Littérature scientifique sur le sujet « (Joseph Marie Antoine Hubert) »

Abstract Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and <70yrs (68%). Tumors were mainly non-squamous (79%) with >1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p<0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p<0.05), albumin (MV OR=0.4, p<0.01) and PDL1 TC % (MV OR=0.27, p<0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). >65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.

IntroductionThe European will to modify the natural world emerged through English landscape design during the eighteenth century. Released from the neo-classical aesthetic dichotomy of the beautiful and the ugly, new categories of the picturesque and the sublime gestured towards an affective relationship to nature. Europeans began to see the world as a picture, the elements of which were composed as though part of a theatrical scene. Quite literally, as I shall discuss below, gardens were “composed with ‘pantomimic’ elements – ruins of castles and towers, rough hewn bridges, Chinese pagodas and their like” (McGillivray 134–35) transforming natural vistas into theatrical scenes. Such a transformation was made possible by a habit of spectating that was informed by the theatrical metaphor or theatrum mundi, one version of which emphasised the relationship between spectator and the thing seen. The idea of the natural world as an aesthetic object first developed in poetry and painting and then through English landscape garden style was wrought in three dimensions on the land itself. From representations of place a theatrical transformation occurred so that gardens became a places of representation.“The Genius of the Place in All”The eighteenth century inherited theatrum mundi from the Renaissance, although the genealogy of its key features date back to ancient times. Broadly speaking, theatrum mundi was a metaphorical expression of the world and humanity in two ways: dramaturgically and formally. During the Renaissance the dramaturgical metaphor was a moral emblem concerned with the contingency of human life; as Shakespeare famously wrote, “men and women [were] merely players” whose lives consisted of “seven ages” or “acts” (2.7.139–65). In contrast to the dramaturgical metaphor with its emphasis on role-playing humanity, the formalist version highlighted a relationship between spectator, theatre-space and spectacle. Rooted in Renaissance neo-Platonism, the formalist metaphor configured the world as a spectacle and “Man” its spectator. If the dramaturgical metaphor was inflected with medieval moral pessimism, the formalist metaphor was more optimistic.The neo-Platonist spectator searched in the world for a divine plan or grand design and spectatorship became an epistemological challenge. As a seer and a knower on the world stage, the human being became the one who thought about the world not just as a theatre but also through theatre. This is apparent in the etymology of “theatre” from the Greek theatron, or “seeing place,” but the word also shares a stem with “theory”: theaomai or “to look at.” In a graceful compression of both roots, Martin Heidegger suggests a “theatre” might be any “seeing place” in which any thing being beheld offers itself to careful scrutiny by the beholder (163–65). By the eighteenth century, the ancient idea of a seeing-knowing place coalesced with the new empirical method and aesthetic sensibility: the world was out there, so to speak, to provide pleasure and instruction.Joseph Addison, among others, in the first half of the century reconsidered the utilitarian appeal of the natural world and proposed it as the model for artistic inspiration and appreciation. In “Pleasures of the Imagination,” a series of essays in The Spectator published in 1712, Addison claimed that “there is something more bold and masterly in the rough careless strokes of nature, than in the nice touches and embellishments of art,” and compared to the beauty of an ordered garden, “the sight wanders up and down without confinement” the “wide fields of nature” and is “fed with an infinite variety of images, without any certain stint or number” (67).Yet art still had a role because, Addison argues, although “wild scenes [. . .] are more delightful than any artificial shows” the pleasure of nature increases the more it begins to resemble art; the mind experiences the “double” pleasure of comparing nature’s original beauty with its copy (68). This is why “we take delight in a prospect which is well laid out, and diversified, with fields and meadows, woods and rivers” (68); a carefully designed estate can be both profitable and beautiful and “a man might make a pretty landskip of his own possessions” (69). Although nature should always be one’s guide, nonetheless, with some small “improvements” it was possible to transform an estate into a landscape picture. Nearly twenty years later in response to the neo-Palladian