Podcasts about microm

Il se présente comme un plombier de l'infiniment petit et nous ouvre de nouveaux horizons à l'échelle nano, micro et méga. Rencontre avec l'un des esprits les plus libres de la recherche française, le physicien Lydéric Bocquet, ou comment passer de la science des ricochets à la friction quantique ?  Faisons des ponts entre notre monde macroscopique et le monde nanoscopique, en compagnie de l'un des esprits les plus inspirants et inspirés de la recherche française : le physicien Lydéric Bocquet, professeur attaché à l'ENS où il dirige l'équipe Micromégas. Il faut dire que Lydéric Bocquet, qui se définit comme un « plombier de l'infiniment petit », ose tout pour percer les mystères de la vitesse d'écoulement des liquides à l'échelle nano, à commencer par l'art et la science des ricochets. Comment faire des ricochets dans l'eau a pu l'entraîner jusqu'à la friction quantique, à faire le lien entre mécanique des fluides et mécanique quantique ? Comment des recherches aussi fondamentales ouvrent tant de pistes encore inexplorées et d'applications inédites pour faire face aux défis environnementaux et énergétiques ?Avec Lydéric Bocquet, directeur de recherche au CNRS et professeur attaché à l'École normale supérieure. Il dirige l'équipe Micromégas à l'ENS, qui combine expériences, théorie et modélisation pour explorer la mécanique intime des fluides et de leurs interfaces, du niveau macroscopique jusqu'aux échelles moléculaires. L'un de ses principaux axes de recherche au cours des dix dernières années est la nanofluidique, la science des flux moléculaires. Lydéric Bocquet a reçu la médaille de l'innovation CNRS 2024.Cette émission est une rediffusion du 10 septembre 2024.

Il se présente comme un plombier de l'infiniment petit et nous ouvre de nouveaux horizons à l'échelle nano, micro et méga. Rencontre avec l'un des esprits les plus libres de la recherche française, le physicien Lydéric Bocquet, ou comment passer de la science des ricochets à la friction quantique ?  Faisons des ponts entre notre monde macroscopique et le monde nanoscopique, en compagnie de l'un des esprits les plus inspirants et inspirés de la recherche française : le physicien Lydéric Bocquet, professeur attaché à l'ENS où il dirige l'équipe Micromégas. Il faut dire que Lydéric Bocquet, qui se définit comme un « plombier de l'infiniment petit », ose tout pour percer les mystères de la vitesse d'écoulement des liquides à l'échelle nano, à commencer par l'art et la science des ricochets. Comment faire des ricochets dans l'eau a pu l'entraîner jusqu'à la friction quantique, à faire le lien entre mécanique des fluides et mécanique quantique ? Comment des recherches aussi fondamentales ouvrent tant de pistes encore inexplorées et d'applications inédites pour faire face aux défis environnementaux et énergétiques ?Avec Lydéric Bocquet, directeur de recherche au CNRS et professeur attaché à l'École normale supérieure. Il dirige l'équipe Micromégas à l'ENS, qui combine expériences, théorie et modélisation pour explorer la mécanique intime des fluides et de leurs interfaces, du niveau macroscopique jusqu'aux échelles moléculaires. L'un de ses principaux axes de recherche au cours des dix dernières années est la nanofluidique, la science des flux moléculaires. Lydéric Bocquet a reçu la médaille de l'innovation CNRS 2024.Cette émission est une rediffusion du 10 septembre 2024.

Nghe trọn sách nói Chàng Ngây Thơ  trên ứng dụng Fonos: https://fonos.link/podcast-tvsn --Về Fonos:Fonos là Ứng dụng âm thanh số - Với hơn 13.000 nội dung gồm Sách nói có bản quyền, PodCourse, Podcast, Ebook, Tóm tắt sách, Thiền định, Truyện ngủ, Nhạc chủ đề, Truyện thiếu nhi. Bạn có thể nghe miễn phí chương 1 của tất cả sách nói trên Fonos. Tải app để trải nghiệm ngay!--Từ khi ra đời, Candide hay chủ nghĩa lạc quan (Candide ou l'optimisme) đã gắn liền với tên tuổi của Voltaire và trở thành một trong những tác phẩm kinh điển cả về văn chương lẫn triết học. Candide luôn có mặt trong tất cả các tuyển tập tác phẩm văn xuôi của Voltaire. Bên cạnh Zadig, Memnon, Micromégas, đây là tác phẩm lừng danh nhất của ông, được đánh giá là tác phẩm văn chương giàu tính triết học nhất mà Voltaire từng viết. Tuyển tập tác phẩm gần đây nhất của tủ sách La Pléiade, được tập hợp dưới cái tên “Romans et contes” (tiểu thuyết và truyện) có 26 tác phẩm, thì Candide được xếp thứ 11, nghĩa là ở vào khoảng giữa, và cũng thường được coi là được viết vào giai đoạn Voltaire đạt đến đỉnh cao của tài năng.Tác phẩm được viết để trả lời cho triết thuyết của Rousseau về Thượng đế và nhất là để phản đối chủ trương của triết gia Leibniz.Câu chuyện bắt đầu với chàng trai trẻ Candide, sống một cuộc sống sung sướng trong một nơi hoàn hảo như thiên đường và được truyền bá tinh thần lạc quan bởi Giáo sư Pangloss (đại diện cho Leibniz). Tác phẩm mô tả sự chấm dứt đột ngột của lối sống này, kéo theo đó là sự vỡ mộng dần dần và đau đớn của Candide khi anh chứng kiến và trải qua những gian khổ lớn lao trên thế giới. Voltaire kết thúc câu chuyện với Candide tin tưởng vào nguyên tắc rằng "chúng ta phải chăm sóc khu vườn của mình", thay cho tư tưởng Leibniz rằng thế giới này là "tốt nhất trong tất cả các thế giới" rồi, và mọi thứ đang diễn ra cũng đều là "tốt nhất có thể".Chống đối một lý thuyết trừu tượng hão huyền, Voltaire đề xuất một hoạt động cho sự vận hành của loài người: chủ động thay đổi thế giới của chúng ta. Quan điểm này được thuật lại bằng những cuộc phiêu lưu thú vị của Candide, cùng sự chối tai khôi hài và lúc nào cũng thấm đượm sự mỉa mai, trào lộng.--Tìm hiểu thêm về Fonos: https://fonos.vn/Theo dõi Facebook Fonos: https://www.facebook.com/fonosvietnam/

