Radioaktivität: Was man wissen muss./nEine allgemeinverständliche Darstellung (German Edition)

Zudem ist am April der "March for Science" in Washington geplant. Allerdings fallen die Skeptiker und ggf. Nicht ganz neu also, aber andere Akteure. From my point of view, Klimazwiebel has mainly served a purpose for its authors. Like any blog, this is a kind of diary, in which thoughts and comments are written, which might otherwise have faded. Since we have practiced an extremely liberal moderation, visitors of the blog could also document themselves in a similar way. At first there was a certain enthusiasm, fueled by great Copenhagen , or some shady events climategate.

We also have a multidisciplinary team which made the exchange of perspectives very interesting. It is true that there was less energy, or should I say productivity? Much has been said, over and over again. Did we fail to make an impact? This is difficult to tell. Sometimes ideas have a long-term effect, and people who stopped passing by may have been deeply influenced, in some way.

We are also a multi-lingual blog, with English being the prevalent language, and German coming to the fore much more strongly recently. Sometimes people even commented in Danish or Spanish, adding to the lingo complexity. This provokes the question of cultural and political reference points. The discussions ranged about many global and foreign aspects, by no means restricted to German affairs.

Here lies a problem I want highlight with regard to the discourse dynamics, and the role of Klimazwiebel in it. Edward Elgar , climate skepticism arose in the USA, mainly as a result of its political and institutional structure. Public policy decisions involving science claims normally go through Senate hearings. Here the evidence is elicited by the two parties dominating the proceedings, very much in an adversarial style of cross examination and interrogation. Scientists get drawn into the maelstrom.

Nevertheless, climate skeptical attitudes and statements were covered by the New York Times as normal or neutral for a long time. Things changed as the preparations for the Kyoto Protocol went underway. Ever since then, the term climate skeptic has become a bad word. And it went from bad to worse. Polarization in climate politics led to polarization of climate science, and to politicization of climate science. What has this to do with the Klimazwiebel?

Two things are important. First, in Germany climate skepticism has no public legitimacy. It plays no significant role in parliamentary hearings or media reporting. And in Germany there is no political polarization about climate policy, and not about the science either. This was a body expressing the consensus among science and policy communities which made clear that in climate policies precautionary policies were in order, and that rich Northern countries should lead. That skeptics in Germany, or on the blogosphere, have won the day? And skepticism about what?

About the science, or about the policy questions? I very much doubt any of these assertions, apart from the first. Trump will support climate skepticism symbolically. How much difference it will make on the ground remains to be seen. US states, cities, companies and citizens have started to move in a direction that might be difficult and imprudent for him to revert. It is these nuanced discussions we used to have here. But maybe no longer, as exhaustion has taken over enthusiasm.

Schon in der Vergangenheit waren Sie oft am Rande oder jenseits des Randes, was akzeptabel ist. Mein Rat an Sie: Oder fragen Sie Ihre Mutter, was Sie meint. Das ist nicht besonders viel. Gefunden habe ich noch: Die hier besonders interessante LT Variante sei aber noch nicht released. Und darum gibt es dazu auch wohl keine Aussage. Auch das ist nicht wirklich das, was Sie vermutlich meinten: Ich sehe keinen Grund, warum ich hier Spencer und Christy nicht folgen sollte.

Ach, gibt es bei WFT noch nicht? Oder vielleicht bei RSS selbst: Aber wir haben doch schon das Ergebnis: Das ist der Grund, warum ich Bodendaten bevorzuge. Ich mag GISS, weil es so benutzerfreundlich ist man kann eigene Maps mit eigenen Baselines erstellen und weil es einen guten polaren Abdeckungsgrad hat. Mir erscheint das ziemlich Sinn frei, aber evt. Indirekt hat es doch etwas mit dem Artikelthema zu tun. In Skeptikerblogs wird gerne so getan, als sei UAH 6.

Sustainable use of KLIMAZWIEBEL

Darauf wollte ich Herrn Landvoigt aufmerksam machen. Dort darf ich aber nichts schreiben. Da ist die Klimazwiebel der einzige Ort, wo ich Herrn Landvoigt direkt ansprechen kann. Da kann sich jeder selbst eine Meinung bilden. Ich denke, Reiner traft den Nagel auf den Kopf.

Ich habe Sie darum gebeten, entsprechende Quellen zu nennen, die hier belastbare Argumente bringen. Sie antworten mit einer argumentfreien angeblichen Meinung anderer. So aber gibt es keinen Grund, argumentfreien Behauptungen zu folgen. Andreas Aber wir haben doch schon das Ergebnis: Also ein akademisches Interesse. Und das stellt dann die Frage nach der Wissenschaft und dem Diskurs. Ohne ins konkrete Beispiel zu gehen, bleiben derartige Diskussionen oft substanzlos. Das Thema, dass Sie hier behandeln ist ja technisch durchaus sehr komplex - und auf diese weise erzeugen Sie nur eine aufgeregte Stimmung, die der Sache nicht gerecht wird.

Warten Sie doch einfach ab, wie sich die wissenschaftliche Diskussion unter Fachwissenschaftlern entwickelt. Aber Sinn macht das kaum. Hans von Storch ' Hans von Storch Sie sind offenbar klimawissenschaftlicher Laie Ich habe auch nichts anderes behauptet. Anscheinend ist das nicht der Fall Hans von Storch Warten Sie doch einfach ab, wie sich die wissenschaftliche Diskussion unter Fachwissenschaftlern entwickelt.

Deswegen habe ich auch bei Spencer nachgelesen Ich hatte den Term 'Honest Broker' eben missverstanden Martin Landvoigt, reagieren Sie da im letzten Abschnitt nicht etwas heftig? Es ist noch mal deutlich gemacht worden, dass man auf der Klimazwiebel sich thematisch ziemlich austoben konnte. Und man kann es auch weiterhin tun, so lange die Seite existiert. Das wird auf einer pluralistischen Plattform nicht funktionieren.

Es gibt einige Alternativen, die mehr oder weniger realistisch sind. Oder ihr macht es auf Primaklima, die perse einen Off-Topic-Thread hat. Oder man richtet hier einen offenen themenfreien Thread ein. Ich kann ihnen das Klimatologie Forum der Wetterzentrale empfehlen.

Ich bin dort selbst auch aktiv. Karten- und Zeitserienanalysen usw. Sie treffen dort auf interessierte Laien, Skeptiker, Meteorologen und Klimaforscher. I have rarely visited this blog and other climate sites for quite some time simply because I believe that the climate issue is not as important any more as compared to other pressing problems: The topic is dead and will remain so as long as measured temps continue to trail the prophesized ones.

A stark indicator for this is that effective mitigation is in a swift process of being replaced by repentence payments to developing countries. But I also think that the Klimazwiebel has become particularly unattractive in recent years. In contrast to e. Judith Curry, there is just a lack of new ideas when it comes to topics raised.

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Yes, Curry may be labeled a sceptic or denier and what not, but her intellectual horizon, her ability to view the climate problem time and again from completely new and unexpected angles, is the complete opposite of what I can read here, where the same concepts and related arguments are being reurgitated since inception in posts and comments.

This is why I most stuck to her site but I never read the comments while abandoning all others more or less. I am tired of witnessing something that does not work: I developed an allergy against this term in recent years. You can't build bridges in public discussions. What builds up in limitless anonymized public discussions is antipathy, inadvertedly. It is a basic human fact. Public discussions have the function to give the public a chance to listen to an exchange of arguments, and decide which side has the better arguments.

It is not and never has been the purpose of public discussions to 'build bridges' between the panelists. The best you can get is a civilized exchange of arguments and rhetoric, and it only stays civilized if the exchange is strictly moderated and limited in length. Unlimited discussions about polarized, existential issues among partly anonymous parties lead to frustrations, anger, and mutual insults - always, inadvertedly. They make no sense.

From that perspective, the entire internet discussion culture is completely useless, and is, in my opinion, the prime reason for the rise of speech that is considered as hateful A nice counterexample was the show 'Pro und Contra' in German TV that unfortunately does not exist any more. Here, the studio audience voted on a divisive topic before and after having listened to two or were it four? That is, in a nutshell, the purpose of public debates. Noone would have expected that the discussants would convince each other, or even like each other more afterwards more than before.

This polit-show was discontinued, and, quite honestly, it would be hard to imagine how it could work in today's consensus-obsessed, no-alternative, 'bridge-building' political climate. A special Klimazwiebel problem is language. Often topics are started in English, but quickly the well-known teutonic zealots take over. What's the point for international visitors to translate those?

My recommendations to revive this blog: Stick to English 2. Only publish a small number of strictly selected comments 3. Limit commenting to 7 days after publication 4. Just publish what you find interesting 5. Forget bridge-building - most pivotal political decisions were not consensus decisions apart from some infamous ones Scientists are started to publishing the results in German, but now the well-known anglo-saxon limeys take over.

