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CENTRE DE LA RECHERCHE SCIENTIFIQUE DU KURDISTAN C.R.S.K.

Dr Ali KILIC On the philosophy of the New Microbiology and biological Sciences Paris May 14, Dedicated to academician Jean Franois Bach The Inter Academy symposium was organized by Academy of Sciences of France by German National Academy of Sciences Leopoldina and by The Royal Society in Paris between 14 15 and 16 2012 on the subject The New Mocrobiology. During this symposium, scientists and academics from these countries as well as researchers in other states discussed in seven sessions fundamental we appear very important in terms of division of labor and research scientists in the field of New Microbiology. This is new and Regulatory Small RNAs mecanisms and Cellular Microbiology Bacterial Communities Microniota Signaling and Cell Biology and Microbial Manipulation of innate and cellular immunity syntetic Genomic and Biology.

The truth is that there is a cart of centuries the biological sciences were the object constituting a doctorate in philosophy of science. As was also cited in our project for the Foundation of the Academy of Sciences it should be noted this historical and philosophical academic. There are twenty one years of the century cyncoper in my PhD thesis of my analyzes on the biological sciences that have been one of the principal foundations of the Project for the Foundation of Science Academie Kurdistan we have put in evidence the scientific reality of as follows. Before developing the symposium issue of the New Mocrobiology I would like to pay tribute to the academician Jean Franois Bach. About our project for the Foundation of the Academy of Sciences academician Jean Franois Bach responded affirmatively. I received your letter to me both interested and excited. with great pleasure that the Academy of Sciences of France and myself, especially, will do everything we can to assist in the establishment of an Academy of Sciences in Kurdistan. In practice, I send your letter and the folder that accompanies the one hand to the other Brchignac Permanent Secretary Academy currently in charge of international relations and,

secondly, to Daniel Ricquier Vice President for Relations International. Believe me, dear Dr. Kilic, the assurances of my feelings best. "1

I hereby pay tribute to the academician and dedicated to Jean-Franois Bach was elected June 21, 2005 Permanent Secretary of the Academy of Sciences Born June 8, 1940, Jean-Franois Bach is Professor of Immunology at the Ren Descartes University and directs a laboratory at Necker Hospital. Both physician and researcher, he has remarkably successful synthesis of these two activities are mutually enriched throughout his career. He discovered thymulin, a thymic hormone ensuring the maturation of T lymphocytes and highlighted the role of regulatory T cells in controlling self-recognition.Passionate about the pathophysiology of autoimmune diseases, he studied especially the insulindependent diabetes that has inspired new therapeutic approaches. Thus, the work of Jean-Franois Bach, marked by a highly original concept, made him one of the most respected immunologists internationally.But the biologist does not stop there and has kept informed on an opening, and subtle linksmoving between Science and Society. He is particularly involved in the organization of research and of science education in college. My research has been developed in the field of immunology. My work was, above all,or experimental procedures in mice, especially in the remarkable models of spontaneous autoimmune diseases such as lupus NZB mice and NOD diabetic mice. Nevertheless,whenever it has been possible, I was able to transfer the results obtained in animals to human diseases, particularly regarding new immunotherapy strategies. Of this entanglement between basic research, its concepts and techniques, and investigation resulting clinical advances in medical knowledge. It's Jean Hamburger who impregnated me, at the very beginning of my scientific career, his vision of modern medical research. I had thechance to engage them while the fundamentals of cellular immunology began just to be arrested. The rapid development of this new discipline has allowed me to surround me, over the four decades of my career, a
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Academician Jean Franois Bach, 3 mai 2012

significant number of young researchers through which our group was able to establish and maintain an international presence to this day. 1. Discovery of a peptide hormone produced by the thymus Was known since the late 1950s the central role of the thymus in the differentiation one of two broad categories of lymphocytes, T cells, in particular regarding rejection grafts, defense against viruses and certain bacteria. We knew that this differentiation dependent interactions between lymphoid precursors from bone marrow and the epithelium thymus. We have demonstrated the existence of a hormone produced by the thymic epithelium,capable of inducing the differentiation markers of major T cells on the surface of lymphoid precursors. We isolated this hormone from the blood circulating. Quantities of pure peptide sufficient for sequencing with the techniques of the time were obtained from several hundred liters of pig's blood. Sequenced in 1977 proved to be the hormone peptide of nine amino acids, coupled to zinc. The synthetic hormone stimulates the immune responses in various models in vitro and in vivo. Its therapeutic activity in humans is demonstrated in certain immunodeficiencies and in rheumatoid arthritis. More recently, and so Unexpectedly, it appeared that some of the hormone and its analogues, has potent activity to the extent that these analogues is under development in the pharmaceutical indication. 2. Highlighting the role of regulatory T cells in controlling the recognition the self (autoimmunity) It exists in every normal individual autoreactive T cells recognizing self antigens, specific to the various host tissues. The question arose as to how this autoreactivity is consistent with the absence of pathological cases outside of autoimmune disease proved. We were the first to show in early 1980 that the main mechanism explaining this paradox is related to the existence of subpopulations of regulatory T cells that oppose the differentiation of pathogenic T cells responsible for autoimmune diseases. These observations, which were initially obtained in autoimmune diabetes mellitus mice, were at the time against the current dogma that the absence of autoimmunity in healthy individuals could be explained by the elimination or paralysis of T cells self-reactive pathogens. The concept of immune regulation is now well established and is the subject of avery large number of basic and applied research. We continued the characterization phenotypic and functional regulatory T cells involved in the control of diabetes,gastritis and colitis of autoimmune origin. We have recently shown that, inSurprisingly, distinct subpopulations of regulatory T cells control the occurrence of these three diseases. We have also begun to decipher the genes and molecules involved in these immunoregulatory phenomena. 3. A new treatment for diabetes mellitus can lead to healing disease Diabetes mellitus is a frequent and severe disorder whose treatment is
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now still only palliative and is based on the chronic administration of insulin failed to prevent degenerative complications, including vascular disease. The demonstration of autoimmune diabetes mellitus should logically lead to try to stop the course of the disease a direct pharmacological action on T cells involved in its pathogenesis. We realized in 1985 a randomized clinical trial demonstrating for the first Once, beyond doubt, the efficacy of immunosuppressive therapy (using the cyclosporine) in patients from a diabetes declare. Complete remissions and sustainable disease were obtained. Unfortunately, the maintenance of remission required continued treatment, which was hardly acceptable in young patients it was not reasonable exposing the risks of prolonged immunosuppression. We therefore decided to seek new methods to restore immune tolerance to self (ie cell antigens islet insulin-producing). We achieved this goal in 1994 in an experimental model of autoimmune diabetes, NOD mice. The simple administration for 5 consecutive days, a monoclonal antibody directed against the chain of _CD3 complex bound to the receptor for T-cell recognition of antigen induced, in therecently become diabetic mice, a permanent remission of the disease. This remission is intervene for the bulk of regulatory T cells such as those described above, dependenta cytokine, TGF- (transforming growth factor ). These spectacular results in the mice led us to develop a treatment protocol in humans based on same principles. We had, for many, many years, in the context of organ transplantation, studied the mode of action and side effects of anti-CD3 antibody, which were the first monoclonal antibodies used in human therapy, a few years after the discovery of hybridomas. The use of anti-CD3 antibodies in autoimmune diseases was difficult to implement, because of their strong mitogenic originally severe side effects associated with a massive release of cytokines. Building on recent accessibility of an antibody genetically modified non-mitogenic, we were able to up a randomized trial in 80 diabetic patients from their disease state. The results this test, which are about to be announced on the occasion of their publication in the New England Journal of Medicine, show that the therapeutic effect that we described in mice is found in humans. Sixty five percent of patients treated with anti-CD3 before the autoimmune process has completely destroyed their beta cells have become insulinoindpendants and are still 18 months after treatment for only one week by the antibody. This strategy, which opens, as we had hoped the prospect of a cure of the disease, should be able to relate to most if not all, of the recent diabetic patients the day information for doctors and patients, encouraged by these results, a diagnosis will allow moreearly disease. Experimental and clinical data also indicate that this same approach could be extended to other autoimmune

diseases such as diabetes to multiple sclerosis, to rheumatoid arthritis, Crohn's disease and psoriasis.
4. Role of environment in increasing frequency of allergic diseases and

autoimmune in industrialized countriesEpidemiological evidence in recent years indicated that the increase in frequencyallergic diseases, including asthma, could be related to the decrease in infections observed for over two decades in industrialized countries. We have assembled a arguments of epidemiological, clinical and experimental especially confirming this hypothesis and extending to the autoimmune diseases, in particular insulin-dependent diabetes and multiple sclerosisplates. Experiments in NOD mice have indicated the essential role in this effect protective infections stimulation of Toll receptors whose key role in immune responses was first described in Drosophila. Beyond the explanation that this assumption provides a considerable increase in the frequency of occurrence allergic diseases and autoimmune diseases, and possibly some lymphomas and leukemias, these observations open therapeutic perspectives important in providing the hope of substitute for infections "protective" administration defined product derived from infectious agents. This interest in the role of environment in the etiology of autoimmune diseases we had already asked to implement and carry out a campaign of eradication of rheumatic acute in the French Antilles, which helped to eliminate this disease in less than ten years. This disease was responsible for the majority of acquired heart disease of children, to the point to represent a leading cause of hospitalization in pediatric wards. Fact Interestingly, in this particular case, the environment does not play a protective role but a role trigger: the disease is due to the existence of common antigenic determinants between streptococci and cardiac tissue. We know that After the great discoveries of Franois Jacob, Andr Lwoff and Jacques Monod (Nobel Prize in Medicine 1965) and their colleagues fifty years ago, it was thought that the regulation of gene expression had revealed all its secrets. One realizes now that as in higher organisms, bacteria and other microorganisms have more diverse strategies previously thought to express themselves and adapt. They use so cleverly RNAs to regulate very fine their genes survival, replication, etc. to capture food. These regulations are put to use in all situations encountered by bacteria. Pathogenic bacteria, for example, interact during infection with commensal flora, whether in the gut, skin or other organs (nose, throat, ears ...). Studies of these complex flora, these "assemblies of microorganisms" grow at a pace incredible. The tools are there: approaches genomic, transcriptomic,
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proteomic, metabolomic can finally have access to understanding the signals that regulate the community life of these floras, their composition and balance. And we begin to understand the languages used by chemical bacteria to recognize, to communicate with each other and sometimes work together or otherwise destroy. But in our PhD in philosophy of science we have asked the phylosophy of Microbiology

