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Article ; Online: CD25-T

Solomon, Isabelle / Amann, Maria / Goubier, Anne / Arce Vargas, Frederick / Zervas, Dimitrios / Qing, Chen / Henry, Jake Y / Ghorani, Ehsan / Akarca, Ayse U / Marafioti, Teresa / Śledzińska, Anna / Werner Sunderland, Mariana / Franz Demane, Dafne / Clancy, Joanne Ruth / Georgiou, Andrew / Salimu, Josephine / Merchiers, Pascal / Brown, Mark Adrian / Flury, Reto /

Eckmann, Jan / Murgia, Claudio / Sam, Johannes / Jacobsen, Bjoern / Marrer-Berger, Estelle / Boetsch, Christophe / Belli, Sara / Leibrock, Lea / Benz, Joerg / Koll, Hans / Sutmuller, Roger / Peggs, Karl S / Quezada, Sergio A

Nature cancer

2020 Volume 1, Issue 12, Page(s) 1153–1166

Abstract: Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and ... receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here ... IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade ...

Abstract	Intratumoral regulatory T cell (Treg) abundance associates with diminished anti-tumor immunity and poor prognosis in human cancers. Recent work demonstrates that CD25, the high affinity receptor subunit for IL-2, is a selective target for Treg depletion in mouse and human malignancies; however, anti-human CD25 antibodies have failed to deliver clinical responses against solid tumors due to bystander IL-2 receptor signaling blockade on effector T cells, which limits their anti-tumor activity. Here we demonstrate potent single-agent activity of anti-CD25 antibodies optimized to deplete Tregs whilst preserving IL-2-STAT5 signaling on effector T cells, and demonstrate synergy with immune checkpoint blockade in vivo. Pre-clinical evaluation of an anti-human CD25 (RG6292) antibody with equivalent features demonstrates, in both non-human primates and humanized mouse models, efficient Treg depletion with no overt immune-related toxicities. Our data supports the clinical development of RG6292 and evaluation of novel combination therapies incorporating non-IL-2 blocking anti-CD25 antibodies in clinical studies.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Interleukin-2/pharmacology ; Mice ; Neoplasms ; Signal Transduction ; T-Lymphocytes, Regulatory
Chemical Substances	Antibodies, Monoclonal ; Interleukin-2
Language	English
Publishing date	2020-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-020-00133-0
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Article ; Online: Tsyn-Seq: a T-cell Synapse-Based Antigen Identification Platform.

Cancer immunology research

2024 Volume 12, Issue 5, Page(s) 530–543

Abstract: Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T ... the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible ... NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter ...

Abstract	Tools for genome-wide rapid identification of peptide-major histocompatibility complex targets of T-cell receptors (TCR) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APC) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally screen for target antigens from a cDNA library, productively interacting T cell-APC aggregates were detected by dual-reporter activity and enriched by flow sorting followed by antigen identification quantified by deep sequencing (Tsyn-seq). When applied to a previously characterized TCR specific for the E7 antigen derived from human papillomavirus type 16 (HPV16), Tsyn-seq successfully enriched the correct cognate antigen from a cDNA library derived from an HPV16-positive cervical cancer cell line. Tsyn-seq provides a method for rapidly identifying antigens recognized by TCRs of interest from a tumor cDNA library. See related Spotlight by Makani and Joglekar, p. 515.
MeSH term(s)	Humans ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes/immunology ; High-Throughput Nucleotide Sequencing ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/genetics ; Gene Library ; Antigen-Presenting Cells/immunology ; NFATC Transcription Factors/metabolism ; NFATC Transcription Factors/immunology ; Cell Line, Tumor ; NF-kappa B/metabolism ; Immunological Synapses/immunology ; Human papillomavirus 16/immunology ; Human papillomavirus 16/genetics ; Female
Chemical Substances	Receptors, Antigen, T-Cell ; Papillomavirus E7 Proteins ; NFATC Transcription Factors ; oncogene protein E7, Human papillomavirus type 16 ; NF-kappa B
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0467
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Article ; Online: Simultaneous T

Sharafi, Azadeh / Medina, Katherine / Zibetti, Marcelo W V / Rao, Smita / Cloos, Martijn A / Brown, Ryan / Regatte, Ravinder R

Magnetic resonance in medicine

2021 Volume 86, Issue 1, Page(s) 372–381

Abstract: ... to : Methods: We implemented a totally balanced spin-lock (TB-SL) module to encode T: Results: The phantom ...

