50 results on '"Tsien J"'
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2. La poésie philosophique de Voltaire; Voltaire and the Temple of bad taste: a study of La Pucelle d'Orleans
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Boucher, G and Tsien, J
- Abstract
I. Gwénaëlle Boucher, La Poésie philosophique de Voltaire La poésie de Voltaire, désormais aussi décriée que sa philosophie, constitue un réel enjeu philosophique: le vers possède des vertus heuristiques relayant la raison lorsque celle-ci achoppe sur une difficulté et la pensée se nourrit de la forme même du poème. Certes, Voltaire fait ses premières armes poétiques dans la polémique, propageant en vers sa philosophie portative fondée sur l’allégorie militante ou le vers gnomique, au risque de voir ses vers-maximes inlassablement ressassés devenir clichés rhétoriques et lieux communs de la pensée. Mais avant d’être actif, le vers philosophique voltairien est d’abord réactif, empreint des émotions du poète devant les astres ou les désastres terrestres. Ainsi, si la philosophie est la condition de la ‘vraie’ poésie, ce sont peut-être surtout les impuissances et les démissions philosophiques qui permettent l’expression poétique. Accédant à la poésie lorsque ses idées échouent à trouver des certitudes devant les incohérences du monde, Voltaire serait-il un poète de l’irrationnel? II. Jennifer Tsien, Voltaire and the Temple of bad taste: a study of La Pucelle d’Orléans Voltaire’s mock-epic poem La Pucelle d’Orléans has delighted, offended, and baffled readers throughout the centuries. In addition to its calculated chaos of genre and style, the poem also contains an improbable number of episodic characters and subplots whose fantastic nature is worthy of Orlando furioso. This study makes sense of La Pucelle d’Orléans by demonstrating the way in which it represents Voltaire’s definition of bad writing, in view of his criticism and the literary debates of the period. In contrast to the classical ideal that Voltaire championed, his mock epic is filled with precisely those elements that he condemned in the works of other writers, including mixed genres, préciosité, vulgar language, magic, and grotesque metamorphoses. La Pucelle d’Orléans shows us the underside of Voltaire’s professed neoclassical aesthetics while allowing his readers to indulge in the pleasures of bad taste. Gwénaëlle Boucher, La poésie philosophique de Voltaire Introduction I. Poésie et philosophie chez Voltaire 1. La philosophie dans l’art poétique au dix-huitième siècle 2. Les idées de Voltaire sur le vers 3. La dialectique du vers 4. Réévaluation des vues poétiques de Voltaire 5. Prose et vers chez Voltaire II. La raison ardente 6. Poésie et éthique 7. Les armes poétiques 8. Vers un lyrisme philosophique? 9. Conclusion Corpus de la poésie philosophique voltairienne Bibliographie Jennifer Tsien, Voltaire and the Temple of bad taste: a study of La Pucelle d’Orléans Introduction 1. The effeminate epic 2. The lower-class epic 3. The animal epic 4. The mad epic Conclusion Works cited more...
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- 2017
Catalog
3. Rousseau et l'idee d'education: essai suivi de 'Pestalozzi juge de Jean-Jacques'
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Tsien, J., primary
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- 2013
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4. Statistics of natural action structures and human action recognition
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Zhu, X., primary, Yang, Z., additional, and Tsien, J., additional
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- 2012
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5. Cognition Enhancement Strategies
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Bibb, J. A., primary, Mayford, M. R., additional, Tsien, J. Z., additional, and Alberini, C. M., additional
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- 2010
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6. Natural scenes statistics and visual saliency
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Xu, J., primary, Tsien, J., additional, and Yang, Z., additional
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- 2010
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7. Object recognition based on hierarchically organized structures of natural objects
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He, X., primary, Tsien, J., additional, and Yang, Z., additional
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- 2010
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8. Neuronal PPAR Deficiency Increases Susceptibility to Brain Damage after Cerebral Ischemia
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Zhao, X., primary, Strong, R., additional, Zhang, J., additional, Sun, G., additional, Tsien, J. Z., additional, Cui, Z., additional, Grotta, J. C., additional, and Aronowski, J., additional
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- 2009
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9. In Vivo Evidence for NMDA Receptor-Mediated Excitotoxicity in a Murine Genetic Model of Huntington Disease
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Heng, M. Y., primary, Detloff, P. J., additional, Wang, P. L., additional, Tsien, J. Z., additional, and Albin, R. L., additional
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- 2009
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10. Linking Hebb's coincidence-detection to memory formation
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Tsien, J, primary
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- 2000
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11. Differential effects of enrichment on learning and memory function in NR2B transgenic mice
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Tang, Y. P., Wang, H., Feng, R., Kyin, M., and Tsien, J. Z.
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- 2001
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12. Effect of transgenic overexpression of NR2B on NMDA receptor function and synaptic plasticity in visual cortex
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Philpot, B. D., Weisberg, M. P., Ramos, M. S., Sawtell, N. B., Tang, Y. P., Tsien, J. Z., and Bear, M. F.
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- 2001
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13. Action recognition using Natural Action Structures
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Zhu Xiaoyuan, Yang Zhiyong, and Tsien Joe Z
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Published
- 2012
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14. Forebrain overexpression of CaMKII abolishes cingulate long term depression and reduces mechanical allodynia and thermal hyperalgesia
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Tsien Joe Z, Wang Huimin, Shokat Kevan M, Zhang Chao, Wang Guo-Du, Wei Feng, Liauw Jason, and Zhuo Min
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Pathology ,RB1-214 - Abstract
Abstract Activity-dependent synaptic plasticity is known to be important in learning and memory, persistent pain and drug addiction. Glutamate NMDA receptor activation stimulates several protein kinases, which then trigger biochemical cascades that lead to modifications in synaptic efficacy. Genetic and pharmacological techniques have been used to show a role for Ca2+/calmodulin-dependent kinase II (CaMKII) in synaptic plasticity and memory formation. However, it is not known if increasing CaMKII activity in forebrain areas affects behavioral responses to tissue injury. Using genetic and pharmacological techniques, we were able to temporally and spatially restrict the over expression of CaMKII in forebrain areas. Here we show that genetic overexpression of CaMKII in the mouse forebrain selectively inhibits tissue injury-induced behavioral sensitization, including allodynia and hyperalgesia, while behavioral responses to acute noxious stimuli remain intact. CaMKII overexpression also inhibited synaptic depression induced by a prolonged repetitive stimulation in the ACC, suggesting an important role for CaMKII in the regulation of cingulate neurons. Our results suggest that neuronal CaMKII activity in the forebrain plays a role in persistent pain. more...