On the philosophy of the New Microbiology and biological Sciences -I


No doubt the Molecular biology has revolutionized the science of World kids living in proportions that quantum theory has revolutionized the nuclear physics that there are forty years. The intense study of the biological functions of living beings. from the analysis of the structure and molecular interactions gave biochemistry leadership, leading to a relatively new science - molecular biology. In kid time, the establishment of the principle of catalytic functioning of living matter was a fundamental for the development of biological science. The ferments are in many ways incomparably superior to artificial catalysts. Before their power by any action, thousands of chemical reactions take place in living organisms. Using ferments, in the absence of high temperatures and pressures, millions and billions of times faster in the presence of the best chemical catalysts. The ferments have yet another benefit - the most important. They differ catalysts artificial rationality surprising for their actions, strictly oriented and maximum efficiency. Each closing act in an optimum manner, without finding technological solutions optimal 'in transforming not only one compound or a group of very close. and transforming them in a direction strictly determined.) The discovery and description of a growing number of biochemical reactions put the agenda the task of trying to establish the fundamental principles that govern the nature and interdependence of these reactions. Without that. it was impossible to develop a systematic process alive, countless biochemical terms. The solution of these problems was first linked two basic discoveries made in the thirties and forties and have been essential elements of the revolution in the biological sciences, particularly on the biochemical level. The

first is the discovery of "conservation." Energy of biochemical reactions in the form of chemical bonds in a particular matter which received the name of adenosine triphosphate. The second is the discovery of the principle of combination reactions in biological systems, ie that the surplus energy formed in response to a course can be transmitted to another reaction that would not be d 'Itself possible. These two basic discoveries immediately bring the logic in research on the biochemical organization of the activity of cells to distinguish combinations reactions energy. eligible and ineligible. Thus began the assembly of biochemical elements in separate groups or mechanisms intact, and when the researchers took fiai to operate on a certain segment, they found they managed to swallow train, from components, or as Such physiological process whose biochemists had initiated the development thirty years ago. ' " [7] The subsequent progress of science, a deeper penetration of the secrets of life discovered was able to process more complex than photosynthesis and respiration, biochemistry did not yet understand. It was primarily the process of growth and development as well as the phenomena of heredity and its transmission. Neither the methods and experiences of physiology, nor those of biochemistry were unable to highlight the properties of living matter which constitute the substance of these phenomena. Only with the advent of electron microscopy that we put into the unknown world of the infinitesimally small particles of the living cell. Thus the practical results of the revolution. Intervened in physics were a powerful catalyst for the revolution in biology. If the power separator ordinary microscope can achieve a magnification of two to three thousand times, the electron microscope can magnify objects of study of hundreds of thousand times and even more than a million times. The amount converts to quality basic opportunities have opened to the study of microscopic organizations, intimate process taking place in the living cell. In entering ever more deeply into the secrets of the process alive,. Biological science learns about the mechanism for the use of genetic information. Thus, biology was brought to explore the giant molecules of organic polymers: nucleic acids, proteins and some carbohydrates, ie training, which play a decisive role in the performance of vital functions essential. The study of these molecules required methods and processes hoc analysis and constituted one of the key orientations of a science booming molecular biology, we talk a little further. The results of the biological chemistry were and still are today an grazing tool knowledge of life processes. But the language of chemistry did not allow itself to penetrate the mysteries of life. The biophysical came to the rescue. The
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search continued for solving the problem of living has enormous methodological and practical importance for the development and improvement of material production, Academician G. Frank wrote "What we call the living can not be translated into language purely chemical. In addition to the list of reactions involved in the process of exchanging chemical substances, in addition to the catalytic reactions and chemical kinetics of these processes, there must be some organization in space (structure) of all rnacromolculaires, which is beyond the framework representations purely chemical. "2 This organization, writes G. Frank is not only the location of chemical processes; acting itself is changing, determines their conduct and organise. That is why, alongside the chemistry and molecular approaches, we need what might be called conventional language of 'approaches surmolculaires "These approachessurmolculaires can not already under the sole jurisdiction of chemistry and biochemistry. We are witnessing here are qualitatively different processes and chemicals added to the forces of interaction phenomena characteristics of the system surmolculaire complex. The study of these phenomena is usually biophysics or physical chemical biology "3 The biological sciences naturally attach particular importance nature of the activities of living organisms and their smallest components in the cell and components of the cell itself. Science has entered into the inframicroscopique structure of the cell, which allowed him to make the most unexpected discoveries, forcing a radical revision of current ideas on the principles biochemical, biophysical and physicochemical properties of cellular processes. "How is born. a new science, a new specialty? "asks P. Thuiflier thy has not answered both general and satisfactory this question, although various assumptions have been made. "4 This interpretation seems skeptical, because the development of a new discipline and the birth of a new science does not depend on the identity or the intellectual originality of ideas. Rather, it depends on the character of the nature of the subject of science itself method of exposure in the wider it is the means to achieve an objective, an activity according to a certain orderly fashion. It is by methodological role that tears the veil to the extraordinary complex phenomena of nature, society and the human conscience and directs the science to the release of natural links, objectives, forcing the researcher to stay on Field facts rigorously established. For example, lob jet of molecular biology is to study the events essential activity vital to their elementary levels in the cell and its
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G.Frank,Lopinion du savant, Moscou,Editions de lAcadmie des Sciences 1963 p.480 Franois Jacob Biologie Molculaire In Atomr 1969 La Recherche p.55 4 F.Jacob Opus Cit.p.58

components, the nucleus and the cytoplasm, in the tiny intra-cellular structures, systems the simplest located on the border of living and not living like virus and bacteriophages, and finally, in systems of biological macromolecular polymers and proteins nuclides acids that carry out its essential functions in training live ... There is a particularly intensive development of molecular biology research related to problems of proliferation, heredity, structure and. properties of macromolecular compounds, their biosynthesis and laws of their reproduction in the process of growth, division and cell development. In other words, bios macromolecular polymers and nucleic acids are essential objects of research in molecular biology. Over the past thirty years, biology has undergone a profound transformation by the convergence of disciplines for a long time remained independent of both the problems they saw as the equipment and methodology they used. Thus, the cellular physiology, genetics, biochemistry, virology, microbiology have melted into a common discipline, which is now known as themolecular biology. It aims to interpret the phenomena that take place withinliving organisms in office structures and functional interrelationships that occur between macromolecular constituents of the cell5. In its first stage, molecular biology has sought to analyze the material the simplest cell, namely the bacterial cell, that some discoveries were made accessible. such a study. In recent years, the elucidation of the main structure of biological macromolecules, proteins and nucleic acids, the interpretation of their functions in terms of structure, recognition of their biosynthetic pathways and their regulations have renewed our knowledge of heredity and cellular mechanisms. " This feels the development and differentiation, more interconnection of science that results, models and methods of some sciences are becoming more widely used in other (for example the use of physical and chemical dodles in biology and medicine), and this shows the problem of interdisciplinary research. Another important feature of the current stage of development of science is to increase the role of constructive elements in scientific knowledge. "On the one hand. In entire body, others share in somatic cell cultures taken from the bodies complex.[12] "Because the discovery of the nature and structure of nuclei acids demonstrates the rationality of the exceptional nature and organization of his creatures, in fact, nucleic acids are composed wholly of four elements: the four nucleotide that does differ from one another by their nitrogen content - adenine, guanine, cytosine, themine. Thus, the tremendous diversity of. life on. Terre A. always a basic biochemical perfectly unique and universal. Moreover, the principle of complementarity, which explains the old secret of heredity, is one of the essential bases. molecular biology with which it was established that in a
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V.Enguelgardt Naouka i Jinz 1975 N 5 p II

DNA molecule, the amount of guanine is always equal to. the amount of cytosine, adenine quantity is a gaie. the amount of themine. During the vital activity of the body, the DNA molecules involved in trade undergo many cellular damage under the influence of internal and external factors. Thus, the new directions of development of molecular biology and its revolutionary continuous progress based on solid methodology. "It is the combination of organic synthesis and very fruitful, two methodological approaches. the study of nature and properties of the simplest components of a complex, and the study of the structure, organization, the properties of complex body as a whole, forces and processes that constitute the system as. Than anything else. The key question is how simple it gives birth to the complex, what are the forces and laws that are operating here, how to structure new properties of the complex system. It is a focus of scientific research that part of the molecular levels the most primitive and the most basic driving , levels of organization of increasing complexity,. systems with new properties and functions.[ " The essential feature of this passage from simple to complex is an integrated process, we propose the term of fundamentalism to define the orientation of cognitive science. If one analyses the development of natural sciences, technical and social, one finds much in common in their methodology and practice. Thus, this methodology is it absolutely necessary as regards the creation of automated systems that the development of the vast majority of complex programs, as it is to solve the problems of the relationship between the party and everything between simple and compound. The need for such a methodological approach is more apparent than ever today as regards the solving of economic and socio-economic and development programmes in which we have always dealing with large complex systems to several components . D'oc current problem 1 "fundamentalism" for all the natural sciences, technical and social. The mechanism of development of science in their process of unification of the different branches of science plays an important role in guiding scientific thought and technology of our century. 11 opens two possibilities for developing and refining the material productive forces, through which we can see the development of the revolution in the natural sciences, technical, social interaction and their dialectic in two aspects: First, humanity will affect so focused on the processes of organic life and from it. Raising a colossal effectiveness of social production, and also increase the possibilities of the man himself - the first productive force of society - and the perfect considerably. Secondly, the company will continuously introduce into production the results of technological and organizational organic life> and. From then allow a
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new scientific and technological revolution which, it has every reason to think, leave it far behind the possibilities opened up by the current scientific and technological revolution. This revolution in the biological sciences wakes up the "technical", technology "and the organization of operating systems which exceed in complexity all the systems that man has been able to create and productivity have never seen in practice the global industry at the same time that capacity, an infinite number of dimensions, economic performance and reliability unimaginable. The active phase of the revolution in the biological sciences began, it seems, most recently as physics and chemistry, and its practical results may not be as clear and important that the results achieved by physicists and chemists, but it is already visible today that the possibilities, both cognitive and practical, opened by the revolution in science are of a magnitude that they can serve as a springboard . a new revolution in science and information technology, which means the development of physical sciences, chemical, biological as the basis for development and differentiation branches scientific computing.6 The question is what relationship established between the development of the New Microbiology and prospects for the future of biological sciences and the role of philosophy of science from New Microbiology and place of our analysis there are twenty five years philosophical philosophical after the philosophy of science with the purpose of the symposium Inter Academy? Position of the philosophical and scientific questions First, what is microbiology? what is its specialty and originality as scientific and philosophical questions asked? how it relates to the philosophy of science? Secondly what is the philosophy of biology and microbiology new? From the perspective of the philosophy of dialectical materialist philosophy of science is based surquoi trends of positivist philosophy and neo positivist? What is his philosophy is based on the creation of the world and the universe? What is the contribution of participants in the Symposium prospects? What are spots academic and scientific problem solving of new microbiology? Microbiology (from Greek , mkros, "small"; , bios, "life"; and -, -logia) is the study of microscopic organisms, which are defined as any living organism that is either a single cell (unicellular), a cell cluster, or has no
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Dr Ali KILIC La classification des Sciences et lInformatique Fondements philosophiques de lInformatique T pp.hese pour le Doctorat en Philosophie Faccult de Philosophie de lUniversite de Bourgogne 1988 pp.324330.

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cells at all (acellular )7. This includes eukaryotes, such as fungi and protists, and prokaryotes. Viruses[8 and prions, though not strictly classed as living organisms, are also studied. Microbiology typically includes the study of the immune system, or Immunology. Generally, immune systems interact with pathogenic microbes; these two disciplines often intersect which is why many colleges offer a paired degree such as "Microbiology and Immunology". Microbiology is a broad term which includes virology, mycology, parasitology, bacteriology, immunology and other branches. A microbiologist is a specialist in microbiology and these related topics. Microbiological procedures usually must be aseptic, and use a variety of tools such as light microscopes with a combination of stains and dyes.The most commonly used stains are called basic dyes, and are composed of positively charged molecules. Two types of basic dyes are simple stains and differential stains. simple stains consist of one dye and identify the shape and multicell arrangement of bacteria. Methylene blue, carbolfuchsin, safranin, and crystal violet are some of the most commonly used stains. Differential stains on the other hand, use two or more dyes and help us to distinguish between two or more organisms or two or different parts of the organism. Types of differential stains are gram, Ziehl-Neelsen acid fast, negative, flagella, and endospore. Specific constraints apply to particular fields of microbiology, such as parasitology, which heavily utilizes the light microscopy, whereas microscopy's utility in bacteriology is limited due to the similarity is many cells physiology. Indeed, most means of differentiating bacteria is based on growth or biochemical reactions. Virology has very little need for light microscopes, relying on almost entirely molecular means. Mycology relies on all technologies the most evenly, from macroscopy to molecular techniques. Microbiology is actively researched, and the field is advancing continuously. It is estimated that only about one percent of the microorganisms present in a given environmental sample are culturable9 and the number of bacterial cells and species on Earth is still not possible to be determined, recent estimates indicate that it can be extremely high (5 Exp 30 cells on Earth, unknown number of species). Although microbes were directly observed over three hundred years ago, the precise determination, quantitation and description of its functions is far to be complete, given the overwhelming diversity detected by genetic and culture-independent means.
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^ a b c d e f Madigan M, Martinko J (editors) (2006). Brock Biology of Microorganisms (13th ed.). Pearson Education. p. 1096. ISBN 0-321-73551-X. 8 Rice G (2007-03-27). "Are Viruses Alive?". http://serc.carleton.edu/microbelife/yellowstone/viruslive.html. Retrieved 2007-07-23. 9 Nitesh RAI, Ludwig W, Schleifer KH (2011). "Phylogenetic identification and in situ detection of individual microbial cells without cultivation". Microbiology Rev. 59 (1):

