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A quantitative analysis of the interplay of environment,neighborhood, and cell state in 3D spheroids
Vito RT Zanotelli Matthias Leutenegger XiaoKang Lun Fanny Georgi Natalie de Souza Bernd Bodenmiller 《Molecular systems biology》2020,16(12)
Cells react to their microenvironment by integrating external stimuli into phenotypic decisions via an intracellular signaling network. To analyze the interplay of environment, local neighborhood, and internal cell state effects on phenotypic variability, we developed an experimental approach that enables multiplexed mass cytometric imaging analysis of up to 240 pooled spheroid microtissues. We quantified the contributions of environment, neighborhood, and intracellular state to marker variability in single cells of the spheroids. A linear model explained on average more than half of the variability of 34 markers across four cell lines and six growth conditions. The contributions of cell‐intrinsic and environmental factors to marker variability are hierarchically interdependent, a finding that we propose has general implications for systems‐level studies of single‐cell phenotypic variability. By the overexpression of 51 signaling protein constructs in subsets of cells, we also identified proteins that have cell‐intrinsic and cell‐extrinsic effects. Our study deconvolves factors influencing cellular phenotype in a 3D tissue and provides a scalable experimental system, analytical principles, and rich multiplexed imaging datasets for future studies. 相似文献
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Phosphorylation of the GABAa /Benzodiazepine Receptor α Subunit by a Receptor-Associated Protein Kinase 总被引:3,自引:3,他引:0
Paul M. Sweetnam Jack Lloyd Peter Gallombardo Robert T. Malison Dorothy W. Gallager John F. Tallman Eric J. Nestler 《Journal of neurochemistry》1988,51(4):1274-1284
Abstract: Partially purified preparations of GABAa/benzodiazepine receptor from rat brain were found to contain high levels of a protein kinase activity that phosphorylated a small number of proteins in the receptor preparations, including a 50-kilodalton (kD) phosphoprotein that comigrated on two-dimensional electrophoresis with purified, immunolabeled, and photolabeled receptor α subunit. Further evidence that the comigrating 50-kD phosphoprotein was, in fact, the receptor α subunit was obtained by peptide mapping analysis: the 50-kD phosphoprotein yielded one-dimensional peptide maps identical to those obtained from iodinated, purified α subunit. Phosphoamino acid analysis revealed that the receptor α subunit is phosphorylated on serine residues by the protein kinase activity present in receptor preparations. Preliminary characterization of the receptor-associated protein kinase activity suggested that it may be a second messenger-independent protein kinase. Protein kinase activity was unaltered by cyclic AMP, cyclic GMP, calcium plus calmodulin, calcium plus phosphatidylserine, and various inhibitors of these protein kinases. Examination of the substrate specificity of the receptor-associated protein kinase indicated that the enzyme preferred basic proteins as substrates. Endogenous phosphorylation experiments indicated that the receptor α subunit may also be phosphorylated in crude membranes by a protein kinase activity present in those membranes. As with phosphorylation of the receptor in purified preparations, its phosphorylation in crude membranes also appeared to be unaffected by activators and inhibitors of second messenger-dependent protein kinases. These findings raise the possibility that the phosphorylation of the α subunit of the GABAa/ benzodiazepine receptor by a receptor-associated protein kinase plays a role in modulating the physiological activity of the receptor in vivo. 相似文献
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Total cortisol, free cortisol and percent free cortisol were all significantly higher in semelparous male chinook salmon Oncorhynchus tshawytscha than in iteroparous and immature fish. The findings suggest that the regulation of both total and free cortisol concentrations may play key roles in mediating the post-spawning death of semelparous Pacific salmon. 相似文献
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Ittiwut C Listman J Mutirangura A Malison R Covault J Kranzler HR Sughondhabirom A Thavichachart N Gelernter J 《Genomics》2008,91(1):61-69
GABRA2 and GABRG1, which encode the alpha-2 and gamma-1 subunits, respectively, of the GABA(A) receptor, are located in a cluster on chromosome 4p. The GABRA2 locus has been found to be associated with alcohol dependence in several studies, but no functional variant that can account for this association has been identified. To understand the reported associations, we sought to understand the linkage disequilibrium (LD) patterns and haplotype structures of these genes. With close intergenic distance, approximately 90 kb, it was anticipated that some markers might show intergenic LD. Variation in 13-SNP haplotype block structure was observed in five different populations: European American, African American, Chinese (Han and Thai), Thai, and Hmong. In the Hmong, a 280-kb region of considerably higher LD spans the intergenic region, whereas in other populations, there were two or more LD blocks that cross this region. These findings may aid in understanding the genetic association of this locus with alcohol dependence in several populations. 相似文献
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Rachel L. Malison Mark S. Lorang Diane C. Whited Jack A. Stanford 《Freshwater Biology》2014,59(6):1229-1246
Our aim was to determine how beavers affect habitats and food resources for juvenile salmon in the Kwethluk River in western Alaska.
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Tobamoviruses, mostly isolated from solanaceous plants, may represent
ancient virus lineages that have codiverged with their hosts. Recently
completed nucleotide sequences of six nonsolanaceous tobamoviruses allowed
assessment of the codivergence hypothesis and support a third subgroup
within tobamoviruses. The genomic sequences of 12 tobamoviruses and the
partial sequences of 11 others have been analyzed. Comparisons of the
predicted protein sequences revealed three clusters of tobamoviruses,
corresponding to those infecting solanaceous species (subgroup 1), those
infecting cucurbits and legumes (subgroup 2), and those infecting
crucifers. The orchid-infecting odontoglossum ringspot tobamovirus was
associated with subgroup 1 genomes by its coat and movement protein
sequences, but with the crucifer-pathogenic tobamoviruses by the remainder
of its genome, suggesting that it is the progeny of a recombinant. For four
of five genomic regions, subgroup 1 and 3 genomes were equidistant from a
subgroup 2 genome chosen for comparison, suggesting uniform rates of
evolution. A phylogenetic tree of plant families based on the tobamoviruses
they harbor was congruent with that based on rubisco sequences but had a
different root, suggesting that codivergence was tempered by rare events of
viruses of one family colonizing another family. The proposed subgroup 3
viruses probably have an origin of virion assembly in the movement protein
gene, a large (25-codon) overlap of movement and coat protein open reading
frames, and a comparably shorter genome. Codon-position- dependent base
compositions and codon prevalences suggested that the coat protein frame of
the overlap region was ancestral. Bootstrapped parsimony analysis of the
nucleotides in the overlap region and of the sequences translated from the
-1 frame (the subgroup 3 movement protein frame) of this region produced
trees inconsistent with those deduced from other regions. The results are
consistent with a model in which a no or short overlap organization was
ancestral. Despite encoding of subgroup 2 and 3 movement protein C-termini
by nonhomologous nucleotides, weak similarities between their amino acid
sequences suggested convergent sequence evolution.
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