Author: "Uehara Memorial Foundation" - Searchworks@Jio Institute Digital Library Search Results

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31 results on '"Uehara Memorial Foundation"'

1. PRC1 suppresses a female gene regulatory network to ensure testicular differentiation

Author: Japan Society for the Promotion of Science, Takeda Science Foundation, Tokyo Biochemical Research Foundation, Daiichi Sankyo Foundation of Life Science, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Sumitomo Foundation for Basic Science Research, Senri Life Science Foundation, Uehara Memorial Foundation, Naito Foundation, Tokyo University of Science, National Institutes of Health (US), Maezawa, So [0000-0002-9060-2042], Masashi, Yukawa [0000-0003-1798-2410], Hasegawa, Kazuteru [0000-0001-5975-6521], Hu, Mengwen [0000-0002-7480-6432], Sakashita, Akihiko [0000-0002-3398-8436], Vidal, Miguel [0000-0003-4374-6761], Koseki, Haruhiko [0000-0001-8424-5854], Barski, A. [0000-0002-1861-5316], DeFalco, Tony 0000-0003-4133-7040], Namekawa, Satoshi H. [0000-0002-1052-943X], Maezawa, So, Masashi, Yukawa, Hasegawa, Kazuteru, Sugiyama, Ryo, Iizuka, Mizuho, Hu, Mengwen, Sakashita, Akihiko, Vidal, Miguel, Koseki, Haruhiko, Barski, A., DeFalco, Tony, Namekawa, Satoshi H., Japan Society for the Promotion of Science, Takeda Science Foundation, Tokyo Biochemical Research Foundation, Daiichi Sankyo Foundation of Life Science, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Sumitomo Foundation for Basic Science Research, Senri Life Science Foundation, Uehara Memorial Foundation, Naito Foundation, Tokyo University of Science, National Institutes of Health (US), Maezawa, So [0000-0002-9060-2042], Masashi, Yukawa [0000-0003-1798-2410], Hasegawa, Kazuteru [0000-0001-5975-6521], Hu, Mengwen [0000-0002-7480-6432], Sakashita, Akihiko [0000-0002-3398-8436], Vidal, Miguel [0000-0003-4374-6761], Koseki, Haruhiko [0000-0001-8424-5854], Barski, A. [0000-0002-1861-5316], DeFalco, Tony 0000-0003-4133-7040], Namekawa, Satoshi H. [0000-0002-1052-943X], Maezawa, So, Masashi, Yukawa, Hasegawa, Kazuteru, Sugiyama, Ryo, Iizuka, Mizuho, Hu, Mengwen, Sakashita, Akihiko, Vidal, Miguel, Koseki, Haruhiko, Barski, A., DeFalco, Tony, and Namekawa, Satoshi H.
Abstract: Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes.
Published: 2023

2. Cross-hierarchical plasticity of corticofugal projections to dLGN after neonatal monocular enucleation

Author: Medical Research Council (UK), Wellcome Trust, Royal Society (UK), Daiichi-Sankyo, Uehara Memorial Foundation for International Students, Giasafaki, Chrysoula, Grant, Eleanor, Hoerder-Suabedissen, Anna, Hayashi, Shuichi, Lee, Sheena, Molnár, Zoltán, Medical Research Council (UK), Wellcome Trust, Royal Society (UK), Daiichi-Sankyo, Uehara Memorial Foundation for International Students, Giasafaki, Chrysoula, Grant, Eleanor, Hoerder-Suabedissen, Anna, Hayashi, Shuichi, Lee, Sheena, and Molnár, Zoltán
Abstract: Perception is the result of interactions between the sensory periphery, thalamus, and cerebral cortex. Inputs from the retina project to the first-order dorsal lateral geniculate nucleus (dLGN), which projects to the primary visual cortex (V1). In return, the cortex innervates the thalamus. While layer 6 projections innervate all thalamic nuclei, cortical layer 5 neurons selectively project to the higher order lateral posterior nucleus (LP) and not to dLGN. It has been demonstrated that a subpopulation of layer 5 (Rbp4-Cre+) projections rewires to dLGN after monocular or binocular enucleation in young postnatal mice. However, the exact cortical regional origin of these projections was not fully determined, and it remained unclear whether these changes persisted into adulthood. In this study, we report gene expression changes observed in the dLGN after monocular enucleation at birth using microarray, qPCR at P6, and in situ hybridization at P8. We report that genes that are normally enriched in dLGN, but not LP during development are preferentially downregulated in dLGN following monocular enucleation. Comparisons with developmental gene expression patters in dLGN suggest more immature and delayed gene expression in enucleated dLGN. Combined tracing and immuno-histochemical analysis revealed that the induced layer 5 fibers that innervate enucleated dLGN originate from putative primary visual cortex and they retain increased VGluT1+ synapse formation into adulthood. Our results indicate a new form of plasticity when layer 5 driver input takes over the innervation of an originally first-order thalamic nucleus after early sensory deficit.
Published: 2022

3. Meikin is a conserved regulator of meiosis-I-specific kinetochore function

Author: Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Ministry of Education, Culture, Sports, Science and Technology (Japan), Kim, Jihye, Pendás, Alberto M., Watanabe, Yoshinori, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Ministry of Education, Culture, Sports, Science and Technology (Japan), Kim, Jihye, Pendás, Alberto M., and Watanabe, Yoshinori
Abstract: The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.
Published: 2015

4. Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

Author: Ragnar Söderberg Foundation, European Commission, European Research Council, Swedish Medical Research Council, Karolinska Institute, Uehara Memorial Foundation, Borgius, Lotta, Nishimaru, Hiroshi, Caldeira, Vanessa, Kunugise, Yuka, Löw, Peter, Reig, Ramón, Itohara, Shigeyoshi, Iwasato, Takuji, Kiehn, Ole, Ragnar Söderberg Foundation, European Commission, European Research Council, Swedish Medical Research Council, Karolinska Institute, Uehara Memorial Foundation, Borgius, Lotta, Nishimaru, Hiroshi, Caldeira, Vanessa, Kunugise, Yuka, Löw, Peter, Reig, Ramón, Itohara, Shigeyoshi, Iwasato, Takuji, and Kiehn, Ole
Abstract: EphA4 signaling is essential for the spatiotemporal organization of neuronal circuit formation. In mice, deletion of this signaling pathway causes aberrant midline crossing of axons from both brain and spinal neurons and the complete knock-outs (KOs) exhibit a pronounced change in motor behavior, where alternating gaits are replaced by a rabbit-like hopping gait. The neuronal mechanism that is responsible for the gait switch in these KO mice is not known. Here, using intersectional genetics, we demonstrate that a spinal cord-specific deletion of EphA4 signaling is sufficient to generate the overground hopping gait. In contrast, selective deletion of EphA4 signaling in forebrain neurons, including the corticospinal tract neurons, did not result in a change in locomotor pattern. The gait switch was attributed to the loss of EphA4 signaling in excitatory Vglut2+ neurons, which is accompanied by an increased midline crossing of Vglut2+ neurons in the ventral spinal cord. Our findings functionally define spinal EphA4 signaling in excitatory Vglut2+ neurons as required for proper organization of the spinal locomotor circuitry, and place these cells as essential components of the mammalian locomotor network.
Published: 2014

5. Broad action of Hsp90 as a host chaperone required for viral replication

Author: National Institutes of Health (US), Naito Foundation, Uehara Memorial Foundation, Geller, Ron, Taguwa, Shuhei, Frydman, Judith, National Institutes of Health (US), Naito Foundation, Uehara Memorial Foundation, Geller, Ron, Taguwa, Shuhei, and Frydman, Judith
Abstract: Viruses are intracellular pathogens responsible for a vast number of human diseases. Due to their small genome size, viruses rely primarily on the biosynthetic apparatus of the host for their replication. Recent work has shown that the molecular chaperone Hsp90 is nearly universally required for viral protein homeostasis. As observed for many endogenous cellular proteins, numerous different viral proteins have been shown to require Hsp90 for their folding, assembly, and maturation. Importantly, the unique characteristics of viral replication cause viruses to be hypersensitive to Hsp90 inhibition, thus providing a novel therapeutic avenue for the development of broad-spectrum antiviral drugs. The major developments in this emerging field are hereby discussed. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
Published: 2012

6. Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

Author: Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, National Institutes of Health (US), G. Harold & Leila Y. Mathers Foundation, Alzheimer's Association, Shi, Song-Hai, Hayashi, Yasunori, Esteban, José A., Malinow, Roberto, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, National Institutes of Health (US), G. Harold & Leila Y. Mathers Foundation, Alzheimer's Association, Shi, Song-Hai, Hayashi, Yasunori, Esteban, José A., and Malinow, Roberto
Abstract: AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.
Published: 2001

7. Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction

Author: Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, Human Frontier Science Program, National Institutes of Health (US), G. Harold & Leila Y. Mathers Foundation, Hayashi, Yasunori, Shi, Song-Hai, Esteban, José A., Piccini, Antonella, Poncer, Jean-Christophe, Malinow, Roberto, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, Human Frontier Science Program, National Institutes of Health (US), G. Harold & Leila Y. Mathers Foundation, Hayashi, Yasunori, Shi, Song-Hai, Esteban, José A., Piccini, Antonella, Poncer, Jean-Christophe, and Malinow, Roberto
Abstract: To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/ calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein.
Published: 2000

8. Cross‐hierarchical plasticity of corticofugal projections to dLGN after neonatal monocular enucleation

Author: Chrysoula Giasafaki, Eleanor Grant, Anna Hoerder‐Suabedissen, Shuichi Hayashi, Sheena Lee, Zoltán Molnár, Medical Research Council (UK), Wellcome Trust, Royal Society (UK), Daiichi-Sankyo, and Uehara Memorial Foundation for International Students
Subjects: Cross hierarchical cortico-thalamic plasticity, Rbp4-cre, General Neuroscience, Geniculate Bodies, layer 5, Mice, cortex, cross hierarchical cortico-thalamic plasticity, Thalamus, Thalamic Nuclei, thalamus, Cortex, Layer 5, Animals, Visual Pathways, Visual Cortex
Abstract: Perception is the result of interactions between the sensory periphery, thalamus, and cerebral cortex. Inputs from the retina project to the first-order dorsal lateral geniculate nucleus (dLGN), which projects to the primary visual cortex (V1). In return, the cortex innervates the thalamus. While layer 6 projections innervate all thalamic nuclei, cortical layer 5 neurons selectively project to the higher order lateral posterior nucleus (LP) and not to dLGN. It has been demonstrated that a subpopulation of layer 5 (Rbp4-Cre+) projections rewires to dLGN after monocular or binocular enucleation in young postnatal mice. However, the exact cortical regional origin of these projections was not fully determined, and it remained unclear whether these changes persisted into adulthood. In this study, we report gene expression changes observed in the dLGN after monocular enucleation at birth using microarray, qPCR at P6, and in situ hybridization at P8. We report that genes that are normally enriched in dLGN, but not LP during development are preferentially downregulated in dLGN following monocular enucleation. Comparisons with developmental gene expression patters in dLGN suggest more immature and delayed gene expression in enucleated dLGN. Combined tracing and immuno-histochemical analysis revealed that the induced layer 5 fibers that innervate enucleated dLGN originate from putative primary visual cortex and they retain increased VGluT1+ synapse formation into adulthood. Our results indicate a new form of plasticity when layer 5 driver input takes over the innervation of an originally first-order thalamic nucleus after early sensory deficit., Thanks goes to Isabel Martinez‐Garay for her advice and help with the in situ hybridization. The microarray facility was funded by the Wellcome Trust Integrative Physiology Initiative on Ion Channels (OXION). EG held an MRC graduate studentship. The work in the laboratory of Z. M. was supported by Medical Research Council (G00900901), The Wellcome Trust, The Royal Society, and Einstein Stiftung. SH was funded by the Daiichi Sankyo Foundation of Life Science, The Uehara Memorial Foundation and KAKENHI (Grant‐in‐Aid for Research Activity Start‐up, 19K23786 to S.H.).
Published: 2022