Et s'il existait sur notre planète une source d'énergie naturelle que l'être humain n'a pas encore vraiment exploitée. Une énergie au potentiel gigantesque et disponible en abondance. Une énergie propre qui permettrait de continuer de produire sans polluer. Une énergie qui représenterait l'équivalent de 1000 à 2000 réacteurs nucléaires.Cette énergie s'appelle « l'énergie osmotique ». Elle est produite lorsque l'eau salée et l'eau douce se rencontrent. On connait cette source d'énergie depuis longtemps mais jusque là, les scientifiques manquaient de technologies pour l'exploiter. Jusqu'à ce que des chercheurs aux EU, au Japon, en Norvège et en France réussissent à les mettre au point. C'est le cas du physicien Lydéric Bocquet, directeur de recherche au CNRS, professeur attaché à l'École normale supérieure dans l'équipe Micromégas au laboratoire de physique et cofondateur de la start-up Sweetch Energy.Il est l'invité de ce 3e épisode spécial « énergie » de « La fabrique du savoir », un podcast du Monde réalisé en partenariat avec la Nuit de l'énergie 2024, organisée par l' Ecole normale supérieure de Paris. « La fabrique du savoir » est un podcast écrit et animé par Joséfa Lopez et Marion Dupont, pour Le Monde. Réalisation : Diane Jean. Mixage : Eyeshot. Identité graphique : Thomas Steffen. Partenariat : Sonia Jouneau, Cécile Juricic. Partenaire : Ecole normale supérieure. Hébergé par Audion. Visitez https://www.audion.fm/fr/privacy-policy pour plus d'informations.

Il se présente comme un plombier de l'infiniment petit et nous ouvre de nouveaux horizons à l'échelle nano, micro et méga. Rencontre avec l'un des esprits les plus libres de la recherche française, le physicien Lydéric Bocquet, ou comment passer de la science des ricochets à la friction quantique ?  Faisons des ponts entre notre monde macroscopique et le monde nanoscopique, en compagnie de l'un des esprits les plus inspirants et inspirés de la recherche française : le physicien Lydéric Bocquet, professeur attaché à l'ENS où il dirige l'équipe Microméga. Il faut dire que Lydéric Bocquet, qui se définit comme un « plombier de l'infiniment petit », ose tout pour percer les mystères de la vitesse d'écoulement des liquides à l'échelle nano, à commencer par l'art et la science des ricochets. Comment faire des ricochets dans l'eau a pu l'entrainer jusqu'à la friction quantique, à faire le lien entre mécanique des fluides et mécanique quantique ? Comment des recherches aussi fondamentales ouvrent tant de pistes encore inexplorées et d'applications inédites pour faire face aux défis environnementaux et énergétiques ?Avec Lydéric Bocquet, directeur de recherche au CNRS et professeur attaché à l'École normale supérieure. Il dirige l'équipe Micromégas à l'ENS, qui combine expériences, théorie et modélisation pour explorer la mécanique intime des fluides et de leurs interfaces, du niveau macroscopique jusqu'aux échelles moléculaires. L'un de ses principaux axes de recherche au cours des dix dernières années est la nanofluidique, la science des flux moléculaires. Lydéric Bocquet a reçu la médaille de l'innovation CNRS 2024.

