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Sample records for blood transcriptional network

  1. Characterization of transcription factor networks involved in umbilical cord blood CD34+ stem cells-derived erythropoiesis.

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    Biaoru Li

    Full Text Available Fetal stem cells isolated from umbilical cord blood (UCB possess a great capacity for proliferation and differentiation and serve as a valuable model system to study gene regulation. Expanded knowledge of the molecular control of hemoglobin synthesis will provide a basis for rational design of therapies for β-hemoglobinopathies. Transcriptome data are available for erythroid progenitors derived from adult stem cells, however studies to define molecular mechanisms controlling globin gene regulation during fetal erythropoiesis are limited. Here, we utilize UCB-CD34+ stem cells induced to undergo erythroid differentiation to characterize the transcriptome and transcription factor networks (TFNs associated with the γ/β-globin switch during fetal erythropoiesis. UCB-CD34+ stem cells grown in the one-phase liquid culture system displayed a higher proliferative capacity than adult CD34+ stem cells. The γ/β-globin switch was observed after day 42 during fetal erythropoiesis in contrast to adult progenitors where the switch occurred around day 21. To gain insights into transcription factors involved in globin gene regulation, microarray analysis was performed on RNA isolated from UCB-CD34+ cell-derived erythroid progenitors harvested on day 21, 42, 49 and 56 using the HumanHT-12 Expression BeadChip. After data normalization, Gene Set Enrichment Analysis identified transcription factors (TFs with significant changes in expression during the γ/β-globin switch. Forty-five TFs were silenced by day 56 (Profile-1 and 30 TFs were activated by day 56 (Profile-2. Both GSEA datasets were analyzed using the MIMI Cytoscape platform, which discovered TFNs centered on KLF4 and GATA2 (Profile-1 and KLF1 and GATA1 for Profile-2 genes. Subsequent shRNA studies in KU812 leukemia cells and human erythroid progenitors generated from UCB-CD34+ cells supported a negative role of MAFB in γ-globin regulation. The characteristics of erythroblasts derived from UCB-CD34

  2. A module of human peripheral blood mononuclear cell transcriptional network containing primitive and differentiation markers is related to specific cardiovascular health variables.

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    Leni Moldovan

    Full Text Available Peripheral blood mononuclear cells (PBMCs, including rare circulating stem and progenitor cells (CSPCs, have important yet poorly understood roles in the maintenance and repair of blood vessels and perfused organs. Our hypothesis was that the identities and functions of CSPCs in cardiovascular health could be ascertained by analyzing the patterns of their co-expressed markers in unselected PBMC samples. Because gene microarrays had failed to detect many stem cell-associated genes, we performed quantitative real-time PCR to measure the expression of 45 primitive and tissue differentiation markers in PBMCs from healthy and hypertensive human subjects. We compared these expression levels to the subjects' demographic and cardiovascular risk factors, including vascular stiffness. The tested marker genes were expressed in all of samples and organized in hierarchical transcriptional network modules, constructed by a bottom-up approach. An index of gene expression in one of these modules (metagene, defined as the average standardized relative copy numbers of 15 pluripotency and cardiovascular differentiation markers, was negatively correlated (all p<0.03 with age (R2 = -0.23, vascular stiffness (R2 = -0.24, and central aortic pressure (R2 = -0.19 and positively correlated with body mass index (R2 = 0.72, in women. The co-expression of three neovascular markers was validated at the single-cell level using mRNA in situ hybridization and immunocytochemistry. The overall gene expression in this cardiovascular module was reduced by 72±22% in the patients compared with controls. However, the compactness of both modules was increased in the patients' samples, which was reflected in reduced dispersion of their nodes' degrees of connectivity, suggesting a more primitive character of the patients' CSPCs. In conclusion, our results show that the relationship between CSPCs and vascular function is encoded in modules of the PBMCs transcriptional

  3. Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure.

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    Ahmari, Niousha; Schmidt, Jordan T; Krane, Gregory A; Malphurs, Wendi; Cunningham, Bruce E; Owen, Jennifer L; Martyniuk, Christopher J; Zubcevic, Jasenka

    2016-07-01

    Hypertension (HTN) is a prevalent condition with complex etiology and pathophysiology. Evidence exists of significant communication between the nervous system and the immune system (IS), and there appears to be a direct role for inflammatory bone marrow (BM) cells in the pathophysiology of hypertension. However, the molecular and neural mechanisms underlying this interaction have not been characterized. Here, we transplanted whole BM cells from the beta 1 and 2 adrenergic receptor (AdrB1(tm1Bkk)AdrB2(tm1Bkk)/J) knockout (KO) mice into near lethally irradiated C57BL/6J mice to generate a BM AdrB1.B2 KO chimera. This allowed us to evaluate the role of the BM beta 1 and beta 2 adrenergic receptors in mediating BM IS homeostasis and regulating blood pressure (BP) in an otherwise intact physiological setting. Fluorescence-activated cell sorting demonstrated that a decrease in systolic and mean BP in the AdrB1.B2 KO chimera is associated with a decrease in circulating inflammatory T cells, macrophage/monocytes, and neutrophils. Transcriptomics in the BM identified 7,419 differentially expressed transcripts between the C57 and AdrB1.B2 KO chimera. Pathway analysis revealed differentially expressed transcripts related to several cell processes in the BM of C57 compared with AdrB1.B2 KO chimera, including processes related to immunity (e.g., T-cell activation, T-cell recruitment, cytokine production, leukocyte migration and function), the cardiovascular system (e.g., blood vessel development, peripheral nerve blood flow), and the brain (e.g., central nervous system development, neurite development) among others. This study generates new insight into the molecular events that underlie the interaction between the sympathetic drive and IS in modulation of BP. PMID:27235450

  4. Transcription regulatory networks analysis using CAGE

    KAUST Repository

    Tegnér, Jesper N.

    2009-10-01

    Mapping out cellular networks in general and transcriptional networks in particular has proved to be a bottle-neck hampering our understanding of biological processes. Integrative approaches fusing computational and experimental technologies for decoding transcriptional networks at a high level of resolution is therefore of uttermost importance. Yet, this is challenging since the control of gene expression in eukaryotes is a complex multi-level process influenced by several epigenetic factors and the fine interplay between regulatory proteins and the promoter structure governing the combinatorial regulation of gene expression. In this chapter we review how the CAGE data can be integrated with other measurements such as expression, physical interactions and computational prediction of regulatory motifs, which together can provide a genome-wide picture of eukaryotic transcriptional regulatory networks at a new level of resolution. © 2010 by Pan Stanford Publishing Pte. Ltd. All rights reserved.

  5. Dynamics of transcription-translation networks

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    Hudson, D.; Edwards, R.

    2016-09-01

    A theory for qualitative models of gene regulatory networks has been developed over several decades, generally considering transcription factors to regulate directly the expression of other transcription factors, without any intermediate variables. Here we explore a class of models that explicitly includes both transcription and translation, keeping track of both mRNA and protein concentrations. We mainly deal with transcription regulation functions that are steep sigmoids or step functions, as is often done in protein-only models, though translation is governed by a linear term. We extend many aspects of the protein-only theory to this new context, including properties of fixed points, description of trajectories by mappings between switching points, qualitative analysis via a state-transition diagram, and a result on periodic orbits for negative feedback loops. We find that while singular behaviour in switching domains is largely avoided, non-uniqueness of solutions can still occur in the step-function limit.

  6. Studying Dynamic Features in Myocardial Infarction Progression by Integrating miRNA-Transcription Factor Co-Regulatory Networks and Time-Series RNA Expression Data from Peripheral Blood Mononuclear Cells.

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    Hongbo Shi

    Full Text Available Myocardial infarction (MI is a serious heart disease and a leading cause of mortality and morbidity worldwide. Although some molecules (genes, miRNAs and transcription factors (TFs associated with MI have been studied in a specific pathological context, their dynamic characteristics in gene expressions, biological functions and regulatory interactions in MI progression have not been fully elucidated to date. In the current study, we analyzed time-series RNA expression data from peripheral blood mononuclear cells. We observed that significantly differentially expressed genes were sharply up- or down-regulated in the acute phase of MI, and then changed slowly until the chronic phase. Biological functions involved at each stage of MI were identified. Additionally, dynamic miRNA-TF co-regulatory networks were constructed based on the significantly differentially expressed genes and miRNA-TF co-regulatory motifs, and the dynamic interplay of miRNAs, TFs and target genes were investigated. Finally, a new panel of candidate diagnostic biomarkers (STAT3 and ICAM1 was identified to have discriminatory capability for patients with or without MI, especially the patients with or without recurrent events. The results of the present study not only shed new light on the understanding underlying regulatory mechanisms involved in MI progression, but also contribute to the discovery of true diagnostic biomarkers for MI.

