The DOI matches its Crossref record; 151 of the 151 references it cites were found in a registry or an index; 106 of the 139 sources its claims cite were checked for support.
Reactive astrocyte nomenclature, definitions, and future directions
Open accessAbstract
Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
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Claims the paper makes
28 Partly supported · 21 Own interpretation · 15 Supported · 12 No basis given · 10 No full text of the sources · 7 Supported so far · 1 Couldn’t confirm · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“these phenomena mainly occur when there is disruption of the blood–brain barrier (Fig. 1a)7.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Too many names
What the sources say
- Partly supportedcites [7] Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015). sourceExperimental — accuracy not yet measured
The ‘Astrocyte restriction of CNS inflammation’ section describes proliferation, scar-border formation and inflammatory-cell trafficking at sites of CNS damage. The ‘Astrocyte anti-inflammatory mechanisms’ section links newly proliferated scar-forming astrocytes to blood–brain barrier repair after traumatic injury and describes a mechanism by which astrocytes disrupt the barrier and increase leukocyte extravasation. Neither section establishes that these phenomena mainly occur when the blood–brain barrier is disrupted; page numbers were not available in our copy. (LLM, conf=0.83)
plainconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“Membrane proteins such as the glutamate transporters EAAT1 and EAAT2 are not optimal candidates to assess complex astrocyte morphology, as they tend to produce widespread and diffuse staining24.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Partly supportedcites [24] Sosunov, A. A. et al. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J. Neurosci. 34, 2285–2298 (2014). sourceExperimental — accuracy not yet measured
The section “Astrocyte domain localizations and microheterogeneity among astrocyte types” (page unavailable) reports that EAAT1- and EAAT2-positive processes from neighboring astrocytes penetrate CD44-positive astrocyte domains, supporting a limitation in using these markers to delineate individual cells. It does not say that EAAT1 or EAAT2 staining is generally widespread and diffuse, or explicitly conclude that they are unsuitable for assessing complex morphology. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Astrocytes may also exhibit cell-autonomous disturbances8, as happens in astrocytopathies resulting from mutated alleles of astrocytic genes (for example, GFAP in Alexander disease)9, as well as from direct viral infections or exposure to toxic substances that specifically damage astrocytes (for example, ammonium in hepatic encephalopathy)10.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Too many names
What the sources say
- Supportedcites [8] Verkhratsky, A., Zorec, R. & Parpura, V. Stratification of astrocytes in healthy and diseased brain. Brain Pathol 27, 629–644 (2017). source
Citation 8 is attached to the statement that astrocytes may exhibit cell-autonomous disturbances. The paper’s ‘Classification and complexity of astrogliopathies’ section describes abnormal astroglial properties that drive pathology, including mutant GFAP expression in Alexander disease; its ‘Concluding remarks’ distinguish primary astroglial pathogenic events from secondary responses. The viral-infection and ammonium examples are attached to a different citation and are not needed to support this verdict. (LLM, conf=0.91)
- Supportedcites [9] Messing, A., Brenner, M., Feany, M. B., Nedergaard, M. & Goldman, J. E. Alexander disease. J. Neurosci. 32, 5017–5023 (2012). source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [10] Brusilow, S. W., Koehler, R. C., Traystman, R. J. & Cooper, A. J. Astrocyte glutamine synthetase: importance in hyperammonemic syndromes and potential target for therapy. Neurotherapeutics 7, 452–470 (2010). source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Transcriptomics has contributed to a fundamental discovery: astrocytes in the healthy brain are diverse and specialized to perform specific roles in distinct CNS circuits14,65.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Not checked — no full text of the sourcecites [14] Ben Haim, L. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017). source
- Supportedcites [65] Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549.e9 (2017). source
The Discussion reports functional, morphological, transcriptomic and proteomic differences between astrocytes in the adult hippocampus and striatum, calling this evidence for neural circuit-specialized astrocytes. The source supports the citing sentence’s general point, though its direct comparison is limited to those two circuits. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Notably, aging is also associated with pronounced regional differences in astrocyte gene expression in mouse brains90,91.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
What the sources say
- Supportedcites [90] Boisvert, M. M., Erikson, G. A., Shokhirev, M. N. & Allen, N. J. The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22, 269–285 (2018). source
The Results section, “Identification of Gene Expression Changes Between Adult and Aging Astrocytes from Multiple Brain Regions” (page not provided), reports substantially different numbers of aging-related gene-expression changes across mouse brain regions. It also identifies genes whose expression changes with age in particular regions, directly supporting the claim. (LLM, conf=0.93)
- Supportedcites [91] Clarke, L. E. et al. Normal aging induces A1-like astrocyte reactivity. Proc. Natl Acad. Sci. USA 115, E1896–E1905 (2018). source
The Results section, “Comparison of Astrocyte Transcriptomes Throughout Aging” (Fig. 2; page not provided), reports significant regional heterogeneity in aging-related astrocyte gene expression in mice. Striatal and hippocampal astrocytes had substantially more differentially expressed genes than cortical astrocytes. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
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In the paper
“For example, single-cell and single-nucleus RNAseq (scRNAseq and snRNAseq, respectively) studies in mouse models and human brains of chronic neurodegenerative diseases have unraveled numerous stage-dependent transcriptomic states in HD74, AD75,78, and MS40 that do not clearly comply with A1–A2 profiles.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Partly supportedcites [74] Al-Dalahmah, O. et al. Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol. Commun. 8, 19 (2020). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [75] Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019). source
- Supportedcites [78] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [40] Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). The first study combining scRNAseq to characterize reactive astrocytes with targeted molecular manipulations demonstrates, in a mouse model of MS, that reactive astrocytes are molecularly and functionally heterogeneous, depending on brain area and disease stage. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosted- Asserted: passes — The authors put it forward as true.
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- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“In normal conditions, astrocyte Ca2+-based responses, and downstream signaling via neuroactive mediators, exert multifarious effects on synaptic function and plasticity, neural-network oscillations, and, ultimately, on behavior51,52.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [51] Santello, M., Toni, N. & Volterra, A. Astrocyte function from information processing to cognition and cognitive impairment. Nat. Neurosci. 22, 154–166 (2019). source
The Introduction says astrocyte interactions with synaptic circuits occur under physiological conditions and contribute to behavior. The sections on synaptic plasticity and neuronal ensembles describe Ca2+-linked release of mediators, effects on synaptic function and plasticity, and regulation of network oscillations. The indexed passages provide no page numbers. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [52] Semyanov, A., Henneberger, C. & Agarwal, A. Making sense of astrocytic calcium signals - from acquisition to interpretation. Nat. Rev. Neurosci. 21, 551–564 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Importantly, only a subset, often a mix of A1 and A2 or pan-reactive transcripts, are upregulated in astrocytes from brains of study participants with HD74 or AD75,76, or from several mouse models of acute injuries and chronic diseases of the CNS42,69,76,77.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Supportedcites [74] Al-Dalahmah, O. et al. Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol. Commun. 8, 19 (2020). source
The Results section reports that a subset of A1, A2, and pan-reactive genes increased in HD tissue. The Discussion further identifies differentially expressed genes in HD astrocytes from those categories. The citation attached to HD supports that part of the citing sentence; the AD and mouse-model claims have separate citations. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [75] Grubman, A. et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 22, 2087–2097 (2019). source
- Partly supportedcites [76] Zhou, Y. et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat. Med. 26, 131–142 (2020). sourceExperimental — accuracy not yet measured
The Results report limited astrocyte transcriptional changes in the 5XFAD mouse model, while the Results and Discussion identify upregulated astrocyte genes in human AD. The paper does not characterize those upregulated genes as a mix of A1, A2, or pan-reactive transcripts; it says the human AD astrocyte profile was quite different from the A1 profile. The HD and other-model portions of the citing sentence carry separate citations and are not assessed against this source. (LLM, conf=0.84)
- Partly supportedcites [42] Ceyzériat, K. et al. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease. Acta Neuropathol. Commun. 6, 104 (2018). sourceExperimental — accuracy not yet measured
The Results section (‘SOCS3 normalizes multiple reactive astrocyte markers in AD mice’; page unavailable) reports induced pan-reactive, A1 and A2 markers in astrocytes from an AD mouse model, supporting the mixed-marker portion of the claim. This paper does not establish that pattern in astrocytes from human AD participants or across several models of acute CNS injury and chronic disease. The HD portion is attached to a different citation. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [69] Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019). source
- Partly supportedcites [77] Das, S., Li, Z., Noori, A., Hyman, B. T. & Serrano-Pozo, A. Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration. J. Neuroinflammation 17, 227 (2020). sourceExperimental — accuracy not yet measured
The Results section on A1 and A2 signatures (page not provided) reports that A1, A2, and pan-reactive genes were generally upregulated across the mouse acute-injury and neurodegeneration models, supporting the mixed-signature portion of the claim. But the Results section on human validation says none of the three mouse signatures was clearly present in the two astrocyte-specific AD datasets; the AD concordance it found came from bulk-tissue datasets. Thus this source does not establish the claimed upregulation in astrocytes from people with AD. The HD portion is attached to a different citation. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“Nonetheless, two new names have recently been coined to describe the extremes of six astrocytic transcriptional clusters detected by snRNAseq in the hippocampus of AD transgenic and wild-type mice78.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
What the sources say
- Partly supportedcites [78] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). sourceExperimental — accuracy not yet measured
The passage on astrocyte states reports six transcriptional sub-clusters from single-nucleus RNA-seq of WT and 5xFAD mouse hippocampi. It says the authors coined “Disease-Associated Astrocytes” for cluster 4, but does not say they coined two new names for the extremes: it describes Gfap-low and Gfap-high states as consistent with previous observations, and the DAA state as an additional state. (LLM, conf=0.85)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“In addition, advanced statistics using multidimensional data and co-clustering approaches reveals that the A1 and A2 transcriptomes represent only two of many potential astrocyte transcriptomes segregating along several latent variables79.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Partly supportedcites [79] Henrik Heiland, D. et al. Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nat. Commun. 10, 2541 (2019). sourceExperimental — accuracy not yet measured
The Results section (page unavailable) describes a multidimensional analysis of astrocyte expression along maturation and inflammatory–alternative activation axes. The Discussion says the A2 phenotype may hide multiple reactive stages. The copy does not establish that A1 and A2 are just two of many astrocyte transcriptomes segregating along several latent variables, or describe a co-clustering approach to that conclusion. (LLM, conf=0.84)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Importantly, not only are these cells removed from their original milieu, but the serum pervasively used in culture media may render them reactive84.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Human stem cells.
