Publications
Est-Witte, S.E., Shannon, S.R., Gong, D.H. et al. Particle elasticity influences polymeric artificial antigen presenting cell effectiveness in vivo via CD8+ T cell activation, macrophage uptake, and the protein corona. Nano Res. (2024).
Helms RS, Marin-Gonzalez A, Patel CH, et al. SIKs regulate HDAC7 stabilization and cytokine recall in late-stage T cell effector differentiation. J Immunol. 2023;211(12):1767-1782. doi:10.4049/jimmunol.2300248
Lai J, Madan V, Qadri A, et al. Lymphocyte activation gene 3 expression, γδ T-Cell/major histocompatibility complex class I interactions, and prognosis in merkel cell carcinoma. Lab Invest. Published online November 5, 2024. doi:10.1016/j.labinv.2024.102178
Leonard EK, Tomala J, Gould JR, et al. Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity. JCI Insight. 2024;9(18):e173469. Published 2024 Sep 24. doi:10.1172/jci.insight.173469
Livingston NK, Hickey JW, Sim H, et al. In vivo stimulation of therapeutic antigen-specific T cells in an artificial lymph node matrix. Adv Mater. 2024;36(23):e2310043. doi:10.1002/adma.202310043
Jain, M., Yu, X., Schneck, J.P. and Green, J.J., Nanoparticle targeting strategies for lipid and polymer-based gene delivery to immune cells in vivo. Small Sci. 2024; 2400248. https://doi.org/10.1002/smsc.202400248
Omotoso MO, Est-Witte SE, Shannon SR, et al. Alginate-based artificial antigen presenting cells expand functional CD8+ T cells with memory characteristics for adoptive cell therapy. Biomaterials. Published online August 24, 2024. doi:10.1016/j.biomaterials.2024.122773
Rocher EE, Luly KM, Tzeng SY, Sunshine JC, Green JJ. Efficient polymeric nanoparticle gene gelivery enabled via tri- and tetrafunctional branching. Biomacromolecules. 2024;25(11):7260-7273. doi:10.1021/acs.biomac.4c00954
Surwase SS, Zhou XMM, Luly KM, et al. Highly multiplexed immunofluorescence phenocycler panel for murine formalin-fixed paraffin-embedded tissues yields insight into tumor microenvironment immunoengineering. Lab Invest. Published online October 26, 2024. doi:10.1016/j.labinv.2024.102165
Zhu Y, Ma J, Shen R, et al. Screening for lipid nanoparticles that modulate the immune activity of helper T cells towards enhanced antitumour activity. Nat Biomed Eng. 2024;8(5):544-560. doi:10.1038/s41551-023-01131-0
Ben-Akiva E, Hickey JW, Meyer RA, et al. Shape matters: Biodegradable anisotropic nanoparticle artificial antigen presenting cells for cancer immunotherapy. Acta Biomater. 2023;160:187-197. doi:10.1016/j.actbio.2023.02.023
Ben-Akiva E, Karlsson J, Hemmati S, et al. Biodegradable lipophilic polymeric mRNA nanoparticles for ligand-free targeting of splenic dendritic cells for cancer vaccination. Proc Natl Acad Sci U S A. 2023;120(26):e2301606120. doi:10.1073/pnas.2301606120
Doyle J, Green BF, Eminizer M, et al. Whole-Slide Imaging, Mutual Information Registration for Multiplex Immunohistochemistry and Immunofluorescence. Lab Invest. 2023;103(8):100175. doi:10.1016/j.labinv.2023.100175
Luly KM, Green JJ, Sunshine JC, Tzeng SY. Biomaterial-Mediated Genetic Reprogramming of Merkel Cell Carcinoma and Melanoma Leads to Targeted Cancer Cell Killing In Vitro and In Vivo. ACS Biomater Sci Eng. 2023;9(11):6438-6450. doi:10.1021/acsbiomaterials.3c00885
