Pub Date : 2024-02-28DOI: 10.1101/2023.02.27.530254
Tia A Tummino, Christos Iliopoulos-Tsoutsouvas, Joao M Braz, Evan S O'Brien, Reed M Stein, Veronica Craik, Ngan K Tran, Suthakar Ganapathy, Fangyu Liu, Yuki Shiimura, Fei Tong, Thanh C Ho, Dmytro S Radchenko, Yurii S Moroz, Sian Rodriguez Rosado, Karnika Bhardwaj, Jorge Benitez, Yongfeng Liu, Herthana Kandasamy, Claire Normand, Meriem Semache, Laurent Sabbagh, Isabella Glenn, John J Irwin, Kaavya Krishna Kumar, Alexandros Makriyannis, Allan I Basbaum, Brian K Shoichet
Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.
{"title":"Large library docking for cannabinoid-1 receptor agonists with reduced side effects.","authors":"Tia A Tummino, Christos Iliopoulos-Tsoutsouvas, Joao M Braz, Evan S O'Brien, Reed M Stein, Veronica Craik, Ngan K Tran, Suthakar Ganapathy, Fangyu Liu, Yuki Shiimura, Fei Tong, Thanh C Ho, Dmytro S Radchenko, Yurii S Moroz, Sian Rodriguez Rosado, Karnika Bhardwaj, Jorge Benitez, Yongfeng Liu, Herthana Kandasamy, Claire Normand, Meriem Semache, Laurent Sabbagh, Isabella Glenn, John J Irwin, Kaavya Krishna Kumar, Alexandros Makriyannis, Allan I Basbaum, Brian K Shoichet","doi":"10.1101/2023.02.27.530254","DOIUrl":"10.1101/2023.02.27.530254","url":null,"abstract":"<p><p>Large library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking new agonists for the cannabinoid-1 receptor (CB1R), we docked 74 million tangible molecules, prioritizing 46 high ranking ones for de novo synthesis and testing. Nine were active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 uM) led to '4042, a 1.9 nM ligand and a full CB1R agonist. A cryo-EM structure of the purified enantiomer of '4042 ('1350) in complex with CB1R-Gi1 confirmed its docked pose. The new agonist was strongly analgesic, with generally a 5-10-fold therapeutic window over sedation and catalepsy and no observable conditioned place preference. These findings suggest that new cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from their analgesia, supporting the further development of cannabinoids as pain therapeutics.</p>","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10849508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74092979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In Insister – À Jacques Derrida Cixous declares that she will have to write ‘the book of words’, among which ‘words of power’ will be vermögen (to be able), together with Unvermöglickeit (impossibility), and tragen (to carry), along with austragen (to bear to term) and übertragen (to transfer, translate, also in the sense of metaphor). By examining Derrida's reading of Cixous in H. C. pour la vie, c'est à dire … this article deepens the association of tragen with life and power that fascinates Derrida in the second year of his final seminar where he tracks a thread between Austrag, Walten, Trieb, and Vermögen. Its point of departure is a passage towards the end of H. C. pour la vie where Derrida speaks of the trap of metalanguage or, rather, metaphrasis that lurks in the c’est of c'est à dire. I link this passage both to the discussion of metaphorization in the earlier ‘Le puits et la pyramide’ and the characterization of puisse as ‘the exhaustion [ l'épuisement] of the sun before its time’ in the essay on Cixous to associate puissance with the wearing-out of the world and its usure in the double sense elaborated in ‘La mythologie blanche’.
