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Expression, purification, crystallization, and preliminary X-ray crystallographic studies of the human adiponectin receptors, AdipoR1 and AdipoR2

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Journal of Structural and Functional Genomics 2015年第1期16卷 11-23页

作者： Tanabe, Hiroaki Motoyama, Kanna Ikeda, Mariko Wakiyama, Motoaki Terada, Takaho Ohsawa, Noboru Hosaka, Toshiaki Hato, Masakatsu Fujii, Yoshifumi Nakamura, Yoshihiro Ogasawara, Satoshi Hino, Tomoya Murata, Takeshi Iwata, So Okada-Iwabu, Miki Iwabu, Masato Hirata, Kunio Kawano, Yoshiaki Yamamoto, Masaki Kimura-Someya, Tomomi Shirouzu, Mikako Yamauchi, Toshimasa Kadowaki, Takashi Yokoyama, Shigeyuki RIKEN Systems and Structural Biology Center 1-7-22 Suehiro-cho Tsurumi-ku Yokohama 230-0045 Japan Department of Biophysics and Biochemistry and Laboratory of Structural Biology Graduate School of Science The University of Tokyo Hongo Bunkyo-ku Tokyo 113-0033 Japan Division of Structural and Synthetic Biology RIKEN Center for Life Science Technologies 1-7-22 Suehiro-cho Tsurumi-ku Yokohama 230-0045 Japan RIKEN Structural Biology Laboratory 1-7-22 Suehiro-cho Tsurumi-ku Yokohama 230-0045 Japan Department of Cell Biology Graduate School of Medicine Kyoto University Yoshida-Konoe-cho Sakyo-ku Kyoto 606-8501 Japan JST Research Acceleration Program Membrane Protein Crystallography Project Yoshida-Konoe-cho Sakyo-ku Kyoto 606-8501 Japan Department of Chemistry Graduate School of Science Chiba University Yayoi-cho Inage Chiba 263-8522 Japan Division of Molecular Biosciences Membrane Protein Crystallography Group Imperial College London SW7 2AZ United Kingdom Diamond Light Source Harwell Science and Innovation Campus Chilton Didcot Oxfordshire OX11 0DE United Kingdom RIKEN SPring-8 Center Harima Institute Kouto Sayo 679-5148 Hyogo Japan Department of Diabetes and Metabolic Diseases Graduate School of Medicine The University of Tokyo Hongo Bunkyo-ku Tokyo 113-0033 Japan Department of Integrated Molecular Science on Metabolic Diseases 22nd Century Medical and Research Center The University of Tokyo Hongo Bunkyo-ku Tokyo 113-0033 Japan CREST Japan Science and Technology Agency Kawaguchi 332-0012 Saitama Japan

The adiponectin receptors (AdipoR1 and AdipoR2) are membrane proteins with seven transmembrane helices. These receptors regulate glucose and fatty acid metabolism, thereby ameliorating type 2 diabetes. The full-length human AdipoR1 and a series of N-terminally truncated mutants of human AdipoR1 and AdipoR2 were expressed in insect cells. In small-scale size exclusion chromatography, the truncated mutants AdipoR1Δ88 (residues 89–375) and AdipoR2Δ99 (residues 100–386) eluted mostly in the intact monodisperse state, while the others eluted primarily as aggregates. However, gel filtration chromatography of the large-scale preparation of the tag-affinity-purified AdipoR1Δ88 revealed the presence of an excessive amount of the aggregated state over the intact state. Since aggregation due to contaminating nucleic acids may have occurred during the sample concentration step, anion-exchange column chromatography was performed immediately after affinity chromatography, to separate the intact AdipoR1Δ88 from the aggregating species. The separated intact AdipoR1Δ88 did not undergo further aggregation, and was successfully purified to homogeneity by gel filtration chromatography. The purified AdipoR1Δ88 and AdipoR2Δ99 proteins were characterized by thermostability assays with 7-diethylamino-3-(4-maleimidophenyl)-4-methyl coumarin, thin layer chromatography of bound lipids, and surface plasmon resonance analysis of ligand binding, demonstrating their structural integrities. The AdipoR1Δ88 and AdipoR2Δ99 proteins were crystallized with the anti-AdipoR1 monoclonal antibody Fv fragment, by the lipidic mesophase method. X-ray diffraction data sets were obtained at resolutions of 2.8 and 2.4 Å, respectively. © 2015, The Author(s).