What the sources say
- Supportedcites [84] Perriot, S. et al. Human induced pluripotent stem cell-derived astrocytes are differentially activated by multiple sclerosis-associated cytokines. Stem Cell Reports 11, 1199–1210 (2018). source
The Discussion reports that FBS-treated hiPSC-derived astrocytes acquire a reactive phenotype. The Introduction also says serum was used in most of the earlier differentiation studies it discusses, supporting the claim that serum use was common. (LLM, conf=0.94)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“ScRNAseq and snRNAseq are becoming established as valuable tools to gain insight into basal94 and reactive-astrocyte heterogeneity (Fig. 1e)40,78,95.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
What the sources say
- Partly supportedcites [94] Batiuk, M. Y. et al. Identification of region-specific astrocyte subtypes at single cell resolution. Nat. Commun. 11, 1220 (2020). sourceExperimental — accuracy not yet measured
The Abstract and Results show that single-cell RNA sequencing identified distinct astrocyte subtypes in adult mouse cortex and hippocampus, supporting its use to study basal heterogeneity. This paper does not establish the corresponding claim for single-nucleus RNA sequencing; its own study also does not examine reactive astrocyte heterogeneity. (LLM, conf=0.83)
- Partly supportedcites [40] Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). The first study combining scRNAseq to characterize reactive astrocytes with targeted molecular manipulations demonstrates, in a mouse model of MS, that reactive astrocytes are molecularly and functionally heterogeneous, depending on brain area and disease stage. sourceExperimental — accuracy not yet measured
The ‘scRNA-seq analysis of astrocytes in EAE’ section reports that scRNA-seq identified several astrocyte subpopulations during CNS inflammation, supporting its value for studying reactive-astrocyte heterogeneity. The cited paper does not establish the corresponding point for snRNA-seq. The sentence cites a different source for basal heterogeneity. (LLM, conf=0.86)
- Supportedcites [78] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). source
The paper reports using single-nucleus RNA-seq to distinguish homeostatic, Gfap-high and disease-associated astrocyte states in wild-type and Alzheimer’s-model mice. Its astrocyte-clustering results support the citing sentence’s point that sequencing can reveal reactive-astrocyte heterogeneity; this source is an example using snRNA-seq. (LLM, conf=0.88)
- Supportedcites [95] Mathys, H. et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570, 332–337 (2019). First snRNAseq analysis in human AD samples identifies sub-populations of reactive astrocytes. source
In ‘Identification of AD-associated cellular subpopulations’ (page unavailable), the paper reports four astrocyte subclusters, including one associated with Alzheimer’s pathology. It identifies marker genes in that subpopulation and relates one to reactive astrocytes, supporting the cited point that single-nucleus sequencing provides insight into reactive-astrocyte heterogeneity. (LLM, conf=0.90)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“An example is neuronal damage due to nitrosative stress caused by astrocyte-derived nitric oxide in MS33.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Partly supportedcites [33] Colombo, E. et al. Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration. J. Exp. Med. 209, 521–535 (2012). Demonstration that astrocytes may become neurotoxic by releasing nitric oxide. sourceExperimental — accuracy not yet measured
The Results report nitrosylation in MS lesions, including affected axons near a TrkB-positive glial network. The Discussion establishes astrocyte-derived nitric oxide as a cause of neuronal damage in vitro, but says its contribution to neuronal damage in MS is speculative; it does not establish that causal chain in patients. Page numbers are not provided in our copy. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Reactive microglia may shift astrocyte signaling from physiological to pathological by increasing production of tumor necrosis factor α (TNFα), thus altering synaptic functions and behavior57.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [57] Habbas, S. et al. Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163, 1730–1741 (2015). This study illustrates how modulation of astrocyte signaling via TNFα can switch from physiological to pathological. source
The section ‘Astrocyte TNFR1 Is Required for Induction of Synaptic and Cognitive Defects’ identifies activated microglia, alongside infiltrating macrophages, as the most likely cause of increased TNFα in the mouse disease model. It links downstream astrocyte TNFR1 activation to synaptic and behavioral defects. The signaling-mechanism section contrasts physiological and pathological TNFα levels, supporting the claimed shift. (LLM, conf=0.90)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
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In the paper
“Likewise, reactive astrocytes are also diverse, as unequivocally demonstrated by microarray-based66–68 and RNAseq-based48,69–71 transcriptomic profiling of mouse bulk astrocytes48,66–70 or of astrocyte populations preselected according to cell-surface markers71.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Supportedcites [66] Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012). First evidence for molecular heterogeneity of reactive astrocytes using microarray-based transcriptomics of acutely isolated astrocytes from mouse models of ischemia and septic shock. Studies in virtually all models of CNS diseases followed. source
The Abstract reports Affymetrix GeneChip profiling of reactive astrocyte populations from two mouse injury models and finds that at least 50% of altered gene expression is injury-specific. The Discussion (‘Reactive astroglial phenotype depends on the nature of the inducing stimulus’) explicitly concludes that distinct subtypes of reactive astrocytes exist. This supports the microarray-based mouse astrocyte profiling portion of the multi-citation sentence. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [67] Orre, M. et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746–2760 (2014). source
- Partly supportedcites [68] Sirko, S. et al. Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. Glia 63, 2340–2361 (2015). sourceExperimental — accuracy not yet measured
The Results section, “Injury-Induced Changes of Gene Expression in the Cerebral Cortex GM Astrocytes” (page unavailable), reports microarray profiling of sorted mouse reactive astrocytes. The Discussion, “Insights from Genomewide Expression Analysis” (page unavailable), describes heterogeneity, but says transcriptomic comparison of the GFAP-positive and GFAP-negative subsets remains to be done. Thus this paper supports the use of transcriptomic profiling and evidence of diversity, but not the claim that profiling itself demonstrated diversity among reactive astrocyte subsets. (LLM, conf=0.84)
- Supportedcites [48] Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016). source
The Results section, “Genomic Dissection of SCI lesions,” reports RNA-seq profiling of mouse astrocyte RNA and distinct expression patterns in reactive astrocytes from WT and STAT3-CKO mice. Extended Data Figure 4 also compares astrocyte responses after spinal cord injury and stroke. The cell-surface-marker-selected populations in the citing sentence are attributed to a different citation, not this paper. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [69] Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019). source
- Supportedcites [70] Itoh, N. et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc. Natl Acad. Sci. USA 115, E302–E309 (2018). source
The Results section, ‘Regional Differences in Astrocyte-Specific Gene Expression During EAE’ (page not provided), reports RNA-seq differences among astrocytes from four mouse CNS regions during disease. This supports the cited paper’s contribution to the claim that reactive astrocytes are diverse; the sentence’s microarray and cell-surface-marker methods are attributed to other citations. (LLM, conf=0.92)
- Partly supportedcites [71] John Lin, C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017). sourceExperimental — accuracy not yet measured
The Results section, “Heterogeneity of Aldh1l1–GFP+ astrocyte subpopulations” (page unavailable), reports RNA-seq profiling of FACS-isolated mouse astrocyte populations and distinct molecular signatures. This supports the marker-preselected-populations part of the citation, but the profiled populations are not identified as reactive astrocytes; the paper therefore does not establish the claim about reactive astrocyte diversity. (LLM, conf=0.87)
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“The excessive release of GABA by reactive astrocytes in AD63 and Parkinson’s disease64 may be a case of gain of detrimental function.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [63] Jo, S. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med. 20, 886–896 (2014). Demonstration of astrocyte-targeted pharmacological manipulations to restore neural circuit homeostasis by correcting production of GABA by astrocytes in an AD mouse model. source
This citation is attached to the AD portion of the sentence, not the Parkinson’s disease portion. The Abstract reports abnormal GABA release from reactive astrocytes in AD mouse models and restoration of impaired memory when that production or release is suppressed; the Discussion links the released GABA to impaired synaptic plasticity and memory. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [64] Heo, J. Y. et al. Aberrant tonic inhibition of dopaminergic neuronal activity causes motor symptoms in animal models of Parkinson’s disease. Curr. Biol. 30, 276–291.e9 (2020). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Finally, a classical gain of beneficial function is the restriction of immune cell infiltration in open injuries by scar-border forming reactive astrocytes7.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [7] Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015). source
The “Astrocyte restriction of CNS inflammation” section says scar borders at sites of tissue damage restrict the entry of inflammatory cells into viable CNS tissue. The “Trauma and stroke” section describes this barrier function after focal injury as adaptive and protective. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Thus, instead of individual markers, signatures composed of a combination of markers with specified levels of expression or relative fold-changes are required to identify astrocyte phenotypes74.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
What the sources say
- Partly supportedcites [74] Al-Dalahmah, O. et al. Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol. Commun. 8, 19 (2020). sourceExperimental — accuracy not yet measured
The Methods section ('Supervised classification of astrocytes'; page unavailable) assigns astrocytes to states using specified expression thresholds for three genes, supporting the use of combined marker signatures. The paper does not establish the broader claim that such signatures are required, rather than individual markers, to identify astrocyte phenotypes generally. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“morphological and transcriptomic comparisons have revealed prominent differences between mice and humans101–103”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Supportedcites [101] Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89, 37–53 (2016). First study reporting transcriptomes of human astrocytes, paving the way for the highly used open-source database of gene expression for all brain cell types in humans and mice (https://www.brainrnaseq.org/). source
The Introduction reports that human astrocytes are larger and more complex than mouse astrocytes. The Results section, “Comparing human and mouse astrocyte transcriptomes,” reports substantial differences in astrocyte-enriched gene expression. Together, these support the claim for astrocytes; the supplied passages do not give page numbers. (LLM, conf=0.91)
- Partly supportedcites [102] Oberheim, N. A. et al. Uniquely hominid features of adult human astrocytes. J. Neurosci. 29, 3276–3287 (2009). sourceExperimental — accuracy not yet measured
The Discussion reports marked morphological differences between human and rodent astrocytes, and the Results include a direct comparison with mouse astrocytes. The paper does not report a transcriptomic comparison, so it supports the morphological part of the sentence but not the transcriptomic part. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [103] Oberheim, N. A., Wang, X., Goldman, S. & Nedergaard, M. Astrocytic complexity distinguishes the human brain. Trends Neurosci. 29, 547–553 (2006). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Classical knockout-, knockdown-, or CRISPR-based approaches to inactivate gene expression are available to gain insight into the impact on disease of a given pathway within previously identified astrocyte subsets40.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
What the sources say
- Partly supportedcites [40] Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). The first study combining scRNAseq to characterize reactive astrocytes with targeted molecular manipulations demonstrates, in a mouse model of MS, that reactive astrocytes are molecularly and functionally heterogeneous, depending on brain area and disease stage. sourceExperimental — accuracy not yet measured
The paper identifies astrocyte subpopulations by scRNA-seq (scRNA-seq analysis of astrocytes in EAE) and uses Nfe2l2 knockdown, astrocyte-directed CRISPR–Cas9 inactivation, and an astrocyte-specific Csf2rb knockout to examine effects on EAE (NRF2 in astrocytes suppresses EAE; MAFG drives pathogenic astrocytes; GM-CSF boosts pathogenic astrocytes; pages unavailable). These perturbations targeted astrocytes generally, not specifically the previously identified subpopulations, so the subset-specific part of the claim is not established. (LLM, conf=0.84)
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Although some basic functional properties of astrocytes have been shown to be evolutionarily conserved between humans and rodents100”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Supportedcites [100] Bedner, P., Jabs, R. & Steinhäuser, C. Properties of human astrocytes and NG2 glia. Glia 68, 756–767 (2020). source
The Conclusions state that human and rodent astrocytes share many functional properties. The paper cautions that human functional data are available only from the neocortex and hippocampus, but the claim’s reference to 'some' basic properties is consistent with that limit. (LLM, conf=0.91)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“For example, the now widely-used cocktail of factors released by LPS-treated neonatal microglia72 cannot be simply assumed to model reactive astrocytes in diseases other than neonatal septic shock due to infection by gram-negative bacteria.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
What the sources say
- Supportedcites [72] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). source
The citation is attached to the identification of the factor cocktail, not to the citing authors’ caution about its use as a disease model. Section 2 reports that LPS-activated microglia secrete IL-1α, TNFα and C1q and that this combination closely mimics their conditioned medium; the Methods describe cultures purified from postnatal day 5 animals. The source does not itself state the septic-shock limitation. (LLM, conf=0.90)
plain- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“To complicate things further, the outcome of activating a signaling pathway may depend on the upstream stimuli82 or priming caused by previous exposure to other stimuli97, perhaps through epigenetic control40.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
What the sources say
- Supportedcites [82] Tyzack, G. E. et al. A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models. Nat. Commun. 8, 1164 (2017). source
Citation 82 is attached to the upstream-stimuli part of the sentence, not the separately cited claims about priming or epigenetic control. The Results section (‘EphB1 invokes a STAT3 target-linked astrocyte transcriptome’) reports that EphB1 and IL-6 both activate STAT3 pathways but produce different transcriptional profiles and inflammatory outcomes. (LLM, conf=0.92)
- Supportedcites [97] Hennessy, E., Griffin, E. W. & Cunningham, C. Astrocytes are primed by chronic neurodegeneration to produce exaggerated chemokine and cell infiltration responses to acute stimulation with the cytokines IL-1β and TNF-α. J. Neurosci. 35, 8411–8422 (2015). source
The ‘Astrocyte priming and chemokine production’ section defines priming as an exaggerated response to a subsequent stimulus and reports that astrocytes in the degenerating brain respond more strongly to IL-1β and TNF-α. It also describes earlier work in which exposure to inflammatory stimuli primed astrocytes for a later challenge. This source supports the priming clause attached to citation 97; the epigenetic-control suggestion is attached to citation 40, not this source. (LLM, conf=0.88)
- Supportedcites [40] Wheeler, M. A. et al. MAFG-driven astrocytes promote CNS inflammation. Nature 578, 593–599 (2020). The first study combining scRNAseq to characterize reactive astrocytes with targeted molecular manipulations demonstrates, in a mouse model of MS, that reactive astrocytes are molecularly and functionally heterogeneous, depending on brain area and disease stage. source
The citation to this paper is attached to “perhaps through epigenetic control,” not to the separate claim about priming by previous exposure. The Discussion reports that MAFG and MAT2α establish DNA methylation marks controlling disease-promoting astrocyte activity, and that GM-CSF amplifies the resulting pro-inflammatory program. This supports the proposed epigenetic mechanism in the paper’s astrocyte setting. (LLM, conf=0.86)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Every source the paper cites for this claim was checked and supports it.