Abstract	Purpose: To develop a novel MR-fingerprinting (MRF) pulse sequence that is insensitive to Methods: We implemented a totally balanced spin-lock (TB-SL) module to encode T Results: The phantom relaxation times measured with TB-SL and SC-SL MRF were in good agreement with reference values in regions with low B Conclusion: The proposed TB-SL MRF sequence is fast and insensitive to
MeSH term(s)	Humans ; Image Processing, Computer-Assisted ; Leg ; Magnetic Resonance Imaging ; Muscle, Skeletal/diagnostic imaging ; Phantoms, Imaging
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605774-3
ISSN	1522-2594 ; 0740-3194
ISSN (online)	1522-2594
ISSN	0740-3194
DOI	10.1002/mrm.28704
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Article ; Online: Targeting the dendritic cell-T cell axis to develop effective immunotherapies for glioblastoma.

Gardam, Bryan / Gargett, Tessa / Brown, Michael P / Ebert, Lisa M

Frontiers in immunology

2023 Volume 14, Page(s) 1261257

Abstract: ... development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell ... while T cells are essential effector cells for tumor control, dendritic cells play an equally important role ... in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply ...

Abstract	Glioblastoma is an aggressive primary brain tumor that has seen few advances in treatments for over 20 years. In response to this desperate clinical need, multiple immunotherapy strategies are under development, including CAR-T cells, immune checkpoint inhibitors, oncolytic viruses and dendritic cell vaccines, although these approaches are yet to yield significant clinical benefit. Potential reasons for the lack of success so far include the immunosuppressive tumor microenvironment, the blood-brain barrier, and systemic changes to the immune system driven by both the tumor and its treatment. Furthermore, while T cells are essential effector cells for tumor control, dendritic cells play an equally important role in T cell activation, and emerging evidence suggests the dendritic cell compartment may be deeply compromised in glioblastoma patients. In this review, we describe the immunotherapy approaches currently under development for glioblastoma and the challenges faced, with a particular emphasis on the critical role of the dendritic cell-T cell axis. We suggest a number of strategies that could be used to boost dendritic cell number and function and propose that the use of these in combination with T cell-targeting strategies could lead to successful tumor control.
MeSH term(s)	Humans ; Glioblastoma ; T-Lymphocytes ; Immunotherapy ; Oncolytic Viruses ; Dendritic Cells ; Tumor Microenvironment
Language	English
Publishing date	2023-10-20
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1261257
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Article: Expansion of endogenous T cells in CSF of pediatric CNS tumor patients undergoing locoregional delivery of IL13R〿2-targeting CAR T cells: an interim analysis.

Wang, Leo / Oill, Angela Taravella / Blanchard, M / Wu, Melody / Hibbard, Jonathan / Sepulveda, Sean / Peter, Lance / Kilpatrick, Julie / Munoz, Margarita / Stiller, Tracey / Shulkin, Noah / Wagner, Jamie / Dolatabadi, Ally / Nisis, Monica / Shepphird, Jennifer / Sanchez, Gabriela / Lingaraju, Chetan / Manchanda, Mishika / Natri, Heini /

Kouakanou, Léonce / Sun, Grace / Oliver-Cervantes, Cheryl / Georges, Joseph / Aftabizadeh, Maryam / Forman, Stephen / Priceman, Saul / Ressler, Julie / Arvanitis, Leonidas / Cotter, Jennifer / D'Apuzzo, Massimo / Tamrazi, Benita / Badie, Behnam / Davidson, Tom / Banovich, Nicholas / Brown, Christine

Research square

2023

Abstract: ... antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six ... pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T ...

Abstract	Outcomes for pediatric brain tumor patients remain poor, and there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six pediatric patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles, identifying clonal expansion of endogenous CAR-negative CD8
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3454977/v1
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Article ; Online: Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma.

Haematologica

2024 Volume 109, Issue 5, Page(s) 1373–1384

Abstract: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare ... therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient ... transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line ...

