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Article ; Online: An esophagus cell atlas reveals dynamic rewiring during active eosinophilic esophagitis and remission.

Ding, Jiarui / Garber, John J / Uchida, Amiko / Lefkovith, Ariel / Carter, Grace T / Vimalathas, Praveen / Canha, Lauren / Dougan, Michael / Staller, Kyle / Yarze, Joseph / Delorey, Toni M / Rozenblatt-Rosen, Orit / Ashenberg, Orr / Graham, Daniel B / Deguine, Jacques / Regev, Aviv / Xavier, Ramnik J

Nature communications

2024 Volume 15, Issue 1, Page(s) 3344

Abstract: Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the ... ...

Abstract	Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15
MeSH term(s)	Humans ; Eosinophilic Esophagitis/genetics ; Eosinophilic Esophagitis/pathology ; Endothelial Cells/metabolism ; Interleukin-13 ; Inflammation/genetics
Chemical Substances	Interleukin-13
Language	English
Publishing date	2024-04-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47647-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Integrated multi-omics analyses reveal homology-directed repair pathway as a unique dependency in near-haploid leukemia.

Liu-Lupo, Yunpeng / Ham, James Dongjoo / Jeewajee, Swarna K A / Nguyen, Lan / Delorey, Toni / Ramos, Azucena / Weinstock, David M / Regev, Aviv / Hemann, Michael T

Blood cancer journal

2023 Volume 13, Issue 1, Page(s) 92

Abstract: ... revealed significantly increased sensitivity of RAD51-mediated repair to RAD51B loss in the G2/M stage ... Elevated G2/M and G1/S checkpoint signaling was part of a RAD51B signature expression program in response ...

Abstract	Whole chromosome losses resulting in near-haploid karyotypes are found in a rare subgroup of treatment-refractory acute lymphoblastic leukemia. To systematically dissect the unique physiology and uncover susceptibilities that can be exploited in near-haploid leukemia, we leveraged single-cell RNA-Seq and computational inference of cell cycle stages to pinpoint key differences between near-haploid and diploid leukemia cells. Combining cell cycle stage-specific differential expression with gene essentiality scores from a genome-wide CRISPR-Cas9-mediated knockout screen, we identified the homologous recombination pathway component RAD51B as an essential gene in near-haploid leukemia. DNA damage analyses revealed significantly increased sensitivity of RAD51-mediated repair to RAD51B loss in the G2/M stage of near-haploid cells, suggesting a unique role of RAD51B in the homologous recombination pathway. Elevated G2/M and G1/S checkpoint signaling was part of a RAD51B signature expression program in response to chemotherapy in a xenograft model of human near-haploid B-ALL, and RAD51B and its associated programs were overexpressed in a large panel of near-haploid B-ALL patients. These data highlight a unique genetic dependency on DNA repair machinery in near-haploid leukemia and demarcate RAD51B as a promising candidate for targeted therapy in this treatment-resistant disease.
MeSH term(s)	Humans ; Haploidy ; Multiomics ; Chromosome Aberrations ; DNA Repair ; Proteins ; Leukemia, Lymphoid
Chemical Substances	Proteins
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2600560-8
ISSN	2044-5385 ; 2044-5385
ISSN (online)	2044-5385
ISSN	2044-5385
DOI	10.1038/s41408-023-00863-1
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Article ; Online: Remodeling of colon plasma cell repertoire within ulcerative colitis patients.

Scheid, Johannes F / Eraslan, Basak / Hudak, Andrew / Brown, Eric M / Sergio, Dallis / Delorey, Toni M / Phillips, Devan / Lefkovith, Ariel / Jess, Alison T / Duck, Lennard W / Elson, Charles O / Vlamakis, Hera / Plichta, Damian R / Deguine, Jacques / Ananthakrishnan, Ashwin N / Graham, Daniel B / Regev, Aviv / Xavier, Ramnik J

The Journal of experimental medicine

2023 Volume 220, Issue 4

Abstract: Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We ... ...

Abstract	Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.
MeSH term(s)	Humans ; Colitis, Ulcerative/genetics ; Plasma Cells ; Colon ; Inflammation/metabolism ; Antigens, Bacterial ; Bacteria ; Immunoglobulin A/metabolism ; Intestinal Mucosa
Chemical Substances	Antigens, Bacterial ; Immunoglobulin A
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20220538
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Ua VI Zs.107: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 45: Show issues

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Article ; Online: The CD4

Pedersen, Thomas K / Brown, Eric M / Plichta, Damian R / Johansen, Joachim / Twardus, Shaina W / Delorey, Toni M / Lau, Helena / Vlamakis, Hera / Moon, James J / Xavier, Ramnik J / Graham, Daniel B

Immunity

2022 Volume 55, Issue 10, Page(s) 1909–1923.e6

Abstract: Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed ...

