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  • 1
    Publication Date: 2012-07-24
    Description: Bacterial pathogens have evolved specific effector proteins that, by interfacing with host kinase signalling pathways, provide a mechanism to evade immune responses during infection. Although these effectors contribute to pathogen virulence, we realized that they might also serve as valuable synthetic biology reagents for engineering cellular behaviour. Here we exploit two effector proteins, the Shigella flexneri OspF protein and Yersinia pestis YopH protein, to rewire kinase-mediated responses systematically both in yeast and mammalian immune cells. Bacterial effector proteins can be directed to inhibit specific mitogen-activated protein kinase pathways selectively in yeast by artificially targeting them to pathway-specific complexes. Moreover, we show that unique properties of the effectors generate new pathway behaviours: OspF, which irreversibly inactivates mitogen-activated protein kinases, was used to construct a synthetic feedback circuit that shows novel frequency-dependent input filtering. Finally, we show that effectors can be used in T cells, either as feedback modulators to tune the T-cell response amplitude precisely, or as an inducible pause switch that can temporarily disable T-cell activation. These studies demonstrate how pathogens could provide a rich toolkit of parts to engineer cells for therapeutic or biotechnological applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422413/" 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/PMC3422413/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wei, Ping -- Wong, Wilson W -- Park, Jason S -- Corcoran, Ethan E -- Peisajovich, Sergio G -- Onuffer, James J -- Weiss, Arthur -- Lim, Wendell A -- P50 GM081879/GM/NIGMS NIH HHS/ -- P50GM081879/GM/NIGMS NIH HHS/ -- PN2 EY016546/EY/NEI NIH HHS/ -- PN2EY016546/EY/NEI NIH HHS/ -- R01 GM055040/GM/NIGMS NIH HHS/ -- R01 GM062583/GM/NIGMS NIH HHS/ -- R01GM055040/GM/NIGMS NIH HHS/ -- R01GM062583/GM/NIGMS NIH HHS/ -- T32 GM007618/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Aug 16;488(7411):384-8. doi: 10.1038/nature11259.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22820255" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/genetics/metabolism ; Bacterial Proteins/genetics/*metabolism ; Biotechnology/*methods ; Cell Proliferation ; Cells, Cultured ; Feedback, Physiological ; Genetic Engineering/*methods ; Humans ; Interleukin-2/immunology ; Jurkat Cells ; Lymphocyte Activation/genetics ; *MAP Kinase Signaling System ; Osmolar Concentration ; Protein Tyrosine Phosphatases/genetics/metabolism ; Saccharomyces cerevisiae/*enzymology/genetics/metabolism ; Shigella flexneri/genetics/metabolism/pathogenicity ; T-Lymphocytes/cytology/*enzymology/immunology/metabolism ; Virulence Factors/genetics/*metabolism ; Yersinia pestis/genetics/metabolism/pathogenicity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-05-27
    Description: Topological insulators are insulating materials that display conducting surface states protected by time-reversal symmetry, wherein electron spins are locked to their momentum. This unique property opens up new opportunities for creating next-generation electronic, spintronic and quantum computation devices. Introducing ferromagnetic order into a topological insulator system without compromising its distinctive quantum coherent features could lead to the realization of several predicted physical phenomena. In particular, achieving robust long-range magnetic order at the surface of the topological insulator at specific locations without introducing spin-scattering centres could open up new possibilities for devices. Here we use spin-polarized neutron reflectivity experiments to demonstrate topologically enhanced interface magnetism by coupling a ferromagnetic insulator (EuS) to a topological insulator (Bi2Se3) in a bilayer system. This interfacial ferromagnetism persists up to room temperature, even though the ferromagnetic insulator is known to order ferromagnetically only at low temperatures (〈17 K). The magnetism induced at the interface resulting from the large spin-orbit interaction and the spin-momentum locking of the topological insulator surface greatly enhances the magnetic ordering (Curie) temperature of this bilayer system. The ferromagnetism extends ~2 nm into the Bi2Se3 from the interface. Owing to the short-range nature of the ferromagnetic exchange interaction, the time-reversal symmetry is broken only near the surface of a topological insulator, while leaving its bulk states unaffected. The topological magneto-electric response originating in such an engineered topological insulator could allow efficient manipulation of the magnetization dynamics by an electric field, providing an energy-efficient topological control mechanism for future spin-based technologies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katmis, Ferhat -- Lauter, Valeria -- Nogueira, Flavio S -- Assaf, Badih A -- Jamer, Michelle E -- Wei, Peng -- Satpati, Biswarup -- Freeland, John W -- Eremin, Ilya -- Heiman, Don -- Jarillo-Herrero, Pablo -- Moodera, Jagadeesh S -- England -- Nature. 2016 May 9;533(7604):513-6. doi: 10.1038/nature17635.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Plasma Science and Fusion Center, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Quantum Condensed Matter Division, Neutron Sciences Directorate, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. ; Institut fuer Theoretische Physik III, Ruhr-Universitaet Bochum, D-44801 Bochum, Germany. ; Institute for Theoretical Solid State Physics, Institut fuer Festkoerper- und Werkstoffforschung, Dresden, D-01069 Dresden, Germany. ; Department of Physics, Northeastern University, Boston, Massachusetts 02115, USA. ; Departement de Physique, Ecole Normale Superieure, Centre National de la Recherche Scientifique, Paris Sciences et Lettres Research University, Paris 75005, France. ; Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata 64, India. ; Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27225124" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-08-01