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The existence of microorganisms was hypothesized for many centuries before their actual discovery. The existence of unseen microbiological life was postulated by Jainism which is based on Mahaviras teachings as early as 6th century BCE.10 Paul Dundas notes that Mahavira asserted existence of unseen microbiological creatures living in earth, water, air and fire.11 Jain scriptures also describe nigodas which are sub-microscopic creatures living in large clusters and having a very short life and are said to pervade each and every part of the universe, even in tissues of plants and flesh of animals.12 The Roman Marcus Terentius Varro made references to microbes when he warned against locating a homestead in the vicinity of swamps "because there are bred certain minute creatures which cannot be seen by the eyes, which float in the air and enter the body through the mouth and nose and there by cause serious diseases.13" In 1546 Girolamo Fracastoro proposed that epidemic diseases were caused by transferable seedlike entities that could transmit infection by direct or indirect contact, or vehicle transmission.14[ However, early claims about the existence of microorganisms were speculative, and not based on microscopic observation. Actual observation and discovery of microbes had to await the invention of the microscope in the 17th century. Anton van Leeuwenhoek , is considered to be the first to observe microorganisms using a microscope.In 1676, Anton van Leeuwenhoek observed bacteria and other microorganisms, using a single-lens microscope of his own design While Van Leeuwenhoek is often cited as the first to observe microbes, Robert Hooke made the first recorded microscopic observation, of the fruiting bodies of molds, in 1665 The first observation of microbes using a microscope is generally credited to the Dutch draper and haberdasher, Antonie van Leeuwenhoek, who lived for most of his life in Delft, Holland. It has, however, been suggested that a Jesuit priest called Athanasius Kircher was the first to observe micro-organisms.[10] He was among the first to design magic lanterns for projection purposes, so he must have been well acquainted with the properties of lenses.[10] One of his books contains a chapter in Latin, which reads in translation Concerning the wonderful structure of things in nature, investigated by Microscope. Here, he wrote who would believe that vinegar and milk abound with an innumerable multitude of worms. He also noted that putrid
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Mahavira is dated 599 BCE - 527 BC. See. Dundas, Paul; John Hinnels ed. (2002). The Jain. London: Routledge. ISBN 0-415-26606-8. p. 24 11 Dundas, Paul (2002) p. 88 12 aini, Padmanabh (1998). The Jaina Path of Purification. New Delhi: Motilal Banarsidass. ISBN 81-208-15785. p. 109 13 Varro on Agriculture 1, xii Loeb. 14 Fracastoro, Girolamo (1546), De Contagione et Contagiosis Morbis transl. Wilmer Cave Wright (1930). New York: G.P. Putnam's

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material is full of innumerable creeping animalcule. These observations antedate Robert Hookes Micrographia by nearly 20 years and were published some 29 years before van Leeuwenhoek saw protozoa and 37 years before he described having seen bacteria.

Innovative laboratory glassware and experimental methods developed by Louis Pasteur and other biologists contributed to the young field of bacteriology in the late 19th century. The field of bacteriology (later a subdiscipline of microbiology) was founded in the 19th century by Ferdinand Cohn, a botanist whose studies on algae and photosynthetic bacteria led him to describe several bacteria including Bacillus and Beggiatoa. Cohn was also the first to formulate a scheme for the taxonomic classification of bacteria and discover spores. Louis Pasteur and Robert Koch were contemporaries of Cohns and are often considered to be the father of microbiology and medical microbiology, respectively. Pasteur is most famous for his series of experiments designed to disprove the then widely held theory of spontaneous generation, thereby solidifying microbiologys identity as a biological science.Pasteur also designed methods for food preservation (pasteurization) and vaccines against several diseases such as anthrax, fowl cholera and rabies. Koch is best known for his contributions to the germ theor of disease, proving that specific diseases were caused by specific pathogenic micro-organisms. He developed a series of criteria that have become known as the Koch's postulates. Koch was one of the first scientists to focus on the isolation of bacteria in pure culture resulting in his description of several novel bacteria including Mycobacterium tuberculosis, the causative agent of tuberculosis. While Pasteur and Koch are often considered the founders of microbiology, their work did not accurately reflect the true diversity of the microbial world because of their exclusive focus on micro-organisms having direct medical relevance. It was not until the late 19th century and the work of

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Martinus Beijerinck and Sergei Winogradsky, the founders of general microbiology (an older term encompassing aspects of microbial physiology, diversity and ecology), that the true breadth of microbiology was revealed.[1] Beijerinck made two major contributions to microbiology: the discovery of viruses and the development of enrichment culture techniques.[ While his work on the Tobacco Mosaic Virus established the basic principles of virology, it was his development of enrichment culturing that had the most immediate impact on microbiology by allowing for the cultivation of a wide range of microbes with wildly different physiologies. Winogradsky was the first to develop the concept of chemolithotrophy and to thereby reveal the essential role played by microorganisms in geochemical processes. He was responsible for the first isolation and description of both nitrifying and nitrogen-fixing bacteria. The philosophy of biology The philosophy of biology is a subfield of philosophy of science, which deals with epistemological, metaphysical, and ethical issues in the biological and biomedical sciences. Although philosophers of science and philosophers generally have long been interested in biology (e.g., Aristotle, Descartes, and even Kant), philosophy of biology only emerged as an independent field of philosophy in the 1960s and 1970s. Philosophers of science then began paying increasing attention to biology, from the rise of Neodarwinism in the 1930s and 1940s to the discovery of the structure of DNA in 1953 to more recent advances in genetic engineering. Other key ideas include the reduction of all life processes to biochemical reactions, and the incorporation of psychology into a broader neuroscience. The philosophy of biology can be seen as following an empirical tradition, favoring naturalism . Many contemporary philosophers of biology have largely avoided traditional questions about the distinction between life and non-life. Instead, they have examined the practices, theories, and concepts of biologists with a view toward better understanding biology as a scientific discipline (or group of scientific fields). Scientific ideas are philosophically analyzed and their consequences are explored. It is sometimes difficult to delineate philosophy of biology as separate from theoretical biology. A few of the questions philosophers of biology have attempted to answer, for example, include: "What is a biological species?" "How is rationality possible, given our biological origins?" "How do organisms coordinate their common behavior?" "Are there genome editing agents?" "How might our biological understandings of race, sexuality, and gender reflect social values?" "What is natural selection, and how does it operate in nature?" "How do medical doctors explain disease?"

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"From where do language and logic stem?"; "How is ecology related to medicine?" A subset of philosophers of biology with a more explicitly naturalistic orientation hope that biology will provide scientific answers to such fundamental problems of epistemology, ethics, aesthetics, anthropology and even metaphysics. Furthermore, progress in biology urges modern societies to rethink traditional values concerning all aspects of human life. The possibility of genetic modification of human stem cells, for example, has led to an ongoing controversy on how certain biological techniques could infringe upon ethical consensus (see bioethics). Some of the questions addressed by these philosophers of biology include: "What is life?" "What makes humans uniquely human?"; "What is the basis of moral thinking?";"What are the factors we use for aesthetic judgments?"; "Is evolution compatible with Christianity or other religious systems?" Increasingly, ideas drawn from philosophical ontology and logic are being used by biologists in the domain of bioinformatics. Ontologies such as the Gene Ontology are being used to annotate the results of biological experiments in a variety of model organisms in order to create logically tractable bodies of data available for reasoning and search. The Gene Ontology itself is a species-neutral graph-theoretical representation of biological types joined together by formally defined relations. Marjorie Grene, David Depew15 have combined forces to produce an episodic history of the philosophy of biology from Aristotle to the present. As the title of this book implies, they are writing a history of the philosophy of biology, not a history of biology. Even so, in writing a history of the philosophy of biology, they cannot very well ignore biology. Grene and Depew begin dealing with life itself. Evolution, as it should, comes in only much later. The first four chapters of their book concern the views of a half dozen of the most important scholars ranging from Aristotle and the Aristotelians to William Harvey, Descartes and Newton. These chapters range over two thousand year--from the fourth century BC to the 17th century. As might be expected these discussions are abbreviated but hardly superficial. Grene and Depew have to deal not only with the writings of these men but also the highly technical secondary literature that has grown up around them. I am afraid that
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The Philosophy of Biology: An Episodic History Published: January 02, 2005 Grene, Marjorie and David Depew, The Philosophy of Biology: An Episodic History, Cambridge University Press, 2004, 438pp, $29.99 (pbk), ISBN 0521643805. Reviewed by David Hull, Northwestern University

