Julie Zikherman, MD

Title(s)Professor, Medicine
SchoolSchool of Medicine
Address513 Parnassus Ave, HSW, #1201E
San Francisco CA 94143
Phone415-476-1689
ORCID ORCID Icon0000-0002-0873-192X Additional info
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    Collapse Biography 
    Collapse Education and Training
    Harvard University, Cambridge, MAB.A.1996Chemistry
    Cornell University, New York, NYM.D.2002School of Medicine
    Brigham and Women's Hospital, Boston, MA2005Internal Medicine Residency
    UCSF, San Francisco, CA2008Rheumatology Fellowship

    Collapse Overview 
    Collapse Overview
    Our laboratory is interested in understanding how B cell behavior is regulated after encounter with either “self” or “foreign” antigens. We postulate that overlapping mechanisms are at play in both scenarios. The lab seeks to define the rules that govern B cell responses to specific features of foreign antigens, including antigen affinity, valency and co-stimulatory signals. We are also interested in how the clonal composition of both the pre- and post-immune B cell repertoires is regulated. Against this backdrop, we want to understand how self-reactive B cells, despite chronic antigen engagement of the B cell receptor, are restrained from inappropriate activation and differentiation into antibody-secreting plasma cells. We want to define how this process is disrupted in a variety of autoimmune disease states, and how normal regulatory mechanisms (both biochemical and transcriptional) can be harnessed to restore tolerance and optimize vaccine responses.

    To do so, our lab takes a range of creative approaches that span mouse genetics, cellular immunology, and genomics in order to address these questions. In particular, we have characterized and exploited novel reporter mice (NUR77-eGFP BAC transgenic) in which B cell receptor signaling drives expression of eGFP. This reporter serves as an in vivo sensor of both self and foreign antigen encounter, and serves to unmask enormous clonal heterogeneity among superficially uniform populations of B cells. Recent work has focused on dissecting the distinct roles of the IgM and IgD B cell receptor isotypes in regulating the immune responses of self-reactive B cells. Newer projects seek to define how NUR77 and related orphan nuclear hormone receptors of the NR4A family function to restrain activation of chronically antigen-activated B cells and to regulate B responses to foreign antigen.

    Collapse Research 
    Collapse Research Activities and Funding
    Regulation of CD4 T cell tolerance by the NR4A family of nuclear receptors
    NIH R01AI165706Sep 19, 2022 - Jul 31, 2027
    Role: Principal Investigator
    Mechanisms of B cell responses to particulate antigens
    NIH R01AI155653Jul 1, 2021 - Jun 30, 2026
    Role: Principal Investigator
    Nuclear Receptors in B Cell Tolerance and Humoral Immune Responses
    NIH R01AI148487Jun 15, 2020 - May 31, 2025
    Role: Principal Investigator
    Dissecting unique functions of IgM and IgD BCRs in tolerance and autoimmunity
    NIH R01AR069520Jun 1, 2016 - Mar 31, 2021
    Role: Principal Investigator
    Titrating CD45 expression in mice to study development of T cell tolerance
    NIH K08AR059723Jul 1, 2010 - Jun 30, 2015
    Role: Principal Investigator

    Collapse ORNG Applications 
    Collapse Featured Publications

    Collapse Bibliographic 
    Collapse Publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help. to make corrections and additions.
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    1. Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Sci Transl Med. 2024 Jun 26; 16(753):eadl3758. Pluvinage JV, Ngo T, Fouassier C, McDonagh M, Holmes BB, Bartley CM, Kondapavulur S, Hurabielle C, Bodansky A, Pai V, Hinman S, Aslanpour A, Alvarenga BD, Zorn KC, Zamecnik C, McCann A, Asencor AI, Huynh T, Browne W, Tubati A, Haney MS, Douglas VC, Louine M, Cree BAC, Hauser SL, Seeley W, Baranzini SE, Wells JA, Spudich S, Farhadian S, Ramachandran PS, Gillum L, Hales CM, Zikherman J, Anderson MS, Yazdany J, Smith B, Nath A, Suh G, Flanagan EP, Green AJ, Green R, Gelfand JM, DeRisi JL, Pleasure SJ, Wilson MR. PMID: 38924428.