Il se présente comme un plombier de l'infiniment petit et nous ouvre de nouveaux horizons à l'échelle nano, micro et méga. Rencontre avec l'un des esprits les plus libres de la recherche française, le physicien Lydéric Bocquet, ou comment passer de la science des ricochets à la friction quantique ?  Faisons des ponts entre notre monde macroscopique et le monde nanoscopique, en compagnie de l'un des esprits les plus inspirants et inspirés de la recherche française : le physicien Lydéric Bocquet, professeur attaché à l'ENS où il dirige l'équipe Microméga. Il faut dire que Lydéric Bocquet, qui se définit comme un « plombier de l'infiniment petit », ose tout pour percer les mystères de la vitesse d'écoulement des liquides à l'échelle nano, à commencer par l'art et la science des ricochets. Comment faire des ricochets dans l'eau a pu l'entrainer jusqu'à la friction quantique, à faire le lien entre mécanique des fluides et mécanique quantique ? Comment des recherches aussi fondamentales ouvrent tant de pistes encore inexplorées et d'applications inédites pour faire face aux défis environnementaux et énergétiques ?Avec Lydéric Bocquet, directeur de recherche au CNRS et professeur attaché à l'École normale supérieure. Il dirige l'équipe Micromégas à l'ENS, qui combine expériences, théorie et modélisation pour explorer la mécanique intime des fluides et de leurs interfaces, du niveau macroscopique jusqu'aux échelles moléculaires. L'un de ses principaux axes de recherche au cours des dix dernières années est la nanofluidique, la science des flux moléculaires. Lydéric Bocquet a reçu la médaille de l'innovation CNRS 2024.

In the first episode of Hugos There 2.0, Seth is joined by returning guest Emmanuel Dubois to discuss The Planet of the Apes, by Pierre Boulle, the 1963 novel (originally written in French) that spawned a major film franchise. Emmanuel’s links: https://twitter.com/manu_photo https://twitter.com/lafayettepod Notes/Mentions: https://www.lafayettepodcast.com/1969630/13073537-de-gaulle-jfk-and-the-new-world-order-with-sean-j-mclaughlin Micromégas, by Voltaire

https://micromaquina.com • @gabriel@micromaquina.com • https://writefreely.org — La música de la entradilla es “If Pigs Could Sing”, de Rolemusic, y se distribuye con licencia CC-BY 3.0 (https://creativecommons.org/licenses/by/3.0/deed.es) Puedes enviarme tus comentarios a través de los siguientes canales: * Puedes unirte al grupo de oyentes en Telegram en https://t.me/sobre_la_marcha * A través de Mastodon: https://fedi.gvisoc.com/@gabriel * A través de mensajes directos en Telegram (sólo mensajes de texto

Das fantasievolle Kunstmärchen von Hans Christian Andersen, auf dänisch Tommelise, wurde 1835 erstmals veröffentlicht. Ob Andersen von Gullivers Reisen (1726), Voltaires Erzählung Micromégas (1752), E.T.A. Hoffmanns Meiser Floh (1822) oder Prinzessin Brambilla (1821) inspiriert worden ist, weiß man nicht || Gelesen von Dustin Peters || Blumenkind, Kröte, Feldmaus, Maulwurf, Schwalbe || Das exklusiv-gemalte Bild zur Geschichte gibt es auf Instagram im Profil @dustins.maerchen.podcast || Nun hoffe ich, dass ihr die Folge oder den Podcast weiterempfehlt und freue mich auf die nächste Geschichte || Und wenn sie nicht gestorben sind, dann...Unsere allgemeinen Datenschutzrichtlinien finden Sie unter https://art19.com/privacy. Die Datenschutzrichtlinien für Kalifornien sind unter https://art19.com/privacy#do-not-sell-my-info abrufbar.

Micromégas est un géant vivant sur une planète de l'étoile Sirius. Après une déconvenue judiciaire, il part en voyage dans l'univers... Et il découvre la Terre ! Écoutez le résumé de ce conte philosophique, écrit par Voltaire et paru en 1752. Si vous aimez ce podcast, pensez à vous abonner

À l'occasion de la sortie de Nope de Jordan Peele au cinéma, on a décidé de faire un épisode sur les invasions extraterrestres

W Fin de Semana habló con Angelique Coetzee, la doctora sudafricana responsable de descubrir esta nueva variante.

Segundo o consultor de agronegócios Vlamir Brandalizze, o trigo foi levado pela onda do ômicron e acabou perdendo força e a pressão negativa veio também para o mercado brasileiro. Mas não muda a potência e aperto da safra.

Primeira semana de dezembro começa com mercados atentos ao comportamento da nova variante do coronavirus e os impactos que ela pode causar na saúde das pessoas e nas economias. Semana passada as bolsas tiveram um fechamento de semana ruim, saiba o que esperar para essa semana. Para acessar o Telegram: http://t.me/itauinvestimentos Essa é uma comunicação geral sobre investimentos. Antes de contratar qualquer produto, confira sempre se é adequado ao seu perfil.