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most readers, excluding professional philosophers, will find the chapters on Aristotle and the Aristotelians formidable, but they are worth studying. No one is better able to explain Aristotle and his "biology" than is Marjorie Grene. Her introductory text on Aristotle remains in print to this day. One of the purposes of these early chapters is to show that the contrast between physics and biology has been around from the beginning of Western thought. Grene and Depew note that the "subject matter of biology has something about it that is not quite the same as physics" (p. xv). One of the challenges that Grene and Depew face is that two of the major figures whom they treat--Descartes and Newton--were far more concerned with physics than with biology. Aristotle and Harvey were certainly "biologists." Descartes and Newton were not. Kant opposed polygenism and supported his position by reference to Buffon's species concept. The contrast is between species as eternal forms defined in terms of essential characteristics (perhaps clusters) or as historical entities maintained by successive breeding (p. 80). Are species kinds (Arten), lineages (Gattungen) or both (p. 118)? Life would be easier if these two species concepts always divided up the living world in the same way, but they don't. Because miscegenation was far from unknown at the time, Kant concluded that all human beings belong to a single species. In the following century, a temporal dimension was added to this dispute. One species might split into two or more species, and a single species might have its origin in two or more species. As always Darwin provides the watershed for biology. Geology was the chief impetus. In addition, British scientists took it on themselves to develop philosophy of science as a professional discipline, just in time to be confronted by a theory that seriously challenged their philosophies. John Herschel and William Whewell were the founding fathers of philosophy of science in Great Britain, and in the case of Whewell at least biology played a role. For some reason, Grene and Depew do not discuss John Stuart Mill at any length, possibly because he came along later. What is disturbing is that all three of these men-the very men who devoted a good part of their professional lives studying science as science--rejected Darwin's theory. Species do not evolve, and if they do, they certainly do not do so by means of natural selection--the law of higgledy piggledy. After the chapter on Darwin, Grene and Depew proceed along a familiar path beginning with the "non-rediscovery" of Mendel's laws at the turn of the century. In the early years scientists tended to refer to the "discovery" of Mendel's laws, but historians were put off. Mendel discovered these laws. At the turn of the century, they were "rediscovered." Then later as historians dug more deeply into the literature, they decided that their predecessors had seriously
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misunderstood Mendel, reading present-day concerns into his work. Mendel was no Mendelian. Hence, the early "rediscovers" of Mendel's laws were actually "non-rediscoverers." The contrast between philosophers and scientists is even harder to draw. For example, most people today think of Descartes as a philosopher and Newton as a scientist because of the very different fates that their work received, but in their day Descartes and Newton were engaged in much the same array of activities. Present-day philosophy of biology and biology merge seamlessly. Both philosophers and biologists contribute to this endeavor. In this penultimate chapter of their book, Grene and Depew evaluate the contributions made by biologists and philosophers of biology to such issues as the species problem, reducibility, function and teleology--issues that have been debated in some form or other from Aristotle to the present. In the final chapter, Grene and Depew address a grab bag of topics that are not all that related to the book as a whole--the descent of man, polygenism and monogenism once again, the nature/nurture controversy, brains, language, mind and the human genome project. Because of my own interests, I might be excused for treating one issue in my own work that Grene and Depew discuss-the metaphysical status of species as the things that evolve. A fairly standard distinction in philosophy from at least Plato and Aristotle to the present is between classes and individuals. The terms change, but the distinction remains fairly constant. Classes are groups or sets of entities. All the planets in the universe form a class. A subset of these classes is important because they function in laws of nature -- at least for those philosophers who think that such things as laws of nature exist. Even though the universe is finite, laws of nature are commonly characterized as being spatiotemporally unrestricted. Hence, the classes that function in them must also be spatiotemporally unrestricted. Some philosophers of biology have attempted to explain the rise and fall of reductionism, vitalism, and holism throughout the history of biology. For example, these philosophers claim that the ideas of Charles Darwin ended the last remainders of teleological views from biology. Debates in these areas of philosophy of biology turn on how one views reductionism. An autonomous philosophy of biology All processes in organisms obey physical laws, the difference from inanimate processes lying in their organisation and their being subject to control by coded information. This has led some biologists and philosophers (for example, Ernst Mayr and David Hull) to return to the strictly philosophical reflections of Charles Darwin to resolve some of the problems which confronted them when they tried to employ a philosophy of science derived from classical
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physics. This latter, positivist approach emphasised a strict determinism (as opposed to high probability) and to the discovery of universally applicable laws, testable in the course of experiment. It was difficult for biology, beyond a basic microbiological level, to live up to these structures. Standard philosophy of science seemed to leave out a lot of what characterised living organisms namely, a historical component in the form of an inherited genotype. Biologists with philosophic interests responded, emphasising the dual nature of the living organism. On the one hand there was the genetic programme (represented in nucleic acids) - the genotype. On the other there was its extended body or soma - the phenotype. In accommodating the more probabilistic and non-universal nature of biological generalisations, it was a help that standard philosophy of science was in the process of accommodating similar aspects of 20th century physics. This led to a distinction between proximate causes and explanations "how" questions dealing with the phenotype; and ultimate causes - "why" questions, including evolutionary causes, focused on the genotype. This clarification was part of the great reconciliation, by Ernst Mayr, among others, in the 1940s, between Darwinian evolution by natural selection and the genetic model of inheritance. A commitment to conceptual clarification has characterised many of these philosophers since. Trivially, this has reminded us of the scientific basis of all biology, while noting its diversity - from microbiology to ecology. A complete philosophy of biology would need to accommodate all these activities. Less trivially, it has unpacked the notion of "teleology". Since 1859, scientists have had no need for a notion of cosmic teleology - a programme or a law that can explain and predict evolution. Darwin provided that. But teleological explanations (relating to purpose or function) have remained stubbornly useful in biology - from the structural configuration of macromolecules to the study of co-operation in social systems. By clarifying and restricting the use of the term to describe and explain systems controlled strictly scientifically by genetic programmes, or other physical systems, teleological questions can be framed and investigated while remaining committed to the physical nature of all underlying organic processes. Similar attention has been given to the concepts of natural selection (what is the target of natural selection? - the individual? the environment? the genome? the species?); adaptation; diversity and classification; species and speciation; and macroevolution. Just as biology has developed as an autonomous discipline in full conversation with the other sciences, there is a great deal of work now being carried on by biologists and philosophers to develop a dedicated philosophy of biological science which, while in full conversation with all other philosophic
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disciplines, attempts to give answers to the real questions raised by scientific investigations in biology. Other perspectives While the overwhelming majority of English-speaking scholars operating under the banner of "philosophy of biology" work within the Anglo-American tradition of analytical philosophy, there is a stream of philosophic work in continental philosophy which seeks to deal with issues deriving from biological science. The communication difficulties involved between these two traditions are well known, not helped by differences in language. Gerhard Vollmer is often thought of as a bridge but, despite his education and residence in Germany, he largely works in the Anglo-American tradition, particularly pragmatism, and is famous for his development of Lorenz's and Quine's idea of evolutionary epistemology. On the other hand, one scholar who has attempted to give a more continental account of the philosophy of biology is Hans Jonas. His "The Phenomenon of Life" (New York, 1966) sets out boldly to offer an "existential interpretation of biological facts", starting with the organism's response to stimulus and ending with man confronting the Universe, and drawing upon a detailed reading of phenomenology. This is unlikely to have much influence on mainstream philosophy of biology, but indicates, as does Vollmer's work, the current powerful influence of biological thought on philosophy. A more engaging account is given by the late Virginia Tech philosopher Marjorie Grene.

The growth of philosophical interest in biology over the past thirty years reflects the increasing prominence of the biological sciences in the same period. There is now an extensive literature on many different biological topics, and it would be impossible to summarise this body of work in this single entry. Instead, this entry sets out to explain what philosophy of biology is. Why does biology matter to philosophy and vice versa? A list of the entries in the encyclopedia which address specific topics in the philosophy of biology is provided at the end of the entry. Three different kinds of philosophical enquiry fall under the general heading of philosophy of biology. First, general theses in the philosophy of science are addressed in the context of biology. Second, conceptual puzzles within biology itself are subjected to philosophical analysis. Third, appeals to biology are made in discussions of traditional philosophical questions. The first two kinds of philosophical work are typically conducted in the context of a detailed knowledge of actual biology, the third less so.

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Philosophy of biology can also be subdivided by the particular areas of biological theory with which it is concerned. Biology is a diverse set of disciplines, ranging from historical sciences such as paleontology to engineering sciences such as biotechnology. Different philosophical issues occur in each field. The latter part of the entry discusses how philosophers have approached some of the main disciplines within biology. 1. Pre-history of Philosophy of Biology 2. Three Types of Philosophy of Biology.3. Philosophy of Evolutionary Biology 4. Philosophy of Systematic Biology 5. Philosophy of Molecular Biology.6. Philosophy of Developmental Biology.7. Philosophy of Ecology and Conservation Biology.8. Methodology in Philosophy of Biology 1. Pre-history of Philosophy of Biology As is the case for most apparent novelties, closer inspection reveals a prehistory for the philosophy of biology. In the 1950's the biologist J. H Woodger and the philosopher Morton Beckner both published major works on the philosophical of biology (Woodger 1952; Beckner 1959), but these did not give rise to a subsequent philosophical literature. Some philosophers of science also made claims about biology based on general epistemological and metaphysical considerations. Perhaps the most famous example is J. J. C Smart's claim that the biology is not an autonomous science, but a technological application of more basic sciences, like radio-engineering (Smart 1959, 366). Like engineering, biology cannot make any addition to the laws of nature. It can only reveal how the laws of physics and chemistry play out in the context of particular sorts of initial and boundary conditions. Even in 1969 the zoologist Ernst Mayr could complain that books with philosophy of science in the title were all misleading and should be re-titled philosophy of physics (Mayr 1969). The encouragement of prominent biologists such as Mayr and F.J Ayala (Ayala 1976; Mayr 1982) was one factor in the emergence of the new field. The first sign of philosophy of biology becoming a mainstream part of philosophy of science was the publication of David Hull's Philosophy of Biological Science in the prominent Prentice-Hall Foundations of Philosophy series (Hull 1974). From then on the field developed rapidly. Robert Brandon could say of the late 1970's that I knew five philosophers of biology: Marjorie Grene, David Hull, Michael Ruse, Mary Williams and William Wimsatt. (Brandon 1996, xiixiii) By 1986, however, there were more than enough to fill the pages of Michael Ruse's new journal Biology and Philosophy. 2. Three Types of Philosophy of Biology Three different kinds of philosophical enquiry fall under the general heading of philosophy of biology. First, general theses in the philosophy of
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science are addressed in the context of biology. Second, conceptual puzzles within biology itself are subjected to philosophical analysis. Third, appeals to biology are made in discussions of traditional philosophical questions. The first major debate in the philosophy of biology exemplified the first of these, the use of biological science to explore a general theme in philosophy of science. Kenneth F. Schaffner applied the logical empiricist model of theory reduction to the relationship between classical, Mendelian genetics and the new molecular genetics (Schaffner 1967a; Schaffner 1967b; Schaffner 1969). David Hull argued that the lesson of this attempt was that Mendelian genetics is irreducible to molecular genetics (Hull 1974; Hull 1975). This debate reinforced the nearconsensus in the 1970's and 1980's that the special sciences are autonomous from the more fundamental sciences (Fodor 1974; Kitcher 1984). However, the apparent absurdity of the claim that the molecular revolution in biology was not a successful instance of scientific reduction also led the formulation of increasingly more adequate models of theory reduction (Wimsatt 1976; Wimsatt 1980; Schaffner 1993; Waters 1994; Sarkar 1998). In another important early debate philosophers set out to solve a conceptual puzzle within biology itself. The concept of reproductive fitness is at the heart of evolutionary theory, but its status has always been problematic. It has proved surprisingly hard for biologists to avoid the criticism that, [i]f we try to make laws of evolution in the strict sense we seem to reduce to tautologies. Thus suppose we say that even in Andromeda the fittest will survive we say nothing, for fittest has to be defined in terms of survival (Smart 1959, 366). In the 1970's the new generation of philosophers of biology began by noting that fitness is a supervenient property of organisms: the fitness of each particular organism is a consequence of some specific set of physical characteristics of the organism and its particular environment, but two organisms that have identical levels of fitness may do so in virtue very different sets of physical characteristics (Rosenberg 1978). Alexander Rosenberg and Mary B. Williams went on to argue that fitness is an irreducible primitive which derives its meaning from its place in an axiomatic formulation of evolutionary theory (Rosenberg 1983; Sober 1984a; Williams and Rosenberg 1985). But by far the most widely-favoured solution to the tautology problem was to argue that this supervenient property is a propensitya probability distribution over possible numbers of offspring (Mills and Beatty 1979). Although fitness is defined in terms of reproductive success, it is not a tautology that the fittest organisms have the most offspring, any more than it is a tautology that dice produce even numbers more often than they produce sixes. The propensities of fit organisms to survive and of dice to fall equally often on each side both allow us to make fallible predictions about what will happen, predictions that become more reliable as the size of the sample increases. It remains unclear, however,

