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  • 1
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    Increasing the potency and breadth of an HIV antibody by using structure-based rational design (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-10-29
    Description: Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diskin, Ron -- Scheid, Johannes F -- Marcovecchio, Paola M -- West, Anthony P Jr -- Klein, Florian -- Gao, Han -- Gnanapragasam, Priyanthi N P -- Abadir, Alexander -- Seaman, Michael S -- Nussenzweig, Michel C -- Bjorkman, Pamela J -- P01 AI081677-01/AI/NIAID NIH HHS/ -- RR00862/RR/NCRR NIH HHS/ -- RR022220/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Dec 2;334(6060):1289-93. doi: 10.1126/science.1213782. Epub 2011 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22033520" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines ; Amino Acid Sequence ; Antibodies, Neutralizing/chemistry/*immunology/metabolism ; Antibody Affinity ; Antigens, CD4/chemistry/metabolism ; Binding Sites ; Complementarity Determining Regions ; Crystallography, X-Ray ; HIV Antibodies/chemistry/*immunology/metabolism ; HIV Envelope Protein gp120/chemistry/*immunology/metabolism ; HIV-1/*immunology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin Fab Fragments/chemistry/immunology/metabolism ; Immunoglobulin Heavy Chains/chemistry/immunology/metabolism ; Molecular Mimicry ; Molecular Sequence Data ; Mutant Proteins/chemistry/immunology/metabolism ; Protein Conformation ; *Protein Engineering ; Protein Structure, Tertiary
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Temporal specificity in the cortical plasticity of visual space representation (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-06-18
    Description: The circuitry and function of mammalian visual cortex are shaped by patterns of visual stimuli, a plasticity likely mediated by synaptic modifications. In the adult cat, asynchronous visual stimuli in two adjacent retinal regions controlled the relative spike timing of two groups of cortical neurons with high precision. This asynchronous pairing induced rapid modifications of intracortical connections and shifts in receptive fields. These changes depended on the temporal order and interval between visual stimuli in a manner consistent with spike timing-dependent synaptic plasticity. Parallel to the cortical modifications found in the cat, such asynchronous visual stimuli also induced shifts in human spatial perception.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fu, Yu-Xi -- Djupsund, Kaj -- Gao, Hongfeng -- Hayden, Benjamin -- Shen, Kai -- Dan, Yang -- New York, N.Y. -- Science. 2002 Jun 14;296(5575):1999-2003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12065829" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Brain Mapping ; Cats ; Conditioning (Psychology) ; Humans ; *Neuronal Plasticity ; Neurons/physiology ; Normal Distribution ; *Photic Stimulation ; Retina/*physiology ; *Space Perception ; Synapses/*physiology ; Time Factors ; Visual Cortex/*physiology ; Visual Pathways
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    Landscape of transcription in human cells (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-09-08
    Description: Eukaryotic cells make many types of primary and processed RNAs that are found either in specific subcellular compartments or throughout the cells. A complete catalogue of these RNAs is not yet available and their characteristic subcellular localizations are also poorly understood. Because RNA represents the direct output of the genetic information encoded by genomes and a significant proportion of a cell's regulatory capabilities are focused on its synthesis, processing, transport, modification and translation, the generation of such a catalogue is crucial for understanding genome function. Here we report evidence that three-quarters of the human genome is capable of being transcribed, as well as observations about the range and levels of expression, localization, processing fates, regulatory regions and modifications of almost all currently annotated and thousands of previously unannotated RNAs. These observations, taken together, prompt a redefinition of the concept of a gene.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684276/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684276/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Djebali, Sarah -- Davis, Carrie A -- Merkel, Angelika -- Dobin, Alex -- Lassmann, Timo -- Mortazavi, Ali -- Tanzer, Andrea -- Lagarde, Julien -- Lin, Wei -- Schlesinger, Felix -- Xue, Chenghai -- Marinov, Georgi K -- Khatun, Jainab -- Williams, Brian A -- Zaleski, Chris -- Rozowsky, Joel -- Roder, Maik -- Kokocinski, Felix -- Abdelhamid, Rehab F -- Alioto, Tyler -- Antoshechkin, Igor -- Baer, Michael T -- Bar, Nadav S -- Batut, Philippe -- Bell, Kimberly -- Bell, Ian -- Chakrabortty, Sudipto -- Chen, Xian -- Chrast, Jacqueline -- Curado, Joao -- Derrien, Thomas -- Drenkow, Jorg -- Dumais, Erica -- Dumais, Jacqueline -- Duttagupta, Radha -- Falconnet, Emilie -- Fastuca, Meagan -- Fejes-Toth, Kata -- Ferreira, Pedro -- Foissac, Sylvain -- Fullwood, Melissa J -- Gao, Hui -- Gonzalez, David -- Gordon, Assaf -- Gunawardena, Harsha -- Howald, Cedric -- Jha, Sonali -- Johnson, Rory -- Kapranov, Philipp -- King, Brandon -- Kingswood, Colin -- Luo, Oscar J -- Park, Eddie -- Persaud, Kimberly -- Preall, Jonathan B -- Ribeca, Paolo -- Risk, Brian -- Robyr, Daniel -- Sammeth, Michael -- Schaffer, Lorian -- See, Lei-Hoon -- Shahab, Atif -- Skancke, Jorgen -- Suzuki, Ana Maria -- Takahashi, Hazuki -- Tilgner, Hagen -- Trout, Diane -- Walters, Nathalie -- Wang, Huaien -- Wrobel, John -- Yu, Yanbao -- Ruan, Xiaoan -- Hayashizaki, Yoshihide -- Harrow, Jennifer -- Gerstein, Mark -- Hubbard, Tim -- Reymond, Alexandre -- Antonarakis, Stylianos E -- Hannon, Gregory -- Giddings, Morgan C -- Ruan, Yijun -- Wold, Barbara -- Carninci, Piero -- Guigo, Roderic -- Gingeras, Thomas R -- 062023/Wellcome Trust/United Kingdom -- 1RC2HG005591/HG/NHGRI NIH HHS/ -- 249968/European Research Council/International -- P30 CA045508/CA/NCI NIH HHS/ -- R01 HG003700/HG/NHGRI NIH HHS/ -- R01HG003700/HG/NHGRI NIH HHS/ -- R37 GM062534/GM/NIGMS NIH HHS/ -- RC2 HG005591/HG/NHGRI NIH HHS/ -- U01 HG003147/HG/NHGRI NIH HHS/ -- U54 HG004555/HG/NHGRI NIH HHS/ -- U54 HG004557/HG/NHGRI NIH HHS/ -- U54 HG004558/HG/NHGRI NIH HHS/ -- U54 HG004576/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- U54HG004555/HG/NHGRI NIH HHS/ -- U54HG004557/HG/NHGRI NIH HHS/ -- U54HG004558/HG/NHGRI NIH HHS/ -- U54HG004576/HG/NHGRI NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):101-8. doi: 10.1038/nature11233.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Genomic Regulation and UPF, Doctor Aiguader 88, Barcelona 08003, Catalonia, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22955620" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line ; DNA/*genetics ; DNA, Intergenic/genetics ; *Encyclopedias as Topic ; Enhancer Elements, Genetic ; Exons/genetics ; Gene Expression Profiling ; Genes/genetics ; Genome, Human/*genetics ; Genomics ; Humans ; *Molecular Sequence Annotation ; Polyadenylation/genetics ; Protein Isoforms/genetics ; RNA/biosynthesis/genetics ; RNA Editing/genetics ; RNA Splicing/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Repetitive Sequences, Nucleic Acid/genetics ; Sequence Analysis, RNA ; Transcription, Genetic/*genetics ; Transcriptome/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Cerebellum implicated in sensory acquisition and discrimination rather than motor control (1996)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1996-04-26
    Description: Recent evidence that the cerebellum is involved in perception and cognition challenges the prevailing view that its primary function is fine motor control. A new alternative hypothesis is that the lateral cerebellum is not activated by the control of movement per se, but is strongly engaged during the acquisition and discrimination of sensory information. Magnetic resonance imaging of the lateral cerebellar output (dentate) nucleus during passive and active sensory tasks confirmed this hypothesis. These findings suggest that the lateral cerebellum may be active during motor, perceptual, and cognitive performances specifically because of the requirement to process sensory data.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, J H -- Parsons, L M -- Bower, J M -- Xiong, J -- Li, J -- Fox, P T -- MH/DA52145/MH/NIMH NIH HHS/ -- P20 DA52176-01/DA/NIDA NIH HHS/ -- New York, N.Y. -- Science. 1996 Apr 26;272(5261):545-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Imaging Center, Medical School, University of Texas Health Science Center, San Antonio, TX 78284-6240, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8614803" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Cerebellar Nuclei/blood supply/*physiology ; Cerebrovascular Circulation ; Discrimination (Psychology)/*physiology ; Humans ; Magnetic Resonance Imaging ; Male ; Motor Activity/physiology ; Perception/*physiology ; Physical Stimulation ; Psychomotor Performance/*physiology ; Sensation/physiology ; Touch/physiology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Local and long-range reciprocal regulation of cAMP and cGMP in axon/dendrite formation (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-01-30