In the paper
“Artificial intelligence can identify patterns of Ca2+ signaling in astrocytes55,120.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Use of systems biology.
What the sources say
- Supportedcites [55] Agarwal, A. et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93, 587–605.e7 (2017). Technically refined application of Ca2+ imaging approaches and machine learning unraveled dysregulation of Ca2+ responses in a mouse model of ALS. source
In the Results section, the authors describe CaSCaDe, software that uses a machine-learning algorithm to identify active regions in astrocytes. It maps regions with changing Ca2+-related fluorescence and measures the frequency, amplitude, and time course of their signals. (LLM, conf=0.92)
- Supportedcites [120] Wang, Y. et al. Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat. Neurosci. 22, 1936–1944 (2019). source
The Methods section (‘AQuA algorithm and event detection’; page not provided) says AQuA extensively uses machine-learning techniques to model astrocytic events. The Results (‘In vivo astrocytic Ca2+ bursts display anatomical directionality’; page not provided) report that AQuA detected patterns of astrocyte Ca2+ activity, including focal activity and coordinated bursts. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“An example of functional data is 2D and 3D Ca2+ imaging that generates kinetic profiles and maps for single astrocytes and 2D or 3D networks (Fig. 1c)119,120.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Use of systems biology.
What the sources say
- Not checked — no full text of the sourcecites [119] Bindocci, E. et al. Three-dimensional Ca2+ imaging advances understanding of astrocyte biology. Science 356, eaai8185 (2017). source
- Partly supportedcites [120] Wang, Y. et al. Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nat. Neurosci. 22, 1936–1944 (2019). sourceExperimental — accuracy not yet measured
The Results section on single-cell physiological heterogeneities describes extracting time courses and mapping Ca2+ activity in individual astrocytes, while the Introduction describes analysis across cellular and population-wide scales. But the Discussion says AQuA was optimized for 2D data and that its 3D version was only a prototype tested on simulated data; this paper does not establish the claimed 3D network mapping. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Finally, interventional strategies such as classical pharmacology56,98, genetic manipulation42,56, and biomaterials99 are available tools to modify pathological signaling in reactive astrocytes for therapeutic purposes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
What the sources say
- Supportedcites [56] Reichenbach, N. et al. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J. Exp. Med. 215, 1649–1663 (2018). source
This citation is attached to pharmacology and genetic manipulation, not biomaterials. The Results describe chronic treatment with a P2Y1R antagonist to reduce astroglial hyperactivity, and astrocyte-specific deletion of metabotropic signaling to attenuate network dysfunction and improve spatial memory in an Alzheimer’s disease mouse model. The Discussion identifies both approaches as potential ways to address pathological astrocytic signaling. (LLM, conf=0.91)
- Supportedcites [98] Park, J. H. et al. Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer’s disease. Sci. Adv. 5, v0316 (2019). source
The citation to this paper supports the classical-pharmacology example, not the separately cited genetic-manipulation or biomaterials examples. The Discussion (page not provided) identifies KDS2010 as a pharmacological tool to prevent astrogliosis and reports reduced reactivity in astrocytes after treatment in Alzheimer’s model mice. (LLM, conf=0.92)
- Partly supportedcites [42] Ceyzériat, K. et al. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease. Acta Neuropathol. Commun. 6, 104 (2018). sourceExperimental — accuracy not yet measured
The Discussion section reports that astrocyte-targeted viral gene transfer altered JAK2–STAT3 signaling in Alzheimer’s disease mouse models, supporting genetic manipulation as an intervention. The cited paper does not establish classical pharmacology as a tool for this purpose; the biomaterials example is attached to a different citation. (LLM, conf=0.85)
- Supportedcites [99] Zuidema, J. M., Gilbert, R. J. & Gottipati, M. K. Biomaterial approaches to modulate reactive astroglial response. Cells Tissues Organs 205, 372–395 (2018). source
Citation 99 is attached to biomaterials, not to pharmacology or genetic manipulation. The Conclusion describes biomaterials as an approach to target mechanisms underlying reactive astrocyte states and shift astrocytes toward a neuroprotective phenotype, supporting their proposed therapeutic use. It also notes that few studies have shown improved functional recovery. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Currently, molecular data (for example, -omics) can be transformed into mathematical maps by artificial intelligence118, thereby providing quantitative representations of the otherwise-vague notion of phenotypes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Use of systems biology.
What the sources say
- Supportedcites [118] Romeo-Guitart, D. et al. Neuroprotective drug for nerve trauma revealed using artificial intelligence. Sci. Rep. 8, 1879 (2018). source
The Materials and Methods section (“TPMS technology”; page unavailable) describes an AI-based process that builds condition-specific molecular maps, converts them into mathematical models, and uses proteomic data to constrain those models. The Results section identifies the modeled conditions as neurodegeneration and neuroprotection. The description of phenotypes as “otherwise vague” is the citing authors’ framing, not a separate finding attributed to this source. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hiPSC glial mouse chimeric brains, in which hiPSC differentiate into human astrocytes, oligodendrocytes, and their progenitors, offer the possibility to study human astrocytes from patients in contexts amenable to in vivo experimentation113,114”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Partly supportedcites [113] Han, X. et al. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342–353 (2013). sourceExperimental — accuracy not yet measured
The Discussion describes human glial-chimeric mice as a model for studying human glial cells, including pathological aspects of their biology, in the live adult brain. However, the Experimental Procedures say the transplanted progenitors came from fetal tissue, not patient-derived hiPSCs. The Results also report no detectable human oligodendroglia in these mice, so the cited paper does not support that detail of the citing sentence. (LLM, conf=0.88)
- Partly supportedcites [114] Osipovitch, M. et al. Human ESC-derived chimeric mouse models of Huntington’s disease reveal cell-Intrinsic defects in glial progenitor cell differentiation. Cell Stem Cell 24, 107–122.e7 (2019). sourceExperimental — accuracy not yet measured
The Results section ('mHTT impairs human astroglial differentiation in vivo'; page not provided) describes studying human astrocytes in glial-engrafted mouse brains, supporting the in vivo model. But the Experimental Model section (page not provided) says the Huntington’s disease glial progenitors came from human embryonic stem cells, not patient-derived hiPSCs; the iPSC line mentioned in the Results was a control. (LLM, conf=0.88)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, changes in GFAP expression may also reflect physiological adaptive plasticity rather than being simply a reactive response to pathological stimuli.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
hedgedconditional- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Indeed, upregulation of GFAP mRNA and protein, as shown with multiple techniques including quantitative PCR (qPCR), RNA sequencing (RNAseq), in situ hybridization, electron microscopy, and immunostaining (Fig. 1a,d), is a prominent feature of many, but not necessarily all, reactive astrocytes”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“(i) increased GFAP content occurs across diverse types of CNS disorders”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
plaincorrelational- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“(ii) is an early response to injury”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“(iii) is a sensitive indicator, detectable even in the absence of overt neuronal death (for example, when there is synapse loss, minor demyelination, and extracellular amyloid-β oligomers).”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Animal models expressing fluorescent proteins in the astrocyte cytosol or membrane through astrocyte-specific transgenesis or after gene transfer with viral vectors25 circumvent the limitations of immunohistochemical analysis.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Not checked — no full text of the sourcecites [25] Yu, X., Nagai, J. & Khakh, B. S. Improved tools to study astrocytes. Nat. Rev. Neurosci. 21, 121–138 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In other words, cytoskeletal reorganization does not necessarily equal astrocyte hypertrophy.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Glial fibrillary acidic protein (GFAP)—a major protein constituent of astrocyte intermediate filaments—is the most widely used marker of reactive astrocytes (Table 1)12.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
What the sources say
- Not checked — no full text of the sourcecites [12] Eng, L. F., Vanderhaeghen, J. J., Bignami, A. & Gerstl, B. An acidic protein isolated from fibrous astrocytes. Brain Res. 28, 351–354 (1971). The first identification of human GFAP in astrocytes from old multiple sclerosis plaques, post-leucotomy scars, and the occipital and frontal horns of the lateral ventricles in aged individuals with hydrocephalus ex vacuo. source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“It is observed in neuropathological specimens after severe trauma and ischemia, as well as in the aged brain29.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Not checked — no full text of the sourcecites [29] Tachibana, M. et al. Clasmatodendrosis is associated with dendritic spines and does not represent autophagic astrocyte death in influenza-associated encephalopathy. Brain Dev 41, 85–95 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Translation from scRNAseq or snRNAseq data to in situ immunohistochemical detection and functional validations is far from trivial, because the molecular profiles of astrocyte clusters and subpopulations partly overlap.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, steadily increasing evidence indicates that any binary polarization of reactive astrocytes falls short of capturing their phenotypic diversity across disorders.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The analyses also indicate that multidimensional data are necessary to establish the distinctiveness of astrocyte phenotypes (Fig. 2).”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, although the data suggest complex changes in aging astrocytes, the evidence is not yet sufficient to qualify astrocytes as being bona fide reactive during physiological aging.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the mere expression of some or even all these marker genes does not prove the presence of functions that these genes have not been demonstrated to exert.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We do not support generalization of this ‘disease-associated’ classification to other conditions because only one disease was studied.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Moreover, the functions of these genes are not known, because, to date, no experimental evidence has causally linked any of the proposed marker genes of A1 or A2 astrocytes to either toxic or protective functions.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Specifically, complement factor 3 (C3) should not be regarded as a single and definitive marker that unequivocally labels astrocytes with a net detrimental effect.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
plain- Asserted: passes — The authors put it forward as true.