在Insister - À中，雅克·德里达·西克索宣称她必须写“文字之书”，其中“权力的文字”将是vermögen(能够)，Unvermöglickeit(不可能)，tragen(携带)，以及austragen(承担)和 bertragen(转移，翻译，也在隐喻的意义上)。通过考察德里达在《生活，生活，生活》中对西克修斯的阅读，这篇文章加深了悲剧与生命和权力的联系，这让德里达在他最后一次研讨会的第二年着迷，在那里他追踪了澳大利亚、瓦尔滕、特里布和Vermögen之间的线索。它的出发点是通往人生结尾的一段，德里达在那里谈到了元语言的陷阱，或者更确切地说，潜伏在人生之最深处的隐喻。我把这段话和之前的" Le puits et la pyramide "中关于隐喻的讨论联系起来，以及在关于Cixous的文章中将puisse描述为"太阳在它的时间之前的耗尽[l' samuisement] "将puissance与世界的损耗和它在" la mythologie blanche "中阐述的双重意义上的生存联系起来。
{"title":"Life, Would That it Might Be To Say – Power, Metaphor, <i>Tragen</i>, <i>Épuis(s)ement</i>","authors":"Naomi Waltham-Smith","doi":"10.3366/drt.2023.0315","DOIUrl":"https://doi.org/10.3366/drt.2023.0315","url":null,"abstract":"In Insister – À Jacques Derrida Cixous declares that she will have to write ‘the book of words’, among which ‘words of power’ will be vermögen (to be able), together with Unvermöglickeit (impossibility), and tragen (to carry), along with austragen (to bear to term) and übertragen (to transfer, translate, also in the sense of metaphor). By examining Derrida's reading of Cixous in H. C. pour la vie, c'est à dire … this article deepens the association of tragen with life and power that fascinates Derrida in the second year of his final seminar where he tracks a thread between Austrag, Walten, Trieb, and Vermögen. Its point of departure is a passage towards the end of H. C. pour la vie where Derrida speaks of the trap of metalanguage or, rather, metaphrasis that lurks in the c’est of c'est à dire. I link this passage both to the discussion of metaphorization in the earlier ‘Le puits et la pyramide’ and the characterization of puisse as ‘the exhaustion [ l'épuisement] of the sun before its time’ in the essay on Cixous to associate puissance with the wearing-out of the world and its usure in the double sense elaborated in ‘La mythologie blanche’.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"375 3","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This article examines the conflicting representations of plasticity and epigenetics in the work of philosopher Catherine Malabou and evolutionary theorists Mary Jane West-Eberhard and Eva Jablonka. In order to speak of a new biological ‘paradigm’ and to attribute values of novelty or inventiveness to life itself, Malabou has to suppress the unsettled debates within the life sciences. The aporias of evolutionary narrative and causality reveal a necessary differentiality and textuality that belongs neither to life nor science itself, but leaves a haunting remanence within every corpus. New materialism resists this necessity of life-science, which calls for a deconstructive reading.
本文考察了哲学家Catherine Malabou和进化理论家Mary Jane West-Eberhard和Eva Jablonka的作品中可塑性和表观遗传学的相互矛盾的表述。为了谈论一种新的生物学“范式”，并将新颖性或创造性的价值归因于生命本身，Malabou必须压制生命科学中尚未解决的争论。进化叙事和因果关系的漏洞揭示了一种必要的差异性和文本性，这种差异性和文本性既不属于生命，也不属于科学本身，但在每个语料库中都留下了挥之不去的余韵。新唯物主义抵制这种生命科学的必要性，它要求解构主义的解读。
{"title":"The Epic of Genesis: Catherine Malabou and the <i>gêne</i> of Epigenetics","authors":"Jonathan Basile","doi":"10.3366/drt.2023.0311","DOIUrl":"https://doi.org/10.3366/drt.2023.0311","url":null,"abstract":"This article examines the conflicting representations of plasticity and epigenetics in the work of philosopher Catherine Malabou and evolutionary theorists Mary Jane West-Eberhard and Eva Jablonka. In order to speak of a new biological ‘paradigm’ and to attribute values of novelty or inventiveness to life itself, Malabou has to suppress the unsettled debates within the life sciences. The aporias of evolutionary narrative and causality reveal a necessary differentiality and textuality that belongs neither to life nor science itself, but leaves a haunting remanence within every corpus. New materialism resists this necessity of life-science, which calls for a deconstructive reading.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"376 6","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recent efforts in soft robotics and Artificial Life are attempting to construct homeostatically functioning machines with ‘feeling’ analogues. Such robots are designed to be ‘vulnerable’ and, thus, depart from traditional approaches to machine design and construction. In this paper, I explore a representative proposal by Antonio Damasio and Kingson Man, and ask how we can understand the deconstruction of ‘life’ in Derrida, Stiegler, Malabou and Wills to relate to such efforts. I argue that the adoption of biological and phenomenological principles in machine design calls for attention to the precise extent that it may not result in robots that adhere either to biological or to mechanical models. It is with this admission, of the essentially unknowable character of what may result from these efforts, that deconstruction can assist roboticists and synthetic biologists today.
