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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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- Campbell, Christine, et al.
(författare)
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Markers of steroid receptor, kinase signalling pathways and Ki-67 expression in relation to tamoxifen sensitivity and resistance
- 2020
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Ingår i: Translational Breast Cancer Research. - : AME Publishing Company. - 2218-6778. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It remains clinically important to identify ER positive breast cancers likely to respond to tamoxifen (TAM) and so we aimed to select a group of biomarkers able to predict response. We also assessed whether data from different sample types [tumor microarrays (TMAs) and core biopsies] or tumor sites could be combined for biomarker studies.Methods: A total of 123 endocrine treatment naïve patients with known ER and HER2 status treated with TAM had paraffin-embedded tumor tissue available either as TMAs (n=102) or core biopsies (n=21). TMA cores were collected from three different tumor sites, two central and one peripheral. Ten biomarkers were evaluated by immunohistochemistry, for % positivity and/or H-Score, comprising: ER, HER2, Ki-67, phosphorylated forms of ER (Ser118), IGF1R, PRAS40, Akt & MAPK (ERK1/2), and PTEN & androgen receptor expression (AR). Each tumor was analysed for Akt1 E17K somatic mutation using BEAMing technology. Patient outcome was assessed by clinical benefit (CB) rate & survival analyses [time to progression (TTP) and time to death (TTD)].Results: There was no significant difference in % positivity or H-Score between central & peripheral tumor sites for all biomarkers examined. After False Discovery Rate (FDR) correction differences (P<0.05) were observed between the two central samples only for HER2 & pER118 and pPRAS40. However, differences in biomarker expression were common between core biopsies and TMAs. Only 2/123 (1.6%) tumors had Akt1 E17K mutations. Univariate and multivariate analyses identified that lower levels of PTEN and higher levels of Ki-67 (% positivity) were predictive of poor outcome (TTP & TTD) following TAM. Higher ER. lower Ki-67 and AR/ER ratio <2 predicted increased CB rate.Conclusions: There were few differences in marker expression between TMAs from different intra-tumoral sites. More marked differences between TMAs and core biopsies suggest caution if combining such datasets. Loss of PTEN, a key regulator of the PI3K/Akt pathway, was the only RTK/kinase signaling biomarker related to poorer clinical outcome. PTEN along with ER & lower Ki-67 proved the most predictive markers for better outcome (TTP & TTD and/or CBR) following TAM treatment.Keywords: ER+ breast cancer; Akt pathway; tamoxifen
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- Kroll, Thomas, et al.
(författare)
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Effect of 3d/4p Mixing on 1s2p Resonant Inelastic X-ray Scattering : Electronic Structure of Oxo-Bridged Iron Dimers
- 2021
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 143:12, s. 4569-4584
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Tidskriftsartikel (refereegranskat)abstract
- 1s2p resonant inelastic X-ray scattering (1s2p RIXS) has proven successful in the determination of the differential orbital covalency (DOC, the amount of metal vs ligand character in each d molecular orbital) of highly covalent centrosymmetric iron environments including heme models and enzymes. However, many reactive intermediates have non-centrosymmetric environments, e.g., the presence of strong metal-oxo bonds, which results in the mixing of metal 4p character into the 3d orbitals. This leads to significant intensity enhancement in the metal K-pre-edge and as shown here, the associated 1s2p RIXS features, which impact their insight into electronic structure. Binuclear oxo bridged high spin Fe(III) complexes are used to determine the effects of 4p mixing on 1s2p RIXS spectra. In addition to developing the analysis of 4p mixing on K-edge XAS and 1s2p RIXS data, this study explains the selective nature of the 4p mixing that also enhances the analysis of L-edge XAS intensity in terms of DOC. These 1s2p RIXS biferric model studies enable new structural insight from related data on peroxo bridged biferric enzyme intermediates. The dimeric nature of the oxo bridged Fe(III) complexes further results in ligand-to-ligand interactions between the Fe(III) sites and angle dependent features just above the pre-edge that reflect the superexchange pathway of the oxo bridge. Finally, we present a methodology that enables DOC to be obtained when L-edge XAS is inaccessible and only 1s2p RIXS experiments can be performed as in many metalloenzyme intermediates in solution.
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