关键词： Adiponectin receptors AdipoR1 and AdipoR2 Antibody Crystallization Lipidic mesophase Membrane protein Purification

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Current md forcefields fail to capture key features of protein structure and fluctuations: a case study of cyclophilin a and t4 lysozyme

arXiv

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arXiv 2020年

作者： Mei, Zhe Grigas, Alex T. Treado, John D. Corres, Gabriel Melendez Vuorte, Maisa Sammalkorpi, Maria Regan, Lynne Levine, Zachary A. O’Hern, Corey S. Department of Chemistry Yale University New HavenCT06520 United States Integrated Graduate Program in Physical and Engineering Biology Yale University New HavenCT06520 United States Graduate Program in Computational Biology and Bioinformatics Yale University New HavenCT06520 United States Department of Mechanical Engineering and Materials Science Yale University New HavenCT06520 United States Department of Biology UPR Humacao Puerto RicoHumacao00792 Puerto Rico Department of Chemistry and Materials Science School of Chemical Engineering Aalto University Aalto Finland Department of Bioproducts and Biosystems School of Chemical Engineering Aalto University Aalto Finland Institute of Quantitative Biology Biochemistry and Biotechnology Center for Synthetic and Systems Biology School of Biological Sciences University of Edinburgh Edinburgh United Kingdom Department of Pathology Yale School of Medicine New HavenCT06520 United States Department of Molecular Biophysics and Biochemistry Yale University New HavenCT06520 United States Department of Physics Yale University New HavenCT06520 United States Department of Applied Physics Yale University New HavenCT06520 United States

Globular proteins undergo thermal fluctuations in solution, while maintaining an overall well-defined folded structure. In particular, studies have shown that the core structure of globular proteins differs in small, but significant ways when they are solved by x-ray crystallography versus solution-based NMR spectroscopy. Given these discrepancies, it is unclear whether molecular dynamics (MD) simulations can accurately recapitulate protein conformations. We therefore perform extensive MD simulations across multiple force fields and sampling techniques to investigate the degree to which computer simulations can capture the ensemble of conformations observed in experiments. By analyzing fluctuations in the atomic coordinates and core packing, we show that conformations sampled in MD simulations both move away from and sample a larger conformational space than the ensemble of structures observed in NMR experiments. However, we find that adding inter-residue distance restraints that match those obtained via Nuclear Overhauser Effect measurements enables the MD simulations to sample more NMR-like conformations, though significant differences between the core packing features in restrained MD and the NMR ensemble remain. Given that the protein structures obtained from the MD simulations possess smaller and less dense protein cores compared to those solved by NMR, we suggest that future improvements to MD forcefields should aim to increase the packing of hydrophobic residues in protein cores. © 2020, CC BY.

关键词： Molecular dynamics

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Cover Picture: Influence of Plasma Stimulation on Si Nanowire Nucleation and Orientation Dependence (Adv. Mater. 18/2007)

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Advanced Materials 2007年第18期19卷

作者： P. Aella S. Ingole W. T. Petuskey S. T. Picraux School of Materials Arizona State University Tempe AZ 85287 (USA) Department of Chemistry and Biochemistry Science and Engineering of Materials Graduate Program Arizona State University Tempe AZ 85287 (USA) Center for Integrated Nanotechnologies Los Alamos National Laboratory Los Alamos NM 87545 (USA)

On p. 2603, Tom Picraux and co‐workers report on the use of plasma excitation to strongly enhance the nucleation of Si nanowires by the vapor–liquid–solid growth method. This control allows the preferential formation of very small diameter [110] oriented nanowires, as well as significant enhancements in low temperature nanowire growth.

关键词： Nanowires, inorganic Plasmas Silicon Synthesis

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A GATA-1-Regulated microRNA Cluster That Is Essential for Erythropoiesis.