Neshat SY, Bauer SJ, Rhodes KR, et al. Improvement of Islet Engrafts via Treg Induction Using Immunomodulating Polymeric Tolerogenic Microparticles. ACS Biomater Sci Eng. 2023;9(6):3522-3534. doi:10.1021/acsbiomaterials.3c00329
Rhodes KR, Tzeng SY, Iglesias M, et al. Bioengineered particles expand myelin-specific regulatory T cells and reverse autoreactivity in a mouse model of multiple sclerosis. Sci Adv. 2023;9(22):eadd8693. doi:10.1126/sciadv.add8693
Wilson DR, Tzeng SY, Rui Y, et al. Biodegradable Polyester Nanoparticle Vaccines Deliver Self-Amplifying mRNA in Mice at Low Doses. Adv Ther (Weinh). 2023;6(5):2200219. doi:10.1002/adtp.202200219
Xu W, Patel CH, Zhao L, et al. GOT1 regulates CD8+ effector and memory T cell generation. Cell Rep. 2023;42(1):111987. doi:10.1016/j.celrep.2022.111987
Yang J, Luly KM, Green JJ. Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2023;15(2):e1853. doi:10.1002/wnan.1853
Almodovar Cruz GE, Kaunitz G, Stein JE, et al. Immune cell subsets in interface cutaneous immune-related adverse events associated with anti-PD-1 therapy resemble acute graft versus host disease more than lichen planus. J Cutan Pathol. 2022;49(8):701-708. doi:10.1111/cup.14242
Casciola-Rosen L, Thiemann DR, Andrade F, et al. IgM anti-ACE2 autoantibodies in severe COVID-19 activate complement and perturb vascular endothelial function. JCI Insight. 2022;7(9):e158362. Published 2022 May 9. doi:10.1172/jci.insight.158362
Chaisawangwong W, Wang H, Kouo T, et al. Cross-reactivity of SARS-CoV-2- and influenza A-specific T cells in individuals exposed to SARS-CoV-2. JCI Insight. 2022;7(18):e158308. Published 2022 Sep 22. doi:10.1172/jci.insight.158308
Dammen-Brower K, Epler P, Zhu S, et al. Strategies for Glycoengineering Therapeutic Proteins. Front Chem. 2022;10:863118. Published 2022 Apr 13. doi:10.3389/fchem.2022.863118
de Rutte J, Dimatteo R, Archang MM, et al. Suspendable Hydrogel Nanovials for Massively Parallel Single-Cell Functional Analysis and Sorting [published online ahead of print, 2022 Mar 24]. ACS Nano. 2022;10.1021/acsnano.1c11420. doi:10.1021/acsnano.1c11420
Gong D, Ben-Akiva E, Singh A, et al. Machine learning guided structure function predictions enable in silico nanoparticle screening for polymeric gene delivery. Acta Biomater. 2022;154:349-358. doi:10.1016/j.actbio.2022.09.072
Harbison RA, Pandey R, Considine M, et al. Interrogation of T Cell-Enriched Tumors Reveals Prognostic and Immunotherapeutic Implications of Polyamine Metabolism. Cancer Res Commun. 2022;2(7):639-652. doi:10.1158/2767-9764.crc-22-0061
Isser A, Silver AB, Pruitt HC, et al. Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy. Nat Commun. 2022;13(1):6086. Published 2022 Oct 14. doi:10.1038/s41467-022-33597-y
Kavanagh EW, Green JJ. Toward Gene Transfer Nanoparticles as Therapeutics. Adv Healthc Mater. 2022;11(7):e2102145. doi:10.1002/adhm.202102145
Krohl PJ, Spangler JB. A Hybrid Adherent/Suspension Cell-Based Selection Strategy for Discovery of Antibodies Targeting Membrane Proteins. Methods Mol Biol. 2022;2491:195-216. doi:10.1007/978-1-0716-2285-8_11
Li S, Hu Y, Li A, et al. Payload distribution and capacity of mRNA lipid nanoparticles. Nat Commun. 2022;13(1):5561. Published 2022 Sep 23. doi:10.1038/s41467-022-33157-4