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- 2006
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15. Hierarchies of Host Factor Dynamics at the Entry Site of Shigella flexneri during Host Cell Invasion
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Christophe Zimmer, Laurent Audry, Philippe J. Sansonetti, Jost Enninga, Ricardo Henriques, Cristina Rodrigues, Soudeh Ehsani, Guy Tran Van Nhieu, José Carlos Santos, Langlais, Laurence, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto = University of Porto, Imagerie et Modélisation, Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), S.E. was supported by a grant from the Fondation Schlumberger pour l'Education et la Recherche. J.C.S. and C.D.R. were the recipients of fellowships from the Portuguese Fundaçāo para a Ciência e Tecnologia, FCT (SFRH/BD/51006/2010 and SFRH/BPD/41004/2007, respectively). C.D.R. is presently a Marie Curie fellow, We thank C. Parsot, R. Tsien, J. Swanson, and A. M. Pendergast for providing us with plasmids and/or bacterial strains. We are particularly thankful to M. Lelek for support in the PALM experiments. We acknowledge the members of the PFID at the Institut Pasteur for excellent microscopy support., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Universidade do Porto, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Chaire Microbiologie et Maladies infectieuses, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM) more...
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Cytoplasm ,Time Factors ,MESH: Shigella flexneri ,Immunology ,Endocytic cycle ,MESH: Microscopy, Fluorescence ,Vacuole ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Time-Lapse Imaging ,Microbiology ,MESH: Vacuoles ,Shigella flexneri ,03 medical and health sciences ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,MESH: Cytoskeleton ,Humans ,MESH: Time-Lapse Imaging ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Cytoskeleton ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Actin ,030304 developmental biology ,Host factor ,0303 health sciences ,Cellular Microbiology: Pathogen-Host Cell Molecular Interactions ,MESH: Humans ,biology ,030306 microbiology ,MESH: Cytoplasm ,MESH: Time Factors ,MESH: Host-Pathogen Interactions ,Epithelial Cells ,biology.organism_classification ,Entry into host ,3. Good health ,Cell biology ,Infectious Diseases ,Microscopy, Fluorescence ,MESH: Epithelial Cells ,Host-Pathogen Interactions ,Vacuoles ,MESH: HeLa Cells ,Parasitology ,HeLa Cells - Abstract
Shigella flexneri , the causative agent of bacillary dysentery, induces massive cytoskeletal rearrangement, resulting in its entry into nonphagocytic epithelial cells. The bacterium-engulfing membrane ruffles are formed by polymerizing actin, a process activated through injected bacterial effectors that target host small GTPases and tyrosine kinases. Once inside the host cell, S. flexneri escapes from the endocytic vacuole within minutes to move intra- and intercellularly. We quantified the fluorescence signals from fluorescently tagged host factors that are recruited to the site of pathogen entry and vacuolar escape. Quantitative time lapse fluorescence imaging revealed simultaneous recruitment of polymerizing actin, small GTPases of the Rho family, and tyrosine kinases. In contrast, we found that actin surrounding the vacuole containing bacteria dispersed first from the disassembling membranes, whereas other host factors remained colocalized with the membrane remnants. Furthermore, we found that the disassembly of the membrane remnants took place rapidly, within minutes after bacterial release into the cytoplasm. Superresolution visualization of galectin 3 through photoactivated localization microscopy characterized these remnants as small, specular, patchy structures between 30 and 300 nm in diameter. Using our experimental setup to track the time course of infection, we identified the S. flexneri effector IpgB1 as an accelerator of the infection pace, specifically targeting the entry step, but not vacuolar progression or escape. Together, our studies show that bacterial entry into host cells follows precise kinetics and that this time course can be targeted by the pathogen. more...
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- 2012
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16. Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.
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Nie Z, Bonnert R, Tsien J, Deng X, Higgs C, El Mazouni F, Zhang X, Li R, Ho N, Feher V, Paulsen J, Shackleford DM, Katneni K, Chen G, Ng ACF, McInerney M, Wang W, Saunders J, Collins D, Yan D, Li P, Campbell M, Patil R, Ghoshal A, Mondal P, Kundu A, Chittimalla R, Mahadeva M, Kokkonda S, White J, Das R, Mukherjee P, Angulo-Barturen I, Jiménez-Díaz MB, Malmstrom R, Lawrenz M, Rodriguez-Granillo A, Rathod PK, Tomchick DR, Palmer MJ, Laleu B, Qin T, Charman SA, and Phillips MA more...
- Abstract
Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts. more...
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- 2024
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17. Isosteric 3D Bicyclo[1.1.1]Pentane (BCP) Core-Based Lipids for mRNA Delivery and CRISPR/Cas Gene Editing.
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Wu S, Yang Y, Lian X, Zhang F, Hu C, Tsien J, Chen Z, Sun Y, Vaidya A, Kim M, Sung YC, Xiao Y, Bian X, Wang X, Tian Z, Guerrero E, Robinson J, Basak P, Qin T, and Siegwart DJ
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- Animals, Bridged Bicyclo Compounds chemistry, Mice, Nanoparticles chemistry, Humans, Gene Editing methods, CRISPR-Cas Systems, RNA, Messenger chemistry, RNA, Messenger genetics, Lipids chemistry
- Abstract
Lipid nanoparticles (LNPs) are an essential component of messenger RNA (mRNA) vaccines and genome editing therapeutics. Ionizable amino lipids, which play the most crucial role in enabling mRNA to overcome delivery barriers, have, to date, been restricted to two-dimensional (2D) architectures. Inspired by improved physicochemical properties resulting from the incorporation of three-dimensionality (3D) into small-molecule drugs, we report the creation of 3D ionizable lipid designs through the introduction of bicyclo[1.1.1]pentane (BCP) core motifs. BCP-based lipids enabled efficient in vivo mRNA delivery to the liver and spleen with significantly greater performance over 2D benzene- and cyclohexane-based analogues. Notably, lead BCP-NC2-C12 LNPs mediated ∼90% reduction in the PCSK9 serum protein level via CRISPR/Cas9 gene knockout, outperforming 2D controls and clinically used DLin-MC3-DMA LNPs at the same dose. Here, we introduce BCP-based designs with superior in vivo activity, thereby expanding the chemical scope of ionizable amino lipids from 2D to 3D and offering a promising avenue to improve mRNA and gene editing efficiency for the continued development of genetic medicines. more...
