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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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- Bakken, TE, et al.
(författare)
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Comparative cellular analysis of motor cortex in human, marmoset and mouse
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 111-
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Tidskriftsartikel (refereegranskat)abstract
- The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.
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| 19. |
- Butt, Naveed, et al.
(författare)
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Robust Multichannel Detection of Mixtures Using Nuclear Quadrupole Resonance'
- 2008
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Ingår i: IEEE Transactions on Signal Processing. - 1053-587X. ; 56:10, s. 5042-5050
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear quadrupole resonance (NQR) is a radio-frequency (RF) spectroscopic technique, able to detect the presence of many high explosives and narcotics. In practice, the weak NQR signal is often corrupted by strong RF interference (RFI); therefore, various multichannel detection algorithms have recently been proposed for NQR. However, these algorithms allow for only a single compound/polymorph, whose associated amplitudes are assumed to be known to within a scaling. Regrettably, these amplitudes are typically prone to some level of uncertainty; and, in several cases of interest, signals from a mixture of NQR compounds/polymorphs may be present, leading to performance degradation in the aforementioned algorithms. In this paper, we develop a robust multisensor hybrid algorithm able to process NQR signals from mixtures while also allowing for errors in the assumed amplitudes. Numerical investigations indicate that the proposed algorithm provides significant performance gains as compared to existing algorithms in the case when there are multiple polymorphs present and/or when uncertainties in the amplitudes exist.
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| 21. |
- Jensen, Christina T, et al.
(författare)
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Dissection of progenitor compartments resolves developmental trajectories in B-lymphopoiesis
- 2018
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 215:7, s. 1947-1963
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Tidskriftsartikel (refereegranskat)abstract
- To understand the developmental trajectories in early lymphocyte differentiation, we identified differentially expressed surface markers on lineage-negative lymphoid progenitors (LPs). Single-cell polymerase chain reaction experiments allowed us to link surface marker expression to that of lineage-associated transcription factors (TFs) and identify GFRA2 and BST1 as markers of early B cells. Functional analyses in vitro and in vivo as well as single-cell gene expression analyses supported that surface expression of these proteins defined distinct subpopulations that include cells from both the classical common LPs (CLPs) and Fraction A compartments. The formation of the GFRA2-expressing stages of development depended on the TF EBF1, critical both for the activation of stage-specific target genes and modulation of the epigenetic landscape. Our data show that consecutive expression of Ly6D, GFRA2, and BST1 defines a developmental trajectory linking the CLP to the CD19+ progenitor compartment.
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| 22. |
- Mondal, B, et al.
(författare)
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Integrative functional genomic analysis identifies epigenetically regulated fibromodulin as an essential gene for glioma cell migration.
- 2017
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 36, s. 71-83
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Tidskriftsartikel (refereegranskat)abstract
- An integrative functional genomics study of multiple forms of data are vital for discovering molecular drivers of cancer development and progression. Here, we present an integrated genomic strategy utilizing DNA methylation and transcriptome profile data to discover epigenetically regulated genes implicated in cancer development and invasive progression. More specifically, this analysis identified fibromodulin (FMOD) as a glioblastoma (GBM) upregulated gene because of the loss of promoter methylation. Secreted FMOD promotes glioma cell migration through its ability to induce filamentous actin stress fiber formation. Treatment with cytochalasin D, an actin polymerization inhibitor, significantly reduced the FMOD-induced glioma cell migration. Small interfering RNA and small molecule inhibitor-based studies identified that FMOD-induced glioma cell migration is dependent on integrin-FAK-Src-Rho-ROCK signaling pathway. FMOD lacking C-terminus LRR11 domain (ΔFMOD), which does not bind collagen type I, failed to induce integrin and promote glioma cell migration. Further, FMOD-induced integrin activation and migration was abrogated by a 9-mer wild-type peptide from the FMOD C-terminus. However, the same peptide with mutation in two residues essential for FMOD interaction with collagen type I failed to compete with FMOD, thus signifying the importance of collagen type I-FMOD interaction in integrin activation. Chromatin immunoprecipitation-PCR experiments revealed that transforming growth factor beta-1 (TGF-β1) regulates FMOD expression through epigenetic remodeling of FMOD promoter that involved demethylation and gain of active histone marks with a simultaneous loss of DNMT3A and EZH2 occupancy, but enrichment of Sma- and Mad-related protein-2 (SMAD2) and CBP. FMOD silencing inhibited the TGF-β1-mediated glioma cell migration significantly. In univariate and multivariate Cox regression analysis, both FMOD promoter methylation and transcript levels predicted prognosis in GBM. Thus, this study identified several epigenetically regulated alterations responsible for cancer development and progression. Specifically, we found that secreted FMOD as an important regulator of glioma cell migration downstream of TGF-β1 pathway and forms a potential basis for therapeutic intervention in GBM.
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| 23. |
- Somasundaram, Samuel D., et al.
(författare)
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Enhancing Signals
- 2008
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Patent (populärvet., debatt m.m.)abstract
- A method of testing a sample comprising the steps of: applying an excitation to the sample; detecting a response signal from the sample; processing a first part and a second part of the response signal; and determining from the second part of the response signal information with which to enhance the first part of the response signal.
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| 24. |
- Somasundaram, Samuel D., et al.
(författare)
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Enhancing Signals
- 2008
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Patent (populärvet., debatt m.m.)
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| 25. |
- Somasundaram, Samuel D., et al.
(författare)
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Robust Detection of Stochastic Nuclear Quadrupole Resonance Signals
- 2008
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Ingår i: IEEE Transactions on Signal Processing. - 1053-587X. ; 56:9, s. 4221-4229
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear quadrupole resonance (NQR) is a solid-state radio frequency (RF) spectroscopic technique, allowing the detection of compounds containing quadrupolar nuclei, a requirement fulfilled by many high explosives and narcotics. The practical use of NQR is restricted by the inherently low signal-to-noise ratio (SNR) of the observed signals, a problem that is further exacerbated by the presence of strong RF interference (RFI). The current literature focuses on the use of conventional, multiple-pulsed NQR (cNQR) to obtain signals. Here, we investigate an alternative method called stochastic NQR (sNQR), having many advantages over cNQR, one of which is the availability of signal-of-interest free samples. In this paper, we exploit these samples forming a matched subspace-type detector and a detector employing a prewhitening approach,, both of which are able to efficiently reduce the influence of RFI. Further, man), of the ideas already developed for cNQR, including providing robustness to uncertainties in the assumed complex amplitudes and exploiting the temperature dependencies of the NQR spectral components, are recast for sNQR. The presented detectors are evaluated on both simulated and measured trinitrotoluene (TNT) data.
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