      View in: PubMed   Mentions:    Fields:    Translation:Humans
    2. Minimal Determinants for Lifelong Antiviral Antibody Responses in Mice from a Single Exposure to Virus-like Immunogens at Low Doses. Vaccines (Basel). 2024 Apr 11; 12(4). Wholey WY, Meyer AR, Yoda ST, Chackerian B, Zikherman J, Cheng W. PMID: 38675787; PMCID: PMC11054763.
      View in: PubMed   Mentions:
    3. Minimal determinants for lifelong antiviral antibody responses in BALB/c mice from a single exposure to virus-like immunogens at low doses. bioRxiv. 2024 Feb 18. Wholey WY, Meyer AR, Yoda ST, Chackerian B, Zikherman J, Cheng W. PMID: 36865112; PMCID: PMC9979986.
      View in: PubMed   Mentions:
    4. An integrated signaling threshold initiates IgG response towards virus-like immunogens. bioRxiv. 2024 Jan 31. Wholey WY, Meyer AR, Yoda ST, Mueller JL, Mathenge R, Chackerian B, Zikherman J, Cheng W. PMID: 38469153; PMCID: PMC10926662.
      View in: PubMed   Mentions:
    5. Validation of a murine proteome-wide phage display library for identification of autoantibody specificities. JCI Insight. 2023 Dec 08; 8(23). Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu D, Zamecnik CR, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, DeRisi JL. PMID: 37934865; PMCID: PMC10795829.
      View in: PubMed   Mentions:    Fields:    Translation:HumansAnimalsCells
    6. Molecular basis for potent B cell responses to antigen displayed on particles of viral size. Nat Immunol. 2023 Oct; 24(10):1762-1777. Brooks JF, Riggs J, Mueller JL, Mathenge R, Wholey WY, Meyer AR, Yoda ST, Vykunta VS, Nielsen HV, Cheng W, Zikherman J. PMID: 37653247; PMCID: PMC10950062.
      View in: PubMed   Mentions: 4     Fields:    Translation:Cells
    7. Nr4a nuclear receptors: markers and modulators of antigen receptor signaling. Curr Opin Immunol. 2023 04; 81:102285. Bending D, Zikherman J. PMID: 36764055.
      View in: PubMed   Mentions: 3     Fields:    Translation:HumansCells
    8. Many Achilles' heels of B and T cell tolerance. Immunol Rev. 2022 05; 307(1):5-11. Pelanda R, Zikherman J. PMID: 35301733; PMCID: PMC8986605.
      View in: PubMed   Mentions:    Fields:    Translation:HumansCells
    9. Establishment of fetomaternal tolerance through glycan-mediated B cell suppression. Nature. 2022 03; 603(7901):497-502. Rizzuto G, Brooks JF, Tuomivaara ST, McIntyre TI, Ma S, Rideaux D, Zikherman J, Fisher SJ, Erlebacher A. PMID: 35236989; PMCID: PMC9592526.
      View in: PubMed   Mentions: 14     Fields:    Translation:AnimalsCells
    10. NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance. Immunol Rev. 2022 05; 307(1):116-133. Hiwa R, Brooks JF, Mueller JL, Nielsen HV, Zikherman J. PMID: 35174510.
      View in: PubMed   Mentions: 6     Fields:    Translation:HumansCells
    11. Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation. Immunity. 2022 02 08; 55(2):254-271.e7. Cautivo KM, Matatia PR, Lizama CO, Mroz NM, Dahlgren MW, Yu X, Sbierski-Kind J, Taruselli MT, Brooks JF, Wade-Vallance A, Caryotakis SE, Chang AA, Liang HE, Zikherman J, Locksley RM, Molofsky AB. PMID: 35139352; PMCID: PMC8852844.
      View in: PubMed   Mentions: 22     Fields:    Translation:AnimalsCells
    12. ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR. Nat Chem Biol. 2021 11; 17(11):1148-1156. Feldman HC, Ghosh R, Auyeung VC, Mueller JL, Kim JH, Potter ZE, Vidadala VN, Perera BGK, Olivier A, Backes BJ, Zikherman J, Papa FR, Maly DJ. PMID: 34556859; PMCID: PMC8551014.
      View in: PubMed   Mentions: 4     Fields:    Translation:HumansCells
    13. NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity. JCI Insight. 2021 09 08; 6(17). Hiwa R, Nielsen HV, Mueller JL, Mandla R, Zikherman J. PMID: 34343134; PMCID: PMC8492309.