Abstract	Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.
MeSH term(s)	CD4-Positive T-Lymphocytes ; Crohn Disease ; Epitopes, T-Lymphocyte ; Humans ; Immunodominant Epitopes ; Interleukin-10 ; Interleukin-17
Chemical Substances	Epitopes, T-Lymphocyte ; Immunodominant Epitopes ; Interleukin-17 ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2022-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.08.016
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 69: Show issues

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Article: Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq.

bioRxiv : the preprint server for biology

2023

Abstract: E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the ... ...

Abstract	E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the balance of DC1, DC2, migratory DC and macrophage states and a gradient of DC maturation. Family members grouped into co-functional modules that were enriched for physical interactions and impacted specific programs through substrate transcription factors. E3s and their adaptors co-regulated the same processes, but partnered with different substrate recognition adaptors to impact distinct aspects of the DC life cycle. Genetic interactions were more prevalent within than between modules, and a deep learning model, comβVAE, predicts the outcome of new combinations by leveraging modularity. The E3 regulatory network was associated with heritable variation and aberrant gene expression in immune cells in human inflammatory diseases. Our study provides a general approach to dissect gene function.
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.23.525198
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Article ; Online: Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity.

Schnell, Alexandra / Huang, Linglin / Singer, Meromit / Singaraju, Anvita / Barilla, Rocky M / Regan, Brianna M L / Bollhagen, Alina / Thakore, Pratiksha I / Dionne, Danielle / Delorey, Toni M / Pawlak, Mathias / Meyer Zu Horste, Gerd / Rozenblatt-Rosen, Orit / Irizarry, Rafael A / Regev, Aviv / Kuchroo, Vijay K

Cell

2021 Volume 184, Issue 26, Page(s) 6281–6298.e23

Abstract: While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 ... ...

Abstract	While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1
MeSH term(s)	Animals ; Autoimmunity ; Cell Movement ; Clone Cells ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Homeostasis ; Humans ; Interferon-gamma/metabolism ; Interleukin-17/metabolism ; Intestines/immunology ; Mice, Inbred C57BL ; Organ Specificity ; RNA/metabolism ; RNA-Seq ; Receptors, Antigen, T-Cell/metabolism ; Receptors, CXCR6/metabolism ; Receptors, Interleukin/metabolism ; Reproducibility of Results ; Signaling Lymphocytic Activation Molecule Family/metabolism ; Single-Cell Analysis ; Spleen/metabolism ; Stem Cells/metabolism ; Th17 Cells/immunology ; Mice
Chemical Substances	CXCR6 protein, human ; IL23R protein, human ; Interleukin-17 ; Receptors, Antigen, T-Cell ; Receptors, CXCR6 ; Receptors, Interleukin ; SLAMF6 protein, human ; Signaling Lymphocytic Activation Molecule Family ; RNA (63231-63-0) ; Interferon-gamma (82115-62-6) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
Language	English
Publishing date	2021-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.11.018
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article ; Online: B-cell-specific checkpoint molecules that regulate anti-tumour immunity.

Bod, Lloyd / Kye, Yoon-Chul / Shi, Jingwen / Torlai Triglia, Elena / Schnell, Alexandra / Fessler, Johannes / Ostrowski, Stephen M / Von-Franque, Max Y / Kuchroo, Juhi R / Barilla, Rocky M / Zaghouani, Sarah / Christian, Elena / Delorey, Toni Marie / Mohib, Kanishka / Xiao, Sheng / Slingerland, Nadine / Giuliano, Christopher J / Ashenberg, Orr / Li, Zhaorong /

Rothstein, David M / Fisher, David E / Rozenblatt-Rosen, Orit / Sharpe, Arlene H / Quintana, Francisco J / Apetoh, Lionel / Regev, Aviv / Kuchroo, Vijay K

Nature

2023 Volume 619, Issue 7969, Page(s) 348–356

Abstract: The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour ... ...