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Blood 2007年第11期110卷 378-378页

作者： Louis C. Dore Camila O. dos Santos Julio Amigo Christine Dorman Weisheng Wu Ross C. Hardison Barry H. Paw Mitchell J. Weiss Integrated Graduate Program Feinberg School of Medicine Northwestern University Chicago IL USA Division of Hematology Children's Hospital of Philadelphia Philadelphia PA USA Division of Hematology Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA USA Department of Biochemistry and Molecular Biology Pennsylvania State University University Park PA USA

The nuclear factor GATA-1 controls erythropoiesis by regulating transcription of numerous protein-encoding genes. Here we show that GATA-1 also activates the expression of a critical erythroid microRNA (miR) locus. MicroRNAs regulate gene expression and tissue differentiation by binding the 3′ untranslated regions of mRNA transcripts to inhibit their translation or stability. We used an oligonucleotide-based microarray to analyze miR expression in G1E cells, a GATA-1-null erythroid line that undergoes terminal maturation when GATA-1 activity is restored. We identified 8 miRs that are significantly upregulated during GATA-1-induced erythroid maturation. Two of the most highly induced miRs, 144 and 451, are encoded in tandem on mouse chromosome 11 and are transcribed on the same primary microRNA transcript. Northern blot studies showed that the miR144/451 locus is strongly induced by GATA-1 and specifically expressed at high levels in human and murine erythroid precursors. Bioinformatic analysis of the miR144/451 locus identified a conserved region containing three closely-spaced GATA binding motifs located about 2.7 kb upstream of the transcriptional start. In erythroid cells, this region exhibits enhancer activity and binds GATA-1 and its cofactor FOG-1, as determined by chromatin immunoprecipitation studies. MicroRNAs 144 and 451 are conserved between mammals and zebrafish, facilitating further in vivo studies. Whole mount in situ hybridization of zebrafish embryos showed both miRs to be exclusively expressed in the developing blood islands (intermediate cell mass) at 24h post-fertilization (hpf), colocalizing with gata-1 and β -globinE1 expression. Both miRs are deficient in the gata-1 null mutant, vlad tepes , consistent with their epistatic relationship to gata-1 . Transient inactivation of miR-451 function using anti-sense morpholino oligomers selectively ablated hemoglobin staining cells in embryos at 48 hpf. These morphant embryos also exhibited dramatically

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Erratum to: The real cost of sequencing: scaling computation to keep pace with data generation

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Genome biology 2016年第1期17卷 78页

作者： Paul Muir Shantao Li Shaoke Lou Daifeng Wang Daniel J Spakowicz Leonidas Salichos Jing Zhang George M Weinstock Farren Isaacs Joel Rozowsky Mark Gerstein Department of Molecular Cellular and Developmental Biology Yale University New Haven CT 06520 USA. Systems Biology Institute Yale University West Haven CT 06516 USA. Integrated Graduate Program in Physical and Engineering Biology Yale University New Haven CT 06520 USA. Program in Computational Biology and Bioinformatics Yale University New Haven CT 06520 USA. Department of Molecular Biophysics and Biochemistry Yale University New Haven CT 06520 USA. The Jackson Laboratory for Genomic Medicine Farmington CT 06032 USA. Program in Computational Biology and Bioinformatics Yale University New Haven CT 06520 USA. mark@***. Department of Molecular Biophysics and Biochemistry Yale University New Haven CT 06520 USA. mark@***. Department of Computer Science Yale University New Haven CT 06520 USA. mark@***.

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Cover Image, Volume 86, Issue 5

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Proteins: Structure, Function, and Bioinformatics 2018年第5期86卷

作者： J. C. Gaines S. Acebes A. Virrueta M. Butler L. Regan C. S. O'Hern Program in Computational Biology and Bioinformatics Yale University New Haven Connecticut 06520 Integrated Graduate Program in Physical and Engineering Biology (IGPPEB) Yale University New Haven Connecticut 06520 Department of Mechanical Engineering and Materials Science Yale University New Haven Connecticut 06520 Department of Physics and Astronomy University of Southern California Los Angeles California 90007 Department of Molecular Biophysics & Biochemistry Yale University New Haven Connecticut 06520 Department of Chemistry Yale University New Haven Connecticut 06520 Department of Physics Yale University New Haven Connecticut 06520 Department of Applied Physics Yale University New Haven Connecticut 06520

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SARS-CoV-2 identified through crystallographic screening and computational docking

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Science Advances 2021年第16期7卷