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- 2024
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18. A General Three-Component Alkyl Petasis Boron-Mannich Reaction.
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Hu C, Tsien J, Chen SJ, Kong M, Merchant RR, Kanda Y, and Qin T
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Aryl amines are one of the most common moieties in biologically active molecules, and approximately 37% of drug candidates contain aromatic amines. Recent advancements in medicinal chemistry, coined "escaping from flatland", have led to a greater focus on accessing highly functionalized C ( sp
3 )-rich amines to improve the physicochemical and pharmacokinetic properties of compounds. This article presents a modular and operationally straightforward three-component alkyl Petasis boron-Mannich (APBM) reaction that utilizes ubiquitous starting materials, including amines, aldehydes, and alkyl boronates. By adaptation of this transformation to high-throughput experimentation (HTE), it offers rapid access to an array of diverse C( sp3 )-rich complex amines, amenable for rapid identification of drug candidates. more...- Published
- 2024
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19. Three-dimensional saturated C(sp 3 )-rich bioisosteres for benzene.
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Tsien J, Hu C, Merchant RR, and Qin T
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Benzenes, the most ubiquitous structural moiety in marketed small-molecule drugs, are frequently associated with poor 'drug-like' properties, including metabolic instability, and poor aqueous solubility. In an effort to overcome these limitations, recent developments in medicinal chemistry have demonstrated the improved physicochemical profiles of C(sp
3 )-rich bioisosteric scaffolds relative to arenes. In the past two decades, we have witnessed an exponential increase in synthetic methods for accessing saturated bioisosteres of monosubstituted and para-substituted benzenes. However, until recent discoveries, analogous three-dimensional ortho-substituted and meta-substituted biososteres have remained underexplored, owing to their ring strain and increased s-character hybridization. This Review summarizes the emerging synthetic methodologies to access such saturated motifs and their impact on the application of bioisosteres for ortho-substituted, meta-substituted and multi-substituted benzene rings. It concludes with a perspective on the development of next-generation bioisosteres, including those within novel chemical space., (© 2024. Springer Nature Limited.) more...- Published
- 2024
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20. Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.
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Faulkner RA, Yang Y, Tsien J, Qin T, and DeBose-Boyd RA
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- Endoplasmic Reticulum-Associated Degradation, Sterol Regulatory Element Binding Protein 1 genetics, Intracellular Signaling Peptides and Proteins metabolism, Cholesterol metabolism, Hydroxymethylglutaryl CoA Reductases metabolism, Carbon metabolism, Diphosphonates, Sterols metabolism, Phytosterols
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The maintenance of cholesterol homeostasis is crucial for normal function at both the cellular and organismal levels. Two integral membrane proteins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and Scap, are key targets of a complex feedback regulatory system that operates to ensure cholesterol homeostasis. HMGCR catalyzes the rate-limiting step in the transformation of the 2-carbon precursor acetate to 27-carbon cholesterol. Scap mediates proteolytic activation of sterol regulatory element-binding protein-2 (SREBP-2), a membrane-bound transcription factor that controls expression of genes involved in the synthesis and uptake of cholesterol. Sterol accumulation triggers binding of HMGCR to endoplasmic reticulum (ER)-localized Insig proteins, leading to the enzyme's ubiquitination and proteasome-mediated ER-associated degradation (ERAD). Sterols also induce binding of Insigs to Scap, which leads to sequestration of Scap and its bound SREBP-2 in the ER, thereby preventing proteolytic activation of SREBP-2 in the Golgi. The oxygenated cholesterol derivative 25-hydroxycholesterol (25HC) and the methylated cholesterol synthesis intermediate 24,25-dihydrolanosterol (DHL) differentially modulate HMGCR and Scap. While both sterols promote binding of HMGCR to Insigs for ubiquitination and subsequent ERAD, only 25HC inhibits the Scap-mediated proteolytic activation of SREBP-2. We showed previously that 1,1-bisphosphonate esters mimic DHL, accelerating ERAD of HMGCR while sparing SREBP-2 activation. Building on these results, our current studies reveal specific, Insig-independent photoaffinity labeling of HMGCR by photoactivatable derivatives of the 1,1-bisphosphonate ester SRP-3042 and 25HC. These findings disclose a direct sterol binding mechanism as the trigger that initiates the HMGCR ERAD pathway, providing valuable insights into the intricate mechanisms that govern cholesterol homeostasis., Competing Interests: Competing interests statement:The authors declare no competing interest. more...
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- 2024
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21. Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.
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Yang Y, Tsien J, Dykstra R, Chen SJ, Wang JB, Merchant RR, Hughes JME, Peters BK, Gutierrez O, and Qin T
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Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C
2 -substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C3 )-boronic pinacol esters (Bpin), leaving the C2 -Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C3 ) and bridge (C2 ) positions enable access to C1 ,C2 -disubstituted and C1 ,C2 ,C3 -trisubstituted BCPs that encompass previously unexplored chemical space., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...- Published
- 2024
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22. Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp 3 ) bioisosteres.
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Zhou M, Tsien J, Dykstra R, Hughes JME, Peters BK, Merchant RR, Gutierrez O, and Qin T
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In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp
3 )-C(sp2 ) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...- Published
- 2023
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23. Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis .
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Wang Z, Cheong MC, Tsien J, Deng H, Qin T, Stoltzfus JD, Jaleta TG, Li X, Lok JB, Kliewer SA, and Mangelsdorf DJ
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- Animals, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins chemistry, Dogs, Gerbillinae, Ligands, Male, Strongyloidiasis drug therapy, Anthelmintics pharmacology, Ivermectin pharmacokinetics, Receptors, Cytoplasmic and Nuclear agonists, Strongyloides stercoralis drug effects, Strongyloidiasis parasitology
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A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, Ss- DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss- DAF-12 ligand and elucidated the hormone's biosynthetic pathway. Genetic loss of function of the ligand's rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits Ss- DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease., Competing Interests: ZW, MC, JT, HD, TQ, JS, TJ, XL, JL, SK, DM No competing interests declared, (© 2021, Wang et al.) more...
