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439 results on '"Weissman A"'

1. Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Author

Quinn, Jeffrey J, Jones, Matthew G, Okimoto, Ross A, Nanjo, Shigeki, Chan, Michelle M, Yosef, Nir, Bivona, Trever G, and Weissman, Jonathan S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Lung, Cancer, Biotechnology, Lung Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, CRISPR-Cas Systems, Cell Line, Tumor, Cell Lineage, Clone Cells, Gene Expression Regulation, Neoplastic, Humans, Keratin-17, Lung Neoplasms, Mice, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Seeding, Neoplasm Transplantation, Phenotype, RNA-Seq, Single-Cell Analysis, Transcriptome, Transplantation, Heterologous, General Science & Technology
Abstract

Detailed phylogenies of tumor populations can recount the history and chronology of critical events during cancer progression, such as metastatic dissemination. We applied a Cas9-based, single-cell lineage tracer to study the rates, routes, and drivers of metastasis in a lung cancer xenograft mouse model. We report deeply resolved phylogenies for tens of thousands of cancer cells traced over months of growth and dissemination. This revealed stark heterogeneity in metastatic capacity, arising from preexisting and heritable differences in gene expression. We demonstrate that these identified genes can drive invasiveness and uncovered an unanticipated suppressive role for KRT17 We also show that metastases disseminated via multidirectional tissue routes and complex seeding topologies. Overall, we demonstrate the power of tracing cancer progression at subclonal resolution and vast scale.

Published
2021

2. Pervasive functional translation of noncanonical human open reading frames

Author

Chen, Jin, Brunner, Andreas-David, Cogan, J Zachery, Nuñez, James K, Fields, Alexander P, Adamson, Britt, Itzhak, Daniel N, Li, Jason Y, Mann, Matthias, Leonetti, Manuel D, and Weissman, Jonathan S

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, 1.1 Normal biological development and functioning, Generic health relevance, CRISPR-Cas Systems, Humans, Open Reading Frames, Operon, Peptides, Protein Biosynthesis, RNA, Messenger, Ribosomes, Transcriptome, General Science & Technology
Abstract

Ribosome profiling has revealed pervasive but largely uncharacterized translation outside of canonical coding sequences (CDSs). In this work, we exploit a systematic CRISPR-based screening strategy to identify hundreds of noncanonical CDSs that are essential for cellular growth and whose disruption elicits specific, robust transcriptomic and phenotypic changes in human cells. Functional characterization of the encoded microproteins reveals distinct cellular localizations, specific protein binding partners, and hundreds of microproteins that are presented by the human leukocyte antigen system. We find multiple microproteins encoded in upstream open reading frames, which form stable complexes with the main, canonical protein encoded on the same messenger RNA, thereby revealing the use of functional bicistronic operons in mammals. Together, our results point to a family of functional human microproteins that play critical and diverse cellular roles.

Published
2020

3. Exploring genetic interaction manifolds constructed from rich single-cell phenotypes

Author

Norman, Thomas M, Horlbeck, Max A, Replogle, Joseph M, Ge, Alex Y, Xu, Albert, Jost, Marco, Gilbert, Luke A, and Weissman, Jonathan S

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Apoptosis, CRISPR-Cas Systems, Calcium-Binding Proteins, Cell Cycle Checkpoints, Cell Line, Tumor, Epistasis, Genetic, Erythroid Cells, Erythropoiesis, Female, Gene Expression Profiling, Granulocytes, Humans, Microfilament Proteins, Proto-Oncogene Proteins c-cbl, Sequence Analysis, RNA, Single-Cell Analysis, General Science & Technology
Abstract

How cellular and organismal complexity emerges from combinatorial expression of genes is a central question in biology. High-content phenotyping approaches such as Perturb-seq (single-cell RNA-sequencing pooled CRISPR screens) present an opportunity for exploring such genetic interactions (GIs) at scale. Here, we present an analytical framework for interpreting high-dimensional landscapes of cell states (manifolds) constructed from transcriptional phenotypes. We applied this approach to Perturb-seq profiling of strong GIs mined from a growth-based, gain-of-function GI map. Exploration of this manifold enabled ordering of regulatory pathways, principled classification of GIs (e.g., identifying suppressors), and mechanistic elucidation of synergistic interactions, including an unexpected synergy between CBL and CNN1 driving erythroid differentiation. Finally, we applied recommender system machine learning to predict interactions, facilitating exploration of vastly larger GI manifolds.