Karl Kuhn I wouldt not disqualify people prefering to discuss in German as " teutonic zealots". Not everybody is qualified to learn easily foreign languages, a lot is depending from personal ability, teachers, interest, even the school and its targets, whatever. As well French speaking educated, I read more books in French than in English, job s had more orientation to France and French than to English, seen that at school, sciences has been teached in French biology, physics, chemistry, history, geoghraphy, maths.

Writing, discussing in English is a translting job for me, French and German come directly from brain to tongue. Interessanterweise sinken die Leserzahlen trotzdem nicht unter einen durchaus beachtlichen Schwellenwert. Stattdessen beginnen die Leute wieder alte Artikel zu lesen und sogar zu kommentieren. Ansonsten hier mein Eindruck von der Veranstaltung in Hannover, have Fun: Auf die Aufzeichnung ist bei Tichy auch verlinkt. Podcast oder besuchte Podiumsdiskussion.

Sondern auf deren Interpretation. Schade, nur eine Audiofile von der Veranstaltung. Dann brauchen wir nicht nur Systemwissen. Und es braucht Transformationswissen. Was bewegt Menschen zum Handeln? Was gibt ihnen Vertrauen? Quentin und Hans von Storch Genau zu dieser Thematik aus dem Audiofile und Peters Artikel fand ich die Klimazwiebel immer besonders spannend und auch einzigartig, weil neben dem Naturwissenschaftler HvS auch Ethnologen und Soziologen wie Werner Kraus oder Reiner Grundmann wichtige Einsichten liefern und lieferten aus denen man lernen kann.

Da sind auf der einen Seite die, die im Klimaproblem als eigentliche Ursache den Kapitalismus sehen und die Systemfrage stellen. Das sind Sie, Peter Heller und die allermeisten Skeptiker. Habt keine Angst, vertraut der Mitte. Es ist ja legitim, dass jeder Pol um Mehrheiten ringt. Anpassung an die Begebenheiten. Sie konstruieren daher falsche Sachverhalte. Ohne das die CO2-Emissionen nennenswert abnehmen.

Und die Energiewende wird durch Rohstoffe aus der "3. Kupfer, Lithium, Seltene Erden, etc.. Die Ernten sind so hoch wie noch nie in Mitteleuropa und Deutschland! Eine statistisch signifikante Zunahme von Extremwetter kann bisher nicht beobachtet werden. Auch keine Beschleunigung im Meeresspiegelanstieg und in der Zunahme der Globaltemperatur,trotz global weiter leicht steigender CO2-Emissionen. Die Energiewende in Deutschland wird alleine ca.

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Eiszeiten waren hingegen immer Zeiten der Not. Aber was ist jetzt neu an ihren Argumenten, welche Sie in anderen Diskussionen nicht schon mehrfach genannt haben? Von daher kannte ich wirklich alle Aussagen und Zahlen. Das verstehe ich als Anpassung. Da ich hier im Blog die Fakten noch nicht genannt habe, habe ich sie nochmal zusammengefasst. Damit ist aller Klimaschutz opsolet. So machen es auch die Vulkane. Die Kneipen bestehen weil man dort saufen und labern kann.

Wir haben hier eine Klimakneipe, Klimapizza Pelles Pizza. Und dann weiter um das Vokabular. Radiologie optik und akustik, mechanik und solche Dinge,.. Ich habe es ausgeliefert und "Das Consensus-Buch.. Lindzen war frisch in Erinnerung. Niemand hat es gewagt es aufzumachen. Aber dort wo "Die Bibel" auf dem Schreibtisch oder in der Bibliothek aufgeschlagen liegt, da macht man Science. Jenes ist meine solidste Erfahrung, aber das ist lange her. Wenn man dort "Duden! Denn, da ging es wohl um die soziale Definitions- macht.

Trotzdem spricht man davon. In diesem Sinne spreche ich auch von "Der Klimawissenschaft". Mir ging es aber um etwas anderes, um den immer wiederkehrenden Eindruck einer sogenannten false balance. Was mich immer genervt hat, ist, dass z. QQ mich in seinem Lagerdenken dem Lager der "Alarmisten" zurechnet. Interessiert nicht, der Gegner bin ich schon so. Die skeptische Debatte krankte daran, dass nie zwischen Politik und Wissenschaft unterschieden wurde. Andere politische Ziele verschwammen mit einer anderen, "alternativen" Wissenschaft. Wir sollten aufpassen, dieses falsche Spiel nicht mitzuspielen.

Wir hatten gerade ein paar Mails, die den Unterschied zur hufigen Praxis von flachen unhinterfragten Behauptungen deutlich demonstrieren. Der Hinweis auf "Die Klimawissenschaft gibt es nicht" hat damit zu tun, dass ich auf darauf verweise, dass die Klimawissenschaft ein sozialer Prozess ist.

Wissenschaft soll Zeuge sein in einer Verhandlung und nicht Anklage oder Verteidigung und schon gar nicht Richter. So laufen eben Verhandlungen ab, ob bei Gericht oder Anderswo. Hier frage ich mich schon: Woher kommt diese Angst? Hat eine Zeuge Angst, stimmt irgendwas mit der Verhandlung nicht mehr. Ich denke, der Vergleich mit einer Gerichtsverhandlung hinkt. Uns eine Emotion habe ich noch nie bei HvS erlebt: Es gabe durchaus eine Pause: Ist die Veranstaltung mit Heller und HvS nicht schon lange her?

Soweit ich mich erinnere, waren seine Fragen an Reiner durchaus berechtigt, wenn auch sehr mit dem Holzhammer formuliert. Aber da ist er nicht der einzige, siehe oben -: Denn ebenso wie Adel, so verpflichtet auch Wissen. Nichts desto trotz bedarf es mehr, als nur dessen Behauptung. Ich denke, das ist auch Geschmacksfrage. Wie lautet die Formulierung, die mit weniger als Zeichen auskommt? Aber das hatten wir ja auch schon: Aber wenn es darum geht, ca. Das Papier dazu findet sich im Internet. Concerning the issue of the drift in the Von Storch run: I think this argues for leaving the ECHO-G I curve out of the graphs, and just having one sentence in the text stating this is not shown as it was found to drift, and has been superseded.

It is an outlier that messes up the graph, and if it is known and even acknowledged by its authors that it is a model artifact, why show it in IPCC? Also, from the view of Rahmstorf and I will admit, to me , the other two mails you refer to also make complete sense. According to Rahmstorf, Von Storch criticized the hockeystick based on his paper in which a mistake Irrtum was made the above-mentioned drift.

Correcting that mistake significantly reduced the potential issues with the hockeystick to "maybe the error bars are a little bit bigger, but not much". It is of course possible that Prof. Bam, I do not know where this quote comes from. But let me clarify. We began with implementing the Hockeystick-methodology with subtracting the trend in the data prior to the regression, as is common in statistical analysis.

The simulation with this method was published. Later, it became clear that the hockeystick method used the data with trend, which is statistically rather problematic, because when the trend is strong, as it was in this case, it is merely relating one trend to another regression with one or very few degrees of freedom. Using this ansatz gave better results for our test case, but when we modified the simplest form of assumed noise, from white to red, the old problem reemerged, even when using the trend to guide the regression.

In our original critique, we used the simplest form of noise white , because we got the effect already in this set-up; in the second step, we made the noise a little more complex, namely red, and got the effect with using the trend. Here, one has to recognize that the difference between proxies and geophysical data likely cannot me modelled with a stochastic ansatz, as the variations are likely not made up of random variations with memory. Simulations to this end have also been published: Interessant, auf diesem thread noch einmal in einer Zeitschlaufe zu landen.

Diese Fragen leiteten mein Interesse als Ethnologe hier, und es finden sich viele Posts und Debatten, die ich selbst schon wieder vergessen habe und heute wieder mit Interesse lese. Was man schon alles gedacht und geschrieben hat! Man kann hier in vielen Details den Kampf um die Diskursvorherrschaft in der deutschen Klimaforschung nachverfolgen, mit Hans von Storch als einem der Player mit Einfluss.

Dieses sind nur einige der Prozesse, deren Verlauf mich als Ethnologe und teilnehmenden Beobachter immer fasziniert haben. Wir sind nie modern gewesen: Wenn wir wissen wollen, wer wir auch mal waren zwischen und , und wie das mit der Klimaforschung und der Klimapolitik so geworden ist wie es ist: Den gesamten Sachverhalt um Herrn Storch kann man hier nachlesen: So wird er in der Mail-Datei Michael Mann gibt sich denn auch in Das was hinter den Kulissen mit Herrn von Storch passiert ist, ist auch mit anderen sog. Aber ich finde, zu einer Bestandsaufnahme bzw.

Ich denke, da hat auch die kleine Zwiebel ihren Beitrag geleistet. Und dazu noch in Deutschland ;-. Wie gesagt, das Thema Trump vs. Klimawissenschaft wird ein spannendes Thema bleiben. Und hier noch eine Studie, die ans Herz der Klimazwiebelanliegen geht: Results from a Randomized National Survey Experiment" http: Wir bedanken uns bei den Klimazwiebel-Autoren.