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- 2021
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24. An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates.
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Yang Y, Tsien J, Hughes JME, Peters BK, Merchant RR, and Qin T
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- Boronic Acids chemistry, Bridged Bicyclo Compounds chemistry, Cyclization, Molecular Structure, Boronic Acids chemical synthesis
- Abstract
Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons., (© 2021. Merck Sharp & Dohme corp. under exclusive licence to Springer Nature Limited.) more...
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- 2021
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25. Corrigendum: Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings.
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Zhou M, Tsien J, and Qin T
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- 2021
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26. Practical and Modular Construction of C(sp 3 )-Rich Alkyl Boron Compounds.
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Yang Y, Tsien J, Ben David A, Hughes JME, Merchant RR, and Qin T
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Alkyl boronic acids and esters play an important role in the synthesis of C(sp
3 )-rich medicines, agrochemicals, and material chemistry. This work describes a new type of transition-metal-free mediated transformation to enable the construction of C(sp3 )-rich and sterically hindered alkyl boron reagents in a practical and modular manner. The broad generality and functional group tolerance of this method is extensively examined through a variety of substrates, including synthesis and late-stage functionalization of scaffolds relevant to medicinal chemistry. The strategic significance of this approach, with alkyl boronic acids as linchpins, is demonstrated through various downstream functionalizations of the alkyl boron compounds. This two-step concurrent cross-coupling approach, resembling formal and flexible alkyl-alkyl couplings, provides a general entry to synthetically challenging high Fsp3 -containing drug-like scaffolds. more...- Published
- 2021
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27. Sulfur(IV)-Mediated Unsymmetrical Heterocycle Cross-Couplings.
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Zhou M, Tsien J, and Qin T
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Despite the tremendous utilities of metal-mediated cross-couplings in modern organic chemistry, coupling reactions involving nitrogenous heteroarenes remain a challenging undertaking - coordination of Lewis basic atoms into metal centers often necessitate elevated temperature, high catalyst loading, etc. Herein, we report a sulfur (IV) mediated cross-coupling amendable for the efficient synthesis of heteroaromatic substrates. Addition of heteroaryl nucleophiles to a simple, readily-accessible alkyl sulfinyl (IV) chloride allows formation of a trigonal bipyramidal sulfurane intermediate. Reductive elimination therefrom provides bis-heteroaryl products in a practical and efficient fashion., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...
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- 2020
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28. Functional Brain Connectivity Revealed by Sparse Coding of Large-Scale Local Field Potential Dynamics.
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Wang H, Xie K, Xie L, Li X, Li M, Lyu C, Chen H, Chen Y, Liu X, Tsien J, and Liu T
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- Alpha Rhythm, Animals, Behavior, Animal physiology, Brain Mapping, Electroencephalography, Magnetic Resonance Imaging, Male, Mice, Theta Rhythm, Brain physiology, Evoked Potentials physiology, Neural Pathways physiology
- Abstract
Exploration of brain dynamics patterns has attracted increasing attention due to its fundamental significance in understanding the working mechanism of the brain. However, due to the lack of effective modeling methods, how the simultaneously recorded LFP can inform us about the brain dynamics remains a general challenge. In this paper, we propose a novel sparse coding based method to investigate brain dynamics of freely-behaving mice from the perspective of functional connectivity, using super-long local field potential (LFP) recordings from 13 distinct regions of the mouse brain. Compared with surrogate datasets, six and four reproducible common functional connectivities were discovered to represent the space of brain dynamics in the frequency bands of alpha and theta respectively. Modeled by a finite state machine, temporal transition framework of functional connectivities was inferred for each frequency band, and evident preference was discovered. Our results offer a novel perspective for analyzing neural recording data at such high temporal resolution and recording length, as common functional connectivities and their transition framework discovered in this work reveal the nature of the brain dynamics in freely behaving mice. more...
- Published
- 2019
- Full Text
- View/download PDF
29. Large-Scale Circuitry Interactions Upon Earthquake Experiences Revealed by Recurrent Neural Networks.
- Author
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Wang H, Xie K, Lian Z, Cui Y, Chen Y, Zhang J, Xie L, Tsien J, and Liu T
- Subjects
- Algorithms, Animals, Bayes Theorem, Brain Mapping, Evoked Potentials physiology, Fear physiology, Gamma Rhythm, Learning physiology, Male, Memory physiology, Mice, Models, Psychological, Theta Rhythm, Brain physiology, Earthquakes, Nerve Net physiology
- Abstract
Brain dynamics has recently received increasing interest due to its significant importance in basic and clinical neurosciences. However, due to inherent difficulties in both data acquisition and data analysis methods, studies on large-scale brain dynamics of mouse with local field potential (LFP) recording are very rare. In this paper, we did a series of works on modeling large-scale mouse brain dynamic activities responding to fearful earthquake. Based on LFP recording data from 13 brain regions that are closely related to fear learning and memory and the effective Bayesian connectivity change point model, we divided the response time series into four stages: "Before," "Earthquake," "Recovery," and "After." We first reported the changes in power and theta-gamma coupling during stage transitions. Then, a recurrent neural network model was designed to model the functional dynamics in these thirteen brain regions and six frequency bands in response to the fear stimulus. Interestingly, our results showed that the functional brain connectivities in theta and gamma bands exhibited distinct response processes: in theta band, there is a separated-united-separated alternation in whole-brain connectivity and a low-high-low change in connectivity strength; however, gamma bands have a united-separated-united transition and a high-low-high alternation in connectivity pattern and strength. In general, our results offer a novel perspective in studying functional brain dynamics under fearful stimulus and reveal its relationship to the brain's structural connectivity substrates. more...
