Luigi Orsenigo passed away in May 2018, leaving all of us with a major loss. This special issue in his honour brings several contributions in the areas in which Gigi contributed in a significant way in the course of his career: the pharmaceutical and biotechnology industries, innovation and industrial dynamics, evolutionary theory and modelling.After graduating in Economics at Bocconi University, Luigi obtained a Ph.D. from the Science Policy Research Unit (SPRU), University of Sussex. Over the course of his career, he has been affiliated with Bocconi University, the University of Brescia and the Open University. At the moment of his death, Luigi Orsenigo was R.M. Phillips Professor of Economics of Innovation at SPRU and Professor of Applied Economics at IUSS (Institute for Advanced Studies) at Pavia. He had also been Fellow of Cespri first, and ICRIOS later, both at Bocconi University. For a long time, he has served as Editor of the Journal of Evolutionary Economics, Advisory Editor of Research Policy and Associate Editor of Industrial and Corporate Change, the main journals devoted to economics of innovation and industrial change. He also has been advising several Italian and international institutions on matters of innovation and industrial policy, including the European Commission and the World Intellectual Property Organization (WIPO).Luigi has been the author of four books and has published many articles on major international journals. The bibliography at the end of this introduction includes his main contributions. In 2012, he has been awarded the Schumpeter Prize for the book “Innovation and the Evolution of Industries. History Friendly Models”, together with F. Malerba, R. Nelson and S. Winter, Cambridge University Press.in this Special Issue reconstructs Luigi’s intellectual development and also provides personal memories.Since his graduation from SPRU Luigi has consistently developed a series of lines of research that have span over a set of areas that are broad but interconnected. One of us, Franco Malerba, In this Special Issue we want to honour Luigi’s memory with contributions that are related to his research. The papers are written by some of the key co-authors of Orsenigo and reflect his main areas of research.file rouge during his life, concerns innovation and the evolution of the pharmaceutical and biotechnology industries, with the role of science playing a prominent role. Among the many papers and book written by Luigi on this topic, here we want to mention “The Emergence of Biotechnology. Institutions and Markets in Industrial Innovation”, Pinter Publishers, London, 1989; “Technological Change and the Dynamics of Networks of Collaborative Relations. The Case of the Bio-pharmaceutical Industry”, (with F. Pammolli and M. Riccaboni), Research Policy, 2001; “The Economics of Biotechnology”, , Edward Elgar, Cheltenham, 2006.A first area of major research by Luigi Orsenigo, a real Luigi has been interested in the biotechnology revolution and the changes that have consequently occurred in the pharmaceutical industry. Due to this revolution, an industry dominated by a stable core of large firms moved to a market structure in which a division of scientific, innovative and production labour has taken place between large incumbent firms and innovative start-ups. This major change and the evolution that followed is also related to a new role that science has taken place in the pharmaceutical industry and to the new relevance of universities and university spin-offs. This new scientific knowledge base changed the type of competition among large incumbents and entrants and led to the rise of networks of collaborations in R&D among actors of different types. Luigi also examined the changes in the industry in the most recent period, in which some of the new entrants have become also integrated pharmaceutical companies, while at the same time some of the large pharmaceutical companies developed their own in-house capabilities in science and biotechnology. In all these dynamics, the high appropriability conditions that characterize the pharmaceutical industry, in which patents play a major role, have fostered and also limited technological change, competition and economic development, in various and complex ways.Exploring Network Dynamics in Complex Fields of Science: The Formation of Ties to Knowledge Translatorsstart from Luigi’s interest in the analysis of the relationship between individual scientists, knowledge evolution and the structure of the pharmaceutical industry. In a sample of 9543 cancer clinical trials over the period 2002–2012 they examine how changes in networks are influenced by the structure of networks as well as the behaviours and characteristics of key individual scientists. Using temporal exponential random graph models, they examine whether the mechanisms of preferential attachment, multi-connectivity, and homophily drive the formation of new collaborative relations to investigators who have knowledge in basic and clinical research. Results indicate that, first, the fragmentation of the network remains high, due to a considerably increasing number of investigators in the network and, secondly, that this fragmentation limits opportunities for knowledge transfer. Homophily in research fields and country of investigators’ affiliation as well as heterophily in terms of publication output are drivers for tie formation to these knowledge translators.Two papers in this Special Issue focus on the pharmaceutical industry and on the role of scientists and R&D and knowledge networks. Bastian Rake, Pablo D’Este and Maureen McKelvey in The Network Origins of Schumpeterian Innovation investigate the evolving division of innovative labour in biotechnology and pharmaceuticals from 1981 to 2012, with particular reference to the roles of large and small firms. Relying on topological methods they find that, while a regime of polarization through preferential attachment driven by large pharmaceutical companies dominated the early stages of the biotechnology revolution, in recent years the evolution of the collaborative network has been shaped by roles’ transitions between originators and developers of innovative ideas. In particular, starting from the early 2000s, the emergence of general purpose research technologies and the scientific and technological transformations in genomics have led to a promiscuity of roles, as small and large firms act both as originators and developers, in a less polarized network. The authors then propose a parsimonious model of network formation and evolution able to account for some of the features of the processes underlying the evolution of the network.Fabio Pammolli, Massimo Riccaboni and Alessandro Spelta in Cambridge Journal of Economics, 1995; “Technological Regimes and Sectoral Patterns of Innovative Activities” , Industrial and Corporate Change,1997 and “Technological regimes and Schumpeterian patterns of innovation” , The Economic Journal, April, 2000. In these and other contributions the view that the specific properties of the technology of an industry in terms of opportunity, appropriability and cumulativeness conditions and of the knowledge base affect the industrial patterns of innovation is proposed. In particular, a technological regime in which opportunity conditions are high, the appropriability of innovation is low and the cumulativeness of innovation lead to a sectoral pattern supportive to new firms, turbulent industrial dynamics and a changing hierarchy of major innovators (Schumpeter Mark I); on the contrary, a technological regime characterized by medium or high technological opportunities, high appropriability and cumulativeness are conducive to a more stable and concentrated industrial pattern of innovation (Schumpeter Mark II). These relationships have been discussed at the theoretical level and in several contributions tested empirically for many technologies, industries and countries.A second area of Orsenigo’s research regards the factors affecting the diversity in the patters of innovative activities across industries and the role of the learning environment in affecting these patterns. In several of his work, Orsenigo used the concept of technological regime as one key factor affecting market structure in an industry. Among his various contributions on the issue, one could mention “Schumpeterian patterns of innovation”, , in Regimes reloaded! A reappraisal of Schumpeterian patterns of innovation, 1977–2011 revisit this concept and perform a quasi-replication of the original empirical exercise. By using more recent data and an expanded dataset of innovations in several industries and countries compared to the original ones of the 1990s and early 2000, they confirm that that the distinction between Schumpeterian Mark I and Mark II patterns of innovation and their explanation in terms of technological regimes has still a major validity and yields relevant insights concerning on the connection between inventive activities and industrial dynamics.In this special issue, Roberto Fontana, Arianna Martinelli and Alessandro Nuvolari in Industrial and Corporate Change, Vol.5, n.1, 1996; “Industrial Dynamics: Stylized Facts, Empirical Evidence and Theoretical Interpretations” , Industrial and Corporate Change, 1997, “Technological Entry, Exit and Survival” , Research Policy, 1999; “The Persistence of Innovative Activities: A Cross-Country and Cross-Sectors Comparative Analysis” (with E. Cefis), Research Policy, 2001. Industrial dynamics has been identified by Luigi as one of the fundamental aspects of change in the economies and the typical example of Schumpeterian competition. In his empirical work, Luigi has examined the processes that lead to the entry and exit of innovators across a broad range of technologies and the persistence of those firms that continue of innovate over time. Moreover, the analysis has been conducted at the micro level over a long period of time and has used patent data at the firm level across different technologies and different countries. The main findings are that the entry and exit processes are technology specific and that a lot of persistency of innovative activities is usually present. However persistency is not very high in the aggregate and declines as time goes by.A third area of inquiry has concerned industrial dynamics, and particular firms’ persistence in innovative activity and the entry and exit of innovators. Among Luigi’s papers, we would like to highlight “The Dynamics and Evolution of Industries” , Along these lines, in this Special Issue Elena Cefis, Franco Malerba and Orietta Marsili present a paper initially discussed with Luigi, “Revolving door effect” or “Schumpeterian gale of creative destruction?”