Abstract	T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.
MeSH term(s)	Humans ; Receptor, Platelet-Derived Growth Factor beta/genetics ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Animals ; Mice ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; Myosin Heavy Chains/genetics ; Myosin Heavy Chains/metabolism ; Molecular Targeted Therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Disease Models, Animal
Chemical Substances	Receptor, Platelet-Derived Growth Factor beta (EC 2.7.10.1) ; PDGFRB protein, human (EC 2.7.10.1) ; Oncogene Proteins, Fusion ; MYH9 protein, human ; Myosin Heavy Chains (EC 3.6.4.1) ; Protein Kinase Inhibitors
Language	English
Publishing date	2024-05-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.283981
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Article: Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

Kimura, Shunsuke / Polonen, Petri / Montefiori, Lindsey / Park, Chun Shik / Iacobucci, Ilaria / Yeoh, Allen Ej / Attarbaschi, Andishe / Moore, Andrew S / Brown, Anthony / Manabe, Atsushi / Buldini, Barbara / Freeman, Burgess B / Chen, Chelsey / Cheng, Cheng / Kean Hui, Chiew / Li, Chi-Kong / Pui, Ching-Hon / Qu, Chunxu / Tomizawa, Daisuke /

Teachey, David T / Varotto, Elena / Paietta, Elisabeth M / Arnold, Elizabeth D / Locatelli, Franco / Escherich, Gabriele / Elisa Muhle, Hannah / Marquart, Hanne Vibeke / de Groot-Kruseman, Hester A / Rowe, Jacob M / Stary, Jan / Trka, Jan / Choi, John Kim / Meijerink, Jules P P / Yang, Jun J / Takita, Junko / Pawinska-Wasikowska, Katarzyna / Roberts, Kathryn G / Han, Katie / Caldwell, Kenneth J / Schmiegelow, Kjeld / Crews, Kristine R / Eguchi, Mariko / Schrappe, Martin / Zimmerman, Martin / Takagi, Masatoshi / Maybury, Mellissa / Svaton, Michael / Reiterova, Michaela / Kicinski, Michal / Prater, Mollie S / Kato, Motohiro / Reyes, Noemi / Spinelli, Orietta / Thomas, Paul / Mazilier, Pauline / Gao, Qingsong / Masetti, Riccardo / Kotecha, Rishi S / Pieters, Rob / Elitzur, Sarah / Luger, Selina M / Mitchell, Sharnise / Pruett-Miller, Shondra M / Shen, Shuhong / Jeha, Sima / Köhrer, Stefan / Kornblau, Steven M / Skoczeń, Szymon / Miyamura, Takako / Vincent, Tiffaney L / Imamura, Toshihiko / Conter, Valentino / Tang, Yanjing / Liu, Yen-Chun / Chang, Yunchao / Gu, Zhaohui / Cheng, Zhongshan / Yinmei, Zhou / Inaba, Hiroto / Mullighan, Charles G

medRxiv : the preprint server for health sciences

2023

Abstract: Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high ... risk but poorly characterized disease.: Methods: We studied clinical features of 200 pediatric γδ T ... ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were ...

Abstract	Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. Results: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], Conclusion: γδ T-ALL in children under the age of three is extremely high-risk and enriched for Support: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
Language	English
Publishing date	2023-11-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.06.23298028
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Article ; Online: Obesity Differs from Diabetes Mellitus in Antibody and T Cell Responses Post COVID-19 Recovery.

Ali, Mohammad / Longet, Stephanie / Neale, Isabel / Rongkard, Patpong / Chowdhury, Forhad Uddin Hassan / Hill, Jennifer / Brown, Anthony / Laidlaw, Stephen / Tipton, Tom / Hoque, Ashraful / Hassan, Nazia / Hackstein, Carl-Philipp / Adele, Sandra / Akther, Hossain Delowar / Abraham, Priyanka / Paul, Shrebash / Rahman, Md Matiur / Alam, Md Masum / Parvin, Shamima /

Hoque Mollah, Forhadul / Hoque, Md Mozammel / Moore, Shona C / Biswas, Subrata K / Turtle, Lance / de Silva, Thushan I / Ogbe, Ane / Frater, John / Barnes, Eleanor / Tomic, Adriana / Carroll, Miles W / Klenerman, Paul / Kronsteiner, Barbara / Chowdhury, Fazle Rabbi / Dunachie, Susanna J

Clinical and experimental immunology

2024

Abstract: ... In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR ... 19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell ... production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell ...

Abstract	Obesity and type 2 diabetes (DM) are risk factors for severe COVID-19 outcomes, which disproportionately affect South Asian populations. This study aims to investigate the humoral and cellular immune responses to SARS-CoV-2 in adult COVID-19 survivors with obesity and DM in Bangladesh. In this cross-sectional study, SARS-CoV-2-specific antibody and T cell responses were investigated in 63 healthy and 75 PCR-confirmed COVID-19 recovered individuals in Bangladesh, during the pre-vaccination first wave of the COVID-19 pandemic in 2020. In COVID-19 survivors, SARS-CoV-2 infection induced robust antibody and T cell responses, which correlated with disease severity. After adjusting for age, sex, DM status, disease severity, and time since onset of symptoms, obesity was associated with decreased neutralising antibody titers, and increased SARS-CoV-2 spike-specific IFN-γ response along with increased proliferation and IL-2 production by CD8+ T cells. In contrast, DM was not associated with SARS-CoV-2-specific antibody and T cell responses after adjustment for obesity and other confounders. Obesity is associated with lower neutralising antibody levels and higher T cell responses to SARS-CoV-2 post COVID-19 recovery, while antibody or T cell responses remain unaltered in DM.
Language	English
Publishing date	2024-04-20
Publishing country	England
Document type	Journal Article
ZDB-ID	218531-3
ISSN	1365-2249 ; 0009-9104 ; 0964-2536
ISSN (online)	1365-2249
ISSN	0009-9104 ; 0964-2536
DOI	10.1093/cei/uxae030
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Article ; Online: CAR T cells ignite antitumor immunity.

Alizadeh, Darya / Brown, Christine E

Trends in immunology

2023 Volume 44, Issue 10, Page(s) 748–750

Abstract: ... T cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically ...

Abstract	Broadening immune responses through antigen spreading remains the 'Holy Grail' of cancer immunotherapy. A study by Ma and colleagues reveals that vaccine boosting of chimeric antigen receptor (CAR)-T cells in mice promotes endogenous immunity and elicits antigen spread to eliminate antigenically heterogenous solid tumors through a mechanism crucially dependent on interferon (IFN)γ.
MeSH term(s)	Mice ; Animals ; Receptors, Antigen, T-Cell ; Immunotherapy, Adoptive ; Neoplasms/therapy ; T-Lymphocytes
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-08-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2023.08.002
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Article ; Online: Spatiotemporal regulation of peripheral T cell tolerance.

Brown, Chrysothemis C / Rudensky, Alexander Y

Science (New York, N.Y.)

2023 Volume 380, Issue 6644, Page(s) 472–478

Abstract: The incomplete removal of T cells that are reactive against self-proteins during ... in the investigation of peripheral T cell tolerance, focusing on new insights into mechanisms of tolerance to the gut ... While emphasizing the intestine as a model tissue for studying peripheral T cell tolerance, we highlight overlapping ...

Abstract	The incomplete removal of T cells that are reactive against self-proteins during their differentiation in the thymus requires mechanisms of tolerance that prevent their effector function within the periphery. A further challenge is imposed by the need to establish tolerance to the holobiont self, which comprises a highly complex community of commensal microorganisms. Here, we review recent advances in the investigation of peripheral T cell tolerance, focusing on new insights into mechanisms of tolerance to the gut microbiota, including tolerogenic antigen-presenting cell types and immunomodulatory lymphocytes, and their layered ontogeny that underlies developmental windows for establishing intestinal tolerance. While emphasizing the intestine as a model tissue for studying peripheral T cell tolerance, we highlight overlapping and distinct pathways that underlie tolerance to self-antigens versus commensal antigens within a broader framework for immune tolerance.
MeSH term(s)	Autoantigens ; Peripheral Tolerance ; T-Lymphocytes/immunology ; Thymus Gland/cytology ; Humans ; Animals ; Mice
Chemical Substances	Autoantigens
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.adg6425
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