architectural ambitions of Richard Boyle, the third Earl of Burlington, and with a similarly pictorial eye to nature, Alexander Pope advised:To build, to plant, whatever you intend,To rear the Column, or the Arch to bend,To swell the Terras, or to sink the Grot;In all, let Nature never be forgot.But treat the Goddess like a modest fair,Nor over-dress, nor leave her wholly bare;Let not each beauty ev’ry where be spy’d,Where half the skill is decently to hide.He gains all points, who pleasingly confounds,Surprizes, varies, and conceals the Bounds.Consult the Genius of the Place in all;That tells the Waters or to rise, or fall,Or helps th’ ambitious Hill the heav’ns to scale,Or scoops in circling theatres the Vale,Calls in the Country, catches opening glades, Joins willing woods, and varies shades from shades,Now breaks or now directs, th’ intending Lines;Paints as you plant, and, as you work, designs. (Epistle IV, ll 47–64) Whereas Addison still gestured towards estate management, Pope explicitly advocated a painterly approach to garden design. His epistle articulated some key principles that he enacted in his own garden at Twickenham and which would inform later garden design. No matter what one added to a landscape, one needed to be guided by nature; one should be moderate in one’s designs and neither plant too much nor too little; one must be aware of the spectator’s journey through the garden and take care to provide variety by creating “surprises” that would be revealed at different points. Finally, one had to find the “spirit” of the place that gave it its distinct character and use this to create the cohesion in diversity that was aspired to in a garden. Nature’s aestheticisation had begun with poetry, developed into painting, and was now enacted on actual natural environments with the emergence of English landscape style. This painterly approach to gardening demanded an imaginative, emotional, and intellectual engagement with place and it stylistically rejected the neo-classical geometry and regularity of the baroque garden (exemplified by Le Nôtre’s gardens at Versailles). Experiencing landscape now took on a third dimension as wealthy landowners and their friends put themselves within the picture frame and into the scene. Although landscape style changed during the century, a number of principles remained more or less consistent: the garden should be modelled on nature but “improved,” any improvements should not be obvious, pictorial composition should be observed, the garden should be concerned with the spectator’s experience and should aim to provoke an imaginative or emotional engagement with it. During the seventeenth century, developments in theatrical technology, particularly the emergence of the proscenium arch theatre with moveable scenery, showed that poetry and painting could be spectacularly combined on the stage. Later in the eighteenth century the artist and stage designer Philippe Jacques de Loutherbourg combined picturesque painting aesthetics with theatrical design in works such as The Wonders of Derbyshire in 1779 (McGillivray 136). It was a short step to shift the onstage scene outside. Theatricality was invoked when pictorial principles were applied three dimensionally; gardens became sites for pastoral genre scenes that ambiguously positioned their visitors both as spectators and actors. Theatrical SceneryGardens and theatres were explicitly connected. Like “theatre,” the word “garden” was sometimes used to describe a collection, in book form, which promised “a whole world of items” which was not always “redeemable” in “straightforward ways” (Hunt, Gardens 54–55). Theatrum mundi could be emblematically expressed in a garden through statues and architectural fabriques which drew spectators into complex chains of associations involving literature, art, and society, as they progressed through it.In the previous century, writes John Dixon Hunt, “the expectation of a fine garden [. . .] was that it work upon its visitor, involving him [sic] often insidiously as a participant in its dramas, which were presented to him as he explored its spaces by a variety of statues, inscriptions and [. . .] hydraulically controlled automata” (Gardens 54). Such devices, which featured heavily in the Italian baroque garden, were by the mid eighteenth century seen by English and French garden theorists to be overly contrived. Nonetheless, as David Marshall argues, “eighteenth-century garden design is famous for its excesses [. . .] the picturesque garden may have aimed to be less theatrical, but it aimed no less to be theater” (38). Such gardens still required their visitors’ participation and were designed to deliver an experience that stimulated the spectators’ imaginations and emotions as they moved through them. Theatrum mundi is implicit in eighteenth-century gardens through a common idea of the world reimagined into four geographical quadrants emblematically represented