) Closed loop observers bundle for uncertain biotechnological models. J Process Control 14:765–774Bernard O, Hadj-Sadok Z, Dochain D et al (2001a) Dynamical model development and parameter identification for an anaerobic wastewater treatment process. Biotechnol Bioeng 75:424–438Bernard O, Polit M, Hadj-Sadok Z, Pengov M, Dochain D, Estaben M, Labat P (2001b) Advanced monitoring and control of anaerobic wastewater treatment plants: software sensors and controllers for an anaerobic digester. Water Sci Technol 43:175–182Bernard O, Chachuat B, Hélias A, Rodriguez J (2005a) Can we assess the model complexity for a bioprocess? Theory and example of the anaerobic digestion process. Water Sci Technol 53:85–92Bernard O, Chachuat B, Hélias A, Le Dantec B, Sialve B, Steyer JP, Lavigne JF (2005b) An integrated system to remote monitor and control anaerobic wastewater treatment plants through the internet. Water Sci Technol 52:457–464Björnsson L, Hörnsten EG, Mattiasson B (2001a) Utilization of a palladium–metal oxide semiconductor (Pd-MOS) sensor for on-line monitoring of dissolved hydrogen in anaerobic digestion. Biotechnol Bioeng 73:35–43Björnsson L, Murto M, Jantsch TG, Mattiasson B (2001b) Evaluation of new methods for the monitoring of alkalinity, dissolved hydrogen and the microbial community in anaerobic digestion. Water Res 35:2833–2840Boe K (2006) Online monitoring and control of the biogas process. Technical University of DenmarkBoe K, Batstone D, Angelidaki I (2007) An innovative online VFA monitoring system for the anerobic process, based on headspace gas chromatography. Biotechnol Bioeng 96:712–721Boe K, Steyer JP, Angelidaki I (2008) Monitoring and control of the biogas process based on propionate concentration using online VFA measurement. Water Sci Technol 57:661–766Boe K, Batstone DJ, Steyer JP, Angelidaki I (2010) State indicators for monitoring the anaerobic digestion process. Water Res 44:5973–5980Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254Brinkmann K, Blaschke L, Polle A (2002) Comparison of different methods for lignin determination as a basis for calibration of near-infrared reflectance spectroscopy and implications of lignoproteins. J Chem Ecol 28:2483–2501Buendía IM, Fernández FJ, Villaseñor J, Rodríguez L (2008) Biodegradability of meat industry wastes under anaerobic and aerobic conditions. Water Res 42:3767–3774Buffiere P, Loisel D, Bernet N, Delgenes JP (2006) Towards new indicators for the prediction of solid waste anaerobic digestion properties. Water Sci Technol 53:233–241Cao Y, Pawlowski A (2012) Sewage sludge-to-energy approaches based on anaerobic digestion and pyrolysis: brief overview and energy efficiency assessment. Renew Sust Energ Rev 16:1657–1665Carballa M, Regueiro L, Lema JM (2015) Microbial management of anaerobic digestion: exploiting the microbiome-functionality nexus. Curr Opin Biotechnol 33:103–111Carlos-Hernandez S, Beteau JF, Sanchez EN (2007) Intelligent control strategy for an anaerobic fluidized bed reactor. In: Michel P (ed) Computer applications in biotechnology, vol 1. Cancun, Mexico, pp 73–78Carlos-Hernandez S, Sanchez EN, Bueno JA (2010) Neurofuzzy control strategy for an abattoir wastewater treatment process. In: Banga JR, Bogaerts P, Van Impe J, Dochain D, Smets I (eds) 11th International symposium on computer applications in biotechnology. Leuven, Belgium, pp 84–89Chandler JA, Jewell WJ, Gossett JM (1980) Predicting methane fermentation biodegradability. Biotechnol Bioeng Symp 10:93–107Chen YH (1990) Adaptive robust observers for non-linear uncertain systems. Int J Syst Sci 21:803–814Chen Y, Cheng JJ, Creamer KS (2008) Inhibition of anaerobic digestion process: a review. Bioresour Technol 99:4044–4064Chynoweth DP, Turick CE, Owens JM, Jerger DE, Peck MW (1993) Biochemical methane potential of biomass and waste feedstocks. Biomass Bioenerg 5:95–111Cirne DG, van der Zee FP, Fernandez-Polanco M, Fernandez-Polanco F (2008) Control of sulphide during anaerobic treatment of S-containing wastewaters by adding limited amounts of oxygen or nitrate. Rev Environ Sci Biotechnol 7:93–105Colombié S, Latrille E, Sablayrolles JM (2007) Online estimation of assimilable nitrogen by electrical conductivity measurement during alcoholic fermentation in enological conditions. J Biosci Bioeng 103:229–235Cord-Ruwisch R, Mercz TI, Hoh CY, Strong GE (1997) Dissolved hydrogen concentration as an on-line control parameter for the automated operation and optimization of anaerobic digesters. Biotechnol Bioeng 56:626–634Cossu R, Raga R (2008) Test methods for assessing the biological stability of biodegradable waste. Waste Manage 28:381–388Cresson R, Pommier S, Béline F et al (2014) Etude interlaboratoires pour l’harmonisation des protocoles de mesure du potentiel bio-méthanogène des matrices solides hétérogènes—Final report (in French) ADEMEDalmau J, Comas J, Rodríguez-Roda I, Pagilla K, Steyer JP (2010) Model development and simulation for predicting risk of foaming in anaerobic digestion systems. Bioresour Technol 101:4306–4314Davidsson A, Gruvberger C, Christensen TH, Hansen TL, Jansen J (2007) Methane yield in source-sorted organic fraction of municipal solid waste. Waste Manage 27:406–414De Baere L (2000) Anaerobic digestion of solid waste: state-of-the-art. Water Sci Technol 41:283–290De Baere L (2008) Partial stream digestion of residual municipal solid waste. Water Sci Technol 57:1073–1077De Gracia M, Grau P, Huete E et al (2009) New generic mathematical model for WWTP sludge digesters operating under aerobic and anaerobic conditions: model building and experimental verification. Water Res 43:4626–4642De Vrieze J, Verstraete W, Boon N (2013) Repeated pulse feeding induces functional stability in anaerobic digestion. Microb Biotechnol 6:414–424Delattre C, Dochain D, Winkin J (2004) Observability analysis of nonlinear tubular (bio)reactor models: a case study. J Process Control 14:661–669Di Pinto AC, Limoni N, Passino R, Rozzi A, Tomei MC (1990) Instrumentation, control and automation of water and wastewater treatment and transport systems. In: Proceedings of the 5th IAWPRC workshop, pp 51–58Díaz I, Pérez C, Alfaro N, Fdz-Polanco F (2015) A feasibility study on the bioconversion of CO2 and H2 to biomethane by gas sparging through polymeric membranes. Bioresour Technol 185:246–253Dochain D (2003) State and parameter estimation in chemical and biochemical processes: a tutorial. J Process Control 13:801–818Dochain D, Tali-Maamar N, Babary JP (1997) On modelling, monitoring and control of fixed bed bioreactors. Comput Chem Eng 21:1255–1266Dochain D, Perrier M, Guay M (2011) Extremum seeking control and its application to process and reaction systems: a survey. Math Comput Simulat 82:369–380Donoso-Bravo A, Garcia G, Pérez-Elvira S, Fernandez-Polanco F (2011) Initial rates technique as a procedure to predict the anaerobic digester operation. Biochem Eng J 53(3):275–280Doublet J, Boulanger A, Ponthieux A, Laroche C, Poitrenaud M, Cacho Rivero JA (2013) Predicting the biochemical methane potential of wide range of organic substrates by near infrared spectroscopy. Bioresour Technol 128:252–258Dreywood R (1946) Qualitative test for carbohydrate material. Industrial & Engineering Chemistry Analytical Edition. Am Chem Soc 18:499Dubois M, Gilles KA, Hamilton JK, Rebers PA, Smith F (1956) Colorimetric method for determination of sugars and related substances. Anal Chem 28:350–356Ekama GA, Sotemann SW, Wentzel MC (2007) Biodegradability of activated sludge organics under anaerobic conditions. Water Res 41:244–252Ellison WJ, Pedarros-Caubet F, Caubet R (2007) Automatic and rapid measurement of microbial suspension growth parameters: application to the evaluation of effector agents. J Rapid Meth Aut Mic 15:369–410Fang HHP (2012) Bioenergy production from waste and wastewater in China. In: Technical proceedings of the 2012 NSTI nanotechnology conference and expo, NSTI-nanotech 2012, pp 381–383Fannin KF, Chynoweth DP, Isaacson R (1987) Start-up, operation, stability, and control. Anaerob Dig Biomass 171–196Fdz-Polanco M, Díaz I, Pérez SI, Lopes AC, Fdz-Polanco F (2009a) Hydrogen sulphide removal in the anaerobic digestion of sludge by micro-aerobic processes: pilot plant experience. Water Sci Technol 60:3045–3050Fdz-Polanco M, Pérez-Elvira SI, Díaz I, García L, Torío R, Acevedo AF (2009b) Eliminación de H2S en digestión anaerobia de lodos por procesos microaerofílicos: experiencia en planta piloto. Tecnol del Agua 29:58–64Feitkenhauer H, von Sachs J, Meyer U (2002) On-line titration of volatile fatty acids for the process control of anaerobic digestion plants. Water Res 36:212–218Fernández YB, Soares A, Villa R, Vale P, Cartmell E (2014) Carbon capture and biogas enhancement by carbon dioxide enrichment of anaerobic digesters treating sewage sludge or food waste. Bioresour Technol 159:1–7Fountoulakis MS, Stamatelatou K, Lyberatos G (2008) The effect of pharmaceuticals on the kinetics of methanogenesis and acetogenesis. Bioresour Technol 99:7083–7090Francioso O, Rodriguez-Estrada MT, Montecchio D, Salomoni C, Caputo A, Palenzona D (2010) Chemical characterization of municipal wastewater sludges produced by two-phase anaerobic digestion for biogas production. J Hazard Mater 175:740–746Frigon JC, Roy C, Guiot SR (2012) Anaerobic co-digestion of dairy manure with mulched switchgrass for improvement of the methane yield. Bioprocess Biosyst Eng 35:341–349Frings CS, Dunn RT (1970) A colorimetric method for determination of total serum lipids based on the sulfo-phospho-vanillin reaction. Am J Clin Pathol 53:89–91Frølund B, Palmgren R, Keiding K, Nielsen PH (1996) Extraction of extracellular polymers from activated sludge using a cation exchange resin. Water Res 30:1749–1758Gaida D, Wolf C, Meyer C, Stuhlsatz A, Lippel J, Bäck T, Bongards M, McLoone S (2012) State estimation for anaerobic digesters using the ADM1. Water Sci Technol 66:1088–1095Ganesh R, Torrijos M, Sousbie P et al (2013) Anaerobic co-digestion of solid waste: effect of increasing organic loading rates and characterization of the solubilised organic matter. Bioresource Technol 130:559–569García-Diéguez C, Molina F, Roca E (2011) Multi-objective cascade controller for an anaerobic digester. Process Biochem 46:900–909García-Gen (2015) Modelling, optimisation and control of anaerobic co-digestion processes (2015), Ph.D. Thesis, Universidad de Santiago de Compostela, Departamento de Ingeniería QuímicaGarcía-Gen S, Sousbie P, Rangaraj G et al (2015) Kinetic modelling of anaerobic hydrolysis of solid wastes, including disintegration processes. Waste Manag 35:96–104Gauthier JP, Kupka IAK (1994) Observability and observers for nonlinear systems. SIAM J Control Optim 32:975–994Gauthier JP, Hammouri H, Othman S (1992) A simple observer for nonlinear systems applications to bioreactors. Autom Control IEEE Trans 37:875–880Ge H, Jensen PD, Batstone DJ (2011) Increased temperature in the thermophilic stage in temperature phased anaerobic digestion (TPAD) improves degradability of waste activated sludge. J Hazard Mater 187:355–361Gendron S, Perrier M, Barrett J, Legault N (1993) Adaptive control of brightness: the model weighting approach. Annual meeting—technical section, Canadian Pulp and Paper Association, Preprints. Publ by Canadian Pulp & Paper AssocGhosh S, Conrad JR, Klass DL (1975) Anaerobic acidogenesis of waste activated sludge, WPCF 47Goffaux G, Van de Wouwer A (2005) Bioprocess state estimation: some classical and less classical approaches. Springer, BerlinGornall AG, Bardawill CJ, David MM (1949) Determination of serum proteins by means of the biuret reaction. J Biochem Chem 177:751–766Gouzé JL, Rapaport A, Hadj-Sadok MZ (2000) Interval observers for uncertain biological systems. Ecol Model 133:45–56Grau P, de Gracia M, Vanrolleghem PA, Ayesa E (2007) A new plant-wide modelling methodology for WWTPs. Water Res 41:4357–4372Gregersen KH (2003) Økonomien i biogasfællesanlæg, Udvikling og status medio (2002) Report no. 150. Institute of Food and Resource Economic, Rolighedsvej 25, DK 1958, Frederiksberg C, DenmarkGrepmeier M (2002) Experimentelle Untersuchungen an einer zweistufigen fuzzy-geregelten anaeroben Abwasserreinigungsanlage mit neuartigem Festbettmaterial. TU MunichGuay M, Dochain D, Perrier M (2004) Adaptive extremum seeking control of continuous stirred tank bioreactors with unknown growth kinetics. Automatica 40:881–888Gunaseelan VN (2007) Regression models of ultimate methane yields of fruits and vegetable solid wastes, sorghum and napiergrass on chemical composition. Bioresour Technol 98:1270–1277Gunaseelan VN (2009) Predicting ultimate methane yields of Jatropha curcus and Morus indica from their chemical composition. Bioresour Technol 100:3426–3429Guwy AJ, Hawkes FR, Wilcox SJ, Hawkes DL (1997) Neural network and on-off control of bicarbonate alkalinity in a fluidised-bed anaerobic digester. Water Res 31:2019–2025Guwy AJ, Dinsdale RM, Kim JR et al (2011) Fermentative biohydrogen production systems integration. Bioresour Technol 102:8534–8542Hao OJ (2003) Sulphate-reducing bacteria. In: Mara D, Horan N (eds) Handbook of water and wastewater microbiology. Academic Press Inc, London, pp 459–468Harremoës P, Capodaglio AG, H