Li L, Zhang Y, Zhou Y, et al. Quaternary nanoparticles enable sustained release of bortezomib for hepatocellular carcinoma [published online ahead of print, 2022 May 21]. Hepatology. 2022;10.1002/hep.32584. doi:10.1002/hep.32584
Lopez-Bertoni H, Johnson A, Rui Y, et al. Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications. Signal Transduct Target Ther. 2022;7(1):37. Published 2022 Feb 9. doi:10.1038/s41392-021-00857-0
Ludwig SD, Bernstein ZJ, Agatemor C, et al. A versatile design platform for glycoengineering therapeutic antibodies. MAbs. 2022;14(1):2095704. doi:10.1080/19420862.2022.2095704
Luly KM, Yang H, Lee SJ, et al. Poly(Beta-Amino Ester)s as High-Yield Transfection Reagents for Recombinant Protein Production. Int J Nanomedicine. 2022;17:4469-4479. Published 2022 Sep 23. doi:10.2147/IJN.S377371
McCurdy SR, Radojcic V, Tsai HL, et al. Signatures of GVHD and relapse after posttransplant cyclophosphamide revealed by immune profiling and machine learning. Blood. 2022;139(4):608-623. doi:10.1182/blood.2021013054
Patel CH, Heikamp EB, Xu W, et al. Cutting Edge: mTORC2 Regulates CD8+ Effector and Memory T Cell Differentiation through Serum and Glucocorticoid Kinase 1. J Immunol. 2022;209(12):2287-2291. doi:10.4049/jimmunol.2100669
Rui Y, Wilson DR, Tzeng SY, et al. High-throughput and high-content bioassay enables tuning of polyester nanoparticles for cellular uptake, endosomal escape, and systemic in vivo delivery of mRNA. Sci Adv. 2022;8(1):eabk2855. doi:10.1126/sciadv.abk2855
Sargunas PR, Spangler JB. Joined at the hip: The role of light chain complementarity determining region 2 in antibody self-association. Proc Natl Acad Sci U S A. 2022;119(28):e2208330119. doi:10.1073/pnas.2208330119
Shannon SR, Ben-Akiva E, Green JJ. Approaches towards biomaterial-mediated gene editing for cancer immunotherapy. Biomater Sci. 2022;10(23):6675-6687. Published 2022 Nov 22. doi:10.1039/d2bm00806h
Singh AK, Praharaj M, Lombardo KA, et al. Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer. Nat Commun. 2022;13(1):878. Published 2022 Feb 15. doi:10.1038/s41467-022-28509-z
Sung BY, Lin YH, Kong Q, et al. Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1. J Clin Invest. 2022;132(2):e140508. doi:10.1172/JCI140508
VanDyke D, Iglesias M, Tomala J, et al. Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection. Cell Rep. 2022;41(3):111478. doi:10.1016/j.celrep.2022.111478
VanDyke D, Taylor JD, Kaeo KJ, Hunt J, Spangler JB. Biologics-based degraders – an expanding toolkit for targeted-protein degradation [published online ahead of print, 2022 Sep 27]. Curr Opin Biotechnol. 2022;78:102807. doi:10.1016/j.copbio.2022.102807
Vaughan HJ, Zamboni CG, Hassan LF, et al. Polymeric nanoparticles for dual-targeted theranostic gene delivery to hepatocellular carcinoma. Sci Adv. 2022;8(29):eabo6406. doi:10.1126/sciadv.abo6406
Yang J, Luly KM, Green JJ. Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2023;15(2):e1853. doi:10.1002/wnan.1853
Zhu Y, Shen R, Vuong I, et al. Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression. Nat Commun. 2022;13(1):4282. Published 2022 Jul 25. doi:10.1038/s41467-022-31993-y
Ahn HH, Carrington C, Hu Y, et al. Nanoparticle-mediated tumor cell expression of mIL-12 via systemic gene delivery treats syngeneic models of murine lung cancers. Sci Rep. 2021;11(1):9733. Published 2021 May 6. doi:10.1038/s41598-021-89124-4 (work enabled by the center).