Sowohl das Set-Up als auch das Ergebnis. We conducted a randomized controlled experiment to test public reactions to six different advocacy statements made by a scientist Klartext, wie weit kann ich gehen in meinem Engagement. Und die Antwort ist ebenso entsetzlich: Ziemlich viel - Wissenschaftler haben Carte Blanche, irgend was zu behaupten. Martin Landvoigt Wir haben diese Frage an verschiedenen Stellen hier kontrovers diskutiert.

Mir sind immer die Menschen lieber, die klare Ich-Botschaften senden. Ich muss deren Meinung ja nicht teilen, aber diese Menschen wirken auf mich authentisch und ehrlich. Was sonst treibt einen James Hansen an? Damit will ich auf keinen Fall eine Hansen-Diskussion anfangen. Wenn sich das IPCC z. Denn das sei etwa "politisch Der Vorwurf ist leicht, der Nachweis schwieriger. Aber das praktische ist, dass Sie und M.

Landvoigt dann automatisch auf der richtigen Seite stehen. Mir fehlt auch die Lust. Martenstein war mal ein Thema hier. Vielmehr gebrauche ich Ideologie normalerweise synonym zur Weltanschauung. Ich denke, dass dies zum Teil sehr wohl erkennbar ist. Nicht wegen der Inhalte, die in Kontrast zur eigenen Ansicht stehen, sondern in der Argumentationsweise. Doch was machen Sie jetzt mit dieser Antwort? Doch welche Schlussfolgerung will man jetzt daraus ziehen? Eine Bindung an eine Weltanschauung - auch eine 'wahre' - kann dieses Ideal verletzen, muss es aber nicht.

Die Gefahren liegen an zwei Stellen: Ferner muss auch deutlich werden, dass der Grad der Gewissheit des Expertenurteils nicht dem eines robusten Beleges gleicht. Statt dessen wird oft ein gegenteiliger Ansatz verfolgt: Man kann Irrtum im Erkenntnisprozess auch als Rauschen auffassen. Das wird durch eine weitere andere Irrtumswahrscheinlichkeit nicht ausgesetzt. A medieval marketplace was what the Zwiebel felt like at its best. Not the metaphorical campfire, which as been also evoked multiple times or the regular's table.

That are the other blogs, where commenters get pats on their backs in return for patting others and mocking the stupid evil Others who won't be allowed in or very quickly leave voluntarily. You would stroll the place that was populated with familiar faces, weird wizards, funny clothed people from foreign lands, clowns, wise men hardly any women though and shady crooks.

You could listen in to the elaborations of masters of occult practices such as "regularized optimal fingerprinting" or "multitapering" the series of time. While still contemplating whether that could possibly hold any practical value you would nod in passing to the snake oil merchant and end up in the fortune teller's tent. While knowing for sure that he is a fraud you would still listen and who knows, there could be entertainment and psychological know-how to be had. And on your way home you'd get drawn into a philosopher's dispute carried out among the disciples of deconstruction who believe that there is no such thing as objective reality.

The atmosphere was not one of cushy coziness. On the contrary, you would walk among a crowd that included spies from evil powers that are set to destroy the Earth, bring about eco-fascist global dictatorship and who eat little children. And of course there was the occasional brawl with low kicks, hair-pulling an biting to keep you martial-art skills up to snuff. The general attitude among the regulars however was one of learning.

When all went well, serious effort was spent to put aside ideological disagreements and hatred to make room for trying to understand. That probably never ever worked in the sense of convincing anybody that "the other side" was right after all. I am sure that nobody moved from "warner" to "skeptic", or vice versa, because of participation on the Zwiebel or in any other other blog. That is not a failure. That is an important result.

And, astonishingly, that would work to some extent even if that meaning attached to a concept would still differ from that of your counterpart. Even if my idea about the nature of scientific activity and its results is still diametrically opposed to that of Reiner Grundmann, I still have integrated the idea of "construction of scientific facts" into my view of the world and realize that there is a rich scholary tradition behind these words that might be worthwhile exploring.

Of course there was also reward in the form of mutual agreement "against" the Others. But I think that was often based on a more refined understanding of how the Others are wrong than in other environments. Sometimes it was quite surprising too see that the perception of even fine details and subtle nuances of an argument could be shared among semi-anonymous strangers; Andreas comes to mind. I am grateful to the hosts of the Zwiebel that they spent considerable time to hold up and sometimes enforce the Marktfrieden.

The modest moderation activity was only a small part of it. Sometimes Hans von Storch's demands at polite and correct wording seemed overly picky but in retrospect I believe that insisting on form actually helped quite a bit to keep the content of posts from degenerating. More important were the Zwiebel-Team's input in the form of interesting and often enough provocative articles and very importantly their participation in the comment section. It might not be politically correct, but I believe that their scholary credentials and authority and living up to them helped a lot.

With HvS and Eduardo Zorita as hosts there was an implicit expectation that science-nonsense would not remain uncommented, mostly. Werner Krauss and Reiner Grundmann would frequently call out kitchen-philosophical elaborations and provide pointers to the real stuff. In particular I am very grateful to Werner in that respect.

He even made me buy books. It is nice to hear from some of the Zwiebel-hosts that they could draw some professional benefits from their blogging activity and I hope that they will embark on similar projects in the future. I agree with previous comments that the Zwiebel's mission seems to be over because the rest of the world has changed. The main talking points that were motivated by actual events in have become folklore by now. Memory of climate modelers who would actually demand a particular policy by authority of their scientific results has faded.

While the interpretations of "Climategate" in both camps are still the opposite of each other, nothing new can be analyzed or interpreted into that event. It is all repetition. Follow-up foci that I would be interested in, such as "what about policy prescriptions by economists who mainly seem to publish in the WSJ", or "how does research-agenda setting happen" are not in the Zwiebel's realm. For me that changes things quite a bit. Previously, I would just accept Reiner placing an article by David Rose next to a Guardian piece and resisting any judgment about journalistic quality or truth content, because that would appear to be just part of his method to analyze the finer details of media coverage.

Today, I am also concerned about a different kind of anthropogenic climate change , I return Bruno Latour and borrow Hannah Arendt. The strategies and mechanisms we have seen with regard to climate change now point well beyond this topic. That would be interesting to discuss, but such a discussion would require, for example, that an analogy between Breitbart and J. Curry can be stated and analyzed and that there was consensus about Rose's article being pure, wrong, unwanted propaganda. I don't think that would work on Klimazwiebel.

So in a way I am not happy with the Zwiebel's terms of the Marktfrieden anymore as it will only allow discussions that I perceive as rather besides the point, today. Anyway, thanks again to the hosts for pulling that through for so long. Klimazwiebel should be long-term archived someplace reliable not Google ; it might well be quite interesting for future social scientists. Habe nie verstanden warum. Mein Pseudonym hier ist ein nobody-Name, der echte "Andreas" ist ebenfalls ein nobody.

Ok, war ein seltsamer Satz -- nimm es einfach mal als Kompliment. Vor allem weil "Karl Kuhn" ja auch nicht weniger anonym ist als "Andreas". So interessant das Schreiben im Netz auch ist, ich finde es genauso unergiebig Entweder als Abend- oder Wochenendveranstaltung. Es kann auch dazu dienen, des Gesagte leichter wahrnehmen. Diskussionsbretter bestellen, die vom Boxbetreiber als Pakete verpackt verteilt wurden und mit geeigneter Software dann jeweils diesen Brettern zugeordnet wurden, gelesen und beantwortet werden konnten.

Auch die Mailbox Betreiber organisierten Treffen mit den Usern und anderen Boxen der Region, die immer reichlich besucht waren und wo man sich austauschte und diskutierte. Es war alles viel weniger anonym. Ich nehme das alles mal zur Kenntnis Und? Hr von Storch Ich habe Sie naher untersucht und kann Charakter setzen: Waldsterben, da bin ich wohl ziehmlich einig. Ich war da und habe es untersucht. Und festgestellt dass man vor allem falsch bewirtschaftet. Die Fichte Picea exelsa ist der Baum des Friedens und eher sozial.

Dazu noch, man kann nicht ein wilder Baum in nur Generationen in eine Ackerpflanze verwandeln. Daran liegt es auch. Der Wald wuchert in Deutschland habe ich gesagt, aber man nennt in "unkraut" Weide und Erle und Pappelholz ist auch sehr wervoll. Alarmismus, das kommentiere ich nicht. Ich alarmiere selbst und lasse mich weniger alarmieren.

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Aber ich habe eher den klaaren Eindruck dass solche Alarmisten kaum Ernst zu nehmen sind, weil sie die resultatlosen Forscher sind. Aber bei Klima wissen Sie weniger. Der Hiatus war Wunschdenken und Aberglaube. Sonst braucht man nur die Daten sehen, 0. Ob man Heute schon dringend was unternehmen sollte? Ja, das denke ich, aber einsichtsvoll bitte. Ob man sich richtig und klug in East Anglian University benommen hat? Sie waren, und sind eher die besseren. Ordnung muss sein, ganz klaar. Aber bei welchen Sachen und auf welche Ebene?