ATF3 Plays a Key Role in Kdo2-Lipid A-Induced TLR4-Dependent Gene Expression via NF-κB Activation

Background: Activating transcription factor 3 (ATF3) is a negative regulator of proinflammatory cytokine expression in macrophages, and ATF3 deficient mice are more susceptible to endotoxic shock. This study addresses the role of ATF3 in the Kdo 2-Lipid A-induced Toll-like receptor 4 (TLR4) signaling pathway in mouse embryonic fibroblasts (MEF). Kdo 2-Lipid A upregulates ATF3 expression in wild type MEF cells and induces both nuclear factor kappa B (NF-kB) and c-Jun N-terminal kinase (JNK) activation via the TLR4 signaling pathway, while neither of these pathways is activated in ATF3-/- MEF cells. Interestingly, in contrast to Kdo 2-Lipid A, the activation of both NF-kB and JNK by TNF-a was normal in ATF3-/- MEF cells. Methodology/Principal Findings: We found that several genes were dramatically upregulated in ATF3+/+ MEF cells in response to Kdo2-Lipid A treatment, while little difference was observed in the ATF3-/- MEF cells. However, we also found that the signal intensities of IkBf in ATF3-/- MEF cells were substantially higher than those in wild type MEF cells upon microarray analyses, and upregulated IkBf expression was detected in the cytosol fraction. Conclusions/Significance: Our findings indicate that ATF3 deficiency affects Kdo 2-Lipid A-induced TLR4 signaling pathways in MEF cells, that it may upregulate IkBf expression and that the high levels of IkBf expression in ATF3-/- cells disrupts Kdo2-Lipid A-mediated signaling pathways