Berry S, Giraldo NA, Green BF, et al. Analysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade. Science. 2021;372(6547):eaba2609. doi:10.1126/science.aba2609
Caushi JX, Zhang J, Ji Z, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers [published correction appears in Nature. 2021 Oct;598(7881):E1]. Nature. 2021;596(7870):126-132. doi:10.1038/s41586-021-03752-4
Douglass J, Hsiue EH, Mog BJ, et al. Bispecific antibodies targeting mutant RAS neoantigens. Sci Immunol. 2021;6(57):eabd5515. doi:10.1126/sciimmunol.abd5515
Dykema AG, Zhang B, Woldemeskel BA, et al. Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses. J Clin Invest. 2021;131(10):e146922. doi:10.1172/JCI146922
Est-Witte SE, Livingston NK, Omotoso MO, Green JJ, Schneck JP. Nanoparticles for generating antigen-specific T cells for immunotherapy. Semin Immunol. 2021;56:101541. doi:10.1016/j.smim.2021.101541
Green JJ. Immunoengineering has arrived. J Biomed Mater Res A. 2021;109(4):397-403. doi:10.1002/jbm.a.37041
Hou J, Yang R, Vuong I, Li F, Kong J, Mao HQ. Biomaterials strategies to balance inflammation and tenogenesis for tendon repair. Acta Biomater. 2021;130:1-16. doi:10.1016/j.actbio.2021.05.043 (work enabled by the center).
Howard GP, Bender NG, Khare P, et al. Immunopotentiation by lymph-node targeting of a malaria transmission-blocking nanovaccine. Front Immunol. 2021;12:729086. Published 2021 Aug 27. doi:10.3389/fimmu.2021.729086 (work enabled by the center).
Hu Y, Zhu Y, Sutherland ND, et al. Size-Controlled and Shelf-Stable DNA Particles for Production of Lentiviral Vectors. Nano Lett. 2021;21(13):5697-5705. doi:10.1021/acs.nanolett.1c01421
Hsiue EH, Wright KM, Douglass J, et al. Targeting a neoantigen derived from a common TP53 mutation. Science. 2021;371(6533):eabc8697. doi:10.1126/science.abc8697
Hwang MS, Miller MS, Thirawatananond P, et al. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nat Commun. 2021;12(1):5271. Published 2021 Sep 6. doi:10.1038/s41467-021-25605-4
Isser A, Livingston NK, Schneck JP. Biomaterials to enhance antigen-specific T cell expansion for cancer immunotherapy. Biomaterials. 2021;268:120584. doi:10.1016/j.biomaterials.2020.120584
Karlsson J, Luly KM, Tzeng SY, Green JJ. Nanoparticle designs for delivery of nucleic acid therapeutics as brain cancer therapies. Adv Drug Deliv Rev. 2021;179:113999. doi:10.1016/j.addr.2021.113999
Karlsson J, Tzeng SY, Hemmati S, et al. Photocrosslinked bioreducible polymeric nanoparticles for enhanced systemic siRNA delivery as cancer therapy. Adv Funct Mater. 2021;31(17):2009768. doi:10.1002/adfm.202009768
Kim J, Vaughan HJ, Zamboni CG, Sunshine JC, Green JJ. High-throughput evaluation of polymeric nanoparticles for tissue-targeted gene expression using barcoded plasmid DNA. J Control Release. 2021;337:105-116. doi:10.1016/j.jconrel.2021.05.047
Kouo T, Chaisawangwong W. SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children. J Clin Invest. 2021;131(10):e149327. doi:10.1172/JCI149327
Leone RD, Powell JD. Fueling the Revolution: Targeting metabolism to enhance immunotherapy. Cancer Immunol Res. 2021;9(3):255-260. doi:10.1158/2326-6066.CIR-20-0791
Liu HW, Hu Y, Ren Y, et al. Scalable Purification of Plasmid DNA Nanoparticles by Tangential Flow Filtration for Systemic Delivery. ACS Appl Mater Interfaces. 2021;13(26):30326-30336. doi:10.1021/acsami.1c05750
Luly KM, Choi J, Rui Y, Green JJ, Jackson EM. Safety considerations for nanoparticle gene delivery in pediatric brain tumors. Nanomedicine (Lond). 2020;15(18):1805-1815. doi:10.2217/nnm-2020-0110
McCurdy SR, Radojcic V, Tsai HL, et al. Signatures of GVHD and relapse after post-transplant cyclophosphamide revealed by immune profiling and machine learning [published online ahead of print, 2021 Oct 17]. Blood. 2021;blood.2021013054.