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A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“However, only a few studies have directly assessed astrocyte functions in the aging mouse brain85,92.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
What the sources say
- Not checked — no full text of the sourcecites [85] Rodríguez-Arellano, J. J., Parpura, V., Zorec, R. & Verkhratsky, A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323, 170–182 (2016). source
- Not checked — no full text of the sourcecites [92] Peters, O. et al. Astrocyte function is modified by Alzheimer’s disease-like pathology in aged mice. J. Alzheimers Dis. 18, 177–189 (2009). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Astrocyte diversity in healthy tissue arises from embryonic patterning programs or local neuronal cues14.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Not checked — no full text of the sourcecites [14] Ben Haim, L. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, pathways inducing astrocyte reactivity may be beneficial in one disease and detrimental in another.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, the existence of fixed categories defined by molecular and functional features consistently observed in different disease contexts is not yet certain.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Aged human brains display only mild and heterogeneous changes in astrocyte morphology or GFAP levels86.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
What the sources say
- Not checked — no full text of the sourcecites [86] Jyothi, H. J. et al. Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiol. Aging 36, 3321–3333 (2015). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“proteins released by injured astrocytes are currently being considered as fluid biomarkers of neurological trauma31”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Not checked — no full text of the sourcecites [31] Halford, J. et al. New astroglial injury-defined biomarkers for neurotrauma assessment. J. Cereb. Blood Flow Metab. 37, 3278–3299 (2017). These data led to the first clinically used kit based on astrocyte-derived fluid biomarkers for neurotrauma assessments. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“which provides important topographical information (Table 1)117”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Not checked — no full text of the sourcecites [117] Carter, S. F. et al. Astrocyte biomarkers in Alzheimer’s disease. Trends Mol. Med. 25, 77–95 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An important implication of the disease-specific induction of distinct reactive astrocyte states is that the damage- and pathogen-associated stimuli from one disorder cannot be assumed to be active in another.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 36
- Probably not a substantial claim. 12
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Expression of GFAP is also modulated by physiological stimuli such as physical activity19, exposure to enriched environments19, and glucocorticoids20, and it fluctuates with circadian rhythms in the suprachiasmatic nucleus21.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
What the sources say
- Partly supportedcites [19] Rodríguez, J. J., Terzieva, S., Olabarria, M., Lanza, R. G. & Verkhratsky, A. Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis 4, e678 (2013). sourceExperimental — accuracy not yet measured
The paper reports that voluntary running and enriched environments increased the surface area and volume of GFAP-positive astrocyte profiles in the hippocampus of mice (main text; page not provided). It does not establish that GFAP expression itself changed. The glucocorticoid and circadian-rhythm clauses are attached to other citations, not this source. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [20] O’Callaghan, J. P., Brinton, R. E. & McEwen, B. S. Glucocorticoids regulate the synthesis of glial fibrillary acidic protein in intact and adrenalectomized rats but do not affect its expression following brain injury. J. Neurochem. 57, 860–869 (1991). source
- Not checked — no full text of the sourcecites [21] Gerics, B., Szalay, F. & Hajós, F. Glial fibrillary acidic protein immunoreactivity in the rat suprachiasmatic nucleus: circadian changes and their seasonal dependence. J. Anat. 209, 231–237 (2006). Early demonstration that GFAP is regulated in a physiological context. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“However, while the degree of GFAP upregulation in reactive astrocytes often parallels the severity of the injury6, this correlation is not always proportional, perhaps due to regional differences of astrocytes, including basal GFAP content13,14.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
What the sources say
- Could not verifycites [6] Escartin, C., Guillemaud, O. & Carrillo-de Sauvage, M. A. Questions and (some) answers on reactive astrocytes. Glia 67, 2221–2247 (2019). sourceExperimental — accuracy not yet measured
The passages available from our copy are repository metadata and navigation text, not the paper’s discussion; they have no section or page labels. Searches for GFAP upregulation, injury severity, regional differences, and basal GFAP content returned no passage addressing the claim, so it cannot be assessed from this copy. (LLM, conf=0.72)
- Supportedcites [13] Griemsmann, S. et al. Characterization of panglial gap junction networks in the thalamus, neocortex, and hippocampus reveals a unique population of glial cells. Cereb. Cortex 25, 3420–3433 (2015). source
Citation 13/14 is attached to the proposed regional differences in astrocytes, including baseline GFAP, rather than to the injury-severity finding cited to reference 6. The Discussion (page unavailable) says GFAP is rarely expressed in thalamic astrocytes, supporting regional variation in GFAP expression. This paper does not establish that such variation explains a nonproportional injury response, but the citing sentence presents that explanation as a possibility. (LLM, conf=0.87)
- Not checked — no full text of the sourcecites [14] Ben Haim, L. & Rowitch, D. H. Functional diversity of astrocytes in neural circuit regulation. Nat. Rev. Neurosci. 18, 31–41 (2017). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Further, dye-filling methods can be used to visualize whole astrocytes in mice23, as well as in human brain samples from surgical resections (Fig. 1b)24.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Supportedcites [23] Wilhelmsson, U. et al. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl Acad. Sci. USA 103, 17513–17518 (2006). The complete visualization of astrocytes using whole-cell filling techniques revealed that reactive astrocytes display subtle morphological changes and remain in their 3D territorial domain, highlighting that GFAP immunostaining overestimates the true degree of astrocyte hypertrophy. source
The Abstract says the authors used dye-filling to reveal the full three-dimensional shape of astrocytes in mice, and the Methods describe injecting dye into astrocytes in mouse brain slices. In the citing sentence, this source is attached to the mice claim (reference 23); the human surgical-sample claim has a separate citation (reference 24). (LLM, conf=0.93)
- Supportedcites [24] Sosunov, A. A. et al. Phenotypic heterogeneity and plasticity of isocortical and hippocampal astrocytes in the human brain. J. Neurosci. 34, 2285–2298 (2014). source
The methods section (page not available) describes whole-cell recordings in freshly resected human brain slices. It says fluorescent dyes were added to assess cell morphology, with Alexa Fluor 594 allowing the shape of the patched cell to be evaluated. This supports the human-sample portion attached to citation 24; the mouse portion is attached to citation 23. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“GFAP is also expressed by progenitor cells15 and its expression depends on developmental stages16,17.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
What the sources say
- Supportedcites [15] Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009). source
In “Transformation of Neuroepithelial Cells and the Origin of Radial Glia” (page unavailable), the review describes GFAP expression in some radial glial cells, which serve as neural precursors. It also says the GFAP promoter is expressed by radial glia at a later stage and may become active in the mouse ventral telencephalon only later in development, supporting the developmental-stage qualification. (LLM, conf=0.88)
- Could not verifycites [16] Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008). This study represented a technical and conceptual breakthrough in the neurosciences as the first unbiased classification of brain cell populations based on transcriptomic profiles using early microarray analyses. The resulting transcriptomes are a powerful tool to gain insight into novel brain cell functions. More recently, the classification of brain cells has been further refined and enriched by sc/snRNAs sourceExperimental — accuracy not yet measured
The citation to this paper is attached to the developmental-stage part of the sentence, not the progenitor-cell part. The section on gene expression changes during astrocyte and oligodendrocyte development compares developmental stages, and the Aldh1L1 marker section discusses GFAP, but neither passage says that GFAP expression changes with developmental stage. Searches for GFAP at P1, P7, and P17 found no decisive passage. (LLM, conf=0.70)
- Supportedcites [17] Roybon, L. et al. Human stem cell-derived spinal cord astrocytes with defined mature or reactive phenotypes. Cell Rep 4, 1035–1048 (2013). source
The Introduction describes GFAP as appearing during an early, mainly embryonic phase of astrocyte development and being downregulated during later maturation, though it persists in white-matter astrocytes. This supports the developmental-stage portion of the sentence, to which citations 16 and 17 are attached; the progenitor-cell portion is separately attributed to citation 15. No page number is available in our copy. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Thorough visualization is necessary because astrocytes undergo distinct morphological changes other than hypertrophy in pathological contexts, including elongation, process extension toward injury site, and some three-dimensional (3D) domain overlap26.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Supportedcites [26] Schiweck, J., Eickholt, B. J. & Murk, K. Important shapeshifter: mechanisms allowing astrocytes to respond to the changing nervous system during development, injury and disease. Front. Cell. Neurosci. 12, 261 (2018). source
The review’s “Dealing With Insults” section describes polarized, elongated reactive astrocytes extending long processes toward injury sites. It also reports that, after more severe injury, processes extend into adjacent astrocyte domains, supporting the claim of some domain overlap. The indexed passages do not provide page numbers. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Increased GFAP immunoreactivity largely reflects changes in the astrocytic cytoskeleton and tends to exaggerate the degree of hypertrophy because, with the exception of scar-border astrocytes, the volume accessed by reactive astrocytes does not change, as they remain in their territorial domains23.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Partly supportedcites [23] Wilhelmsson, U. et al. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl Acad. Sci. USA 103, 17513–17518 (2006). The complete visualization of astrocytes using whole-cell filling techniques revealed that reactive astrocytes display subtle morphological changes and remain in their 3D territorial domain, highlighting that GFAP immunostaining overestimates the true degree of astrocyte hypertrophy. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In addition, the expression of some of these proteins may change in reactive astrocytes22 (Table 1), and some might be expressed by other cell types in specific brain regions13.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Supportedcites [22] Serrano-Pozo, A., Gómez-Isla, T., Growdon, J. H., Frosch, M. P. & Hyman, B. T. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am. J. Pathol. 182, 2332–2344 (2013). source