9. Podocytes maintain high basal levels of autophagy independent of mtor signaling

Author: Bjoern Hartleben, Wei Liang, Shuya Liu, Kosuke Yamahara, Ketan Patel, Kathrin Thedieck, Tillmann Bork, Olivia Lenoir, Philipp Lee, Christoph Schell, Tobias B. Huber, Zhejia Tian, Pierre-Louise Tharaux, Department of Medicine IV [Freiburg, Germany] (Faculty of Medicine), University of Freiburg [Freiburg], Division of Nephrology [Wuhan, China], Wuhan University [China]-Renmin Hospital [Wuhan, China], Department of Medicine [Otsu, Japan], Shiga University of Medical Science, Department of Medicine [Hamburg, Germany], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Molecular Biosciences Innsbruck [Innsbruck, Austria] (Institute of Biochemistry), University of Innsbruck, University Medical Center Groningen [Groningen] (UMCG), University of Oldenburg, Hannover Medical School [Hannover] (MHH), Freiburg Institute for Advanced Studies [Freiburg, Germany], Albert-Ludwigs-Universität Freiburg, School of Biological Sciences [Reading], University of Reading (UOR), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie [Hôpital Européen Georges Pompidou - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This work was supported by the German Research Foundation [CRC1140, CRC1192], European Foundation for the Study of Diabetes (EFSD), German Research Foundation Heisenberg Program [HU1016/ 5-1], German Research Foundation Heisenberg Program [HU1016/8-2], EC | European Research Council (ERC), H2020-IMI2 BEAt-DKD [115974], BMBF-STOP-FSGS [01GM1518C], Excellence Initiative of the German Federal and State Governments BIOSS, FRIAS Freiburg Institute of Advanced Studies, Alexander von Humboldt Foundation, German Research Foundation [CRC992], National Natural Science Foundation of China (NSFC) [81470912], Berta Ottenstein Program, Else Kroener Fresenius Foundation NAKSYS, BMBF GlioPATH [01ZX1402B], BMBF MAPTor-NET [031A426B], German Research Foundation [TH 1358/3-1], MESI-STRAT [754688], Uehara Memorial Foundation, German TS Foundation, Stichting TSC Fonds (calls 2015 and 2017), PoLiMeR Innovative Training Network (Marie SklodowskaCurie grant agreement No. 812616, Rosalind-Franklin Fellowship of the Universitiy of Groningen., Tharaux, Pierre-Louis, Leopold Franzens Universität Innsbruck - University of Innsbruck, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: AMPK, 0301 basic medicine, podocyte, Research Paper - Basic Science, PROTEIN, glomerulus, Podocyte, ACTIVATION, LC3, PHOSPHORYLATION, ULK1, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, CELL-LINE, biology, Podocytes, TOR Serine-Threonine Kinases, MTOR, Raptor, Cell biology, medicine.anatomical_structure, signaling, Signal Transduction, Research Article, autophagy, kidney, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mechanistic Target of Rapamycin Complex 1, DIABETIC-NEPHROPATHY, Nephrin, 03 medical and health sciences, medicine, Animals, Humans, Protein kinase A, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Sirolimus, 030102 biochemistry & molecular biology, rapamycin, RPTOR, Autophagy, KIDNEY-DISEASE, Cell Biology, Tsc1, 030104 developmental biology, MAMMALIAN TARGET, biology.protein, Podocin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; While constant basal levels of macroautophagy/autophagy are a prerequisite to preserve long-lived podocytes at the filtration barrier, MTOR regulates at the same time podocyte size and compensatory hypertrophy. Since MTOR is known to generally suppress autophagy, the apparently independent regulation of these two key pathways of glomerular maintenance remained puzzling. We now report that long-term genetic manipulation of MTOR activity does in fact not influence high basal levels of autophagy in podocytes either in vitro or in vivo. Instead we present data showing that autophagy in podocytes is mainly controlled by AMP-activated protein kinase (AMPK) and ULK1 (unc-51 like kinase 1). Pharmacological inhibition of MTOR further shows that the uncoupling of MTOR activity and autophagy is time dependent. Together, our data reveal a novel and unexpected cell-specific mechanism, which permits concurrent MTOR activity as well as high basal autophagy rates in podocytes. Thus, these data indicate manipulation of the AMPK-ULK1 axis rather than inhibition of MTOR as a promising therapeutic intervention to enhance autophagy and preserve podocyte homeostasis in glomerular diseases.Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: AMP-activated protein kinase; ATG: autophagy related; BW: body weight; Cq: chloroquine; ER: endoplasmic reticulum; ESRD: end stage renal disease; FACS: fluorescence activated cell sorting; GFP: green fluorescent protein; i.p.: intra peritoneal; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; NPHS1: nephrosis 1, nephrin; NPHS2: nephrosis 2, podocin; PLA: proximity-ligation assay; PRKAA: 5'-AMP-activated protein kinase catalytic subunit alpha; RPTOR/RAPTOR: regulatory associated protein of MTOR, complex 1; RFP: red fluorescent protein; TSC1: tuberous sclerosis 1; ULK1: unc-51 like kinase 1.
Published: 2019

10. Direct Readout of Neural Stem Cell Transgenesis with an Integration-Coupled Gene Expression Switch

Author: Kumamoto, Takuma, Maurinot, Franck, Barry-Martinet, Raphaëlle, Vaslin, Célia, Vandormael-Pournin, Sandrine, Le, Mickaël, Lerat, Marion, Niculescu, Dragos, Cohen-Tannoudji, Michel, Rebsam, Alexandra, Loulier, Karine, Nedelec, Stéphane, Tozer, Samuel, Livet, Jean, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Fer à Moulin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (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)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Embryon précoce de mammifères et cellules souches, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (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)-École normale supérieure - Paris (ENS-PSL), This work was funded by fellowships from the Uehara Memorial Foundation and Naito Foundation to T.K., the French Ministry of Research (F.M. and C.V.), Fondation pour la Recherche Médicale (DBI20141231328), the European Research Council (ERC-CoG 649117), and Agence Nationale de la Recherche under contracts ANR-10-LABX-65 (Labex Lifesenses), ANR-18-IAHU-0001 (IHU FOReSIGHT), ANR-10-LABX-73-01, ANR-15-CE13-0010, ANR-19-CE11-0005, and ANR-19-CE16-0019. S.N. was funded by ATIP/Avenir and Association Française contre les Myopathies. A.R. was funded by ANR-12-BSV4-0002, Fondation NRJ, and Genespoir., We thank X. Morin, G. Le Dréau, and G. Orieux for scientific discussions and comments on the manuscript, X. Nicol for the Kras sequence, J.-M. Matter for the Atoh7 promoter, C. Marcelle for the NICD-expressing plasmid, and all members of the Livet lab for assistance. We thank L. Riancho and P.-H. Commère from the Saint-Antoine and Institut Pasteur cytometry facilities and A. Potey, C. Condroyer, S. Fouquet, and the Institut de la Vision core facilities., ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), ANR-15-CE13-0010,STEMDYN,COMMUNICATION CELLULE-CELLULE ET DYNAMIQUE DES POPULATIONS DE CELLULES SOUCHES NEURALES EMBRYONNAIRES(2015), ANR-12-BSV4-0002,STEMIMUS,Utilisation des cellules souches hematopeietiques pour cibler les signaux de remyelinisation dans la sclérose en plaques(2012), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, and Université Paris sciences et lettres (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)
Subjects: DNA vectors, genetic engineering, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genetic Vectors, Gene Transfer Techniques, Gene Expression, mosaic analysis, transposon systems, Article, Mice, somatic transgenesis, lineage tracing, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Animals, Humans, Cell Lineage, Transgenes, genetic switch, genomic integration, [SDV.BDD]Life Sciences [q-bio]/Development Biology, neural stem cells
Abstract: Summary Stable genomic integration of exogenous transgenes is essential in neurodevelopmental and stem cell studies. Despite tools driving increasingly efficient genomic insertion with DNA vectors, transgenesis remains fundamentally hindered by the impossibility of distinguishing integrated from episomal transgenes. Here, we introduce an integration-coupled On genetic switch, iOn, which triggers gene expression upon incorporation into the host genome through transposition, thus enabling rapid and accurate identification of integration events following transfection with naked plasmids. In vitro, iOn permits rapid drug-free stable transgenesis of mouse and human pluripotent stem cells with multiple vectors. In vivo, we demonstrate faithful cell lineage tracing, assessment of regulatory elements, and mosaic analysis of gene function in somatic transgenesis experiments that reveal neural progenitor potentialities and interaction. These results establish iOn as a universally applicable strategy to accelerate and simplify genetic engineering in cultured systems and model organisms by conditioning transgene activation to genomic integration., Graphical Abstract, Highlights • A gene expression switch powered by genomic integration • Accelerated readout of additive transgenesis with one or multiple vectors • Faithful lineage tracing and mosaic analysis by somatic transfection • Near-universal applicability in cultured cells and animal models, Kumamoto et al. introduce iOn, a genetic switch that conditions exogenous transgene expression to integration in the host cell genome by DNA transposition. This system radically simplifies stable transgenesis with one or multiple plasmid vectors, opening new options to genetically manipulate cells in cultured systems and model organisms.
Published: 2020