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whether it is possible to specify a probability distribution or set of distributions that can play all the roles actually played by fitness in population biology. The phrase conceptual puzzles should be understood very broadly. The conceptual work done by philosophers of biology in many cases merges smoothly into theoretical biology. It also sometimes leads philosophers to criticise the chains of argument constructed by biologists, and thus to enter directly into ongoing biological debates. In the same way, the first kind of philosophy of biology I have describedthe use of biological examples to work through general issues in the philosophy of sciencesometimes feeds back into biology itself through specific recommendations for improving biological methodology. It is a striking feature of the philosophy of biology literature that philosophers often publish in biology journals and that biologists often contribute to philosophy of biology journals. The philosophy of biology also has a potentially important role as a mediator between biology and society. Popular representations of biology derive broad lessons from large swathes of experimental findings. Philosophers of science have an obvious role in evaluating these interpretations of the significance of specific biological findings (Stotz and Griffiths 2008). A third form of philosophy of biology occurs when philosophers appeal to biology to support positions on traditional philosophical topics, such as ethics or epistemology. The extensive literature on biological teleology is a case in point. After a brief flurry of interest in the wake of the modern synthesis, during which the term teleonomy was introduced to denote the specifically evolutionary interpretation of teleological language (Pittendrigh 1958), the ideas of function and goal directedness came to be regarded as relatively unproblematic by evolutionary biologists. In the 1970's, however, philosophers started to look to biology to provide a solid, scientific basis for normative concepts, such as illness or malfunction (Wimsatt 1972; Wright 1973; Boorse 1976). Eventually, the philosophical debate produced an analysis of teleological language fundamentally similar to the view associated with modern synthesis biology (Millikan 1984; Neander 1991). According to the etiological theory of function, the functions of a trait are those activities in virtue of which the trait was selected. The idea of etiological or proper function has become part of the conceptual toolkit of philosophy in general and of the philosophy of language and the philosophy of mind in particular. 3. Philosophy of Evolutionary Biology Philosophy of biology can also be subdivided by the particular areas of biological theory with which it is concerned. Until recently, evolutionary theory has attracted the lion's share of philosophical attention. This work has sometimes been designed to support a general thesis in the philosophy of
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science, such as the semantic view of theories (Lloyd 1988). But most of this work is concerned with conceptual puzzles that arise inside the theory itself, and the work often resembles theoretical biology as much as pure philosophy of science. Elliott Sober's classic study The Nature of Selection: Evolutionary theory in philosophical focus (Sober 1984b) marks the point at which most philosophers became aware of the philosophy of biology. Sober analyzed the structure of explanations in population genetics via an analogy with the composition of forces in dynamics, treating the actual change in gene frequencies over time as the result of several different forces, such as selection, drift, and mutation. This sort of careful, methodological analysis of population genetics, the mathematical core of conventional evolutionary theory, continues to give rise to interesting results (Pigliucci and Kaplan 2006; Okasha 2007). The intense philosophical interest in evolutionary theory in the 1980's can partly be explained by the controversies over sociobiology that were provoked by the publications of E.O. Wilson's eponymous textbook (Wilson 1975) and still more by Richard Dawkins's The Selfish Gene (Dawkins 1976). The claim that the real unit of evolution is the individual Mendelian allele created an explosion of philosophical work on the units of selection question (Brandon and Burian 1984) and the issue of adaptationism (Dupr 1987). Arguably, philosophers made a significant contribution to the rehabilitation of some forms of group selection within evolutionary biology in the 1990's, following two decades of neglect (Sober and Wilson 1998). The debates over adaptationism turned out to involve a diffuse set of worries about whether evolution produces optimal designs, the methodological role of optimality assumptions, and the explanatory goals of evolutionary theory. Philosophical work has helped to distinguish these strands in the debate and reduce the confusion seen in the heated and polemical biological literature for and against adaptationism (Orzack and Sober 2001). 4. Philosophy of Systematic Biology Philosophical discussion of systematics was a response to a scientific revolution in that discipline in the 1960's and 1970's, a revolution which saw the discipline transformed first by the application of quantitative methods, and then by the cladistic approach, which argues that the sole aim of systematics should be to represent the evolutionary relationships between groups of organisms (phylogeny). Ideas from the philosophy of science were used to argue for both transformations, and the philosopher David L. Hull was an active participant in scientific debates throughout these two revolutions (Hull 1965; Hull 1970; Hull 1988; see also Sober 1988).

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The biologist Michael Ghiselin piqued the interest of philosophers when he suggested that systematics was fundamentally mistaken about the ontological status of biological species (Ghiselin 1974). Species are not types of organisms in the way that chemical elements are types of matter. Instead, they are historical particulars like nations or galaxies. Individual organisms are not instances of species, as my wedding ring is an instance of gold. Instead, they are parts of species, as I am a part of my family. As Smart had earlier noticed, this has the implication that there can be no laws of nature about biological species, at least in the traditional sense of laws true at every time and place in the universe (Smart 1959). This has led some philosophers of biology to argue for a new conception of laws of nature (Mitchell 2000). However, the view that species are individuals leaves other important questions about species unsolved and raises new problems of its own. Around twenty different so-called species concepts are represented in the current biological literature, and the merits, interrelations, and mutual consistency or inconsistency of these has been a major topic of philosophical discussion. Biological species are one of the classic examples of a natural kind. The philosophy of systematics has had a major influence on recent work on classification and natural kinds in the general philosophy of science (Dupr 1993; Wilson 1999). 5. Philosophy of Molecular Biology I mentioned above that the reduction of Mendelian genetics to molecular genetics one of the first topics to be discussed in the philosophy of biology. The initial debate between Schaffner and Hull was followed by the so-called antireductionist consensus (Kitcher 1984). The reductionist position was revived in a series of important papers by Kenneth Waters (Waters 1990; Waters 1994) and debate over the cognitive relationship between the two disciplines continues today, although the question is not now framed as a simple choice between reduction and irreducibility. Lindley Darden, Schaffner and others have argued that explanations in molecular biology are not neatly confined to one ontological level, and hence that ideas of reduction derived from classical examples like the reduction of the phenomenological gas laws to molecular kinematics in nineteenth century physics are simply inapplicable (Darden and Maull 1977; Schaffner 1993). Moreover, molecular biology does not have the kind of grand theory based around a set of laws or a set of mathematical models that is familiar from the physical sciences. Instead, highly specific mechanisms that have been uncovered in detail in one model organism seem to act as exemplars allowing the investigation of similar, although not necessarily identical, mechanisms in other organisms that employ the same, or related, molecular interactants. Darden and others have argued that these mechanismsspecific
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collections of entities and their distinctive activitiesare the fundamental unit of scientific discovery and scientific explanation, not only in molecular biology, but in a wide range of special sciences (Machamer, Darden et al. 2000; see also Bechtel and Richardson 1993). Another important topic in the philosophy of molecular biology has been the definition of the gene (Beurton, Falk and Rheinberger 2000; Griffiths and Stotz 2007). Philosophers have also written extensively on the concept of genetic information, the general tenor of the literature being that it is difficult to reconstruct this idea precisely in a way that does justice to the apparent weight placed on it by molecular biologists (Sarkar 1996; Maynard Smith 2000; Griffiths 2001; Jablonka 2002). 6. Philosophy of Developmental Biology The debates over adaptationism in the 1980's made philosophers familiar with the complex interactions between explanations of traits in evolutionary biology and explanations of the same traits in developmental biology. Developmental biology throws light on the kinds of variation that are likely to be available for selection, posing the question of how far the results of evolution can be understood in terms of the options that were available (developmental constraints) rather than the natural selection of those options (Maynard Smith, Burian et al. 1985). The debate over developmental constraints looked at developmental biology solely from the perspective of whether it could provide answers to evolutionary questions. However, as Ron Amundson pointed out, developmental biologists are addressing questions of their own, and, he argued, a different concept of constraint is needed to address those questions (Amundson 1994). The emergence in the 1990's of a new field promising to unite both kinds of explanation, evolutionary developmental biology, has given rise to a substantial philosophical literature aimed at characterizing this field from a methodological viewpoint (Maienschein and Laublicher 2004; Robert 2004; Amundson 2005; Brandon and Sansom 2007). 7. Philosophy of Ecology and Conservation Biology Until recently this was a severely underdeveloped field in the philosophy of biology. This is surprising, because there is obvious potential for all three of the approaches to philosophy of biology discussed above. There is also a substantial body of philosophical work in environmental ethics, and it seems reasonable to suppose that answering the questions that arise there would require a critical examination of ecology and conservation biology. In fact, an important book which sought to provide just those underpinningsKristin ShraderFrechette and Earl McCoy's Method in Ecology: Strategies for Conservation

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(1993)was an honorable exception to the philosophical neglect of ecology in earlier decades. In the past decade philosophers have started to remedy the neglect of ecology and a number of major books have appeared (Cooper 2003, Ginzburg and Colyvan 2004, Sarkar 2005, MacLaurin and Sterelny 2008). Discussion has focused on the troubled relationship between mathematical models and empirical data in ecology, on the idea of ecological stability and the 'balance of nature', and on the definition of biodiversity. 8. Methodology in Philosophy of Biology Most work in the philosophy of biology is self-consciously naturalistic, recognizing no profound discontinuity in either method or content between philosophy and science. Ideally, philosophy of biology differs from biology itself not in its knowledge base, but only in the questions it asks. The philosopher aims to engage with the content of biology at a professional level, although typically with greater knowledge of its history than biologists themselves, and less hands-on skills. It is common for philosophers of biology to have academic credentials in the fields that are the focus of their research, and to be closely involved with scientific collaborators. Philosophy of biology's naturalism and the continuity of its concerns with science itself is shared with much other recent work in the philosophy of science, perhaps most notably in the philosophy of neuroscience (Bechtel, Mandlik et al. 2001). Even the distinction between the questions of biology and those of philosophy of biology is not absolutely clear. As noted above, philosophers of biology address three types of questions: general questions about the nature of science, conceptual puzzles within biology, and traditional philosophical questions that seem open to illumination from the biosciences. When addressing the second sort of question, there is no clear distinction between philosophy of biology and theoretical biology. But while this can lead to the accusation that philosophers of biology have abandoned their calling for amateur hour biology it can equally well be said that a book like The Selfish Gene (Dawkins 1976) is primarily a contribution to philosophical discussion of biology. Certainly, the professional skills of the philosopher are as relevant to these internal conceptual puzzles as they are to the other two types of question. All three types of questions can be related to the specific findings of the biological sciences only by complex chains of argument. INTER-ACADEMY SYMPOSIUM-II Acadmie des sciences, German National Academy of Sciences Leopoldina and The Royal Society on The New Microbiology

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In the InterAcademy symposion after the opening made by Jean Bach perpetual secretary of the Academy of Sciences is Prof.Jorg Vogel spoke. The prose of his presentation is An RNA perspective on bad microbes and their eukaryotic hosts. According to Jrg Vogel16m Institute for Molecular Infection Biology, University of Wrzburg, Germany This talk will discuss emerging concepts and mechanisms of gene regulation by small noncoding RNAs (sRNAs) in bacteria, for example, programmed target mRNA decay, seed pairing, and 3 adenosine dependence of those sRNAs that act by the common RNA chaperone, Hfq. Furthermore, I will present examples of how RNA deep sequencing technologies have been facilitating new approaches to the global discovery and functional study of diverse functional sRNAs in many bacterial species, and how these can be used for parallel analysis of gene expression programs in a bacterial pathogen and its eukaryotic. The RNA Biology group is interested in gene regulation by noncoding RNA molecules in bacterial pathogens and eukaryotic host cells. We use a wide range of biochemical, genetic, biocomputational and RNA deep sequencing approaches to discover new regulatory RNA molecules and their functions. Our work is aided by many fruitful collaborations with laboratories in Germany, Europe and overseas. Research

Small regulatory RNAs in bacteria A major focus of our research is in small regulatory RNAs (sRNAs) that associate with the conserved RNA-binding protein Hfq in the model pathogen Salmonella Typhimurium. Hfq-dependent sRNAs constitute the largest posttranscriptional network presently known in bacteria, rivaling the complex
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2009 Full Professor and Chair, Institute for Molecular Infection Biology University of Wrzburg, Germany 2004 2010 Max Planck Research Group Leader (W2) RNA Biology group, MPI for Infection Biology, Berlin, Germany Ph.D. student and Postdoc at Humboldt University Berlin, Germany Ph.D. thesis: Group II intron splicing in higher plant chloroplasts, supervised by Thomas Brner and Wolfgang Hess, Department of Genetics 1991 1996 Undergraduate Studies in Biochemistry Humboldt University, Berlin, Germany Imperial College, London, UK

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regulations by eukaryotic microRNAs. Salmonella expresses ~100 sRNAs from both core genomic regions that are conserved in closely related Escherichia coli and from Salmonella-specific, pathogenicity islands. The Hfq-dependent sRNAs typically modulate protein synthesis by using short imperfect base-pairing with target mRNAs, thus altering translation and stability of the mRNA. We now understand that a single sRNA can regulate many target mRNAs using a highlyconserved short (7 nucleotide) seed sequence, yet how sRNAs act select with high specificity their targets in the background of thousands of other cellular transcripts is not understood. Equally, do proteins other than Hfq help mediate sRNA activity? Other fundamental questions which we are addressing are what are the benefits of using an RNA regulator versus a transcriptional factor in complex regulatory networks; how are the sRNAs themselves regulated; and how does this relate to virulence. RNA sequencing Massively parallel sequencing of cellular transcripts has been revolutionizing the discovery of coding and noncoding RNAs in virtually any organism. We were one of the first groups to use RNA deep sequencing in bacteria, and developed generic methods such as differential RNA sequencing (dRNA-seq) to report the primary transcriptomes of the major human pathogen, Helicobacter pylori, and many other species. We also pioneered the use of deep sequencing to identify the interaction partners of bacterial RNA binding proteins, for example, the small noncoding RNAs and mRNA targets of Hfq, for which we combined chromosomal epitope tagging of the protein with sequencing the co-immunoprecipitated RNA. Current projects use Illumina sequencing to discover new RNA-binding proteins and the landscape of posttranscriptional regulations in bacteria and host. Furthermore, we want to develop RNA deep sequencing as a robust tool to studyin parallelthe transcriptomes of bacterial pathogens and eukaryotic host over the course of infection, ideally at the single-cell level. RNA-protein interactions Whereas there has been much progress on base pairing RNAs, the abundance and mechanisms of RNA molecules that target proteins to modulate their activity is little understood. For example, may RNA molecules serve to tether virulence proteins until they are needed, or how many enzymes are targeted by regulatory RNAs to fine-tune metabolism? We are using in vivo cross-linking and RNA deep sequencing (CLIP-seq) to discover new RNAbinding proteins and map RNA-protein contacts in pathogenic bacteria. The ultimate goal is to understand how many proteins a regulatory RNA or even mRNA sees from its birth to death, how many RNA-protein interactions there