Ich bin klug und weisse, heisst das auf Deutsch. Ich habe vorgeschlagen und behauptet dass King Donald der schreckliche soviel wie Holbergs politische Kannengieser ist, jenes ergab sich sogar in Hamburg. Dazu noch "USA ist pleite". Mit Umwelt und allem. Ihr haupt-motiv ist wohl klar zu erkennen. Putin ist neulich auf Franz Josefs Land gewesen und ist da klimasurrealist geworden.

Hans von Storch wird nie zugegeben, dass er politisch falsch lag, dass er versagte, dass er die falschen angriff. Seine und Stehrs Arbeit War schlicht falsch. Mehr als 20 Jahre Forschung auf Basis einer Illusion. Wie konnte das passieren? Ingolf Gut zu wissen Ek heb mol en Hamborger Viermaster seen Und der politische Kannengiesser schon wieder los in Hamburg Wann will die Menschheit auch noch die Humaniora Ernst nehmen und was davon lernen?

Ich frage mich, warum das nicht erfolgt? Das Gute an der Klimazwiebel fand ich war, dass man aus naturwissenschaftlicher Sicht zumindest mal Aspekte aus der Soziologie herangezogen hat und nicht immer gleich sagte, iiiiiiiiih, Geisteswissenschaften Entschuldigung, Herr Krauss ;. Vielleicht mal ein anderes Thema. Sich als Wissenschaftler politisch zu engagieren ist die eine Seite, Wissenschat u. Man ist von der Seege- brunst besessen. Are provided for asthma processes and products for molecular detection of a genetic susceptibility of people.

The present invention relates to the identification and characterization of conditions associated with asthma, biallelic marker in a FLAP encoding gene, as well as identification of associated with asthma, significant polymorphisms. The identified polymorphisms are used to design assays for reliable detection of genetic susceptibility to asthma. They can be used for the development of protocols for screening for drugs also to provide an accurate and efficient evaluation of the therapeutic potential and the potential for side effects of new or existing drugs.

Before the invention is described in more detail, the following definitions are set forth to illustrate the meaning and scope of the terms used to describe the invention herein and defined. Further, in the case of a genomic sequence, the FLAP gene includes native regulatory regions which control the expression of the coding sequence of the FLAP gene. The term "nucleotide" is also used herein as a noun and refers to individual nucleotides or a plurality of nucleotides that are the same meaning a molecule or individual unit in a larger nucleic acid molecule, comprising a purine or pyrimidine, a ribose or deoxyribose sugar moiety and a phosphate group, or in the case of nucleotides within an oligonucleotide or polynucleotide a phosphodiester bond.

The term "nucleotide" as used herein further includes "modified nucleotides" which comprise at least a modification in the form of a an alternative linking group, b an analogous form of purine, c an analogous form of pyrimidine or d comprise an analog sugar. For examples of analogous linking groups, purine, pyrimidine and sugar for example, see PCT publication no.

The polynucleotide sequences of the invention can be prepared by any known method, including synthetic production thereof, a recombinant production, ex vivo generation, or a combination, as will be prepared by techniques known purification methods as well using any. The purity or homogeneity of a polynucleotide may be indicated by a number of means known in the art, such as agarose or polyacrylamide gel electrophoresis of a sample, followed by visualizing a single Polynukleotidbande by staining of the gel.

For certain purposes higher resolution can be provided by using HPLC or other means known in the art. This term also does not represent a specification of polypeptides or shoots postexpressionale modifications of polypeptides from. For example, polypeptides comprising covalently bound glycosyl groups, acetyl groups, phosphate groups, lipid groups and the like, specifically encompassed within the term polypeptide.

Further polypeptides encompassed by the definition of what a or more analogs of an amino acid not including, for example, naturally occurring amino acids only in an order unrelated biological system naturally occurring amino acids, modified amino acids from mammalian systems etc. The term "purified" is used herein to describe a polypeptide of the invention, which, however, not limited by other compounds comprising on, nucleic acids, lipids, carbohydrates and other proteins, was separated. The purity or homogeneity of the polypeptide is indicated by a number of well known means in the art, such as agarose or polyacrylamide gel electrophoresis of a sample, followed by visualizing a single polypeptide by staining of the gel.

For certain purposes higher resolution can be provided by using HPLC or other well-known in the art means. The term "recombinant polypeptide" is used herein to refer to polypeptides that have been artificially designed and comprise at least two polypeptide sequences that do not occur as consecutive polypeptide sequences in their initial natural environment, or be used to refer to polypeptides which are expressed from a recombinant polynucleotide were. Antibodies comprise the binding domains comprising recombinant proteins as well as fragments, including Fab, Fab ', F ab 2 -, and F ab' 2 fragments.

As used herein, an "antigenic determinant" means that part of an antigen molecule, in this case a FLAP polypeptide, that determines the specificity of the antigen-antibody reaction. An "epitope" refers to an antigenic determinant of a polypeptide. An epitope may comprise a lower limit of amino acids of up to 3 amino acids in a spatial conformation which is unique to the epitope. Generally, an epitope consists of at least 6 such amino acids, and usually such a greater degree of at least 8 to 10 amino acids.

A method for determining an epitope-forming amino acids include X-ray crystallography, two-dimensional nuclear magnetic resonance, and epitope mapping, z. Mario Geysen et al. On the present description of time, the term "nucleotide sequence" to the indifferent designation of a polynucleotide or a nucleic acid can be used.

More specifically, the term "nucleotide sequence", the nucleic material itself and is thus not restricted to the sequence information ie, the sequence of letters which is selected from the initials of the four bases that characterizes a specific DNA or RNA molecule biochemically. The term "upstream" is used herein to refer to a location which is toward the 5 'end of the polynucleotide from a specific reference point. This term is applied to polynucleotide pairs only on the basis of their sequences and not due to a particular set of conditions under which the two polynucleotides actually bind.

The term "allele" is used herein to refer to variants of a nucleotide sequence. Diploid organisms may be homozygous or in respect of an allelic form to be heterozygous. A "promoter" refers to a DNA sequence which is recognized by the synthetic machinery of the cell, and is required to initiate the specific transcription of a gene. A sequence which is "operably linked" to a regulatory sequence such as a promoter means that said regulatory element is located relative to the nucleic acid at the right place and in the correct orientation to the initiation of RNA polymerase as well as the to control expression of the nucleic acid of interest.

As used herein, the term "operatively linked" means a linkage of polynucleotide elements in a functional relationship. Thus, a promoter or enhancer is, for example, operably linked to a coding sequence if it affects the transcription of the coding sequence. The term "primer" denotes a specific oligonucleotide sequence which is complementary to a target nucleotide sequence and used to hybridize to the target nucleotide sequence.

A primer serves as an initiation site for either DNA polymerase, RNA polymerase or reverse transcriptase-catalyzed nucleotide polymerization. The term "probe" denotes a defined nucleic acid segment or nucleotide analog segment, z. To be in genetic studies of benefits, a genetic marker should have an adequate level of heterozygosity to allow a reasonable probability that a randomly selected individual is heterozygous. The term "genotype" is used herein to refer to the identity existing in an individual or in a sample alleles. Im Rahmen der vorliegenden Erfindung bezeichnet ein Genotyp bevorzugt die Beschreibung der in einem Individuum oder in einer Probe vorhandenen biallelischen Markerallele.

In the present invention, a genotype preferably refers to the description of the present in an individual or in a sample of biallelic marker alleles. The term "genotyping" a sample or an individual for a biallelic marker consists of determining the specific allele carried by an individual or specific nucleotide at a biallelic marker. The term "haplotype" refers to a combination of alleles, which is present in an individual or in a sample.

In the present invention, a haplotype preferably refers to a combination of biallelic marker alleles which are found in a given individual and can be associated with a phenotype. The term "polymorphism" is used herein to refer to the occurrence of two or more alternative genomic sequences or alleles between or among different genomes or individuals.

A "polymorphic site" is the locus at which the variation occurs. Ein Einzelnukleotidpolymorphismus ist der Austausch eines einzelnen Basenpaares. A single nucleotide is the exchange of a single base pair. Typischerweise handelt es sich bei einem Einzelnukleotidpolymorphismus um den Austausch eines Nukleotids durch ein anderes Nukleotid an der polymorphen Stelle. Typically, in a single nucleotide to facilitate the exchange of one nucleotide by another nucleotide at the polymorphic site.

Die Deletion eines einzelnen Nukleotids oder die Insertion eines einzelnen Nukleotids haben ebenfalls Einzelnukleotidpolymorphismen zur Folge. The deletion of a single nucleotide or insertion of a single nucleotide also have single nucleotide polymorphisms result. Typischerweise kann die polymorphe Stelle in unterschiedlichen Genomen oder in unterschiedlichen Individuen von zwei unterschiedlichen Nukleotiden besetzt sein.