. The authors claim that two basic patterns of exit can be identified from the literature: the revolving door and the gale of creative destruction. In the first, the liability of newness is a driver of the exit process, while in the second it is the displacement of non-innovators. The authors test these two patterns of exit on the population of Dutch firms exiting in 2018. They find confirmation that exit is industry specific: in fact, these two patterns characterize different types of industries. In industries in which innovation does not play a major role, the revolving door effect is the typical pattern and exit is concentrated among the adolescent and small firms. On the contrary, in industries in which innovation is relevant, exit takes place both among infant as well as mature firms and does not necessarily involve only the smaller firms. In particular, in a highly innovative environment, the exit of mature firms is driven by the innovation of young firms as a case of gale of creative destruction.The Economic Journal, 1988, a model with firms heterogeneous in their behaviour and with feedback loops driving the diffusion process. The model shows that diffusion is a dynamic process with a dynamic coupling between the behaviour of individual agents and the environment in which they operate.As an evolutionary economist, Luigi has often emphasized the widespread and persistent heterogeneity of firms in innovation and diffusion. On this theme, Luigi published “Innovation, Diversity and Diffusion: A Self-Organisation Model”, (with G. Silverberg and G. Dosi), In this Special Issue, firms’ heterogeneity is at the base of the paper by Stefano Brusoni, Lorenzo Cassi and Simge Tuna “Reinventing the tire: knowledge integration between technical change and strategy making”. In the article, heterogeneity is examined in terms of the different strategies that Pirelli and Michelin (two of the tire industry’s major companies), followed to exploit robotized modular manufacturing, a radical process innovation. Of the two firms, Pirelli, the technological follower, was more successful because it had a more nuanced strategy due to its superior knowledge integration capabilities. By examining the structural characteristics and evolution of inventors’ networks in the two companies, the authors are able to take into account knowledge integration capabilities. Pirelli leveraged a more connected, cohesive and structured skills than Michelin and developed and deployed a more complex strategy that could better fit the characteristics of the new process technology.Industrial and Corporate Change, 1999. “Innovation and Market Structure in the Dynamics of the Pharmaceutical Industry and Biotechnology: Towards a History-Friendly Model” , Industrial and Corporate Change, 2002. History friendly models represent a second generation of evolutionary models that focus on the evolution of industries, the dynamics of technologies and industrial change and pay attention to the specificities and histories of industries. In these models a dialogue between empirical analyses of industries, appreciative theorizing derived from these analyses and formal models is developed. The result is that history-friendly models are empirically-grounded, based on a specific empirical evolution of an industry, and aim to capture the causal arguments of the appreciative theory in a stylized and simplified form. The building of the model provides a vehicle for checking out the consistency and relevance completeness of the arguments presented in the appreciative theory. Like most evolutionary models, history-friendly models take the form of computer simulations, and are “agent-based modelling”.One last area in which Luigi has been involved in the last part of his life has been the development of a second generation of evolutionary models: history friendly models. Please see in this respect the book “Innovation and the Evolution of Industries: History Friendly Models” , Cambridge University Press, 2016; and the articles “A History-Friendly Model of the Evolution of the Computer Industry”, , The Journal of Evolutionary Economics, 2007). Another model looks at the presence of a variety of market segments that allow entrants to compete in environmental niches that are rather separate one from another .Some of history-friendly models however do not concern industry evolution but examine specific topics in innovation and industrial dynamics. Among these topics, some models analyse the role of demand. A model examines the role of experimental users able to nurture a new technology that may then improve over time and challenge the dominant technology , the advancements of our understanding of the dynamics of industries in general, and of biotechnology in particular, so much pushed and led by Luigi are not only impressive but agenda setting. Remarkable above all is Luigi’s ability to putting empirical regularities into a dynamic instead of a static approach in a clever way, developing a sense for, and understanding of the endogenous forces of change, and striping the complexity of real world phenomena down to a set of dynamic mechanisms and forces. That requires a sound understanding of economic theory, a good sense of scientific ingenuity, as well as a superb competence to creatively put together pieces of puzzles. Luigi quite obviously demonstrated such abilities in a superb way and his contributions to advancing the theory and empirics of industrial dynamics and evolution have been outstanding and path-breaking.So far, this Introduction has been mainly centred on Luigi’s scientific and scholarly work. In the following pages we expand the scope of the tribute to Luigi, by including the talk given by one of us at the opening of the Conference in honour of Luigi Orsenigo in 2018. The Conference gathered his friends, colleagues and former students, and represented a significant testimony of his work, personality and social life.Innovation and the Evolution of Industries:History Friendly Models” , Cambridge University Press, 2016Leveraging Science for Innovation. Swedish Policy for University-Industry Collaboration (with M. Jacob), 1990–2005, SNS, Stockholm, 2007The Economics of Biotechnology (with M. Mc Kelvey (eds.)), Edward Elgar, Cheltenham, 2006Tra continuita’ e cambiamento. La storia dell’Agip Petroli (with G. Sapelli and P. Toninelli), Bologna, Il Mulino, 1993The Emergence of Biotechnology. Institutions and Markets in Industrial Innovation, Pinter Publishers, London, 1989Booksb)Eurasian Business Review (2019) 9:1–23History friendly models: retrospective and future perspectives , Industrial and Corporate Change, 2019Spinoffs in context , Journal of Economic Policy, 2016Industrial Policies for Biotechnology: Limits and New Perspectives, , Business History, Special Issue on “Making Sense of Today’s Structures, by Re-introducing Evolutionary  Theory to Business History”, 2015The Evolution of the Pharmaceutical Industry” Journal of Artificial Societies and Social Simulation, 2013A Simulation Model of the Evolution of the Pharmaceutical Industry , Long Range Planning, 2013Are Switching Costs Always Effective in Creating First Mover Advantage? The Moderating Role of Demand and Technological Regimes , Journal of Economics and Statistics, 2013Innovation and market structure in the evolution of the pharmaceutical industry: a history friendly model, , The Journal of Evolutionary Economics, 2012Technological regimes and demand structure in the evolution of the pharmaceutical industry , Structural Change and Economic Dynamics, 2010User-producer relations, innovation and the evolution of market structures under alternative contractual regimes , Research Policy, 2010In Defence of the Linear Model: An Essay , Capitalism and Society, Berkeley Electronic Press, 2008Technological Revolutions and the Evolution of Industrial Structures. Assessing the Impact of New Technologies upon Size, Patterns of Growth and Boundaries of Firms, , Health Partnerships Review, 2008Beyond market failures: IAVI and the organizational challenges of vaccine development (with S. Brusoni and E. Cacciatori), International Journal of Biotechnology, Special Issue on The Evolution of the Life Science Industries (ed. with J. Tait), 2008Editorial, International Journal of Biotechnology, 2008Special Issue on The Evolution of the Life Science Industries (ed. with J. Tait), Journal of Economic Behaviour and Organisation, 2008Public Policies and Changing Boundaries of Firms in a “History Friendly” Model of the Co-Evolution of the Computer and Semiconductors Industries , ), Industrial and Corporate Change, 2008The Italian Connection: the origins of Giovanni Dosi’s thinking and a note on some lost, or