Mo F, Yu Z, Li P, et al. An engineered IL-2 partial agonist promotes CD8+ T cell stemness. Nature. 2021;597(7877):544-548. doi:10.1038/s41586-021-03861-0
Paul S, Pearlman AH, Douglass J, et al. TCR β chain-directed bispecific antibodies for the treatment of T cell cancers. Sci Transl Med. 2021;13(584):eabd3595. doi:10.1126/scitranslmed.abd3595
Rhodes KR, Isser A, Hickey JW, et al. Biodegradable cationic polymer blends for fabrication of enhanced artificial antigen presenting cells to treat melanoma. ACS Appl Mater Interfaces. 2021;13(7):7913-7923. doi:10.1021/acsami.0c19955
Rui Y, Green JJ. Overcoming delivery barriers in immunotherapy for glioblastoma. Drug Deliv Transl Res. 2021;11(6):2302-2316. doi:10.1007/s13346-021-01008-2
Shenderov K, Collins SL, Powell JD, Horton MR. Immune dysregulation as a driver of idiopathic pulmonary fibrosis. J Clin Invest. 2021;131(2):e143226. doi:10.1172/JCI143226
Thompson EA, Cascino K, Ordonez AA, et al. Metabolic programs define dysfunctional immune responses in severe COVID-19 patients. Cell Rep. 2021;34(11):108863. doi:10.1016/j.celrep.2021.108863
Thompson EA, Powell JD. Inhibition of the adenosine pathway to potentiate cancer immunotherapy: Potential for combinatorial approaches. Annu Rev Med. 2021;72:331-348. doi:10.1146/annurev-med-060619-02315
Vaughan HJ, Green JJ. Recent advances in gene therapy for cancer theranostics. Curr Opin Biomed Eng. 2021;20:100300. doi:10.1016/j.cobme.2021.100300
Vaughan HJ, Zamboni CG, Radant NP, et al. Poly(beta-amino ester) nanoparticles enable tumor-specific TRAIL secretion and a bystander effect to treat liver cancer. Mol Ther Oncolytics. 2021;21:377-388. Published 2021 Apr 16. doi:10.1016/j.omto.2021.04.004
Targeting Metabolism as a Platform for Inducing Allograft Tolerance in the Absence of Long-Term Immunosuppression. Front Immunol. 2020;11:572. doi: 10.3389/fimmu.2020.00572.
Est-Witte SE, Farris AL, Tzeng SY, et al. Non-viral gene delivery of HIF-1α promotes angiogenesis in human adipose-derived stem cells. Acta Biomater. 2020;113:279-288. doi:10.1016/j.actbio.2020.06.042
Hollinger KR, Zhu X, Khoury ES, et al. Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice. J Alzheimers Dis. 2020;77(1):437-447. doi:10.3233/JAD-190588
Ichikawa J, Yoshida T, Isser A, Laino AS, Vassallo M, Woods D, Kim S, Oelke M, Jones K, Schneck JP, Weber JS. Rapid Expansion of Highly Functional Antigen-Specific T cells from Melanoma Patients by Nanoscale Artificial Antigen Presenting Cells. Clin Cancer Res. 2020 Apr 2;. doi: 10.1158/1078-0432.CCR-19-3487.