Published
2019

4. Defining the physiological role of SRP in protein-targeting efficiency and specificity

Author

Costa, Elizabeth A, Subramanian, Kelly, Nunnari, Jodi, and Weissman, Jonathan S

Subjects
Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Endoplasmic Reticulum, Indoleacetic Acids, Mitochondria, Protein Sorting Signals, Protein Transport, Proteolysis, RNA, Messenger, Ribosomes, Saccharomyces cerevisiae, Signal Recognition Particle, General Science & Technology
Abstract

The signal recognition particle (SRP) enables cotranslational delivery of proteins for translocation into the endoplasmic reticulum (ER), but its full in vivo role remains incompletely explored. We combined rapid auxin-induced SRP degradation with proximity-specific ribosome profiling to define SRP's in vivo function in yeast. Despite the classic view that SRP recognizes amino-terminal signal sequences, we show that SRP was generally essential for targeting transmembrane domains regardless of their position relative to the amino terminus. By contrast, many proteins containing cleavable amino-terminal signal peptides were efficiently cotranslationally targeted in SRP's absence. We also reveal an unanticipated consequence of SRP loss: Transcripts normally targeted to the ER were mistargeted to mitochondria, leading to mitochondrial defects. These results elucidate SRP's essential roles in maintaining the efficiency and specificity of protein targeting.

Published
2018

5. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap

Author

Gandal, Michael J, Haney, Jillian R, Parikshak, Neelroop N, Leppa, Virpi, Ramaswami, Gokul, Hartl, Chris, Schork, Andrew J, Appadurai, Vivek, Buil, Alfonso, Werge, Thomas M, Liu, Chunyu, White, Kevin P, Horvath, Steve, Geschwind, Daniel H, Sestan, Nenad, Vaccarino, Flora, Gerstein, Mark, Weissman, Sherman, Pochareddy, Sirisha, State, Matthew, Knowles, James, Farnham, Peggy, Akbarian, Schahram, Pinto, Dalila, Van Baekl, Harm, Dracheva, Stella, Jaffe, Andrew, Hyde, Thomas, Zandi, Peter, Crawford, Gregory, Sullivan, Pat, Thompson, Wesley Kurt, Mortensen, Preben Bo, Agerbo, Esben, Pedersen, Marianne Giørtz, Pedersen, Carsten Bøcker, Mors, Ole, Børglum, Anders D, Nordentoft, Merete, Hougaard, David M, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Martin, Alicia R, Dumont, Ashley, Stevens, Christine, Churchhouse, Claire, Howrigan, Daniel P, Palmer, Duncan S, Robinson, Elise B, Satterstrom, Kyle F, Cerrato, Felecia, Huang, Hailiang, Goldstein, Jacqueline, Moran, Jennifer, Julian, Joanna Martin, Kimberly, Maller, Patrick, Chambert, Turley, Patrick, Walters, Raymond, Belliveau, Rich, Ripke, Stephan, Poterba, Timothy, Daly, Mark J, Neale, Benjamin, Fromer, Menachem, Roussos, Panos, Johnson, Jessica S, Shah, Hardik R, Mahajan, Milind C, Schadt, Eric, Haroutunian, Vahram, Ruderfer, Douglas M, Buxbaum, Joseph D, Sieberts, Solveig K, Dang, Kristen, Logsdon, Ben, Mangravite, Lara M, Peters, Mette, Gur, Raquel E, Hahn, Chang-Gyu, Devlin, Bernie, Klei, Lambertus L, Lewis, David, Lipska, Barbara, Hirai, Keisuke, Toyoshiba, Hiroyoshi, and Domenici, Enrico

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Biological Psychology, Psychology, Pharmacology and Pharmaceutical Sciences, Serious Mental Illness, Brain Disorders, Human Genome, Mental Health, Schizophrenia, Neurosciences, Bipolar Disorder, Depression, Mental Illness, 2.1 Biological and endogenous factors, Aetiology, Mental health, Good Health and Well Being, Cerebral Cortex, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Mental Disorders, Multifactorial Inheritance, Nervous System Diseases, Polymorphism, Single Nucleotide, Transcription, Genetic, CommonMind Consortium, PsychENCODE Consortium, iPSYCH-BROAD Working Group, General Science & Technology
Abstract

The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Published
2018

6. CAT-tailing as a fail-safe mechanism for efficient degradation of stalled nascent polypeptides

Author

Kostova, Kamena K, Hickey, Kelsey L, Osuna, Beatriz A, Hussmann, Jeffrey A, Frost, Adam, Weinberg, David E, and Weissman, Jonathan S

Subjects
Alanine, Lysine, Peptides, Proteolysis, Proteostasis, Ribosomes, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Threonine, Transcription Elongation, Genetic, Ubiquitin, Ubiquitin-Protein Ligases, General Science & Technology
Abstract