A Novel Role for IκBζ in the Regulation of IFNγ Production

IκBζ is a novel member of the IκB family of NFκB regulators, which modulates NFκB activity in the nucleus, rather than controlling its nuclear translocation. IκBζ is specifically induced by IL-1β and several TLR ligands and positively regulates NFκB-mediated transcription of genes such as IL-6 and NGAL as an NFκB binding co-factor. We recently reported that the IL-1 family cytokines, IL-1β and IL-18, strongly synergize with TNFα for IFNγ production in KG-1 cells, whereas the same cytokines alone have minimal effects on IFNγ production. Given the striking similarities between the IL-1R and IL-18R signaling pathways we hypothesized that a common signaling event or gene product downstream of these receptors is responsible for the observed synergy. We investigated IκBζ protein expression in KG-1 cells upon stimulation with IL-1β, IL-18 and TNFα. Our results demonstrated that IL-18, as well as IL-1β, induced moderate IκBζ expression in KG-1 cells. However, TNFα synergized with IL-1β and IL-18, whereas by itself it had a minimal effect on IκBζ expression. NFκB inhibition resulted in decreased IL-1β/IL-18/TNFα-stimulated IFNγ release. Moreover, silencing of IκBζ expression led to a specific decrease in IFNγ production. Overall, our data suggests that IκBζ positively regulates NFκB-mediated IFNγ production in KG-1 cells