作者： Schuller, Marion Correy, Galen J. Gahbauer, Stefan Fearon, Daren Wu, Taiasean Díaz, Roberto Efraín Young, Iris D. Martins, Luan Carvalho Smith, Dominique H. Schulze-Gahmen, Ursula Owens, Tristan W. Deshpande, Ishan Merz, Gregory E. Thwin, Aye C. Biel, Justin T. Peters, Jessica K. Moritz, Michelle Herrera, Nadia Kratochvil, Huong T. Aimon, Anthony Bennett, James M. Neto, Jose Brandao Cohen, Aina E. Dias, Alexandre Douangamath, Alice Dunnett, Louise Fedorov, Oleg Ferla, Matteo P. Fuchs, Martin R. Gorrie-Stone, Tyler J. Holton, James M. Johnson, Michael G. Krojer, Tobias Meigs, George Powell, Ailsa J. Rack, Johannes Gregor Matthias Rangel, Victor L. Russi, Silvia Skyner, Rachael E. Smith, Clyde A. Soares, Alexei S. Wierman, Jennifer L. Zhu, Kang O Brien, Peter Jura, Natalia Ashworth, Alan Irwin, John J. Thompson, Michael C. Gestwicki, Jason E. Von Delft, Frank Shoichet, Brian K. Fraser, James S. Ahel, Ivan Sir William Dunn School of Pathology University of Oxford South Parks Road OxfordOX1 3RE United Kingdom Department of Bioengineering and Therapeutic Sciences University of California San Francisco San FranciscoCA94158 United States Department of Pharmaceutical Chemistry University of California San Francisco San FranciscoCA94158 United States Diamond Light Source Ltd. Harwell Science and Innovation Campus DidcotOX11 0DE United Kingdom Institute for Neurodegenerative Disease University of California San Francisco San FranciscoCA94158 United States Chemistry and Chemical Biology Graduate Program University of California San Francisco San FranciscoCA94158 United States Tetrad Graduate Program University of California San Francisco San FranciscoCA94158 United States Coronavirus Research Group Structural Biology Consortium University of California San Francisco San FranciscoCA94158 United States Biochemistry Department Institute for Biological Sciences Federal University of Minas Gerais Belo Horizonte Brazil Helen Diller Family Comprehensive Cancer University of California San Francisco San FranciscoCA94158 United States Centre for Medicines Discovery University of Oxford South Parks Road HeadingtonOX3 7DQ United Kingdom Stanford Synchrotron Radiation Lightsource Slac National Accelerator Center Menlo ParkCA94025 United States Wellcome Centre for Human Genetics University of Oxford Old Road Campus OxfordOX3 7BN United Kingdom National Synchrotron Light Source Ii Brookhaven National Laboratory UptonNY11973 United States Department of Biochemistry and Biophysics University of California San Francisco San FranciscoCA94158 United States Department of Molecular Biophysics and Integrated Bioimaging Lawrence Berkeley National Laboratory BerkeleyCA94720 United States ChemPartner Corporation South San FranciscoCA94080 United States Structural Genomics Consortium University of Oxford Old Road Campus HeadingtonOX3 7DQ United Kingdom School of

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors. © 2021 American Association for the Advancement of Science. All rights reserved.

关键词： Coronavirus

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Author Correction: O-GlcNAc modification of leucyl-tRNA synthetase 1 integrates leucine and glucose availability to regulate mTORC1 and the metabolic fate of leucine

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Nature communications 2022年第1期13卷 6253页

作者： Kibum Kim Hee Chan Yoo Byung Gyu Kim Sulhee Kim Yulseung Sung Ina Yoon Ya Chun Yu Seung Joon Park Jong Hyun Kim Kyungjae Myung Kwang Yeon Hwang Sunghoon Kim Jung Min Han Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. Yonsei Institute of Pharmaceutical Sciences College of Pharmacy Yonsei University Incheon 21983 South Korea. Center for Genomic Integrity Institute for Basic Science Ulsan 44919 South Korea. Department of Biotechnology College of Life Sciences and Biotechnology Korea University Seoul 02841 South Korea. Institute for Artificial Intelligence and Biomedical Research Medicinal Bioconvergence Research Center Yonsei University Incheon 21983 South Korea. College of Medicine Gangnam Severance Hospital Yonsei University Seoul 06273 South Korea. Department of Biochemistry School of Medicine Catholic University of Daegu Daegu 42472 South Korea. Department of Biomedical Engineering Ulsan National Institute of Science and Technology Ulsan 44919 South Korea. Interdisciplinary Program of Integrated OMICS for Biomedical Science Graduate School Yonsei University Seoul 03722 South Korea. jhan74@yonsei.ac.kr. Yonsei Institute of Pharmaceutical Sciences College of Pharmacy Yonsei University Incheon 21983 South Korea. jhan74@yonsei.ac.kr. POSTECH Biotech Center Pohang University of Science and Technology Pohang 37673 South Korea. jhan74@yonsei.ac.kr.