Ribosome stalling leads to recruitment of the ribosome quality control complex (RQC), which targets the partially synthesized polypeptide for proteasomal degradation through the action of the ubiquitin ligase Ltn1p. A second core RQC component, Rqc2p, modifies the nascent polypeptide by adding a carboxyl-terminal alanine and threonine (CAT) tail through a noncanonical elongation reaction. Here we examined the role of CAT-tailing in nascent-chain degradation in budding yeast. We found that Ltn1p efficiently accessed only nascent-chain lysines immediately proximal to the ribosome exit tunnel. For substrates without Ltn1p-accessible lysines, CAT-tailing enabled degradation by exposing lysines sequestered in the ribosome exit tunnel. Thus, CAT-tails do not serve as a degron, but rather provide a fail-safe mechanism that expands the range of RQC-degradable substrates.

Published
2017

7. CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells

Author

Liu, S John, Horlbeck, Max A, Cho, Seung Woo, Birk, Harjus S, Malatesta, Martina, He, Daniel, Attenello, Frank J, Villalta, Jacqueline E, Cho, Min Y, Chen, Yuwen, Mandegar, Mohammad A, Olvera, Michael P, Gilbert, Luke A, Conklin, Bruce R, Chang, Howard Y, Weissman, Jonathan S, and Lim, Daniel A

Subjects
Stem Cell Research, Regenerative Medicine, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research - Embryonic - Human, Biotechnology, Human Genome, Genetics, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Cell Growth Processes, Cell Line, Clustered Regularly Interspaced Short Palindromic Repeats, Gene Knockdown Techniques, Gene Regulatory Networks, Genetic Loci, Genetic Testing, Genome, Human, Humans, Induced Pluripotent Stem Cells, Machine Learning, RNA Interference, RNA, Long Noncoding, Transcription, Genetic, Transcriptome, General Science & Technology
Abstract

The human genome produces thousands of long noncoding RNAs (lncRNAs)-transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type-specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs.

Published
2017

8. Lift NIH restrictions on chimera research

Author

Sharma, Arun, Sebastiano, Vittorio, Scott, Christopher T, Magnus, David, Koyano-Nakagawa, Naoko, Garry, Daniel J, Witte, Owen N, Nakauchi, Hiromitsu, Wu, Joseph C, Weissman, Irving L, and Wu, Sean M

Subjects
General Science & Technology
Published
2015

9. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains

Author

Shen, Peter S, Park, Joseph, Qin, Yidan, Li, Xueming, Parsawar, Krishna, Larson, Matthew H, Cox, James, Cheng, Yifan, Lambowitz, Alan M, Weissman, Jonathan S, Brandman, Onn, and Frost, Adam

Subjects
Genetics, Generic health relevance, Cryoelectron Microscopy, Nucleic Acid Conformation, Peptide Biosynthesis, Nucleic Acid-Independent, Protein Conformation, RNA, Messenger, RNA, Transfer, Ala, RNA, Transfer, Thr, RNA-Binding Proteins, Ribosome Subunits, Large, Eukaryotic, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Ubiquitin-Protein Ligases, General Science & Technology
Abstract

In Eukarya, stalled translation induces 40S dissociation and recruitment of the ribosome quality control complex (RQC) to the 60S subunit, which mediates nascent chain degradation. Here we report cryo-electron microscopy structures revealing that the RQC components Rqc2p (YPL009C/Tae2) and Ltn1p (YMR247C/Rkr1) bind to the 60S subunit at sites exposed after 40S dissociation, placing the Ltn1p RING (Really Interesting New Gene) domain near the exit channel and Rqc2p over the P-site transfer RNA (tRNA). We further demonstrate that Rqc2p recruits alanine- and threonine-charged tRNA to the A site and directs the elongation of nascent chains independently of mRNA or 40S subunits. Our work uncovers an unexpected mechanism of protein synthesis, in which a protein--not an mRNA--determines tRNA recruitment and the tagging of nascent chains with carboxy-terminal Ala and Thr extensions ("CAT tails").