ATTENTION vous pouvez reçevoir un livre numérique gratuit en envoyant "LIVRE" à l'adresse "cyrilc42@gmail.com". Vous pouvez, ensuite, reçevoir un livre de philosophie ou d'actualité tous les mois pour 5 euros/mois. Pour le Paiement, cela s'effectue ici : https://www.youtube.com/channel/UCXwv... ou sur Paypal ici : https://paypal.me/CyrilChevrot?countr... Télégram par ici : https://t.me/joinchat/QdzA6Dnb11MwMWQ0 S'abonner à la chaîne : https://www.youtube.com/channel/UCXwv... blog perso : https://cyrilc42blog.wordpress.com/ Pour me rejoindre sur Facebook : Cyril Chevrot Page : https://www.facebook.com/EnfantsduSie... Et : https://www.facebook.com/CyrilLector/... Twiter : https://twitter.com/cyrilc42mobile Instagram : https://www.instagram.com/cyrilbaldas... Le podcast sur Itunes et sur tous vos lecteurs de podcasts préférés : https://itunes.apple.com/us/podcast/i... Podcast Google : https://podcasts.google.com/?feed=aHR... Podcast Spotify : https://open.spotify.com/show/3ZgM93n... Et taper "Enfants du siècle" ou "Cyril CHEVROT" dans tous les bons lecteurs de podcasts. Merci à toutes et tous et à bientôt. #387. Critique du réformisme islamique par la critique du livre de l'un d'entre eux. #islam #réforme Débat complet entre Malik Bezouh et moi-même : https://www.youtube.com/watch?v=V3nTDLReX78&t=1492s Critique vidéo du livre "Ils ont trahi Allah" : https://www.youtube.com/watch?v=WLDfT7FJdlY&t=134s Le livre de Volataire dont je parle, "Micromégas": https://www.youtube.com/watch?v=xSVLV8Ox6Bw&t=10s Initiation à l'Ethique de Spinoza pour se convaincre qu'il n'était pas matérialiste : https://www.youtube.com/watch?v=IMvwbKUG8yQ&t=936s Rejoignez cette chaîne pour bénéficier d'avantages exclusifs : https://www.youtube.com/channel/UCXwvQs9S59csWFCZjT3Fc_A/join Me rejoindre sur Télégram pour du contenu inédit et intimiste par ici : https://t.me/joinchat/QdzA6Dnb11MwMWQ0 ↓ Déroule pour plus d'infos ↓ ________________________________________­­_____ #booktube #book #booklover #lecture #livraddict S'abonner à la chaîne : https://www.youtube.com/channel/UCXwvQs9S59csWFCZjT3Fc_A?view_as=subscriber Pour continuer à voir des extraits de livres ou pousser la réflexion , voici l'adresse du blog perso : https://cyrilc42blog.wordpress.com/ Pour me rejoindre sur Facebook : Cyril Chevrot Page : https://www.facebook.com/EnfantsduSiecle/?ref=your_pages Et : https://www.facebook.com/CyrilLector/?ref=your_pages Tweeter : https://twitter.com/cyrilc42mobile instagram : https://www.instagram.com/cyrilbaldassare/?hl=fr Pour me soutenir activement au prix d'un café et participer à l'aventure voici : https://www.tipeee.com/cyril-chevrot Le podcast sur Itunes et sur tous vos lecteurs de podcasts préférés : https://itunes.apple.com/us/podcast/id1337908168 Podcast Google : https://podcasts.google.com/?feed=aHR0cHM6Ly9wb2RjYXN0cy5wb2RteXR1YmUuY29tL1VDWHd2UXM5UzU5Y3NXRkNaalQzRmNfQS8&ved=0CAAQ4aUDahcKEwiAmMze-tvnAhUAAAAAHQAAAAAQAQ&hl=fr Podcast Spotify : https://open.spotify.com/show/3ZgM93nK8BfnG75Qbz9H7E?si=Dhqpm5T8SFSRbwbd4KHp1Q Et taper "Enfants du siècle" ou "Cyril CHEVROT" dans tous les bons lecteurs de podcasts. Merci à toutes et tous et à bientôt.

Patrick Ngobani alias Lyricomane, militant du quotidien est l'invité du Podcast de la Culture. Licencié en mathématique-informatique de l'Université Pédagogique Nationale (UPN), il est aussi habile dans les lettres et touche quasiment tous les genres littéraires ou presque. Connu sur la scène kinoise comme poète-slameur, il est auteur de deux recueils de slams. Le lyricomane, comme il se fait appelé, a une passion pour l'écriture. Il écrit de la poésie, des pièces de théâtre, des essais, des romans et des nouvelles. Il a évolué au sein du groupe KINSHASLAM en 2015 avant de rejoindre “Lipoposlam” de microMéga. Depuis 2017, il gère sa propre structure littéraire dénommée Collectif Envie d'Ecrire promouvant les auteurs congolais et leurs œuvres. Actuellement, il anime les rencontres et émissions littéraires sur des espaces culturels et les chaînes de télévision. Lyricomane a déjà enregistré 6 singles de slam parmi lesquels “Non au tribalisme”, “E zalaka te” et ‘‘Tika, o yebi ko kumba te''. Dans la poésie, il est auteur de ‘‘Mon pays va à vau-l'eau'' et “Echo de l'espoir”. Il est en préparation d'un album slam et d'un recueil de poèmes “Miroire terne” en hommage au poète Jean-Luc Kadiayi, décédé en novembre 2020. Il organise également la première édition du prix littéraire JL Kadiayi en hommage à ce poète. Ecoutez cet entretien avec Emmanuel Kuzamba. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.19.255794v1?rss=1 Authors: Hmaied, C., Koulchitsky, S., Gladwyn-Ng, I., Seutin, V. Abstract: Although the fast antidepressant effect of ketamine is now well established clinically, neither its mechanism(s) nor its main site(s) of action is clearly defined. Because enhanced serotoninergic (5-HT) transmission is an important part of the antidepressant effect of various drug classes, we asked whether ketamine and one of its metabolites (hydroxynorketamine [HNK]), both used in their racemic form, may modulate the excitatory drive onto these neurons. Using whole-cell recordings from pharmacologically identified 5-HT and non-5-HT neurons in juvenile rat dorsal raphe slices, we found that both ketamine and HNK (10 microM) increase excitatory AMPA neurotransmission onto a subset (50%) of 5-HT neurons, whereas other 5-HT cells were unaffected. Both compounds increased the amplitude as well as the frequency of spontaneous excitatory post-synaptic currents (sEPSCs) mediated by AMPA receptors. The effect of ketamine was more robust than the one of HNK, since it significantly enhanced the charge transfer through AMPA channels, whereas HNK did not. The increase in the excitatory drive induced by ketamine was dependent on NMDA receptor blockade. In the presence of tetrodotoxin, the effect of ketamine was markedly reduced. Non-5-HT neurons, on the other hand, were unaffected by the drugs. We conclude that ketamine and HNK increase the excitatory drive onto a subset of 5-HT neurons by promoting glutamate release and possibly also through a postsynaptic action. The effect of ketamine is dependent on NMDA receptor modulation and appears to involve a network effect. These findings improve our understanding of the fast-acting antidepressant effect of ketamine. Copy rights belong to original authors. Visit the link for more info