never written, manuscripts , European Planning Studies, 2008, pp. 337–357A Critical Assessment of Regional Innovation Policy in Pharmaceutical Biotechnology (with A.Rosiello), Structural Change and Economic Dynamics, 2007Testing Gibrat’s Law: A Bayesian Approach to the Study of Firms’ Growth (with E. Cefis and M. Ciccarelli), The Journal of Evolutionary Economics, 2007Demand, Innovation and the Dynamics of Market Structure: the Role of Experimental Users and Diverse Preferences , European Journal of Development Research, 2007The International AIDS Vaccine Initiative (IAVI) in a Changing Landscape of Vaccine Development: A Public – Private Partnership as Knowledge Broker and Integrator , Revista de Economia, 2003History Friendly Models of Industrial Evolution: Aims, Applications and Pitfalls, International Journal of Technology Management, 2003Variables Influencing Industrial Funding of Academic Research in Italy: an Empirical Analysis (with G. Bruno), Revue d’Economie Industrielle, 2002The Intensity of Competition After Patent Expiry in Pharmaceuticals. A Cross-Country Analysis (with L. Magazzini and F. Pammolli), Industrial and Corporate Change, 2002Innovation and Market Structure in the Dynamics of the Pharmaceutical Industry and Biotechnology: Towards a History-Friendly Model , Journal of Artificial Societies and Social Simulation, 2001History-Friendly Models: An Overview of the case of the Computer Industry , Research Policy, 2001The Persistence of Innovative Activities: A Cross-Country and Cross-Sectors Comparative Analysis (with E. Cefis), Small Business Economics, 2001The (failed?) development of a biotechnology cluster. The case of Lombardy, Research Policy, 2001Technological Change and the Dynamics of Networks of Collaborative Relations. The Case of the Bio-pharmaceutical Industry (with F. Pammolli and M. Riccaboni), Sistemi Intelligenti, 2000Mente e società: soluzione di problemi e organizzazioni , International Journal of Industrial Organization, 2000Competition and industrial policies in a “history-friendly” model of the evolution of the computer industry , Industrial and Corporate Change, Special Issue on “The Codification of Knowledge” (eds: P. Cohendet and W.E. Steinmueller), 2000Knowledge, Innovative Activities and Industry Evolution , The Economic Journal, April, 2000Technological regimes and Schumpeterian patterns of innovation , Industrial and Corporate Change, 1999A History-Friendly Model of the Evolution of the Computer Industry , International Journal of Biotechnology, 1999The evolution of the forms of organization of innovative activities in biotechnology (with P. Barbanti e A. Gambardella), in Research Policy, 1999Technological Entry, Exit and Suvival , Journal of Management and Governance, 1998The Dynamics of Knowledge and the Evolution of an Industry Network , The International Journal of Industrial Organization, 1997Technological Persistence and Heterogeneity of Innovative Activities, Sectoral Patterns of Innovation and International Specialization , Industrial and Corporate Change, Special Issue on Technological Regimes and the Evolution of Industrial Structures, edited by G. Dosi, F. Malerba and L. Orsenigo, 1997Technological Regimes and Sectoral Patterns of Innovative Activities , Industrial and Corporate Change, Special Issue on Technological Regimes and the Evolution of Industrial Structures”, edited by G. Dosi, F. Malerba and L. Orsenigo, 1997Industrial Dynamics: Stylized Facts, Empirical Evidence and Theoretical Interpretations , , Industrial and Corporate Change, edited by G. Dosi, F. Malerba and L. Orsenigo, 1997Special Issue on Technological Regimes, Industrial Demography and the Evolution of Industrial StructuresCahiers de Economie et Sociologie Rurale, 1996Technological regimes, patterns of innovative activities and industrial dynamics. A survey of empirical evidence and of some theoretical models, Industrial and Corporate Change, Vol.5, n.1, 1996The Dynamics and Evolution of Industries , Research Policy, 1996Schumpeterian patterns of innovation are technology-specific , The Journal of Evolutionary Economics, 1995Choice and action , Small Business Economics, 1995Technological Regimes, Selection and Market Structures , Cambridge Journal of Economics, 1995Schumpeterian patterns of innovation , Biotechnology Review, Special Issue of The International Journal of Technology Management, 1993Scientific gatekeepers and industrial development in biotechnology (with N. Buratti and A. Gambardella), Industrial and Corporate Change, 1993Technological Regimes and Firm Behaviour”, , Ekonomiaz, 1992Regularidades en las actividades de innovacion: una investigacion preliminar para cuatro paises europeos, CSC Ricerche, n. 112, Roma, 1995Competenze tecnologiche nei settori ad alta tecnologia, , Centro Studi Confindustria, Business and Economic History, 1992The evolution of strategy and structure of a state-owned company: the case of Agip Petroli (1960-1990) (with G. Sapelli and P. Toninelli), L’impresa, no. 4, 1989Concorrenza e collaborazione tra imprese nel processo innovativo: il caso della biotecnologia, The Economic Journal, Vol. 98, December 1988Innovation, Diversity and Diffusion: A Self-Organisation Model (with G. Silverberg and G. Dosi), Rivista Trimestrale di Scienze dell’ Amministrazione, n.2, 1988Tecnologie emergenti e politica industriale in Italia (with P.Adams), Politica ed Economia”, Agosto 1987Modelli di diffusione dell’innovazione, Papersiii)Technological Regimes and Demand Structure in the Evolution of the Pharmaceutical Industry , in“: Andreas Pyka, Esben Sloth Andersen (eds.) Long Term Economic Development, Demand, Finance, Organization, Policy and Innovation in a Schumpeterian Perspective, Springer, 2013Intellectual Property Rights: Legal and Economic Challenges for Development, Initiative for Policy Dialogue, Oxford, Oxford University Press, 2014IPRs, Public Health and the Pharmaceutical Industry. Issues in the Post-2005 TRIPS agenda” (with B. Coriat), in M. Cimoli, G. Dosi, K.E. Maskus, R. L. Okediji and J. H. Reichman, The Palgrave Encyclopedia for Strategic Management, Macmillan, London, 2013Pharmaceuticals, in M. Augier and D. Teece (eds.), Capitalism and Society 3.1 (2008)Technological Revolutions and the Evolution of Industrial Structures. Assessing the Impact of New Technologies upon Size, Patterns of Growth and Boundaries of Firms”, , The Development Agenda: Global Intellectual Property and Developing Countries”, Oxford University Press, 2008IPRs, technological and industrial development and growth: the case of the pharmaceutical industry (with F. Laforgia and F. Montobbio), in N. Netanel (ed.), “Business Performance in the twentieth Century: A Comparative Perspective, Cambridge University Press, Cambridge, UK, 2008Innovate or Die? A critical review of the literature on innovation and performance (with S. Brusoni and E. Cefis), in Y. Cassis and A. Colli (eds), The Elgar Companion to Neo-Schumpeterian Economics, Elgar, Cheltenham, 2007“History Friendly” Models of Industrial Evolution, in H. Hanusch and A. Pyka (eds.), Promoting innovation, productivity and industrial growth and reducing poverty: bridging the policy gap London: Routledge,. (2008)The International AIDS Vaccine Initiative (IAVI) in a changing landscape of vaccine development: a Public Private Partnership as knowledge broker and integrator  in Chataway, J.C., Mackintosh, M. and Wuyts, M. (eds.) The Genesis of Clusters of Innovation, Oxford, Oxford University Press, 2006Clusters and Clustering in Biotechnology: Stylised Facts, Issues and Theories. From Clusters to network structures and their dynamics, in P. Braunerhjelm and M. Feldman (eds.), New Frontiers in the Economics of Innovation and New Technology. Essays in Honour of Paul A. David, Edward Elgar, Cheltenham, 2006A history-friendly model of innovation, market structure and regulation in the age of random screening in the pharmaceutical industry , in C. Antonelli, D. Foray, B. H. Hall and W.E. Steinmueller (eds.), Knowledge Accumulation and Industry Evolution. The Case of Pharma-Biotech””, Oxford University Press, Cambridge, Cambridge University Press, 2006The Dynamics of Knowledge Accumulation, Regulation and Appropriability in the Pharma-Biotech Sector: Policy Issues (with G. Dosi and M. Mazzucato), in G. Dosi and M. Mazzuccato (eds.), Knowledge Accumulation and Industry Evolution. The Case of Pharma-Biotech”, Oxford University Press, Cambridge, Cambridge University Press, 2006Entry, Market Structure and Innovation in a History-Friendly Model of the Evolution of the Pharmaceutical Industry , in G. Dosi and M. Mazzuccato (eds.), Revue del’OFCE, 2006Biotechnologies et industrie pharmaceutique. Un modéle évolutionaire conforme à l’histoire , Knowledge Accumulation and Industry Evolution. The Case of Pharma-Biotech, Cambridge, Cambridge University Press, 2006Heterogeneity in Firms’Growth in the Pharmaceutical Industry (with E. Cefis and M. Ciccarelli), in G. Dosi and M. Mazzuccato (eds.), Flexibility and Stability in the Evolving Economy, Oxford University Press, 2005Changing Boundaries of firms in the evolution of the computer industry: towards a history-friendly model , in M. McKelvey and M. Holmen (eds.), Saggi di economia evolutiva, Franco Angeli, Milano, 2005Prefazione, in F.M. Lombardi and F. Squazzoni (eds.), Imprese e Storia, 31, gennaio-giugno 2005Modelli “history-friendly” della evoluzione industriale, “Multidisciplinary Economics”, Springer, Dordrecht, The Netherlands, 2005History Friendly Models of Industrial Evolution: An Overview, in P. De Gijsel and H. Schenk, The Economic Dynamics of Modern Biotechnology, Edward Elgar, London, 2005Reflections and Ways Forward (with H. Kettler e M. McKelvey), in M. McKelvey, A. Rickne