Host Transcription Factors in the Immediate Pro-Inflammatory Response to the Parasitic Mite Psoroptes ovis

BACKGROUND: Sheep scab, caused by infestation with the ectoparasitic mite Psoroptes ovis, results in the rapid development of cutaneous inflammation and leads to the crusted skin lesions characteristic of the disease. We described previously the global host transcriptional response to infestation with P. ovis, elucidating elements of the inflammatory processes which lead to the development of a rapid and profound immune response. However, the mechanisms by which this response is instigated remain unclear. To identify novel methods of intervention a better understanding of the early events involved in triggering the immune response is essential. The objective of this study was to gain a clearer understanding of the mechanisms and signaling pathways involved in the instigation of the immediate pro-inflammatory response. RESULTS: Through a combination of transcription factor binding site enrichment and pathway analysis we identified key roles for a number of transcription factors in the instigation of cutaneous inflammation. In particular, defined roles were elucidated for the transcription factors NF-kB and AP-1 in the orchestration of the early pro-inflammatory response, with these factors being implicated in the activation of a suite of inflammatory mediators. CONCLUSIONS: Interrogation of the host temporal response to P. ovis infestation has enabled the further identification of the mechanisms underlying the development of the immediate host pro-inflammatory response. This response involves key regulatory roles for the transcription factors NF-kB and AP-1. Pathway analysis demonstrated that the activation of these transcription factors may be triggered following a host LPS-type response, potentially involving TLR4-signalling and also lead to the intriguing possibility that this could be triggered by a P. ovis allergen

A 6-items questionnaire (6-QMD) captures a Mediterranean like dietary pattern and is associated with memory performance and hippocampal volume in elderly and persons at risk for Alzheimer’s disease

BACKGROUND: There is evidence that adherence to Mediterranean-like diet reduces cognitive decline and brain atrophy in Alzheimer's disease (AD). However, lengthy dietary assessments, such as food frequency questionnaires (FFQs), discourage more frequent use. OBJECTIVE: Here we aimed to validate a 6-items short questionnaire for a Mediterranean-like diet (6-QMD) and explore its associations with memory performance and hippocampal atrophy in healthy elders and individuals at risk for AD. METHODS: We analyzed 938 participants (N = 234 healthy controls and N = 704 participants with an increased AD risk) from the DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). The 6-QMD was validated against the Mediterranean Diet (MeDi) score and the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND) score, both derived from a detailed FFQ. Furthermore, associations between the 6-QMD and memory function as well as hippocampal atrophy were evaluated using linear regressions. RESULTS: The 6-QMD was moderately associated with the FFQ-derived MeDi adherence score (ρ = 0.25, p < 0.001) and the MIND score (ρ = 0.37, p= < 0.001). Higher fish and olive oil consumption and lower meat and sausage consumption showed significant associations in a linear regression, adjusted for diagnosis, age, sex and education, with memory function (β = 0.1, p = 0.008) and bilateral hippocampal volumes (left: β = 0.15, p < 0.001); (right: β = 0.18, p < 0.001)). CONCLUSIONS: The 6-QMD is a useful and valid brief tool to assess the adherence to MeDi and MIND diets, capturing associations with memory function and brain atrophy in healthy elders and individuals at increased AD dementia risk, making it a valid alternative in settings with time constraints

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Power of Counting Steps in Quantitative Games

We study deterministic games of infinite duration played on graphs and focus on the strategy complexity of quantitative objectives. Such games are known to admit optimal memoryless strategies over finite graphs, but require infinite-memory strategies in general over infinite graphs. We provide new lower and upper bounds for the strategy complexity of mean-payoff and total-payoff objectives over infinite graphs, focusing on whether step-counter strategies (sometimes called Markov strategies) suffice to implement winning strategies. In particular, we show that over finitely branching arenas, three variants of lim sup mean-payoff and total-payoff objectives admit winning strategies that are based either on a step counter or on a step counter and an additional bit of memory. Conversely, we show that for certain lim inf total-payoff objectives, strategies resorting to a step counter and finite memory are not sufficient. For step-counter strategies, this settles the case of all classical quantitative objectives up to the second level of the Borel hierarchy