  7. Controllability analysis of transcriptional regulatory networks reveals circular control patterns among transcription factors

    DEFF Research Database (Denmark)

    Österlund, Tobias; Bordel, Sergio; Nielsen, Jens

    2015-01-01

    Transcriptional regulation is the most committed type of regulation in living cells where transcription factors (TFs) control the expression of their target genes and TF expression is controlled by other TFs forming complex transcriptional regulatory networks that can be highly interconnected. Here...... we analyze the topology and organization of nine transcriptional regulatory networks for E. coli, yeast, mouse and human, and we evaluate how the structure of these networks influences two of their key properties, namely controllability and stability. We calculate the controllability for each network...... as a measure of the organization and interconnectivity of the network. We find that the number of driver nodes n(D) needed to control the whole network is 64% of the TFs in the E. coli transcriptional regulatory network in contrast to only 17% for the yeast network, 4% for the mouse network and 8...

  8. Systematic genetic analysis of transcription factors to map the fission yeast transcription-regulatory network.

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    Chua, Gordon

    2013-12-01

    Mapping transcriptional-regulatory networks requires the identification of target genes, binding specificities and signalling pathways of transcription factors. However, the characterization of each transcription factor sufficiently for deciphering such networks remains laborious. The recent availability of overexpression and deletion strains for almost all of the transcription factor genes in the fission yeast Schizosaccharomyces pombe provides a valuable resource to better investigate transcription factors using systematic genetics. In the present paper, I review and discuss the utility of these strain collections combined with transcriptome profiling and genome-wide chromatin immunoprecipitation to identify the target genes of transcription factors.

  9. Power graph compression reveals dominant relationships in genetic transcription networks.

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    Ahnert, Sebastian E

    2013-11-01

    We introduce a framework for the discovery of dominant relationship patterns in transcription networks, by compressing the network into a power graph with overlapping power nodes. Our application of this approach to the transcription networks of S. cerevisiae and E. coli, paired with GO term enrichment analysis, provides a highly informative overview of the most prominent relationships in the gene regulatory networks of these two organisms.

  10. Transcriptional networks and chromatin remodeling controlling adipogenesis

    DEFF Research Database (Denmark)

    Siersbæk, Rasmus; Nielsen, Ronni; Mandrup, Susanne

    2012-01-01

    Adipocyte differentiation is tightly controlled by a transcriptional cascade, which directs the extensive reprogramming of gene expression required to convert fibroblast-like precursor cells into mature lipid-laden adipocytes. Recent global analyses of transcription factor binding and chromatin...... remodeling have revealed 'snapshots' of this cascade and the chromatin landscape at specific time-points of differentiation. These studies demonstrate that multiple adipogenic transcription factors co-occupy hotspots characterized by an open chromatin structure and specific epigenetic modifications....... Such transcription factor hotspots are likely to represent key signaling nodes which integrate multiple adipogenic signals at specific chromatin sites, thereby facilitating coordinated action on gene expression....

  11. Transcriptional Network growing Models using Motif-based Preferential Attachment

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    Ahmed Farouk Abdelzaher

    2015-10-01

    Full Text Available Understanding relationships between architectural properties of gene-regulatory networks (GRNs has been one of the major goals in systems biology and bioinformatics, as it can provide insights into, e.g., disease dynamics and drug development. Such GRNs are characterized by their scale-free degree distributions and existence of network motifs--i.e., small-node subgraphs that occur more abundantly in GRNs than expected from chance alone. Because these transcriptional modules represent ``building blocks'' of complex networks and exhibit a wide range of functional and dynamical properties, they may contribute to the remarkable robustness and dynamical stability associated with the whole of GRNs. Here we developed network-construction models to better understand this relationship, which produce randomized GRNs by using transcriptional motifs as the fundamental growth unit in contrast to other methods that construct similar networks on a node-by-node basis. Because this model produces networks with a prescribed lower bound on the number of choice transcriptional motifs (e.g., downlinks, feed-forward loops, its fidelity to the motif distributions observed in model organisms represents an improvement over existing methods, which we validated by contrasting their resultant motif and degree distributions against existing network-growth models and data from the model organism of the bacterium Escherichia coli. These models may therefore serve as novel testbeds for further elucidating relationships between the topology of transcriptional motifs and network-wide dynamical properties.

  12. Elucidating MicroRNA Regulatory Networks Using Transcriptional, Post-transcriptional, and Histone Modification Measurements

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    Sara J.C. Gosline

    2016-01-01

    Full Text Available MicroRNAs (miRNAs regulate diverse biological processes by repressing mRNAs, but their modest effects on direct targets, together with their participation in larger regulatory networks, make it challenging to delineate miRNA-mediated effects. Here, we describe an approach to characterizing miRNA-regulatory networks by systematically profiling transcriptional, post-transcriptional and epigenetic activity in a pair of isogenic murine fibroblast cell lines with and without Dicer expression. By RNA sequencing (RNA-seq and CLIP (crosslinking followed by immunoprecipitation sequencing (CLIP-seq, we found that most of the changes induced by global miRNA loss occur at the level of transcription. We then introduced a network modeling approach that integrated these data with epigenetic data to identify specific miRNA-regulated transcription factors that explain the impact of miRNA perturbation on gene expression. In total, we demonstrate that combining multiple genome-wide datasets spanning diverse regulatory modes enables accurate delineation of the downstream miRNA-regulated transcriptional network and establishes a model for studying similar networks in other systems.

  13. Characterizing disease states from topological properties of transcriptional regulatory networks

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    Kluger Harriet M

    2006-05-01

    Full Text Available Abstract Background High throughput gene expression experiments yield large amounts of data that can augment our understanding of disease processes, in addition to classifying samples. Here we present new paradigms of data Separation based on construction of transcriptional regulatory networks for normal and abnormal cells using sequence predictions, literature based data and gene expression studies. We analyzed expression datasets from a number of diseased and normal cells, including different types of acute leukemia, and breast cancer with variable clinical outcome. Results We constructed sample-specific regulatory networks to identify links between transcription factors (TFs and regulated genes that differentiate between healthy and diseased states. This approach carries the advantage of identifying key transcription factor-gene pairs with differential activity between healthy and diseased states rather than merely using gene expression profiles, thus alluding to processes that may be involved in gene deregulation. We then generalized this approach by studying simultaneous changes in functionality of multiple regulatory links pointing to a regulated gene or emanating from one TF (or changes in gene centrality defined by its in-degree or out-degree measures, respectively. We found that samples can often be separated based on these measures of gene centrality more robustly than using individual links. We examined distributions of distances (the number of links needed to traverse the path between each pair of genes in the transcriptional networks for gene subsets whose collective expression profiles could best separate each dataset into predefined groups. We found that genes that optimally classify samples are concentrated in neighborhoods in the gene regulatory networks. This suggests that genes that are deregulated in diseased states exhibit a remarkable degree of connectivity. Conclusion Transcription factor-regulated gene links and

  14. Global Analysis of Photosynthesis Transcriptional Regulatory Networks

    OpenAIRE

    Imam, Saheed; Noguera, Daniel R.; Donohue, Timothy J.

    2014-01-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen met...

  15. Global analysis of photosynthesis transcriptional regulatory networks.

    OpenAIRE

    Saheed Imam; Noguera, Daniel R.; Donohue, Timothy J.

    2014-01-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen met...

  16. Global analysis of photosynthesis transcriptional regulatory networks.

    Science.gov (United States)

    Imam, Saheed; Noguera, Daniel R; Donohue, Timothy J

    2014-12-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis.

  17. Global analysis of photosynthesis transcriptional regulatory networks.

    Science.gov (United States)

    Imam, Saheed; Noguera, Daniel R; Donohue, Timothy J

    2014-12-01

    Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis. PMID:25503406

  18. Global analysis of photosynthesis transcriptional regulatory networks.

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    Saheed Imam

    2014-12-01

    Full Text Available Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888, which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ∼34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a ΔFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis.

  19. Transcriptional networks implicated in human nonalcoholic fatty liver disease.

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    Ye, Hua; Liu, Wei

    2015-10-01

    The transcriptome of nonalcoholic fatty liver disease (NAFLD) was investigated in several studies. However, the implications of transcriptional networks in progressive NAFLD are not clear and mechanisms inducing transition from nonalcoholic simple fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are still elusive. The aims of this study were to (1) construct networks for progressive NAFLD, (2) identify hub genes and functional modules in these networks and (3) infer potential linkages among hub genes, transcription factors and microRNAs (miRNA) for NAFLD progression. A systems biology approach by combining differential expression analysis and weighted gene co-expression network analysis (WGCNA) was utilized to dissect transcriptional profiles in 19 normal, 10 NAFL and 16 NASH patients. Based on this framework, 3 modules related to chromosome organization, proteasomal ubiquitin-dependent protein degradation and immune response were identified in NASH network. Furthermore, 9 modules of co-expressed genes associated with NAFL/NASH transition were found. Further characterization of these modules defined 13 highly connected hub genes in NAFLD progression network. Interestingly, 11 significantly changed miRNAs were predicted to target 10 of the 13 hub genes. Characterization of modules and hub genes that may be regulated by miRNAs could facilitate the identification of candidate genes and pathways responsible for NAFL/NASH transition and lead to a better understanding of NAFLD pathogenesis. The identified modules and hub genes may point to potential targets for therapeutic interventions. PMID:25851235

  20. Transcriptional network of p63 in human keratinocytes.

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    Silvia Pozzi

    Full Text Available p63 is a transcription factor required for the development and maintenance of ectodermal tissues in general, and skin keratinocytes in particular. The identification of its target genes is fundamental for understanding the complex network of gene regulation governing the development of epithelia. We report a list of almost 1000 targets derived from ChIP on chip analysis on two platforms; all genes analyzed changed in expression during differentiation of human keratinocytes. Functional annotation highlighted unexpected GO terms enrichments and confirmed that genes involved in transcriptional regulation are the most significant. A detailed analysis of these transcriptional regulators in condition of perturbed p63 levels confirmed the role of p63 in the regulatory network. Rather than a rigid master-slave hierarchical model, our data indicate that p63 connects different hubs involved in the multiple specific functions of the skin.