    Description: Members of the family of nuclear factor B (NF-B) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-B complexes are retained in the cytoplasm by the inhibitory protein IBα, whereas noncanonical NF-B complexes are retained by p100. Although activation of canonical NF-B signaling through the IBα kinase complex is well studied, few regulators of the NF-B–inducing kinase (NIK)–dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have been identified. We discovered a role for cyclin-dependent kinase 12 (CDK12) in transcriptionally regulating the noncanonical NF-B pathway. High-content phenotypic screening identified the compound 919278 as a specific inhibitor of the lymphotoxin β receptor (LTβR), and tumor necrosis factor (TNF) receptor superfamily member 12A (FN14)–dependent nuclear translocation of p52, but not of the TNF-α receptor–mediated nuclear translocation of p65. Chemoproteomics identified CDK12 as the target of 919278. CDK12 inhibition by 919278, the CDK inhibitor THZ1, or siRNA-mediated knockdown resulted in similar global transcriptional changes and prevented the LTβR- and FN14-dependent expression of MAP3K14 (which encodes NIK) as well as NIK accumulation by reducing phosphorylation of the carboxyl-terminal domain of RNA polymerase II. By coupling a phenotypic screen with chemoproteomics, we identified a pathway for the activation of the noncanonical NF-B pathway that could serve as a therapeutic target in autoimmunity and cancer.
    Print ISSN: 1945-0877
    Topics: Medicine
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  • 4
    Publication Date: 2018-09-13
    Description: A novel well-dispersed Pd@HHSS catalyst was synthesized by reduction of Pd(OAc) 2 immobilized on HHSS we reported. When the ratios of Pd/SiO 2 were 5 : 100 and 10 : 100, the Pd nanoparticles size was about 5–10 nm. The Pd@HHSS catalyst (Pd/SiO 2 = 10 : 100) showed high catalytic activity in Suzuki-reaction with yields of 91–99% and the catalyst is reusable after four successive cycles without obvious loss of catalytic activity.
    Keywords: materials science, nanotechnology, organic chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 5
    Publication Date: 2018-02-09
    Description: Understanding transcriptome complexity is crucial for understanding human biology and disease. Technologies such as Synthetic long-read RNA sequencing (SLR-RNA-seq) delivered 5 million isoforms and allowed assessing splicing coordination. Pacific Biosciences and Oxford Nanopore increase throughput also but require high input amounts or amplification. Our new droplet-based method, sparse isoform sequencing (spISO-seq), sequences 100k–200k partitions of 10–200 molecules at a time, enabling analysis of 10–100 million RNA molecules. SpISO-seq requires less than 1 ng of input cDNA, limiting or removing the need for prior amplification with its associated biases. Adjusting the number of reads devoted to each molecule reduces sequencing lanes and cost, with little loss in detection power. The increased number of molecules expands our understanding of isoform complexity. In addition to confirming our previously published cases of splicing coordination (e.g., BIN1 ), the greater depth reveals many new cases, such as MAPT . Coordination of internal exons is found to be extensive among protein coding genes: 23.5%–59.3% (95% confidence interval) of highly expressed genes with distant alternative exons exhibit coordination, showcasing the need for long-read transcriptomics. However, coordination is less frequent for noncoding sequences, suggesting a larger role of splicing coordination in shaping proteins. Groups of genes with coordination are involved in protein–protein interactions with each other, raising the possibility that coordination facilitates complex formation and/or function. We also find new splicing coordination types, involving initial and terminal exons. Our results provide a more comprehensive understanding of the human transcriptome and a general, cost-effective method to analyze it.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2018-02-24
    Description: Sub-cellular In-situ Characterization of Ferritin(iron) in a Rodent Model of Spinal Cord Injury Sub-cellular 〈i〉In-situ〈/i〉 Characterization of Ferritin(iron) in a Rodent Model of Spinal Cord Injury, Published online: 23 February 2018; doi:10.1038/s41598-018-21744-9 Sub-cellular In-situ Characterization of Ferritin(iron) in a Rodent Model of Spinal Cord Injury
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
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  • 7
    Publication Date: 2018-02-09
    Description: Nonmuscle myosin II has been implicated in regulation of von Willebrand factor (VWF) release from endothelial Weibel-Palade bodies (WPBs), but the specific role of myosin IIa isoform is poorly defined. Here, we report that myosin IIa is expressed both in primary human endothelial cells and intact mouse vessels, essential for cyclic adenosine monophosphate (cAMP)-mediated endothelial VWF secretion. Downregulation of myosin IIa by shRNAs significantly suppressed both forskolin- and epinephrine-induced VWF secretion. Endothelium-specific myosin IIa knockout mice exhibited impaired epinephrine-stimulated VWF release, prolonged bleeding time, and thrombosis. Further study showed that in resting cells, myosin IIa deficiency disrupted the peripheral localization of Rab27-positive WPBs along stress fibers; on stimulation by cAMP agonists, myosin IIa in synergy with zyxin promotes the formation of a functional actin framework, which is derived from preexisting cortical actin filaments, around WPBs, facilitating fusion and subsequent exocytosis. In summary, our findings not only identify new functions of myosin IIa in regulation of WPB positioning and the interaction between preexisting cortical actin filaments and exocytosing vesicles before fusion but also reveal myosin IIa as a physiological regulator of endothelial VWF secretion in stress-induced hemostasis and thrombosis.