Published
2015

10. A pause sequence enriched at translation start sites drives transcription dynamics in vivo

Author

Larson, Matthew H, Mooney, Rachel A, Peters, Jason M, Windgassen, Tricia, Nayak, Dhananjaya, Gross, Carol A, Block, Steven M, Greenleaf, William J, Landick, Robert, and Weissman, Jonathan S

Subjects
Genetics, Human Genome, Emerging Infectious Diseases, Base Sequence, Codon, Initiator, Consensus Sequence, DNA-Directed RNA Polymerases, Escherichia coli, Gene Expression Regulation, Bacterial, Peptide Chain Initiation, Translational, Regulatory Elements, Transcriptional, Transcription, Genetic, General Science & Technology
Abstract

Transcription by RNA polymerase (RNAP) is interrupted by pauses that play diverse regulatory roles. Although individual pauses have been studied in vitro, the determinants of pauses in vivo and their distribution throughout the bacterial genome remain unknown. Using nascent transcript sequencing, we identified a 16-nucleotide consensus pause sequence in Escherichia coli that accounts for known regulatory pause sites as well as ~20,000 new in vivo pause sites. In vitro single-molecule and ensemble analyses demonstrate that these pauses result from RNAP-nucleic acid interactions that inhibit next-nucleotide addition. The consensus sequence also leads to pausing by RNAPs from diverse lineages and is enriched at translation start sites in both E. coli and Bacillus subtilis. Our results thus reveal a conserved mechanism unifying known and newly identified pause events.

Published
2014

11. Identification of a Colonial Chordate Histocompatibility Gene

Author

Voskoboynik, Ayelet, Newman, Aaron M, Corey, Daniel M, Sahoo, Debashis, Pushkarev, Dmitry, Neff, Norma F, Passarelli, Benedetto, Koh, Winston, Ishizuka, Katherine J, Palmeri, Karla J, Dimov, Ivan K, Keasar, Chen, Fan, H Christina, Mantalas, Gary L, Sinha, Rahul, Penland, Lolita, Quake, Stephen R, and Weissman, Irving L

Subjects
Biological Sciences, Genetics, Transplantation, Human Genome, Biotechnology, Alleles, Animals, Genes, Genome, Genotype, Histocompatibility, Immune Tolerance, Molecular Sequence Data, Sequence Analysis, DNA, Transcriptome, Up-Regulation, Urochordata, General Science & Technology
Abstract

Histocompatibility is the basis by which multicellular organisms of the same species distinguish self from nonself. Relatively little is known about the mechanisms underlying histocompatibility reactions in lower organisms. Botryllus schlosseri is a colonial urochordate, a sister group of vertebrates, that exhibits a genetically determined natural transplantation reaction, whereby self-recognition between colonies leads to formation of parabionts with a common vasculature, whereas rejection occurs between incompatible colonies. Using genetically defined lines, whole-transcriptome sequencing, and genomics, we identified a single gene that encodes self-nonself and determines "graft" outcomes in this organism. This gene is significantly up-regulated in colonies poised to undergo fusion and/or rejection, is highly expressed in the vasculature, and is functionally linked to histocompatibility outcomes. These findings establish a platform for advancing the science of allorecognition.