- Published
- 2018
- Full Text
- View/download PDF
30. Building C(sp 3 )-rich complexity by combining cycloaddition and C-C cross-coupling reactions.
- Author
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Chen TG, Barton LM, Lin Y, Tsien J, Kossler D, Bastida I, Asai S, Bi C, Chen JS, Shan M, Fang H, Fang FG, Choi HW, Hawkins L, Qin T, and Baran PS
- Subjects
- Biological Products chemical synthesis, Biological Products chemistry, Drug Discovery, Carbon chemistry, Chemistry Techniques, Synthetic, Cycloaddition Reaction
- Abstract
Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres
1 , cycloaddition reactions have featured in numerous total syntheses2 and are a key component in the education of chemistry students3 . Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability4 . Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp2 manner5 . Despite the ability of cycloadditions to introduce multiple carbon sp3 centres in a single step, they are less used6 . This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery. more...- Published
- 2018
- Full Text
- View/download PDF
31. Enhancement of Contralesional Motor Control Promotes Locomotor Recovery after Unilateral Brain Lesion.
- Author
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Hua XY, Qiu YQ, Wang M, Zheng MX, Li T, Shen YD, Jiang S, Xu JG, Gu YD, Tsien J, and Xu WD
- Subjects
- Animals, Behavior, Animal, Brain Injuries diagnosis, Disease Models, Animal, Motor Cortex pathology, Motor Cortex physiopathology, Positron-Emission Tomography, Rats, Time Factors, X-Ray Microtomography, Brain Injuries physiopathology, Brain Injuries rehabilitation, Functional Laterality, Motor Activity, Recovery of Function
- Abstract
There have been controversies on the contribution of contralesional hemispheric compensation to functional recovery of the upper extremity after a unilateral brain lesion. Some studies have demonstrated that contralesional hemispheric compensation may be an important recovery mechanism. However, in many cases where the hemispheric lesion is large, this form of compensation is relatively limited, potentially due to insufficient connections from the contralesional hemisphere to the paralyzed side. Here, we used a new procedure to increase the effect of contralesional hemispheric compensation by surgically crossing a peripheral nerve at the neck in rats, which may provide a substantial increase in connections between the contralesional hemisphere and the paralyzed limb. This surgical procedure, named cross-neck C7-C7 nerve transfer, involves cutting the C7 nerve on the healthy side and transferring it to the C7 nerve on the paretic side. Intracortical microstimulation, Micro-PET and histological analysis were employed to explore the cortical changes in contralesional hemisphere and to reveal its correlation with behavioral recovery. These results showed that the contralesional hemispheric compensation was markedly strengthened and significantly related to behavioral improvements. The findings also revealed a feasible and effective way to maximize the potential of one hemisphere in controlling both limbs. more...
- Published
- 2016
- Full Text
- View/download PDF
32. Revealing the mystery. Interview by Kristie Nybo.
- Author
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Tsien J
- Subjects
- Animals, Brain cytology, Brain physiology, Humans, Mice, Mice, Knockout, Biotechnology, Neurosciences
- Published
- 2013
33. Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling.
- Author
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Haigh JJ, Morelli PI, Gerhardt H, Haigh K, Tsien J, Damert A, Miquerol L, Muhlner U, Klein R, Ferrara N, Wagner EF, Betsholtz C, and Nagy A
- Subjects
- Animals, Integrases genetics, Integrases metabolism, Intermediate Filament Proteins genetics, Intermediate Filament Proteins metabolism, Mice, Mice, Transgenic, Neovascularization, Physiologic physiology, Nestin, Viral Proteins genetics, Viral Proteins metabolism, Cerebral Cortex abnormalities, Nerve Tissue Proteins, Paracrine Communication physiology, Retina abnormalities, Vascular Endothelial Growth Factor A metabolism
- Abstract
To determine the function of VEGF-A in nervous system development, we have utilized the Nestin promoter-driven Cre recombinase transgene, in conjunction with a conditional and hypomorphic VEGF-A allele, to lower VEGF-A activity in neural progenitor cells. Mice with intermediate levels of VEGF-A activity showed decreased blood vessel branching and density in the cortex and retina, resulting in a thinner retina and aberrant structural organization of the cortex. Severe reductions in VEGF-A led to decreases in vascularity and subsequent hypoxia, resulting in the specific degeneration of the cerebral cortex and neonatal lethality. Decreased neuronal proliferation and hypoxia was evident at E11.5, leading to increased neuronal apoptosis in the cortex by E15.5. In order to address whether the observed changes in the structural organization of the nervous system were due to a direct and autocrine role of VEGF-A on the neural population, we conditionally inactivated the main VEGF-A receptor, Flk1, specifically in neuronal lineages, by using the Nestin Cre transgene. The normality of these mice ruled out the possibility that VEGF-A/Flk1 signaling has a significant autocrine role in CNS development. VEGF-A dosage is therefore a critical parameter regulating the density of the vascular plexus in the developing CNS that is in turn a key determinant in the development and architectural organization of the nervous system. more...
- Published
- 2003
- Full Text
- View/download PDF
34. Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.
- Author
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Feng R, Rampon C, Tang YP, Shrom D, Jin J, Kyin M, Sopher B, Miller MW, Ware CB, Martin GM, Kim SH, Langdon RB, Sisodia SS, and Tsien JZ
- Subjects
- Alzheimer Disease genetics, Amyloid beta-Protein Precursor metabolism, Animals, Brain Chemistry genetics, Electrophysiology, Hippocampus pathology, Memory Disorders genetics, Memory Disorders pathology, Memory Disorders physiopathology, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Knockout, Mice, Transgenic, Neurons pathology, Presenilin-1, Prosencephalon pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Amyloid beta-Protein Precursor analogs & derivatives, Hippocampus growth & development, Membrane Proteins deficiency, Membrane Proteins genetics, Memory physiology, Prosencephalon growth & development
- Abstract
To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain. more...
- Published
- 2001
- Full Text
- View/download PDF
35. Genome-wide gene expression profiles of the developing mouse hippocampus.
- Author
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Mody M, Cao Y, Cui Z, Tay KY, Shyong A, Shimizu E, Pham K, Schultz P, Welsh D, and Tsien JZ
- Subjects
- Animals, Animals, Newborn, Female, Gene Expression Profiling, Hippocampus embryology, Male, Mice, Mice, Inbred C57BL, Transcription, Genetic, Up-Regulation, Gene Expression Regulation, Developmental, Hippocampus growth & development
- Abstract
We have analyzed the developmental molecular programs of the mouse hippocampus, a cortical structure critical for learning and memory, by means of large-scale DNA microarray techniques. Of 11,000 genes and expressed sequence tags examined, 1,926 showed dynamic changes during hippocampal development from embryonic day 16 to postnatal day 30. Gene-cluster analysis was used to group these genes into 16 distinct clusters with striking patterns that appear to correlate with major developmental hallmarks and cellular events. These include genes involved in neuronal proliferation, differentiation, and synapse formation. A complete list of the transcriptional changes has been compiled into a comprehensive gene profile database (http://BrainGenomics.Princeton.edu), which should prove valuable in advancing our understanding of the molecular and genetic programs underlying both the development and the functions of the mammalian brain. more...