11. MitoBlue as a tool to analyze the mitochondria-lysosome communication

Author: Ezequiel Perez-Inestrosa, Yolanda Vida, M. Eugenio Vázquez, José L. Mascareñas, Mateo I. Sánchez, Ayumu Sugiura, José Martínez-Costas, [Sánchez,MI, Mascareñas,JL, Vázquez,ME] Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [Sugiura,A] Montreal Neurological Institute, McGill University, Montreal, QC, Canada. [Sugiura,A] Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada. [Vida,Y, Pérez-Inestrosa,E] Centro Andaluz de Nanomedicina y Biotecnología-BIONAND. Campanillas, Málaga, Spain. [Martínez-Costas,J] Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Bioquímica y Biología Molecular, Universidade de Santiago de Compostela, Santiago de, Compostela, Spain. [Vida,Y, Pérez-Inestrosa,E] Universidad de Málaga-IBIMA, Departamento de Química Orgánica, Málaga, Spain., The support was given by the Spanish grants BFU2013-43513-R, SAF2016-76689-R, CTQ2015-70698-R, RTI2018-099877-B-I00, CTQ2013-49317-EXP, CTQ2013-41339-P, CTQ2016-75870-P, CTQ2015-71896-REDT (Red de Fotoquímica Biológica) and Instituto de Salud Carlos III (ISCIII, RETIC ARADYAL D16/0006/0012), Junta de Andalucía (PI0250-2016 and UMA18-FEDERJA-007), Orfeo-cinqa network CTQ2016-81797-REDC, the Xunta de Galicia (2015-CP082, ED431C 2017/19, Centro Singular de investigación de Galicia accreditation 2019–2022, ED431G 2019/03), the European Union (European Regional Development Fund - ERDF), and the European Research Council (Advanced Grant No. 340055) are gratefully acknowledged. M.E.V. also acknowledges the support provided by the Fundación AECC IDEAS197VAZQ grant). A.S. was supported by the Uehara Memorial Foundation and a JSPS Postdoctoral Fellowship for Research Abroad., Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Universidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular, and Universidade de Santiago de Compostela. Departamento de Química Orgánica
Subjects: 0301 basic medicine, Mitochondrial Degradation, Amidines, lcsh:Medicine, Chick Embryo, Mitochondrion, Bisamidine, 01 natural sciences, Imaging, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Microscopy::Microscopy, Fluorescence [Medical Subject Headings], Microscopía, Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Cytoplasmic Vesicles::Lysosomes [Medical Subject Headings], 2-Naphthylamine, Organisms::Eukaryota::Animals [Medical Subject Headings], lcsh:Science, Mitocondrias, Mitochondrial degradation, Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm::Cytoplasmic Structures::Organelles::Mitochondria [Medical Subject Headings], Microscopy, Multidisciplinary, Anatomy::Cells::Connective Tissue Cells::Fibroblasts [Medical Subject Headings], Chemistry, Lysosome, Cell biology, Mitochondria, medicine.anatomical_structure, Proteínas, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Histological Techniques::Histocytological Preparation Techniques::Staining and Labeling [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Amidines [Medical Subject Headings], Mitofagia, Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Indicators and Reagents::Luminescent Agents::Fluorescent Dyes [Medical Subject Headings], 010402 general chemistry, Chemicals and Drugs::Organic Chemicals::Amines::2-Naphthylamine [Medical Subject Headings], Article, 03 medical and health sciences, medicine, Animals, Membranes, lcsh:R, Proteins, Quality control, Fibroblasts, 0104 chemical sciences, 030104 developmental biology, Microscopy, Fluorescence, Control de calidad, lcsh:Q, Anatomy::Embryonic Structures::Embryo, Nonmammalian::Chick Embryo [Medical Subject Headings], Lysosomes, Lisosomas
Abstract: MitoBlue is a fluorescent bisamidine that can be used to easily monitor the changes in mitochondrial degradation processes in different cells and cellular conditions. MitoBlue staining pattern is exceptional among mitochondrial dyes and recombinant fluorescent probes, allowing the dynamic study of mitochondrial recycling in a variety of situations in living cells. MitoBlue is a unique tool for the study of these processes that will allow the detailed characterization of communication between mitochondria and lysosomes We are thankful for the support given by the Spanish grants BFU2013-43513-R, SAF2016-76689-R, CTQ2015-70698-R, RTI2018-099877-B-I00, CTQ2013-49317-EXP, CTQ2013-41339-P, CTQ2016-75870-P, CTQ2015-71896-REDT (Red de Fotoquímica Biológica) and Instituto de Salud Carlos III (ISCIII; RETIC ARADYALRD16/0006/0012), Junta de Andalucía (PI0250-2016 and UMA18-FEDERJA-007), Orfeo-cinqa network CTQ2016-81797-REDC; the Xunta de Galicia (2015-CP082, ED431C 2017/19, Centro Singular de investigación de Galicia accreditation 2019–2022, ED431G 2019/03), the European Union (European Regional Development Fund - ERDF), and the European Research Council (Advanced Grant No. 340055) are gratefully acknowledged. M.E.V. also acknowledges the support provided by the Fundación AECC (IDEAS197VAZQ grant) SI
Published: 2020

12. Dietary l-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut

Author: Shrinivas Bishu, Harry L. T. Mobley, Malak H Bazzi, Christopher J. Alteri, Mohamad El-Zaatari, Kathryn A. Eaton, Michael Rodrigues, Nobuhiko Kamada, John Y. Kao, Helmut Grasberger, Chiharu Ishii, Tina L. Morhardt, Naohiro Inohara, Hiroko Nagao-Kitamoto, Sho Kitamoto, Atsushi Hayashi, Tatsuki Nishioka, Kenneth W. Simpson, Peter Kuffa, Kohei Sugihara, Belgin Dogan, Nicolas Barnich, Shinji Fukuda, Stephanie D. Himpsl, Mao Miyoshi, Akiyoshi Hirayama, Hiroko Nagao-Kitamoto, Laboratoire d'automatique et de génie des procédés (LAGEP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Clinical Sciences, College of Veterinary Medicine, Cornell University [New York], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Division of Gastroenterology, Department of Internal Medicine [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, University of Michigan Center for Gastrointestinal Research, Host Microbiome Initiative NIH 5P30DK034933Kenneth Rainin Foundation United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USADK110146DK108901DK119219Crohn's and Colitis Foundation of America Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science Uehara Memorial Foundation University of Michigan Clinical and Translational Science Awards Program Prevent Cancer Foundation Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of ScienceGrants-in-Aid for Scientific Research (KAKENHI)16H0490117H0565418H04805Japan Science & Technology Agency (JST)JPMJPR1537Japan Science & Technology Agency (JST)JPMJER1902AMED-CREST JP19gm1010009Takeda Science Foundation (TSF) Food Science Institute Foundation Universite Clermont Auvergne Inserm U1071 INRA USC-2018 DK094775, and Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), Immunology, Inflammation, medicine.disease_cause, Applied Microbiology and Biotechnology, Microbiology, Article, 03 medical and health sciences, Mice, Enterobacteriaceae, Genetics, medicine, Citrobacter rodentium, Escherichia coli, Serine, Animals, Intestinal Mucosa, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Catabolism, Pathogenic bacteria, Cell Biology, Metabolism, Gene Expression Regulation, Bacterial, biology.organism_classification, Colitis, Specific Pathogen-Free Organisms, Diet, Mice, Inbred C57BL, Metabolic pathway, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Microbial Interactions, medicine.symptom, Metabolic Networks and Pathways
Abstract: International audience; Metabolic reprogramming is associated with the adaptation of host cells to the disease environment, such as inflammation and cancer. However, little is known about microbial metabolic reprogramming or the role it plays in regulating the fitness of commensal and pathogenic bacteria in the gut. Here, we report that intestinal inflammation reprograms the metabolic pathways of Enterobacteriaceae, such as Escherichia coli LF82, in the gut to adapt to the inflammatory environment. We found that E. coli LF82 shifts its metabolism to catabolize L-serine in the inflamed gut in order to maximize its growth potential. However, L-serine catabolism has a minimal effect on its fitness in the healthy gut. In fact, the absence of genes involved in L-serine utilization reduces the competitive fitness of E. coli LF82 and Citrobacter rodentium only during inflammation. The concentration of luminal L-serine is largely dependent on dietary intake. Accordingly, withholding amino acids from the diet markedly reduces their availability in the gut lumen. Hence, inflammation-induced blooms of E. coli LF82 are significantly blunted when amino acids-particularly L-serine-are removed from the diet. Thus, the ability to catabolize L-serine increases bacterial fitness and provides Enterobacteriaceae with a growth advantage against competitors in the inflamed gut.
Published: 2020

13. Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones

Author: Isabel Cuesta, Makiko Iwafuchi, Pilar Santisteban, Kenneth S. Zaret, Naomi Takenaka, Greg Donahue, Heinrich Roder, Steven H. Seeholzer, Anna B. Osipovich, Mark A. Magnuson, Japan Society for the Promotion of Science, Astellas Pharma, Uehara Memorial Foundation for International Students, Comunidad de Madrid, Ministerio de Economía y Competitividad (España), European Commission, and National Institutes of Health (US)
Subjects: Transcription, Genetic, Gene regulatory network, Biology, Article, Cell Line, Histones, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Genetics, Animals, Humans, Nucleosome, Gene Regulatory Networks, Amino Acid Sequence, Transcription factor, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Gene Expression Regulation, Developmental, DNA, Chromatin, Nucleosomes, Cell biology, Mice, Inbred C57BL, Histone, chemistry, biology.protein, Female, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. However, a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short α-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming., M.I. was supported by postdoctoral fellowships from Japan Society for the Promotion of Science Foundation (H26-683), Naito Foundation (RYU10000032), Astellas Foundation for Research on Metabolic Disorders (K0076) and Uehara Memorial Foundation (H24-20124). P.S. was supported by grant nos. SAF2016-75531-R (MICINN/FEDER, UE) and B2017/BMD-3724 (Comunidad de Madrid). The research was supported by NIH grant no. GM36477 to K.S.Z.
Published: 2020

14. Actin filaments regulate microtubule growth at the centrosome

Author: Ana-Maria Lennon-Duménil, Manuel Théry, Dorian Obino, Laurent Blanchoin, Francesca Farina, Daisuke Inoue, Christophe Guérin, Judith Pineau, Jérémie Gaillard, UMR 1417 PCV Laboratoire de Physiologie Cellulaire Végétale. Centre de recherche Auvergne-Rhône-Alpes, Institut National de la Recherche Agronomique (INRA), Institut Curie [Paris], Physiologie cellulaire et végétale (LPCV), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Uehara Memorial Foundation, Fondation pour la Recherche Medicale FDT20150532056, Association Nationale pour la Recherche ANR-PoLyBex-12-BSV3-0014-001 ANR-Mitotube-12-BSV5-0004-01, European Research Council (ERC) ERC-Strapacemi-GA 243103 ERC-SpiCy 310472, and Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG)
Subjects: [SDV]Life Sciences [q-bio], macromolecular substances, Biology, Microtubules, General Biochemistry, Genetics and Molecular Biology, Jurkat Cells, Mice, 03 medical and health sciences, 0302 clinical medicine, Microtubule, Animals, Humans, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Cell adhesion, Molecular Biology, Cells, Cultured, Actin, 030304 developmental biology, Cell spreading, 0303 health sciences, General Immunology and Microbiology, General Neuroscience, cell adhesion, Articles, Actins, Cell biology, Actin Cytoskeleton, Crosstalk (biology), centrosome, Physical Barrier, Centrosome, Lymphocyte activation, Cattle, Microtubule-Associated Proteins, actin, 030217 neurology & neurosurgery, microtubule
Abstract: International audience; The centrosome is the main microtubule-organizing centre. It also organizes a local network of actin filaments. However, the precise function of the actin network at the centrosome is not well understood. Here, we show that increasing densities of actin filaments at the centrosome of lymphocytes are correlated with reduced amounts of microtubules. Furthermore, lymphocyte activation resulted in disassembly of centrosomal actin and an increase in microtubule number. To further investigate the direct crosstalk between actin and microtubules at the centrosome, we performed in vitro reconstitution assays based on (i) purified centrosomes and (ii) on the co-micropatterning of microtubule seeds and actin filaments. These two assays demonstrated that actin filaments constitute a physical barrier blocking elongation of nascent microtubules. Finally, we showed that cell adhesion and cell spreading lead to lower densities of centrosomal actin, thus resulting in higher microtubule growth. We therefore propose a novel mechanism, by which the number of centrosomal microtubules is regulated by cell adhesion and actin-network architecture.
Published: 2019

15. Molecular Insights into Function and Competitive Inhibition of Pseudomonas aeruginosa Multiple Virulence Factor Regulator