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are in the cell, how many of these are productive versus non-productive, and what the productive ones look like at the molecular level. RNA localization Contrary to previous beliefs, the bacterial cell contains complex structures with many proteins, and indeed mRNAs, localized in distinct foci within the cell. An emerging focus of our research is to investigate the sub-cellular localization of sRNAs and other major components of the post-transcriptional regulon in an attempt to decipher whether sRNAs are localized in distinct regions within the cell and determine how this localization may relate to the function of each sRNA. MicroRNAs and Long Noncoding RNAs in infected eukaryotic hosts Research over the last decade has implicated microRNAs in a plethora of eukaryotic disease-related pathways, including the mammalian immune response, but surprisingly little remains known as to the microRNA response to bacterial infections. Likewise, it is estimated that the human and mouse genomes express several hundred long noncoding RNA (lncRNA) molecules, with transcript lengths in the range of less than 1 to more than 100 kilobases. These lncRNA seem to play important roles in the epigenetic control of gene expression and in organizing RNA-protein particles. We are investigating which microRNAs and lncRNAs play a role in the response to infections by Salmonella and other bacterial pathogens, again using systematic screening approaches followed by in-depth characterization of differentially expressed candidate molecule. For example, we recently showed that the conserved Let-7 microRNA family is down-regulated by bacterial LPS in mouse and human cells, and that this removes a post-transcriptional break on the IL-6 and IL-10 cytokine mRNAs upon infection with Salmonella. Jrgen Johansson17 think the key issue of new microbiology is Light and dark oscillations coordinate multicellular differentiation in Listeria colonies through a blue-light receptor. And this issue of Listeria monocytogenes, a Grampositive bacterium frequently found in decaying soil, can occasionally cause serious life-threatening infections. Unlike many other bacteria, Listeria monocytogenes is only motile at low temperatures (<30C), due to a complex regulatory system preventing motility at higher temperatures. We show that colonies of Listeria monocytogenes undergo ring-formation (opaque and translucent rings) on agar plates in response to oscillating light/dark conditions. The ring formation is strictly dependent on a blue-light receptor, acting through the stress-sigma factor. Expression of the blue-light receptor is induced by H2O2 and a strain lacking Lmo0799 display a reduced survival at oxidative
17

Umea University, Sweden

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stress. A saturated transposon mutant screening identified 65 different genes/operons required for ring-formation, mainly modulating activity in response to altered Reactive Oxygen Species (ROS) levels. Due to carbon limitation, the bacteria from the inner part of the colony rapidly enter a resting state, preventing translucent rings to form opaque rings when exposed to light. Our results show that night and day cycles coordinate a differentiation of a Listeria colony, by a process requiring a blue-light receptor . Jrgen Johansson attaches particular importance to the biological reality that diversify into multicellular Listreria and the Control of virulence by small regulatory RNAs in the human pathogen Listeria monocytogenes Listeria monocytogenes is a grampositive human pathogen causing several different diseases, like meningitis, septicaemia and abortions. Listeria has an unique ability to cross the intestinal barrier, the placental barrier and the blood-brain barrier during infection. The bacteria is able to invade most tissues and shows a specific cell-infection cycle (Figure 1).One characteristic of Listeria monocytogenes is its ability to polymerise the actin within the host in order to spread between cells (Figure 2) During the last few years, it has become evident that all living organisms contain small regulatory RNAs (sRNAs). These sRNAs affect diverse cellular functions such as transcription, translation, protein degradation, mRNA stability etc. RNA interfence (RNAi) has arisen as a very versatile method to do functional knockout mutants in eukaryotes and could prove important when curing diseases, such as cancer. In bacteria, sRNAs can function as antisense RNA (Figure 3) thereby affecting translation or inducing target mRNA degradation. They can also act by binding specific proteins and thereby sequester all such proteins.

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Jrgen Johansson said my project involves the identification and characterisation of all sRNAs found in Listeria monocytogenes . The identified sRNAs will be knocked out and the phenotype of such mutants will be characterised and my future work will especially focus on sRNAs involved in virulence. I am planning to find the targets of these sRNAs by various methods, including in silico methods, transcriptome filters and 2D-gels. The mechanism by which the sRNAs function will be determined by different in vitro and genetic techniques. Also, the function of the sRNAs at the different steps of Listeria infection will be determined The Gram-positive bacterium Listeria monocytogenes uses a wide range of virulence factors for its pathogenesis. Expression of five of these factors has previously been shown to be subjected to posttranscriptional regulation as a result of their long 5-untranslated region (5-UTR). We have investigated the presence of 5-UTRs among the other known virulence genes and genes that encode putatively virulence-associated surface proteins. Our results strongly suggest that L. monocytogenes controls many of its virulence genes by a mechanism that involves the 5-UTR. These findings further emphasize the importance of post-transcriptional control for L. monocytogenes virulence. Dr Rotem Sorek18 tink in the field Genomic probing into the immune system of Bacteria are constantly exposed to phage attacks in the environment. To survive these attacks, bacteria had developed multiple lines of molecular defense mechanisms such as restriction enzymes, abortive infection mechanisms, and the adaptive immune system CRISPR. We have developed high throughput genomic tools to discover and characterize novel bacterial immune systems that protect against phage. These methods, and the nature of the immune systems we detected, will be discussed in the talk. I think the research scientists of the State of Israel give a hope and an absolute guarantee for the future of their country. This is the case of the group of Dr. Rotem Sorek researchers. More than 2000 microbial genomes were sequenced to date, each of which containing ~3000 genes on average. But having the genome sequence alone does not mean that we understand the biology of an organism: about 50% of all genes in every newly sequenced species are of unknown function. Among the thousands of sequenced microbial genomes, millions of sequenced genes are so far uncharacterized.

18

Dr. Rotem Sorek Office: Meyer Building, Room 210A Institute of Science, Department of Molecular Genetics, Israel

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Our lab is committed to develop innovative approaches that would allow elucidation of the novel biological functions "hiding" within uncharacterized genes. Current research directions in the lab include: .

Fig 1. Increased drug resistance among pathogens versus reduced development of new drugs. A) Growing proportions of selected pathogens resistant against the antibiotic drug

ciprofloxacin. Similar increase in resistance was measured for most commonly used antibiotics. B) The number of new antimicrobial drugs approved by the FDA between the years 1983-2007. There is a growing need for new antimicrobial agents in the clinic. Drug resistance is spreading among pathogens, but the number of new antibiotics in the market is constantly decreasing. As a result, hospital-acquired bacterial infections now affect 1.7 million patients annually in the U.S. alone, and are responsible for 99,000 deaths every year. There is, therefore, a clear and urgent need to expand our clinical arsenal of antimicrobial drugs We are developing a computational method that detects, among a large number of microbial genomes, genes producing products that are toxic to bacteria. These genes are tested for their antimicrobial activity. Our approach is based on a byproduct of the genome sequencing process, where initial assemblies invariably contain gaps due to DNA fragments that cannot be cloned in bacteria (Fig 1). We discovered that these uncloneable gaps are caused by genes that are toxic to E. coli (Sorek et al., Science 2007). Thousands of such genes from hundreds of bacteria were collected into the PanDaTox database. Among these toxic genes we were able to discover new types of microbial toxins, new restrictions enzymes, toxic small RNAs and toxic DNA binding motifs (Kimelman et al, 2012).

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Fig. 2. Microbial genes discovered via our approach are toxic to E. coli. Shown are toxicity results for nine gap-residing genes tested and a control gene (Betagalactosidase). The coding regions of these genes were cloned into E. coli under the control of an inducible promoter system that is active only in the presence of IPTG. (A) Cells grown without the expression inducer IPTG; (B) grown with 250uM IPTG; (C) with 800uM IPTG. We are using the Illumina high-throughput sequencing platform to sequence whole microbial genomes and transcriptomes. This technology generates hundreds of millions of short reads per run, reaching multiple giga bases of sequence per day. The Illumina technology enables us to study the evolution of bacteria, discover phenotype altering mutations, and document dynamic evolutionary processes. Bacterial whole genome evolution Using this technology, we documented processes of genome shrinkage in bacteria (Moran et al, Science 2009), and found how bacterial genomes evolve in response to phage attacks (Avrani et al, Nature 2011). We also develop methods for accurate detection of individual mutations in genomes using shortread sequencing technologies (Wurtzel et al, 2010). RNA-mediated regulation in bacteria studied with RNA-seq We employ RNA-seq to perform gene expression studies in bacteria and archaea and to understand their complex transcriptomes. Although prokaryotic transcriptomes were considered simple until recently, RNA-seq studies now revolutionize our understanding of the complexity, plasticity and regulation of microbial transcriptomes (Sorek & Cossart, Nature Reviews Genetics 2010). We know that two years ago To mark the 50th anniversary of the founding of the Israeli Academy of Science and Humanity (Israel Academy of Sciences and Humanities), 17 presidents and heads of national science academies and
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international around the world gathered in Jerusalem "to express their confidence and recognize the accomplishments of Israeli science." The conference which took place during the "National Week of Science" which marked the anniversary of the birth of Albert Einstein, March 14. The Israel Academy of Sciences and Humanities is a public research institution located in Jerusalem. It brings together the best researchers in Israel in all fields: Natural Sciences, Social Sciences and Humanities. Martin Buber, Scholem Gershon Aaron Katzir and his first presidents were. The purpose of the Academy is to promote scientific activity, to advise the government in the research program and to represent Israeli science worldwide. International Conference of Presidents "Science and Responsibility" was held all week in Jerusalem at the Israel Academy of Sciences with the participation of the State President Shimon Peres, the Knesset Speaker Reuven Rivlin and Israeli Minister of Science, Prof. Daniel Hershkovitz. Among the participants at this conference was attended by national leaders of the academies of science and scientists from countries and regions: BerlinBrandenburg, China, Estonia, France, Germany, Great Britain, India, Japan, Poland, Sweden, Taiwan , USA and others. Prominent Israeli public figures and members of the academies were present and among them four Israelis Nobel Laureates: Professors Israel Aumann, Aaron Ciechanover, Avram Hershko and Ada Yonath. The President of the Israel Academy of Sciences, Professor Menahem Yaari, described the conference as a milestone in the development of international scientific relations of the State of Israel and an Israeli honor for science in the world. The Academy of Science of Israel is celebrating its 50th was established in 1960 at the initiative of Prime Minister Ben-Gurion, who also chaired the first meeting of the General Assembly of the Academy. Ratified by law in 1961, the National Academy of Sciences has 98 academic scientists and the most eminent of Israel. In June 1961, after a long preparation, the parliament voted in favor of legislation to govern the Academy. According to the latter, the main purpose of the Academy is to bring its members the best scientists in Israel, to advance research of the natural sciences, to advise the government on scientific issues of national importance and represent the State before similar institutions established abroad. The Academy has two sections: one for Humanities and the Sciences of Nature.
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The membership of each section is 35, not counting those who are aged 75; elected officials remain in the Academy member for life. The Academy meets at least once a year for a general meeting, and each section meets three times a year. The Academy President is appointed by the Head of State on the recommendation of the Academy for a period of three years. Vice President of the Academy, is elected directly by members of the Academy for the same duration. Today the Academy continues his scientific work. The current president is Professor Menahem Yaari of the Hebrew University of Jerusalem, and the Vice President Professor Ruth Arnon of the Weizmann Institute in Rehovot. In the section of the Humanities, a very important research work is done on the history and development of Jewish liturgy and religious poetry. The Academy publishes widely in almost all areas of science, but also in the field of Arts. According to Professor Yaari: "The founding fathers considered the establishment of the Academy of Sciences as representing the creation of a center of knowledge and a scientific authority that can help the young state on matters of scientific nature to implement . During the past 50 years, the state has rarely helped the Academy, but recently it has been taking a significant share. " Professor Yaari reaffirms the desire to improve the knowledge base for decision makers, as long as they ask.

