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- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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- Chyu, KY, et al.
(författare)
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Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells
- 2004
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Ingår i: Vascular Medicine. - : SAGE Publications. - 1477-0377 .- 1358-863X. ; 9:3, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that injury-induced medial vascular smooth muscle cell (VSMC) proliferation and neointima formation in carotid arteries of inducible nitric oxide synthase knockout ( iNOS KO) mice were significantly reduced compared with wild type (WT). However, the molecular pathway underlying such differences is not known. In this in vitro study, we discovered that the AP-1/Ref-1/thioredoxin signaling pathway is altered in aortic VSMC from iNOS KO mice, which leads to reduced growth response when compared with aortic VSMC from WT mice. After equal initial seeding, the cell number after 7 days in serum medium was less in iNOS KO cells compared with WT VSMC (1.2 +/- 0.6 x 10(5) vs 3.2 +/- 1.1 x 10(5); p < 0.05). Significantly more iNOS KO cells remained in the G0/G1 phase compared with WT cells after 24-h serum treatment (82.6 +/- 13.7% vs 62.3 +/- 14.6%; p < 0.05) by cell-cycle analysis. Nuclear PCNA expression was also less in the iNOS KO cells, which was not affected by exogenous NO or superoxide. Superoxide generation after 24-h serum stimulation was less in the iNOS KO cells compared with WT cells. After 30-min serum stimulation, AP-1 DNA binding was reduced and a lack of increase in nuclear c-Jun protein was observed in iNOS KO VSMC. RT-PCR analysis confirmed a lack of inducible c-Jun mRNA after serum stimulation in the KO cells. In addition, KO cells had less nuclear reducing factor-1 (Ref-1) and serum-inducible thioredoxin protein expression. Reduced proliferative response of iNOS KO VSMC to serum treatment is associated with altered AP-1/Ref-1/thioredoxin pathway activation.
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- Chyu, KY, et al.
(författare)
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Immunization using an Apo B-100 related epitope reduces atherosclerosis and plaque inflammation in hypercholesterolemic apo E(-/-) mice
- 2005
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 338:4, s. 1982-1989
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Tidskriftsartikel (refereegranskat)abstract
- Immune system modulates atherosclerosis and immunization using homologous LDL reduces atherosclerosis in hyperlipidemic animals. The nature of athero-protective antigenic epitopes in LDL remains unclear. We have recently identified nearly a 100 antigenic epilopes in human apo B-100 and in this study we evaluated the effects of immunization with two such epitopes on atherosclerosis in hypercholesterolemic apo E (-/-) mice. Male apo E (-/-) mice were immunized at 6-7 weeks of age with two different apo B-100 related peptide sequences using alum as adjuvant and mice immunized with alum alone served as controls. Peptide-2 immunization reduced aortic atherosclerosis by 40% and plaque inflammation by 80% compared to controls without a reduction in circulating cholesterol levels whereas Peptide-1 immunization had no effect. Peptide-2 immunization also reduced the progression of aortic lesions when mice were immunized at 16 weeks of age, suggesting the possibility of immuno-modulation in treating established atherosclerosis. The athero-protective effect of Peptide-2 immunization was absent in splenectomized mice but could be conveyed to non-immunized mice via adoptive transfer of splenocytes from peptide-2 immunized mice. In conclusion, immunization with a specific apo B-100 related peptide sequence reduces aortic atherosclerosis and plaque inflammation. Such acquired immunity and athero -protective effect appears to be mediated by splenocytes. These data demonstrate the feasibility of peptide based immunomodulating therapy for atherosclerosis.
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| 7. |
- Chyu, KY, et al.
(författare)
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Timing affects the efficacy of LDL immunization on atherosclerotic lesions in apo E (-/-) mice
- 2004
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 176:1, s. 27-35
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Tidskriftsartikel (refereegranskat)abstract
- Background: Immunization of animals with LDL reduces atherosclerosis. However, whether the timing of immunization affects its efficacy is not known. In this study, we evaluated the influence of timing of immunization on the athero-protective effects of LDL immunization in apo E (-/-) mice. Methods and results: Hypercholesterolemic apo E (-/-) mice were immunized with native LDL (nLDL) at age of 6-7 weeks old or at 20 weeks old. Compared to adjuvant group, mice that were immunized at the age of 6-7 weeks developed significantly smaller aortic sinus plaques with reduced gelatinolytic activity and increased collagen content. This was associated with an increase of oxidized LDL (oxLDL) antibody titer and a marked decrease in splenic IL-4 mRNA expression. Immunization at 20 weeks of age also increased oxLDL antibody titer but did not reduce plaque size, gelatinolytic activity or collagen content but resulted in a modest decrease in macrophage infiltration. Late immunization did not alter splenic IL-4 mRNA expression. Conclusions: Our findings demonstrate that, only early nLDL immunization modulates humoral and cellular immune responses and affects plaques size and composition in apo E (-/-) mice, indicating the critical importance of timing of immunization for its antiatherogenic efficacy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
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