- Published
- 2001
- Full Text
- View/download PDF
36. Do 'smart' mice feel more pain, or are they just better learners?
- Author
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Tang Y, Shimizu E, and Tsien JZ
- Subjects
- Animals, Autophagy-Related Proteins, Mice, Pain genetics, Pain Measurement, Trans-Activators biosynthesis, Trans-Activators genetics, Transcription Factors, Intelligence genetics, Intelligence physiology, Pain psychology
- Published
- 2001
- Full Text
- View/download PDF
37. The effects of aging on gene expression in the hypothalamus and cortex of mice.
- Author
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Jiang CH, Tsien JZ, Schultz PG, and Hu Y
- Subjects
- Animals, Endopeptidases genetics, Enzyme Induction, Enzymes genetics, Gene Expression Profiling, Mice, Mice, Inbred BALB C, Neurodegenerative Diseases metabolism, Stress, Physiological metabolism, Synapses metabolism, Aging genetics, Cerebral Cortex metabolism, Gene Expression, Hypothalamus metabolism
- Abstract
A better understanding of the molecular effects of aging in the brain may help to reveal important aspects of organismal aging, as well as processes that lead to age-related brain dysfunction. In this study, we have examined differences in gene expression in the hypothalamus and cortex of young and aged mice by using high-density oligonucleotide arrays. A number of key genes involved in neuronal structure and signaling are differentially expressed in both the aged hypothalamus and cortex, including synaptotagmin I, cAMP-dependent protein kinase C beta, apolipoprotein E, protein phosphatase 2A, and prostaglandin D. Misregulation of these proteins may contribute to age-related memory deficits and neurodegenerative diseases. In addition, many proteases that play essential roles in regulating neuropeptide metabolism, amyloid precursor protein processing, and neuronal apoptosis are up-regulated in the aged brain and likely contribute significantly to brain aging. Finally, a subset of these genes whose expression is affected by aging are oppositely affected by exposure of mice to an enriched environment, suggesting that these genes may play important roles in learning and memory. more...
- Published
- 2001
- Full Text
- View/download PDF
38. NMDA receptor-dependent synaptic reinforcement as a crucial process for memory consolidation.
- Author
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Shimizu E, Tang YP, Rampon C, and Tsien JZ
- Subjects
- Animals, Conditioning, Psychological, Doxycycline pharmacology, Excitatory Postsynaptic Potentials, Fear, Green Fluorescent Proteins, Long-Term Potentiation, Luminescent Proteins biosynthesis, Maze Learning, Mice, Mice, Knockout, Mice, Transgenic, Receptors, AMPA physiology, Receptors, N-Methyl-D-Aspartate genetics, Retention, Psychology, Synaptic Transmission, Time Factors, Hippocampus physiology, Memory physiology, Receptors, N-Methyl-D-Aspartate physiology, Synapses physiology
- Abstract
The hippocampal CA1 region is crucial for converting new memories into long-term memories, a process believed to continue for week(s) after initial learning. By developing an inducible, reversible, and CA1-specific knockout technique, we could switch N-methyl-D-aspartate (NMDA) receptor function off or on in CA1 during the consolidation period. Our data indicate that memory consolidation depends on the reactivation of the NMDA receptor, possibly to reinforce site-specific synaptic modifications to consolidate memory traces. Such a synaptic reinforcement process may also serve as a cellular means by which the new memory is transferred from the hippocampus to the cortex for permanent storage. more...
- Published
- 2000
- Full Text
- View/download PDF
39. Effects of environmental enrichment on gene expression in the brain.
- Author
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Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, and Hu Y
- Subjects
- Animals, Brain physiology, Gene Expression Profiling, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Time Factors, Brain metabolism, Cognition physiology, Gene Expression
- Abstract
An enriched environment is known to promote structural changes in the brain and to enhance learning and memory performance in rodents [Hebb, D. O. (1947) Am. Psychol. 2, 306-307]. To better understand the molecular mechanisms underlying these experience-dependent cognitive changes, we have used high-density oligonucleotide microarrays to analyze gene expression in the brain. Expression of a large number of genes changes in response to enrichment training, many of which can be linked to neuronal structure, synaptic plasticity, and transmission. A number of these genes may play important roles in modulating learning and memory capacity. more...
- Published
- 2000
- Full Text
- View/download PDF
40. A chemical switch for inhibitor-sensitive alleles of any protein kinase.
- Author
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Bishop AC, Ubersax JA, Petsch DT, Matheos DP, Gray NS, Blethrow J, Shimizu E, Tsien JZ, Schultz PG, Rose MD, Wood JL, Morgan DO, and Shokat KM
- Subjects
- Amino Acid Sequence, CDC28 Protein Kinase, S cerevisiae antagonists & inhibitors, CDC28 Protein Kinase, S cerevisiae genetics, Carbazoles pharmacology, Cell Cycle, Fungal Proteins antagonists & inhibitors, Gene Expression, Humans, Indole Alkaloids, Mitogen-Activated Protein Kinases antagonists & inhibitors, Molecular Sequence Data, Mutagenesis, Protein Structure, Tertiary, Proteins pharmacology, Saccharomyces cerevisiae, Sequence Homology, Amino Acid, Transcription, Genetic, Alleles, Enzyme Inhibitors pharmacology, Protein Kinase Inhibitors, Protein Kinases genetics, Saccharomyces cerevisiae Proteins
- Abstract
Protein kinases have proved to be largely resistant to the design of highly specific inhibitors, even with the aid of combinatorial chemistry. The lack of these reagents has complicated efforts to assign specific signalling roles to individual kinases. Here we describe a chemical genetic strategy for sensitizing protein kinases to cell-permeable molecules that do not inhibit wild-type kinases. From two inhibitor scaffolds, we have identified potent and selective inhibitors for sensitized kinases from five distinct subfamilies. Tyrosine and serine/threonine kinases are equally amenable to this approach. We have analysed a budding yeast strain carrying an inhibitor-sensitive form of the cyclin-dependent kinase Cdc28 (CDK1) in place of the wild-type protein. Specific inhibition of Cdc28 in vivo caused a pre-mitotic cell-cycle arrest that is distinct from the G1 arrest typically observed in temperature-sensitive cdc28 mutants. The mutation that confers inhibitor-sensitivity is easily identifiable from primary sequence alignments. Thus, this approach can be used to systematically generate conditional alleles of protein kinases, allowing for rapid functional characterization of members of this important gene family. more...