Abstract	The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth
MeSH term(s)	Animals ; Mice ; B-Lymphocytes/cytology ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Lymphocyte Activation ; Melanoma/immunology ; Melanoma/pathology ; Melanoma/prevention & control ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Flow Cytometry ; Melanoma, Experimental/immunology ; Melanoma, Experimental/pathology ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Antigen Presentation ; Receptors, Antigen, B-Cell/genetics ; Single-Cell Gene Expression Analysis ; Tumor Burden ; Interferon Type I
Chemical Substances	Havcr1 protein, mouse ; Lag3 protein, mouse ; T cell Ig and ITIM domain protein, mouse ; Receptors, Antigen, B-Cell ; Interferon Type I
Language	English
Publishing date	2023-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-023-06231-0
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 9: Show issues
Zs.MO 244: Show issues

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Article: Multi-modal skin atlas identifies a multicellular immune-stromal community associated with altered cornification and specific T cell expansion in atopic dermatitis.

Fiskin, Evgenij / Eraslan, Gökcen / Alora-Palli, Maria B / Leyva-Castillo, Juan Manuel / Kim, Sean / Choe, Heather / Lareau, Caleb A / Lau, Helena / Finan, Emily P / Teixeira-Soldano, Isabella / LaBere, Brenna / Chu, Anne / Woods, Brian / Chou, Janet / Slyper, Michal / Waldman, Julia / Islam, Sabina / Schneider, Lynda / Phipatanakul, Wanda /

Platt, Craig / Rozenblatt-Rosen, Orit / Delorey, Toni M / Deguine, Jacques / Smith, Gideon P / Geha, Raif / Regev, Aviv / Xavier, Ramnik

bioRxiv : the preprint server for biology

2023

Abstract: In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic ... ...

Abstract	In healthy skin, a cutaneous immune system maintains the balance between tolerance towards innocuous environmental antigens and immune responses against pathological agents. In atopic dermatitis (AD), barrier and immune dysfunction result in chronic tissue inflammation. Our understanding of the skin tissue ecosystem in AD remains incomplete with regard to the hallmarks of pathological barrier formation, and cellular state and clonal composition of disease-promoting cells. Here, we generated a multi-modal cell census of 310,691 cells spanning 86 cell subsets from whole skin tissue of 19 adult individuals, including non-lesional and lesional skin from 11 AD patients, and integrated it with 396,321 cells from four studies into a comprehensive human skin cell atlas in health and disease. Reconstruction of human keratinocyte differentiation from basal to cornified layers revealed a disrupted cornification trajectory in AD. This disrupted epithelial differentiation was associated with signals from a unique immune and stromal multicellular community comprised of
Language	English
Publishing date	2023-10-31
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.29.563503
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Article ; Online: Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling.

Immunity

2022 Volume 55, Issue 9, Page(s) 1663–1679.e6

Abstract: Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter ... ...

Abstract	Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.
MeSH term(s)	Animals ; Colitis ; Inflammation/metabolism ; Interleukin-23/metabolism ; Mice ; Mice, Inbred C57BL ; Phenotype ; Receptors, Interleukin/genetics ; Receptors, Interleukin/metabolism ; Th1 Cells ; Th17 Cells
Chemical Substances	Interleukin-23 ; Receptors, Interleukin
Language	English
Publishing date	2022-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.08.007
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 69: Show issues

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Article ; Online: Stepwise-edited, human melanoma models reveal mutations' effect on tumor and microenvironment.

Science (New York, N.Y.)

2022 Volume 376, Issue 6592, Page(s) eabi8175

Abstract: Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly ... ...

Abstract	Establishing causal relationships between genetic alterations of human cancers and specific phenotypes of malignancy remains a challenge. We sequentially introduced mutations into healthy human melanocytes in up to five genes spanning six commonly disrupted melanoma pathways, forming nine genetically distinct cellular models of melanoma. We connected mutant melanocyte genotypes to malignant cell expression programs in vitro and in vivo, replicative immortality, malignancy, rapid tumor growth, pigmentation, metastasis, and histopathology. Mutations in malignant cells also affected tumor microenvironment composition and cell states. Our melanoma models shared genotype-associated expression programs with patient melanomas, and a deep learning model showed that these models partially recapitulated genotype-associated histopathological features as well. Thus, a progressive series of genome-edited human cancer models can causally connect genotypes carrying multiple mutations to phenotype.
MeSH term(s)	Humans ; Melanocytes/metabolism ; Melanoma/pathology ; Mutation ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Tumor Microenvironment/genetics
Language	English
Publishing date	2022-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abi8175
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