Published
2013

13. Deep Impact: Observations from a Worldwide Earth-Based Campaign

Author

Meech, K. J., Ageorges, N., Arpigny, C., Ates, A., Aycock, J., Bagnulo, S., Bailey, J., Barber, R., Barrera, L., Barrena, R., Bauer, J. M., Belton, M. J. S., Bensch, F., Bhattacharya, B., Biver, N., Blake, G., Bockelée-Morvan, D., Boehnhardt, H., Bonev, B. P., Bonev, T., Buie, M. W., Burton, M. G., Butner, H. M., Cabanac, R., Campbell, R., Campins, H., Capria, M. T., Carroll, T., Chaffee, F., Charnley, S. B., Cleis, R., Coates, A., Cochran, A., Colom, P., Conrad, A., Coulson, I. M., Crovisier, J., deBuizer, J., Dekany, R., de Léon, J., Russo, N. Dello, Delsanti, A., DiSanti, M., Drummond, J., Dundon, L., Etzel, P. B., Farnham, T. L., Feldman, P., Fernández, Y. R., Filipovic, M. D., Fisher, S., Fitzsimmons, A., Fong, D., Fugate, R., Fujiwara, H., Fujiyoshi, T., Furusho, R., Fuse, T., Gibb, E., Groussin, O., Gulkis, S., Gurwell, M., Hadamcik, E., Hainaut, O., Harker, D., Harrington, D., Harwit, M., Hasegawa, S., Hergenrother, C. W., Hirst, P., Hodapp, K., Honda, M., Howell, E. S., Hutsemékers, D., Iono, D., Jackson, W., Jehin, E., Jiang, Z. J., Jones, G. H., Jones, P. A., Kadono, T., Kamath, U. W., Käufl, H. U., Kasuga, T., Kawakita, H., Kelley, M. S., Kerber, F., Kidger, M., Kinoshita, D., Knight, M., Lara, L., Larson, S. M., Lederer, S., Levasseur-Regourd, A. C., Li, J. Y., Licandro, J., Lisse, C. M., LoCurto, G., Lovell, A. J., Lowry, S. C., Lyke, J., Lynch, D., Ma, J., Magee-Sauer, K., Maheswar, G., Manfroid, J., Marco, O., Martin, P., Melnick, G., Miller, S., Miyata, T., Moriarty-Schieven, G. H., Moskovitz, N., Mueller, B. E. A., Mumma, M. J., Muneer, S., Neufeld, D. A., Ootsubo, T., Osip, D., Pandea, S. K., Pantin, E., Paterno-Mahler, R., Patten, B., Penprase, B. E., Peck, A., Petitas, G., Pinilla-Alonso, N., Pittichova, J., Pompei, E., Prabhu, T. P., Qi, C., Rao, R., Rauer, H., Reitsema, H., Rodgers, S. D., Rodriguez, P., Ruane, R., Ruch, G., Rujopakarn, W., Sahu, D. K., Sako, S., Sakon, I., Samarasinha, N., Sarkissian, J. M., Saviane, I., Schirmer, M., Schultz, P., Schulz, R., Seitzer, P., Sekiguchi, T., Selman, F., Serra-Ricart, M., Sharp, R., Snell, R. L., Snodgrass, C., Stallard, T., Stecklein, G., Sterken, C., Stüwe, J. A., Sugita, S., Sumner, M., Suntzeff, N., Swaters, R., Takakuwa, S., Takato, N., Thomas-Osip, J., Thompson, E., Tokunaga, A. T., Tozzi, G. P., Tran, H., Troy, M., Trujillo, C., Van Cleve, J., Vasundhara, R., Vazquez, R., Vilas, F., Villanueva, G., von Braun, K., Vora, P., Wainscoat, R. J., Walsh, K., Watanabe, J., Weaver, H. A., Weaver, W., Weiler, M., Weissman, P. R., Welsh, W. F., Wilner, D., Wolk, S., Womack, M., Wooden, D., Woodney, L. M., Woodward, C., Yamashita, T., Yang, B., Yokogawa, S., Zook, A. C., Zauderer, A., Zhao, X., and Zhou, X.

Published
2005

18. "Fluorescent Timer": Protein That Changes Color with Time

Author

Terskikh, Alexey, Fradkov, Arkady, Ermakova, Galina, Zaraisky, Andrey, Tan, Patrick, Kajava, Andrey V., Zhao, Xiaoning, Lukyanov, Sergey, Matz, Mikhail, Kim, Stuart, Weissman, Irving, and Siebert, Paul

Published
2000

23. Near-Infrared Spectroscopy and Spectral Mapping of Jupiter and the Galilean Satellites: Results from Galileo's Initial Orbit

Author

Carlson, R., Smythe, W., Baines, K., Barbinis, E., Becker, K., Burns, R., Calcutt, S., Calvin, W., Clark, R., Danielson, G., Davies, A., Drossart, P., Encrenaz, T., Fanale, F., Granahan, J., Hansen, G., Herrera, P., Hibbitts, C., Hui, J., Irwin, P., Johnson, T., Kamp, L., Kieffer, H., Leader, F., Lellouch, E., Lopes-Gautier, R., Matson, D., McCord, T., Mehlman, R., Ocampo, A., Orton, G., Roos-Serote, M., Segura, M., Shirley, J., Soderblom, L., Stevenson, A., Taylor, F., Torson, J., Weir, A., and Weissman, P.

Published
1996

24. CAR T cells produced in vivo to treat cardiac injury

Author

Joel G. Rurik, István Tombácz, Amir Yadegari, Pedro O. Méndez Fernández, Swapnil V. Shewale, Li Li, Toru Kimura, Ousamah Younoss Soliman, Tyler E. Papp, Ying K. Tam, Barbara L. Mui, Steven M. Albelda, Ellen Puré, Carl H. June, Haig Aghajanian, Drew Weissman, Hamideh Parhiz, and Jonathan A. Epstein

Subjects
Heart Failure, Male, Receptors, Chimeric Antigen, Multidisciplinary, Heart Diseases, Myocardium, T-Lymphocytes, Membrane Proteins, Fibroblasts, CD5 Antigens, Adoptive Transfer, Fibrosis, Immunotherapy, Adoptive, Trogocytosis, Mice, Inbred C57BL, Mice, HEK293 Cells, Endopeptidases, Liposomes, Animals, Humans, Nanoparticles, RNA, Messenger, Cell Engineering, Spleen
Abstract