  1. Iterative reconstruction of transcriptional regulatory networks: an algorithmic approach.

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    Christian L Barrett

    2006-05-01

    Full Text Available The number of complete, publicly available genome sequences is now greater than 200, and this number is expected to rapidly grow in the near future as metagenomic and environmental sequencing efforts escalate and the cost of sequencing drops. In order to make use of this data for understanding particular organisms and for discerning general principles about how organisms function, it will be necessary to reconstruct their various biochemical reaction networks. Principal among these will be transcriptional regulatory networks. Given the physical and logical complexity of these networks, the various sources of (often noisy data that can be utilized for their elucidation, the monetary costs involved, and the huge number of potential experiments approximately 10(12 that can be performed, experiment design algorithms will be necessary for synthesizing the various computational and experimental data to maximize the efficiency of regulatory network reconstruction. This paper presents an algorithm for experimental design to systematically and efficiently reconstruct transcriptional regulatory networks. It is meant to be applied iteratively in conjunction with an experimental laboratory component. The algorithm is presented here in the context of reconstructing transcriptional regulation for metabolism in Escherichia coli, and, through a retrospective analysis with previously performed experiments, we show that the produced experiment designs conform to how a human would design experiments. The algorithm is able to utilize probability estimates based on a wide range of computational and experimental sources to suggest experiments with the highest potential of discovering the greatest amount of new regulatory knowledge.

  2. Transcriptional control in the segmentation gene network of Drosophila.

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    Mark D Schroeder

    2004-09-01

    Full Text Available The segmentation gene network of Drosophila consists of maternal and zygotic factors that generate, by transcriptional (cross- regulation, expression patterns of increasing complexity along the anterior-posterior axis of the embryo. Using known binding site information for maternal and zygotic gap transcription factors, the computer algorithm Ahab recovers known segmentation control elements (modules with excellent success and predicts many novel modules within the network and genome-wide. We show that novel module predictions are highly enriched in the network and typically clustered proximal to the promoter, not only upstream, but also in intronic space and downstream. When placed upstream of a reporter gene, they consistently drive patterned blastoderm expression, in most cases faithfully producing one or more pattern elements of the endogenous gene. Moreover, we demonstrate for the entire set of known and newly validated modules that Ahab's prediction of binding sites correlates well with the expression patterns produced by the modules, revealing basic rules governing their composition. Specifically, we show that maternal factors consistently act as activators and that gap factors act as repressors, except for the bimodal factor Hunchback. Our data suggest a simple context-dependent rule for its switch from repressive to activating function. Overall, the composition of modules appears well fitted to the spatiotemporal distribution of their positive and negative input factors. Finally, by comparing Ahab predictions with different categories of transcription factor input, we confirm the global regulatory structure of the segmentation gene network, but find odd skipped behaving like a primary pair-rule gene. The study expands our knowledge of the segmentation gene network by increasing the number of experimentally tested modules by 50%. For the first time, the entire set of validated modules is analyzed for binding site composition under a

  3. Resetting the transcription factor network reverses terminal chronic hepatic failure.

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    Nishikawa, Taichiro; Bell, Aaron; Brooks, Jenna M; Setoyama, Kentaro; Melis, Marta; Han, Bing; Fukumitsu, Ken; Handa, Kan; Tian, Jianmin; Kaestner, Klaus H; Vodovotz, Yoram; Locker, Joseph; Soto-Gutierrez, Alejandro; Fox, Ira J

    2015-04-01

    The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement.

  4. Metabolic constraint-based refinement of transcriptional regulatory networks.

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    Chandrasekaran, Sriram; Price, Nathan D

    2013-01-01

    There is a strong need for computational frameworks that integrate different biological processes and data-types to unravel cellular regulation. Current efforts to reconstruct transcriptional regulatory networks (TRNs) focus primarily on proximal data such as gene co-expression and transcription factor (TF) binding. While such approaches enable rapid reconstruction of TRNs, the overwhelming combinatorics of possible networks limits identification of mechanistic regulatory interactions. Utilizing growth phenotypes and systems-level constraints to inform regulatory network reconstruction is an unmet challenge. We present our approach Gene Expression and Metabolism Integrated for Network Inference (GEMINI) that links a compendium of candidate regulatory interactions with the metabolic network to predict their systems-level effect on growth phenotypes. We then compare predictions with experimental phenotype data to select phenotype-consistent regulatory interactions. GEMINI makes use of the observation that only a small fraction of regulatory network states are compatible with a viable metabolic network, and outputs a regulatory network that is simultaneously consistent with the input genome-scale metabolic network model, gene expression data, and TF knockout phenotypes. GEMINI preferentially recalls gold-standard interactions (p-value = 10(-172)), significantly better than using gene expression alone. We applied GEMINI to create an integrated metabolic-regulatory network model for Saccharomyces cerevisiae involving 25,000 regulatory interactions controlling 1597 metabolic reactions. The model quantitatively predicts TF knockout phenotypes in new conditions (p-value = 10(-14)) and revealed potential condition-specific regulatory mechanisms. Our results suggest that a metabolic constraint-based approach can be successfully used to help reconstruct TRNs from high-throughput data, and highlights the potential of using a biochemically-detailed mechanistic framework to

  5. Transcriptional regulation of the carbohydrate utilization network in Thermotoga maritima

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    Dmitry A Rodionov

    2013-08-01

    Full Text Available Hyperthermophilic bacteria from the Thermotogales lineage can produce hydrogen by fermenting a wide range of carbohydrates. Previous experimental studies identified a large fraction of genes committed to carbohydrate degradation and utilization in the model bacterium Thermotoga maritima. Knowledge of these genes enabled comprehensive reconstruction of biochemical pathways comprising the carbohydrate utilization network. However, transcriptional factors (TFs and regulatory mechanisms driving this network remained largely unknown. Here, we used an integrated approach based on comparative analysis of genomic and transcriptomic data for the reconstruction of the carbohydrate utilization regulatory networks in 11 Thermotogales genomes. We identified DNA-binding motifs and regulons for 19 orthologous TFs in the Thermotogales. The inferred regulatory network in T. maritima contains 181 genes encoding TFs, sugar catabolic enzymes and ABC-family transporters. In contrast to many previously described bacteria, a transcriptional regulation strategy of Thermotoga does not employ global regulatory factors. The reconstructed regulatory network in T. maritima was validated by gene expression profiling on a panel of mono- and disaccharides and by in vitro DNA-binding assays. The observed upregulation of genes involved in catabolism of pectin, trehalose, cellobiose, arabinose, rhamnose, xylose, glucose, galactose, and ribose showed a strong correlation with the UxaR, TreR, BglR, CelR, AraR, RhaR, XylR, GluR, GalR, and RbsR regulons. Ultimately, this study elucidated the transcriptional regulatory network and mechanisms controlling expression of carbohydrate utilization genes in T. maritima. In addition to improving the functional annotations of associated transporters and catabolic enzymes, this research provides novel insights into the evolution of regulatory networks in Thermotogales.

  6. Transcriptional regulatory networks for CD4 T cell differentiation.

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    Christie, Darah; Zhu, Jinfang

    2014-01-01

    CD4(+) T cells play a central role in controlling the adaptive immune response by secreting cytokines to activate target cells. Naïve CD4(+) T cells differentiate into at least four subsets, Th1Th1 , Th2Th2 , Th17Th17 , and inducible regulatory T cellsregulatory T cells , each with unique functions for pathogen elimination. The differentiation of these subsets is induced in response to cytokine stimulation, which is translated into Stat activation, followed by induction of master regulator transcription factorstranscription factors . In addition to these factors, multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. This review will focus on the network of transcription factors that control CD4(+) T cell differentiation.

  7. Uncovering Transcriptional Regulatory Networks by Sparse Bayesian Factor Model

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    Meng, Jia; Zhang, Jianqiu(Michelle); Qi, Yuan(Alan); Chen, Yidong; Huang, Yufei

    2010-12-01

    The problem of uncovering transcriptional regulation by transcription factors (TFs) based on microarray data is considered. A novel Bayesian sparse correlated rectified factor model (BSCRFM) is proposed that models the unknown TF protein level activity, the correlated regulations between TFs, and the sparse nature of TF-regulated genes. The model admits prior knowledge from existing database regarding TF-regulated target genes based on a sparse prior and through a developed Gibbs sampling algorithm, a context-specific transcriptional regulatory network specific to the experimental condition of the microarray data can be obtained. The proposed model and the Gibbs sampling algorithm were evaluated on the simulated systems, and results demonstrated the validity and effectiveness of the proposed approach. The proposed model was then applied to the breast cancer microarray data of patients with Estrogen Receptor positive ([InlineEquation not available: see fulltext.]) status and Estrogen Receptor negative ([InlineEquation not available: see fulltext.]) status, respectively.