Citation 22 is attached to the first clause, about protein expression changing in reactive astrocytes; the claim about expression by other cell types is attached to citation 13. In “Phenotypic Change But Constant Number of Astrocytes in AD,” the paper distinguishes resting GFAP-negative astrocytes from reactive GFAP-positive astrocytes, supporting the cited clause. (LLM, conf=0.92)
- Supportedcites [13] Griemsmann, S. et al. Characterization of panglial gap junction networks in the thalamus, neocortex, and hippocampus reveals a unique population of glial cells. Cereb. Cortex 25, 3420–3433 (2015). source
Citation 13 is attached to the second clause, about proteins expressed by other cell types in specific brain regions; the reactive-astrocyte clause has a different citation. The Discussion (page not provided) reports that glutamine synthetase, used as an astrocyte marker, is also expressed by thalamic oligodendrocytes. (LLM, conf=0.93)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Such transcriptomic profiling specifically shows that reactive astrocytes adopt distinct molecular states in different disease models48,66–70, in different CNS regions70, and in brain tumors71.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Partly supportedcites [48] Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016). sourceExperimental — accuracy not yet measured
The Extended Data compare RNA-seq profiles of spinal-cord-injury reactive astrocytes with previously reported forebrain stroke-reactive astrocytes; only 58.5% of the top elevated forebrain genes were also significantly elevated after spinal cord injury. This supports molecular differences between those contexts, but disease model and CNS region change together, so the paper does not establish distinct states attributable to region independently. The brain-tumor clause is attached to a different citation. (LLM, conf=0.83)
- Supportedcites [66] Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012). First evidence for molecular heterogeneity of reactive astrocytes using microarray-based transcriptomics of acutely isolated astrocytes from mouse models of ischemia and septic shock. Studies in virtually all models of CNS diseases followed. source
This source is cited for the different-disease-models portion of the sentence, not the CNS-regions or brain-tumors portions. The Introduction describes transcriptomic profiling after ischemic stroke and LPS-induced neuroinflammation and reports gene-expression differences between the two reactive-astrocyte populations. (LLM, conf=0.92)
- Not checked — no full text of the sourcecites [67] Orre, M. et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746–2760 (2014). source
- Partly supportedcites [68] Sirko, S. et al. Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. Glia 63, 2340–2361 (2015). sourceExperimental — accuracy not yet measured
The Results section, “Injury-Induced Changes of Gene Expression in the Cerebral Cortex GM Astrocytes” (page unavailable), reports transcriptomic differences between reactive and nonreactive astrocytes after cortical injury. The Introduction describes a stab-wound model and comparison with neural stem cells, not reactive astrocytes across different disease models or CNS regions. The brain-tumor clause is attached to citation 71, not this source. (LLM, conf=0.83)
- Not checked — no full text of the sourcecites [69] Diaz-Castro, B., Gangwani, M. R., Yu, X., Coppola, G. & Khakh, B. S. Astrocyte molecular signatures in Huntington’s disease. Sci. Transl. Med. 11, eaaw8546 (2019). source
- Partly supportedcites [70] Itoh, N. et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc. Natl Acad. Sci. USA 115, E302–E309 (2018). sourceExperimental — accuracy not yet measured
The Results section, “Regional Differences in Astrocyte-Specific Gene Expression During EAE” (page unavailable), reports distinct astrocyte gene-expression patterns across CNS regions during EAE. This paper studies one disease model, so it does not itself establish differences between disease models. The brain-tumor clause is attached to citation 71, not this source. (LLM, conf=0.86)
- Partly supportedcites [71] John Lin, C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017). sourceExperimental — accuracy not yet measured
The Results section on malignant glioma reports distinct expression-profile correlations between astrocyte subpopulations and glioblastoma subtypes, and the Discussion describes molecularly distinct populations emerging during tumor progression. This supports the brain-tumor portion attached to this citation, but the paper does not establish that reactive astrocytes adopt those states; it studies astrocyte subpopulations and their malignant glioma analogs. (LLM, conf=0.86)
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“For example, the manipulation of reactive astrocytes has resulted in improved outcomes38,42,43, worse35 outcomes, and no change44 in mouse models of AD and MS40,45,46.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [38] Furman, J. L. et al. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J. Neurosci. 32, 16129–16140 (2012). source
The citation supports the improved-outcomes part of the sentence. In Results, “Astrocytic CN/NFAT inhibition improves cognition” reports that astrocyte-targeted Gfa2-VIVIT treatment improved cognitive performance in APP/PS1 mice, a mouse model of AD. The worse-outcomes and no-change parts have separate citations and are not attributed to this paper. (LLM, conf=0.92)
- Supportedcites [42] Ceyzériat, K. et al. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease. Acta Neuropathol. Commun. 6, 104 (2018). source
The citation is attached to the improved-outcomes portion of the sentence, not the worse, no-change, or MS examples. The Discussion reports that inhibiting astrocyte reactivity through the JAK2-STAT3 pathway reduced amyloid deposition, improved spatial learning, and restored synaptic function in mouse models of AD. (LLM, conf=0.94)
- Supportedcites [43] Reichenbach, N. et al. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer’s disease model. EMBO Mol. Med. 11, e9665 (2019). source
The Discussion reports that genetic modulation of astrogliosis improved pathology and cognition in a mouse model of AD. In the citing sentence, this paper supports the improved-outcomes example; the worse-outcomes, no-change, and MS examples have separate citations. (LLM, conf=0.93)
- Supportedcites [35] Kraft, A. W. et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 27, 187–198 (2013). source
The citation to this paper is attached to “worse outcomes,” not to the improved, unchanged, or MS outcomes. The Abstract reports that deleting Gfap and Vim to attenuate astrocyte activation in APP/PS1 mice doubled amyloid plaque load and increased dystrophic neurites; the Discussion likewise reports increased plaque load. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [44] Kamphuis, W. et al. GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia 63, 1036–1056 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In this study, ‘homeostatic astrocytes’ were predominant in healthy mice, whereas ‘disease-associated astrocytes’ were unique to AD mice.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
What the sources say
- Partly supportedcites [78] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). sourceExperimental — accuracy not yet measured
The paper reports a homeostatic Gfap-low state in wild-type mice and a disease-associated astrocyte state observed only in AD mice in its initial comparison (Abstract; no page given). But its age-series analysis also finds DAA-like cells in older wild-type mice, so the unqualified claim that they were unique to AD mice overstates the finding. (LLM, conf=0.87)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Functions lost or altered in reactive astrocytes include neurotransmitter and ion buffering in mouse HD models58, communication via gap junctions in the sclerotic hippocampus of patients with epilepsy59, phagocytic clearance of dystrophic neurites60, and metabolic coupling by glycolysis-derived d-serine61 and lactate62 in mouse AD models.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Partly supportedcites [58] Tong, X. et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nat. Neurosci. 17, 694–703 (2014). Demonstration with targeted molecular manipulations that loss of astrocyte homeostatic functions contributes to HD pathogenesis. sourceExperimental — accuracy not yet measured
The Discussion reports reduced GLT-1 and Kir4.1 expression and impaired extracellular potassium maintenance in HD mouse models, supporting altered neurotransmitter and ion buffering. But it says these early functional changes occurred without astrogliosis; the Results likewise found little or no striatal astrogliosis at symptomatic ages. This source therefore does not support describing the affected astrocytes as reactive. (LLM, conf=0.90)
- Supportedcites [59] Bedner, P. et al. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain 138, 1208–1222 (2015). source
The Discussion reports a complete lack of glial gap-junction coupling in the sclerotic hippocampus of patients with mesial temporal lobe epilepsy. This supports the portion of the citing sentence attached to citation 59; the other functions are attributed to other citations. No page number was available in our copy. (LLM, conf=0.94)
- Supportedcites [60] Gomez-Arboledas, A. et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia 66, 637–653 (2018). source
The Discussion reports that reactive astrocytes enwrap, internalize and degrade presynaptic dystrophies in APP/PS1 mice, with evidence of phagocytosis of dystrophies in human AD samples. It also notes that this phagocytic capacity might become impaired during disease progression. Citation 60 supports the phagocytic-clearance portion of the sentence; the other functions have separate citations. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“hiPSC-derived astrocytes are also amenable to study responses to viral infection83 and to specific stimuli84.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Human stem cells.
What the sources say
- Supportedcites [83] Ledur, P. F. et al. Zika virus infection leads to mitochondrial failure, oxidative stress and DNA damage in human iPSC-derived astrocytes. Sci. Rep. 10, 1218 (2020). source
The Results section (‘Human iPSC-derived astrocytes are preferentially infected...’; page not provided) describes infecting hiPSC-derived astrocytes with Zika virus and measuring their infection rate and cellular changes. This supports the viral-infection part attached to citation 83; the separate claim about specific stimuli is attached to citation 84. (LLM, conf=0.93)
- Supportedcites [84] Perriot, S. et al. Human induced pluripotent stem cell-derived astrocytes are differentially activated by multiple sclerosis-associated cytokines. Stem Cell Reports 11, 1199–1210 (2018). source
Citation 84 is attached to the claim about responses to specific stimuli; the viral-infection claim is attributed to citation 83, not this paper. The Introduction says the authors assessed astrocyte profiles triggered by different neuroinflammatory stimuli, and the Discussion reports distinct responses to those stimuli. (LLM, conf=0.93)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Studies in rodents document region-dependent and often contradictory changes in aging astrocytes, such as an increase in cellular volume and overlap of astrocyte processes, but also atrophy, increase in GFAP content, or even a reduction in the number of GFAP+ and GS+ astrocytes87–89.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
What the sources say
- Not checked — no full text of the sourcecites [87] Rodríguez, J. J. et al. Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol. Aging 35, 15–23 (2014). source
- Partly supportedcites [88] Cerbai, F. et al. The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS One 7, e45250 (2012). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [89] O’Callaghan, J. P. & Miller, D. B. The concentration of glial fibrillary acidic protein increases with age in the mouse and rat brain. Neurobiol. Aging 12, 171–174 (1991). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Interestingly, astrocytes generated from hiPSC derived from fibroblasts obtained from patients with CNS diseases (usually with a genetic mutation causative of disease or a risk polymorphism) show pathological phenotypes, including dysregulation of lipid metabolism11, alteration in the contents of the extracellular vesicles released by astrocytes80, reduced autophagy81, or altered STAT3 signaling82”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Human stem cells.