Typically, the polymorphic site may be occupied in different genomes or in different individuals from two different nucleotides. Jeder biallelische Marker entspricht daher zwei Formen einer in einem Gen umfassten Polynukleotidsequenz, welche, wenn sie miteinander verglichen werden, an einer Position eine Nukleotidmodifikation zeigen. Typically, the Nukleotidmodifikation comprises the substitution of one nucleotide by another for example C instead of T.

As used herein, the terminology "defining a biallelic marker" means that a sequence includes a polymorphic base from a biallelic marker. The a biallelic marker defining sequences may be in accordance with their intended use of any length, provided that they contain a polymorphic base from a biallelic marker. The sequence has a length between 1 and nucleotides, preferably between 5, 10, 15, 20, 25, or 40 and nucleotides, and more preferably a length between 30 and 50 nucleotides. Preferably, the defining a biallelic marker include a polymorphic base sequences, which is selected from the group consisting of the biallelic markers A1 to A In some embodiments, the biallelic markers include a defining sequences one of the sequences, which is selected from the group consisting of P1 to P Similarly, the term "marker" or "biallelic marker" requires that the sequence is of sufficient length to the polymorphic allele in an appropriate manner although not necessarily unambiguously identify which usually has a length of at least 4, 5, 6, 10 implies 15, 20, 25 or 40 nucleotides.

The invention further relates FLAP -related biallelic marker properties that are associated with asthma. The location of nucleotides in a polynucleotide with respect to the center of the polynucleotide described herein in the following manner. Includes a polynucleotide has an odd number of nucleotides, the nucleotide is considered equidistant from the 3 'and 5' ends of the polynucleotide as "at the center" of the polynucleotide, and any nucleotide which is immediately adjacent to the nucleotide at the center or the nucleotide at the center itself is considered "viewed within a nucleotide from the center" than.

Weist ein Polynukleotid eine gerade Anzahl von Nukleotiden auf, so befindet sich eine Bindung und nicht ein Nukleotid im Zentrum des Polynukleotids. With an odd number of nucleotides in a polynucleotide any of the five nucleotide positions in the middle of the polynucleotide is considered to be within 2 nucleotides from the center of view, etc. Assigns a polynucleotide has an even number of nucleotides, so there is a bond and not a nucleotide in the center of the polynucleotide. Consequently, one of the two central nucleotides is considered "viewed within a nucleotide from the center" than, and any of the four nucleotides in the middle of the polynucleotide is considered "viewed within 2 nucleotides from the center" than, etc.

For polymorphisms that include the substitution, insertion or deletion of a nucleotide or several nucleotides, is the polymorphism, allele or biallelic marker is "at the center" of a polynucleotide if the difference between the distance of the substituted, inserted, or deleted polynucleotides of the polymorphism of the 3 ' -end of the polynucleotide and the distance of the substituted, inserted, or deleted polynucleotides of the polymorphism of the 5 'end of the polynucleotide is zero or is a nucleotide.

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If the difference is 0 to 3, then the polymorphism is "viewed from inside of a nucleotide from the center" as viewed. If the difference is 0 to 5, the polymorphism is considered to be "within 2 nucleotides viewed from the center" as. If the difference is 0 to 7, the polymorphism is "considered within 3 nucleotides of the center" as viewed, etc.

The terms "trait" and "phenotype" are used herein interchangeably to refer to any visible, detectable or otherwise measurable property of an organism such as symptoms of a disease or susceptibility to a disease used. Typically the terms "trait" or "phenotype" are used herein to refer to symptoms of a disease or susceptibility to a disease in which the leukotriene pathway is involved, or to designate the responsiveness of an individual to an agent which the leukotriene signaling pathway acts, or to refer to symptoms of, or susceptibility to side effects to an agent out acting on the leukotriene pathway used.

The term "disease in which the leukotriene pathway is involved" refers to a condition which is associated with impairment of the expression, production or cellular response to leukotrienes. Diseases in which the leukotriene pathway is involved include, but are not limited to, such as angina, endotoxic shock, psoriasis, atopic dermatitis, rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, tendonitis, bursitis, ulcerative colitis, allergic bronchial asthma, allergic rhinitis , allergic conjunctivitis, glomerulonephritis, migraine headaches, and especially asthma.

The term "responsiveness to an agent acting on the leukotriene pathway" refers to drug efficacy, including but not limited to, ability to metabolize a compound, to the ability to convert the precursor of a drug into an active drug, and the pharmacokinetics absorption, distribution, elimination and the pharmacodynamics receptor-related of a drug in an individual. In the context of the present invention can be defined to the effect on a drug a "positive responsiveness" means that a reduction in the symptoms which the stand with the disease to be treated or condition to be treated in relation, is included.

In the present invention, a "negative responsiveness" are defined to the effect on a drug that either a positive responsiveness to the drug fails, resulting in no reduction in symptoms, or an observed at the administration of the drug following side effect is comprises ,. The treatment with agents acting on the leukotriene pathway, related side effects is preferably an acute exacerbation of inflammatory diseases such as asthma, infection and headache, and more preferably by an increase in transaminase levels in the Liver.

The term "agent acting on the leukotriene pathway" preferably refers to a drug or a compound which modulates the activity or concentration of any enzyme or regulatory molecule involved in the leukotriene pathway of a cell or animal. Further, "agent acting on the leukotriene pathway" refers to compounds that modulate the formation and action of leukotrienes.

Einige der vorstehend zitierten Verbindungen sind in den Some of the compounds cited above are in the US Patenten 4,, US patents 4,, ,. The term "individual" is used herein to refer to vertebrates, particularly members of the mammalian species, and includes but is not limited to, pets, sports animals, laboratory animals, primates and humans. Bevorzugt ist ein Individuum ein Mensch. Preferably an individual is a human. Varianten und Fragmente Variants and fragments. The invention also discloses variants and fragments of the polynucleotides described herein, particularly a FLAP gene containing one or more of the biallelic markers described in the invention.

Varianten von Polynukleotiden, wie der Begriff hierin verwendet wird, sind Polynukleotide, welche sich von einem Referenzpolynukleotid unterscheiden. Variants of polynucleotides, as the term is used herein, are polynucleotides that differ from a reference. A variant of a polynucleotide may be a naturally occurring variant such as a naturally occurring allelic variant, or it may be a variant for which the natural occurrence is unknown. Such non-naturally occurring variants of the polynucleotide may be made by mutagenesis techniques, including those which are applied to polynucleotides, cells or organisms.

In general, the differences are so limited that the nucleotide sequences of the reference and the variant overall have a high similarity and in many regions are identical. Changes in the nucleotide of a variant may be silent, which means that they do not alter the protein encoded by the polynucleotide amino acids.

However, nucleotide changes may also result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence polypeptide. The substitutions, deletions or additions may comprise a nucleotide or more nucleotides. The variants may be altered in coding or non-coding regions or both regions. Changes in the coding regions may produce conservative or non-conservative amino acid substitutions, deletions or additions produce. In the present invention, particularly preferred embodiments are those in which the polynucleotides encoding polypeptides that retain substantially the same biological function or activity as the mature FLAP protein.

A polynucleotide fragment is a polynucleotide is a sequence having a predetermined nucleotide sequence, preferably the nucleotide sequence of a FLAP gene and variants thereof, with respect to a part of the nucleotide sequence, but not with respect to the entire nucleotide sequence completely matches. The fragment may be a part of an exon or of an intron of a FLAP gene.

It may also be a part of the regulatory sequences of the FLAP gene. Preferably, such fragments comprise the polymorphic base of at least one of the biallelic markers A1 to A28, or the complement thereof. Such fragments can be "free-standing", ie, not be part of other polynucleotides, or be fused to other polynucleotides, or they may be comprised within a single larger polynucleotide of which they form a part or region. However, it may be included within a single larger polynucleotide several fragments.

As representative examples of polynucleotide fragments that may be mentioned which comprises a length of about 4, 6, 8, 15, 20, 25, 40, 10 to 20, 10 to 30, 30 to 55, 50 to , 75 to or to nucleotides possess. It is understood of course that the polynucleotides P1 to P28 to be shorter or longer, although it is preferred that they at least contain the polymorphic base of the biallelic marker which can be located at one end of the fragment. The invention also discloses variants, fragments, analogs and derivatives of the polypeptides described herein, including mutated FLAP proteins. Derartige Varianten werden als innerhalb der Kenntnisse eines Fachmanns liegend angesehen.

Such variants are considered to be within the knowledge of a skilled person. A polypeptide fragment is a polypeptide having a sequence is that with a given polypeptide sequence, preferably thereof with a polypeptide encoded by a FLAP gene polypeptide and variants, consistent in relation to a part of the polypeptide, but not with respect to the entire polypeptide sequence completely. Preferred fragments include those of the active region of the FLAP protein that play a role in the biosynthesis of leukotrienes, and those regions possessing antigenic properties and can be used to generate antibodies against the FLAP protein.