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Technology Roadmap for Flexible Sensors

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ACS NANO 2023年第6期17卷 5211-5295页

作者： Luo, Yifei Abidian, Mohammad Reza Ahn, Jong-Hyun Akinwande, Deji Andrews, Anne M. Antonietti, Markus Bao, Zhenan Berggren, Magnus Berkey, Christopher A. Bettinger, Christopher John Chen, Jun Chen, Peng Cheng, Wenlong Cheng, Xu Choi, Seon-Jin Chortos, Alex Dagdeviren, Canan Dauskardt, Reinhold H. Di, Chong-an Dickey, Michael D. Duan, Xiangfeng Facchetti, Antonio Fan, Zhiyong Fang, Yin Feng, Jianyou Feng, Xue Gao, Huajian Gao, Wei Gong, Xiwen Guo, Chuan Fei Guo, Xiaojun Hartel, Martin C. He, Zihan Ho, John S. Hu, Youfan Huang, Qiyao Huang, Yu Huo, Fengwei Hussain, Muhammad M. Javey, Ali Jeong, Unyong Jiang, Chen Jiang, Xingyu Kang, Jiheong Karnaushenko, Daniil Khademhosseini, Ali Kim, Dae-Hyeong Kim, Il-Doo Kireev, Dmitry Kong, Lingxuan Lee, Chengkuo Lee, Nae-Eung Lee, Pooi See Lee, Tae-Woo Li, Fengyu Li, Jinxing Liang, Cuiyuan Lim, Chwee Teck Lin, Yuanjing Lipomi, Darren J. Liu, Jia Liu, Kai Liu, Nan Liu, Ren Liu, Yuxin Liu, Yuxuan Liu, Zhiyuan Liu, Zhuangjian Loh, Xian Jun Lu, Nanshu Lv, Zhisheng Magdassi, Shlomo Malliaras, George G. Matsuhisa, Naoji Nathan, Arokia Niu, Simiao Pan, Jieming Pang, Changhyun Pei, Qibing Peng, Huisheng Qi, Dianpeng Ren, Huaying Rogers, John A. Rowe, Aaron Schmidt, Oliver G. Sekitani, Tsuyoshi Seo, Dae-Gyo Shen, Guozhen Sheng, Xing Shi, Qiongfeng Someya, Takao Song, Yanlin Stavrinidou, Eleni Su, Meng Sun, Xuemei Takei, Kuniharu Tao, Xiao-Ming Tee, Benjamin C. K. Thean, Aaron Voon-Yew Trung, Tran Quang Wan, Changjin Wang, Huiliang Wang, Joseph Wang, Ming Wang, Sihong Wang, Ting Wang, Zhong Lin Weiss, Paul S. Wen, Hanqi Xu, Sheng Xu, Tailin Yan, Hongping Yan, Xuzhou Yang, Hui Yang, Le Yang, Shuaijian Yin, Lan Yu, Cunjiang Yu, Guihua Yu, Jing Yu, Shu-Hong Yu, Xinge Zamburg, Evgeny Zhang, Haixia Zhang, Xiangyu Zhang, Xiaosheng Zhang, Xueji Zhang, Yihui Zhang, Yu Zhao, Siyuan Zhao, Xuanhe Zheng, Yuanjin Zheng, Yu-Qing Zheng, Zijian Zhou, Tao Zhu, Bowen Zhu, Ming Zhu, Rong Zhu, Yangzhi Zhu, Yong Zou, Guijin Chen, Xiaodong 08-03 Innovis Singapore 138634 Republic of Singapore Innovative Centre for Flexible Devices (iFLEX) School of Materials Science and Engineering Nanyang Technological University Singapore 639798 Singapore Department of Biomedical Engineering University of Houston Houston Texas 77024 United States School of Electrical and Electronic Engineering Yonsei University Seoul 03722 Republic of Korea Department of Electrical and Computer Engineering The University of Texas at Austin Austin Texas 78712 United States Microelectronics Research Center The University of Texas at Austin Austin Texas 78758 United States Department of Chemistry and Biochemistry California NanoSystems Institute and Department of Psychiatry and Biobehavioral Sciences Semel Institute for Neuroscience and Human Behavior and Hatos Center for Neuropharmacology University of California Los Angeles Los Angeles California 90095 United States Colloid Chemistry Department Max Planck Institute of Colloids and Interfaces 14476 Potsdam Germany Department of Chemical Engineering Stanford University Stanford California 94305 United States Laboratory of Organic Electronics Department of Science and Technology Campus Norrköping Linköping University 83 Linköping Sweden Wallenberg Initiative Materials Science for Sustainability (WISE) and Wallenberg Wood Science Center (WWSC) SE-100 44 Stockholm Sweden Department of Materials Science and Engineering Stanford University Stanford California 94301 United States Department of Biomedical Engineering and Department of Materials Science and Engineering Carnegie Mellon University Pittsburgh Pennsylvania 15213 United States Department of Bioengineering University of California Los Angeles Los Angeles California 90095 United States School of Chemistry Chemical Engineering and Biotechnology Nanyang Technological University Singapore 637457 Singapore Nanobionics Group Department of Chemical and Biological Engineering Monash University Clayton Australia 3800 Monash

