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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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R&D Systems mouse mcp 1 elisa assay kit
( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the <t>Ccl2</t> transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).
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Image Search Results


( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the Ccl2 transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).

Journal: eLife

Article Title: DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response

doi: 10.7554/eLife.92173

Figure Lengend Snippet: ( A–B ) Expression of Gdf15 mRNA and GDF-15 protein in the brain of eIF2B homozygous (HOM) or wild-type mice treated with DNL343 or vehicle. ( C–D ) GDF-15 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( E–F ) Expression of brain Gfap mRNA and plasma GFAP protein in eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( G–H ) GFAP protein levels in the CSF and plasma of VWMD patients and healthy controls. ( I–J ) TIMP-1 protein levels in the brain and CSF of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( K–L ) TIMP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( M–N ) Expression of the Ccl2 transcript, which encodes the MCP-1 protein, and levels of MCP-1 protein in the brain of eIF2B HOM or wild-type mice treated with DNL343 or vehicle. ( O–P ) MCP-1 protein levels in the CSF and plasma of VWMD patients and healthy controls. ( Q–R ) NfL protein levels in the CSF and plasma of VWMD patients and healthy controls. ( S ) Heatmap visualization of relative changes in NfL, GDF-15, GFAP, and MCP-1 in the CSF of VWMD patients vs healthy controls, presented in log 2 scale. VWMD patient ID#s correspond across (CSF) and (plasma). Statistical significance was set at p<0.05. For all animal model panels, DNL343 dose is indicated on the x-axis and data is presented as mean ± SEM of N=9–18 mice per group. Statistical significance for DNL343 effect in the mouse model was determined by a one-way ANOVA followed by Dunn’s multiple comparison tests against vehicle-dosed animals of the same genotype (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001). Data from VWMD patients and healthy controls is presented as mean ± SEM. Statistical significance for the difference between samples from VWMD patients and healthy controls was assessed on log 2 fold change data using Welch’s t test (*, p<0.05. **, p<0.01, ***, p<0.001, ****, p<0.0001).

Article Snippet: ELISA kits were used to determine the levels of GDF-15 (mouse/rat GDF-15 Quantikine ELISA Kit, R&D Systems, catalog # MGD150), TIMP-1 (mouse TIMP-1 Quantikine ELISA Kit, R&D Systems, catalog # MTM100), and MCP-1 (Mouse CCL2/JE/MCP-1 Quantikine ELISA Kit, R&D Systems, catalog # MJE00B) in the brain, plasma, or CSF samples.

Techniques: Expressing, Animal Model, Comparison