and J.L. Hellman, Sectoral Systems of Innovation, Cambridge University Press, Cambridge, 2004Pharmaceuticals Analyzed through the Lens of a Sectoral Innovation System (with M. McKelvey and F. Pammolli), in F. Malerba (ed.), Informacion Comercial Espanola”, 2004Los “modelos amistosos de la istoria” en el analisis de la evolucion de las industria: objetivos y aplicaciones, Handbook of Economic Sociology, Cambridge (Mass.), Russell Sage, 2004Technology and the Economy (with G. Dosi and M. Sylos Labini), in N. Smelser and R. Swedberg, The SMS Blackwell Handbook of Organizational Capabilities. Emergence, Development and Change, Blackwell, Oxford, 2003Firm Capabilities, Competition and Industrial Policies in a History-Friendly Model of the Computer Industry , in C. Helfat (ed.), The Economics of Choice, Change and Organization. Essays in honour of R. Cyert, Edward Elgar London 2001“A behavioral and evolutionary model of the dynamics of the computer industry” , in M. Augier and J. March (eds.), Economia e Politica Industriale, 2001Modelli History friendly della evoluzione delle industrie: il caso dell’industria dei computer , “Simulating organizational societies.”, Cambridge (Ma.), MIT Press, 2001Product Diversification in a “History-Friendly Model of the Evolution of the Computer Industry , in E. Larsen and A. Lomi (eds.), The Competitive Renaissance of the US Industry, Washington DC, The National Academy, 2000The Determinants of Research Productivity in Pharmaceuticals and Biotechnology: Implications for Public Policies , paper prepared for the STEP Board Conference on Technological and Non-technological Factors in Industry Performance, Washington D.C., 19,997; D. Mowery (ed.), The Sources of Industrial Leadership, edited by D. Mowery and R. Nelson, Cambridge, Cambridge University Press, 1999The Pharmaceutical Industry and the Revolution in Molecular Biology: Exploring the Interactions Between Scientific, Institutional and Organizational Change (with R. 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L’internazionalizzazione dell’impresa, Atti, Vol. II, Roma, 1992La competitivita’ tecnologica internazionale dell’industria italiana negli anni ottanta , in Ministero del Commercio Estero e Istituto Nazionale per il Commercio estero, Technology and Productivity. The Challenge for Economic Policy, OECD, Paris, 1991Microeconomic dynamics and macro regularities: an “evolutionary“ approach to technological and institutional change (with F. Coricelli e G. Dosi), in State Policy and Techno- Industrial Innovation, London, Routledge, 1991State Policies on Techno-Industrial Innovation in Weaker Economies. The Case of Biotechnology in Britain and Italy (with W. Faulkner), in U. Hilpert (ed.) Struttura, risultati e problemi dell’industria chimica in Italia, Milano, SC Sviluppo Chimica, 1991L’ evoluzione dell’industria chimica italiana negli anni ‘80 (with G. Mussati e A. Soru); La piccola e media industria chimica in Italia: i risultati dell’indagine” (with A. Soru); “Le grandi multinazionali chimiche in Italia (with A. Soru), in CeRIC-Federchimica, Innovazione tecnologica e teoria economica, edited by M. Amendola, Bologna, Il Mulino, 1990Teoria evolutiva e innovazione industriale: gli anni ‘80 , in Alle origini dell’imprenditorialita’, a cura di G. Mussati, Milano, Etas Kompass, 1990Processi di formazione di nuove imprese e dinamica industriale: uno schema di riferimento concettuale (with Marco Vivarelli), in Evolving Technology and Market Structure, Ann Arbor, Michigan University Press, 1990Technological Regimes and Patterns of Innovation: A Theoretical and Empirical Investigation of the Italian Case , in M. Perlman and A. Heertje (eds.), Il settore dei servizi nella societa’ e nell’economia italiana. Matrice 1970-1988., edited by R. Fiori and F. Stellatelli, Milano, CESDIT, 1989Crescita del terziario per l’industria, processi di esternalizzazione e innovazione, in Tecnologia: collaborare e’ d’obbligo, edited by G. Mussati, Confindustria, Comitato Nazionale Piccola Industria, Sipi, Roma, 1989Processi innovativi nelle piccole e medie imprese, in Industria italiana e alte tecnologie” edited by F. Onida and R. Malaman, Milano, F. Angeli, 1989I pattern di sviluppo della biotecnologia: il quadro di riferimento internazionale nei primi anni ‘80, in “Technical Change and Economic Theory.”, Frances Pinter, London,1988Coordination and Transformation: An Overview of Structures, Behaviour and Change in Evolutionary Environments (with G.Dosi),in G. Dosi, C. Freeman, R. Nelson, L. Soete and G. Silverberg (eds.), “Technology, Innovation and Finance”, Oxford, Basil Blackwell, 1988; translations in Italian, French, German and SpanishIndustrial Structure and Technical Change (with G. Dosi), in A. Heertje (ed.), Evoluzione della struttura finanziaria, ruolo degli Istituti di credito a medio e lungo termine e tendenze del credito agevolato, edited by P. Ranci, Assireme, Milano 1983La riforma del credito agevolato (with P. Ranci e G. Verga) in Evoluzione della struttura finanziaria, ruolo degli Istituti di credito a medio e lungo termine e tendenze del credito agevolato, edited by P. Ranci, Assireme, Milano 1983Il finanziamento delle piccole e medie imprese, in La programmazione dei flussi finanziari, edited by G. Vaciago, Il Mulino, Bologna, 1983Il finanziamento delle imprese nella programmazione dei flussi finanziari, in Chapters in books


In the published article, there was an error regarding the affiliations for Ayyad Zartasht Khan. As well as having affiliations “Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway, Department of Surgery, Sørlandet Hospital Arendal, Arendal, Norway, Department of Ophthalmology, Sørlandet Hospital Arendal, Arendal, Norway,” he should also have the following affiliation: “Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Joachim Robert Kalden, Born 23, 1937 in Marburg; †passed away February 6, 2021 in Erlangen.The VIII European Workshop for Rheumatology research held in Corfu, Greece, in the spring of 1988, gave the opportunity to a handful of experts on Autoimmune Rheumatic disorders (ARDs), from different European counties, to constitute a group with a main goal to transform EULAR from a physical medicine and orthopaedics society to a contemporary League, supporting research towards understanding the pathogenesis and development of novel therapies for ARDs. This group consisted of Professors Ravinder Maini, JR Kalden, LBA van de Putte, Allan Wiik, I Lundberg, Lars Klareskog, J Smolen, P Youinou, and myself. I invited these experts for further discussions towards the materialisation of our goal, in a follow up meeting. For everyone’s convenience, this meeting was held close to the Athens airport, in the Astir palace hotel in Vouliagmeni, Attiki, Greece. Among these experts, a leading role was held by the now late Joachim Robert Kalden, a Lupus expert and subsequently a member of the leading group that introduced anti-TNF therapy for rheumatoid arthritis. Professor Kalden developed in Erlangen a world-renowned and respected centre for diagnosis, understanding the pathogenesis of lupus and application of novel therapeutic interventions in ARDs. In addition to research, Johan has edited, in collaboration with other colleagues, three books: (1) Progress in Immunology: Vol. VII: Proceedings of the 7th International Congress of Immunology Berlin 1989; (2) Rheumatoid Arthritis: Recent Research Advances in 1992; and (3) Der IL-1-Rezeptor-Antagonist im Zytokin-Netzwerk: Funktion und Stellenwert in 2013. Furthermore, he shared his knowledge and accomplishments with pleasure, everywhere he was invited to speak.These memoirs came to my mind when I heard from Prof J Smolen that our beloved colleague and one of the founders of research centres in Europe for the study of ARDs, lost the war after a prolonged fight with SARS-COV2.We will remember him as a well-organized personality, a thoughtful investigator, a didactic teacher, and sincere mentor for the development of younger colleagues as clinicians, therapists, and researchers.We, his friends and colleagues, lost a great friend, an advisor in difficulties, and a joyful companion to have a glass of wine with good food. The Aegean Sea and islands will miss a lover of their unique bright light, blue sky and waters. Johan, we will always remember you.


Author Contributions appears below.Julian Maier was not included as an author in the published article. The corrected “MI, ML, GL, MB, HS, and DL designed the study. MI, JM, MH, KJ, and DL conducted the experiments. MI, MB, HS, and DL analyzed data. MI and DL wrote the manuscript with significant input from all other authors.”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Artificial intelligence (AI) is a new technical discipline that uses computer technology to research and develop the theory, method, technique, and application system for the simulation, extension, and expansion of human intelligence. With the assistance of new AI technology, the traditional medical environment has changed a lot. For example, a patient’s diagnosis based on radiological, pathological, endoscopic, ultrasonographic, and biochemical examinations has been effectively promoted with a higher accuracy and a lower human workload. The medical treatments during the perioperative period, including the preoperative preparation, surgical period, and postoperative recovery period, have been significantly enhanced with better surgical effects. In addition, AI technology has also played a crucial role in medical drug production, medical management, and medical education, taking them into a new direction. The purpose of this review is to introduce the application of AI in medicine and to provide an outlook of future trends.