by fabriques in the garden. The model here is Alexander Pope’s influential poem, “The Temple of Fame” (1715), which depicted the eponymous temple with four different geographic faces: its western face was represented by western classical architecture, its east face by Chinese, Persian, and Assyrian, its north was Gothic and Celtic, and its south, Egyptian. These tropes make their appearance in eighteenth-century landscape gardens. In Désert de Retz, a garden created between 1774 and 1789 by François Racine de Monville, about twenty kilometres west of Paris, one can still see amongst its remaining fabriques: a ruined “gothic” church, a “Tartar” tent (it used to have a Chinese maison, now lost), a pyramid, and the classically inspired Temple of Pan. Similar principles underpin the design of Jardin (now Parc) Monceau that I discuss below. Retz: Figure 1. Tartar tent.Figure 2. Temple of PanStowe Gardens in Buckinghamshire has a similar array of structures (although the classical predominates) including its original Chinese pavillion. It, too, once featured a pyramid designed by the architect and playwright John Vanbrugh, and erected as a memorial to him after his death in 1726. On it was carved a quote from Horace that explicitly referenced the dramaturgical version of theatrum mundi: You have played, eaten enough and drunk enough,Now is time to leave the stage for younger men. (Garnett 19) Stowe’s Elysian Fields, designed by William Kent in the 1730s according to picturesque principles, offered its visitor two narrative choices, to take the Path of Virtue or the Path of Vice, just like a re-imagined morality play. As visitors progressed along their chosen paths they would encounter various fabriques and statues, some carved with inscriptions in either Latin or English, like the Vanbrugh pyramid, that would encourage associations between the ancient world and the contemporary world of the garden’s owner Richard Temple, Lord Cobham, and his circle. Stowe: Figure 3. Chinese Pavillion.Figure 4. Temple of VirtueKent’s background was as a painter and scene designer and he brought a theatrical sensibility to his designs; as Hunt writes, Kent particularly enjoyed designing “recessions into woodland space where ‘wings’ [were] created” (Picturesque 29). Importantly, Kent’s garden drawings reveal his awareness of gardens as “theatrical scenes for human action and interaction, where the premium is upon more personal experiences” and it this spatial dimension that was opened up at Stowe (Picturesque 30).Picturesque garden design emphasised pictorial composition that was similar to stage design and because a garden, like a stage, was a three-dimensional place for human action, it could also function as a set for that action. Unlike a painting, a garden was experiential and time-based and a visitor to it had an experience not unlike, to cautiously use an anachronism, a contemporary promenade performance. The habit of imaginatively wandering through a theatre in book-form, moving associatively from one item to the next, trying to discern the author’s pattern or structure, was one educated Europeans were used to, and a garden provided an embodied dimension to this activity. We can see how this might have been by visiting Parc Monceau in Paris which still contains remnants of the garden designed by Louis Carrogis (known as Carmontelle) for the Duc de Chartres in the 1770s. Carmontelle, like Kent, had a theatrical background and his primary role was as head of entertainments for the Orléans family; as such he was responsible for designing and writing plays for the family’s private theatricals (Hays 449). According to Hunt, Carmontelle intended visitors to Jardin de Monceau to take a specific itinerary through its “quantity of curious things”:Visitors entered by a Chinese gateway, next door to a gothic building that served as a chemical laboratory, and passed through greenhouses and coloured pavilions. Upon pressing a button, a mirrored wall opened into a winter garden painted with trompe-l’œil trees, floored with red sand, filled with exotic plants, and containing at its far end a grotto in which supper parties were held while music was played in the chamber above. Outside was a farm. Then there followed a series of exotic “locations”: a Temple of Mars, a winding river with an island of rocks and a Dutch mill, a dairy, two flower gardens, a Turkish tent poised, minaret-like, above an icehouse, a grove of tombs [. . .], and an Italian vineyard with a classical Bacchus at its center, regularly laid out to contrast with an irregular wood that succeeded it. The final stretches of the itinerary included a Naumachia or Roman water-theatre [. . .], more Turkish and Chinese effects, a ruined castle, yet another water-mill, and an island on which sheep grazed. (Picturesque 121) Monceau: Figure 5. Naumachia.Figure 6. PyramidIn its presentation of a multitude of different times and different places one can trace a