54 research outputs found
Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal
Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.Determination of the biological consequences of ultradian cortisol pulsatility.A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function
Quarkonium production in high energy proton-proton and proton-nucleus collisions
We present a brief overview of the most relevant current issues related to
quarkonium production in high energy proton-proton and proton-nucleus
collisions along with some perspectives. After reviewing recent experimental
and theoretical results on quarkonium production in pp and pA collisions, we
discuss the emerging field of polarisation studies. Thereafter, we report on
issues related to heavy-quark production, both in pp and pA collisions,
complemented by AA collisions. To put the work in a broader perspective, we
emphasize the need for new observables to investigate quarkonium production
mechanisms and reiterate the qualities that make quarkonia a unique tool for
many investigations in particle and nuclear physics.Comment: Overview for the proceedings of QUARKONIUM 2010: Three Days Of
Quarkonium Production in pp and pA Collisions, 29-31 July 2010, Palaiseau,
France; 34 pages, 30 figures, Late
Sustained Oscillations of NF-ΞΊB Produce Distinct Genome Scanning and Gene Expression Profiles
NF-ΞΊB is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-ΞΊB in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-ΞΊB activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NF-ΞΊB were sustained in most cells, with several cycles of transient nuclear translocation after TNF-Ξ± stimulation. Mathematical modeling suggests that NF-ΞΊB oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like IΞΊBΞ±. The ability of NF-ΞΊB to scan and interact with the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-ΞΊB oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-ΞΊB in the nucleus, and these oscillations are functionally advantageous
Measurement of the photon-jet production differential cross section in collisions at \sqrt{s}=1.96~\TeV
We present measurements of the differential cross section dsigma/dpT_gamma
for the inclusive production of a photon in association with a b-quark jet for
photons with rapidities |y_gamma|< 1.0 and 30<pT_gamma <300 GeV, as well as for
photons with 1.5<|y_gamma|< 2.5 and 30< pT_gamma <200 GeV, where pT_gamma is
the photon transverse momentum. The b-quark jets are required to have pT>15 GeV
and rapidity |y_jet| < 1.5. The results are based on data corresponding to an
integrated luminosity of 8.7 fb^-1, recorded with the D0 detector at the
Fermilab Tevatron Collider at sqrt(s)=1.96 TeV. The measured cross
sections are compared with next-to-leading order perturbative QCD calculations
using different sets of parton distribution functions as well as to predictions
based on the kT-factorization QCD approach, and those from the Sherpa and
Pythia Monte Carlo event generators.Comment: 10 pages, 9 figures, submitted to Phys. Lett.
Cell Cycle Phase Regulates Glucocorticoid Receptor Function
The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G1. This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase
Biological Process Linkage Networks
BACKGROUND. The traditional approach to studying complex biological networks is based on the identification of interactions between internal components of signaling or metabolic pathways. By comparison, little is known about interactions between higher order biological systems, such as biological pathways and processes. We propose a methodology for gleaning patterns of interactions between biological processes by analyzing protein-protein interactions, transcriptional co-expression and genetic interactions. At the heart of the methodology are the concept of Linked Processes and the resultant network of biological processes, the Process Linkage Network (PLN). RESULTS. We construct, catalogue, and analyze different types of PLNs derived from different data sources and different species. When applied to the Gene Ontology, many of the resulting links connect processes that are distant from each other in the hierarchy, even though the connection makes eminent sense biologically. Some others, however, carry an element of surprise and may reflect mechanisms that are unique to the organism under investigation. In this aspect our method complements the link structure between processes inherent in the Gene Ontology, which by its very nature is species-independent. As a practical application of the linkage of processes we demonstrate that it can be effectively used in protein function prediction, having the power to increase both the coverage and the accuracy of predictions, when carefully integrated into prediction methods. CONCLUSIONS. Our approach constitutes a promising new direction towards understanding the higher levels of organization of the cell as a system which should help current efforts to re-engineer ontologies and improve our ability to predict which proteins are involved in specific biological processes.Lynn and William Frankel Center for Computer Science; the Paul Ivanier center for robotics research and production; National Science Foundation (ITR-048715); National Human Genome Research Institute (1R33HG002850-01A1, R01 HG003367-01A1); National Institute of Health (U54 LM008748
In Vivo Monitoring of mRNA Movement in Drosophila Body Wall Muscle Cells Reveals the Presence of Myofiber Domains
Background: In skeletal muscle each muscle cell, commonly called myofiber, is actually a large syncytium containing numerous nuclei. Experiments in fixed myofibers show that mRNAs remain localized around the nuclei in which they are produced. Methodology/Principal Findings: In this study we generated transgenic flies that allowed us to investigate the movement of mRNAs in body wall myofibers of living Drosophila embryos. We determined the dynamic properties of GFP-tagged mRNAs using in vivo confocal imaging and photobleaching techniques and found that the GFP-tagged mRNAs are not free to move throughout myofibers. The restricted movement indicated that body wall myofibers consist of three domains. The exchange of mRNAs between the domains is relatively slow, but the GFP-tagged mRNAs move rapidly within these domains. One domain is located at the centre of the cell and is surrounded by nuclei while the other two domains are located at either end of the fiber. To move between these domains mRNAs have to travel past centrally located nuclei. Conclusions/Significance: These data suggest that the domains made visible in our experiments result from prolonged interactions with as yet undefined structures close to the nuclei that prevent GFP-tagged mRNAs from rapidly moving between the domains. This could be of significant importance for the treatment of myopathies using regenerative cellbase
Effective field theory approach to open heavy flavor production in heavy-ion collisions
Dynamics of nuclear receptor target gene regulation
Ligand-regulated nuclear receptors, such as estrogen receptors, glucocorticoid receptor, vitamin D receptor, and peroxisome proliferator-activated receptors, belong to the most widely studied and best understood transcription factors. Therefore, the dynamic nature of transcriptional regulation was observed first with different members of the nuclear receptor superfamily, but is now also extended to other transcription factors, such as nuclear factor ΞΊB. Dynamic and in part cyclical processes were observed on the level of translocation into the nucleus, association with genomic binding sites, exchange of co-regulators and chromatin modifiers, occurrence of chromatin marks, and activities of RNA polymerase II resulting in mRNA synthesis. In this review, we summarize recent findings on the dynamic regulation of nuclear receptor target genes in the chromatin context
A Protein Inventory of Human Ribosome Biogenesis Reveals an Essential Function of Exportin 5 in 60S Subunit Export
A systematic search for human ribosome biogenesis factors shows conservation of many aspects of eukaryotic ribosome synthesis with the well-studied process in yeast and identifies an export route of 60S subunits that is specific for higher eukaryotes
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