Hello / Bonjour everyone! Welcome to my  podcast. The content is meant for sleep and relaxation, and it's unintenional ASMR content. In this episode where I narrate "Micromégas" by Voltaire, I apply rain sounds and other sound effects to accompany the story. ​​All sound effects and music where purchased for use via audiojungle.net The rain sounds, steps and bird sounds were recorded by Somni Rosae. If you like this work, please consider supporting this podcast on patreon.com/somnirosae To learn more about the podcaster, visit the page somnirosae.com The short story "Micromégas" was published in 1752 and is now considered public domain.Letters can be sent at this address thepinkmoonpodcast@gmail.com Please remember to leave a positive review wherever possible. Thank you for stopping by and for listening to this episode. This podcast is dedicated to the memory of Prince, my sweet handsome boy. Princess and I miss you so much. We know how much you loved our building's hallway. May you be exploring many hallways in heaven. We love you and miss you so much. Support the show (https://www.patreon.com/somnirosae)

Pour continuer à voir des extraits de livres ou pousser la réflexion , voici l'adresse du site : https://www.lire-pour-se-liberer.fr/ Grace à ce service en ligne "Enfants du siècle" est disponible gratuitement en Podcast : https://itunes.apple.com/us/podcast/id1337908168 Pour me rejoindre sur Facebook : https://www.facebook.com/cyrilc526vhvv Pour me soutenir activement au prix d'un café et participer à l'aventure voici : https://www.tipeee.com/cyril-chevrot Merci à toutes et tous et à bientôt.

durée : 00:01:48 - Un jour une entreprise dans les Landes -

Aron Anderson är professionell äventyrare, föreläsare och inspiratör. När han var 7 år fick han cancer i korsbenet. Det blev en tuff period med många operationer, vilket gjorde honom rullstolsburen. Tack vare hans livsgnista och mentala inställning lever han livet fullt ut och inspirerar andra till att våga göra detsamma. I det här avsnittet får du bland annat ta del av hur han tänker kring mental strategi, entreprenörskap och företagande.  Du får också höra hur det gick till när han simmade över Ålands hav med bara armarna.

The widely used atypical antipsychotic clozapine is a potent competitive antagonist at 5-HT(3) receptors which may contribute to its unique psychopharmacological profile. Clozapine binds to 5-HT(3) receptors of various species. However, the structural requirements of the respective binding site for clozapine remain to be determined. Differences in the primary sequences within the 5-HT(3A) receptor gene in schizophrenic patients may result in an alteration of the antipsychotic potency and/or the side effect profile of clozapine. To determine these structural requirements we constructed chimeras with different 5-HT(3A) receptor sequences of murine and human origin and expressed these mutants in human embryonic kidney (HEK) 293 cells. Clozapine antagonises recombinant mouse 5-HT(3A) receptors with higher potency compared to recombinant human 5-HT(3A) receptors. 5-HT activation curves and clozapine inhibition curves yielded the parameters EC(50) and IC(50) for all receptors tested in the range of 0.6 - 2.7 microM and 1.5 - 83.3 nM, respectively. The use of the Cheng-Prusoff equation to calculate the dissociation constant K(b) values for clozapine revealed that an extracellular sequence (length 86 aa) close to the transmembrane domain M1 strongly determines the binding affinity of clozapine. K(b) values of clozapine were significantly lower (0.3-1.1 nM) for receptors containing the murine sequence and higher when compared with receptors containing the respective human sequence (5.8-13.4 nM). Thus, individual differences in the primary sequence of 5-HT(3) receptors may be crucial for the antipsychotic potency and/or the side effect profile of clozapine.