- Published
- 2000
- Full Text
- View/download PDF
41. Building a brainier mouse.
- Author
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Tsien JZ
- Subjects
- Animals, Genetic Engineering, Learning, Memory, Mice, Mice, Inbred Strains genetics, Receptors, N-Methyl-D-Aspartate genetics, Intelligence genetics, Receptors, N-Methyl-D-Aspartate physiology
- Published
- 2000
- Full Text
- View/download PDF
42. Enrichment induces structural changes and recovery from nonspatial memory deficits in CA1 NMDAR1-knockout mice.
- Author
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Rampon C, Tang YP, Goodhouse J, Shimizu E, Kyin M, and Tsien JZ
- Subjects
- Animals, Conditioning, Psychological physiology, Cues, Dendrites physiology, Dendrites ultrastructure, Electroshock, Exploratory Behavior physiology, Fear physiology, Female, Food Preferences physiology, Long-Term Potentiation physiology, Male, Memory Disorders genetics, Memory Disorders physiopathology, Mice, Mice, Knockout, Pattern Recognition, Visual physiology, Pyramidal Cells cytology, Pyramidal Cells growth & development, Pyramidal Cells ultrastructure, Receptors, N-Methyl-D-Aspartate deficiency, Receptors, N-Methyl-D-Aspartate genetics, Smell physiology, Space Perception physiology, Synapses physiology, Synapses ultrastructure, Memory physiology, Pyramidal Cells physiology, Receptors, N-Methyl-D-Aspartate physiology
- Abstract
We produced CA1-specific NMDA receptor 1 subunit-knockout (CA1-KO) mice to determine the NMDA receptor dependence of nonspatial memory formation and of experience-induced structural plasticity in the CA1 region. CA1-KO mice were profoundly impaired in object recognition, olfactory discrimination and contextual fear memories. Surprisingly, these deficits could be rescued by enriching experience. Using stereological electron microscopy, we found that enrichment induced an increase of the synapse density in the CA1 region in knockouts as well as control littermates. Therefore, our data indicate that CA1 NMDA receptor activity is critical in hippocampus-dependent nonspatial memory, but is not essential for experience-induced synaptic structural changes. more...
- Published
- 2000
- Full Text
- View/download PDF
43. Genetic analysis of learning behavior-induced structural plasticity.
- Author
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Rampon C and Tsien JZ
- Subjects
- Animals, Brain ultrastructure, Environment, Genetic Techniques, Synapses physiology, Synapses ultrastructure, Brain physiology, Learning physiology, Neuronal Plasticity physiology
- Abstract
It is well-documented that enriched environment and behavioral training can lead to improved learning and memory, as well as structural and morphological changes in the brain. It has been hypothesized that such experience-dependent behavioral improvement results from structural modifications that may represent some forms of possible memory substrates for these behavioral experiences. It was generally assumed until now that, like the activity-dependent structural plasticity observed in the developing brain, behavioral experience-induced structural plasticity would require the activation of the NMDA receptor, a molecular switch for learning and memory. Recent genetic and anatomical analyses reveal that behavioral experience-induced increases in spine and synapse density in the hippocampal CA1 region occur despite the deletion of the NMDA receptor in conditional knockout mice. Recent studies indicate that the molecular mechanism of behavioral experience-induced structural plasticity in the adult brain differs from that of the developing brain, and can be disassociated from the NMDA-mediated long-term potentiation (LTP) phenomenon. Deepening the understanding of the molecular mechanism of experience-induced structural plasticity should facilitate the study of the relationship between structural changes and memory formation. Using an integrated approach with genomic, genetic, and modern histological techniques should move us closer in this direction. more...
- Published
- 2000
- Full Text
- View/download PDF
44. Genetic enhancement of learning and memory in mice.
- Author
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Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, and Tsien JZ
- Subjects
- Animals, Association Learning physiology, Cells, Cultured, Conditioning, Classical, Cues, Electric Stimulation, Excitatory Postsynaptic Potentials, Fear physiology, Glutamic Acid physiology, Hippocampus physiology, In Vitro Techniques, Long-Term Potentiation, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuronal Plasticity, Prosencephalon physiology, Receptors, AMPA physiology, Receptors, N-Methyl-D-Aspartate genetics, Synapses physiology, Visual Perception physiology, Learning, Memory, Receptors, N-Methyl-D-Aspartate physiology
- Abstract
Hebb's rule (1949) states that learning and memory are based on modifications of synaptic strength among neurons that are simultaneously active. This implies that enhanced synaptic coincidence detection would lead to better learning and memory. If the NMDA (N-methyl-D-aspartate) receptor, a synaptic coincidence detector, acts as a graded switch for memory formation, enhanced signal detection by NMDA receptors should enhance learning and memory. Here we show that overexpression of NMDA receptor 2B (NR2B) in the forebrains of transgenic mice leads to enhanced activation of NMDA receptors, facilitating synaptic potentiation in response to stimulation at 10-100 Hz. These mice exhibit superior ability in learning and memory in various behavioural tasks, showing that NR2B is critical in gating the age-dependent threshold for plasticity and memory formation. NMDA-receptor-dependent modifications of synaptic efficacy, therefore, represent a unifying mechanism for associative learning and memory. Our results suggest that genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible. more...