{"title":"Artificial Life, Feeling Machines, and the Text of Deconstruction","authors":"Adam R. Rosenthal","doi":"10.3366/drt.2023.0313","DOIUrl":"https://doi.org/10.3366/drt.2023.0313","url":null,"abstract":"Recent efforts in soft robotics and Artificial Life are attempting to construct homeostatically functioning machines with ‘feeling’ analogues. Such robots are designed to be ‘vulnerable’ and, thus, depart from traditional approaches to machine design and construction. In this paper, I explore a representative proposal by Antonio Damasio and Kingson Man, and ask how we can understand the deconstruction of ‘life’ in Derrida, Stiegler, Malabou and Wills to relate to such efforts. I argue that the adoption of biological and phenomenological principles in machine design calls for attention to the precise extent that it may not result in robots that adhere either to biological or to mechanical models. It is with this admission, of the essentially unknowable character of what may result from these efforts, that deconstruction can assist roboticists and synthetic biologists today.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"376 7","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Hillis Miller (1928–2021) was one of the most prominent figures in literary criticism and theory. After receiving his Ph.D. from Harvard University, he taught at Johns Hopkins University, Yale University and the University of California at Irvine. He retired as Professor Emeritus in 2002. Miller was president of the Modern Language Association of America in 1986 and contributed significantly to professional academic institutions and organizations throughout his career. As an important representative of the Yale School, he had close relationships with Derrida, Paul de Man, Geoffrey Hartman and Harold Bloom. Dr. Ning Yizhong did postdoctoral research under his supervision at UCI from 1997 to 1998. This is part of his interviews with Professor Miller during that time. In this interview, Miller talks about the Yale School in general, and Jacques Derrida, Paul de Man and Harold Bloom in particular. 1
{"title":"Deconstruction and the Yale School: An Interview with J. Hillis Miller","authors":"Ning Yizhong, J. Hillis Miller","doi":"10.3366/drt.2023.0316","DOIUrl":"https://doi.org/10.3366/drt.2023.0316","url":null,"abstract":"J. Hillis Miller (1928–2021) was one of the most prominent figures in literary criticism and theory. After receiving his Ph.D. from Harvard University, he taught at Johns Hopkins University, Yale University and the University of California at Irvine. He retired as Professor Emeritus in 2002. Miller was president of the Modern Language Association of America in 1986 and contributed significantly to professional academic institutions and organizations throughout his career. As an important representative of the Yale School, he had close relationships with Derrida, Paul de Man, Geoffrey Hartman and Harold Bloom. Dr. Ning Yizhong did postdoctoral research under his supervision at UCI from 1997 to 1998. This is part of his interviews with Professor Miller during that time. In this interview, Miller talks about the Yale School in general, and Jacques Derrida, Paul de Man and Harold Bloom in particular. 1","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"376 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
While working on the Italian translation of Life Death, I became aware of some inaccuracies on Derrida’s part that might weaken the effectiveness of his deconstruction of the notion of ‘reproduction’. Not only, such inaccuracies seem to lead Derrida’s interpretation of reproduction toward a conception of ‘life’ that might even hint at an undeconstructed metaphysical background. I have already dealt with such inaccuracies in detail in two articles published in French, here I will recall their outcomes in order to try to test the most problematic hypothesis they have led me to formulate: the Derridean conception of ‘life’ implies a metaphysical background.
{"title":"Schizogonies: Deconstruction of Derrida’s Deconstruction of Reproduction","authors":"Francesco Vitale","doi":"10.3366/drt.2023.0314","DOIUrl":"https://doi.org/10.3366/drt.2023.0314","url":null,"abstract":"While working on the Italian translation of Life Death, I became aware of some inaccuracies on Derrida’s part that might weaken the effectiveness of his deconstruction of the notion of ‘reproduction’. Not only, such inaccuracies seem to lead Derrida’s interpretation of reproduction toward a conception of ‘life’ that might even hint at an undeconstructed metaphysical background. I have already dealt with such inaccuracies in detail in two articles published in French, here I will recall their outcomes in order to try to test the most problematic hypothesis they have led me to formulate: the Derridean conception of ‘life’ implies a metaphysical background.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"374 7-8","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Here I pursue a deconstructive reading of astrobiology, the emerging science dedicated to a double quest: solving the mystery of life's origin and discovering life beyond Earth. Astrobiology, I argue, is organized as a response to the aporetic formulation assumed by the origin of life in modern molecular biology, where (as Derrida's argues in Life Death) it becomes the origin of textuality. Because all Earth life shares a single genetic code, astrobiologists are seeking a second; hoping that a sort of multi-planetary comparative genomics may reveal the secret to life's origin. But the aporia repeats in the figure of the biosignature, the trace of life.
{"title":"Biosignature, Technosignature, Event: Deconstruction, Astrobiology, and the Search for a Wholly Other Origin","authors":"Armando M. Mastrogiovanni","doi":"10.3366/drt.2023.0312","DOIUrl":"https://doi.org/10.3366/drt.2023.0312","url":null,"abstract":"Here I pursue a deconstructive reading of astrobiology, the emerging science dedicated to a double quest: solving the mystery of life's origin and discovering life beyond Earth. Astrobiology, I argue, is organized as a response to the aporetic formulation assumed by the origin of life in modern molecular biology, where (as Derrida's argues in Life Death) it becomes the origin of textuality. Because all Earth life shares a single genetic code, astrobiologists are seeking a second; hoping that a sort of multi-planetary comparative genomics may reveal the secret to life's origin. But the aporia repeats in the figure of the biosignature, the trace of life.","PeriodicalId":42836,"journal":{"name":"Derrida Today","volume":"377 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135111437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号