Glucocorticoid hormones suppress the secretion of ACTH evoked by secretagogues such as CRF and arginine vasopressin. In this study, we investigated the effects of glucocorticoids on ACTH release induced by oxytocin (OT) and on intracellular free calcium ion levels in corticotropes prepared from the adenohypophyses of female Wistar rats. Pulsatile additions of physiological concentration of OT (10 nM) to superfused anterior pituitary cells caused pulsatile ACTH release about 4-fold above basal secretion with similar peak amounts of ACTH during subsequent OT pulses. Exposure of the cells to corticosterone (100 nM) or to a selective glucocorticoid receptor agonist RU 28362 (100 nM) for 30 min suppressed OT-stimulated but not basal ACTH release by approximately 60%. Inhibition gradually disappeared during subsequent pulses of OT in the absence of corticosterone. Pretreatment with the selective antagonist RU 38486 (1 microM) completely blocked the inhibitory effect of corticosterone on OT-induced ACTH secretion. Changes in free cytosolic calcium levels in single cultured pituitary cells were measured using the calcium indicator Fura-2. OT caused calcium transients in corticotropes, which were identified by immunocytochemistry. They responded in a similar manner to a second OT stimulus when preincubated for 30 min with corticosterone (1 microM) or with RU 28362 (1 microM). Our data indicate that glucocorticoids, via glucocorticoid receptors, rapidly inhibit OT-stimulated ACTH secretion by corticotropes without affecting intracellular calcium transients due to OT. Therefore, we conclude that rapid inhibition of ACTH release by glucocorticoids interferes with cellular signal transduction beyond the step of calcium mobilization.

The potency of oxytocin (OT) in evoking ACTH secretion by isolated, superfused rat adenohypophyseal corticotrophs and its enhancement by CRF and arginine vasopressin (AVP) were analyzed. Each secretagogue effectively released ACTH from adenohypophyseal cells when added separately in pulsatile fashion in physiological concentrations based on hypophyseal portal blood (OT, 10 nM; AVP, 0.5 nM; CRF, 0.1 nM). OT released ACTH at concentrations as low as 1 nM. Moreover, a dose- response relationship up to 10 microM was revealed. Combinations of a constant amount of CRF (0.1 nM) with increasing concentrations of OT exerted a synergistic effect on ACTH release. In contrast, OT given in various concentrations in combination with AVP (0.5 nM) produced an additive effect on ACTH release. To study the mechanism of action of OT on ACTH secretion, cytosolic free calcium levels in single pituitary cells exposed to OT or AVP were measured using the calcium-sensitive fluorescent indicator Fura-2. Corticotrophs among mixed adenohypophyseal cell types in the primary cultures were identified by immunocytochemistry. More than 500 cells were individually stimulated with OT or AVP. Basal cytosolic free calcium levels ranged between 80- 130 nM free calcium. The addition of 100 nM OT or 1 microM AVP increased the cytosolic free calcium concentration within 3 sec to values ranging from 500-800 nM. An increase in intracellular calcium ranging from 200-500 nM due to OT could still be observed after extracellular calcium depletion. Taken together, our data demonstrate that physiological concentrations of OT stimulate ACTH secretion, independent of the other ACTH secretagogues, by mobilizing calcium mainly from intracellular stores.

The molecular requirements for amylase release and the intracellular effects of botulinum A toxin and tetanus toxin on amylase release were investigated using rat pancreatic acinar cells permeabilized with streptolysin O. Micromolar concentrations of free Ca2+ evoked amylase release from these cells. Maximal release was observed in the presence of 30 microM free Ca2+. Ca(2+)-stimulated, but not basal, amylase release was enhanced by guanosine 5'-[gamma-thio]triphosphate (GTP[S]) (3-4 fold) or cyclic AMP (1.5-2 fold). Neither the two-chain forms of botulinum A toxin and tetanus toxin, under reducing conditions, nor the light chains of tetanus toxin, inhibited amylase release triggered by Ca2+, or combinations of Ca2+ + GTP[S] or Ca2+ + cAMP. The lack of inhibition was not due to inactivation of botulinum A toxin or tetanus toxin by pancreatic acinar cell proteolytic enzymes, as toxins previously incubated with permeabilized pancreatic acinar cells inhibited Ca(2+)-stimulated [3H]noradrenaline release from streptolysin O-permeabilized adrenal chromaffin cells. These data imply that clostridial neurotoxins inhibit a Ca(2+)-dependent mechanism which promotes exocytosis in neural and endocrine cells, but not in exocrine cells.

1. In bovine adrenal chromaffin cells made permeable either to molecules less than or equal to 3 kDa with alphatoxin or to proteins less than or equal to 150 kDa with streptolysin O, the GTP analogues guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) and guanosine 5'-[gamma-thio]triphosphate (GTP[S]) differently modulated Ca(2+)-stimulated exocytosis. 2. In alphatoxin-permeabilized cells, p[NH]ppG up to 20 microM activated Ca(2+)-stimulated exocytosis. Higher concentrations had little or no effect. At a free Ca2+ concentration of 5 microM, 7 microM-p[NH]ppG stimulated exocytosis 6-fold. Increasing the free Ca2+ concentration reduced the effect of p[NH]ppG. Pretreatment of the cells with pertussis toxin prevented the activation of the Ca(2+)-stimulated exocytosis by p[NH]ppG. 3. In streptolysin O-permeabilized cells, p[NH]ppG did not activate, but rather inhibited Ca(2+)-dependent catecholamine release under all conditions studied. In the soluble cytoplasmic material that escaped during permeabilization with streptolysin O, different G-protein alpha-subunits were detected using an appropriate antibody. Around 15% of the cellular alpha-subunits were detected in the supernatant of permeabilized control cells. p[NH]ppG or GTP[S] stimulated the release of alpha-subunits 2-fold, causing a loss of about 30% of the cellular G-protein alpha-subunits under these conditions. Two of the alpha-subunits in the supernatant belonged to the G(o) type, as revealed by an antibody specific for G(o) alpha. 4. GTP[S], when present alone during stimulation with Ca2+, activated exocytosis in a similar manner to p[NH]ppG. Upon prolonged incubation, GTP[S], in contrast to p[NH]ppG, inhibited Ca(2+)-induced exocytosis from cells permeabilized by either of the pore-forming toxins. This effect was resistant to pertussin toxin. 5. The p[NH]ppG-induced activation of Ca(2+)-stimulated release from alphatoxin-permeabilized chromaffin cells may be attributed to one of the heterotrimeric G-proteins lost during permeabilization with streptolysin O. The inhibitory effect of GTP[S] on exocytosis is apparently not mediated by G-protein alpha-subunits, but by another GTP-dependent process still occurring after permeabilization with streptolysin O.