  8. Uncovering Transcriptional Regulatory Networks by Sparse Bayesian Factor Model

    Directory of Open Access Journals (Sweden)

    Qi Yuan(Alan

    2010-01-01

    Full Text Available Abstract The problem of uncovering transcriptional regulation by transcription factors (TFs based on microarray data is considered. A novel Bayesian sparse correlated rectified factor model (BSCRFM is proposed that models the unknown TF protein level activity, the correlated regulations between TFs, and the sparse nature of TF-regulated genes. The model admits prior knowledge from existing database regarding TF-regulated target genes based on a sparse prior and through a developed Gibbs sampling algorithm, a context-specific transcriptional regulatory network specific to the experimental condition of the microarray data can be obtained. The proposed model and the Gibbs sampling algorithm were evaluated on the simulated systems, and results demonstrated the validity and effectiveness of the proposed approach. The proposed model was then applied to the breast cancer microarray data of patients with Estrogen Receptor positive ( status and Estrogen Receptor negative ( status, respectively.

  9. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Sang-Min; An, Joo-Hee; Kim, Chul-Hong; Kim, Jung-Woong, E-mail: jungkim@cau.ac.kr; Choi, Kyung-Hee, E-mail: khchoi@cau.ac.kr

    2015-08-07

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer.

  10. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. - Highlights: • Identification of new target genes of FOXA2. • Identifications of novel interaction proteins of FOXA2. • Construction of FOXA2-centered transcriptional regulatory network in non-small cell lung cancer

  11. A systems approach to mapping transcriptional networks controlling surfactant homeostasis

    Directory of Open Access Journals (Sweden)

    Dave Vrushank

    2010-07-01

    Full Text Available Abstract Background Pulmonary surfactant is required for lung function at birth and throughout life. Lung lipid and surfactant homeostasis requires regulation among multi-tiered processes, coordinating the synthesis of surfactant proteins and lipids, their assembly, trafficking, and storage in type II cells of the lung. The mechanisms regulating these interrelated processes are largely unknown. Results We integrated mRNA microarray data with array independent knowledge using Gene Ontology (GO similarity analysis, promoter motif searching, protein interaction and literature mining to elucidate genetic networks regulating lipid related biological processes in lung. A Transcription factor (TF - target gene (TG similarity matrix was generated by integrating data from different analytic methods. A scoring function was built to rank the likely TF-TG pairs. Using this strategy, we identified and verified critical components of a transcriptional network directing lipogenesis, lipid trafficking and surfactant homeostasis in the mouse lung. Conclusions Within the transcriptional network, SREBP, CEBPA, FOXA2, ETSF, GATA6 and IRF1 were identified as regulatory hubs displaying high connectivity. SREBP, FOXA2 and CEBPA together form a common core regulatory module that controls surfactant lipid homeostasis. The core module cooperates with other factors to regulate lipid metabolism and transport, cell growth and development, cell death and cell mediated immune response. Coordinated interactions of the TFs influence surfactant homeostasis and regulate lung function at birth.

  12. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  13. Inferring the role of transcription factors in regulatory networks

    Directory of Open Access Journals (Sweden)

    Le Borgne Michel

    2008-05-01

    Full Text Available Abstract Background Expression profiles obtained from multiple perturbation experiments are increasingly used to reconstruct transcriptional regulatory networks, from well studied, simple organisms up to higher eukaryotes. Admittedly, a key ingredient in developing a reconstruction method is its ability to integrate heterogeneous sources of information, as well as to comply with practical observability issues: measurements can be scarce or noisy. In this work, we show how to combine a network of genetic regulations with a set of expression profiles, in order to infer the functional effect of the regulations, as inducer or repressor. Our approach is based on a consistency rule between a network and the signs of variation given by expression arrays. Results We evaluate our approach in several settings of increasing complexity. First, we generate artificial expression data on a transcriptional network of E. coli extracted from the literature (1529 nodes and 3802 edges, and we estimate that 30% of the regulations can be annotated with about 30 profiles. We additionally prove that at most 40.8% of the network can be inferred using our approach. Second, we use this network in order to validate the predictions obtained with a compendium of real expression profiles. We describe a filtering algorithm that generates particularly reliable predictions. Finally, we apply our inference approach to S. cerevisiae transcriptional network (2419 nodes and 4344 interactions, by combining ChIP-chip data and 15 expression profiles. We are able to detect and isolate inconsistencies between the expression profiles and a significant portion of the model (15% of all the interactions. In addition, we report predictions for 14.5% of all interactions. Conclusion Our approach does not require accurate expression levels nor times series. Nevertheless, we show on both data, real and artificial, that a relatively small number of perturbation experiments are enough to determine

  14. Identification of transcriptional regulatory networks specific to pilocytic astrocytoma

    Directory of Open Access Journals (Sweden)

    Gutmann David H

    2011-07-01

    Full Text Available Abstract Background Pilocytic Astrocytomas (PAs are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours. Methods RNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization. Results In this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, and identified 792 genes that demonstrated consistent differential expression between independent sets of PA and non-malignant specimens. From this entire 792 gene set, we used the previously described PAP tool to assemble a core transcriptional regulatory network composed of 6 transcription factor genes (TFs and 24 target genes, for a total of 55 interactions. A similar analysis of oligodendroglioma and glioblastoma multiforme (GBM gene expression data sets identified distinct, but overlapping, networks. Most importantly, comparison of each of the brain tumor type-specific networks revealed a network unique to PA that included repressed expression of ONECUT2, a gene frequently methylated in other tumor types, and 13 other uniquely predicted TF-gene interactions. Conclusions These results suggest specific transcriptional pathways that may operate to create the unique molecular phenotype of PA and thus opportunities for corresponding targeted therapeutic

  15. [Research on Zhejiang blood information network and management system].

    Science.gov (United States)

    Yan, Li-Xing; Xu, Yan; Meng, Zhong-Hua; Kong, Chang-Hong; Wang, Jian-Min; Jin, Zhen-Liang; Wu, Shi-Ding; Chen, Chang-Shui; Luo, Ling-Fei

    2007-02-01

    This research was aimed to develop the first level blood information centralized database and real time communication network at a province area in China. Multiple technology like local area network database separate operation, real time data concentration and distribution mechanism, allopatric backup, and optical fiber virtual private network (VPN) were used. As a result, the blood information centralized database and management system were successfully constructed, which covers all the Zhejiang province, and the real time exchange of blood data was realised. In conclusion, its implementation promote volunteer blood donation and ensure the blood safety in Zhejiang, especially strengthen the quick response to public health emergency. This project lays the first stone of centralized test and allotment among blood banks in Zhejiang, and can serve as a reference of contemporary blood bank information systems in China.

  16. Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer.

    Science.gov (United States)

    Jang, Sang-Min; An, Joo-Hee; Kim, Chul-Hong; Kim, Jung-Woong; Choi, Kyung-Hee

    2015-08-01

    Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer.

  17. In silico transcriptional regulatory networks involved in tomato fruit ripening

    Directory of Open Access Journals (Sweden)

    Stilianos Arhondakis

    2016-08-01

    Full Text Available ABSTRACTTomato fruit ripening is a complex developmental programme partly mediated by transcriptional regulatory networks. Several transcription factors (TFs which are members of gene families such as MADS-box and ERF were shown to play a significant role in ripening through interconnections into an intricate network. The accumulation of large datasets of expression profiles corresponding to different stages of tomato fruit ripening and the availability of bioinformatics tools for their analysis provide an opportunity to identify TFs which might regulate gene clusters with similar co-expression patterns. We identified two TFs, a SlWRKY22-like and a SlER24 transcriptional activator which were shown to regulate modules by using the LeMoNe algorithm for the analysis of our microarray datasets representing four stages of fruit ripening, breaker, turning, pink and red ripe. The WRKY22-like module comprised a subgroup of six various calcium sensing transcripts with similar to the TF expression patterns according to real time PCR validation. A promoter motif search identified a cis acting element, the W-box, recognized by WRKY TFs that was present in the promoter region of all six calcium sensing genes. Moreover, publicly available microarray datasets of similar ripening stages were also analyzed with LeMoNe resulting in TFs such as SlERF.E1, SlERF.C1, SlERF.B2, SLERF.A2, SlWRKY24, SLWRKY37 and MADS-box/TM29 which might also play an important role in regulation of ripening. These results suggest that the SlWRKY22-like might be involved in the coordinated regulation of expression of the six calcium sensing genes. Conclusively the LeMoNe tool might lead to the identification of putative TF targets for further physiological analysis as regulators of tomato fruit ripening.