In the published article, there was an error in affiliation 1. Instead of “College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China,” it should be “Shenzhen Key Laboratory of Marine Bioresources and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.”In the published article, there was an error regarding the affiliation for Chen Chen. As well as having affiliation 1, they should also have “College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, China.”There was another error regarding the affiliation for Guo-Li Song. As well as having affiliation 1, they should have “Shenzhen Bay Laboratory, Shenzhen, China” and “Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.”The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Cajanus cajan (L.) Huth] plays an important role in preserving poor smallholders' major source of income in the tropics and subtropics by improving food and feed security, particularly protein intake. In the meantime, protein deficiency is frequent in tropical and subtropical regions due to rapidly increasing human populations and the high cost of animal-origin proteins. As a result, pulse crops should be their primary source of protein. Among these, PP is the most important pulse crop utilized as a food component in rain-fed agricultural conditions with the lowest costs, and it is the best source of protein supplements in typical cereal-based diets to fill the nutritional deficit. Despite this, it is the world's least-used pulse crop. Therefore, the primary goal of this review was to provide and synthesize scientifically confirmed and up-to-date information on the dietary usage of pigeon pea for food and feed. Protein, carbohydrates, minerals, vitamins, and essential amino acids are all present in reasonable amounts in both mature and immature PP seeds. PP has the most potential for usage as food and feed, and its nutrients are comparable to those of soybeans and maize. PP's green leaves, roots, seeds, and pods are high in phenolic compounds, which have anti-inflammation, antibacterial, antioxidant, anticarcinogenic, and antidiabetic properties, as well as the ability to cure diseases like measles, smallpox, chicken pox, sickle cell anemia, fever, dysentery, hepatitis, and antimalarial medications for the body. Furthermore, the addition of pigeon pea and its by-products improves ruminant and nonruminant animal feeding performance significantly. In general, PP products such as dried grain, fresh , and green pods are used as a low-cost (low-cost) source of high-quality and quantity of protein food and feed for tropical and subtropical populations' livelihoods.Pigeon pea (PP) [ Cajanus cajan (L.) Huth] is the most prevalent fast-growing and adaptable pulse crop [2, with India accounting for 92% of that [In tropical and subtropical climates, pigeon pea (PP) [lse crop . Cajan plse crop . The tot of that . It is a of that , 5. It h of that . PP prov of that . PP is a of that . PP is w of that , and it  of that .PP seeds contain about 20–22 percent protein and appreciable amounts of essential amino acids and minerals . It is tIn addition to its food and feed value, PP's green leaves, roots, seeds, and pods contain a large number of phenolic compounds, which offer a number of health benefits , 24. FurThis narrative review is based on theories and empirical findings, with saturated information extracted. Experiments and scientific findings were utilized to filter data and focus on recent publications. The period of search for this script is from June 01, 2021, to October 30, 2021. The script's literature search focused primarily on the dietary use of pigeon pea for food and feed. The information provided by Google Scholar, as well as peer-reviewed major indexers such as Web of Science, PubMed, and Scopus, was used to extract useful information during this review script. Thus, key words such as “pigeon pea cultivation,” “nutritive profile of pigeon pea,” “role of pigeon pea as food,” “role of pigeon pea as feed,” and “therapeutic uses of pigeon pea” were used to find journal articles, papers, books, and symposia. The next section of this script will go through some concepts and experimental settings from the perspectives of PP production, pigeon pea nutritional profile, and dietary usage of pigeon pea for food and feed, and pigeon pea medicinal uses.PP was first grown in India, but it is the world's least utilized pulse crop. It does, however, provide certain benefits for smallholders in the tropics and subtropics . India, The early-blowing variants of PP, as shown in For a village production system, three to four PP seeds might be placed on a single hill, and the plants would generate a large number of twigs on both sides of the bund. In other words, a field with a track record of strong soil fertility and drainage should be selected for periurban commercial cultivation. For soil shortages, a 100 kg/ha diammonium phosphate application and other soil adjustments are recommended prior to sowing. Plant PP seed, as shown in PP is a good source of carbs, proteins, fats, and minerals, and it makes a significant contribution to human and animal nutrition. Carbohydrates, proteins, minerals, vital amino acids, and vitamins are abundant in both mature (dry) and immature seeds of PP . PP seedThe main carbohydrates contained in PP are soluble sugars, starch, and dietary fiber. According to a study by , the comProteins are the second most important component of PP, with 21.7 g/100 g of protein in ripe (dry) seeds, as shown in In mature and immature PP seeds , palmitiAccording to Dietary inhibitors such as phytolectins, polyphenols, and enzyme inhibitors are found in small levels in the mature seed of PP . AccordiPP is consumed in a variety of ways as a food . MeanwhiPP's leaves, seeds, and roots are used for a variety of therapeutic purposes . For exaPigeon pea seed extract has also been found in clinical investigations to aid in the reduction of red blood cell sickling, suggesting that it may be beneficial for people with sickle cell anemia. Sickle cell anemia can be treated with pigeon peas. Many sickle cell disease patients in Chhattisgarh utilize pigeon pea to decrease erythrocyte sickling . The PP According to multiple studies, the leaves, seeds, and roots of PP have a significant degree of anti-inflammation and antibacterial characteristics , 80, as Several studies have found that PP and its by-products are excellent fodder (forage) species that are necessary for animal feed . The PP On the other hand, sheep selected fresh PP plants (forage) from eight browse forge species , and theIn chicken and pig feeds, the whole seed, pods, pod husks, hay, and milling by-products of PP could be a superior replacement for soybeans and maize . SimilarAccording to Whiteman and Norton , adding According to Singh and Kush , PP planThe purpose of this narrative review was to discover the nutritional and phenolic components of pigeon pea, as well as their relevance in human and animal nutrition. In the meantime, protein deficiency is frequent in tropical and subtropical regions, owing to a rapidly growing human population and the high cost of animal-origin proteins. As a result, pulse crops should be their primary source of protein. PP is the most important pulse crop utilized as a food component under rain-fed agricultural circumstances, and it is the most important source of protein supplements in traditional cereal-based diets to fill the nutritional deficit. Protein, carbs, minerals, vitamins, and fundamental amino acids are all present at reasonable levels in both mature and immature PP seeds. PP has the most potential for usage as a food and feed source, and its nutrients are comparable to those of soybeans and maize. In addition to its dietary value, PP's green leaves, roots, seeds, and pods contain a large number of phenolic compounds, which have anti-inflammatory, antibacterial, antioxidant, anticarcinogenic, and antidiabetic properties, as well as the ability to treat diseases such as measles, smallpox, chicken pox, sickle cell anemia, fever, dysentery, hepatitis, and antimalarial medications. Furthermore, the addition of PP and its by-products improves the performance of ruminant and nonruminant animal nutrition significantly. In addition to the foregoing explanations, PP contains antinutritional substances that may have an adverse effect on nutrient bioavailability. Chemical soaking and cooking techniques, on the other hand, may help mitigate these antinutritional effects. Smallholder farmers in the tropics and subtropics use PP and its by-products, such as dry grain, green pods and pod husks, and hay, as a low-cost source of edible proteins for food and feed. As a result, significant emphasis should be put on the production and utilization of PP in traditional cereal-based diets in order to fight protein deficiency in developing countries.


Colorectal cancer (CRC) represents one of the most frequent human cancer entities and is still amongst the “top killers” in human cancer, although fundamental progress has been made in recent years in CRC prevention, early diagnosis, basic and translational research, and (targeted) therapy. The current Special Issue, “Colorectal cancers: from present problems to future solutions”, presents 13 highly timely articles, 9 original articles and 4 reviews, which give insights into, and highlight, the latest developments within the scientific, translational and clinical CRC community, presenting views and work of several internationally highly recognized experts in the field. To this end, the special issue covers exciting novel discoveries in basic and mechanistic research that help to understand CRC carcinogenesis, progression and metastasis, tumor cell heterogeneity, and novel microenvironmental components in CRC. It also covers clinical parameters that modify CRC characteristics and therapy response, and tools and models with a high innovative potential to open new chapters in the differential diagnosis of CRC heterogeneity and response to therapy. causes of CRC carcinogenesis, progression, metastasis, and/or CRC interaction with the (micro-) environment. In an exciting review, Nobel Laureate Harald zur Hausen and Ethel-Michele de Villiers give an intriguing overview on a potential, completely novel class of infectious agents, which might open new avenues to our understanding of indirect carcinogenesis, but also further chronic diseases, such as type 2 diabetes, as (co-) caused by bovine meat and milk factors (BMMFs) [Several articles present advances or novel, in part provocative, hypotheses on  (BMMFs) . BMMFs r (BMMFs)  systemat (BMMFs)  in CRC.  (BMMFs)  extends  (BMMFs) .tumor cell heterogeneity is certainly still one of the most unresolved problems we are facing when it comes to  cancer individual diagnosis, prediction, risk classification, and therapy. Ideally, we would like to aim at scenarios and early diagnostic tools that enable us to predict, for every single patient, the likelihood to develop later progressive disease or metastasis, before this actually happens macroscopically. Therefore, methods to identify metastatically “dangerous” tumor cell clones in any primary tumor, or within single disseminated tumor cells that can be identified in, e.g., the blood of cancer patients, would open tremendous opportunities for a more individualized risk prediction and (preventive) therapy stratification. In an interdisciplinary consortium of molecular translational oncology researchers, optical physicists, and chemists, the groups of H.A. Wagenknecht, C. Cremer, and our own group recently succeeded in establishing a first-in-field approach for quantitative single-cell, single molecule localization microscopy (SMLM) at the nanoscale, within resected human CRC tissues [The issue of  tissues . We spec tissues  present  tissues . These cclinical characteristics (age and gender), can have an impact on clinical courses and outcomes in CRC, and, potentially, response to therapy. During recent years, it has been observed that sporadic CRC has been increasing, also, in younger patients. In an attempt to address potential causes for this, in a large multinational cohort of over 2100 newly diagnosed CRC patients, Himbert et al., together with many colleagues involved in the ColoCare study, analyzed patient, demographic, and lifestyle characteristics, compared between age of onset younger than, or over, 50 years [Two further articles of this Special Issue show actual clinical study data, illustrating how, up to now rather neglected 50 years . Althougmodelling colorectal cancer. A highly interesting article by Jens Hoffmann and his group [Translational, and re-translational, research in CRC, and its success and impact for clinical consequences will, ultimately, also depend on the availability of the right models that are able to reflect the situation within a CRC patient as authentically as possible. Therefore, two articles in this special issue introduce novel, and timely, means of is group  introducis group  introducTaken together, with this Special Issue, “Colorectal Cancers: From Present Problems to Future Solutions”, we hope to present an exciting compilation of articles, by well-known international experts, which can deepen discussions and ideas amongst colleagues in all kinds of disciplines working at CRC and beyond. I hope it can encourage, and intensify, even more translational and interdisciplinary collaborations, aiming at an ultimate understanding of strategies to defeat, and prevent, colorectal cancer, its progression and metastasis, and all the suffering and death resulting from it.