We have studied the relationship between insulin activation of insulin-receptor kinase and insulin stimulation of glucose uptake in isolated rat adipocytes. Glucose uptake was half-maximally or maximally stimulated, respectively, when only 4% or 14% of the maximal kinase activity had been reached. To investigate this relationship also under conditions where the insulin effect on activation of receptor kinase was decreased, the adipocytes were exposed to 10 microM-isoprenaline alone or with 5 micrograms of adenosine deaminase/ml. An approx. 30% (isoprenaline) or approx. 50% (isoprenaline + adenosine deaminase) decrease in the insulin effect on receptor kinase activity was found at insulin concentrations between 0.4 and 20 ng/ml, and this could not be explained by decreased insulin binding. The decreased insulin-effect on kinase activity was closely correlated with a loss of insulin-sensitivity of glucose uptake. Moreover, our data indicate that the relation between receptor kinase activity and glucose uptake (expressed as percentage of maximal uptake) remained unchanged. The following conclusions were drawn. (1) If activation of receptor kinase stimulates glucose uptake, only 14% of the maximal kinase activity is sufficient for maximal stimulation. (2) Isoprenaline decreases the coupling efficiency between insulin binding and receptor-kinase activation, this being accompanied by a corresponding decrease in sensitivity of glucose uptake. (3) Our data indicate that the signalling for glucose uptake is closely related to receptor-kinase activity, even when the coupling efficiency between insulin binding and kinase activation is altered. They thus support the hypothesis that receptor-kinase activity reflects the signal which originates from the receptor and which is transduced to the glucose-transport system.

1. Intracellular microelectrodes were used to obtain recordings from neurons in layer II/III of rat frontal cortex. A bipolar electrode positioned in layer IV of the neocortex was used to evoke postsynaptic potentials. Graded series of stimulation were employed to selectively activate different classes of postsynaptic responses. The sensitivity of postsynaptic potentials and iontophoretically applied neurotransmitters to the non-N-methyl-D-asparate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) was examined. 2. As reported previously, low-intensity electrical stimulation of cortical layer IV evoked short-latency early excitatory postsynaptic potentials (eEPSPs) in layer II/III neurons. CNQX reversibly antagonized eEPSPs in a dose-dependent manner. Stimulation at intensities just subthreshold for activation of inhibitory postsynaptic potentials (IPSPs) produced long-latency (10 to 40-ms) EPSPs (late EPSPs or 1EPSPs). CNQX was effective in blocking 1EPSPs. 3. With the use of stimulus intensities at or just below threshold for evoking an action potential, complex synaptic potentials consisting of EPSP-IPSP sequences were observed. Both early, Cl(-)-dependent and late, K(+)-dependent IPSPs were reduced by CNQX. This effect was reversible on washing. This disinhibition could lead to enhanced excitability in the presence of CNQX. 4. Iontophoretic application of quisqualate produced a membrane depolarization with superimposed action potentials, whereas NMDA depolarized the membrane potential and evoked bursts of action potentials. At concentrations up to 5 microM, CNQX selectively antagonized quisqualate responses. NMDA responses were reduced by 10 microM CNQX. D-Serine (0.5-2 mM), an agonist at the glycine regulatory site on the NMDA receptor, reversed the CNQX depression of NMDA responses.