    Keywords: Thrombosis and Hemostasis, Vascular Biology
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2013-03-16
    Description: The quantized version of the anomalous Hall effect has been predicted to occur in magnetic topological insulators, but the experimental realization has been challenging. Here, we report the observation of the quantum anomalous Hall (QAH) effect in thin films of chromium-doped (Bi,Sb)2Te3, a magnetic topological insulator. At zero magnetic field, the gate-tuned anomalous Hall resistance reaches the predicted quantized value of h/e(2), accompanied by a considerable drop in the longitudinal resistance. Under a strong magnetic field, the longitudinal resistance vanishes, whereas the Hall resistance remains at the quantized value. The realization of the QAH effect may lead to the development of low-power-consumption electronics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Cui-Zu -- Zhang, Jinsong -- Feng, Xiao -- Shen, Jie -- Zhang, Zuocheng -- Guo, Minghua -- Li, Kang -- Ou, Yunbo -- Wei, Pang -- Wang, Li-Li -- Ji, Zhong-Qing -- Feng, Yang -- Ji, Shuaihua -- Chen, Xi -- Jia, Jinfeng -- Dai, Xi -- Fang, Zhong -- Zhang, Shou-Cheng -- He, Ke -- Wang, Yayu -- Lu, Li -- Ma, Xu-Cun -- Xue, Qi-Kun -- New York, N.Y. -- Science. 2013 Apr 12;340(6129):167-70. doi: 10.1126/science.1234414. Epub 2013 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Low-Dimensional Quantum Physics, Department of Physics, Tsinghua University, Beijing, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23493424" target="_blank"〉PubMed〈/a〉
    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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  • 9
    Publication Date: 2015-11-21
    Description: Cells must interpret environmental information that often changes over time. In our experiment, we systematically monitored the growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception: The cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing mitogen-activated protein kinase (MAPK) network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges, such as continually increasing osmolarity, it results in a trade-off of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721531/" 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/PMC4721531/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitchell, Amir -- Wei, Ping -- Lim, Wendell A -- P50 GM081879/GM/NIGMS NIH HHS/ -- PN2 EY016546/EY/NEI NIH HHS/ -- R01 GM055040/GM/NIGMS NIH HHS/ -- R01 GM062583/GM/NIGMS NIH HHS/ -- R01 GM55040/GM/NIGMS NIH HHS/ -- R01 GM62583/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1379-83. doi: 10.1126/science.aab0892. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA. Center for Systems and Synthetic Biology, UCSF, San Francisco, CA 94158, USA. ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA. Center for Quantitative Biology, and Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, School of Life Sciences, Peking University, Beijing 100871, China. lim@cmp.ucsf.edu pwei@pku.edu.cn. ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA. Center for Systems and Synthetic Biology, UCSF, San Francisco, CA 94158, USA. Howard Hughes Medical Institute (HHMI), UCSF, San Francisco, CA 94158, USA. lim@cmp.ucsf.edu pwei@pku.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586187" target="_blank"〉PubMed〈/a〉
    Keywords: DNA Mutational Analysis ; Mitogen-Activated Protein Kinases/genetics/*metabolism ; Models, Theoretical ; Osmolar Concentration ; *Osmotic Pressure ; Saccharomyces cerevisiae/enzymology/genetics/*physiology ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Signal Transduction/genetics/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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  • 10
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    German Medical Science; Düsseldorf, Köln
    In:  International Conference on SARS - one year after the (first) outbreak; 20040508-20040511; Lübeck; DOC04sarsP11.04 /20040526/
    Publication Date: 2004-05-26
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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