  18. In silico Transcriptional Regulatory Networks Involved in Tomato Fruit Ripening.

    Science.gov (United States)

    Arhondakis, Stilianos; Bita, Craita E; Perrakis, Andreas; Manioudaki, Maria E; Krokida, Afroditi; Kaloudas, Dimitrios; Kalaitzis, Panagiotis

    2016-01-01

    Tomato fruit ripening is a complex developmental programme partly mediated by transcriptional regulatory networks. Several transcription factors (TFs) which are members of gene families such as MADS-box and ERF were shown to play a significant role in ripening through interconnections into an intricate network. The accumulation of large datasets of expression profiles corresponding to different stages of tomato fruit ripening and the availability of bioinformatics tools for their analysis provide an opportunity to identify TFs which might regulate gene clusters with similar co-expression patterns. We identified two TFs, a SlWRKY22-like and a SlER24 transcriptional activator which were shown to regulate modules by using the LeMoNe algorithm for the analysis of our microarray datasets representing four stages of fruit ripening, breaker, turning, pink and red ripe. The WRKY22-like module comprised a subgroup of six various calcium sensing transcripts with similar to the TF expression patterns according to real time PCR validation. A promoter motif search identified a cis acting element, the W-box, recognized by WRKY TFs that was present in the promoter region of all six calcium sensing genes. Moreover, publicly available microarray datasets of similar ripening stages were also analyzed with LeMoNe resulting in TFs such as SlERF.E1, SlERF.C1, SlERF.B2, SLERF.A2, SlWRKY24, SLWRKY37, and MADS-box/TM29 which might also play an important role in regulation of ripening. These results suggest that the SlWRKY22-like might be involved in the coordinated regulation of expression of the six calcium sensing genes. Conclusively the LeMoNe tool might lead to the identification of putative TF targets for further physiological analysis as regulators of tomato fruit ripening.

  19. In silico Transcriptional Regulatory Networks Involved in Tomato Fruit Ripening.

    Science.gov (United States)

    Arhondakis, Stilianos; Bita, Craita E; Perrakis, Andreas; Manioudaki, Maria E; Krokida, Afroditi; Kaloudas, Dimitrios; Kalaitzis, Panagiotis

    2016-01-01

    Tomato fruit ripening is a complex developmental programme partly mediated by transcriptional regulatory networks. Several transcription factors (TFs) which are members of gene families such as MADS-box and ERF were shown to play a significant role in ripening through interconnections into an intricate network. The accumulation of large datasets of expression profiles corresponding to different stages of tomato fruit ripening and the availability of bioinformatics tools for their analysis provide an opportunity to identify TFs which might regulate gene clusters with similar co-expression patterns. We identified two TFs, a SlWRKY22-like and a SlER24 transcriptional activator which were shown to regulate modules by using the LeMoNe algorithm for the analysis of our microarray datasets representing four stages of fruit ripening, breaker, turning, pink and red ripe. The WRKY22-like module comprised a subgroup of six various calcium sensing transcripts with similar to the TF expression patterns according to real time PCR validation. A promoter motif search identified a cis acting element, the W-box, recognized by WRKY TFs that was present in the promoter region of all six calcium sensing genes. Moreover, publicly available microarray datasets of similar ripening stages were also analyzed with LeMoNe resulting in TFs such as SlERF.E1, SlERF.C1, SlERF.B2, SLERF.A2, SlWRKY24, SLWRKY37, and MADS-box/TM29 which might also play an important role in regulation of ripening. These results suggest that the SlWRKY22-like might be involved in the coordinated regulation of expression of the six calcium sensing genes. Conclusively the LeMoNe tool might lead to the identification of putative TF targets for further physiological analysis as regulators of tomato fruit ripening. PMID:27625653

  20. In silico Transcriptional Regulatory Networks Involved in Tomato Fruit Ripening

    Science.gov (United States)

    Arhondakis, Stilianos; Bita, Craita E.; Perrakis, Andreas; Manioudaki, Maria E.; Krokida, Afroditi; Kaloudas, Dimitrios; Kalaitzis, Panagiotis

    2016-01-01

    Tomato fruit ripening is a complex developmental programme partly mediated by transcriptional regulatory networks. Several transcription factors (TFs) which are members of gene families such as MADS-box and ERF were shown to play a significant role in ripening through interconnections into an intricate network. The accumulation of large datasets of expression profiles corresponding to different stages of tomato fruit ripening and the availability of bioinformatics tools for their analysis provide an opportunity to identify TFs which might regulate gene clusters with similar co-expression patterns. We identified two TFs, a SlWRKY22-like and a SlER24 transcriptional activator which were shown to regulate modules by using the LeMoNe algorithm for the analysis of our microarray datasets representing four stages of fruit ripening, breaker, turning, pink and red ripe. The WRKY22-like module comprised a subgroup of six various calcium sensing transcripts with similar to the TF expression patterns according to real time PCR validation. A promoter motif search identified a cis acting element, the W-box, recognized by WRKY TFs that was present in the promoter region of all six calcium sensing genes. Moreover, publicly available microarray datasets of similar ripening stages were also analyzed with LeMoNe resulting in TFs such as SlERF.E1, SlERF.C1, SlERF.B2, SLERF.A2, SlWRKY24, SLWRKY37, and MADS-box/TM29 which might also play an important role in regulation of ripening. These results suggest that the SlWRKY22-like might be involved in the coordinated regulation of expression of the six calcium sensing genes. Conclusively the LeMoNe tool might lead to the identification of putative TF targets for further physiological analysis as regulators of tomato fruit ripening.

  1. Topology of transcriptional regulatory networks: testing and improving.

    Directory of Open Access Journals (Sweden)

    Dicle Hasdemir

    Full Text Available With the increasing amount and complexity of data generated in biological experiments it is becoming necessary to enhance the performance and applicability of existing statistical data analysis methods. This enhancement is needed for the hidden biological information to be better resolved and better interpreted. Towards that aim, systematic incorporation of prior information in biological data analysis has been a challenging problem for systems biology. Several methods have been proposed to integrate data from different levels of information most notably from metabolomics, transcriptomics and proteomics and thus enhance biological interpretation. However, in order not to be misled by the dominance of incorrect prior information in the analysis, being able to discriminate between competing prior information is required. In this study, we show that discrimination between topological information in competing transcriptional regulatory network models is possible solely based on experimental data. We use network topology dependent decomposition of synthetic gene expression data to introduce both local and global discriminating measures. The measures indicate how well the gene expression data can be explained under the constraints of the model network topology and how much each regulatory connection in the model refuses to be constrained. Application of the method to the cell cycle regulatory network of Saccharomyces cerevisiae leads to the prediction of novel regulatory interactions, improving the information content of the hypothesized network model.

  2. Modeling microRNA-transcription factor networks in cancer.

    Science.gov (United States)

    Aguda, Baltazar D

    2013-01-01

    An increasing number of transcription factors (TFs) and microRNAs (miRNAs) is known to form feedback loops (FBLs) of interactions where a TF positively or negatively regulates the expression of a miRNA, and the miRNA suppresses the translation of the TF messenger RNA. FBLs are potential sources of instability in a gene regulatory network. Positive FBLs can give rise to switching behaviors while negative FBLs can generate periodic oscillations. This chapter presents documented examples of FBLs and their relevance to stem cell renewal and differentiation in gliomas. Feed-forward loops (FFLs) are only discussed briefly because they do not affect network stability unless they are members of cycles. A primer on qualitative network stability analysis is given and then used to demonstrate the network destabilizing role of FBLs. Steps in model formulation and computer simulations are illustrated using the miR-17-92/Myc/E2F network as an example. This example possesses both negative and positive FBLs.

  3. Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction

    Science.gov (United States)

    Yeger-Lotem, Esti; Sattath, Shmuel; Kashtan, Nadav; Itzkovitz, Shalev; Milo, Ron; Pinter, Ron Y.; Alon, Uri; Margalit, Hanah

    2004-04-01

    Genes and proteins generate molecular circuitry that enables the cell to process information and respond to stimuli. A major challenge is to identify characteristic patterns in this network of interactions that may shed light on basic cellular mechanisms. Previous studies have analyzed aspects of this network, concentrating on either transcription-regulation or protein-protein interactions. Here we search for composite network motifs: characteristic network patterns consisting of both transcription-regulation and protein-protein interactions that recur significantly more often than in random networks. To this end we developed algorithms for detecting motifs in networks with two or more types of interactions and applied them to an integrated data set of protein-protein interactions and transcription regulation in Saccharomyces cerevisiae. We found a two-protein mixed-feedback loop motif, five types of three-protein motifs exhibiting coregulation and complex formation, and many motifs involving four proteins. Virtually all four-protein motifs consisted of combinations of smaller motifs. This study presents a basic framework for detecting the building blocks of networks with multiple types of interactions.