Making CAR T cells in vivo Cardiac fibrosis is the stiffening and scarring of heart tissue and can be fatal. Rurik et al . designed an immunotherapy strategy to generate transient chimeric antigen receptor (CAR) T cells that can recognize the fibrotic cells in the heart (see the Perspective by Gao and Chen). By injecting CD5-targeted lipid nanoparticles containing the messenger RNA (mRNA) instructions needed to reprogram T lymphocytes, the researchers were able to generate therapeutic CAR T cells entirely inside the body. Analysis of a mouse model of heart disease revealed that the approach was successful in reducing fibrosis and restoring cardiac function. The ability to produce CAR T cells in vivo using modified mRNA may have a number of therapeutic applications. —PNK

Published
2022

26. A prudent path forward for genomic engineering and germline gene modification: A framework for open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome is urgently needed

Author

Baltimore, David, Berg, Paul, Botchan, Michael, Carroll, Dana, Charo, R. Alta, Church, George, Corn, Jacob E., Daley, George Q., Doudna, Jennifer A., Fenner, Marsha, Greely, Henry T., Jinek, Martin, Martin, G. Steven, Penhoet, Edward, Puck, Jennifer, Sternberg, Samuel H., Weissman, Jonathan S., and Yamamoto, Keith R.

Published
2015

27. Dynamic profiling of the protein life cycle in response to pathogens

Author

Jovanovic, Marko, Rooney, Michael S., Mertins, Philipp, Przybylski, Dariusz, Chevrier, Nicolas, Satija, Rahul, Rodriguez, Edwin H., Fields, Alexander P., Schwartz, Schraga, Raychowdhury, Raktima, Mumbach, Maxwell R., Eisenhaure, Thomas, Rabani, Michal, Gennert, Dave, Lu, Diana, Delorey, Toni, Weissman, Jonathan S., Carr, Steven A., Hacohen, Nir, and Regev, Aviv

Published
2015

28. Rosetta begins its COMET TALE

Author

Taylor, M. G. G. T., Alexander, C., Altobelli, N., Fulle, M., Fulchignoni, M., Grün, E., and Weissman, P.

Published
2015

29. Dust measurements in the coma of comet 67P/Churyumov-Gerasimenko inbound to the Sun

Author

Rotundi, A., Sierks, H., Corte, V. Della, Fulle, M., Gutierrez, P. J., Lara, L., Barbieri, C., Lamy, P. L., Rodrigo, R., Koschny, D., Rickman, H., Keller, H. U., López-Moreno, J. J., Accolla, M., Agarwal, J., A'Hearn, M. F., Altobelli, N., Angrilli, F., Barucci, M. A., Bertaux, J.-L., Bertini, I., Bodewits, D., Bussoletti, E., Colangeli, L., Cosi, M., Cremonese, G., Crifo, J.-F., Da Deppo, V., Davidsson, B., Debei, S., De Cecco, M., Esposito, F., Ferrari, M., Fornasier, S., Giovane, F., Gustafson, B., Green, S. F., Groussin, O., Grün, E., Güttler, C., Herranz, M. L., Hviid, S. F., Ip, W., Ivanovski, S., Jerónimo, J. M., Jorda, L., Knollenberg, J., Kramm, R., Kührt, E., Küppers, M., Lazzarin, M., Leese, M. R., López-Jiménez, A. C., Lucarelli, F., Lowry, S. C., Marzari, F., Epifani, E. Mazzotta, McDonnell, J. A. M., Mennella, V., Michalik, H., Molina, A., Morales, R., Moreno, F., Mottola, S., Naletto, G., Oklay, N., Ortiz, J. L., Palomba, E., Palumbo, P., Perrin, J.-M., Rodríguez, J., Sabau, L., Snodgrass, C., Sordini, R., Thomas, N., Tubiana, C., Vincent, J.-B., Weissman, P., Wenzel, K.-P., Zakharov, V., and Zarnecki, J. C.