Following the publication of this article , the firPLOS ONE Editors retract the article.In light of the data ownership issues, the CJW, YQL, LLL, YRG, and RHB agreed with the retraction. LW, LYZ, and MXZ either did not respond directly or could not be reached.


Nature Communications 10.1038/s41467-021-25027-2, published online 06 August 2021.Correction to: The original version of this Article contained an error in the author list affiliations, which was previously given as Charles Langmuir is from ‘State Key Laboratory of Isotope Geochemistry, Guangzhou Institute of Geochemistry, Chines Academy of Sciences, Guangzhou, China’ and the ‘Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, USA’. The correct version states that Charles Langmuir is from the ‘Department of Earth and Planetary Sciences, Harvard University, Cambridge, MA, USA’. This has been corrected in both the PDF and HTML versions of the Article.


NOT by single effect/mechanism/pathway), these Neurotransmitters and Neuropeptides by themselves can activate, rejuvenate, and improve T cells. “Personalized Adaptive Neuro-Immunotherapy” is a novel method for rejuvenating and improving T cells safely and potently by Neurotransmitters and Neuropeptides, consisting of personalized diagnostic and therapeutic protocols. The patient’s scarce and/or dysfunctional T cells are activated ex vivo once by pre-selected Neurotransmitters and/or Neuropeptides, tested, and re-inoculated to the patient’s body. Neuro-Immunotherapy can be actionable and repeated whenever needed, and allows other treatments. This adoptive Neuro-Immunotherapy calls for testing its safety and efficacy in clinical trials.T cells are essential for eradicating microorganisms and cancer and for tissue repair, have a pro-cognitive role in the brain, and limit Central Nervous System (CNS) inflammation and damage upon injury and infection. However, in aging, chronic infections, acute SARS-CoV-2 infection, cancer, chronic stress, depression and major injury/trauma, T cells are often scarce, exhausted, senescent, impaired/biased and dysfunctional. People with impaired/dysfunctional T cells are at high risk of infections, cancer, other diseases, and eventually mortality, and become multi-level burden on other people, organizations and societies. It is suggested that “Nerve-Driven Immunity” and “Personalized Adoptive Neuro-Immunotherapy” may overcome this problem. Natural Neurotransmitters and Neuropeptides: Glutamate, Dopamine, GnRH-II, CGRP, Neuropeptide Y, Somatostatin and others, bind their well-characterized receptors expressed on the cell surface of naïve/resting T cells and induce multiple direct, beneficial, and therapeutically relevant effects. These Neurotransmitters and Neuropeptides can induce/increase: gene expression, cytokine secretion, integrin-mediated adhesion, chemotactic migration, extravasation, proliferation, and killing of cancer. Moreover, we recently found that some of these Neurotransmitters and Neuropeptides also induce rapid and profound decrease of PD-1 in human T cells. By inducing these beneficial effects in naïve/resting T cells at different times after binding their receptors ( T cells are essential for eradicating infectious organisms and cancer, immune response to injury, organ repair, and for various other health-promoting missions . T cells-left side), the T cells of numerous people in various abnormal conditions (-right) are scarce and/or exhausted, senescent, impaired, biased, and often also suffer from altered stemness and therefore do not function properly.However, in contrast to T cells of healthy subjects  are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis , 9–16. ET cell senescence or biological aging is a process that results from a variety of stresses, and leads to a state of gradual deterioration of functional characteristics and irreversible growth arrest , 16–18.T cell stemness is characterized by the capacity of T cells to self-renew, and be multipotent. T cell stemness combines the ability of a T cell to perpetuate its lineage and give rise to differentiated cells, and to interact with its environment to maintain a balance between quiescence, proliferation, and regeneration , 19.-right and in further detail in its legend, due to word limit of this paper).Individuals who have scarce and/or exhausted, senescent, altered and dysfunctional T cells are very susceptible and at high risk of morbidity and mortality, and become a harsh multi-level clinical, physiological, and economic burden on many other people, organizations, and societies , hepatitis B virus (HBV), hepatitis C virus (HCV), and other microorganisms, and in cancer , 9–16.+ T cells are important for protective immunity against intracellular microorganisms and tumors, but in chronic infections or cancer, the CD8+ T cells are exposed to persistent antigen and/or inflammatory signals, leading to a gradual deterioration of their function, a state called “exhaustion”. Tex are characterized by progressive loss of effector functions (cytokine production and killing function), expression of multiple inhibitory receptors (such as PD-1 and LAG3), dysregulated metabolism, poor memory recall, homeostatic self-renewal, homeostatic proliferation, and distinct transcriptional and epigenetic programs , and these cells suffer from anergy, exhaustion, senescence, and impaired stemness , 14, 15.Thus, the T cells of cancer patients are often dysfunctional and unable to eradicate the cancer cells efficiently, due to many different reasons. On top of the above-mentioned division into general categories, the reasons and factors that limit and/or impair the T cells of cancer patients can be divided into distinct families, each containing multiple specific members, as discussed in detail in . Among tFactor family 1: Lack of antigen processing, T cell recognition and TCR signaling; Factors family 2: Negative immune modulation; Factors family 3: Non-accessibility of tumor to T cells; Factors family 4: Immune editing, equilibrium and escape . Due to On these grounds, an effective and safe rejuvenation of scarce, exhausted and dysfunctional T cells, and induction of multiple beneficial T cell functions in cancer patients, remain an urgent desired clinical goal.+CD25+ and CD4+FoxP3+ regulatory T cells (Tregs), synergistic decreased function of effector T cells (Teffs) and antigen presenting cells (APCs), and a shift of the Th1 to Th2 cytokine responses  have impaired adaptive immunity characterized by a greater vulnerability to viral infections and deficient responses to vaccinations, along with decreased number and/or activity of T cells and natural killer cells (NKCs) .low/CCR4+ Tregs, and memory Tregs, and reduced CD56+CD16- (putative immunoregulatory) NKC counts (+ T cells of MDD patients are characterized by higher frequencies of CD4(+)CD25(high)CD127(low/-) cells, higher FOXP3 mRNA expression, and less diverse TCR Vβ repertoires ,5. Be patient-friendly and painless, do not necessitate hospitalization or any other procedure or treatment, and allow continuation of everyday life during therapy,6. Be applicable to many people in very different ages and abnormal conditions, who suffer from scarce, sub-optimal and dysfunctional T cells,7. Allow repeated and timely therapy whenever needed, and for as long as needed, and as such allow even prolonged periodic treatment over months and years, for people with chronic T cell dysfunction,8. Be flexible and contain several build in options and modalities, allowing higher degree of freedom and action,9. Contain preliminary personalized ex vivo diagnostic cellular functional tests that can be done at any time, using small quantity of the patient's own T cells , and reliable biomarkers. These ex vivo tests should be able to evaluate the present condition of the patient's T cells, and measure their ex vivo responsiveness to the planned adoptive cellular therapy. As such, these diagnostic tests could evaluate and predict the person’s potential benefit from tentative treatment and to tailor personalized regimen,a priori the antigen/s expressed on the disease-causing cells or microorganisms. Therefore, the method should not be limited to, or suitable only for, cases in which either the tumor antigens or the antigens of infectious organisms (e.g. the spike protein of Covid-19) are known and can be used.10. Be independent of a prerequisite of knowing 11. Not depend on, and not utilize, the T cell receptor (TCR) and its associated proteins, for avoiding both further Activation-Induced Cell Death (ACID), T cell exhaustion, and the risk of autoimmunity,12. Not manipulate the T cells genetically,in vitro for prolonged periods, for not losing some essential traits/capabilities. It is especially important that the therapeutic method would not impair T cell ability to migrate and home to, and penetrate into, various organs and tissues which either contain disease-causing cells or infectious organism, or are injured and require T cell help for healing,13. Not park/culture the T cells in vivo activity is dependent on cytokines or growth factors and need such subsequent support in vivo. Thus, the therapeutic method should preferably be free of any detrimental side effects of systematically-administered cytokines (e.g. IL-2), and of any cytokine storms,14. Not use T cells whose 15. Not perform any pre conditioning procedure prior to the therapy itself , and do inject any drug before, during, or after the infusion of the adoptive transfer of the patient's rejuvenated and improved T cells,ex vivo process of T cell rejuvenation, activation and amplification, prior to the inoculation of the patient's improved T cells into his body,16. Not change, inactivate or even suppress transiently any natural receptors, ion channels, or other