- Published
- 1999
- Full Text
- View/download PDF
45. Structural basis for selective inhibition of Src family kinases by PP1.
- Author
-
Liu Y, Bishop A, Witucki L, Kraybill B, Shimizu E, Tsien J, Ubersax J, Blethrow J, Morgan DO, and Shokat KM
- Subjects
- Adenosine Triphosphate metabolism, Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Calcium-Calmodulin-Dependent Protein Kinases chemistry, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Enzyme Inhibitors chemistry, Isoleucine physiology, Models, Molecular, Molecular Sequence Data, Mutagenesis physiology, Mutation, Protein Conformation, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases genetics, Proteins chemistry, Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, p38 Mitogen-Activated Protein Kinases, src-Family Kinases chemistry, src-Family Kinases genetics, Enzyme Inhibitors pharmacology, Mitogen-Activated Protein Kinases, Protein-Tyrosine Kinases antagonists & inhibitors, Proteins pharmacology, src-Family Kinases antagonists & inhibitors
- Abstract
Background: Small-molecule inhibitors that can target individual kinases are powerful tools for use in signal transduction research. It is difficult to find such compounds because of the enormous number of protein kinases and the highly conserved nature of their catalytic domains. Recently, a novel, potent, Src family selective tyrosine kinase inhibitor was reported (PP1). Here, we study the structural basis for this inhibitor's specificity for Src family kinases., Results: A single residue corresponding to Ile338 (v-Src numbering; Thr338 in c-Src) in Src family tyrosine kinases largely controls PP1's ability to inhibit protein kinases. Mutation of Ile338 to a larger residue such as methionine or phenylalanine in v-Src makes this inhibitor less potent. Conversely, mutation of Ile338 to alanine or glycine increases PP1's potency. PP1 can inhibit Ser/Thr kinases if the residue corresponding to Ile338 in v-Src is mutated to glycine. We have accurately predicted several non-Src family kinases that are moderately (IC(50) approximately 1 microM) inhibited by PP1, including c-Abl and the MAP kinase p38., Conclusions: Our mutagenesis studies of the ATP-binding site in both tyrosine kinases and Ser/Thr kinases explain why PP1 is a specific inhibitor of Src family tyrosine kinases. Determination of the structural basis of inhibitor specificity will aid in the design of more potent and more selective protein kinase inhibitors. The ability to desensitize a particular kinase to PP1 inhibition of residue 338 or conversely to sensitize a kinase to PP1 inhibition by mutation should provide a useful basis for chemical genetic studies of kinase signal transduction. more...
- Published
- 1999
- Full Text
- View/download PDF
46. Behavioral genetics: subregion- and cell type-restricted gene knockout in mouse brain.
- Author
-
Tsien JZ
- Subjects
- Animals, Gene Deletion, Hippocampus physiology, Mice, Mice, Knockout, Neuronal Plasticity genetics, Learning physiology, Receptors, N-Methyl-D-Aspartate genetics
- Published
- 1998
47. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice.
- Author
-
McHugh TJ, Blum KI, Tsien JZ, Tonegawa S, and Wilson MA
- Subjects
- Action Potentials, Animals, Behavior, Animal physiology, Electrophysiology, Maze Learning physiology, Memory physiology, Mice, Mice, Knockout, Synapses physiology, Hippocampus physiology, Neuronal Plasticity physiology, Receptors, N-Methyl-D-Aspartate physiology, Space Perception physiology
- Abstract
To investigate the role of synaptic plasticity in the place-specific firing of the hippocampus, we have applied multiple electrode recording techniques to freely behaving mice with a CA1 pyramidal cell-specific knockout of the NMDAR1 gene. We have discovered that although the CA1 pyramidal cells of these mice retain place-related activity, there is a significant decrease in the spatial specificity of individual place fields. We have also found a striking deficit in the coordinated firing of pairs of neurons tuned to similar spatial locations. Pairs have uncorrelated firing even if their fields overlap. These results demonstrate that NMDA receptor-mediated synaptic plasticity is necessary for the proper representation of space in the CA1 region of the hippocampus. more...
- Published
- 1996
- Full Text
- View/download PDF
48. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.
- Author
-
Tsien JZ, Huerta PT, and Tonegawa S
- Subjects
- Animals, Behavior, Animal physiology, Dentate Gyrus physiology, Genetic Engineering methods, Genetic Vectors, In Situ Hybridization, Long-Term Potentiation, Mice, Mice, Knockout, Synaptic Transmission, Hippocampus physiology, Memory physiology, Neuronal Plasticity physiology, Receptors, N-Methyl-D-Aspartate physiology
- Abstract
We have produced a mouse strain in which the deletion of the NMDAR1 gene is restricted to the CA1 pyramidal cells of the hippocampus by using a new and general method that allows CA1-restricted gene knockout. The mutant mice grow into adulthood without obvious abnormalities. Adult mice lack NMDA receptor-mediated synaptic currents and long-term potentiation in the CA1 synapses and exhibit impaired spatial memory but unimpaired nonspatial learning. Our results strongly suggest that activity-dependent modifications of CA1 synapses, mediated by NMDA receptors, play an essential role in the acquisition of spatial memories. more...
- Published
- 1996
- Full Text
- View/download PDF
49. Subregion- and cell type-restricted gene knockout in mouse brain.
- Author
-
Tsien JZ, Chen DF, Gerber D, Tom C, Mercer EH, Anderson DJ, Mayford M, Kandel ER, and Tonegawa S
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinases genetics, Gene Expression, Gene Expression Regulation, Gestational Age, Mice, Mice, Transgenic, Promoter Regions, Genetic, RNA, Messenger genetics, Recombination, Genetic, Sequence Deletion, Genetic Engineering methods, Hippocampus physiology, Integrases genetics, Mice, Knockout genetics, Viral Proteins
- Abstract
Using the phage P1-derived Cre/loxP recombination system, we have developed a method to create mice in which the deletion (knockout) of virtually any gene of interest is restricted to a subregion or a specific cell type in the brain such as the pyramidal cells of the hippocampal CA1 region. The Cre/loxP recombination-based gene deletion appears to require a certain level of Cre protein expression. The brain subregional restricted gene knockout should allow a more precise analysis of the impact of a gene mutation on animal behaviors. more...
- Published
- 1996
- Full Text
- View/download PDF
50. Hippocampal CA1-region-restricted knockout of NMDAR1 gene disrupts synaptic plasticity, place fields, and spatial learning.
- Author
-
Tonegawa S, Tsien JZ, McHugh TJ, Huerta P, Blum KI, and Wilson MA
- Subjects
- Animals, Dentate Gyrus physiology, Electrophysiology, Mice, Mice, Knockout, Mutation physiology, Receptors, N-Methyl-D-Aspartate biosynthesis, Hippocampus metabolism, Learning physiology, Neuronal Plasticity physiology, Receptors, N-Methyl-D-Aspartate genetics, Space Perception physiology, Synapses physiology
- Published
- 1996
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