Author: Michele Negri, Tomoe Kitao, Klaus Maskos, Laurence G. Rahme, Michael J. Pucci, Stefan Steinbacher, Frederick Walte, Seda Babloudi, Michael Blaesse, Antonio Felici, François Lépine, Bob Zahler, Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Shriners Hospitals for Children [Boston], Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Proteros Biostructures, Aptuit, Spero Therapeutics, and This work was supported by NIAID grants AI063433 and AI105902 to L.G.R. T.K. was supported by an International Research Fellowship from the Uehara Memorial Foundation, Japan.
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], 030106 microbiology, Allosteric regulation, Regulator, MvfR, medicine.disease_cause, Microbiology, Virulence factor, PqsR, 03 medical and health sciences, Transcription (biology), Virology, medicine, antivirulence, structural analysis, Transcription factor, X-ray crystallography, Pseudomonas aeruginosa, Chemistry, pathogenesis, quorum sensing, DNA-binding domain, infection, inhibition, QR1-502, 3. Good health, Cell biology, competitive inhibition, Quorum sensing, benzamine-benzimidazole inhibitors
Abstract: New approaches to antimicrobial drug discovery are urgently needed to combat intractable infections caused by multidrug-resistant (MDR) bacteria. M ultiple v irulence f actor r egulator (MvfR or PqsR), a Pseudomonas aeruginosa quorum sensing transcription factor, regulates functions important in both acute and persistent infections. Recently identified non-ligand-based benzamine-benzimidazole (BB) inhibitors of MvfR suppress both acute and persistent P. aeruginosa infections in mice without perturbing bacterial growth. Here, we elucidate the crystal structure of the MvfR ligand binding domain (LBD) in complex with one potent BB inhibitor, M64. Structural analysis indicated that M64 binds, like native ligands, to the MvfR hydrophobic cavity. A hydrogen bond and pi interaction were found to be important for MvfR-M64 affinity. Surface plasmon resonance analysis demonstrated that M64 is a competitive inhibitor of MvfR. Moreover, a protein engineering approach revealed that Gln194 and Tyr258 are critical for the interaction between MvfR and M64. Random mutagenesis of the full-length MvfR protein identified a single-amino-acid substitution, I68F, at a DNA binding linker domain that confers M64 insensitivity. In the presence of M64, I68F but not the wild-type (WT) MvfR protein retained DNA binding ability. Our findings strongly suggest that M64 promotes conformational change at the DNA binding domain of MvfR and that the I68F mutation may compensate for this change, indicating allosteric inhibition. This work provides critical new insights into the molecular mechanism of MvfR function and inhibition that could aid in the optimization of anti-MvfR compounds and improve our understanding of MvfR regulation. IMPORTANCE Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes serious acute, persistent, and relapsing infections. New approaches to antimicrobial drug discovery are urgently needed to combat intractable infections caused by this pathogen. The Pseudomonas aeruginosa quorum sensing transcription factor MvfR regulates functions important in both acute and persistent infections. We used recently identified inhibitors of MvfR to perform structural studies and reveal important insights that would benefit the optimization of anti-MvfR compounds. Altogether, the results reported here provide critical detailed mechanistic insights into the function of MvfR domains that may benefit the optimization of the chemical, pharmacological, and safety properties of MvfR antagonist series.
Published: 2018

16. Phosphocode-dependent functional dichotomy of a common co-receptor in plant signalling

Author: Paul Derbyshire, Daniel Couto, David Séré, Julian Avila, Xingyun Qi, Benjamin Schwessinger, Alberto P. Macho, Keiko U. Torii, Frank L.H. Menke, Lena Stransfeld, Artemis Perraki, Yasuhiro Kadota, Jan Sklenar, Cyril Zipfel, Thomas A. DeFalco, Shushu Jiang, Dept Plant Sci, University of Cambridge [UK] (CAM), Norwich Research Park, The Sainsbury Laboratory [Norwich] (TSL), Universität Zürich [Zürich] = University of Zurich (UZH), Sainsbury Lab, University of Washington [Seattle], Broad Institute of Harvard and MIT, Partenaires INRAE, Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Research School of Biology, Australian National University (ANU), RIKEN Center for Sustainable Resource Science [Yokohama] (RIKEN CSRS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Shanghai Center for Plant Stress Biology, Chinese Academy of Sciences, Shanghai Institute for Biological Sciences, CAS, University of Geneva, Gatsby Charitable Foundation, European Research Council (grant 'PHOSPHinnATE'), Gordon and Betty Moore Foundation [GBMF3035], Howard Hughes Medical Institute, European Molecular Biology Organization (EMBO-LTFs) [100-2017, 225-2015], RIKEN Special Postdoctoral Research Fellowship, JSPS Excellent Young Researcher Overseas Visit Program, Uehara Memorial Foundation, JIC/TSL PhD Rotation Program, University of Zurich, and Zipfel, Cyril
Subjects: 0106 biological sciences, 0301 basic medicine, Co-receptor, [SDV]Life Sciences [q-bio], 580 Plants (Botany), 01 natural sciences, Article, 03 medical and health sciences, 10126 Department of Plant and Microbial Biology, Arabidopsis, Arabidopsis thaliana, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, 10211 Zurich-Basel Plant Science Center, Tyrosine, 1000 Multidisciplinary, Multidisciplinary, biology, Kinase, fungi, Phosphoproteomics, biology.organism_classification, Cell biology, 030104 developmental biology, Phosphorylation, Function (biology), 010606 plant biology & botany
Abstract: International audience; Multicellular organisms use cell-surface receptor kinases to sense and process extracellular signals. Many plant receptor kinases are activated by the formation of ligand-induced complexes with shape-complementary co-receptors(1). The best-characterized co-receptor is BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1 (BAK1), which associates with numerous leucine-rich repeat receptor kinases (LRR-RKs) to control immunity, growth and development(2). Here we report key regulatory events that control the function of BAK1 and, more generally, LRR-RKs. Through a combination of phosphoproteomics and targeted mutagenesis, we identified conserved phosphosites that are required for the immune function of BAK1 in Arabidopsis thaliana. Notably, these phosphosites are not required for BAK1-dependent brassinosteroid-regulated growth. In addition to revealing a critical role for the phosphorylation of the BAK1 C-terminal tail, we identified a conserved tyrosine phosphosite that may be required for the function of the majority of Arabidopsis LRR-RKs, and which separates them into two distinct functional classes based on the presence or absence of this tyrosine. Our results suggest a phosphocode-based dichotomy of BAK1 function in plant signalling, and provide insights into receptor kinase activation that have broad implications for our understanding of how plants respond to their changing environment.
Published: 2018

17. Meikin is a conserved regulator of meiosis-I-specific kinetochore function

Author: Tomoya S. Kitajima, Bungo Akiyoshi, Aya Nambu, Takeshi Sakuno, Alberto M. Pendás, Tadashi Ishiguro, Kei-ichiro Ishiguro, Yogo Sakakibara, Yuji Tanno, Yoshinori Watanabe, Naoki Takeda, Ayano Kagami, Shihori Yokobayashi, Jihye Kim, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, and Ministry of Education, Culture, Sports, Science and Technology (Japan)
Subjects: Male, Saccharomyces cerevisiae Proteins, Chromosomal Proteins, Non-Histone, Centromere, Molecular Sequence Data, education, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Biology, PLK1, Chromosome segregation, Mice, Meiosis, Proto-Oncogene Proteins, Animals, Humans, Kinetochores, Conserved Sequence, Anaphase, Genetics, Multidisciplinary, Cohesin, Kinetochore, Meiosis II, Cell biology, Infertility, Female, Schizosaccharomyces pombe Proteins
Abstract: et al., The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans., This work was supported in part by a JSPS Research Fellowship (to J.K.), SAF2011-25252 (to A.M.P.), a research grant from Uehara Memorial Foundation, a RIKEN CDB intramural grant and a Grant-in-Aid for Young Scientists (B) (to T.S.K.), a Grant-in-Aid for Scientific Research on Innovative Areas, a Grant-in-Aid for Scientific Research (C) (to K.I.), and a Grant-in-Aid for Specially Promoted Research (to Y.W.) from MEXT, Japan.
Published: 2014

18. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions

Author: Bianca Balbino, George Delidakis, Tae Hyun Kang, Makiko Watanabe, Kendra Triplett, Anja Lux, Navin Varadarajan, Odile Richard-Le Goff, Oana I. Lungu, Pierre Bruhns, George Georgiou, Corrine Alford, Gabrielle Romain, Margaret A. Lindorfer, Wissam Charab, Falk Nimmerjahn, Yan Jessie Zhang, Hidetaka Tanno, Wupeng Yan, Nicholas M. Marshall, Moses Donkor, Chang-Han Lee, Jiwon Lee, Ronald P. Taylor, Biliana Todorova, University of Texas at Austin [Austin], University of Houston, Anticorps en Thérapie et Pathologie, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Erlangen-Nürnberg [Germany], University of Virginia School of Medicine [US], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), University of Virginia, Department of Biochemistry and Molecular Genetics (xxx), University of Virginia [Charlottesville], We thank Y. Tanno for assistance with protein expression, A. Bui for assistance with liquid chromatography–tandem mass spectrometry, P. Tucker (University of Texas at Austin) for cancer cell lines, D. Lee (MD Anderson Cancer Center) for patient-derived primary acute lymphocytic leukemia cells, the Macromolecular Crystallography Facility of the University of Texas at Austin, the Berkeley Center for Structural Biology, the Advanced Light Source (supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under contract DE-AC02-05CH11231), the Proteomics Facility at the University of Texas at Austin (supported by grant RP110782 from the Cancer Prevention Research Training Program), and A. Nicola and the Plate-Forme d'Imagerie Dynamique (Institut Pasteur, Paris) for help with the bioluminescence experiments. Supported by the Clayton Foundation, the Institut Pasteur (P.B. laboratory), the Institut National de la Santé et de la Recherche Médicale (P.B. laboratory), the European Research Council Seventh Frame-work Program (ERC-2013-CoG 616050 for the P.B. laboratory), the Pasteur–Paris University International PhD program (B.B.), the Cancer Prevention Research Training Program (RP140108 to M.D., RP160015 to H.T., and RP130570 to N.V.), the American Cancer Society (123506-PF-13-354-01-CDD to N.M.), Uehara Memorial Foundation (H.T.), Japan Society for the Promotion of Science (H.T.), Deutsche Forschungsgemeinschaft (CRC1181-A07 to F.N.), the US National Institutes of Health (R01CA174385 to N.V., and R01 GM104896 to Y.J.Z.) and the Welch Foundation (F-1778 to Y.J.Z.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Cancer Prevention and Research Institute of Texas., European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Martin, Marie, and Role of myeloid cells, their mediators and their antibody receptors in allergic shock (anaphylaxis) using humanized mouse models and clinical samples - MYELOSHOCK - - EC:FP7:ERC2014-09-01 - 2019-08-31 - 616050 - VALID
Subjects: Cytotoxicity, Immunologic, 0301 basic medicine, Cellular immunity, MESH: Complement C1q, MESH: Immunotherapy, Crystallography, X-Ray, Mass Spectrometry, MESH: Antibodies, Monoclonal, Mice, Tandem Mass Spectrometry, Neoplasms, Immunology and Allergy, MESH: Animals, MESH: Neoplasms, Cytotoxicity, Receptor, MESH: Phagocytosis, MESH: Crystallization, MESH: Immunoglobulin G, biology, Effector, Antibodies, Monoclonal, MESH: Enzyme-Linked Immunosorbent Assay, MESH: Chromatography, Gel, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Burkitt Lymphoma, 3. Good health, Cell biology, MESH: Surface Plasmon Resonance, Chromatography, Gel, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, Lymphoma, Large B-Cell, Diffuse, Antibody, Crystallization, Lymphoma, B-Cell, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Enzyme-Linked Immunosorbent Assay, In Vitro Techniques, MESH: Receptors, IgG, MESH: Immunoglobulin Fc Fragments, 03 medical and health sciences, Classical complement pathway, Immune system, Phagocytosis, Cell Line, Tumor, Animals, Humans, MESH: Cytotoxicity, Immunologic, MESH: Mice, MESH: Lymphoma, B-Cell, MESH: In Vitro Techniques, MESH: Mass Spectrometry, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, Complement C1q, Receptors, IgG, MESH: Tandem Mass Spectrometry, Surface Plasmon Resonance, MESH: Crystallography, X-Ray, Immunoglobulin Fc Fragments, Complement system, MESH: Burkitt Lymphoma, 030104 developmental biology, Immunoglobulin G, biology.protein, MESH: Lymphoma, Large B-Cell, Diffuse, MESH: Chromatography, Liquid, Chromatography, Liquid
Abstract: International audience; Engineered crystallizable fragment (Fc) regions of antibody domains, which assume a unique and unprecedented asymmetric structure within the homodimeric Fc polypeptide, enable completely selective binding to the complement component C1q and activation of complement via the classical pathway without any concomitant engagement of the Fcγ receptor (FcγR). We used the engineered Fc domains to demonstrate in vitro and in mouse models that for therapeutic antibodies, complement-dependent cell-mediated cytotoxicity (CDCC) and complement-dependent cell-mediated phagocytosis (CDCP) by immunological effector molecules mediated the clearance of target cells with kinetics and efficacy comparable to those of the FcγR-dependent effector functions that are much better studied, while they circumvented certain adverse reactions associated with FcγR engagement. Collectively, our data highlight the importance of CDCC and CDCP in monoclonal-antibody function and provide an experimental approach for delineating the effect of complement-dependent effector-cell engagement in various therapeutic settings.
Published: 2017

19. Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma

Author: Gregory R. Steinberg, Robert A. Foster, Wenyan Miao, Ting Wang, Vanessa P. Houde, Naoto Fujiwara, Hailing Sun, Jeremy R. Greenwood, Jennifer Rocnik, Geraldine Harriman, Danielle K. DePeralta, Theodoros Tsakiridis, Asish K. Saha, Lan Wei, Jamie Bates, Alexander E. Anagnostopoulos, Alice Wang, Henry Liu, Kenneth K. Tanabe, Omeed Moaven, Paola Muti, Yujin Hoshida, Derek J. Erstad, William F. Westlin, Rebecca J. Ford, Ricard Masia, James S. V. Lally, Bryan C. Fuchs, Adrian S. Ray, H. James Harwood, Lindsay A. Broadfield, Sarani Ghoshal, Rosana Kapeller, Vivian Leong, Sathesh Bhat, daulny, anne, Cell circuits as targets and biomarkers for liver disease and cancer prevention - HEPCIR - - H20202016-01-01 - 2020-12-31 - 671231 - VALID, Department of Medicine [Hamilton, ON, Canada], McMaster University [Hamilton, Ontario], Division of Surgical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital Cancer Center [Boston, MA, USA], Department of Pathology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis], University of Texas Southwestern Medical Center [Dallas], Department of Internal Medicine [Dallas, TX, USA], Department of Oncology [Hamilton, ON, Canada], Department of Pathobiology [Guelph, ON, Canada], University of Guelph-Ontario Veterinary College [Guelph, ON, Canada], Gilead Sciences, Inc. [Foster City, CA, USA], Department of Medicine and Physiology [Boston, MA, USA], Boston University [Boston] (BU)-School of Medicine, Endocrinology, Diabetes, and Nutrition [Boston, MA, USA], Schrodinger [New York, NY, USA], Nimbus Therapeutics [Cambridge, MA, USA], Department of Biochemistry and Biomedical Sciences [Hamilton, ON, Canada], This work was supported by grants from the National Cancer Institute (T32 CA071345 to D.K.D., O.M., and K.K.T. and K01 CA140861 to B.C.F.), the Uehara Memorial Foundation (N.F.), the National Institute of Diabetes and Digestive and Kidney Diseases (DK099558 to Y.H.), the European Union (ERC-2014-AdG-671231 HEPCIR to Y.H.), the Irma T. Hirschl Trust (Y.H.), the U.S. Department of Defense (W81XWH-16-1-0363 to Y.H.), the Canadian Cancer Society Research and Innovation Fund (G.R.S.), the Canadian Institutes of Health Research (G.R.S. 125980-1, 144625-1), Nimbus Therapeutics (to B.C.F.), and Gilead Sciences (to B.C.F.). A.E.G received a scholarship from the Canadian Liver Foundation. G.R.S. is supported by a Canada Research Chair and by the J. Bruce Duncan Chair in Metabolic Diseases., and European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016)
Subjects: 0301 basic medicine, Sorafenib, Male, Carcinoma, Hepatocellular, Physiology, cancer metabolism, Article, fructose, 03 medical and health sciences, Mice, 0302 clinical medicine, malonyl-CoA, NAFLD, medicine, Animals, Humans, Phosphorylation, Rats, Wistar, Protein kinase A, Molecular Biology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Chemistry, Lipogenesis, Fatty liver, fibrosis, Liver Neoplasms, Acetyl-CoA carboxylase, NASH, AMPK, non-alcoholic fatty liver disease, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Hep G2 Cells, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Rats, 030104 developmental biology, inflammation, Hepatocellular carcinoma, Cancer research, non-alcoholic steatohepatitis, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Acetyl-CoA Carboxylase
Abstract: International audience; The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.
Published: 2017

20. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects

Author: Yan Jiang, Carolina Muguruza, Daisuke Ibi, Carlos R. Escalante, Maryum K. Ijaz, Daniel J. Christoffel, Schahram Akbarian, Alexey Kozlenkov, Scott J. Russo, Nebojsa Kezunovic, Vishaka Santosh, Jeremy Seto, Javier González-Maeso, Terrell Holloway, Supriya A Gaitonde, Luis F. Callado, J. Javier Meana, Mario de la Fuente Revenga, José L. Moreno, Stella Dracheva, Mitsumasa Kurita, Grace E. Mosley, George W. Huntley, Juan F. López-Giménez, Aintzane García-Bea, Yongchao Ge, Justin M. Saunders, Japan Society for the Promotion of Science, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), European Commission, Eusko Jaurlaritza, Uehara Memorial Foundation for International Students, and Icahn School of Medicine at Mount Sinai
Subjects: 0301 basic medicine, Male, Transcriptional Activation, Mice, 129 Strain, medicine.medical_treatment, Repressor, Histone Deacetylase 2, Mice, Transgenic, Article, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Downregulation and upregulation, medicine, Animals, Humans, Antipsychotic, Maze Learning, Mice, Knockout, General Neuroscience, HEK 293 cells, NF-kappa B, NF-κB, Frontal Lobe, Mice, Inbred C57BL, IκBα, 030104 developmental biology, HEK293 Cells, chemistry, Synaptic plasticity, Forebrain, Synapses, Psychology, Cognition Disorders, Neuroscience, 030217 neurology & neurosurgery, Antipsychotic Agents
Abstract: Ibi, Daisuke et al., Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment., NIH R01 MH084894 (J.G.M.), NIH R01 MH111940 (J.G.M.), Dainippon Sumitomo Pharma (J.G.M.), NARSAD (J.G.M.), the Japan Society for the Promotion of Science (JSPS) 15H06719 and 16K19786 (D.I.), NIH R01 MH104491 (G.W.H.), NIH R01 MH086509 (S.A.), NIH P50 MH096890 (S.A.), MINECO/ERDF SAF2009-08460 (J.J.M. and L.F.C.), SAF2013-45084R (J.J.M. and L.F.C.), Basque Government IT616-13 (J.J.M.), NIH R21 MH103877 (S.D.) and NIH R01 MH090264 (S.J.R.) participated in the funding of this study. RNA-seq analysis was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and the NIH infrastructure grant S10OD018522. C.M. and A.G.B. were recipients of a postdoctoral and a predoctoral fellowship from the Basque Government, respectively. D.I. was a recipient of postdoctoral fellowships from JSPS (Young Scientists JSPS 23-3454) and the Uehara Memorial Foundation.
Published: 2017

21. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery

Author: Hadeel Adel Al-Lami, Kevin Drew, Yvonne Yeung, Karen J. Liu, Tae Joo Park, Anne Malfroot, Ghislaine Pierquin, Yannis Duffourd, Chanjae Lee, Marcus R. Kelly, Jiang Chen, Daniella Braun, Christel Thauvin-Robinet, Brunella Franco, Ange Line Bruel, Jacqueline M. Tabler, Kerstin Wagner, Deborah Krakow, Sukyoung Kim, Inusha Panigrahi, Edward M. Marcotte, Jean Baptiste Rivière, Armand Biver, Yeon Ja Choi, S. Paige Taylor, Laurence Faivre, Ivan Duran, Peter K. Jackson, Michinori Toriyama, John B. Wallingford, Daniel H. Cohn, Friedhelm Hildebrandt, Department of Molecular Biosciences, The University of Texas at Austin, Departement of human genetics [Los Angeles], Computer Science Department [Los Angeles] ( UCLA ), University of California at Los Angeles [Los Angeles] ( UCLA ) -University of California at Los Angeles [Los Angeles] ( UCLA ), David Geffen School of Medicine [Los Angeles], University of California at Los Angeles [Los Angeles] ( UCLA ), Department of Molecular Cellular and Developmental Biology, University of California at Los Angeles [Los Angeles] ( UCLA ) -Howard Hughes Medical Institute (HHMI), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Department of Microbiology and Immunology, Stanford University School of Medicine, Division of Polar Earth-System Sciences, Korea Polar Research Institute ( KOPRI ), Howard Hughes Medical Institute [Chevy Chase] ( HHMI ), Howard Hugues Medical Institute, Centre de Génétique Humaine, Université de Liège-CHU Liège, Département de Génétique, CHU, Liège, KannerKlinik Pédiatrie générale, Centre Hospitalier de Luxembourg (CHL), Units of Pediatric Pulmonology, Universitair Ziekenhuis Brussel, Advanced Pediatric Center ( PGIMER ), Pediatry center, Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Kings College London Dental Institute, The State University of New York ( SUNY ), Lung GO Sequencing Project HL-102923 WHI Sequencing Project HL-102924 Broad GO Sequencing Project HL-102925 Seattle GO Sequencing Project HL-102926 Heart GO Sequencing Project HL-103010 NHGRI NHLBI 1U54 HG006493 HL117164 Uehara Memorial Foundation Fellowship NIDCR NRSA French Rare Diseases Foundation French Ministry of Health (PHRC national) Regional Council of Burgundy NIDDK DK1068306 NIAMS AR061485 BBSRC BB/K010492/1 MRC MR/L017237/1 NIH NSF CPRIT 2010-A01014-35Welch Foundation F-1515 March of Dimes R01 AR066124 Joseph Drown Foundation NIH/NCATS UCLA CTSI grant UL1TR000124 R01 AR062651 NIGMS GM114276 GM104853 Baxter Laboratory Stanford Department of Research, Clinical sciences, Growth and Development, Computer Science Department [Los Angeles] (UCLA), University of California [Los Angeles] (UCLA), University of California-University of California-University of California [Los Angeles] (UCLA), University of California-University of California, University of California-University of California-Howard Hughes Medical Institute (HHMI), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of Microbiology and Immunology [Stanford], Stanford Medicine, Stanford University-Stanford University, Korea Polar Research Institute (KOPRI), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Advanced Pediatric Center (PGIMER), London Dental Institute (LDI), King‘s College London, State University of New York (SUNY), Toriyama, Michinori, Lee, Chanjae, Taylor, S. Paige, Duran, Ivan, Cohn, Daniel H, Bruel, Ange Line, Tabler, Jacqueline M, Drew, Kevin, Kelly, Marcus R, Kim, Sukyoung, Park, Tae Joo, Braun, Daniella, Pierquin, Ghislaine, Biver, Armand, Wagner, Kerstin, Malfroot, Anne, Panigrahi, Inusha, Franco, Brunella, Al lami, Hadeel Adel, Yeung, Yvonne, Choi, Yeon Ja, Duffourd, Yanni, Faivre, Laurence, Rivière, Jean Baptiste, Chen, Jiang, Liu, Karen J, Marcotte, Edward M, Hildebrandt, Friedhelm, Thauvin Robinet, Christel, Krakow, Deborah, Jackson, Peter K, and Wallingford, John B.
Subjects: 0301 basic medicine, Axoneme, primary ciliary dyskinesia, chlamydomonas flagella, planar cell polarity, Biology, Ciliopathies, Article, 03 medical and health sciences, Mice, Intraflagellar transport, Ciliogenesis, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, axonemal dyneins, medicine, Genetics, Basal body, Animals, Humans, tubulin transport, effector fuz, vesicle docking, embryonic-development, Cilium, Proteins, joubert syndrome, medicine.disease, Cell biology, Transport protein, Ciliopathy, Protein Transport, 030104 developmental biology, Phenotype, Flagella, Mutation, sense organs, ift-a complex, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Protein Binding
Abstract: International audience; Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.
Published: 2016

22. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity

Author: Takeshi Nakamura, Katsuaki Sato, Hideaki Takagi, Keiichi Arimura, Tomohiro Fukaya, Bernard Malissen, Tomofumi Uto, Naoya Kojima, University of Miyazaki, Tokai University, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Ministry of Education, Science and Culture of Japan, Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO) (K.S.), the Uehara Memorial Foundation (K.S.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (K.S.), Takeda Science Foundation (H.T.), Kato Memorial Bioscience Foundation (H.T.), The NOVARTIS Foundation (Japan) for the Promotion of Science (H.T.) and Nagao Memorial Fund (H.T.)., and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, T-Lymphocytes, medicine.medical_treatment, General Physics and Astronomy, Priming (immunology), CD8-Positive T-Lymphocytes, Ligands, Pathogenesis, Epitopes, Transduction, Genetic, Membrane proteins, Receptors, Immunologic, Receptor, Immunity, Cellular, Multidisciplinary, Toll-Like Receptors, Bacterial Infections, 3. Good health, Cell biology, Cytokine, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, medicine.symptom, Protein Binding, Encephalomyelitis, Autoimmune, Experimental, Science, CD8 Antigens, Receptors, Cell Surface, chemical and pharmacologic phenomena, Inflammation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Antigen, Polysaccharides, Immunity, Cell death and immune response, medicine, Animals, Dendritic Cells, General Chemistry, Protein Structure, Tertiary, Mice, Inbred C57BL, Retroviridae, 030104 developmental biology, Immunology
Abstract: Dendritic cells (DCs) comprise several subsets that are critically involved in the initiation and regulation of immunity. Clec4A4/DC immunoreceptor 2 (DCIR2) is a C-type lectin receptor (CLR) exclusively expressed on CD8α− conventional DCs (cDCs). However, how Clec4A4 controls immune responses through regulation of the function of CD8α− cDCs remains unclear. Here we show that Clec4A4 is a regulatory receptor for the activation of CD8α− cDCs that impairs inflammation and T-cell immunity. Clec4a4−/−CD8α− cDCs show enhanced cytokine production and T-cell priming following Toll-like receptor (TLR)-mediated activation. Furthermore, Clec4a4−/− mice exhibit TLR-mediated hyperinflammation. On antigenic immunization, Clec4a4−/− mice show not only augmented T-cell responses but also progressive autoimmune pathogenesis. Conversely, Clec4a4−/− mice exhibit resistance to microbial infection, accompanied by enhanced T-cell responses against microbes. Thus, our findings highlight roles of Clec4A4 in regulation of the function of CD8α− cDCs for control of the magnitude and quality of immune response., Clec4A4 is a C-type lectin receptor highly expressed by CD8α− dendritic cells. Here the authors show that its loss of function results in enhanced T cell responses and exacerbated autoimmunity, implicating Clec4A4 in limiting activation of the CD8α− dendritic cells.
Published: 2016

23. Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

Author: Massimo Iavarone, Ganesh Gunasekaran, Lan Wei, Takaaki Higashi, Hiroki Hoshida, Thomas F. Baumert, Augusto Villanueva, Rosa S. Kim, Anna P. Koh, Suguru Yamada, Scott L. Friedman, Xiaochen Sun, Bin Zhang, Milind Mahajan, Wan-Long Chuang, Angelo Sangiovanni, Yujin Hoshida, Derek J. Erstad, C Billie Bian, Myron E. Schwarz, Won-Min Song, Shigeki Nakagawa, Youngmin A. Lee, Gretchen Bain, Hideo Baba, Masahiro Kobayashi, Noor B. Ahmad, Bryan C. Fuchs, Gregory Y. Lauwers, Michael Lanuti, Kenneth K. Tanabe, Anu Venkatesh, Massimo Colombo, Mohamed El-Abtah, Sarani Ghoshal, Raymond T. Chung, Andrew M. Tager, Josep M. Llovet, Hiromitsu Kumada, Venugopalan D. Nair, Ming-Lung Yu, Chia-Yen Dai, Nicolas Goossens, Aravind Subramanian, Toru Beppu, Universitat de Barcelona, Department of Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department of Gastroenterological Surgery [Kumamoto, Japan], Kumamoto University-Graduate School of Medical Sciences [Kumamoto, Japan], Division of Surgical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital Cancer Center [Boston, MA, USA], Department of Genetics and Genomic Sciences, Division of Gastroenterology and Hepatology [Geneva, Switzerland], Geneva University Hospital (HUG), PharmAkea Therapeutics [San Diego, CA, USA], Department of Pathology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Recanati/Miller Transplantation Institute [New York, NY, USA], Department of Internal Medicine and Hepatitis Center [Kaohsiung, Taiwan] (Hepatobiliary Division), Kaohsiung Medical University Hospital [Taiwan], Center for Infectious Disease and Cancer Research [Kaohsiung, Taiwan], Kaohsiung Medical University [Kaohsiung, Taïwan] (KMU), Institute of Biomedical Sciences [Kaohsiung, Taiwan], National Sun Yat-Sen University (NSYSU), Department of Hepatology [Tokyo, Japan], Toranomon Hospital [Tokyo, Japan], Department of Neurology [New York, NY, USA], Division of Thoracic Surgery [Boston, MA, USA], M. & A. Migliavacca Center for Liver Disease [Milan, Italy] (1st Division of Gastroenterology), University of Milan-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Cancer Program [Cambridge, MA, USA], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT)-Broad Institute [Cambridge, MA, USA], Pulmonary and Critical Care Unit [Boston, MA, USA], Massachusetts General Hospital [Boston]-Center for Immunology and Inflammatory Diseases [Boston, MA, USA], Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle hépato-digestif [Strasbourg], Nouvel Hôpital Civil, Hospices Civils de Strasbourg-Institut Hospitalo-Universitaire de strasbourg, Gastrointestinal Division [Boston, MA, USA] (Liver Center - Department of Medicine), S.N. was supported by Uehara Memorial Foundation. N.G. was supported by FLAGS foundation, Nuovo-Soldati Cancer Research Foundation, and an advanced training grant from Geneva University Hospital. M.Y., W.-L.C., and C.-Y.D. were supported partially by Kaohsiung Medical University ‘‘Aim for the Top Universities Grant, grant No. KMU-TP103E06 & No. KMU-TP103E07 & No. KMUTP103E08,’’ and by a grant from Kaohsiung Medical University Hospital (KMUH102-2T01). T.F.B. was supported by ARC, Paris, Institut Hospitalo-Universitaire, Strasbourg (IHUARC IHU201301187), Laboratory of Excellence HEPSYS (ANR-10-LABX-0028), and European Union (ERC-2014-AdG-671231- HEPCIR). R.T.C. was supported by NIH/NIDDK (DK078772, DK098079). B.C.F. was supported by NIH/NCI (CA140861), NIH/NIDDK (DK104956), and grant from American Institute for Cancer Research. Y.H. was supported by NIH/NIDDK (DK099558), Irma T. Hirschl Trust, Dr. Harold and Golden Lamport Research Award, European Union (ERC-2014-AdG-671231-HEPCIR), and U.S. Department of Defense (W81XWH-16-1-0363)., Massachusetts General Hospital Cancer Center [Boston, MA, USA]-Harvard Medical School [Boston] (HMS), daulny, anne, and Università degli Studi di Milano = University of Milan (UNIMI)-Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
Subjects: Liver Cirrhosis, 0301 basic medicine, Cancer Research, Cirrhosis, Bioinformatics, gene signature, Transcriptome, chemistry.chemical_compound, Risk Factors, Lysophosphatidic acid, Gene Regulatory Networks, cancer chemoprevention, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Liver Neoplasms, hepatocellular carcinoma, Hepatitis B, 3. Good health, Oncology, Hepatic cirrhosis, Hepatocellular carcinoma, Liver cancer, Signal Transduction, Carcinoma, Hepatocellular, Cirrosi hepàtica, Antineoplastic Agents, Biology, Article, prognostic prediction, Càncer de fetge, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Genetic Predisposition to Disease, Gene Expression Profiling, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Gene signature, medicine.disease, Xenograft Model Antitumor Assays, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Rats, 030104 developmental biology, chemistry, Lysophospholipids, Steatohepatitis, transcriptome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Shigeki Nakagawa, Lan Wei and Won MinSong are co-first author.; International audience; Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.
Published: 2016
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24. Method for collecting mouse milk without exogenous oxytocin stimulation

Author: Julien Averous, Yuki Muranishi, Florent Mesclon, Alain Bruhat, Laurent Parry, Céline Jousse, Anne-Catherine Maurin, Valérie Carraro, Pierre Fafournoux, Anne Terrisse, Cédric Chaveroux, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), French National Research Agency (ANR)SFN (Societe Francaise de Nutrition) French National Research Agency (ANR)Uehara Memorial FoundationKanzawa Medical Research FoundationCentre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), ANR (French Agency for Research, EpiMetab), SFN (Societe Francaise de Nutrition), ANR, Uehara Memorial Foundation, Kanzawa Medical Research Foundation, Centre National pour la Recherche Scientifique (CNRS), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, medicine.medical_specialty, Milk ejection, Offspring, [SDV]Life Sciences [q-bio], Mammary gland, Stimulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, Milking, 03 medical and health sciences, Mice, Mammary Glands, Animal, nursing, milking, Internal medicine, oxytocin, medicine, Animals, Humans, Breast, Milk Ejection, mouse, 2. Zero hunger, methodology, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Breast Feeding, Milk, Oxytocin, Oxytocin Injection, Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Biotechnology, medicine.drug
Abstract: It has been reported that breast-feeding more than 6 months strongly decreases the risk of allergy, diabetes, obesity, and hypertension in humans. In order to understand the mechanisms responsible for this benefit, it is important to evaluate precisely the composition of maternal milk, especially in response to environmental cues. Mouse models offer a unique opportunity to study the impact of maternal milk composition on the development and health of offspring. Oxytocin injection of the dam is usually used to stimulate milk ejection; however, exogenous oxytocin might have deleterious effects under some experimental conditions by modifying milk content as well as the physiology and behavior of the dam. Taking advantage of the natural stimulation of the mammary gland that occurs after the reunion of a dam that has been separated from her pups, we developed a new procedure to collect mouse milk without the injection of oxytocin. This method is easy to use, low-cost ,and non-invasive. Moreover, it provides a sufficient amount of milk for use in a wide range of biological analyses.
Published: 2016

25. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity

Author: Biliana Lesic, Valeria Righi, Jianxin He, Laurence G. Rahme, François Lépine, A. Aria Tzika, Arunava Bandyopadhaya, Tomoe Kitao, Damien Maura, Melissa Starkey, Sylvain Milot, Shriners Hospitals for Children [Boston], Department of Microbiology and Immunobiology, Harvard Medical School [Boston] (HMS), Department of Surgery, Harvard Medical School [Boston] (HMS) - Massachusetts General Hospital, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS) - Réseau International des Instituts Pasteur (RIIP) - Institut Armand Frappier, Yersinia, Institut Pasteur [Paris], NMR Surgical Laboratory, Department of Surgery, Harvard Medical School [Boston] (HMS) - Massachusetts General Hospital and Shriners Burn Institute, Athinoula A. Martinos Center of Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Starkey, Melissa, Lepine, Francoi, Maura, Damien, Bandyopadhaya, Arunava, Lesic, Biljana, He, Jianxin, Kitao, Tomoe, Righi, Valeria, Milot, Sylvain, Tzika, Aria, Rahme, Laurence, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Massachusetts General Hospital [Boston], and MS and DM were supported by Shriners Postdoctoral Fellowships #8506, #84206 respectively. TK was supported by International Research Fellowshipfrom Uehara Memorial Foundation. LR was supported by Shriners Grant #87700 and #85300, NIH grants R21AI105902 and R56AI063433-06A1 and Cystic Fibrosis Foundation grant CFF#11P0. NERCE/NSRB was funded by U54 AI057159
Subjects: [SDV]Life Sciences [q-bio], Drug resistance, medicine.disease_cause, Mice, Drug Discovery, Medicine and Health Sciences, Biology (General), Pathogen, Virulence, Quorum Sensing, Drug Resistance, Multiple, 3. Good health, Bacterial Pathogens, Anti-Bacterial Agents, Medical Microbiology, Pseudomonas aeruginosa, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Research Article, Biotechnology, Chromatin Immunoprecipitation, Drug Research and Development, Multidrug tolerance, QH301-705.5, Immunology, Biology, Microbiology, Pseudomonas Infection, Antibiotic resistance, Genetic, Virology, Microbial Control, Anti-Bacterial Agent, Drug Resistance, Bacterial, Genetics, medicine, Animals, Pseudomonas Infections, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Microbial Pathogens, Pharmacology, Animal, Biology and Life Sciences, RC581-607, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Quorum sensing, Disease Models, Animal, Regulon, Small Molecules, Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Immunologic diseases. Allergy
Abstract: Etiological agents of acute, persistent, or relapsing clinical infections are often refractory to antibiotics due to multidrug resistance and/or antibiotic tolerance. Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen that causes recalcitrant and severe acute chronic and persistent human infections. Here, we target the MvfR-regulated P. aeruginosa quorum sensing (QS) virulence pathway to isolate robust molecules that specifically inhibit infection without affecting bacterial growth or viability to mitigate selective resistance. Using a whole-cell high-throughput screen (HTS) and structure-activity relationship (SAR) analysis, we identify compounds that block the synthesis of both pro-persistence and pro-acute MvfR-dependent signaling molecules. These compounds, which share a benzamide-benzimidazole backbone and are unrelated to previous MvfR-regulon inhibitors, bind the global virulence QS transcriptional regulator, MvfR (PqsR); inhibit the MvfR regulon in multi-drug resistant isolates; are active against P. aeruginosa acute and persistent murine infections; and do not perturb bacterial growth. In addition, they are the first compounds identified to reduce the formation of antibiotic-tolerant persister cells. As such, these molecules provide for the development of next-generation clinical therapeutics to more effectively treat refractory and deleterious bacterial-human infections., Author Summary Antibiotic resistant and tolerant bacterial pathogens are responsible for acute, chronic and persistent human infections recalcitrant to any current treatments. Therefore, there is an urgent need to identify new antimicrobial drugs that will help circumvent the current antibiotic resistance crisis. Bacterial pathogens often develop resistance to antibiotic drugs that target bacterial growth or viability. In contrast, strategies that specifically target virulence pathways non-essential for growth could limit selective resistance, and thus are candidates for the development of next-generation antimicrobial therapeutics. In this study we target the bacterial communication system MvfR (PqsR), which is known to control virulence of the opportunistic bacterial pathogen Pseudomonas aeruginosa. We identified and improved upon new small molecules that effectively silence the MvfR communication system, and as a result block P. aeruginosa virulence both in vitro and in vivo. Moreover, these new compounds are the first known to restrict the ability of bacteria to form antibiotic-tolerant cells and consequently proved to be very effective at preventing persistent infection in a mammalian infection model. Because of their ability to simultaneously block acute and persistent infections, these new molecules may provide a very strong basis for the development of next generation antimicrobials.
Published: 2014

26. An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

Author: Christine Petit, Fabrice Giraudet, Aziz El-Amraoui, Isabelle Foucher, Elisabeth Verpy, Samantha Papal, Sébastien Le Gal, Brigitte Riederer, Isabelle Perfettini, Ursula Seidler, Vincent Michel, Kazusaku Kamiya, Weiliang Xia, Paul Avan, Maria-Magdalena Georgescu, Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Department of Otorhinolaryngology, Juntendo University School of Medicine, Equipe Biophysique Neurosensorielle [Neuro-Dol], Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School [Hannover] (MHH), School of Management, Northwestern Polytechnical University [Xi'an] (NPU), Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center [Houston], This work was supported by the Japan Society for the Promotion of Science and Uehara Memorial Foundation (K.K.), EuropeanResearch Council (ERC)-HairBundle (ERC-2011-ADG_20110310), LABEX Lifesenses (ANR-10-LABX-65), Réunica-Prévoyance, Novalis Taitbout, BNP-Paribas, and Fondation Voir et Entendre (C.P.), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), European Project: 294570,EC:FP7:ERC,ERC-2011-ADG_20110310,HAIRBUNDLE(2012), Chaire Génétique et physiologie cellulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Neuro-Dol (Neuro-Dol), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)
Subjects: Auditory perception, Masking (art), medicine.medical_specialty, Sodium-Hydrogen Exchangers, Tectorial membrane, Infrasound, Nherf2, Audiology, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Animals, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Cochlea, 030304 developmental biology, Audio frequency, Mice, Knockout, 0303 health sciences, Multidisciplinary, Chemistry, hearing impairment, Biological Sciences, Phosphoproteins, Hair Cells, Auditory, Outer, off-frequency detection, medicine.anatomical_structure, Sound, Auditory Perception, sense organs, tail hypersensitivity, Cochlear microphonic potential, Auditory fatigue, Usher syndrome, 030217 neurology & neurosurgery
Abstract: A detrimental perceptive consequence of damaged auditory sensory hair cells consists in a pronounced masking effect exerted by low-frequency sounds, thought to occur when auditory threshold elevation substantially exceeds 40 dB. Here, we identified the submembrane scaffold protein Nherf1 as a hair-bundle component of the differentiating outer hair cells (OHCs). Nherf1(-/-) mice displayed OHC hair-bundle shape anomalies in the mid and basal cochlea, normally tuned to mid- and high-frequency tones, and mild (22-35 dB) hearing-threshold elevations restricted to midhigh sound frequencies. This mild decrease in hearing sensitivity was, however, discordant with almost nonresponding OHCs at the cochlear base as assessed by distortion-product otoacoustic emissions and cochlear microphonic potentials. Moreover, unlike wild-type mice, responses of Nherf1(-/-) mice to high-frequency (20-40 kHz) test tones were not masked by tones of neighboring frequencies. Instead, efficient maskers were characterized by their frequencies up to two octaves below the probe-tone frequency, unusually low intensities up to 25 dB below probe-tone level, and growth-of-masker slope (2.2 dB/dB) reflecting their compressive amplification. Together, these properties do not fit the current acknowledged features of a hypersensitivity of the basal cochlea to lower frequencies, but rather suggest a previously unidentified mechanism. Low-frequency maskers, we propose, may interact within the unaffected cochlear apical region with midhigh frequency sounds propagated there via a mode possibly using the persistent contact of misshaped OHC hair bundles with the tectorial membrane. Our findings thus reveal a source of misleading interpretations of hearing thresholds and of hypervulnerability to low-frequency sound interference.
Published: 2014

27. Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice

Author: Eric A. Shikatani, Rohan John, Ling Xia, Laura Stavar, I. George Fantus, Kanta Taniguchi, Elodie A.Y. Masson, Anu Shah, Abdul Momen, Ken W.K. Lee, Howard J. Goldberg, Mansoor Husain, Mount Sinai Hospital (MSH), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), University of Toronto, the Canadian Institutes of Health Research (CIHR) MOP 419409 and CCD 83025 (I.G.F.), the Canadian Diabetes Association (I.G.F.), and the Japan Diabetes Foundation and Uehara Memorial Foundation (K. T.), and in part by the University of Toronto Fred Sorkin Fund for Diabetes Research, Mount Sinai Hospital [Toronto, Canada] (MSH), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Mount Sinai Hospital, Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), and Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS )
Subjects: MAPK/ERK pathway, Collagen Type IV, Male, Transcriptional Activation, medicine.medical_specialty, Complications, Endocrinology, Diabetes and Metabolism, p38 mitogen-activated protein kinases, Biology, ADAM17 Protein, Diabetes Mellitus, Experimental, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Albuminuria, Animals, Diabetic Nephropathies, Extracellular Signal-Regulated MAP Kinases, 030304 developmental biology, Original Research, 0303 health sciences, Kinase, Podocytes, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Rats, ErbB Receptors, ADAM Proteins, Endocrinology, Glucose, Pyrimidines, src-Family Kinases, SU6656, chemistry, 030220 oncology & carcinogenesis, Mesangial Cells, Cancer research, Phosphorylation, Signal transduction, Tyrosine kinase, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction
Abstract: Chronic exposure to high glucose leads to diabetic nephropathy characterized by increased mesangial matrix protein (e.g., collagen) accumulation. Altered cell signaling and gene expression accompanied by oxidative stress have been documented. The contribution of the tyrosine kinase, c-Src (Src), which is sensitive to oxidative stress, was examined. Cultured rat mesangial cells were exposed to high glucose (25 mmol/L) in the presence and absence of Src inhibitors (PP2, SU6656), Src small interfering RNA (siRNA), and the tumor necrosis factor-α–converting enzyme (TACE) inhibitor, TAPI-2. Src was investigated in vivo by administration of PP2 to streptozotocin (STZ)-induced diabetic DBA2/J mice. High glucose stimulated Src, TACE, epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs), extracellular signal–regulated kinase (ERK1/2, p38), and collagen IV accumulation in mesangial cells. PP2 and SU6656 blocked high glucose–stimulated phosphorylation of Src Tyr-416, EGFR, and MAPKs. These inhibitors and Src knockdown by siRNA, as well as TAPI-2, also abrogated high glucose–induced phosphorylation of these targets and collagen IV accumulation. In STZ-diabetic mice, albuminuria, increased Src pTyr-416, TACE activation, ERK and EGFR phosphorylation, glomerular collagen accumulation, and podocyte loss were inhibited by PP2. These data indicate a role for Src in a high glucose-Src-TACE-heparin-binding epidermal growth factor-EGFR-MAPK–signaling pathway to collagen accumulation. Thus, Src may provide a novel therapeutic target for diabetic nephropathy.
Published: 2013