What the sources say
- Supportedcites [11] Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154.e7 (2018). Technically improved generation of hiPSC-derived astrocytes demonstrates that astrocytes harboring a genetic risk factor for AD are diseased astrocytes that may further exacerbate ongoing pathology. source
Citation 11 is attached to the lipid-metabolism example, not the separately cited extracellular-vesicle, autophagy, or STAT3 examples. The Results section (‘APOE4 astrocytes exhibit compromised Aβ uptake’; page not available) reports altered lipid-metabolism gene expression and cholesterol levels in APOE4 iPSC-derived astrocytes. (LLM, conf=0.93)
- Partly supportedcites [80] Varcianna, A. et al. Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS. EBioMedicine 40, 626–635 (2019). sourceExperimental — accuracy not yet measured
The Results section (“MicroRNAs regulating axonal maintenance are selectively dysregulated in C9 patient ADEVs”; page unavailable) reports altered miRNA cargo in extracellular vesicles released by C9orf72-ALS patient astrocytes, supporting the point attached to this citation. However, the Materials and methods section (“Conversion of skin fibroblasts to induced neural progenitor cells”; page unavailable) describes direct conversion of patient fibroblasts to neural progenitor cells and then astrocytes, not generation through hiPSCs. (LLM, conf=0.88)
- Supportedcites [81] di Domenico, A. et al. Patient-specific iPSC-derived astrocytes contribute to non-cell-autonomous neurodegeneration in Parkinson’s disease. Stem Cell Reports 12, 213–229 (2019). source
Citation 81 is attached to the reduced-autophagy example, not to the other phenotypes listed with separate citations. The Results sections on generating patient-specific astrocytes and impaired macroautophagy report that astrocytes derived from iPSCs of patients with LRRK2-associated Parkinson’s disease had reduced autophagic function compared with controls (page not specified). (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Astrocyte Ca2+ dynamics and network responses become aberrant in mouse models of HD53, AD54, and ALS55, possibly contributing to cognitive impairment and neuropathology43,53,56.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Partly supportedcites [53] Jiang, R., Diaz-Castro, B., Looger, L. L. & Khakh, B. S. Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington’s disease model mice. J. Neurosci. 36, 3453–3470 (2016). sourceExperimental — accuracy not yet measured
The Significance Statement (p. 2) and Discussion (p. 16) support aberrant astrocyte Ca2+ signaling and altered circuit engagement in HD model mice. The paper suggests these changes may contribute to altered striatal function, but it does not establish a contribution to cognitive impairment; the Discussion (p. 17) says a mechanism linking the cellular findings to HD symptoms remains unresolved. The AD and ALS portions of the citing sentence have separate citations and are not attributed to this source. (LLM, conf=0.84)
- Supportedcites [54] Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009). source
Citation 54 is attached to the AD portion of the sentence, not the HD or ALS portions. The paper’s Abstract reports elevated resting astrocyte calcium, more frequent and synchronized calcium transients, and intercellular calcium waves in an AD mouse model. It also suggests a possible contribution to memory disorders, without establishing one. (LLM, conf=0.93)
- Supportedcites [55] Agarwal, A. et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93, 587–605.e7 (2017). Technically refined application of Ca2+ imaging approaches and machine learning unraveled dysregulation of Ca2+ responses in a mouse model of ALS. source
The citation to this paper is attached to ALS, not the separately cited HD and AD models or the later claim about cognitive impairment. In the Results section (“Superoxide production enhances microdomain Ca2+ transients”; page unavailable), astrocytes in symptomatic SOD1G93A ALS mice had greater Ca2+ microdomain activity than age-matched controls, supporting the attributed change in astrocyte Ca2+ dynamics. (LLM, conf=0.91)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These studies also suggested complex functional changes in reactive astrocytes, including novel regenerative functions70, proliferation, and neural stem cell potential68, as well as loss of homeostatic functions66.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Transcriptomics and A1–A2 classification.
What the sources say
- Supportedcites [70] Itoh, N. et al. Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc. Natl Acad. Sci. USA 115, E302–E309 (2018). source
Citation 66 is attached to the loss of homeostatic functions, not the separately cited regenerative, proliferative, or stem-cell claims. The Results section on cholesterol synthesis reports decreased expression of that pathway in EAE astrocytes compared with normal astrocytes, supporting the cited point as a suggested change in homeostatic function. (LLM, conf=0.88)
- Supportedcites [68] Sirko, S. et al. Astrocyte reactivity after brain injury-: The role of galectins 1 and 3. Glia 63, 2340–2361 (2015). source
Citation 68 is attached to proliferation and neural stem cell potential, not to the separately cited regenerative or homeostatic claims. The Introduction describes a subset of proliferating reactive astrocytes acquiring neural stem cell potential after injury, and the Discussion reports proliferation-related gene expression while noting that only about 10–20% divide in this injury model. (LLM, conf=0.91)
- Could not verifycites [66] Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012). First evidence for molecular heterogeneity of reactive astrocytes using microarray-based transcriptomics of acutely isolated astrocytes from mouse models of ischemia and septic shock. Studies in virtually all models of CNS diseases followed. sourceExperimental — accuracy not yet measured
Citation 66 is attached to the claim that reactive astrocytes lose homeostatic functions. The Discussion describes extensive gene-expression changes and identifies transporters and channels involved in homeostasis, but does not say that homeostatic functions are lost. Searches for loss of homeostatic function and down-regulation of homeostatic genes found no passage establishing that point. (LLM, conf=0.73)
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For example, activation of STAT3-dependent transcription is beneficial in neonatal white matter injury47, traumatic brain injury30, spinal cord injury48,49, and motor neuron injury50, but detrimental in AD models42,43.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Supportedcites [47] Nobuta, H. et al. STAT3-mediated astrogliosis protects myelin development in neonatal brain injury. Ann. Neurol. 72, 750–765 (2012). source
Citation 47 supports the neonatal white matter injury portion of the sentence, not the separately cited injury and AD claims. The Abstract Results report that deleting astrocytic STAT3 exacerbated injury in a neonatal mouse model, and the Discussion describes a protective role for STAT3-mediated reactive astrocytes and a potential benefit of promoting pathway activation. (LLM, conf=0.88)
- Partly supportedcites [30] Levine, J. et al. Traumatically injured astrocytes release a proteomic signature modulated by STAT3-dependent cell survival. Glia 64, 668–694 (2016). sourceExperimental — accuracy not yet measured
The Results section ('Acute STAT3 activation is important for cell integrity and apoptosis after astrocyte injury'; page unavailable) reports that STAT3-deficient astrocytes survived mechanical stretching less well than controls. The paper also reports protective effects after spinal cord injury, but the cited evidence does not establish a benefit of STAT3-dependent transcription in traumatic brain injury specifically. (LLM, conf=0.85)
- Supportedcites [48] Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016). source
The citation to this paper is attached to the spinal cord injury portion of the sentence, not the other injuries or AD models. In Results, “Axon regrowth in spite of scar formation” reports that STAT3 conditional knockout significantly attenuated stimulated axon regrowth after spinal cord injury, supporting a beneficial role for STAT3-dependent astrocyte responses in that setting. (LLM, conf=0.90)
- Supportedcites [49] Herrmann, J. E. et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J. Neurosci. 28, 7231–7243 (2008). source
The citation to this paper is attached to the spinal cord injury part of the sentence, not the other injury types or AD models. The Discussion (page not provided) says that astrocytic STAT3 signaling restricts inflammation and lesion size, preserving functional tissue after spinal cord injury. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Lastly, responses of reactive astrocytes may be maladaptive and result in malfunctional astrocytes, which, in addition to losing homeostatic functions, may also gain detrimental functions, thus exacerbating ongoing pathology6.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
What the sources say
- Could not verifycites [6] Escartin, C., Guillemaud, O. & Carrillo-de Sauvage, M. A. Questions and (some) answers on reactive astrocytes. Glia 67, 2221–2247 (2019). sourceExperimental — accuracy not yet measured
The indexed passages are a HAL repository listing and site navigation, with no section or page of the paper’s substantive text. Searches for maladaptive responses, loss of homeostatic functions, detrimental functions, and worsening pathology returned no passage addressing the claim. (LLM, conf=0.72)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“are rapidly becoming commonplace in basic research11,82 and therapy development109”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Supportedcites [11] Lin, Y. T. et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98, 1141–1154.e7 (2018). Technically improved generation of hiPSC-derived astrocytes demonstrates that astrocytes harboring a genetic risk factor for AD are diseased astrocytes that may further exacerbate ongoing pathology. source
The citation to this paper is attached to “basic research,” while a separate citation accompanies “therapy development.” In Results (“Generation of isogenic APOE iPSC-derived neurons, astrocytes, and microglia-like cells”; page unavailable), the authors describe deriving iPSC-derived astrocytes for their Alzheimer’s disease experiments. The paper therefore serves as an example of their use in basic research. (LLM, conf=0.86)
- Partly supportedcites [82] Tyzack, G. E. et al. A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models. Nat. Commun. 8, 1164 (2017). sourceExperimental — accuracy not yet measured
The Methods describe experiments with hiPSC-derived astrocytes, and the Discussion says human iPSC models can help identify astrocytic targets for potential treatment. This supports their relevance to therapy development, but the paper does not establish that their use is rapidly becoming commonplace. (LLM, conf=0.84)
- Partly supportedcites [109] Colombo, E. et al. Siponimod (BAF312) activates Nrf2 while hampering NFκB in human astrocytes, and protects from astrocyte-induced neurodegeneration. Front. Immunol. 11, 635 (2020). sourceExperimental — accuracy not yet measured
The Results section (“Generation and Characterization of Human iAstrocytes”; page unavailable) shows that the authors generated hiPSC-derived astrocytes as a research model, and the Methods show their use in testing siponimod. This provides an example relevant to basic research and therapy investigation, but the paper does not establish that such use is rapidly becoming commonplace. (LLM, conf=0.82)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hiPSC-derived astrocytes, which can be generated with a fast protocol in 2D layers104 or integrated in 3D systems such as spheroids and organoids105–108”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Supportedcites [104] Tchieu, J. et al. NFIA is a gliogenic switch enabling rapid derivation of functional human astrocytes from pluripotent stem cells. Nat. Biotechnol. 37, 267–275 (2019). source
The cited paper supports the portion marked 104: it reports rapid generation of astrocytes from human PSCs, including patient-derived iPSCs, and its Methods describe culturing them on coated dishes (2D). The spheroid and organoid portion is assigned to citations 105–108, not to this source. The supplied copy gives section labels but no page numbers. (LLM, conf=0.91)
- Supportedcites [105] Sloan, S. A. et al. Human astrocyte maturation captured in 3D cerebral cortical spheroids derived from pluripotent stem cells. Neuron 95, 779–790.e6 (2017). source
The Results section, “Generation and purification of astrocyte-lineage cells from iPSC-derived hCS,” describes generating human astrocytes in 3D cerebral cortical spheroids. The fast 2D protocol is attached to citation 104, not to this source; Sloan et al. supports the spheroid example in the 3D portion of the sentence. (LLM, conf=0.92)
- Partly supportedcites [106] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). sourceExperimental — accuracy not yet measured
The Results section (‘Generation of cerebral organoids’; page unavailable) reports 3D cerebral organoids generated from human induced pluripotent stem cells. It does not report hiPSC-derived astrocytes being integrated into those organoids or into spheroids. The fast 2D protocol is attached to a different citation and is not assessed here. (LLM, conf=0.85)
- Supportedcites [107] Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017). source
The citation to this paper falls in the 3D-systems portion of the sentence, not the fast 2D-protocol portion. The Methods identify an hiPSC line used to generate cerebral organoids, and “Protracted in vitro development of human whole-brain organoids” reports that GFAP+ astroglia emerged in those organoids. No page numbers are available in our copy. (LLM, conf=0.88)
- Partly supportedcites [108] Giandomenico, S. L. et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat. Neurosci. 22, 669–679 (2019). sourceExperimental — accuracy not yet measured
The Results section (‘Air-liquid interface culture of cerebral organoids leads to improved survival and maturation’; page unavailable) reports astrocytes in cerebral organoids, supporting the 3D-organoid part of the cited claim. The Methods section (‘Human pluripotent stem cell culture and genome editing’; page unavailable) specifies that the organoids were generated from human embryonic stem cells, not hiPSCs. The fast 2D protocol is attached to a different citation and is not assessed here. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Emerging reactive-astrocyte biomarkers are either measured in blood or cerebrospinal fluid (for example, YKL-40)115 or used for brain imaging, such as MAO-B-based positron emission tomography (PET)116”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Humanizing research.