  4. The transcriptional landscape of age in human peripheral blood

    NARCIS (Netherlands)

    M.J. Peters (Marjolein); R. Joehanes (Roby); L.C. Pilling (Luke); C. Schurmann (Claudia); K.N. Conneely (Karen N.); J.E. Powell (Joseph); E. Reinmaa (Eva); G.L. Sutphin (George L.); A. Zhernakova (Alexandra); K. Schramm (Katharina); Y.A. Wilson (Yana A.); S. Kobes (Sayuko); T. Tukiainen (Taru); Y.F.M. Ramos (Yolande); H.H.H. Göring (Harald H.); M. Fornage (Myriam); Y. Liu (Yongmei); S.A. Gharib (Sina); B.E. Stranger (Barbara); P.L. de Jager (Philip); A. Aviv (Abraham); D. Levy (Daniel); J. Murabito (Joanne); P.J. Munson (Peter J.); T. Huan (Tianxiao); A. Hofman (Albert); A.G. Uitterlinden (Andre G.); F. Rivadeneira Ramirez (Fernando); J. van Rooij (Jeroen); L. Stolk (Lisette); L. Broer (Linda); M.M.P.J. Verbiest (Michael); M. Jhamai (Mila); P.P. Arp (Pascal); A. Metspalu (Andres); L. Tserel (Liina); L. Milani (Lili); N.J. Samani (Nilesh); P. Peterson (Pärt); S. Kasela (Silva); V. Codd (Veryan); A. Peters (Annette); C.K. Ward-Caviness (Cavin K.); C. Herder (Christian); M. Waldenberger (Melanie); M. Roden (Michael); P. Singmann (Paula); S. Zeilinger (Sonja); T. Illig (Thomas); G. Homuth (Georg); H.J. Grabe (Hans Jörgen); H. Völzke (Henry); L. Steil (Leif); T. Kocher (Thomas); A. Murray (Anna); D. Melzer (David); H. Yaghootkar (Hanieh); S. Bandinelli; E.K. Moses (Eric); J.W. Kent (Jack); J.E. Curran (Joanne); M.P. Johnson (Matthew); S. Williams-Blangero (Sarah); H.J. Westra (Harm-Jan); A.F. McRae (Allan F.); J.A. Smith (Jennifer A); S.L.R. Kardia (Sharon); I. Hovatta (Iiris); M. Perola (Markus); S. Ripatti (Samuli); V. Salomaa (Veikko); A.K. Henders (Anjali); N.G. Martin (Nicholas); A.K. Smith (Alicia K.); D. Mehta (Divya); E.B. Binder (Elisabeth B.); K.M. Nylocks (K. Maria); E.M. Kennedy (Elizabeth M.); T. Klengel (Torsten); J. Ding (Jingzhong); A. Suchy-Dicey (Astrid); D. Enquobahrie; J. Brody (Jennifer); J.I. Rotter (Jerome I.); Y.-D.I. Chen (Yii-Der I.); J.J. Houwing-Duistermaat (Jeanine); M. Kloppenburg (Margreet); P.E. Slagboom (Eline); Q. Helmer (Quinta); W. den Hollander (Wouter); S. Bean (Shannon); T. Raj (Towfique); N. Bakhshi (Noman); Q.P. Wang (Qiao Ping); L.J. Oyston (Lisa J.); B.M. Psaty (Bruce); R.P. Tracy (Russell); G.W. Montgomery (Grant); S.T. Turner (Stephen); J. Blangero (John); I. Meulenbelt (Ingrid); K.J. Ressler (Kerry); J. Yang (Jian); L. Franke (Lude); J. Kettunen (Johannes); P.M. Visscher (Peter); G.G. Neely (G. Gregory); R. Korstanje (Ron); R.L. Hanson (Robert L.); H. Prokisch (Holger); L. Ferrucci (Luigi); T. Esko (Tõnu); A. Teumer (Alexander); J.B.J. van Meurs (Joyce); A.D. Johnson (Andrew D.); M.A. Nalls (Michael); D.G. Hernandez (Dena); M.R. Cookson (Mark); R.J. Gibbs (Raphael J.); J. Hardy (John); A. Ramasamy (Adaikalavan); A.B. Zonderman (Alan B.); A. Dillman (Allissa); B. Traynor (Bryan); C. Smith (Colin); D.L. Longo (Dan L.); D. Trabzuni (Danyah); J.C. Troncoso (Juan); M.P. van der Brug (Marcel); M.E. Weale (Michael); R. O'Brien (Richard); R. Johnson (Robert); R. Walker (Robert); R.H. Zielke (Ronald H.); S. Arepalli (Sampath); M. Ryten (Mina); A. Singleton

    2015-01-01

    textabstractDisease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) a

  5. The transcriptional landscape of age in human peripheral blood

    NARCIS (Netherlands)

    Peters, Marjolein J; Joehanes, Roby; Pilling, Luke C; Schurmann, Claudia; Conneely, Karen N; Powell, Joseph; Reinmaa, Eva; Sutphin, George L; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A; Kobes, Sayuko; Tukiainen, Taru; Ramos, Yolande F; Göring, Harald H H; Fornage, Myriam; Liu, Yongmei; Gharib, Sina A; Stranger, Barbara E; De Jager, Philip L; Aviv, Abraham; Levy, Daniel; Murabito, Joanne M; Munson, Peter J; Huan, Tianxiao; Hofman, Albert; Uitterlinden, André G; Rivadeneira, Fernando; van Rooij, Jeroen; Stolk, Lisette; Broer, Linda; Verbiest, Michael M P J; Jhamai, Mila; Arp, Pascal; Metspalu, Andres; Tserel, Liina; Milani, Lili; Samani, Nilesh J; Peterson, Pärt; Kasela, Silva; Codd, Veryan; Peters, Annette; Ward-Caviness, Cavin K; Herder, Christian; Waldenberger, Melanie; Roden, Michael; Singmann, Paula; Zeilinger, Sonja; Illig, Thomas; Homuth, Georg; Grabe, Hans-Jörgen; Völzke, Henry; Steil, Leif; Kocher, Thomas; Murray, Anna; Melzer, David; Yaghootkar, Hanieh; Bandinelli, Stefania; Moses, Eric K; Kent, Jack W; Curran, Joanne E; Johnson, Matthew P; Williams-Blangero, Sarah; Westra, Harm-Jan; McRae, Allan F; Smith, Jennifer A; Kardia, Sharon L R; Hovatta, Iiris; Perola, Markus; Ripatti, Samuli; Salomaa, Veikko; Henders, Anjali K; Martin, Nicholas G; Smith, Alicia K; Mehta, Divya; Binder, Elisabeth B; Nylocks, K Maria; Kennedy, Elizabeth M; Klengel, Torsten; Ding, Jingzhong; Suchy-Dicey, Astrid M; Enquobahrie, Daniel A; Brody, Jennifer; Rotter, Jerome I; Chen, Yii-Der I; Houwing-Duistermaat, Jeanine; Kloppenburg, Margreet; Slagboom, P Eline; Helmer, Quinta; den Hollander, Wouter; Bean, Shannon; Raj, Towfique; Bakhshi, Noman; Wang, Qiao Ping; Oyston, Lisa J; Psaty, Bruce M; Tracy, Russell P; Montgomery, Grant W; Turner, Stephen T; Blangero, John; Meulenbelt, Ingrid; Ressler, Kerry J; Yang, Jian; Franke, Lude; Kettunen, Johannes; Visscher, Peter M; Neely, G Gregory; Korstanje, Ron; Hanson, Robert L; Prokisch, Holger; Ferrucci, Luigi; Esko, Tonu; Teumer, Alexander; van Meurs, Joyce B J; Johnson, Andrew D

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify

  6. Transcriptional Regulatory Network for the Development of Innate Lymphoid Cells

    Directory of Open Access Journals (Sweden)

    Chao Zhong

    2015-01-01

    Full Text Available Recent studies on innate lymphoid cells (ILCs have expanded our knowledge about the innate arm of the immune system. Helper-like ILCs share both the “innate” feature of conventional natural killer (cNK cells and the “helper” feature of CD4+ T helper (Th cells. With this combination, helper-like ILCs are capable of initiating early immune responses similar to cNK cells, but via secretion of a set of effector cytokines similar to those produced by Th cells. Although many studies have revealed the functional similarity between helper-like ILCs and Th cells, some aspects of ILCs including the development of this lineage remain elusive. It is intriguing that the majority of transcription factors involved in multiple stages of T cell development, differentiation, and function also play critical roles during ILC development. Regulators such as Id2, GATA-3, Nfil3, TOX, and TCF-1 are expressed and function at various stages of ILC development. In this review, we will summarize the expression and functions of these transcription factors shared by ILCs and Th cells. We will also propose a complex transcriptional regulatory network for the lineage commitment of ILCs.

  7. The transcriptional landscape of age in human peripheral blood

    OpenAIRE

    Peters, Marjolein J.; Joehanes, Roby; Pilling, Luke C; Schurmann, Claudia; Karen N Conneely; Powell, Joseph; Reinmaa, Eva; Sutphin, George L; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A; Kobes, Sayuko; Tukiainen, Taru; Ramos, Yolande F; Göring, Harald H. H.

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for...

  8. Using network component analysis to dissect regulatory networks mediated by transcription factors in yeast.

    Directory of Open Access Journals (Sweden)

    Chun Ye

    2009-03-01

    Full Text Available Understanding the relationship between genetic variation and gene expression is a central question in genetics. With the availability of data from high-throughput technologies such as ChIP-Chip, expression, and genotyping arrays, we can begin to not only identify associations but to understand how genetic variations perturb the underlying transcription regulatory networks to induce differential gene expression. In this study, we describe a simple model of transcription regulation where the expression of a gene is completely characterized by two properties: the concentrations and promoter affinities of active transcription factors. We devise a method that extends Network Component Analysis (NCA to determine how genetic variations in the form of single nucleotide polymorphisms (SNPs perturb these two properties. Applying our method to a segregating population of Saccharomyces cerevisiae, we found statistically significant examples of trans-acting SNPs located in regulatory hotspots that perturb transcription factor concentrations and affinities for target promoters to cause global differential expression and cis-acting genetic variations that perturb the promoter affinities of transcription factors on a single gene to cause local differential expression. Although many genetic variations linked to gene expressions have been identified, it is not clear how they perturb the underlying regulatory networks that govern gene expression. Our work begins to fill this void by showing that many genetic variations affect the concentrations of active transcription factors in a cell and their affinities for target promoters. Understanding the effects of these perturbations can help us to paint a more complete picture of the complex landscape of transcription regulation. The software package implementing the algorithms discussed in this work is available as a MATLAB package upon request.