Such fragments can be "free-standing", ie, not be part of other polypeptides or may be fused to other polypeptides, or they may be comprised within a single larger polypeptide of which they form a part or region. However, it may be comprised within a single larger polypeptide multiple fragments. As representative examples of polypeptide fragments of the invention may be mentioned those which have a length of about 5, 6, 7, 8, 9 or 10 to 15, 10 to 20, 15 to 40 or 30 to 45 amino acids. Stringente Hybridisierungsbedingungen Stringent hybridization conditions.

Exemplary and limiting in any way procedures using conditions of high stringency are as follows: Im Anschluss an die Waschschritte sind die hybridisierten Sonden mittels Autoradiographie detektierbar. Following the wash steps, the hybridized probes are detectable by autoradiography. Andere verwendbare Bedingungen hoher Stringenz sind im Fachbereich wohlbekannt, wobei auf die in Sambrook et al. Other useful high stringency conditions are well known in the art, and reference is hereby made to the in Sambrook et al.

These hybridization conditions are suitable for a nucleic acid molecule having a length of about 20 nucleotides. It is needless to say that the hybridization conditions described above, according to the length of the desired nucleic acid in accordance with techniques which are well known in the art need to be adjusted.

The suitable hybridization conditions may for example, according to the book of Hames and Higgins or in Sambrook et al. The terms "percent sequence identity" and "percentage homology" are used interchangeably herein to refer to comparisons between polynucleotides and polypeptides, and determined by comparing two optimally of balanced sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions ie, gaps compared to the reference sequence which does not comprise additions or deletions for optimal alignment of the two sequences may comprise.

The percentage is calculated by determining the number of positions at which the identical nucleic acid base or the identical amino acid residue occurs in both sequences, whereby the number is obtained by matching positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by to yield the percentage of sequence identity. Homology is evaluated using any of a variety of algorithms and programs known in the art for sequence comparisons.

Higgins et al, ; Altschul et al. Karlin und Altschul, ; Altschul et al. Altschul et al, ; Altschul et al. The BLAST programs identify homologous sequences by identifying similar segments, which are referred to herein as "highly rated segment pairs High-scoring Segment Pairs ", between a desired amino acid or nucleic acid sequence and a test sequence which is preferably obtained from a protein or nucleic acid sequence database becomes.

Highest scoring segment pairs are preferably identified by means of an evaluation matrix scoring matrix ie matched , many of which are known in the art. Schwartz und Dayhoff, Hrgs. Schwartz and Dayhoff, eds. The BLAST programs evaluate the statistical significance of all identified, highly rated from segment pairs and select preferred are those segments which satisfy a user-specified threshold of significance, such as a user-specified percent homology. Karlin und Altschul, Genomic sequences of the FLAP.

Although the FLAP gene in pharmaceutical research is highly relevant, we still have a little knowledge regarding the extent and nature of sequence variation in this gene and its regulatory elements. Dixon et al, The complete genomic sequence of FLAP, including its regulatory elements, was not described. The FLAP genomic sequences comprise exons and introns. The derived from the FLAP intronic polynucleotides, nucleic acids can be used as Oligonukieotidprimer or probes to detect the presence of a copy of the FLAP gene in a test sample, or alternatively, to amplify a target nucleotide sequence within the FLAP sequences.

The genomic FLAP nucleic acid comprises 5 exons. Exon 5 starts with the nucleotide at position and ending with the nucleotide at position of the nucleotide sequence of SEQ ID NO. Die Erfindung betrifft ein isoliertes, gereinigtes oder rekombinantes Polynukleotid, umfassend einen Bereich von mindestens 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , oder aufeinanderfolgenden Nukleotiden von SEQ ID Nr. The invention relates to an isolated, purified or recombinant polynucleotide comprising a region of at least 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , , or consecutive nucleotides of SEQ ID NO.

The genomic sequence of the FLAP gene contains both the non-coding 5'-flanking region and in the non-coding 3'-flanking region that border the exons of this gene containing the 5 transcribed region of FLAP regulatory sequences. Polynucleotides which are both at the 5 'end and carry the localized FLAP at the 3' end of the coding region of the regulatory elements of a heterologous polynucleotide of interest can be used in advantageous manner for the control of transcriptional and translational activity, wherein said polynucleotide is related to the regulatory FLAP region heterologous.

Such a polynucleotide may be included in a recombinant expression vector to express the desired polypeptide or the desired nucleic acid in a host cell or in a host organism. Eine weitere Aufgabe der Erfindung ist ein gereinigtes, isoliertes oder rekombinantes Polynukleotid, umfassend einen Bereich von mindestens 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , oder aufeinanderfolgenden Nukleotiden von SEQ ID Nr. Another object of the invention is a purified, isolated, or recombinant polynucleotide comprising a region of at least 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , , or consecutive nucleotides of SEQ ID NO.

The above disclosed polynucleotide that contains the coding sequence of the FLAP gene of the invention can be expressed in a desired host cell or a desired host organism, when this polynucleotide is placed under the control of suitable expression signals. The expression signals may be either the expression signals contained in the regulatory regions of the FLAP gene of the invention, or they may be exogenous regulatory nucleic sequences.

Such a polynucleotide may, when it is placed under the suitable expression signals, may be inserted for its expression in a vector. Kodierende Regionen coding regions. The This invention also embodies isolated, purified, and recombinant polynucleotides encoding a polypeptide comprising a region of at least 6 consecutive amino acids, preferably at least 8 or 10 consecutive amino acids, more preferably of at least 12, 15, 20, 25, 30, 40, encode 50 or consecutive amino acids of SEQ ID NO.

The above disclosed polynucleotide that contains the coding sequence of the FLAP gene may be expressed in a desired host cell or a desired host organism, when this polynucleotide is placed under the control of suitable expression signals. The expression signals may be either the expression signals contained in the regulatory regions of the FLAP gene of the invention, or the signals by contrast, can be exogenous regulatory nucleic sequences.

The terms "polynucleotide" and "recombinant polynucleotide" are used interchangeably herein to refer to linear or circular, purified or isolated polynucleotides that have been artificially designed and comprise at least two nucleotide sequences that do not occur as successive nucleotide sequences in their initial natural environment. In order to study the physiological and phenotypic consequences of a lack of synthesis of the FLAP protein, both at the cellular level and at the level of a multicellular organism, the invention further discloses DNA constructs and recombinant vectors comprising a conditional expression of a specific allele of the FLAP genomic sequence or the FLAP cDNA and furthermore, a copy of this genomic sequence or cDNA, including the substitutions, deletions or additions of one base or more bases with respect to the FLAP nucleotide sequence of SEQ ID Nos.

In a preferred embodiment, the FLAP sequence comprises a biallelic marker of the present invention, preferably one of the biallelic markers A1 to A The present invention embodies recombinant vectors comprising any polynucleotide of the present invention. It is based a first DNA construct which tet on the tetracycline resistance operon of transposon Tn from E.

Such a DNA construct contains seven tet operator sequences from Tn10 tetOP which are linked to a minimal promoter or a 5'-regulatory sequence of the FLAP gene either, said minimal promoter or the regulatory FLAP sequence operatively linked to a polynucleotide is linked of interest, which encodes either for a sense or an antisense oligonucleotide or for a polypeptide, including a FLAP polypeptide or a peptide fragment thereof.

Indeed, a preferred DNA construct comprises both the polynucleotide containing the tet operator sequences and the polynucleotide containing a sequence coding for the tTA or the rTA repressor sequence. In a specific embodiment, the conditional expression DNA construct contains the sequence encoding the mutant tetracycline repressor rTA sequence, wherein expression of the polynucleotide of interest in the absence of tetracycline and induced in its presence turned off. Austauschvektoren DNA constructs allowing homologous recombination: In a preferred embodiment, the DNA construct also comprises a negative selection marker located upstream the nucleotide sequence a or downstream the nucleotide sequence c localized.

Bevorzugt besteht der negative Selektionsmarker aus dem Thymidinkinase tk -Gen Thomas et al.

Preferably, the negative selection marker consists of the thymidine kinase tk gene Thomas et al. Yagi et al, Diese Austauschvektoren werden beispielsweise von Thomas et al. This exchange vectors are, for example, by Thomas et al. The size of the nucleotide sequences a and c is in the range of 1 to 50 kb, preferably from 1 kb to 10 kb, more preferably 2 to 6 kb and most preferably from 2 to 4 KB. These new DNA constructs make use of the site-specific recombination system of the P1 phage.

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Der P1-Phage besitzt eine als Cre bezeichnete Rekombinase, welche spezifisch mit einer 34 Basenpaare umfassenden loxP-Stelle wechselwirkt. The P1 phage possesses a recombinase called Cre which interacts specifically with a 34 base pair loxP site. Die loxP-Stelle ist aus zwei palindromen Sequenzen von 13 bp zusammengesetzt, welche durch eine konservierte Sequenz von 8 bp voneinander getrennt sind Hoess et al. The loxP site is composed of two palindromic sequences of 13 bp, which are separated by a conserved sequence of 8 bp Hoess et al. The induced by the Cre enzyme recombination between the two identical orientation having loxP sites results in deletion of the DNA fragment.