Published
2015

30. Varshavsky's Contributions

Author

Baumeister, Wolfgang, Bachmair, Andreas, Chau, Vincent, Cohen, Robert, Coffino, Phil, DeMartino, George, Deshaies, Raymond, Dohmen, Juergen, Emr, Scott, Finley, Daniel, Hampton, Randy, Hill, Christopher, Hochstrasser, Mark, Huber, Robert, Jackson, Peter, Jentsch, Stefan, Johnson, Erica, Kwon, Yong Tae, Pagano, Michele, Pickart, Cecile, Rechsteiner, Martin, Scheffner, Martin, Sommer, Thomas, Tansey, William, Tyers, Mike, Vierstra, Richard, Weissman, Allan, Wilkinson, Keith D., and Wolf, Dieter

Published
2004

31. A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes

Author

Arevalo, Claudia P., primary, Bolton, Marcus J., additional, Le Sage, Valerie, additional, Ye, Naiqing, additional, Furey, Colleen, additional, Muramatsu, Hiromi, additional, Alameh, Mohamad-Gabriel, additional, Pardi, Norbert, additional, Drapeau, Elizabeth M., additional, Parkhouse, Kaela, additional, Garretson, Tyler, additional, Morris, Jeffrey S., additional, Moncla, Louise H., additional, Tam, Ying K., additional, Fan, Steven H. Y., additional, Lakdawala, Seema S., additional, Weissman, Drew, additional, and Hensley, Scott E., additional

Published
2022
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32. MTCH2 is a mitochondrial outer membrane protein insertase

Author

Guna, Alina, primary, Stevens, Taylor A., additional, Inglis, Alison J., additional, Replogle, Joseph M., additional, Esantsi, Theodore K., additional, Muthukumar, Gayathri, additional, Shaffer, Kelly C. L., additional, Wang, Maxine L., additional, Pogson, Angela N., additional, Jones, Jeff J., additional, Lomenick, Brett, additional, Chou, Tsui-Fen, additional, Weissman, Jonathan S., additional, and Voorhees, Rebecca M., additional

Published
2022
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34. Something in the Eye of the Beholder

Author

Blau, Helen, Brazelton, Tim, Keshet, Gilmor, Rossi, Fabio, Castro, Raymond F., Jackson, Kathyjo A., Goodell, Margaret A., Robertson, Claudia S., Liu, Hao, Shine, H. David, Wagers, Amy J., Sherwood, Richard I., Christensen, Julie L., and Weissman, Irving L.

Published
2002

37. Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice

Author

Elena N. Atochina-Vasserman, Ande West, Sarah R. Leist, Lisa C. Lindesmith, Alexandra Schäfer, Dapeng Li, Robert Parks, Norbert Pardi, Boyd Yount, Maggie Barr, Kevin O. Saunders, Stephanie A. Montgomery, Drew Weissman, Ralph S. Baric, Gabriela De la Cruz, Barton F. Haynes, and David R. Martinez

Subjects
Sarbecovirus, 0301 basic medicine, Cross Protection, viruses, Antibodies, Viral, Severe Acute Respiratory Syndrome, Virus Replication, Neutralization, Mice, Immunogenicity, Vaccine, 0302 clinical medicine, 030212 general & internal medicine, Mink, skin and connective tissue diseases, Lung, Mice, Inbred BALB C, Vaccines, Synthetic, Multidisciplinary, biology, Immunogenicity, virus diseases, Vaccination, Titer, Severe acute respiratory syndrome-related coronavirus, Spike Glycoprotein, Coronavirus, Cytokines, Female, Spike (software development), Antibody, Coronavirus Infections, COVID-19 Vaccines, Recombinant Fusion Proteins, Heterologous, Immunity, Heterologous, Article, Betacoronavirus, 03 medical and health sciences, Protein Domains, Immunity, biology.animal, Animals, Messenger RNA, SARS-CoV-2, fungi, COVID-19, Viral Vaccines, Breakthrough infection, biology.organism_classification, Antibodies, Neutralizing, Virology, respiratory tract diseases, body regions, universal coronavirus vaccine, mRNA vaccine, 030104 developmental biology, Viral replication, Liposomes, biology.protein, Nanoparticles, SARS-like virus
Abstract

The emergence of SARS-CoV and SARS-CoV-2 in the 21st century highlights the need to develop universal vaccination strategies against the SARS-related Sarbecovirus subgenus. Using structure-guided chimeric spike designs and multiplexed immunizations, we demonstrate protection against SARS-CoV, SARS-CoV-2, and bat CoV (BtCoV) RsSHC014 challenge in highly vulnerable aged mice. Chimeric spike mRNAs containing N-terminal domain (NTD), and receptor binding domains (RBD) induced high levels of broadly protective neutralizing antibodies against three high-risk sarbecoviruses: SARS-CoV, RsSHC014, and WIV-1. In contrast, SARS-CoV-2 mRNA vaccination not only showed a 10 to >500-fold reduction in neutralizing titers against heterologous sarbecovirus strains, but SARS-CoV challenge in mice resulted in breakthrough infection including measurable lung pathology. Importantly, chimeric spike mRNA vaccines efficiently neutralized both the D614G and the South African B.1.351 variants of concern despite some reduction in neutralization activity. Thus, multiplexed-chimeric spikes may provide a novel strategy to prevent pandemic and SARS-like zoonotic coronavirus infections, while revealing the limited efficacy of SARS-CoV-2 spike vaccines against other sarbecoviruses.