      View in: PubMed   Mentions: 8     Fields:    Translation:AnimalsCells
    14. Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses. Cell Rep. 2021 08 31; 36(9):109645. Brooks JF, Tan C, Mueller JL, Hibiya K, Hiwa R, Vykunta V, Zikherman J. PMID: 34469720; PMCID: PMC8564879.
      View in: PubMed   Mentions: 5     Fields:    Translation:AnimalsCellsPHPublic Health
    15. The BAFFling persistence of memory B cells. J Exp Med. 2021 02 01; 218(2). Brooks JF, Zikherman J. PMID: 33185684; PMCID: PMC7671565.
      View in: PubMed   Mentions: 2     Fields:    Translation:Cells
    16. NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting. Nat Immunol. 2020 10; 21(10):1267-1279. Tan C, Hiwa R, Mueller JL, Vykunta V, Hibiya K, Noviski M, Huizar J, Brooks JF, Garcia J, Heyn C, Li Z, Marson A, Zikherman J. PMID: 32868928; PMCID: PMC8081071.
      View in: PubMed   Mentions: 29     Fields:    Translation:AnimalsCells
    17. Synthetic Liposomal Mimics of Biological Viruses for the Study of Immune Responses to Infection and Vaccination. Bioconjug Chem. 2020 03 18; 31(3):685-697. Wholey WY, Mueller JL, Tan C, Brooks JF, Zikherman J, Cheng W. PMID: 31940172; PMCID: PMC7422769.
      View in: PubMed   Mentions: 9     Fields:    Translation:AnimalsCellsPHPublic Health
    18. Self-reactivity on a spectrum: A sliding scale of peripheral B cell tolerance. Immunol Rev. 2019 11; 292(1):37-60. Tan C, Noviski M, Huizar J, Zikherman J. PMID: 31631352; PMCID: PMC6935424.
      View in: PubMed   Mentions: 22     Fields:    Translation:HumansAnimalsCells
    19. Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis. J Am Heart Assoc. 2019 09 17; 8(18):e010952. Rosenthal DG, Parwani P, Murray TO, Petek BJ, Benn BS, De Marco T, Gerstenfeld EP, Janmohamed M, Klein L, Lee BK, Moss JD, Scheinman MM, Hsia HH, Selby V, Koth LL, Pampaloni MH, Zikherman J, Vedantham V. PMID: 31538835; PMCID: PMC6818011.
      View in: PubMed   Mentions: 32     Fields:    Translation:Humans
    20. Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis. Proc Natl Acad Sci U S A. 2019 09 10; 116(37):18517-18527. Ashouri JF, Hsu LY, Yu S, Rychkov D, Chen Y, Cheng DA, Sirota M, Hansen E, Lattanza L, Zikherman J, Weiss A. PMID: 31455730; PMCID: PMC6744919.
      View in: PubMed   Mentions: 13     Fields:    Translation:HumansAnimalsCells
    21. Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens. J Immunol. 2019 07 15; 203(2):418-428. Noviski M, Tan C, Huizar J, Vykunta V, Mueller JL, Zikherman J. PMID: 31167773; PMCID: PMC6668988.
      View in: PubMed   Mentions: 10     Fields:    Translation:AnimalsCells
    22. GC B cells 'AKT' to blunt BCR signaling. Nat Immunol. 2019 06; 20(6):671-674. Zikherman J. PMID: 31011188.
      View in: PubMed   Mentions: 1     Fields:    Translation:Cells
    23. Nur77 Links Chronic Antigen Stimulation to B Cell Tolerance by Restricting the Survival of Self-Reactive B Cells in the Periphery. J Immunol. 2019 05 15; 202(10):2907-2923. Tan C, Mueller JL, Noviski M, Huizar J, Lau D, Dubinin A, Molofsky A, Wilson PC, Zikherman J. PMID: 30962292; PMCID: PMC6504591.
      View in: PubMed   Mentions: 15     Fields:    Translation:AnimalsCells
    24. Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance. Curr Opin Immunol. 2018 12; 55:67-74. Noviski M, Zikherman J. PMID: 30292928; PMCID: PMC6291015.
      View in: PubMed   Mentions: 9     Fields:    Translation:HumansAnimalsCells
    25. IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate. Elife. 2018 03 09; 7. Noviski M, Mueller JL, Satterthwaite A, Garrett-Sinha LA, Brombacher F, Zikherman J. PMID: 29521626; PMCID: PMC5897097.