The Cre-loxP system used in combination with a homologous recombination technique has been first described by Gu et al. Briefly, a to be inserted in a targeted location of the genome nucleotide sequence of interest contains at least two loxP sites, which have the same orientation, and are located at the respective ends of a to be excised from the recombinant genome nucleotide sequence.

The Exzisionsereignis requires the presence of the recombinase Cre enzyme within the nucleus of the recombinant host cell. The recombinase can be provided either at the desired time by a incubating the recombinant host cells in a culture medium containing this enzyme, by directly injecting the Cre enzyme in the desired cell, as described by Araki et al. B transfecting the host cell with a vector comprising the sequence coding for the Cre sequence in operative linkage with a functional in the recombinant host cell promoter, wherein the promoter is optionally inducible, and said vector in the recombinant host cell as described by Gu et al.

C introducing a polynucleotide comprising the sequence coding for the Cre sequence in operative linkage with a functional in the recombinant host cell promoter, into the genome of the host cell, wherein the promoter is optionally inducible, and said polynucleotide homologous either by a random insertion event or by a recombination as described by Gu et al. In a specific embodiment of the vector containing by homologous recombination into the FLAP gene sequence to be inserted, the selection marker is constructed in such a way that selectable markers are flanked by loxP sites of the same orientation, it is possible, by treatment by the Cre enzyme, to eliminate, while the inserted by means of homologous Rekombinationsereignises FLAP sequences of interest remain.

Again, you will need two selection markers: Vectors and methods using the Cre-loxP system are described by Zou et al. The sequences defining a recognizable for a recombinase site, such as a loxP site, are preferably within the nucleotide sequence b located at suitable places, which to the nucleotide sequence for which the conditional excision is intended to abut.

In a specific embodiment, two loxP sites are located on each side of the sequence of the positive selection marker to allow its excision at a desired time after the occurrence of the homologous Rekombinationsereignises. In a preferred embodiment of a method using the third DNA construct described above, the excision of the recognizable of the two for a recombinase sites, preferably two loxP sites, polynucleotide fragment flanked due to the presence of a sequence coding for the Cre enzyme sequence operatively to a promoter sequence, preferably an inducible promoter, more preferably a tissue-specific promoter sequence and most preferably is linked to a both inducible and tissue-specific promoter sequence performed within the genome of the recombinant host cell at a desired time, as described by Gu et al.

The presence of the Cre enzyme within the genome of the recombinant host cell may result from the breeding of two transgenic animals, the first transgenic animal bearing the derived FLAP sequence of interest which as described above contains the loxP sites, and the second transgenic animal operatively linked to a suitable promoter sequence carries for Cre coding sequence as described by Gu et al. A spatio-temporal control of the expression of the Cre enzyme can also be achieved by means of a Cre gene-containing adenovirus based vector, thus infection of cells, or is made possible in vivo infection of organs, for delivery of the Cre enzyme, such as from Anton and Graham and Kanegae et al.

The DNA constructs described above may be used to provide a desired nucleotide sequence of the invention, preferably a genomic FLAP sequence or a FLAP cDNA sequence, and most preferably an altered copy of a FLAP genomic sequence or a FLAP cDNA sequence to bring to a predetermined site of the target genome, which either to produce an altered copy of a targeted gene homologous recombination knockout or replacement of a copy of the targeted gene by another copy of which is sufficiently homologous to allow the occurrence of a homologous Rekombinationsereignises homologous recombination knockin.

In a specific embodiment, the above-described DNA constructs for the sensitivity of a FLAP genomic sequence or a FLAP cDNA sequence can which, preferably at least one of the biallelic markers described in the invention at least one from the group consisting of A1 to A28 and the comprises complements thereof selected biallelic markers can be used. Preferred methods using antisense polynucleotide are the by Sczakiel et al.

Methods described , or those methods described in PCT application no. Preferably, the antisense molecule comprises a 3 'polyadenylation signal has been replaced with a self-cleaving ribozyme sequence, such that RNA polymerase II transcripts are produced at their 3' ends without poly A , these antisense polynucleotides to the outlet from the nucleus are not capable as by Liu et al. In a preferred embodiment, these FLAP antisense polynucleotides also comprise a histone stem-loop structure within the ribozyme cassette, to stabilize cleaved transcripts with regard to a 3'-5 'exonucleolytic degradation, such as by Eckner et al.

Biallelic marker of the FLAP gene. The invention also describes FLAP -related biallelic marker is standing, which are associated with asthma. Die Erfindung beschreibt ferner Reihen dieser biallelischen Marker. The invention further describes rows of these biallelic markers. Diese biallelischen Marker sind in Tabelle 2 von Beispiel 3 offenbart.

These biallelic markers are disclosed in Table 2 of Example 3.

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The primer pairs, which allow the amplification of a nucleic acid, the polymorphic base of a biallelic marker FLAP-containing compounds are listed in Table 1 of Example 2. Three biallelic markers, namely A13, A20 and A21, are located in exonic regions. Two of them do not cause modification of the amino acid sequence of the FLAP protein. However, the biallelic marker A20 effected in the FLAP protein exchanging a valine for an isoleucine.

Die Erfindung offenbart ferner eine einen biallelischen Marker definierende Nukleotidsequenz, welche die polymorphe Base von einem der Polynukleotide P1 bis P13, P15 und P17 bis P28 oder der Komplemente hiervon umfasst. The invention further discloses a a biallelic marker defining nucleotide sequence thereof comprises the polymorphic base of one of the polynucleotides P1 to P13, P15 and P17 to P28 or the complements.

Oligonukleotidsonden und -primer Oligonucleotide probes and primers. Besonders bevorzugte Sonden und Primer umfassen einen Bereich von mindestens 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , oder aufeinanderfolgenden Nukleotiden von SEQ ID Nr. Particularly preferred probes and primers comprise a region of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , , or consecutive nucleotides of SEQ ID. Other preferred nucleic acids of the invention include isolated, purified, or recombinant polynucleotides comprising a region of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , or consecutive nucleotides of SEQ ID NO.

Further preferred nucleic acids of the invention include isolated, purified, or recombinant polynucleotides comprising a region of at least 26, 30, 35, 40, 50, 60, 70, 80, 90, , , , or consecutive nucleotides of SEQ ID. Additional preferred probes and primers comprise a region of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , , or consecutive nucleotides of SEQ ID NO.

Thus, the invention further discloses nucleic acid probes or primers which hybridize under the stringent hybridization conditions defined above, specifically with a nucleic acid selected from the group consisting of the nucleotide sequences , , , , is and thereof of SEQ ID NO. Particularly preferred probes and primers comprise a region of at least 12, 15, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, , , , , or consecutive nucleotides of SEQ ID nr.

The present invention also describes oligonucleotides and groups of oligonucleotides for the detection of alleles that are associated with asthma with an associated polymorphism of the FLAP gene. These oligonucleotides can with a FLAP gene, preferably with a polymorphic FLAP gene and more preferably with a region of a FLAP gene comprising the polymorphic site, the basis of which specific alleles are associated with asthma, hybridize.

The oligonucleotides are either as primers for use in various processes, such as DNA amplification and -Mikrosequenzierung, or as probes for DNA recognition in hybridization analyzes of benefits. In some embodiments, the oligonucleotides contain the polymorphic base of a sequence which is selected from the group consisting of P1 to P28 and the complementary sequence thereto. In other embodiments, the oligonucleotides have a 3 'end which is immediately adjacent to a polymorphic base in the FLAP gene, such as a polymorphic base in one of P1 to P28 and the complementary sequence thereto.

In other embodiments, the oligonucleotide is capable of distinguishing between different alleles of a biallelic marker in the FLAP gene, said biallelic marker is selected from the group consisting of A1 to A28 thereof is selected, and the complements. For example, the oligonucleotide for specific hybridization to an allele of a biallelic marker may be capable of comprising thereof one of the biallelic markers A1 to A28 and the complements. In another embodiment, the invention discloses isolated, purified, and recombinant polynucleotides which consist thereof from a range of 8 to 50 consecutive nucleotides of SEQ ID NO.

In one embodiment, the 3 'end of the polynucleotide is within or at least 2, 4, 6, 8, 10, 12, 15, 18, 20, 25, 50, , , , or nucleotides upstream of a FLAP biallelic marker in said sequence or at any other position that is suitable for their intended use in sequencing, amplification or location of novel sequences or markers localized. D1 bis D28 und E1 bis E D1 to D28 and E1 to E B1 bis B17 und C1 bis C In another embodiment, isolated, purified, or recombinant polynucleotides are described which consists of a compound selected from the following sequences or sequence consists essentially of: B1 to B17 and C1 to C In an additional embodiment, the invention polynucleotides comprising comprising a region of at least 12 consecutive nucleotides of SEQ ID NO.