Humans rely increasingly on sensors to address grand challenges and to improve quality of life in the era of digitalization and big data. For ubiquitous sensing, flexible sensors are developed to overcome the limitations of conventional rigid counterparts. Despite rapid advancement in bench-side research over the last decade, the market adoption of flexible sensors remains limited. To ease and to expedite their deployment, here, we identify bottlenecks hindering the maturation of flexible sensors and propose promising solutions. We first analyze continued...challenges in achieving satisfactory sensing performance for real-world applications and then summarize issues in compatible sensor-biology interfaces, followed by brief discussions on powering and connecting sensor networks. Issues en route to commercialization and for sustainable growth of the sector are also analyzed, highlighting environmental concerns and emphasizing nontechnical issues such as business, regulatory, and ethical considerations. Additionally, we look at future intelligent flexible sensors. In proposing a comprehensive roadmap, we hope to steer research efforts towards common goals and to guide coordinated development strategies from disparate communities. Through such collaborative

关键词： soft materials mechanics engineering flexible electronics conformable sensors bioelectronics human-machine interfaces body area sensor networks technology translation sustainable electronics

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Mitigation of Chromosome Loss in Clinical CRISPR-Cas9-Engineered T Cells

SSRN

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SSRN 2023年

作者： Tsuchida, Connor A. Brandes, Nadav Bueno, Raymund Trinidad, Marena Mazumder, Thomas Yu, Bingfei Hwang, Byungjin Chang, Christopher Liu, Jamin Sun, Yang Hopkins, Caitlin R. Parker, Kevin R. Qi, Yanyan Satpathy, Ansuman T. Stadtmauer, Edward A. Cate, Jamie H.D. Eyquem, Justin Fraietta, Joseph A. June, Carl H. Chang, Howard Y. Ye, Chun Jimmie Doudna, Jennifer A. University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering University of California Berkeley BerkeleyCA United States Innovative Genomics Institute University of California Berkeley BerkeleyCA United States Division of Rheumatology Department of Medicine University of California San Francisco San FranciscoCA United States Center for Personal Dynamic Regulomes Stanford University StanfordCA United States Parker Institute for Cancer Immunotherapy Stanford University School of Medicine StanfordCA United States Biomedical Sciences Graduate Program University of California San Francisco San FranciscoCA United States Medical Scientist Training Program University of California San Francisco San FranciscoCA United States Department of Medicine University of California San Francisco San FranciscoCA United States Parker Institute for Cancer Immunotherapy San FranciscoCA United States Gladstone-UCSF Institute of Genomic Immunology San FranciscoCA United States Department of Biochemistry and Biophysics University of California San Francisco San FranciscoCA United States Abramson Cancer Center Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Parker Institute for Cancer Immunotherapy Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Center for Cellular Immunotherapies Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Microbiology Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department of Pathology Stanford University School of Medicine StanfordCA United States Division of Hematology-Oncology Department of Medicine Perelman School of Medicine University of Pennsylvania PhiladelphiaPA United States Department o

CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome could be a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that partial or entire chromosome loss after Cas9-induced DNA cutting is a rare but generalized phenomenon, occurring also in pre-clinical chimeric antigen receptor T cells. T cells with chromosome loss persist for weeks in culture, implying potential interference with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells, dramatically reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with the protection from chromosome loss observed with this protocol, suggesting both a mechanism and a strategy for T cell engineering that mitigates genotoxicity in the clinic. © 2023, The Authors. All rights reserved.

关键词： T-cells

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