      View in: PubMed   Mentions: 36     Fields:    Translation:AnimalsCells
    26. Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells. Immunohorizons. 2017 Nov 01; 1(9):188-197. Huizar J, Tan C, Noviski M, Mueller JL, Zikherman J. PMID: 29152611; PMCID: PMC5687085.
      View in: PubMed   Mentions: 11     Fields:    
    27. B cell autoimmunity at the extremes. Nat Immunol. 2017 09 19; 18(10):1065-1066. Zikherman J, Lowell CA. PMID: 28926534; PMCID: PMC6334840.
      View in: PubMed   Mentions: 2     Fields:    Translation:Cells
    28. Tonic Signals: Why Do Lymphocytes Bother? Trends Immunol. 2017 11; 38(11):844-857. Myers DR, Zikherman J, Roose JP. PMID: 28754596; PMCID: PMC5669999.
      View in: PubMed   Mentions: 50     Fields:    Translation:HumansAnimalsCells
    29. Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells. Cell Rep. 2017 05 23; 19(8):1558-1571. Myers DR, Lau T, Markegard E, Lim HW, Kasler H, Zhu M, Barczak A, Huizar JP, Zikherman J, Erle DJ, Zhang W, Verdin E, Roose JP. PMID: 28538176; PMCID: PMC5587137.
      View in: PubMed   Mentions: 24     Fields:    Translation:HumansAnimalsCells
    30. IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level. J Immunol. 2017 03 15; 198(6):2445-2456. Au-Yeung BB, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J. PMID: 28159902; PMCID: PMC5340617.
      View in: PubMed   Mentions: 58     Fields:    Translation:AnimalsCells
    31. An extracatalytic function of CD45 in B cells is mediated by CD22. Proc Natl Acad Sci U S A. 2015 Nov 24; 112(47):E6515-24. Coughlin S, Noviski M, Mueller JL, Chuwonpad A, Raschke WC, Weiss A, Zikherman J. PMID: 26561584; PMCID: PMC4664364.
      View in: PubMed   Mentions: 14     Fields:    Translation:AnimalsCells
    32. Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production. J Immunol. 2015 Apr 15; 194(8):3675-86. Mills RE, Lam VC, Tan A, Cresalia N, Oksenberg N, Zikherman J, Anderson M, Weiss A, Hermiston ML. PMID: 25769918; PMCID: PMC4503364.
      View in: PubMed   Mentions: 7     Fields:    Translation:AnimalsCells
    33. Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center. J Immunol. 2015 Apr 01; 194(7):2993-7. Mueller J, Matloubian M, Zikherman J. PMID: 25725108; PMCID: PMC4369439.
      View in: PubMed   Mentions: 39     Fields:    Translation:AnimalsCells
    34. The role of T cell receptor signaling thresholds in guiding T cell fate decisions. Curr Opin Immunol. 2015 Apr; 33:43-8. Zikherman J, Au-Yeung B. PMID: 25660212; PMCID: PMC4397149.
      View in: PubMed   Mentions: 27     Fields:    Translation:HumansAnimalsCells
    35. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. Proc Natl Acad Sci U S A. 2014 Sep 02; 111(35):E3679-88. Au-Yeung BB, Zikherman J, Mueller JL, Ashouri JF, Matloubian M, Cheng DA, Chen Y, Shokat KM, Weiss A. PMID: 25136127; PMCID: PMC4156735.
      View in: PubMed   Mentions: 81     Fields:    Translation:AnimalsCells
    36. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat Immunol. 2014 Jul; 15(7):687-94. Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J, Shokat KM, Robey EA, Weiss A. PMID: 24908390; PMCID: PMC4095875.
      View in: PubMed   Mentions: 34     Fields:    Translation:AnimalsCells
    37. Protein kinase Cδ promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance. Mol Cell Biol. 2014 Apr; 34(8):1474-85. Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP. PMID: 24515435; PMCID: PMC3993585.
      View in: PubMed   Mentions: 9     Fields:    Translation:AnimalsCells
    38. Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45. Cold Spring Harb Symp Quant Biol. 2013; 78:131-139. Tan YX, Zikherman J, Weiss A. PMID: 24100586; PMCID: PMC4039614.
      View in: PubMed   Mentions: 7     Fields:    Translation:HumansAnimalsCells
    39. The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity. J Immunol. 2013 Mar 15; 190(6):2527-35. Zikherman J, Parameswaran R, Hermiston M, Weiss A. PMID: 23396948; PMCID: PMC3593789.
      View in: PubMed   Mentions: 7     Fields:    Translation:AnimalsCells
    40. Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases. Sci Signal. 2013 Jan 01; 6(256):ra1. Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B, Ploegh H, Kuriyan J, Das J, Weiss A. PMID: 23281368; PMCID: PMC3742096.
      View in: PubMed   Mentions: 40     Fields:    Translation:HumansAnimalsCells
    41. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature. 2012 Sep 06; 489(7414):160-4. Zikherman J, Parameswaran R, Weiss A. PMID: 22902503; PMCID: PMC3438375.
      View in: PubMed   Mentions: 180     Fields:    Translation:AnimalsCells
    42. Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival. Proc Natl Acad Sci U S A. 2012 Jan 03; 109(1):E3-12. Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A. PMID: 22135465; PMCID: PMC3252956.
      View in: PubMed   Mentions: 27     Fields:    Translation:AnimalsCells
    43. Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease. J Clin Invest. 2011 Dec; 121(12):4618-21. Zikherman J, Weiss A. PMID: 22080861; PMCID: PMC3226009.
      View in: PubMed   Mentions: 15     Fields:    Translation:AnimalsCells
    44. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Immunity. 2010 Mar 26; 32(3):342-54. Zikherman J, Jenne C, Watson S, Doan K, Raschke W, Goodnow CC, Weiss A. PMID: 20346773; PMCID: PMC2865198.
      View in: PubMed   Mentions: 61     Fields:    Translation:AnimalsCells
    45. Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Sci Signal. 2009 Apr 14; 2(66):pt2. Chakraborty AK, Das J, Zikherman J, Yang M, Govern CC, Ho M, Weiss A, Roose J. PMID: 19366993; PMCID: PMC2755093.
      View in: PubMed   Mentions: 15     Fields:    Translation:HumansAnimalsCells
    46. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. J Immunol. 2009 Apr 01; 182(7):4093-106. Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A, Weiss A. PMID: 19299707; PMCID: PMC2765978.
      View in: PubMed   Mentions: 80     Fields:    Translation:HumansAnimalsCells
    47. CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells. Immunol Rev. 2009 Mar; 228(1):288-311. Hermiston ML, Zikherman J, Zhu JW. PMID: 19290935; PMCID: PMC2739744.
      View in: PubMed   Mentions: 78     Fields:    Translation:HumansAnimalsCells
    48. Antigen receptor signaling in the rheumatic diseases. Arthritis Res Ther. 2009; 11(1):202. Zikherman J, Weiss A. PMID: 19232064; PMCID: PMC2688213.
      View in: PubMed   Mentions: 14     Fields:    Translation:HumansAnimalsCells
    49. Digital signaling and hysteresis characterize ras activation in lymphoid cells. Cell. 2009 Jan 23; 136(2):337-51. Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, Roose JP. PMID: 19167334; PMCID: PMC2662698.
      View in: PubMed   Mentions: 217     Fields:    Translation:HumansAnimalsCells
    50. Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses. Proc Natl Acad Sci U S A. 2009 Jan 13; 106(2):546-51. Hermiston ML, Zikherman J, Tan AL, Lam VC, Cresalia NM, Oksenberg N, Goren N, Brassat D, Oksenberg JR, Weiss A. PMID: 19129486; PMCID: PMC2626740.
      View in: PubMed   Mentions: 9     Fields:    Translation:AnimalsCells
    51. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes. Proc Natl Acad Sci U S A. 2009 Jan 13; 106(2):528-33. Prasad A, Zikherman J, Das J, Roose JP, Weiss A, Chakraborty AK. PMID: 19098101; PMCID: PMC2626737.
      View in: PubMed   Mentions: 39     Fields:    Translation:AnimalsCells
    52. Alternative splicing of CD45: the tip of the iceberg. Immunity. 2008 Dec 19; 29(6):839-41. Zikherman J, Weiss A. PMID: 19100695.
      View in: PubMed   Mentions: 22     Fields:    Translation:HumansAnimalsCells