A preferred polynucleotide may be used in a hybridization assay for determining the identity of the nucleotide at a biallelic marker of the FLAP gene. Another preferred polynucleotide may be used in a sequencing or microsequencing assay for determining the identity of the nucleotide at a biallelic marker of the FLAP gene. A third preferred polynucleotide may be used in an enzyme-based mismatch detection assay base mismatch detection assay can be used to determine the identity of the nucleotide at a biallelic marker of the FLAP gene.

A fourth preferred polynucleotide may be comprising a biallelic marker of the FLAP gene used for amplification of a segment of polynucleotides. Optionally, the polynucleotide to a solid support, array, or addressable array may be attached. Gegebenenfalls kann das Polynukleotid markiert sein. Optionally, the polynucleotide may be labeled. The synthesized primers and probes to be "substantially" complementary to a strand of the FLAP gene to be amplified.

The primer sequence need not reflect the exact sequence of the DNA template. Kleineren Fehlpaarungen kann durch Verringerung der Stringenz der Hybridisierungsbedingungen Rechnung getragen werden. Smaller mismatches can be accommodated by reducing the stringency of the hybridization conditions into account. The formation of stable hybrids depends on the melting temperature Tm of the DNA. Preferably, the length of the primers and probes in the range of 10 to nucleotides can, preferably from 10 to 50, 10 to 30, or more preferably are nucleotides.

Shorter primers and probes tend to lack specificity for a target nucleic acid sequence and require the formation sufficiently stable hybrid complexes with the template generally lower temperatures. Longer primers and probes are expensive to produce and can hybridize with himself at times to form hairpin structures. The appropriate length of primers and probes under a particular set of assay conditions may be empirically determined by a skilled person.

The probes are for a number of purposes. The probes can further be used to detect PCR amplification products. In general, the probes to the coding sequences of the FLAP gene are complementary, although probes to introns and regulatory sequences are also provided. Primers and probes may be prepared by any suitable method, including for example, cloning and restriction of appropriate sequences and direct chemical synthesis by a method such as the phosphodiester method according to Narang et al.

The method described below using a solid support. Depending on the type of labeling of the probe, the probe is used for detection of the amplicon Abgangen and generated by the amplification reaction. The probe is not involved in amplification of the target sequence and therefore may need to be left in a "non-extendable" state in which the probe no additional dNTPs can be added. In and of themselves analogs usually are non-extendible, wherein the nucleic acid probes can be brought into a state of non-extendable by modifying the 3 'end of the probe such that the hydroxyl group is no longer capable of participating in an extension.

Beispielsweise kann das 3'-Ende der Sonde mit der Abfang- oder Detektionsmarkierung funktionalisiert werden, wodurch die Hydroxylgruppe verbraucht oder anderweitig blockiert wird. For example, the 3'-end of the probe with the interception or detection mark can be functionalized to give the hydroxyl group consumed or otherwise blocked. Alternativ kann einfach die 3'-Hydroxylgruppe gespalten, ausgetauscht oder modifiziert werden. Alternatively, the 3 'hydroxyl group simply can be cleaved, replaced or modified.

The probes are preferably directly labeled, indirectly labeled such as with isotopes, for example, reporter molecules or fluorescent labels, or such as with biotin to which at a later stage can bind a streptavidin. Labeling techniques for probes are well known in the art.

By examining the presence of the sample indicates the presence or absence of the target DNA sequence can be detected in a given sample. The same markers can be used in primers. Useful labels include, for example, radioactive substances 32 P, 35 S, 3 H, I , fluorescent dyes 5-bromodeoxyuridine, fluorescein, acetylaminofluorene, digoxigenin. Bevorzugt sind die Polynukleotide an ihren 3'- und 5'-Enden markiert. Preferably, the polynucleotides are labeled at their 3 'and 5' ends. Examples of non-radioactive labeling of nucleic acid fragments are described in French Patent no.

FR FR oder von Urdea et al. In addition, the probes may have structural properties which allow signal amplification according to the present invention, where such structural features, for example, branched DNA probes as those described by Urdea et al. EP 0 EP Chiron beschrieben werden. Chiron will be described. Any primers and probes can be conveniently immobilized on a solid support.

Solid carriers are known in the art and include the walls of wells of a reaction tray, test tubes, polystyrene beads, magnetic beads, micro-cellulose strips, membranes, microparticles such as latex particles, red blood cells of sheep or other animals , duracytes and others.

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The "solid phase" is not critical and can be selected by an expert. Suitable methods for immobilizing nucleic acids on solid phases include ionic, hydrophobic, covalent interactions and the like. A "solid phase", as used herein, refers to any material which is insoluble, or can be made insoluble by a subsequent reaction. The solid phase can be chosen for its intrinsic ability to attract the capture reagent and immobilize. Alternatively, the solid phase can comprise an additional receptor which is capable of attracting and immobilizing the capture reagent.

The additional receptor can include a charged substance that is oppositely charged with respect to the capture reagent itself or in terms of a conjugate with the capture reagent charged substance. As yet another alternative can be any specific binding member, the receptor molecule, which is immobilized on the solid phase bound to the solid phase , and which is capable of immobilizing the capture reagent through a specific binding reaction.

The receptor molecule enables the indirect binding of the capture reagent to a solid phase material before the performance of the assay or during the performance of the assay. The solid phase can thus a plastic, derivatized plastic, magnetic or non-magnetic metal, glass or silicon surface of a test tube, a microtiter well, a film, a bead, a microparticle, chip, red blood cells of sheep or other be suitable animals , duracytes, and others known to those skilled configurations. The polynucleotides of the invention can be bound or on a single solid support to a solid support may be immobilized on this individually or in groups of at least 2, 5, 8, 10, 12, 15, 20 or 25 defined polynucleotides of the invention.

In addition, other polynucleotides may be bonded than those of the invention to the same solid support such as a polynucleotide or more polynucleotides of the invention. The invention further describes a method for detecting the presence of a nucleic acid comprising a thereof from the group consisting of SEQ ID Nos. The invention further describes a kit for detecting the presence of a nucleic acid comprising a thereof from the group consisting of SEQ ID Nos.

In a first preferred embodiment of the detection method and kit, the nucleic acid probe or the plurality of nucleic acid probes with a detectable molecule is labeled. In a second preferred embodiment of the detection method and kit, the nucleic acid probe or the plurality of nucleic acid probes has been immobilized on a substrate. In a third preferred embodiment of the detection method and kit, the nucleic acid probe or the plurality of nucleic acid probes comprises either a sequence which C1 is selected from the group consisting of the nucleotide sequences B1 to B17, to C17, D1 to D28, E1 to E28, P1 is selected to P28 or comprises a biallelic marker which is consisting of A1 to A28 or the complements thereto selected from the group.

A plurality of oligonucleotide primers or probes containing substrate can be used either for detecting or amplifying target sequences in the FLAP gene and may be used also for the detection of mutations in the coding or in the non-coding sequences of the FLAP gene. Any polynucleotide provided herein may be attached in overlapping areas or at random locations on the solid support.

Addressable Polynukleotidarrays typically comprise a plurality of different oligonucleotide probes that are coupled to a surface of a substrate in different known locations. Any known in the art technology on addressable arrays can be used for the novel polynucleotides. These arrays may generally be produced using mechanical synthesis methods or light-directed synthesis methods, which comprise a combination of photolithographic methods and Festphasenoligonukleotidsynthese Fodor et al.

The immobilization of oligonucleotide arrays on solid supports has been made possible by the development of a generally known as "Very Large Scale Immobilized Polymer Synthesis" VLSIPS TM designated technology in which typically probes are immobilized in a high density array on a solid surface of a chip. In designing strategies aimed at providing immobilized on solid supports Nukleotidarrays, more design strategies were developed to order and display the oligonucleotide arrays on the chips in an attempt to maximize hybridization patterns and sequence information.

In another embodiment of the oligonucleotide arrays advantageously a Oligonukleotidsondenmatrix for detecting the occurring in the FLAP gene mutations may be used. For this particular purpose, the probes specifically designed to a nucleotide sequence which enables the hybridization of the probes to the genes that carry known mutations either by deletion, insertion or substitution of one nucleotide or of several nucleotides. Technology used were identified.

Consequently, of oligonucleotides, which are complementary to subsequences of the target gene sequence is used, an existing array to determine the identity of the target sequence and Wildtypgensequenz, to measure its size, as well as for the detection of differences between the target sequence and serving as a reference Wildtypgensequenz of the FLAP gene. In such a configuration, called 4L-disk array, a set of four probes A, C, G, T , preferably oligomers of 15 nucleotides implemented is.

In each set of four probes, the perfect complement hybridize more strongly than mismatched probes. Consequently, a target nucleic acid of length L by means of a 4L containing probes on the disk array is screened for mutations, the entire set of probes includes all the possible mutations in the known, serving as a reference wild-type sequence.