  9. The transcriptional landscape of age in human peripheral blood

    Science.gov (United States)

    Peters, Marjolein J.; Joehanes, Roby; Pilling, Luke C.; Schurmann, Claudia; Conneely, Karen N.; Powell, Joseph; Reinmaa, Eva; Sutphin, George L.; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A.; Kobes, Sayuko; Tukiainen, Taru; Nalls, Michael A.; Hernandez, Dena G.; Cookson, Mark R.; Gibbs, Raphael J.; Hardy, John; Ramasamy, Adaikalavan; Zonderman, Alan B.; Dillman, Allissa; Traynor, Bryan; Smith, Colin; Longo, Dan L.; Trabzuni, Daniah; Troncoso, Juan; van der Brug, Marcel; Weale, Michael E.; O'Brien, Richard; Johnson, Robert; Walker, Robert; Zielke, Ronald H.; Arepalli, Sampath; Ryten, Mina; Singleton, Andrew B.; Ramos, Yolande F.; Göring, Harald H. H.; Fornage, Myriam; Liu, Yongmei; Gharib, Sina A.; Stranger, Barbara E.; De Jager, Philip L.; Aviv, Abraham; Levy, Daniel; Murabito, Joanne M.; Munson, Peter J.; Huan, Tianxiao; Hofman, Albert; Uitterlinden, André G.; Rivadeneira, Fernando; van Rooij, Jeroen; Stolk, Lisette; Broer, Linda; Verbiest, Michael M. P. J.; Jhamai, Mila; Arp, Pascal; Metspalu, Andres; Tserel, Liina; Milani, Lili; Samani, Nilesh J.; Peterson, Pärt; Kasela, Silva; Codd, Veryan; Peters, Annette; Ward-Caviness, Cavin K.; Herder, Christian; Waldenberger, Melanie; Roden, Michael; Singmann, Paula; Zeilinger, Sonja; Illig, Thomas; Homuth, Georg; Grabe, Hans-Jörgen; Völzke, Henry; Steil, Leif; Kocher, Thomas; Murray, Anna; Melzer, David; Yaghootkar, Hanieh; Bandinelli, Stefania; Moses, Eric K.; Kent, Jack W.; Curran, Joanne E.; Johnson, Matthew P.; Williams-Blangero, Sarah; Westra, Harm-Jan; McRae, Allan F.; Smith, Jennifer A.; Kardia, Sharon L. R.; Hovatta, Iiris; Perola, Markus; Ripatti, Samuli; Salomaa, Veikko; Henders, Anjali K.; Martin, Nicholas G.; Smith, Alicia K.; Mehta, Divya; Binder, Elisabeth B.; Nylocks, K Maria; Kennedy, Elizabeth M.; Klengel, Torsten; Ding, Jingzhong; Suchy-Dicey, Astrid M.; Enquobahrie, Daniel A.; Brody, Jennifer; Rotter, Jerome I.; Chen, Yii-Der I.; Houwing-Duistermaat, Jeanine; Kloppenburg, Margreet; Slagboom, P. Eline; Helmer, Quinta; den Hollander, Wouter; Bean, Shannon; Raj, Towfique; Bakhshi, Noman; Wang, Qiao Ping; Oyston, Lisa J.; Psaty, Bruce M.; Tracy, Russell P.; Montgomery, Grant W.; Turner, Stephen T.; Blangero, John; Meulenbelt, Ingrid; Ressler, Kerry J.; Yang, Jian; Franke, Lude; Kettunen, Johannes; Visscher, Peter M.; Neely, G. Gregory; Korstanje, Ron; Hanson, Robert L.; Prokisch, Holger; Ferrucci, Luigi; Esko, Tonu; Teumer, Alexander; van Meurs, Joyce B. J.; Johnson, Andrew D.

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. PMID:26490707

  10. The transcriptional landscape of age in human peripheral blood.

    Science.gov (United States)

    Peters, Marjolein J; Joehanes, Roby; Pilling, Luke C; Schurmann, Claudia; Conneely, Karen N; Powell, Joseph; Reinmaa, Eva; Sutphin, George L; Zhernakova, Alexandra; Schramm, Katharina; Wilson, Yana A; Kobes, Sayuko; Tukiainen, Taru; Ramos, Yolande F; Göring, Harald H H; Fornage, Myriam; Liu, Yongmei; Gharib, Sina A; Stranger, Barbara E; De Jager, Philip L; Aviv, Abraham; Levy, Daniel; Murabito, Joanne M; Munson, Peter J; Huan, Tianxiao; Hofman, Albert; Uitterlinden, André G; Rivadeneira, Fernando; van Rooij, Jeroen; Stolk, Lisette; Broer, Linda; Verbiest, Michael M P J; Jhamai, Mila; Arp, Pascal; Metspalu, Andres; Tserel, Liina; Milani, Lili; Samani, Nilesh J; Peterson, Pärt; Kasela, Silva; Codd, Veryan; Peters, Annette; Ward-Caviness, Cavin K; Herder, Christian; Waldenberger, Melanie; Roden, Michael; Singmann, Paula; Zeilinger, Sonja; Illig, Thomas; Homuth, Georg; Grabe, Hans-Jörgen; Völzke, Henry; Steil, Leif; Kocher, Thomas; Murray, Anna; Melzer, David; Yaghootkar, Hanieh; Bandinelli, Stefania; Moses, Eric K; Kent, Jack W; Curran, Joanne E; Johnson, Matthew P; Williams-Blangero, Sarah; Westra, Harm-Jan; McRae, Allan F; Smith, Jennifer A; Kardia, Sharon L R; Hovatta, Iiris; Perola, Markus; Ripatti, Samuli; Salomaa, Veikko; Henders, Anjali K; Martin, Nicholas G; Smith, Alicia K; Mehta, Divya; Binder, Elisabeth B; Nylocks, K Maria; Kennedy, Elizabeth M; Klengel, Torsten; Ding, Jingzhong; Suchy-Dicey, Astrid M; Enquobahrie, Daniel A; Brody, Jennifer; Rotter, Jerome I; Chen, Yii-Der I; Houwing-Duistermaat, Jeanine; Kloppenburg, Margreet; Slagboom, P Eline; Helmer, Quinta; den Hollander, Wouter; Bean, Shannon; Raj, Towfique; Bakhshi, Noman; Wang, Qiao Ping; Oyston, Lisa J; Psaty, Bruce M; Tracy, Russell P; Montgomery, Grant W; Turner, Stephen T; Blangero, John; Meulenbelt, Ingrid; Ressler, Kerry J; Yang, Jian; Franke, Lude; Kettunen, Johannes; Visscher, Peter M; Neely, G Gregory; Korstanje, Ron; Hanson, Robert L; Prokisch, Holger; Ferrucci, Luigi; Esko, Tonu; Teumer, Alexander; van Meurs, Joyce B J; Johnson, Andrew D

    2015-01-01

    Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts. PMID:26490707

  11. Blood transcriptional signature of recombinant human erythropoietin administration and implications for antidoping strategies.

    Science.gov (United States)

    Durussel, Jérôme; Haile, Diresibachew W; Mooses, Kerli; Daskalaki, Evangelia; Beattie, Wendy; Mooses, Martin; Mekonen, Wondyefraw; Ongaro, Neford; Anjila, Edwin; Patel, Rajan K; Padmanabhan, Neal; McBride, Martin W; McClure, John D; Pitsiladis, Yannis P

    2016-03-01

    Recombinant human erythropoietin (rHuEPO) is frequently abused by athletes as a performance-enhancing drug, despite being prohibited by the World Anti-Doping Agency. Although the methods to detect blood doping, including rHuEPO injections, have improved in recent years, they remain imperfect. In a proof-of-principle study, we identified, replicated, and validated the whole blood transcriptional signature of rHuEPO in endurance-trained Caucasian males at sea level (n = 18) and Kenyan endurance runners at moderate altitude (n = 20), all of whom received rHuEPO injections for 4 wk. Transcriptional profiling shows that hundreds of transcripts were altered by rHuEPO in both cohorts. The main regulated expression pattern, observed in all participants, was characterized by a "rebound" effect with a profound upregulation during rHuEPO and a subsequent downregulation up to 4 wk postadministration. The functions of the identified genes were mainly related to the functional and structural properties of the red blood cell. Of the genes identified to be differentially expressed during and post-rHuEPO, we further confirmed a whole blood 34-transcript signature that can distinguish between samples collected pre-, during, and post-rHuEPO administration. By providing biomarkers that can reveal rHuEPO use, our findings represent an advance in the development of new methods for the detection of blood doping. PMID:26757800

  12. Molecular genetics of blood-fleshed peach reveals activation of anthocyanin biosynthesis by NAC transcription factors.