What the sources say
- Supportedcites [115] Craig-Schapiro, R. et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol. Psychiatry 68, 903–912 (2010). source
The Methods report measuring YKL-40 in CSF and paired plasma samples. The Discussion identifies YKL-40 as an astrocyte-derived CSF biomarker and also describes plasma measurements. The separate citation for MAO-B PET is not being judged here. (LLM, conf=0.93)
- Not checked — no full text of the sourcecites [116] Carter, S. F. et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J. Nucl. Med. 53, 37–46 (2012). Non-invasive imaging of reactive astrocytes in human patients. source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Optogenetics25 and designer receptors exclusively activated by designer drugs (DREADDs)25 are potential tools to manipulate reactive astrocytes or to restore their aberrant Ca2+ signaling observed in mouse models of neurodegenerative diseases53–55.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
What the sources say
- Not checked — no full text of the sourcecites [25] Yu, X., Nagai, J. & Khakh, B. S. Improved tools to study astrocytes. Nat. Rev. Neurosci. 21, 121–138 (2020). source
- Supportedcites [53] Jiang, R., Diaz-Castro, B., Looger, L. L. & Khakh, B. S. Dysfunctional calcium and glutamate signaling in striatal astrocytes from Huntington’s disease model mice. J. Neurosci. 36, 3453–3470 (2016). source
The citation to this paper is attached to aberrant Ca2+ signaling in disease-model mice, not to the proposed use of optogenetics or DREADDs. The Discussion (p. 16) reports altered spontaneous and evoked astrocyte Ca2+ signals in the R6/2 Huntington’s disease mouse model. This paper supports that example, although it does not test those proposed tools. (LLM, conf=0.91)
- Supportedcites [54] Kuchibhotla, K. V., Lattarulo, C. R., Hyman, B. T. & Bacskai, B. J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009). source
The paper reports aberrant astrocytic Ca2+ signaling in an Alzheimer’s disease mouse model: elevated resting calcium, more frequent transients, and intercellular calcium waves (Abstract). The proposed use of optogenetics and DREADDs is not attributed to this source; separate citations accompany those tools in the citing sentence. (LLM, conf=0.92)
- Supportedcites [55] Agarwal, A. et al. Transient opening of the mitochondrial permeability transition pore induces microdomain calcium transients in astrocyte processes. Neuron 93, 587–605.e7 (2017). Technically refined application of Ca2+ imaging approaches and machine learning unraveled dysregulation of Ca2+ responses in a mouse model of ALS. source
The citation to this paper supports the sentence’s claim about aberrant Ca2+ signaling in a mouse model of neurodegenerative disease. In Results, “Superoxide production enhances microdomain Ca2+ transients” (page unavailable), the authors report increased astrocyte microdomain activity in symptomatic SOD1G93A mice, an ALS model. The separate citation to optogenetics and DREADDs is not attributed to this source. (LLM, conf=0.91)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
Every source the paper cites for this claim was checked and supports it.
In the paper
“Alternatively, the diversity within astrocyte populations from mouse models may be dissected out by combining fluorescence-activated cell sorting (FACS) and cell-surface markers identified in screens71.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
What the sources say
- Supportedcites [71] John Lin, C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017). source
The Results section (‘Prospective identification of diverse astrocyte populations’) describes combining an Aldh1l1–GFP reporter mouse with screened cell-surface markers in a FACS-based approach. The authors report that antibodies identified by the screen subdivided the mouse astrocyte population, matching the citing sentence. (LLM, conf=0.94)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Immunohistochemical staining for cytosolic enzymes such as ALDH1L1, ALDOC, GS, and S100B allow the visualization of the somata and proximal processes of astrocytes, although, like GFAP, these markers fail to reveal small processes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In the healthy mouse brain, hippocampal astrocytes have a higher GFAP content than cortical, thalamic, or striatal astrocytes; this, however, does not make hippocampal astrocytes more reactive.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Finally, there are discrepancies between observed GFAP mRNA and protein levels, perhaps due to differential regulation of translation, post-translational modifications, protein half-life, and antibody epitope accessibility.”
§ Reactive astrocyte nomenclature, definitions, and future directions > GFAP as a marker
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“By definition, astrocyte reactivity is secondary to an extrinsic signal, may evolve with time, and, in many situations, is reversible.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Too many names
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Numerous mixed scenarios of malfunctional and resilient astrocytes plausibly exist, with multidirectional transitions among them.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, GFAP upregulation and hypertrophy are useful but insufficient markers of astrocyte reactivity that need to be complemented by additional markers (Table 1 and Box 1).”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Notably, isolation protocols may not always be optimal for astrocytes, resulting in low numbers of cells or nuclei being sequenced, and some highly relevant but weakly expressed transcripts, such as transcription factors and plasma-membrane receptors, may be overlooked, particularly in snRNAseq.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“In addition, generation of astrocytes from neural stem cells is inherently difficult, and derivation and culture conditions have not yet been standardized, leading to diversity of clone phenotypes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > Human stem cells.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, vague and binary terms such as ‘neuroprotective’ or ‘neurotoxic’ are best avoided in describing astrocyte phenotypes as they are too simplistic to be meaningful, unless they are suppor ted by specific molecular mechanisms and direct causative experi mental evidence.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“In addition, although astrocytes appear to be more resistant than neurons to degeneration and death, loss of primary and secondary astrocyte branches has been reported in mouse models of AD27 and ALS18, and in patients with multiple sclerosis (MS)28.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Morphology revisited
What the sources say
- Not checked — no full text of the sourcecites [27] Olabarria, M., Noristani, H. N., Verkhratsky, A. & Rodríguez, J. J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 58, 831–838 (2010). source
- Not checked — no full text of the sourcecites [18] Rossi, D. et al. Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ. 15, 1691–1700 (2008). source
- Not checked — no full text of the sourcecites [28] Black, J. A., Newcombe, J. & Waxman, S. G. Astrocytes within multiple sclerosis lesions upregulate sodium channel Nav1.5. Brain 133, 835–846 (2010). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“That is, STAT3-mediated transcriptional programs may contribute to malfunctional astrocyte states in AD models and to resilient states in other conditions.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the term ‘homeostatic astrocytes’ implies the unproven assumption that other transcriptional astrocyte clusters are dys-homeostatic, while they may be successful homeostasis-preserving adaptations to disease.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
In the paper
“Healthy brain aging is not pathological and may be defined as an adaptive evolution of global cell physiology over time85.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are aging astrocytes reactive or senescent?
What the sources say
- Not checked — no full text of the sourcecites [85] Rodríguez-Arellano, J. J., Parpura, V., Zorec, R. & Verkhratsky, A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323, 170–182 (2016). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Arguably, new names are needed to capture the variety of reactive astrocytes, but current knowledge does not yet allow the objective categorizing of reactive astrocytes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: unclear — It is unclear whether it could be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“An important conclusion drawn from these studies is that the morphological appearance of astrocytes does not correlate with functional phenotypes or with their impact on other cell types.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Impact in CNS diseases > From morphology to functional studies.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We stress that the expression in full or in part of a predetermined correlative signature of molecular markers is not, on its own, sufficient to define a functional phenotype of reactive astrocyte.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Are new names needed?
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, molecular signatures based on the expression of genes or proteins need to be validated by assessing specific astrocyte functions (Table 2), since post-transcriptional and post-translational events critically shape functional outcomes.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Heterogeneity characterization.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Acute metabolic damage with the mitochondrial toxin MPTP does not replicate chronic Parkinson’s disease (PD), to cite another example of in vivo inappropriate modelling.”
§ Reactive astrocyte nomenclature, definitions, and future directions > Toward astrocyte-targeting therapies > Signaling.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
Astrocytes are essentially post-mitotic cells that rarely divide in healthy tissue.
“which are essentially post-mitotic cells that rarely divide in healthy tissue.”
The paper relies on this without support.
There is a scarcity of disease-modifying treatments for chronic diseases and acute injuries of the CNS.
“Given the scarcity of disease-modifying treatments for chronic diseases and acute injuries of the CNS”
The paper relies on this without support.
There are no therapies purposely designed against astrocyte-specific targets in clinical practice.
“there are no therapies purposely designed against astrocyte-specific targets in clinical practice”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These AD neuropathological changes (ADNC) are accompanied by a dramatic loss of synapses and neurons, as well as prominent morphological and functional changes of glial cells, collectively termed reactive gliosis1.”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“( B and C ) Split gene expression violin plots of control (green) and Ts21 (purple) astrocytes for consensus genes upregulated (B) or downregulated (C) in reactive astrocytes (58) (**** p<0.0001, Wilcoxon Rank Sum test).”
From Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex (2026) · cites this paper as [58]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The reactive astrocytes exhibit hypertrophic characteristics with thick and long processes and increased expression level of glial fibrillary acidic protein (GFAP; Liddelow and Barres, 2017;Escartin et al., 2021).”
From Cell Adhesion Molecule Protocadherin-γC5 Ameliorates Aβ Plaque Pathogenesis by Modulating Astrocyte Function in Alzheimer's Disease (2025) · cites this paper as Escartin et al., 2021
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Microglial activation or inflammatory insults induce astrocytes into a reactive state, which can have both neuroprotective and neurotoxic effects [17, 183–185].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“However, these studies evaluated astrocyte state upon NLRP3 inflammasome activation based on the binary “A1/A2” astrocyte description, which does not fully capture the diversity of astrocyte states and phenotypes in different contexts [183].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [183]
The cited source says what the claim attributes to it.
In the citing paper
“the emerging view from experimental data is that reactive astrogliosis may contribute to neurodegeneration through both gains of toxic functions and loss of normal functions1.”
From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [1]
The cited source says what the claim attributes to it.
In the citing paper
“Under pathological conditions, they undergo reactive astrogliosis, characterized by morphological and functional changes such as hypertrophy, process elongation, up-regulation of glial fibrillary acidic protein (GFAP) (2–5), or dynamic relocalization of proteins such as aquaporin-4 (6, 7).”