Published
2021

39. Pills or Placebos?

Author

Trussell, James, Kazdin, Alan E., Antelman, Seymour M., Levine, Joseph, Gershon, Samuel, Caggiula, Anthony R., Fish, Jefferson M., Weissman, Myrna M., and Hankoff, L. D.

Published
1999

40. In vivo hematopoietic stem cell modification by mRNA delivery.

Author

Breda, Laura, Papp, Tyler E., Triebwasser, Michael P., Yadegari, Amir, Fedorky, Megan T., Naoto Tanaka, Abdulmalik, Osheiza, Pavani, Giulia, Yongping Wang, Grupp, Stephan A., Chou, Stella T., Houping Ni, Mui, Barbara L., Tam, Ying K., Weissman, Drew, Rivella, Stefano, and Parhiz, Hamideh

Published
2023
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43. Decoding Human Cytomegalovirus

Author

Stern-Ginossar, Noam, Weisburd, Ben, Michalski, Annette, Le, Vu Thuy Khanh, Hein, Marco Y., Huang, Sheng-Xiong, Ma, Ming, Shen, Ben, Qian, Shu-Bing, Hengel, Hartmut, Mann, Matthias, Ingolia, Nicholas T., and Weissman, Jonathan S.

Published
2012
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46. OpenCell: Endogenous tagging for the cartography of human cellular organization

Author

Cho, Nathan H., primary, Cheveralls, Keith C., additional, Brunner, Andreas-David, additional, Kim, Kibeom, additional, Michaelis, André C., additional, Raghavan, Preethi, additional, Kobayashi, Hirofumi, additional, Savy, Laura, additional, Li, Jason Y., additional, Canaj, Hera, additional, Kim, James Y. S., additional, Stewart, Edna M., additional, Gnann, Christian, additional, McCarthy, Frank, additional, Cabrera, Joana P., additional, Brunetti, Rachel M., additional, Chhun, Bryant B., additional, Dingle, Greg, additional, Hein, Marco Y., additional, Huang, Bo, additional, Mehta, Shalin B., additional, Weissman, Jonathan S., additional, Gómez-Sjöberg, Rafael, additional, Itzhak, Daniel N., additional, Royer, Loïc A., additional, Mann, Matthias, additional, and Leonetti, Manuel D., additional

Published
2022
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48. Pervasive functional translation of noncanonical human open reading frames

Author

Daniel N. Itzhak, Alexander P. Fields, Jonathan S. Weissman, Jin Chen, J. Zachery Cogan, James K. Nuñez, Andreas-David Brunner, Manuel D. Leonetti, Jason Y. Li, Britt Adamson, and Matthias Mann

Subjects
0303 health sciences, Messenger RNA, Multidisciplinary, RNA, Translation (biology), Computational biology, Biology, Transcriptome, Open Reading Frames, 03 medical and health sciences, Open reading frame, 0302 clinical medicine, Protein Biosynthesis, 030220 oncology & carcinogenesis, Operon, Humans, CRISPR, RNA, Messenger, Ribosome profiling, CRISPR-Cas Systems, Peptides, Ribosomes, 030304 developmental biology, Genetic screen
Abstract

Expanding the human proteome Using mass spectrometry, ribosome profiling, and several CRISPR-based screens, Chen et al. identified hundreds of previously uncharacterized functional micropeptides in the human genome (see the Perspective by Wei and Guo). Protein translation outside of annotated open reading frames (ORFs) in messenger RNAs and within ORFs in long noncoding RNAs is pervasive. A functional screen using CRISPR-Cas9 with single-cell transcriptomics suggested critical roles for hundreds of micropeptides. Micropeptides encoded by multiple short, upstream ORFs form stable protein complexes with the downstream canonical proteins encoded on the same messenger RNAs. Science , this issue p. 1140 ; see also p. 1074

Published
2020

49. Variation in Transcription Factor Binding among Humans

Author

Kasowski, Maya, Grubert, Fabian, Heffelfinger, Christopher, Hariharan, Manoj, Asabere, Akwasi, Waszak, Sebastian M., Habegger, Lukas, Rozowsky, Joel, Shi, Minyi, Urban, Alexander E., Hong, Mi-Young, Karczewski, Konrad J., Huber, Wolfgang, Weissman, Sherman M., Gerstein, Mark B., Korbel, Jan O., and Snyder, Michael

Published
2010
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