The President of the Israel Academy of Sciences, Professor Menahem Yaari, described the conference as "a milestone in the promotion of international scientific relations of the State of Israel and a tribute to the reputation of science in the Israeli world ". The Conference of Presidents focused on the responsibility of researchers and scientific communities towards society on economic issues, health and progress of social welfare as well as the ethics of science and security issues . The event Jubilee began on March 14, the anniversary of Albert Einstein, celebrated in Israel as a National Day of Science. To celebrate this jubilee, a rare and unusual exhibition of original manuscripts of Albert Einstein's Theory of Relativity is presented to the Academy. A conference in memory of Albert Einstein was given by the Nobel Prize in Physics French Claude CohenTanoudji. The presidents and heads of Academies of Sciences were received Tuesday, March 16 by the Scientific Committee of the Knesset. They were also received by the State President Shimon Peres during a reception for President. The involvement of all stakeholders in the International Conference of Presidents reflects the importance of such a meeting, the highlight of all the
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more informal appointments that take place regularly every year. Moreover, the presence of President Shimon Peres is a lot for the National Academy of Science of Israel. For Steve Busby19 The last decade has seen a renaissance in the study of transcriptional regulation in Escherichia coli due mainly to the arrival of whole genome sequences and detailed structural information about the multi-subunit RNA polymerase. Until recently, our knowledge was based on case-by-case studies of favorite regulatory regions. However, the application of genomic methodologies, such as transcriptomics, ChIP-on-chip and bioinformatics, has revealed new insights and unexpected complications. Promoters are the main drivers of bacterial gene expression. Some recent results concerning the integration of different signals at complex Escherichia coli promoters will be presented. Transcriptional regulation in bacteria Steve Busbys work concerns the mechanisms by which the expression of different genes is regulated in bacteria. Working with Escherichia coli K-12, over the past 25 years, the lab has elucidated some of the basic rules of promoter recognition by RNA polymerase and some of the fundamental mechanisms by which transcription activators function (see reviews listed below). The work with RNA polymerase has focused on the roles of the alpha and sigma subunits, whilst the work on transcription activation has developed from studies of the cyclic AMP receptor protein (known as CRP or CAP), which have established a paradigm for understanding transcription activation in bacteria. Early work with CRP, and with the related activator, FNR was concerned with simple promoters, such as the E. coli lac or gal promoters, where one molecule of activator is sufficient for full induction. Recently, the lab has turned its attention to more complicated promoters that are regulated by many different factors. Because bacterial gene expression is exquisitely sensitive to the environment, the majority of promoters are complex and the lab has focused on cases where one molecule of activator is insufficient for full induction. 20
19
Professor Steve Busby FRS Professor of Biochemistry Head of SchoolSchool of Biosciences University of Birmingham, UK

20

Selected references Grainger, D, Lee, D & Busby, S (2009) Direct methods for studying transcription regulatory proteins and RNA polymerase in bacteria. Current Opinion in Microbiology 12 531-535 Browning, D, Grainger, D & Busby S (2010) Effects of nucleoid-associated proteins on bacterial chromosome structure and gene expression. Current Opinion in Microbiology 13 773-780 Rossiter, A, Browning, D, Leyton, D, Johnson, M, Godfrey, R, Wardius, C, Desvaux, M, Cunningham, A, Ruiz-Perez, F, Nataro, J, Busby, S & Henderson, I (2011) Transcription of the plasmid-encoded toxin gene from enteroaggregative Escherichia coli is regulated by a novel co-activation mechanism involving CRP and Fis. Molecular Microbiology 81 179-

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Stphane Mresse21 working on Salmonella effector proteins in the regulation of host membrane trafficking. In other words Salmonella is a bacterial pathogen. Ingested bacteria cross the intestinal epithelial barrier and proliferate within host cells. Intracellular replication takes place in a membrane-bound compartment called the Salmonella-containing vacuole (SCV). Infected cells are characterized by a profound reorganisation of late endocytic compartments. While lysosomal contents (i.e. lysosomal enzymes) tend to disappear from infected cells, lysosomal membrane glycoproteins (i.e. LAMP) accumulate on SCVs and on membrane tubular structures that extend from the SCV. These modifications involve the translocation into the host cell of bacterial effector proteins. Among these effector proteins, SifA is required for the SCV stability and the formation of membrane tubular structures. Together with its eukaryotic target SKIP, SifA is also necessary for the removal of kinesin-1, which is recruited on the SCV membrane by the PipB2 effector. We recently showed that the effector protein SopD2 is responsible for the SCV instability that triggers the cytoplasmic release of a sifA- bacterial mutant. Membrane tubular structures that extend from the SCV are the hallmark of Salmonella-infected cells, and until recently, these unique structures had not been observed in the absence of SifA. The deletion of sopD2 in a sifA- mutant strain re-established membrane trafficking from the SCV and led to the formation of new membrane tubular structures, the formation of which is dependent on other Salmonella effector(s). Taken together, our data demonstrate that SopD2 inhibits the vesicular transport and the formation of tubules that extend outward from the SCV and thereby contributes to the phenotypes observed in absence of SifA. The antagonistic roles played by SopD2 and SifA in the membrane dynamics of the vacuole, and the complex actions of SopD2, SifA, PipB2 and other unidentified effector(s) in the biogenesis and maintenance of the Salmonella replicative niche will be discussed. The facultative intracellular pathogen Salmonella enterica causes a variety of diseases, including gastroenteritis and typhoid fever. Inside epithelial cells, Salmonella replicates in vacuoles, which localize in the perinuclear area in close proximity to the Golgi apparatus. Among the effector proteins translocated by the Salmonella pathogenicity island 2-encoded type III secretion system, SifA and SseG have been shown necessary but not sufficient to ensure the intracellular positioning of Salmonella vacuoles. Hence, we have investigated the involvement of other secreted effector proteins in this process. Here we show that SseF interacts
191
21

Centre dImmunologie de Marseille-Luminy, Parc Scientifique de Luminy, case 906,13288 Marseille cedex 9

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functionally and physically with SseG but not SifA and is also required for the perinuclear localization of Salmonella vacuoles. The observations show that the intracellular positioning of Salmonella vacuoles is a complex phenomenon resulting from the combined action of several effector proteins. Hlne Bierne22 made the presentation on Bacterial targeting of chomatin : the Listeria paradigm. The facultative intracellular pathogen Salmonella enterica causes a variety of diseases, including gastroenteritis and typhoid fever. Inside epithelial cells, Salmonella replicates in vacuoles, which localize in the perinuclear area in close proximity to the Golgi apparatus. Among the effector proteins translocated by the Salmonella pathogenicity island 2-encoded type III secretion system, SifA and SseG have been shown necessary but not sufficient to ensure the intracellular positioning of Salmonella vacuoles. Hence, we have investigated the involvement of other secreted effector proteins in this process. Here we show that SseF interacts functionally and physically with SseG but not SifA and is also required for the perinuclear localization of Salmonella vacuoles. The observations show that the intracellular positioning of Salmonella vacuoles is a complex phenomenon resulting from the combined action of several effector proteins. In 2011 Researchers at the Pasteur Institute, INRA, INSERM and CNRS have identified a mechanism for the pathogenic bacterium Listeria monocytogenes to his advantage to reprogram gene expression of the cell it infects. L. monocytogenes secretes a protein that can penetrate the cell nucleus to take control of immune system genes of the host. This work has been published on the website of the journal Science Jan. 20, 2011. During infection, pathogenic bacteria must outwit the immune system of infected hosts to establish a sustainable way in his body. It was known previously that control of the host immune system was through the manipulation of cellular signals responsible for the activation of immune cells. A study in Listeria monocytogenes, the bacteria responsible for human listeriosis, comes first to show that pathogenic bacteria can act directly in the nucleus of the host cell, to their advantage to reprogram genes under the control of interferons, for activating the immune system (1). This study was conducted by Helen Bierne within the unit of Bacteria-Cell Interactions (Institut Pasteur, Inserm Unit 604, INRA USC2020) directed by Pascale Cossart, in collaboration with other teams from the Institut Pasteur, CNRS (Gif-sur-Yvette, University Paris Diderot - Paris 7 and Grenoble) and IBMC (Porto). This work is in line with a study by the same team in 2009. This allowed
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INSTITUT PASTEURBacteria-cell interactions Unit INSERM U604 INRA USC2020 Department of Cell biology and Infection 25 rue du Docteur Roux -75724 PARIS Cedex 15-France.

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the identification of a complex capable of locking gene expression by compacting the DNA (2). Here, the researchers identified a small bacterial protein, called LNTA, able to blow the lock by binding directly to the complex, causing the opening of the compacted DNA and thus access to genes. It is unclear how, and when the bacteria decides to produce this factor LNTA, but its expression is fundamental to the success of infection with Listeria, which can enable or through it at will suppress immunity of the host. These studies suggest the role of epigenetic regulation - changes in gene expression that occur without alteration of the DNA sequence - in infection by L. monocytogenes. This discovery, if it held true for other pathogens, provide valuable information for understanding and ultimately better fight against the infection and immunity. Dr Ali KILIC Paris 7 May 2012

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Biology and Philosophy Special issue: Philosophy and the microbe (tentative titles; order tbc) Philosophy of biology and philosophy of microbiology: Whats happening and whats next? Maureen OMalley (Sydney) and John Dupr (Exeter) Philosophy of microbiology from a microbiologists point of view Ford Doolittle (Dalhousie) Microbes modeling ontogeny? Prospects and limitations Alan Love (Minnesota) and Michael Travisano (Minnesota) Philosophy of microbiology and pluralism: premature consensus Carol Cleland (Colorado @ Boulder)

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Metaphysics of microbial consortia Marc Ereshefsky (Calgary) and Makmiller Pedroso (Calgary) A process ontology of microbial activities Eric Bapteste (UPMC, Paris) and John Dupr (Exeter) Microbial biodiversity as the fundamental biodiversity Rob Knight and colleagues (Colorado @ Boulder) Extending biodiversity to microbes and beyond: the lower-limit problem Christophe Malaterre (IHPST, Paris) Beyond the genome: community-level analysis of the microbial world Jack Gilbert (Argonne National Laboratory, Chicago) Contingency in microbial evolution and its consequences for philosophical debates Laura Franklin-Hall (NYU) Endosymbiosis and its ramifications for evolutionary theory John Archibald (Dalhousie) Viruses, virology and their implications for philosophy of biology Forest Rohwer (San Diego) The other eukaryotes: microbes that arent prokaryotes, and why philosophers should be interested Andrew Roger (Dalhousie), Maureen OMalley (Sydney), Alastair Simpson (Dalhousie) What are fungi: a true kingdom with a boundary or an evolutionary continuum? Thomas Richards (Natural History Museum, London) Selected Publications Stern A., Mick E., Tirosh I., Sagy O., Sorek R. CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome Genome Research, in press (2012). Dominissini D., Moshitch-Moshkovitz S., Schwartz S., Salmon-Divon M., Ungar L., Osenberg S., Cesarkas K., Jakob-Hirsch J., Amariglio N., Kupiec M., Sorek R., Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq Nature, in press (2012). Wurtzel O., Sesto N., Mellin J.R., Karunker I., Edelheit S., Becavin C., Archambaud C., Cossart P., Sorek R. Comparative transcriptomics of pathogenic and non-pathogenic Listeria species Molecular Systems Biology, in press (2012). Kimelman A., Levy A., Sberro H., Kidron S., Leavitt A., Amitai G., Yoder-Himes D., Wurtzel O., Zhu Y., Rubin E.M., Sorek R. A vast collection of microbial genes that are toxic to bacteria Genome Research, 22(4):802-9 (2012). Avrani S., Wurtzel O., Sharon I., Sorek R., Lindell D Genomic island variability facilitates Prochlorococcus-virus coexistence Nature, 474(7353):604-608 (2011). Sorek R., Cossart P. Prokaryotic transcriptomics: a new view on regulation, physiology and pathogenicity. Nature Reviews Genetics, 11(1):9-16 (2010).