From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“Emerging evidence suggests that reactive astrocytes are not monolithic but exist on a spectrum influenced by context, region, and stimuli.”
From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“Even if GFAP-positive astrocytes are suggestive of a reactive phenotype, GFAP and morphology alone are not considered sufficient to qualify astrocytes’ reactivity [57].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [57]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Astrocytes, essential for maintaining central nervous system (CNS) homeostasis and defense, play a vital role in cholesterol synthesis and metabolism within the brain28,29.”
From Cholesterol-driven pathological astrocytic responses in diabetes-associated cognitive impairment through astrocytic SCAP accumulation and NF-κB–C3 signaling modulation (2025) · cites this paper as [28]
Experimental — accuracy not yet measuredIn the citing paper
“It was recommended to be cautious in interpreting the increased number of GFAP+ cells as an increase in reactive astrocytes, as GFAP content alone is not a definitive indicator of their reactivity or altered functions.257”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [257]
In the citing paper
“Reactive astrocytes undergo morphological, molecular, and functional changes in response to injury or CNS diseases; they may adopt multiple, heterogeneous states depending on context (Escartin et al., 2021).”
From What is a cell type and how to define it? (2022) · cites this paper as Escartin et al., 2021
Citations
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971
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Genomic analysis of reactive astrogliosis
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Astrocyte scar formation aids central nervous system axon regeneration
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Self-citation
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Cited by
Sorted by citations
Microglia states and nomenclature: A field at its crossroads
Paolicelli, R. C., Sierra, A., Stevens, B., Tremblay, M.-E., Aguzzi, A., Ajami, B., Amit, I., Audinat, E., Bechmann, I., Bennett, M., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.10.020 · Cited by 1,973
Self-citationMicrobiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Transcriptomic diversity of cell types across the adult human brain
Siletti, K., Hodge, R., Mossi Albiach, A., Lee, K. W., Ding, S.-L., Hu, L., Lönnerberg, P., Bakken, T., Casper, T., Clark, M., et al. (2023) · Science · doi:10.1126/science.add7046 · Cited by 832
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“However, the function of these marker genes are not well known,(137) and no experimental evidence proved the A1/A2 astrocytes marker genes exert either toxic or protective functions.(144) Thus, the meaningful definition of reactive astrocytes subtypes should not solely based on the molecular signatures.”
BackgroundFunction and therapeutic value of astrocytes in neurological diseases
Lee, H.-G., Wheeler, M. A., & Quintana, F. J. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00390-x · Cited by 662
Self-citation
Metadata
- Authors
- Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., Allen, N. J., Araque, A., Barbeito, L., Barzilai, A., Bergles, D. E., Bonvento, G., Butt, A. M., Chen, W.-T., Cohen-Salmon, M., Cunningham, C., Deneen, B., De Strooper, B., Díaz-Castro, B., Farina, C., Freeman, M., Gallo, V., Goldman, J. E., Goldman, S. A., Götz, M., Gutiérrez, A., Haydon, P. G., Heiland, D. H., Hol, E. M., Holt, M. G., Iino, M., Kastanenka, K. V., Kettenmann, H., Khakh, B. S., Koizumi, S., Lee, C. J., Liddelow, S. A., MacVicar, B. A., Magistretti, P., Messing, A., Mishra, A., Molofsky, A. V., Murai, K. K., Norris, C. M., Okada, S., Oliet, S. H. R., Oliveira, J. F., Panatier, A., Parpura, V., Pekna, M., Pekny, M., Pellerin, L., Perea, G., Pérez-Nievas, B. G., Pfrieger, F. W., Poskanzer, K. E., Quintana, F. J., Ransohoff, R. M., Riquelme-Perez, M., Robel, S., Rose, C. R., Rothstein, J. D., Rouach, N., Rowitch, D. H., Semyanov, A., Sirko, S., Sontheimer, H., Swanson, R. A., Vitorica, J., Wanner, I.-B., Wood, L. B., Wu, J., Zheng, B., Zimmer, E. R., Zorec, R., Sofroniew, M. V., & Verkhratsky, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University Hospital Bonn (DE)
- University of Bonn (DE)
- University of Lausanne (CH)
- University of Padua (IT)
- Heidelberg University (DE)
- Salk Institute for Biological Studies (US)
- University of Minnesota (US)
- Institut Pasteur de Montevideo (UY)
- Tel Aviv University (IL)
- Johns Hopkins University (US)
- University of Portsmouth (GB)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Trinity College Dublin (IE)
- Baylor College of Medicine (US)
- IRCCS Ospedale San Raffaele (IT)
- Oregon Health & Science University (US)
- Children's National (US)
- Columbia University (US)
- University of Copenhagen (DK)
- Helmholtz Munich (DE)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Tufts University (US)
- University of Freiburg (DE)
- Utrecht University (NL)
- Nihon University (JP)
- Harvard University (US)
- Max Delbrück Center (DE)
- University of California, Los Angeles (US)
- University of Yamanashi (JP)
- Institute for Basic Science (KR)
- NYU Langone Health (US)
- University of British Columbia (CA)
- Centre Hospitalier Universitaire Vaudois (CH)
- University of Wisconsin–Madison (US)
- University of California, San Francisco (US)
- McGill University Health Centre (CA)
- University of Kentucky (US)
- Kyushu University (JP)
- Université de Bordeaux (FR)
- Universidade Politécnica do Cávado e do Ave (PT)
- University of Alabama at Birmingham (US)
- University of Gothenburg (SE)
- Inserm (FR)
- Consejo Superior de Investigaciones Científicas (ES)
- Broad Institute (US)
- Virginia Tech (US)
- Heinrich Heine University Düsseldorf (DE)
- Sechenov University (RU)
- San Francisco VA Medical Center (US)
- Georgia Institute of Technology (US)
- The University of Texas Health Science Center at Houston (US)
- University of California San Diego (US)
- Universidade Federal do Rio Grande do Sul (BR)
- University of Ljubljana (SI)
- Ikerbasque (ES)
- Corresponding author
- Escartin, Carole
- Galea, Elena
- Sofroniew, Michael V.
- Verkhratsky, Alexei
- ORCID
- Escartin, Carole
- Galea, Elena
- Lakatos, András
- Petzold, Gabor C.
- Serrano-Pozo, Alberto
- Steinhäuser, Christian
- Volterra, Andrea
- Carmignoto, Giorgio
- Agarwal, Amit
- Allen, Nicola J.
- Araque, Alfonso
- Barbeito, Luis
- Barzilai, Ari
- Bergles, Dwight E.
- Bonvento, Gilles
- Butt, Arthur M.
- Chen, Wei-Ting
- Cunningham, Colm
- Deneen, Benjamin
- Farina, Cinthia
- Gallo, Vittorio
- Goldman, Steven A.
- Götz, Magdalena
- Gutiérrez, Antonia
- Haydon, Philip G.
- Heiland, Dieter H.
- Hol, Elly M.
- Holt, Matthew G.
- Iino, Masamitsu
- Kastanenka, Ksenia V.
- Kettenmann, Helmut
- Khakh, Baljit S.
- Koizumi, Schuichi
- Lee, C. Justin
- Liddelow, Shane A.
- MacVicar, Brian A.
- Magistretti, Pierre
- Messing, Albee
- Mishra, Anusha
- Molofsky, Anna V.
- Murai, Keith K.
- Norris, Christopher M.
- Okada, Seiji
- Oliet, Stéphane H. R.
- Oliveira, João F.
- Panatier, Aude
- Parpura, Vladimir
- Pekna, Marcela
- Pekny, Milos
- Pellerin, Luc
- Perea, Gertrudis
- Pfrieger, Frank W.
- Poskanzer, Kira E.
- Quintana, Francisco J.
- Robel, Stefanie
- Rose, Christine R.
- Rothstein, Jeffrey D.
- Rouach, Nathalie
- Rowitch, David H.
- Semyanov, Alexey
- Sirko, Swetlana
- Sontheimer, Harald
- Swanson, Raymond A.
- Wanner, Ina-Beate
- Wood, Levi B.
- Wu, Jiaqian
- Zheng, Binhai
- Zimmer, Eduardo R.
- Zorec, Robert
- Sofroniew, Michael V.
- Verkhratsky, Alexei
- Venue
- Nature Neuroscience
- Published
- 2021-02-15
- Volume
- 24
- Issue
- 3
- Pages
- 312-325
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8007081
- OpenAlex
- W3132240972
- Semantic Scholar
- a3022d571fddad63beb9138c9d897c2d714e57ed
- Cited by
- 2,513
- References
- 151
- Citations by year
- 2026: 485 · 2025: 478 · 2024: 479 · 2023: 448 · 2022: 414 · 2021: 204
- FWCI
- 44.21
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Research Explorer (The University of Manchester) (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- HAL (submittedVersion)
- HAL (submittedVersion, other-oa)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- IRIS (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- DZNE Pub (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- National Science Foundation
- Alzheimer's Association (AACF-17-524184)
- Teva Pharmaceutical Industries
- Wellcome Trust (203151/Z/16/Z)
- Deutsche Forschungsgemeinschaft (STE552/4, SPP-1757, STE552/5)
- Agence Nationale de la Recherche (ANR-10-LABX-0054, 2017-, ANR-11-INBS-0011)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (160620, 173124, 51NF40, 31003A)
- Bundesministerium für Bildung und Forschung (16GW0182, 16GW0182 CONNEXIN)
- Generalitat de Catalunya (PID2019)
- Lundbeckfonden (R191-2015-728)
- Centre National de la Recherche Scientifique
- Novo Nordisk Fonden (NNF13OC0004260)
- National Institutes of Health (CC999999, H2020)
- Centers for Disease Control and Prevention
- Horizon 2020 Framework Programme (H2020-MSCA, PID2019, 722053, H2020-MSCA-ITN)
- Medical Research Council (MC_PC_17230, MR/P008658/1)
- Japan Society for the Promotion of Science (21K19309, 19H04746, 21H04786, 20H05060, 20H05894, 20H03430, 19H03771, 20H05902)
- National Institute on Aging (R56AG060974, RF1AG027297, K08AG064039, RF1AG061774, R01AG066171, R01AG054598, R01AG056998)
- National Institute of Mental Health (R01MH104701)
- National Institute on Drug Abuse (R01DA048822)
- National Institute of General Medical Sciences (R01GM123971)
- National Institute of Neurological Disorders and Stroke (R01NS105807, R01NS102807, R01NS110690, R01NS036692, R01NS084030)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Clinical Neurology › Spinal Cord Injury Research
- Keywords
- reactive astrocytes, central nervous system injury, central nervous system disorders, astrocyte heterogeneity, consensus definition
- MeSH terms
- Aging, Animals, Astrocytes, Brain, Brain Diseases, Brain Injuries, Humans, Spinal Cord, Spinal Cord Injuries
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.
A language model drew the claims from the paper on 2026-10-27, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-27 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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 ›
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