proteins expressed on the T cell surface during the in vivo cytokine storms and competition over natural ingredients and space. Settle with much less T cells injected repeatedly over few weeks or months17. Not necessitate single infusions of billions of improved T cells each time, for avoiding 18. For conditions which are NOT cancer, use and adoptively transfer rejuvenated and improved T cells which can be “friendly” to, and communicate with, other cells, rather than very aggressive T cells which may damage, or compete with other cells for natural resources and space, in lymphoid organs, and in other tissues and organs, and which may also cause autoimmunity,19. The new immunothreapy should stand on its own, as a mono therapy, for saving, prolonging, and improving life, but must not interrupt or compete with any other efficient treatment/drugs from which the person can benefit from, and which may overcome T cell exhaustion and allow better T cell function. Thus, any other prior, simultaneous, in between, or later safe and effective treatment would be possible, as long as they do not harm T cells and do not induce immunosuppression.20. On top of being used on their own, it would be advantageous if the diagnostic and therapeutic methods and protocols of the new immunotherapy could be used also as "add on technologies'', and allow improvement of other adoptively-transferred therapeutic T cells.T cell immunotherapies , 35 haveIn line with this scientific and clinical revolution, there is an enormous number of scientists and clinicians working on T cell immunotherapies, and a meteoric rise of companies developing and utilizing them, primarily for cancer, but also for some infectious diseases. Current adoptive/cellular T cell therapies include mainly the following types: donor lymphocyte infusions, tumor-infiltrating lymphocytes, T-cell receptor-engineered T cells, chimeric antigen receptor (CAR) T cells, and virus-specific T cells. These T cell immunotherapies are reviewed in many papers, among them , 35.While each of these potent T cell immunotherapies has their own clear focus, advantages, and successes, primarily for some types of cancer, to the best of my knowledge none can rejuvenate and rescue T cells from exhaustion and senescence whenever needed and for whoever needs it, and that manage to improve multiple T cell functions simultaneously, among them increase migration, homing and extravasation into tissues .I’m also not aware of adoptive T cell immunotherapies that fulfil all, or at least most, of the 20 suggested criteria specified in the preceding section, and are suitable for broad use for all, at least most conditions of scarce, exhausted, suboptimal, and dysfunctional T cells.How can we safely and potently rejuvenate, activate, and improve scarce, exhausted and/or senescent T cells whenever needed and fulfil the 20 suggested criteria for optimal solution defined in the previous section?ex vivo natural Neurotransmitters and Neuropeptides , many of which are specified below in the next chapters, in the cited papers, and in language , 37, 46,–59, manyi.e. “talks” directly to T cells in various parts of the body via Neurotransmitters and Neuropeptides, that in turn bind to their specific receptors in T cells (as well as many others cells) and induce on their own multiple direct, rapid, potent, timely and beneficial effects. I further hypothesize that T cells need Neurotransmitters, Neuropeptides and their receptors, and the direct, rapid and potent effects they induce, for performing multiple health-guarding T cell tasks, and for communicating with the brain and with other body systems and organs.My idea and suggestion are to try to mimic and translate into therapeutic terms, what I hypothesize that the nervous system most probably normally does in everyday life: Neurotransmitters are traditionally defined as endogenous chemical substances used by the nervous system to transmit messages, either between neurons, or from neurons to muscles, or from neurons to gland cells. In addition, many Neurotransmitters induce direct effects on T cells and other immune cells, as well as on different cell types which express their receptors.i.e. peptides, produced and released by neurons through the regulated secretory route, and acting on neural substrates. Once again, T cells and other immune cells ought to be added as target cells that are affected directly by Neuropeptides.Neuropeptides are traditionally defined as small protein-like molecules, via its own functional Neurotransmitter/Neuropeptide receptors that are highly expressed in these cells , induce multiple direct and potent beneficial effects on resting/naïve T cells  CD3+ T cells of healthy subjects purified from their blood, which are in normal number and condition (+ T cells of few patients with Head and Neck cancer - Head and Neck Squamous Cell Carcinoma (HNSCC)   and of f (HNSCC) .de novo gene expression , evident at various time points after their binding to their receptors in T cells, the above-mentioned Neurotransmitters and Neuropeptides can on their own improve dramatically many essential T cell functions.Together, by inducing all these direct and beneficial effects  that bind to the T cell’s PD-1 and by doing so keep T cells in an inactive/suppressed mode, and prevent T cell reactivity against themselves. Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells. These drugs have shown a great deal of promise and success in treating certain cancers.****+ peripheral T cells of few elderly people aged 79–86 years, suffering from HCC and a kaleidoscope of comorbid conditions. We also tested the effects of these Neurotransmitters and Neuropeptides on CD3+ naïve/resting T cells of additional healthy subjects. In all cases, the CD3+ T cells were purified from small blood samples.In our most recent study (submitted paper) we studied the direct effects of Dopamine, Glutamate, GnRH-II, CGRP or Neuropeptide Y  induced the following effects: A. Decreased significantly both the percentage of PD-1+ T cells and the level of PD-1 expression per cell , B. Increased, up to seven fold, the number of alive T cells that proliferated in vitro in response to human HCC cells (either HepG2 or Huh7 cell line), C. Increased significantly killing of human HCC cells in vitro by the T cells (up to 2 fold increase).We found all the following significant findings: 1. The HCC patients had 5–10 fold less T cells than healthy subjects, 2. The patient’s T cells were abnormal, Moreover, we found that few unexpected combinations of Neurotransmitters and Neuropeptides induced even stronger effects than the single Neurotransmitters/Neuropeptides, and that Dopamine D1-5R agonists, of which D4R was the best, also decreased PD-1 and increased T cell numbers.via their own receptors in T cells, and by inducing multiple beneficial effects. Yet, once again, we found significant inter-individual variability with regard to the effects of these Neurotransmitters and Neuropeptides on human T cells.Together, these findings demonstrate that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, each on its own or in combinations, can activate, rejuvenate, and improve T cells, even when they are scarce and suboptimal T cells of elderly people with cancer and several diseases, and that they do so in low physiological concentration, single exposure and direct manner—Personalized Adoptive Neuro-Immunotherapy”, drawn schematically in Based on the all the experimental findings in hand so far and the corresponding publications , 36–45, I propose that the “Personalized Adoptive Neuro-Immunotherapy” has the ability to rejuvenate, activate and improve T cell number, condition, migration and function. By doing so, this novel type of adoptive cellular therapy may hopefully increase survival, improve life quality, and prevent multiple harsh multi-level implications , proliferative response to cancer, killing of cancer, ability to recruit other immune cells to the site of disease or injury, and most probably additional advantageous effects not revealed yet.T adhesion to extracellular matrix glycoproteins, chemotactic migration, homing, extravasation into solid organs, gene expression, cytokine secretion, expression of key proteins , is essential and beneficial for all involved sides, and can be translated into therapeutic terms , according to the needs of the entire body either in health or disease;2. Direct, accurate, real-time, and beneficial T cell activation, which is dictated by the brain and other parts of the nervous system, in a coordinated and orchestrated manner, and which takes place whenever needed, and wherever needed (via natural Neurotransmitters and Neuropeptides and their respective receptors expressed in T cells, which can take place independent of the TCR and specific foreign antigens. Thus, the activation of T cells via Neurotransmitters and Neuropeptides is not antigen-specific, and as such it can be safer, broader, and maybe even better in few contexts, since it is not expected cause neither TCR-mediated autoimmunity against self antigens, nor TCR-mediated T cell exhaustion upon repeated exposure to tumor antigens or infectious antigens.3. Rapid, transient and advantageous T cell activation Whole body control, orchestration, coordination and adaptation, allowable by the direct real-time information conveyed to, and received from, T cells and other immune cells, in either health or disease.I humbly propose that we may have the ability to protect, improve, and even save many people’s lives, by using and actually mimicking the natural “language” by which the brain “talks” to T cells, for new and potentially very safe and effective mode of therapy—The “Personalized Adoptive Neuro-Immunotherapy” (If the “Personalized Adoptive Neuro-Immunotherapy” turns out to be indeed safe, effective and patient-friendly, an enormous number of people whose T cells are malfunctioning, as well as their relatives, health caregivers, healthy services, hospitals, insurance companies, and entire societies, could benefit from it (Moreover, I foresee that repeated periodic strengthening of T cells of people at risk, especially in older age, can become almost routine, generic, and broad spectrum method of immune-protection, not limited each year only to few selected microbial organisms. The current Covid-19 pandemics teach all of us a devastating and warning lesson: relying only on vaccinations to already identified viruses and other infectious organisms, is not sufficient, and can lead to disastrous worldwide implications.