line of descent from Jardin de Monceau to the great nineteenth-century World Expos and on to Disneyland. This lineage is not as trite as it seems once we realise that Carmontelle himself intended the garden to represent “all times and all places” and Pope’s four quadrants of the world were represented by fabriques at Monceau (Picturesque 121). As Jardin de Monceau reveals, gardens were also sites for smaller performative interventions such as the popular fêtes champêtres, garden parties in which the participants ate, drank, danced, played music, and acted in comedies. Role playing and masquerade were an important part of the fêtes as we see, for example, in Jean-Antoine Watteau’s Fêtes Vénitiennes (1718–19) where a “Moorishly” attired man addresses (or is dancing with) a young woman before an audience of young men and women, lolling around a fabrique (Watteau). Scenic design in the theatre inspired garden designs and gardens “featured prominently as dramatic locations in intermezzi, operas, and plays”, an exchange that encouraged visitors to gardens to see themselves as performers as much as spectators (Hunt, Gardens 64). A garden, particularly within the liminal aegis of a fête was a site for deceptions, tricks, ruses and revelations, assignations and seductions, all activities which were inherently theatrical; in such a garden visitors could find themselves acting in or watching a comedy or drama of their own devising. Marie-Antoinette built English gardens and a rural “hamlet” at Versailles. She and her intimate circle would retire to rustic cottages, which belied the opulence of their interiors, and dressed in white muslin dresses and straw hats, would play at being dairy maids, milking cows (pre-cleaned by the servants) into fine porcelain buckets (Martin 3). Just as the queen acted in pastoral operas in her theatre in the grounds of the Petit Trianon, her hamlet provided an opportunity for her to “live” a pastoral fantasy. Similarly, François Racine de Monville, who commissioned Désert de Retz, was a talented harpist and flautist and his Temple of Pan was, appropriately, a music room.Versailles: Figure 7. Hamlet ConclusionRichard Steele, Addison’s friend and co-founder of The Spectator, casually invoked theatrum mundi when he wrote in 1720: “the World and the Stage [. . .] have been ten thousand times observed to be the Pictures of one another” (51). Steele’s reiteration of a Renaissance commonplace revealed a different emphasis, an emphasis on the metaphor’s spatial and spectacular elements. Although Steele reasserts the idea that the world and stage resemble each other, he does so through a third level of abstraction: it is as pictures that they have an affinity. World and stage are both positioned for the observer within complementary picture frames and it is as pictures that he or she is invited to make sense of them. The formalist version of theatrum mundi invokes a spectator beholding the world for his (usually!) pleasure and in the process nature itself is transformed. No longer were natural landscapes wildernesses to be tamed and economically exploited, but could become gardens rendered into scenes for their aristocratic owners’ pleasure. Désert de Retz, as its name suggests, was an artfully composed wilderness, a version of the natural world sculpted into scenery. Theatrum mundi, through the aesthetic category of the picturesque, emerged in English landscape style and effected a theatricalised transformation of nature that was enacted in the aristocratic gardens of Europe.ReferencesAddison, Joseph. The Spectator. No. 414 (25 June 1712): 67–70. Eighteenth Century Collections Online.Garnett, Oliver. Stowe. Buckinghamshire. The National Trust, 2011.Hays, David. “Carmontelle's Design for the Jardin de Monceau: A Freemasonic Garden in Late-Eighteenth-Century France.” Eighteenth-Century Studies 32.4 (1999): 447–62.Heidegger, Martin. The Question Concerning Technology and Other Essays. Trans. William Lovitt. New York: Harper and Row, 1977.Hunt, John Dixon. Gardens and the Picturesque: Studies in the History of Landscape Architecture. Cambridge, Massachusetts: MIT Press, 1992.———. The Picturesque Garden in Europe. London: Thames and Hudson, 2002.Marshall, David. The Frame of Art. Fictions of Aesthetic Experience, 1750–1815. Baltimore: Johns Hopkins UP, 2005.Martin, Meredith S. Dairy Queens: The Politics of Pastoral Architecture from Catherine de' Medici to Marie-Antoinette. Harvard: Harvard UP, 2011.McGillivray, Glen. "The Picturesque World Stage." Performance Research 13.4 (2008): 127–39.Pope, Alexander. “Epistle IV. To Richard Boyle, Earl of Burlington.” Epistles to Several Persons. London, 1744. Eighteenth Century Collections Online.———. The Temple of Fame: A Vision. By Mr. Pope. 2nd ed. London, 1715. Eighteenth Century Collections Online. Shakespeare, William. As You Like It. Ed. Agnes Latham. London: Routledge, 1991.Steele, Richard. The Theatre. No. 7 (23 January 1720).