1. Intracellular recordings were obtained from neurons in layer II/III of rat frontal cortex. Single-electrode current- and voltage-clamp techniques were employed to compare the sensitivity of excitatory postsynaptic potentials (EPSPs) and iontophoretically evoked responses to N-methyl-D-aspartate (NMDA) to the selective NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-2-APV). The voltage dependence of the amplitudes of the EPSPs before and after pharmacologic changes in the neuron's current-voltage relationship was also examined. 2. NMDA depolarized the membrane potential, increased the neuron's apparent input resistance (RN), and evoked bursts of action potentials. The NMDA-induced membrane current (INMDA) gradually increased with depolarization from -80 to -40 mV. The relationship between INMDA and membrane potential displayed a region of negative slope conductance in the potential range between -70 and -40 mV which was sufficient to explain the apparent increase in RN and the burst discharges during the NMDA-induced depolarization. 3. Short-latency EPSPs (eEPSPs) were evoked by low-intensity electrical stimulation of cortical layer IV. Changes in the eEPSP waveform following membrane depolarization and hyperpolarization resembled those of NMDA-mediated responses. However, the eEPSP was insensitive to D-2-APV applied at concentrations (up to 20 microM) that blocked NMDA responses. 4. EPSPs with latencies between 10 and 40 ms [late EPSPs (lEPSPs)] were evoked by electrical stimulation using intensities just subthreshold to the activation of IPSPs. The amplitude of the lEPSP increased with hyperpolarization and decreased with depolarization. 5. The lidocaine derivative QX-314, injected intracellularly, suppressed sodium-dependent action potentials and depolarizing inward rectification. Simultaneously, the amplitude of the eEPSP significantly decreased with depolarization. Neither the amplitude of a long-latency EPSP nor the amplitude of inhibitory postsynaptic potentials (IPSPs) was significantly affected by QX-314. 6. Cesium ions (0.5-2.0 mM) added to the bathing solution reduced or blocked hyperpolarizing inward rectification. Under these conditions, the amplitude of the eEPSP increased with hyperpolarization. The amplitude of the lEPSP was unaltered or enhanced. 7. The lEPSP was reversibly blocked by D-2-APV (5-20 microM), although the voltage-dependence of its amplitude did not resemble the action of NMDA on neocortical neurons.

1. Intracellular recordings were obtained from neurones in layers 2 and 3 of the rat frontal neocortex in an in vitro slice preparation. Three distinct types of stimulation-evoked post-synaptic potentials were recorded in these neurones: excitatory post-synaptic potentials (e.p.s.p.s); bicuculline-sensitive, chloride-dependent inhibitory post-synaptic potentials (i.p.s.p.s) with times to peak of 20-25 ms (fast(f)-i.p.s.p.s); bicuculline-insensitive, potassium-dependent i.p.s.p.s with bicuculline-insensitive, potassium-dependent i.p.s.p.s with times to peak of 150-250 ms (long(l)-i.p.s.p.s). 2. The effects of baclofen were investigated on seventy-one neurones. Baclofen was applied by ionophoresis or pressure ejection from micropipettes or was added to the superfusion medium. 3. Baclofen depressed stimulation-evoked e.p.s.p.s in fifty-seven of the sixty neurones tested. This effect was associated with an increase in the stimulation intensity required to produce a synaptically evoked action potential for thirty-nine of forty-four neurones. 4. Baclofen depressed f-i.p.s.p.s in thirty-seven of the thirty-nine neurones tested and l-i.p.s.p.s in each one of the seventeen neurones tested. Reversal potential values for each type of i.p.s.p. were not changed by baclofen and its depressions of each were independent of membrane potential (Em). Baclofen reduced the magnitude and the duration of the conductance increases that were associated with f- and l-i.p.s.p.s. 5. Baclofen hyperpolarized forty of seventy-one neurones and produced outward currents in three of four neurones recorded in voltage clamp at holding potentials between -55 and -65 mV. These actions were associated with 10-58% reductions of neuronal input resistance (RN) and 10-20% increases in neuronal input conductance (gN), respectively. Baclofen decreased the direct excitability of twenty-three of twenty-seven neurones tested. Determinations of the reversal potential for baclofen-induced changes of Em indicate that baclofen increases the conductance of rat neocortical neurones to potassium ions. 6. The EC50 for each action of DL-baclofen was approximately 1 microM. L-Baclofen was greater than 100 times more potent than D-baclofen. 7. Concentrations of bicuculline that blocked f-i.p.s.p.s and responses to ionophoretically applied gamma-aminobutyric acid (GABA) had no effect on the depressions of e.p.s.p.s or the hyperpolarizations and decreases in RN that baclofen produced. 8. Baclofen did not reduce the duration of action potentials that were prolonged with intracellular injections of caesium ions or by superfusions with medium that contained 10 mM-tetraethylammonium (TEA).

Coated microvesicles isolated from bovine neurohypophyses could be loaded with Ca2+ in two different ways, either by incubation in the presence of ATP or by imposition of an outwardly directed Na+ gradient. Na+, but not K+, was able to release Ca2+ accumulated by the coated microvesicles. These results suggest the existence of an ATP-dependent Ca2+-transport system as well as of a Na+/Ca2+ carrier in the membrane of coated microvesicles similar to that present in the membranes of secretory vesicles from the neurohypophysis. A kinetic analysis of transport indicates that the apparent Km for free Ca2+ of the ATP-dependent uptake was 0.8 microM. The average Vmax. was 2 nmol of Ca2+/5 min per mg of protein. The total capacity of microvesicles for Ca2+ uptake was 3.7 nmol/mg of protein. Both nifedipine (10 microM) and NH4Cl (50 mM) inhibited Ca2+ uptake. The ATPase activity in purified coated-microvesicles fractions from brain and neurohypophysis was characterized. Micromolar concentrations of Ca2+ in the presence of millimolar concentrations of Mg2+ did not change enzyme activity. Ionophores increasing the proton permeability across membranes activated the ATPase activity in preparations of coated microvesicles from brain as well as from the neurohypophysis. Thus the enzyme exhibits properties of a proton-transporting ATPase. This enzyme seems to be linked to the ion accumulation by coated microvesicles, although the precise coupling of the proton transport to Ca2+ and Na+ fluxes remains to be determined.