28. The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium

Author: Christian A. J. Vosshenrich, Ofer Mandelboim, Laure Dumoutier, Vera S. G. Ribeiro, Naoko Satoh-Takayama, Jean-Christophe Renauld, James P. Di Santo, Sarah Lesjean-Pottier, Vosshenrich, Christian, Cytokines et Développement Lymphoïde, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig Institute for Cancer Research, The Lautenberg Center for General and Tumor Immunology [Jerusalem, Israel], The Hebrew University Hadassah Medical School -BioMedical Research institute Israel Canada of the Faculty of Medicine [Jerusalem, Israel], This work was supported by grants to J.P.D. from the Institut Pasteur, INSERM, and as an 'Equipe Labelisé' by the Ligue Nationale Contre le Cancer. N.S.-T. was the recipient of fellowship from The Uehara Memorial Foundation, Japan., and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Nuclear Receptor Subfamily 1, Group F, Member 3, MESH: Intestine, Small, MESH: Spleen, [SDV]Life Sciences [q-bio], MESH: Citrobacter rodentium, Lymphocyte Activation, Interleukin 22, Mice, 0302 clinical medicine, RAR-related orphan receptor gamma, Intestine, Small, Citrobacter rodentium, Immunology and Allergy, Antigens, Ly, MESH: Animals, Receptor, Cytotoxicity, MESH: Enterobacteriaceae Infections, 0303 health sciences, MESH: Cytokines, Enterobacteriaceae Infections, MESH: Antigens, Ly, Nuclear Receptor Subfamily 1, Group F, Member 3, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Killer Cells, Natural, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, MESH: Immunity, Innate, MESH: Killer Cells, Natural, MESH: Interleukins, [SDV.IMM] Life Sciences [q-bio]/Immunology, CD3, MESH: Natural Cytotoxicity Triggering Receptor 1, Immunology, Biology, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Animals, Interleukin-7 receptor, MESH: Lymphocyte Activation, MESH: Mice, 030304 developmental biology, Natural Cytotoxicity Triggering Receptor 1, Interleukins, Immunity, Innate, Mice, Inbred C57BL, biology.protein, Cytokine secretion, MESH: DNA-Binding Proteins, Spleen, 030215 immunology
Abstract: Natural cytotoxicity receptors (including NKp30, NKp44, and NKp46 in humans and NKp46 in mice) are type I transmembrane proteins that signal NK cell activation via ITAM-containing adapter proteins in response to stress- and pathogen-induced ligands. Although murine NKp46 expression (encoded by Ncr1) was thought to be predominantly restricted to NK cells, the identification of distinct intestinal NKp46(+) cell subsets that express the transcription factor Rorc and produce IL-22 suggests a broader function for NKp46 that could involve intestinal homeostasis and immune defense. Using mice carrying a GFP-modified Ncr1 allele, we found normal numbers of gut CD3(-)GFP(+) cells with a similar cell surface phenotype and subset distribution in the absence of Ncr1. Splenic and intestinal CD3(-)NKp46(+) cell subsets showed distinct patterns of cytokine secretion (IFN-gamma, IL-22) following activation via NK1.1, NKp46, IL-12 plus IL-18, or IL-23. However, IL-22 production was sharply restricted to intestinal CD3(-)GFP(+) cells with the CD127(+)NK1.1(-) phenotype and could be induced in an Ncr1-independent fashion. Because NKp46 ligands can trigger immune activation in the context of infectious pathogens, we assessed the response of wild-type and Ncr-1-deficient Rag2(-/-) mice to the enteric pathogen Citrobacter rodentium. No differences in the survival or clinical score were observed in C. rodentium-infected Rag2(-/-) mice lacking Ncr1, indicating that NKp46 plays a redundant role in the differentiation of intestinal IL-22(+) cells that mediate innate defense against this pathogen. Our results provide further evidence for functional heterogeneity in intestinal NKp46(+) cells that contrast with splenic NK cells. The Journal of Immunology, 2009, 183: 6579-6587.
Published: 2009

29. Essential role for poly (ADP-ribosyl)ation in mouse preimplantation development

Author: Imamura, Takuya, Neildez, Thi My Anh, Thenevin, Catherine, Paldi, Andras, Epigénétique , pathologies et développement, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR117, Division of Behavior and Neurobiology, Department of Regulation Biology, National Institute for Basic Biology [Okazaki], École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Généthon, This work was realized with a financial support from INSERM and GENETHON and research fellowships from Uehara Memorial Foundation and Japan Society for the Promotion of Science., and Maylin, Françoise
Subjects: Male, Poly Adenosine Diphosphate Ribose, lcsh:QH426-470, Polymers, Zygote, [SDV.GEN] Life Sciences [q-bio]/Genetics, Poly(ADP-ribose) Polymerase Inhibitors, Morula, Epigenesis, Genetic, MESH: Oocytes, Embryonic and Fetal Development, Mice, MESH: Benzamides, MESH: Mice, Inbred C57BL, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Epigenesis, Genetic, lcsh:QH573-671, MESH: Mice, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Crosses, Genetic, MESH: Morula, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Mice, Inbred CBA, lcsh:Cytology, MESH: Embryo, MESH: Chromatin Assembly and Disassembly, MESH: Immunohistochemistry, Chromatin Assembly and Disassembly, Embryo, Mammalian, Immunohistochemistry, MESH: Poly Aden, MESH: Crosses, Genetic, MESH: Embryonic and Fetal Development, MESH: Male, Mice, Inbred C57BL, lcsh:Genetics, MESH: Blastocyst, Blastocyst, Benzamides, Mice, Inbred CBA, Oocytes, Female, Poly(ADP-ribose) Polymerases, MESH: Female, Research Article
Abstract: Background Poly (ADP-ribosyl)ation is a covalent modification of many nuclear proteins. It has a strong chromatin modifying potential involved in DNA repair, transcription and replication. Its role during preimplantation development is unknown. Results We have observed strong but transient synthesis of poly ADP-ribose polymers on decondensing chromosomes of fertilized and parthenogenetically activated mouse oocytes. Inhibition of this transient upregulation with a specific enzyme inhibitor, 3-aminobenzamide, has long-term effects on the postimplantation development of the embryos. In addition, inhibition of poly (ADP-ribosyl)ation at the 4–8 cell stage selectively blocks morula compaction. Conclusion These observations suggest that poly (ADP-ribosyl)ation is involved in the epigenetic chromatin remodeling in the zygote.
Published: 2004

30. Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

Author: José A. Esteban, Roberto Malinow, Yasunori Hayashi, Song-Hai Shi, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, National Institutes of Health (US), G. Harold & Leila Y. Mathers Foundation, and Alzheimer's Association
Subjects: Patch-Clamp Techniques, Recombinant Fusion Proteins, Blotting, Western, Long-Term Potentiation, Molecular Sequence Data, Vesicular Transport Proteins, Biology, In Vitro Techniques, Transfection, Hetero-oligomers, Models, Biological, Hippocampus, General Biochemistry, Genetics and Molecular Biology, Cell Line, Synaptic augmentation, Metaplasticity, Excitatory Amino Acid Agonists, Animals, Humans, Amino Acid Sequence, Receptors, AMPA, AMPA-type glutamate receptor, Long-term depression, N-Ethylmaleimide-Sensitive Proteins, Synaptic scaling, Kainic Acid, Neuronal Plasticity, Biochemistry, Genetics and Molecular Biology(all), Pyramidal Cells, musculoskeletal, neural, and ocular physiology, Anatomy, Protein Structure, Tertiary, Rats, Protein Subunits, Protein Transport, Synaptic fatigue, nervous system, Silent synapse, Synaptic plasticity, Synapses, Carrier Proteins, Neuroscience, Ion channel linked receptors
Abstract: AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained., Y.H. was supported by Japan Society for Promotion of Science and Uehara Memorial Foundation. J.A.E. was supported by NARSAD and the Alzheimer’s Association. This study was supported by the NIH, the Mathers Foundation, and the Alle Davis Harrison Endowment to R.M.
Published: 2001

31. Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction

Author: Song-Hai Shi, Antonella Piccini, Yasunori Hayashi, Jean Christophe Poncer, José A. Esteban, Roberto Malinow, Japan Society for the Promotion of Science, Uehara Memorial Foundation for International Students, Brain and Behavior Research Foundation, Human Frontier Science Program, National Institutes of Health (US), and G. Harold & Leila Y. Mathers Foundation
Subjects: Patch-Clamp Techniques, Recombinant Fusion Proteins, PDZ domain, AMPA receptor, Neurotransmission, Biology, Hippocampus, Synaptic Transmission, Cell Line, Membrane Potentials, Organ Culture Techniques, Ca2+/calmodulin-dependent protein kinase, Catalytic Domain, Animals, Humans, Receptors, AMPA, Phosphorylation, Multidisciplinary, CaMKII, Pyramidal Cells, musculoskeletal, neural, and ocular physiology, Glutamate receptor, Proteins, Long-term potentiation, Cell biology, Protein Structure, Tertiary, Rats, Synaptic receptors, Biochemistry, nervous system, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinases, Mutation, Synapses, Calcium-Calmodulin-Dependent Protein Kinase Type 2
Abstract: To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/ calmodulin-dependent protein kinase II (CaMKII) induced delivery of tagged AMPA-Rs into synapses. This effect was not diminished by mutating the CaMKII phosphorylation site on the GluR1 AMPA-R subunit, but was blocked by mutating a predicted PDZ domain interaction site. These results show that LTP and CaMKII activity drive AMPA-Rs to synapses by a mechanism that requires the association between GluR1 and a PDZ domain protein., Y.H. was supported by Japan Society for the Promotion of Science and Uehara Memorial Foundation, J.A.E. by Alzheimer Association and National Alliance for Research on Schizophrenia and Depression, and J.-C.P. by the Human Frontier Science Program Organization. This study was supported by NIH and the Mathers Foundation (to R.M).
Published: 2000

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31 results on '"Uehara Memorial Foundation"'

1. PRC1 suppresses a female gene regulatory network to ensure testicular differentiation

2. Cross-hierarchical plasticity of corticofugal projections to dLGN after neonatal monocular enucleation

3. Meikin is a conserved regulator of meiosis-I-specific kinetochore function

4. Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

5. Broad action of Hsp90 as a host chaperone required for viral replication

6. Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

7. Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction

8. Cross‐hierarchical plasticity of corticofugal projections to dLGN after neonatal monocular enucleation

9. Podocytes maintain high basal levels of autophagy independent of mtor signaling

10. Direct Readout of Neural Stem Cell Transgenesis with an Integration-Coupled Gene Expression Switch

11. MitoBlue as a tool to analyze the mitochondria-lysosome communication

12. Dietary l-serine confers a competitive fitness advantage to Enterobacteriaceae in the inflamed gut

13. Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones

14. Actin filaments regulate microtubule growth at the centrosome

15. Molecular Insights into Function and Competitive Inhibition of Pseudomonas aeruginosa Multiple Virulence Factor Regulator

16. Phosphocode-dependent functional dichotomy of a common co-receptor in plant signalling

17. Meikin is a conserved regulator of meiosis-I-specific kinetochore function

18. IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions

19. Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma

20. Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects

21. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery

22. Clec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity

23. Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

24. Method for collecting mouse milk without exogenous oxytocin stimulation

25. Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity

26. An unusually powerful mode of low-frequency sound interference due to defective hair bundles of the auditory outer hair cells

27. Inhibition of Src kinase blocks high glucose-induced EGFR transactivation and collagen synthesis in mesangial cells and prevents diabetic nephropathy in mice

28. The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium

29. Essential role for poly (ADP-ribosyl)ation in mouse preimplantation development

30. Subunit-Specific Rules Governing AMPA Receptor Trafficking to Synapses in Hippocampal Pyramidal Neurons

31. Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction

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