Defence date: 2 April 2007
Examining Board: Prof. P. Winand (EUI) ; Prof. B. Stråth (EUI) ; Prof. A. Kersten (University of Leyden) ; Prof. W. Loth (University of Essen)
First made available online 2 August 2018

Das Jahrbuch „Extremismus & Demokratie“ fördert die wissenschaftliche Beschäftigung mit dem Problemkreis des politischen Extremismus in seinen verschiedenen Ausprägungen. Es versteht sich als Diskussionsforum, Nachschlagewerk und Orientierungshilfe zugleich. Der 32. Band dokumentiert, kommentiert und analysiert umfassend die Entwicklung im Berichtsjahr 2019. Aktuelle Schwerpunkte bilden u. a. die Auseinandersetzung mit dem Hufeisenmodell und dem Gebot der Äquidistanz, die linkspopulistische Bewegung #aufstehen, die Autonomiebestrebungen in Schottland, der Islamische Staat, die linksextremistische Interventionistische Linke, eine aktuelle Untersuchung der rechtsextremistischen und rechtsterroristischen Akteure in Deutschland sowie eine Ursachsenanalyse der Radikalisierung von Islamisten. Neben Analysen, Daten und Dokumenten findet sich ein umfassender Literaturteil mit Rezensionen der wichtigsten Publikationen zu Fragen von Extremismus und Demokratie in Geschichte und Gegenwart. Mit Beiträgen von Alexander Akel, Uwe Backes, Dirk Baehr, Manuel Becker, Harald Bergsdorf , Klaus von Beyme, Evelyn Bokler-Völkel, Marcel Boldorf, Wilfried von Bredow, Stefan Breuer, Hubertus Buchstein, Juliane Clegg, Philipp Currle, Frank Decker, Norman Domeier, Jost Dülffer, Kristin Eichhorn, Alexander Gallus, Phillipp Gassert, Michael Gehler, Birgit Glorius, Stefan Goertz, Sebastian Gräfe, Bernd Greiner, Katrin Groh, Florian Grotz, Thomas Grumke, Anna-Maria Haase, Jens Hacke, Stephan Hilsberg, Kai Hirschmann, Lukas Hämisch, Thomas Jäger, Helge F. Jani, Hans-Gerd Jaschke, Eckhard Jesse, Ralph Jessen, Thomas Kern, Ilko-Sascha Kowalczuk, Wolfgang Kraushaar, Jakob Kullik, Jürgen P. Lang, Oliver W. Lembcke, Sebastian Liebold, Josefa Loebell, Tom Mannewitz, Miroslav Mareš, Julian Meinelt, Tilman Mayer, Reinhard Mehring, Lazaros Miliopoulos, Werner Müller, Helmut Müller-Enbergs, Herfried Münkler, Beate Neuss, Paul Nolte, Robert Chr. van Ooyen, Torsten Oppelland, Isabelle-Christine Panreck, Anton Pelinka, Armin Pfahl-Traughber, Gert Pickel, Jürgen Plöhn, Kim C. Priemel, Robert Radu, Claudia Ritzi, Gabriel Rolfes, Philp Rosin, Martin Sabrow, Kurt Schilde, Christine Schirrmacher, Mike Schmeitzner, Brigitte Seebacher, Daniel Siemens, Grit Straßenberger, Martina Steber, Roland Sturm, Tom Thieme, Hendrik Thoß, Margarete Tiessen, Heike Tuchscheerer, Daniela Weber, Manès Weisskircher, Bernd Jürgen Wendt, Nikolaus Werz, Gerhard Wettig, Benedikt Wintgens, Sandra Wirth und Samuel Zeitlin.

Antoine Lavoisier was the father of the “chemical revolution”, but the victim of another, the French Revolution. We start with Ben Franklin who was a close friend to Lavoisier and his wife, Marie-Anne. We visit a statue of Franklin in one of most scenic places in all of Paris. After discussing Lavoisier's early career, his involvement with the infamous Ferme Générale, and his “new French Chemistry” in which he replaced phlogistic ideas with his oxidation theory, we visit Lavoisier sites all over Paris – his birthplace, where he was christened, lived, worked, imprisoned, guillotined and is now commemorated. The most important of these is the Musée des Arts et Metiers that has a spectacularly reconstructed Lavoisier Laboratory and a collection of his advanced and beautiful balances. At the end, we briefly describe Lavoisier's successors including Claude Berthollet, Joseph Louis Gay-Lussac, and André-Marie Ampére, their contributions to atomic theory, and sites to visit in Paris, Annecy, and Arcueil. We also describe the Pasteur Museum in the Pasteur Institute as one of the best scientific/historical sites in the world.