    Description: Cytosolic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) often mediate antagonistic cellular actions of extracellular factors, from the regulation of ion channels to cell volume control and axon guidance. We found that localized cAMP and cGMP activities in undifferentiated neurites of cultured hippocampal neurons promote and suppress axon formation, respectively, and exert opposite effects on dendrite formation. Fluorescence resonance energy transfer imaging showed that alterations of the amount of cAMP resulted in opposite changes in the amount of cGMP, and vice versa, through the activation of specific phosphodiesterases and protein kinases. Local elevation of cAMP in one neurite resulted in cAMP reduction in all other neurites of the same neuron. Thus, local and long-range reciprocal regulation of cAMP and cGMP together ensures coordinated development of one axon and multiple dendrites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shelly, Maya -- Lim, Byung Kook -- Cancedda, Laura -- Heilshorn, Sarah C -- Gao, Hongfeng -- Poo, Mu-ming -- NS-22764/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2010 Jan 29;327(5965):547-52. doi: 10.1126/science.1179735.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California, Berkeley, CA 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20110498" target="_blank"〉PubMed〈/a〉
    Keywords: Adenylyl Cyclase Inhibitors ; Adenylyl Cyclases/metabolism ; Animals ; Axons/metabolism/*physiology ; Cell Differentiation ; Cell Line ; Cell Polarity ; Cells, Cultured ; Cyclic AMP/*metabolism ; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/metabolism ; Cyclic GMP/*metabolism ; Dendrites/metabolism/*physiology ; Enzyme Inhibitors/pharmacology ; Fluorescence Resonance Energy Transfer ; Guanylate Cyclase/antagonists & inhibitors/metabolism ; Hippocampus/*cytology ; Humans ; Neurites/metabolism/physiology ; Neurons/cytology/*physiology ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoric Diester Hydrolases/metabolism ; Phosphorylation ; Rats ; Signal Transduction ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    CELL DIVISION CYCLE. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-13
    Description: The spindle checkpoint of the cell division cycle senses kinetochores that are not attached to microtubules and prevents precocious onset of anaphase, which can lead to aneuploidy. The nuclear division cycle 80 complex (Ndc80C) is a major microtubule receptor at the kinetochore. Ndc80C also mediates the kinetochore recruitment of checkpoint proteins. We found that the checkpoint protein kinase monopolar spindle 1 (Mps1) directly bound to Ndc80C through two independent interactions. Both interactions involved the microtubule-binding surfaces of Ndc80C and were directly inhibited in the presence of microtubules. Elimination of one such interaction in human cells caused checkpoint defects expected from a failure to detect unattached kinetochores. Competition between Mps1 and microtubules for Ndc80C binding thus constitutes a direct mechanism for the detection of unattached kinetochores.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Zhejian -- Gao, Haishan -- Yu, Hongtao -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1260-4. doi: 10.1126/science.aaa4029.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. ; Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. hongtao.yu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068854" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding, Competitive ; *Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microtubules/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
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    Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5 (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: 5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mavrakis, Konstantinos J -- McDonald, E Robert 3rd -- Schlabach, Michael R -- Billy, Eric -- Hoffman, Gregory R -- deWeck, Antoine -- Ruddy, David A -- Venkatesan, Kavitha -- Yu, Jianjun -- McAllister, Gregg -- Stump, Mark -- deBeaumont, Rosalie -- Ho, Samuel -- Yue, Yingzi -- Liu, Yue -- Yan-Neale, Yan -- Yang, Guizhi -- Lin, Fallon -- Yin, Hong -- Gao, Hui -- Kipp, D Randal -- Zhao, Songping -- McNamara, Joshua T -- Sprague, Elizabeth R -- Zheng, Bing -- Lin, Ying -- Cho, Young Shin -- Gu, Justin -- Crawford, Kenneth -- Ciccone, David -- Vitari, Alberto C -- Lai, Albert -- Capka, Vladimir -- Hurov, Kristen -- Porter, Jeffery A -- Tallarico, John -- Mickanin, Craig -- Lees, Emma -- Pagliarini, Raymond -- Keen, Nicholas -- Schmelzle, Tobias -- Hofmann, Francesco -- Stegmeier, Frank -- Sellers, William R -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1208-13. doi: 10.1126/science.aad5944. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. ; Novartis Institutes for Biomedical Research, Basel CH-4002, Switzerland. ; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA. ; China Novartis Institutes for Biomedical Research, Shanghai 201203, China. ; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. william.sellers@novartis.com fstegmeier@ksqtx.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912361" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Cell Survival ; Cyclin-Dependent Kinase Inhibitor p16/genetics/*metabolism ; Deoxyadenosines/metabolism ; Gene Deletion ; Humans ; Methionine/*metabolism ; Neoplasms/drug therapy/genetics/*metabolism ; Protein-Arginine N-Methyltransferases/genetics/*metabolism ; Purine-Nucleoside Phosphorylase/genetics/*metabolism ; RNA, Small Interfering/genetics ; Thionucleosides/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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