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Callyspongia  encompasses a group of demosponges including 261 described species, of which approximately 180 have been accepted after taxonomic reviews. The marine organisms of Callyspongia are distributed in tropical ecosystems, especially in the central and western Pacific, but also in the regions of the Indian, the West Atlantic, and the East Pacific Oceans. The reason for the interest in the genus Callyspongia is related to its potential production of bioactive compounds. In this review, we group the chemical information about the metabolites isolated from the genus Callyspongia, as well as studies of the biological activity of these compounds. Through NMR data, 212 metabolites were identified from genus Callyspongia , belonging to classes such as polyacetylenes, terpenoids, steroids, alkaloids, polyketides, simple phenols, phenylpropanoids, nucleosides, cyclic peptides, and cyclic depsipeptides. A total of 109 molecules have been reported with bioactive activity, mainly cytotoxic and antimicrobial  action. Thus, we conclude that polyacetylenes, terpenoids and steroids correspond to the largest classes of compounds of the genus, and that future research involving the anticancer action of the species’ bioactive metabolites may become relevant.The genus  Callyspongia Duchassaing and Michelotti, 1864, belonging to the family Callyspongiidae and the order Haplosclerida, is structured in six subgenera: Callyspongia  Duchassaing and Michelotti, Callyspongia  Carter, Callyspongia  Schmidt, Callyspongia (Euplacella) Lendenfeld, Callyspongia  Ridley, and Callyspongia (Spinosella) Vosmaer indole-3-carboxylic acid (116a) indole-3-carboxylic acid (116b) acetic acid (209); acetic acid (210); and the callypyrones A (211) and B (212). Except for substances 211 and 212 that were isolated from an EtOAc/MeOH 1:1 of Callyspongia diffusa . Ot. Ot5) annd 32–38 . In addictively, .Callyspongia sp. and have driving Th1 polarization and antiproliferative effect against HL-60  and HCT-15  . β-. β-60) alminthic , antimutlminthic , angiogecompound  was founlminthic , antifunium spp. , antidiacompound  was founium spp. , analgesium spp. ,106, antium spp. , anti-inium spp. ,113,114,ium spp. ,113,114,ium spp. , and immium spp. .105) was evaluated as a potential compound for anti-HIV action, by inhibiting type 1 of this virus with an infection vector to 1/3 at 200 nM in a 96-well plate .169 ; c; c196) ictively) ,145. Bas0 5.3 μM . Bastadiof IMPDH , while bXF 22RV1 . Other cctively) . Lastly,Callyspongia is composed of various species of sponges, in which 261 have been described and approximately 180 accepted by reviews of taxonomists [Callyspongia sp. species were also considered in the bibliographic survey, but their non-identification makes the distinction between them impossible, allowing only a speculative approach based on localities of origin of these sponges. However, these results suggest that there are still many Callyspongia sponges that can be studied.The genus onomists ,4. AlthoCallyspongia was published in 1981 [Callyspongia species. Still, during this period, two species of Shiphonochalina have been taxonomically reclassified and are currently known as Callyspongia lindgreni  [Callyspongia siphonella  [The first study about the isolation of metabolites from  in 1981  and the  in 1981 ,63. Analruncata) ,33 and Cphonela) ,61,62,63Callyspongia, in which 103 are categorized in two classes, polyacetylenes (1–47), and terpenoids and steroids (48–104), in agreement with previous studies that present substances of this class as characteristic in the genus. In this sense, because of the greater number of isolations in different species, polyacetylenes could be classified as chemical markers for Callyspongia [In total, 212 metabolites were identified from yspongia ,27.54–88) were also extensively documented, being the first isolated metabolites according to the investigations of this review [Callyspongia siphonella. In addition, most of isolated compounds were collected from sponges of Red Sea regions, China, Japan, Indonesia, and Australia. This fact highlights the potential for further research in regions where the genus is less explored, such as Brazil, Ecuador, and Barbados, for example. It is also important to note that in some studies, no trace was found on the place of origin of the marine material studied [The sipholane triterpenoids , and the isolation of compounds from beings that establish symbiotic relationships with Callyspongia species [Molecules abolites ,42 and tabolites , F [4,22abolites . The unarization , identifrization , Mass Sprization ,147  have been reported as bioactive . In this sense, the results are in agreement with the data that prove the relevance of the metabolites in the genus with anticancer action [Some of the 212 metabolites reported herein were described in original reviews and articles as biologically relevant. Among these compounds, 109 molecules . The species were classified by nomenclature and researched individually. Additional information was obtained by searching for the term “Callyspongia” accompanied by keywords specific to the articles, such as the species name, the collection site, the name of the isolated metabolites and the types of biological activity. In addition, the data of biological activities of metabolites were searches by the name of the structures accompanied by the terms “biological”, “activity” and “biological activity”.The selection of articles proceeded using inclusion criteria, i.e., the characterization of molecules by NMR as the primary criterion and the presence of biological activity as the secondary. The articles were identified by means of a summarized reading of the published content. The investigations reached a total of 973 articles, of which, 145 were considered compatible with the inclusion criteria, and selected for the review.Through NMR data, 212 metabolites were identified from genus Callyspongia , which were classifying into the following groups: polyacetylenes, polyketides, terpenoids and steroids, simple phenols and phenylpropanoids, alkaloids, nucleosides, cyclic peptides and cyclic depsipeptides, and miscellaneous .Callyspongia genus are producers of several classes of primary and secondary metabolites, mainly polyacetylenes and lipids. In addition, many of these compounds are biologically active and have activities that may prove to be promising in fighting diseases. Thus, this literature review gathered essential information for the emergence of new research on the species of the genus.Sponges of the


The authors wish to make the following corrections to the paper : During 1Thi Tuong Vy Phan 1 phanttuongvy4@duytan.edu.vnCenter for Advanced Chemistry, Institute of Research and Development, Duy Tan University, 03 Quang Trung, Hai Chau, Danang 550000, Vietnam; We apologize for this unintentional mistake, which, however, does not affect the results of this manuscript and the conclusions drawn from them.


During original publication of Jaeschke, K., Hanna, F., Ali, S., Chowdhary, N., Dua, T., & Charlson, F. . the disDisclaimer:The authors alone are responsible for the views expressed in this Article and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.


The original version of this article unfortunately contained a mistake. The following affiliation of all three authors had not been included and was added retrospectively: Shriners Hospitals for Children, Northern California, Orthopedics, Sacramento, CA, USA.The original article has been corrected.


In “Precision Public Health Campaign: Delivering Persuasive Messages to Relevant Segments Through Targeted Advertisements on Social Media” :e22313) the authors noted one error.In the originally published manuscript, the order of authors Ingmar Weber and Hanya M Qureshi was reversed. This has been corrected to reflect that Hanya M Qureshi is the paper’s third author and Ingmar Weber is the paper’s fourth author. The author affiliations have been renumbered accordingly.The full list of authorship and affiliations in the originally published version appeared as follows:1, PhD; Haewoon Kwak1, PhD; Ingmar Weber2, PhD; Hanya M Qureshi3, BAJisun An1School of Computing and Information Systems, Singapore Management University, Singapore, Singapore2Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar3Yale School of Medicine, Yale University, New Haven, CT, United StatesThe full list of authorship and affiliations has been updated as follows in the corrected version:1, PhD; Haewoon Kwak1, PhD; Hanya M Qureshi2, BA; Ingmar Weber3, PhDJisun An1School of Computing and Information Systems, Singapore Management University, Singapore, Singapore2Yale School of Medicine, Yale University, New Haven, CT, United States3Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, QatarThe correction will appear in the online version of the paper on the JMIR Publications website on October 5, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories.