CoChat
Sign Up
Cited by 98Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeuroscience and Neuropharmacology Research

Inhibition of Bruton's Tyrosine Kinase Modulates Microglial Phagocytosis: Therapeutic Implications for Alzheimer's Disease

Open access
Keaney, James, Gasser, Julien, Gillet, Gaëlle, Scholz, Diana, Kadiu, Irena·2019·Journal of Neuroimmune Pharmacology
DOI 10.1007/s11481-019-09839-0PMC PMC6707957
Open this paper in CoChat — free accountOpen PDF

Abstract

Bruton's tyrosine kinase (BTK), a critical component of B cell receptor signaling, has recently been implicated in regulation of the peripheral innate immune response. However, the role of BTK in microglia, the resident innate immune cells of the central nervous system, and its involvement in the pathobiology of neurodegenerative disease has not been explored. Here we found that BTK is a key regulator of microglial phagocytosis. Using potent BTK inhibitors and small interfering RNA (siRNA) against BTK, we observed that blockade of BTK activity decreased activation of phospholipase gamma 2, a recently identified genetic risk factor in Alzheimer's disease (AD), and reduced phagocytosis in rodent microglia and human monocyte-derived macrophages. Inhibition of BTK signaling also decreased microglial uptake of synaptosomes but did not have major impacts on other key microglial functions such as migration and cytokine release. Similarly, blocking BTK function ex vivo in acute brain slices reduced microglial phagocytosis and maintained numbers of resting microglia. In brain tissues from the 5xFAD mouse model of AD, levels of microglial BTK were elevated while in two gene expression datasets of post-mortem AD patient brain tissues, upregulation of BTK transcript was observed. Our study provides novel insights into the role of BTK in regulating microglial phagocytosis and uptake of synaptic structures and suggests that inhibiting microglial BTK may improve cognition in AD by preventing microglial activation and synaptic loss. Graphical Abstract Microglial-mediated synapse loss has been implicated in AD pathogenesis. Inhibition of BTK decreases activation of PLCγ2, a genetic risk factor in AD, and reduces microglial phagocytosis and uptake of synaptic structures. As such BTK inhibition may represent a therapeutic route to prevent microglial activation and synapse loss in AD.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s11481-019-09839-0

Cites

19 of 19 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 59

  1. Allen B Ingram E Takao M Smith MJ Jakes R Virdee K Yoshida H Holzer M Craxton M Emson PC Atzori C Migheli A Crowther RA Ghetti B Spillantini MG Goedert M Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein J Neurosci 2002 22 9340 9351 10.1523/JNEUROSCI.22-21-09340.2002 12417659 PMC6758022 · DOI
  2. Amoras AL Kanegane H Miyawaki T Vilela MM Defective fc-, CR1- and CR3-mediated monocyte phagocytosis and chemotaxis in common variable immunodeficiency and X-linked agammaglobulinemia patients J Investig Allergol Clin Immunol 2003 13 181 188 14635468
  3. Amoras AL da Silva MT Zollner RL Kanegane H Miyawaki T Vilela MM Expression of fc gamma and complement receptors in monocytes of X-linked agammaglobulinaemia and common variable immunodeficiency patients Clin Exp Immunol 2007 150 422 428 10.1111/j.1365-2249.2007.03512.x 17900300 PMC2219363 · DOI
  4. Asai H Ikezu S Tsunoda S Medalla M Luebke J Haydar T Wolozin B Butovsky O Kugler S Ikezu T Depletion of microglia and inhibition of exosome synthesis halt tau propagation Nat Neurosci 2015 18 1584 1593 10.1038/nn.4132 26436904 PMC4694577 · DOI · Paper page
  5. Bellucci A Westwood AJ Ingram E Casamenti F Goedert M Spillantini MG Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein Am J Pathol 2004 165 1643 1652 10.1016/S0002-9440(10)63421-9 15509534 PMC1618683 · DOI
  6. Bernard S Goldwirt L Amorim S Brice P Briere J de Kerviler E Mourah S Sauvageon H Thieblemont C Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse Blood 2015 126 1695 1698 10.1182/blood-2015-05-647834 26239089 PMC4591793 · DOI
  7. Bertram L Lange C Mullin K Parkinson M Hsiao M Hogan MF Schjeide BMM Hooli B DiVito J Ionita I Jiang H Laird N Moscarillo T Ohlsen KL Elliott K Wang X Hu-Lince D Ryder M Murphy A Wagner SL Blacker D Becker KD Tanzi RE Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE Am J Hum Genet 2008 83 623 632 10.1016/j.ajhg.2008.10.008 18976728 PMC2668052 · DOI · Paper page
  8. Boche D Perry VH Nicoll JA Review: Activation patterns of microglia and their identification in the human brain Neuropathol Appl Neurobiol 2013 39 3 18 10.1111/nan.12011 23252647 · DOI
  9. Byrne JC, Ni Gabhann J, Stacey KB, Coffey BM, McCarthy E, Thomas W, Jefferies CA (2013) Bruton's tyrosine kinase is required for apoptotic cell uptake via regulating the phosphorylation and localization of calreticulin. Journal of Immunology (Baltimore, md: 1950) 190:5207-5215 23596312
  10. Campbell R, Chong G, Hawkes EA (2018) Novel indications for Bruton's tyrosine kinase inhibitors, beyond hematological malignancies. J Clin Med 7 PMC5920436 29561760
  11. Cavaliere FM Prezzo A Bilotta C Iacobini M Quinti I The lack of BTK does not impair monocytes and polymorphonuclear cells functions in X-linked agammaglobulinemia under treatment with intravenous immunoglobulin replacement PLoS One 2017 12 e0175961 10.1371/journal.pone.0175961 28422989 PMC5397035 · DOI
  12. Chalmers SA Wen J Doerner J Stock A Cuda CM Makinde HM Perlman H Bosanac T Webb D Nabozny G Fine JS Klein E Ramanujam M Putterman C Highly selective inhibition of Bruton's tyrosine kinase attenuates skin and brain disease in murine lupus Arthritis Res Ther 2018 20 10 10.1186/s13075-017-1500-0 29370834 PMC5785891 · DOI
  13. Crawford JJ Johnson AR Misner DL Belmont LD Castanedo G Choy R Coraggio M Dong L Eigenbrot C Erickson R Ghilardi N Hau J Katewa A Kohli PB Lee W Lubach JW McKenzie BS Ortwine DF Schutt L Tay S Wei BQ Reif K Liu L Wong H Young WB Discovery of GDC-0853: a potent, selective, and noncovalent Bruton's tyrosine kinase inhibitor in early clinical development J Med Chem 2018 61 2227 2245 10.1021/acs.jmedchem.7b01712 29457982 · DOI
  14. de Gorter DJ Beuling EA Kersseboom R Middendorp S van Gils JM Hendriks RW Pals ST Spaargaren M Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing Immunity 2007 26 93 104 10.1016/j.immuni.2006.11.012 17239630 · DOI · Paper page
  15. Evans EK Tester R Aslanian S Karp R Sheets M Labenski MT Witowski SR Lounsbury H Chaturvedi P Mazdiyasni H Zhu Z Nacht M Freed MI Petter RC Dubrovskiy A Singh J Westlin WF Inhibition of Btk with CC-292 provides early pharmacodynamic assessment of activity in mice and humans J Pharmacol Exp Ther 2013 346 219 228 10.1124/jpet.113.203489 23709115 · DOI
  16. Farrar JE Rohrer J Conley ME Neutropenia in X-linked agammaglobulinemia Clin Immunol Immunopathol 1996 81 271 276 10.1006/clin.1996.0188 8938104 · DOI
  17. Ginhoux F Greter M Leboeuf M Nandi S See P Gokhan S Mehler MF Conway SJ Ng LG Stanley ER Samokhvalov IM Merad M Fate mapping analysis reveals that adult microglia derive from primitive macrophages 2010 New York Science 841 845 PMC3719181 20966214
  18. Gyorffy BA Kun J Torok G Bulyaki E Borhegyi Z Gulyassy P Kis V Szocsics P Micsonai A Matko J Drahos L Juhasz G Kekesi KA Kardos J Local apoptotic-like mechanisms underlie complement-mediated synaptic pruning Proc Natl Acad Sci U S A 2018 115 6303 6308 10.1073/pnas.1722613115 29844190 PMC6004452 · DOI
  19. Hampton DW Webber DJ Bilican B Goedert M Spillantini MG Chandran S Cell-mediated neuroprotection in a mouse model of human tauopathy J Neurosci 2010 30 9973 9983 10.1523/JNEUROSCI.0834-10.2010 20668182 PMC6633376 · DOI
  20. Hendriks RW Yuvaraj S Kil LP Targeting Bruton's tyrosine kinase in B cell malignancies Nat Rev Cancer 2014 14 219 232 10.1038/nrc3702 24658273 · DOI
  21. Herbst S Shah A Mazon Moya M Marzola V Jensen B Reed A Birrell MA Saijo S Mostowy S Shaunak S Armstrong-James D Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus EMBO Mol Med 2015 7 240 258 10.15252/emmm.201404556 25637383 PMC4364943 · DOI
  22. Ho SY Chao CY Huang HL Chiu TW Charoenkwan P Hwang E NeurphologyJ: an automatic neuronal morphology quantification method and its application in pharmacological discovery BMC Bioinformatics 2011 12 230 10.1186/1471-2105-12-230 21651810 PMC3121649 · DOI
  23. Hong S Stevens B Microglia: phagocytosing to clear, sculpt, and eliminate Dev Cell 2016 38 126 128 10.1016/j.devcel.2016.07.006 27459063 · DOI
  24. Horwood NJ Mahon T McDaid JP Campbell J Mano H Brennan FM Webster D Foxwell BM Bruton's tyrosine kinase is required for lipopolysaccharide-induced tumor necrosis factor alpha production J Exp Med 2003 197 1603 1611 10.1084/jem.20021845 12810683 PMC2193950 · DOI
  25. Horwood NJ, Page TH, McDaid JP, Palmer CD, Campbell J, Mahon T, Brennan FM, Webster D, Foxwell BM (2006) Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production. Journal of immunology (Baltimore, md: 1950) 176:3635-3641 16517732
  26. Ito M Shichita T Okada M Komine R Noguchi Y Yoshimura A Morita R Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury Nat Commun 2015 6 7360 10.1038/ncomms8360 26059659 PMC4490404 · DOI
  27. Jongstra-Bilen J, Puig Cano A, Hasija M, Xiao H, Smith CI, Cybulsky MI (2008) Dual functions of Bruton's tyrosine kinase and Tec kinase during Fcgamma receptor-induced signaling and phagocytosis. Journal of Immunology (Baltimore, md: 1950) 181:288-298 18566394
  28. Jumaa H Hendriks RW Reth M B cell signaling and tumorigenesis Annu Rev Immunol 2005 23 415 445 10.1146/annurev.immunol.23.021704.115606 15771577 · DOI
  29. Karsten CM Kohl J The immunoglobulin, IgG fc receptor and complement triangle in autoimmune diseases Immunobiology 2012 217 1067 1079 10.1016/j.imbio.2012.07.015 22964232 · DOI
  30. Kozlowski C Evans DI Neutropenia associated with X-linked agammaglobulinaemia J Clin Pathol 1991 44 388 390 10.1136/jcp.44.5.388 2045497 PMC496869 · DOI
  31. Lionakis MS Inhibition of B cell receptor signaling by Ibrutinib in primary CNS Lymphoma Cancer Cell 2017 31 833 843.e835 10.1016/j.ccell.2017.04.012 28552327 PMC5571650 · DOI
  32. Liu X Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase J Allergy Clin Immunol 2017 140 1054 1067.e1010 10.1016/j.jaci.2017.01.017 28216434 · DOI
  33. Maphis N Xu G Kokiko-Cochran ON Jiang S Cardona A Ransohoff RM Lamb BT Bhaskar K Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain Brain 2015 138 1738 1755 10.1093/brain/awv081 25833819 PMC4542622 · DOI · Paper page
  34. Marsh SE Abud EM Lakatos A Karimzadeh A Yeung ST Davtyan H Fote GM Lau L Weinger JG Lane TE Inlay MA Poon WW Blurton-Jones M The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function Proc Natl Acad Sci U S A 2016 113 E1316 E1325 10.1073/pnas.1525466113 26884167 PMC4780638 · DOI · Paper page
  35. Mason C Savona S Rini JN Castillo JJ Xu L Hunter ZR Treon SP Allen SL Ibrutinib penetrates the blood brain barrier and shows efficacy in the therapy of Bing Neel syndrome Br J Haematol 2017 179 339 341 10.1111/bjh.14218 27409073 · DOI
  36. Melcher M, Unger B, Schmidt U, Rajantie IA, Alitalo K, Ellmeier W (2008) Essential roles for the Tec family kinases Tec and Btk in M-CSF receptor signaling pathways that regulate macrophage survival. Journal of Immunology (Baltimore, md: 1950) 180:8048-8056 PMC3001193 18523268
  37. Menzies GE Sims R Williams J MOLECULAR DYNAMIC MODELLING OF A NOVEL PLCG2 VARIANT REVEALS KEY PROTEIN STRUCTURAL DIFFERENCES Alzheimers Dement 2017 13 P1489 P1490 10.1016/j.jalz.2017.07.573 · DOI
  38. Mirsafian H Ripen AM Leong WM Chear CT Bin Mohamad S Merican AF Transcriptome profiling of monocytes from XLA patients revealed the innate immune function dysregulation due to the BTK gene expression deficiency Sci Rep 2017 7 6836 10.1038/s41598-017-06342-5 28754963 PMC5533715 · DOI
  39. Mukhopadhyay S, Mohanty M, Mangla A, George A, Bal V, Rath S, Ravindran B (2002) Macrophage effector functions controlled by Bruton's tyrosine kinase are more crucial than the cytokine balance of T cell responses for microfilarial clearance. Journal of Immunology (Baltimore, md: 1950) 168:2914-2921 11884462
  40. Ni Gabhann J Spence S Wynne C Smith S Byrne JC Coffey B Stacey K Kissenpfennig A Johnston J Jefferies CA Defects in acute responses to TLR4 in Btk-deficient mice result in impaired dendritic cell-induced IFN-gamma production by natural killer cells 2012 Orlando Clinical Immunology 373 382 22281426
  41. Ni Gabhann J Hams E Smith S Wynne C Byrne JC Brennan K Spence S Kissenpfennig A Johnston JA Fallon PG Jefferies CA Btk regulates macrophage polarization in response to lipopolysaccharide PLoS One 2014 9 e85834 10.1371/journal.pone.0085834 24465735 PMC3897530 · DOI
  42. Reitz C Meta-analysis of the association between variants in SORL1 and Alzheimer disease Arch Neurol 2011 68 99 106 10.1001/archneurol.2010.346 21220680 PMC3086666 · DOI · Paper page
  43. Ren L Campbell A Fang H Gautam S Elavazhagan S Fatehchand K Mehta P Stiff A Reader BF Mo X Byrd JC Carson WE 3rd Butchar JP Tridandapani S Analysis of the effects of the Bruton's tyrosine kinase (Btk) inhibitor Ibrutinib on monocyte Fcgamma receptor (FcgammaR) function J Biol Chem 2016 291 3043 3052 10.1074/jbc.M115.687251 26627823 PMC4742765 · DOI
  44. Reu P Khosravi A Bernard S Mold JE Salehpour M Alkass K Perl S Tisdale J Possnert G Druid H Frisen J The lifespan and turnover of microglia in the human brain Cell Rep 2017 20 779 784 10.1016/j.celrep.2017.07.004 28746864 PMC5540680 · DOI · Paper page
  45. Salter MW Beggs S Sublime microglia: expanding roles for the guardians of the CNS Cell 2014 158 15 24 10.1016/j.cell.2014.06.008 24995975 · DOI · Paper page
  46. Schmidt RE Gessner JE Fc receptors and their interaction with complement in autoimmunity Immunol Lett 2005 100 56 67 10.1016/j.imlet.2005.06.022 16125792 · DOI
  47. Schmidt NW, Thieu VT, Mann BA, Ahyi AN, Kaplan MH (2006) Bruton's tyrosine kinase is required for TLR-induced IL-10 production. Journal of Immunology (Baltimore, md: 1950) 177:7203-7210 17082638
  48. Stevens B Allen NJ Vazquez LE Howell GR Christopherson KS Nouri N Micheva KD Mehalow AK Huberman AD Stafford B Sher A Litke AM Lambris JD Smith SJ John SW Barres BA The classical complement cascade mediates CNS synapse elimination Cell 2007 131 1164 1178 10.1016/j.cell.2007.10.036 18083105 · DOI · Paper page
  49. Strijbis K Tafesse FG Fairn GD Witte MD Dougan SK Watson N Spooner E Esteban A Vyas VK Fink GR Grinstein S Ploegh HL Bruton's tyrosine kinase (BTK) and Vav1 contribute to Dectin1-dependent phagocytosis of Candida albicans in macrophages PLoS Pathog 2013 9 e1003446 10.1371/journal.ppat.1003446 23825946 PMC3694848 · DOI
  50. Vetrie D Vorechovsky I Sideras P Holland J Davies A Flinter F Hammarstrom L Kinnon C Levinsky R Bobrow M The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases Nature 1993 361 226 233 10.1038/361226a0 8380905 · DOI
  51. Wakselman S Bechade C Roumier A Bernard D Triller A Bessis A Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor J Neurosci 2008 28 8138 8143 10.1523/JNEUROSCI.1006-08.2008 18685038 PMC6670768 · DOI · Paper page
  52. Wang Y Cella M Mallinson K Ulrich JD Young KL Robinette ML Gilfillan S Krishnan GM Sudhakar S Zinselmeyer BH Holtzman DM Cirrito JR Colonna M TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model Cell 2015 160 1061 1071 10.1016/j.cell.2015.01.049 25728668 PMC4477963 · DOI · Paper page
  53. Wanquet A Birsen R Lemal R Hunault M Leblond V Aurran-Schleinitz T Ibrutinib responsive central nervous system involvement in chronic lymphocytic leukemia Blood 2016 127 2356 2358 10.1182/blood-2016-02-697193 26994148 · DOI
  54. Wes PD Easton A Corradi J Barten DM Devidze N DeCarr LB Truong A He A Barrezueta NX Polson C Bourin C Flynn ME Keenan S Lidge R Meredith J Natale J Sankaranarayanan S Cadelina GW Albright CF Cacace AM Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer's disease PLoS One 2014 9 e106050 10.1371/journal.pone.0106050 25153994 PMC4143352 · DOI
  55. Williams AM Baran AM Meacham PJ Feldman MM Valencia HE Newsom-Stewart C Gupta N Janelsins MC Barr PM Zent CS Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies Leukemia & Lymphoma 2018 59 625 632 10.1080/10428194.2017.1347931 28696801 · DOI
  56. Winkelstein JA Marino MC Lederman HM Jones SM Sullivan K Burks AW Conley ME Cunningham-Rundles C Ochs HD X-linked agammaglobulinemia: report on a United States registry of 201 patients Medicine 2006 85 193 202 10.1097/01.md.0000229482.27398.ad 16862044 · DOI
  57. Yin Z Raj D Saiepour N Van Dam D Brouwer N Holtman IR Eggen BJL Moller T Tamm JA Abdourahman A Hol EM Kamphuis W Bayer TA De Deyn PP Boddeke E Immune hyperreactivity of Abeta plaque-associated microglia in Alzheimer's disease Neurobiol Aging 2017 55 115 122 10.1016/j.neurobiolaging.2017.03.021 28434692 · DOI · Paper page
  58. Zhang Y Sloan SA Clarke LE Caneda C Plaza CA Blumenthal PD Vogel H Steinberg GK Edwards MS Li G Duncan JA 3rd Cheshier SH Shuer LM Chang EF Grant GA Gephart MG Barres BA Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional Differences with mouse Neuron 2016 89 37 53 10.1016/j.neuron.2015.11.013 26687838 PMC4707064 · DOI · Paper page
  59. Zhao Y Wu X Li X Jiang LL Gui X Liu Y Sun Y Zhu B Pina-Crespo JC Zhang M Zhang N Chen X Bu G An Z Huang TY Xu H TREM2 is a receptor for beta-amyloid that mediates microglial function Neuron 2018 97 1023 1031.e1027 10.1016/j.neuron.2018.01.031 29518356 PMC5889092 · DOI · Paper page

Cited by

Sorted by citations

Authors
Keaney, J., Gasser, J., Gillet, G., Scholz, D., & Kadiu, I.
Affiliations
UCB Pharma (Belgium) (BE)
Corresponding author
  • Keaney, James
  • Kadiu, Irena
ORCID
Venue
Journal of Neuroimmune Pharmacology
Publisher
Springer Science and Business Media LLC
Published
2019-02-13
Volume
14
Issue
3
Pages
448-461
ISSN
  • 1557-1890 (ISSN-L)
  • 1557-1904
DOI
10.1007/s11481-019-09839-0
PMC
PMC6707957
OpenAlex
W2911270294
Cited by
98
References
19
Citations by year
2026: 13 · 2025: 16 · 2024: 19 · 2023: 14 · 2022: 13 · 2021: 13 · 2020: 8 · 2019: 2
FWCI
3.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroimmune Pharmacology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Bruton's tyrosine kinase, microglial phagocytosis, Alzheimer's disease, microglial activation, synaptic loss, microglia, 5xFAD mice, BTK inhibitors, innate immunity, neurodegeneration
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Acrylamides, Adenine, Alzheimer Disease, Animals, Brain, Cell Line, Cell Movement, Enzyme Induction, Humans, Mice, Inbred C57BL, Nerve Tissue Proteins, Phagocytosis, Piperidines, Pyrazoles, Pyrimidines, Cytokines, Rats, Sprague-Dawley, Microglia, Gene Expression Profiling, RNA Interference, RNA, Small Interfering, Protein Kinase Inhibitors, Mice, Rats, Datasets as Topic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review