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Moran N.A., McLaughlin H.J., Sorek R. The dynamics and timescale of ongoing genomic erosion in symbiotic bacteria. Science, 323(5912):379-382 (2009). Yoder-Himes D.R., Chain P.S.G., Zhu Y., Wurtzel O., Rubin E.M., Tiedje J.M., Sorek R. Mapping the Burkholderia cenocepacia niche response via high-throughput sequencing. PNAS, 106(10):3976-3981 (2009). Sorek R., Kunin V., Hugenholtz P. CRISPR - a widespread anti-viral system that provides acquired resistance against viruses in prokaryotes. Nature Reviews Microbiology, 6(3):181-6 (2008). Sorek R., Zhu Y., Creevey C., Francino M.P., Bork P., Rubin E.M. Genome-wide experimental determination of barriers to horizontal gene transfer. Science, 318(5855):1449-1452 (2007). Warnecke F., Luginbuhl P., Ivanova N., Ghassemian M., Richardson T.H., Stege J.T., Cayouette M., Djordjevic G., Aboushadi N., Sorek, R. et al. Metagenomic and functional analysis of hindgut microbiota of a wood feeding higher termite. Nature, 450(7169):560-565 (2007). Shemesh R., Novik A., Edelheit S., Sorek R. Genomic fossils as a snapshot of alternative splicing in the human transcriptome. PNAS, 103(5):1364-1369 (2006). Sorek R., Lev-Maor G., Reznik M.*, Dagan T., Belinky F., Graur D., Ast G. Minimal conditions for exonization of intronic sequences: 5' splice site formation in alu exons. Molecular Cell, 14(2): 221-231 (2004). Yelin R.*, Dahary D.*, Sorek R.*, Levanon E.Y., Goldstein O., Shoshan A., Diber A., Biton S., Tamir Y., Khosravi R., Nemzer S., Pinner E., Walach S., Bernstein J., Savitsky K., Rotman G. Widespread occurrence of antisense transcription in the human genome. Nature Biotechnology, 21(4): 379-386 (2003). Lev-Maor G.*, Sorek R.*, Shomron N., Ast G. The birth of an alternatively spliced exon: 3' splice-site selection in Alu exons. Science, 300(5623): 1288-1291 (2003). Sorek R., Amitai M. Piecing together the significance of splicing. Nature Biotechnology, 19(3): 196 (2001).

All Publications
Stern A., Mick E., Tirosh I., Sagy O., Sorek R. CRISPR targeting reveals a reservoir of common phages associated with the human gut microbiome Genome Research, in press (2012). Dominissini D., Moshitch-Moshkovitz S., Schwartz S., Salmon-Divon M., Ungar L., Osenberg S., Cesarkas K., Jakob-Hirsch J., Amariglio N., Kupiec M., Sorek R., Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq Nature, in press (2012). Wurtzel O., Sesto N., Mellin J.R., Karunker I., Edelheit S., Becavin C., Archambaud C., Cossart P., Sorek R.

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Comparative transcriptomics of pathogenic and non-pathogenic Listeria species Molecular Systems Biology, in press (2012). Amitai G., Sorek R. PanDaTox: a tool for accelerated metabolic engineering Bioengineered Bugs, in press (2012). Kimelman A., Levy A., Sberro H., Kidron S., Leavitt A., Amitai G., Yoder-Himes D., Wurtzel O., Zhu Y., Rubin E.M., Sorek R. A vast collection of microbial genes that are toxic to bacteria Genome Research, 22(4):802-9 (2012). Danan M., Schwartz S., Edelheit S., Sorek R. Transcriptome-wide discovery of circular RNAs in archaea Nucleic Acids Research, 40(7):3131-42 (2012). Michaeli S., Doniger T., Gupta S.K., Wurtzel O., Romano M., Visnovezky D., Sorek R., Unger R., Ullu E RNA-seq analysis of small RNPs in Trypanosoma brucei reveals a rich repertoire of noncoding RNAs Nucleic Acids Research, 40(3):1282-98 (2012). Sorek R., Serrano L Bacterial genomes: from regulatory complexity to engineering Current Opinion in Microbiology, 14:1-2 (2011). Avrani S., Wurtzel O., Sharon I., Sorek R., Lindell D Genomic island variability facilitates Prochlorococcus-virus coexistence Nature, 474(7353):604-608 (2011). Stern A., Sorek R. The phage-host arms-race: Shaping the evolution of microbes. BioEssays, 33(1):43-51 (2011). He S.*, Wurtzel O.*, Singh K., Froula J., Yilmaz S., Wang Z., Chen F., Lindquist E.A., Sorek R., Hugenholtz P. Validation of two commercial ribosomal RNA removal methods for microbial metatranscriptomics. Nature Methods, 7:807-812 (2010). Wurtzel O., Dori-Bachash M., Pietrokovski S., Jurkevitch E., Sorek R. Mutation detection with next-generation resequencing through a mediator genome. PLoS One, 5(12):e15628 (2010). Stern A., Keren L., Wurtzel O., Amitai G., Sorek R. Self-targeting by CRISPR: gene regulation or autoimmunity? Trends in Genetics, 26(8):335-340 (2010). Sorek R., Cossart P. Prokaryotic transcriptomics: a new view on regulation, physiology and pathogenicity. Nature Reviews Genetics, 11(1):9-16 (2010). Wurtzel O., Sapra R., Chen F., Zhu Y., Simmons B., Sorek R. A single-base resolution map of an archaeal transcriptome. Genome Research, 20(1):133-41 (2010). Sorek R. When new exons are born Heredity, 103:279280 (2009). Yoder-Himes D.R., Chain P.S.G., Zhu Y., Wurtzel O., Rubin E.M., Tiedje J.M., Sorek R. Mapping the Burkholderia cenocepacia niche response via high-throughput sequencing. PNAS, 106(10):3976-3981 (2009).

46

Moran N.A., McLaughlin H.J., Sorek R. The dynamics and timescale of ongoing genomic erosion in symbiotic bacteria. Science, 323(5912):379-382 (2009). Sorek R., Kunin V., Hugenholtz P. CRISPR - a widespread anti-viral system that provides acquired resistance against viruses in prokaryotes Nature Reviews Microbiology, 6(3):181-6 (2008). Sorek R., Zhu Y., Creevey C., Francino M.P., Bork P., Rubin E.M. Genome-wide experimental determination of barriers to horizontal gene transfer. Science, 318(5855):1449-1452 (2007). Warnecke F., Luginbuhl P., Ivanova N., Ghassemian M., Richardson T.H., Stege J.T., Cayouette M., Djordjevic G., Aboushadi N., Sorek, R. et al. Metagenomic and functional analysis of hindgut microbiota of a wood feeding higher termite. Nature, 450(7169):560-565 (2007). Sorek R. The birth of new exons: mechanisms and evolutionary consequences. RNA, 13(10):1603-1608 (2007). Kunin V.*, Sorek R.*, Hugenholtz P. Evolutionary conservation of sequence and secondary structures in CRISPR repeats. Genome Biology, 8(4):R61 (2007). Lev-Maor G.*, Sorek R.*, Levanon E.Y., Paz N., Eisenberg E., Ast G. RNA-editing mediated exon evolution. Genome Biology, 8(2):R29 (2007). Sorek R., Dror G., Shamir R. Assessing the fraction of ancestral alternatively spliced exons in the human genome. BMC Genomics, 7:273(2006). Shemesh R., Novik A., Edelheit S., Sorek R. Genomic fossils as a snapshot of alternative splicing in the human transcriptome. PNAS, 103(5):1364-1369 (2006). Akiva P., Toporik A., Edelheit S., Peretz Y., Diber A., Shemesh R., Novik A., Sorek R. Transcription-mediated gene fusion in the human genome. Genome Research, 16(1):30-36 (2006). Dror G., Sorek R., Shamir R. Accurate identification of alternatively spliced exons using support vector machine. Bioinformatics, 21(7): 897-901 (2005). Eisenberg E., Nemzer S., Kinar Y., Sorek R., Rechavi G., Levanon E.Y. Is abundant A-to-I RNA editing primate-specific? Trends in Genetics, 21(2):77-81 (2005). Neeman Y., Dahary D., Levanon E.Y., Sorek R., Eisenberg E. Is there any sense in antisense editing? Trends in Genetics, 21(10):544-547 (2005). Dahary D., Elroy-Stein O., Sorek R. Naturally occurring antisense: Transcriptional leakage or real overlap? Genome Research, 15(3): 364-368 (2005). Lavorgna G., Dahary D., Lehner B., Sorek R., Sanderson C.M., Casari G. In search of antisense. Trends in Biochemical Sciences, 29(2): 88-94 (2004).

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Dagan T.*, Sorek R.*, Sharon E.*, Ast G., Graur D. AluGene: a database of Alu elements incorporated within protein-coding genes. Nucleic Acids Research, 32: D489-D492 (2004). Sorek R., Shamir R., Ast G. How prevalent is functional alternative splicing in the human genome? Trends in Genetics, 20(2): 68-71 (2004). Sorek R.*, Lev-Maor G.*, Reznik M.*, Dagan T., Belinky F., Graur D., Ast G. Minimal conditions for exonization of intronic sequences: 5' splice site formation in alu exons. Molecular Cell, 14(2): 221-231 (2004). Sorek R., Shemesh R., Cohen Y., Basechess O., Ast G., Shamir R. A non-EST based method for exon-skipping prediction. Genome Research, 14(8): 1617-1623 (2004). Levanon E., Sorek R. The importance of alternative splicing in the drug discovery process. Targets, 2(3): 109-114 (2003). Hazkani-Covo E., Sorek R., Graur D. Evolutionary dynamics of large Numts in the human genome: rarity of independent insertions and abundance of post-insertion duplications. Journal of Molecular Evolution, 56(2): 169-174 (2003). Sorek R., Safer H.M. A Novel method for computational identification of contaminated EST libraries. Nucleic Acids Research, 31(3): 1067-1074 (2003). Yelin R., Dahary D., Sorek R., Levanon E.Y., Goldstein O., Shoshan A., Diber A., Biton S., Tamir Y., Khosravi R., Nemzer S., Pinner E., Walach S., Bernstein J., Savitsky K., Rotman G. Widespread occurrence of antisense transcription in the human genome. Nature Biotechnology, 21(4): 379-386 (2003). Lev-Maor G.*, Sorek R.*, Shomron N., Ast G. The birth of an alternatively spliced exon: 3' splice-site selection in Alu exons. Science, 300(5623): 1288-1291 (2003). Sorek R., Ast G. Intronic sequences flanking alternatively spliced exons are conserved between human and mouse. Genome Research, 13(7): 1631-1637 (2003). Sorek R., Basechess O., Safer H.M. Expressed sequence tags: clean before using. Cancer Research, 63(20):6996 (2003). Sorek R., Ast G., Graur D. Alu containing exons are alternatively spliced. Genome Research, 12(7): 1060-1067 (2002). Sorek R., Amitai M. Piecing together the significance of splicing. Nature Biotechnology, 19(3): 196 (2001).

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