Karlsson J, Rhodes KR, Green JJ, Tzeng SY. Poly(beta-amino ester)s as gene delivery vehicles: challenges and opportunities. Expert Opin Drug Deliv. 2020;17(10):1395-1410. doi:10.1080/17425247.2020.1796628L
Lemberg KM, Zhao L, Wu Y, et al. The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor. Mol Cancer Ther. 2020;19(2):397-408. doi:10.1158/1535-7163.MCT-19-0319
Luly KM, Choi J, Rui Y, Green JJ, Jackson EM. Safety considerations for nanoparticle gene delivery in pediatric brain tumors. Nanomedicine (Lond). 2020;15(18):1805-1815. doi:10.2217/nnm-2020-0110
Neshat SY, Tzeng SY, Green JJ. Gene delivery for immunoengineering. Curr Opin Biotechnol. 2020;66:1-10. doi:10.1016/j.copbio.2020.05.008
Oh MH, Sun IH, Zhao L, Leone RD, Sun IM, Xu W, Collins SL, Tam AJ, Blosser RL, Patel CH, Englert JM, Arwood ML, Wen J, Chan-Li Y, Tenora L, Majer P, Rais R, Slusher BS, Horton MR, Powell JD. Targeting glutamine metabolism enhances tumor specific immunity by modulating suppressive myeloid cells [published online ahead of print, 2020 Apr 23]. J Clin Invest. 2020;131859. doi:10.1172/JCI131859
Rhodes KR, Meyer RA, Wang J, Tzeng SY, Green JJ. Biomimetic tolerogenic artificial antigen presenting cells for regulatory T cell induction. Acta Biomater. 2020;112:136-148. doi:10.1016/j.actbio.2020.06.004
Routkevitch D, Sudhakar D, Conge M, et al. Efficiency of cytosolic delivery with Poly(β-amino ester) nanoparticles is dependent on the effective pKa of the polymer. ACS Biomater Sci Eng. 2020;6(6):3411-3421. doi:10.1021/acsbiomaterials.0c00271
Tzeng SY, Patel KK, Wilson DR, Meyer RA, Rhodes KR, Green JJ. In situ genetic engineering of tumors for long-lasting and systemic immunotherapy. Proc Natl Acad Sci U S A. 2020 Feb 7;. doi: 10.1073/pnas.1916039117.
Hickey JW, Dong Y, Chung JW, et al. Engineering an Artificial T-Cell Stimulating Matrix for Immunotherapy. Adv Mater. 2019;31(23):e1807359. doi:10.1002/adma.201807359
Isser A, Schneck JP. High-affinity T cell receptors for adoptive cell transfer. J Clin Invest. 2019;129(1):69-71. doi:10.1172/JCI125471
Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019 Nov 22;366(6468):1013-1021. doi: 10.1126/science.aav2588. Epub 2019 Nov 7.
Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat Rev Drug Discov. 2019 Sep;18(9):669-688. doi: 10.1038/s41573-019-0032-5. Epub 2019 Jul 30. Review.
Zhu X, Nedelcovych MT, Thomas AG, et al. JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress [published correction appears in Neuropsychopharmacology. 2019 May;44(6):1178]. Neuropsychopharmacology. 2019;44(4):683-694. doi:10.1038/s41386-018-0177-7
Lemberg KM, Vornov JJ, Rais R, Slusher BS. We’re Not “DON” Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine. Mol Cancer Ther. 2018;17(9):1824-1832. doi:10.1158/1535-7163.MCT-17-1148
Riggle BA, Sinharay S, Schreiber-Stainthorp W, et al. MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice. Proc Natl Acad Sci U S A. 2018;115(51):E12024-E12033. doi:10.1073/pnas.1812909115