    Science.gov (United States)

    Zhou, Hui; Lin-Wang, Kui; Wang, Huiliang; Gu, Chao; Dare, Andrew P; Espley, Richard V; He, Huaping; Allan, Andrew C; Han, Yuepeng

    2015-04-01

    Anthocyanin pigmentation is an important consumer trait in peach (Prunus persica). In this study, the genetic basis of the blood-flesh trait was investigated using the cultivar Dahongpao, which shows high levels of cyanidin-3-glucoside in the mesocarp. Elevation of anthocyanin levels in the flesh was correlated with the expression of an R2R3 MYB transcription factor, PpMYB10.1. However, PpMYB10.1 did not co-segregate with the blood-flesh trait. The blood-flesh trait was mapped to a 200-kb interval on peach linkage group (LG) 5. Within this interval, a gene encoding a NAC domain transcription factor (TF) was found to be highly up-regulated in blood-fleshed peaches when compared with non-red-fleshed peaches. This NAC TF, designated blood (BL), acts as a heterodimer with PpNAC1 which shows high levels of expression in fruit at late developmental stages. We show that the heterodimer of BL and PpNAC1 can activate the transcription of PpMYB10.1, resulting in anthocyanin pigmentation in tobacco. Furthermore, silencing the BL gene reduces anthocyanin pigmentation in blood-fleshed peaches. The transactivation activity of the BL-PpNAC1 heterodimer is repressed by a SQUAMOSA promoter-binding protein-like TF, PpSPL1. Low levels of PpMYB10.1 expression in fruit at early developmental stages is probably attributable to lower levels of expression of PpNAC1 plus the presence of high levels of repressors such as PpSPL1. We present a mechanism whereby BL is the key gene for the blood-flesh trait in peach via its activation of PpMYB10.1 in maturing fruit. Partner TFs such as basic helix-loop-helix proteins and NAC1 are required, as is the removal of transcriptional repressors.

  13. Molecular genetics of blood-fleshed peach reveals activation of anthocyanin biosynthesis by NAC transcription factors.

    Science.gov (United States)

    Zhou, Hui; Lin-Wang, Kui; Wang, Huiliang; Gu, Chao; Dare, Andrew P; Espley, Richard V; He, Huaping; Allan, Andrew C; Han, Yuepeng

    2015-04-01

    Anthocyanin pigmentation is an important consumer trait in peach (Prunus persica). In this study, the genetic basis of the blood-flesh trait was investigated using the cultivar Dahongpao, which shows high levels of cyanidin-3-glucoside in the mesocarp. Elevation of anthocyanin levels in the flesh was correlated with the expression of an R2R3 MYB transcription factor, PpMYB10.1. However, PpMYB10.1 did not co-segregate with the blood-flesh trait. The blood-flesh trait was mapped to a 200-kb interval on peach linkage group (LG) 5. Within this interval, a gene encoding a NAC domain transcription factor (TF) was found to be highly up-regulated in blood-fleshed peaches when compared with non-red-fleshed peaches. This NAC TF, designated blood (BL), acts as a heterodimer with PpNAC1 which shows high levels of expression in fruit at late developmental stages. We show that the heterodimer of BL and PpNAC1 can activate the transcription of PpMYB10.1, resulting in anthocyanin pigmentation in tobacco. Furthermore, silencing the BL gene reduces anthocyanin pigmentation in blood-fleshed peaches. The transactivation activity of the BL-PpNAC1 heterodimer is repressed by a SQUAMOSA promoter-binding protein-like TF, PpSPL1. Low levels of PpMYB10.1 expression in fruit at early developmental stages is probably attributable to lower levels of expression of PpNAC1 plus the presence of high levels of repressors such as PpSPL1. We present a mechanism whereby BL is the key gene for the blood-flesh trait in peach via its activation of PpMYB10.1 in maturing fruit. Partner TFs such as basic helix-loop-helix proteins and NAC1 are required, as is the removal of transcriptional repressors. PMID:25688923

  14. What Transcription Factors Can't Do: On the Combinatorial Limits of Gene Regulatory Networks

    OpenAIRE

    Werner, Eric

    2013-01-01

    A proof is presented that gene regulatory networks (GRNs) based solely on transcription factors cannot control the development of complex multicellular life. GRNs alone cannot explain the evolution of multicellular life in the Cambrian Explosion. Networks are based on addressing systems which are used to construct network links. The more complex the network the greater the number of links and the larger the required address space. It has been assumed that combinations of transcription factors...

  15. Unexpected complexity of the Reef-Building Coral Acropora millepora transcription factor network

    Directory of Open Access Journals (Sweden)

    Ravasi Timothy

    2011-04-01

    Full Text Available Abstract Background Coral reefs are disturbed on a global scale by environmental changes including rising sea surface temperatures and ocean acidification. Little is known about how corals respond or adapt to these environmental changes especially at the molecular level. This is mostly because of the paucity of genome-wide studies on corals and the application of systems approaches that incorporate the latter. Like in any other organism, the response of corals to stress is tightly controlled by the coordinated interplay of many transcription factors. Results Here, we develop and apply a new system-wide approach in order to infer combinatorial transcription factor networks of the reef-building coral Acropora millepora. By integrating sequencing-derived transcriptome measurements, a network of physically interacting transcription factors, and phylogenetic network footprinting we were able to infer such a network. Analysis of the network across a phylogenetically broad sample of five species, including human, reveals that despite the apparent simplicity of corals, their transcription factors repertoire and interaction networks seem to be largely conserved. In addition, we were able to identify interactions among transcription factors that appear to be species-specific lending strength to the novel concept of "Taxonomically Restricted Interactions". Conclusions This study provides the first look at transcription factor networks in corals. We identified a transcription factor repertoire encoded by the coral genome and found consistencies of the domain architectures of transcription factors and conserved regulatory subnetworks across eumetazoan species, providing insight into how regulatory networks have evolved.

  16. Using Mutual Information and Answer Set Programming to refine PWM based transcription regulation network

    OpenAIRE

    Aravena, Andres; Guziolowski, Carito; Siegel, Anne; Maass, Alejandro

    2012-01-01

    National audience Transcriptional regulatory network models can be reconstructed ab initio from DNA sequence data by locating the binding sites, defined by position specific score matrices, and identifying transcription factors by homology with known ones in other organisms. In general the resulting network contains spurious elements, because the pattern matching methods for binding site location have low specificity, while homology to known transcription factors does not always identify c...

  17. Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

    Science.gov (United States)

    Locascio, Joseph J; Eberly, Shirley; Liao, Zhixiang; Liu, Ganqiang; Hoesing, Ashley N; Duong, Karen; Trisini-Lipsanopoulos, Ana; Dhima, Kaltra; Hung, Albert Y; Flaherty, Alice W; Schwarzschild, Michael A; Hayes, Michael T; Wills, Anne-Marie; Shivraj Sohur, U; Mejia, Nicte I; Selkoe, Dennis J; Oakes, David; Shoulson, Ira; Dong, Xianjun; Marek, Ken; Zheng, Bin; Ivinson, Adrian; Hyman, Bradley T; Growdon, John H; Sudarsky, Lewis R; Schlossmacher, Michael G; Ravina, Bernard; Scherzer, Clemens R

    2015-09-01

    There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease. PMID:26220939

  18. Blood Genome-Wide Transcriptional Profiles of HER2 Negative Breast Cancers Patients

    Directory of Open Access Journals (Sweden)

    Ovidiu Balacescu

    2016-01-01

    Full Text Available Tumors act systemically to sustain cancer progression, affecting the physiological processes in the host and triggering responses in the blood circulating cells. In this study, we explored blood transcriptional patterns of patients with two subtypes of HER2 negative breast cancers, with different prognosis and therapeutic outcome. Peripheral blood samples from seven healthy female donors and 29 women with breast cancer including 14 triple-negative breast cancers and 15 hormone-dependent breast cancers were evaluated by microarray. We also evaluated the stroma in primary tumors. Transcriptional analysis revealed distinct molecular signatures in the blood of HER2− breast cancer patients according to ER/PR status. Our data showed the implication of immune signaling in both breast cancer subtypes with an enrichment of these processes in the blood of TNBC patients. We observed a significant alteration of “chemokine signaling,” “IL-8 signaling,” and “communication between innate and adaptive immune cells” pathways in the blood of TNBC patients correlated with an increased inflammation and necrosis in their primary tumors. Overall, our data indicate that the presence of triple-negative breast cancer is associated with an enrichment of altered systemic immune-related pathways, suggesting that immunotherapy could possibly be synergistic to the chemotherapy, to improve the clinical outcome of these patients.

  19. Connectivity in the yeast cell cycle transcription network: inferences from neural networks.

    Directory of Open Access Journals (Sweden)

    Christopher E Hart

    2006-12-01

    Full Text Available A current challenge is to develop computational approaches to infer gene network regulatory relationships based on multiple types of large-scale functional genomic data. We find that single-layer feed-forward artificial neural network (ANN models can effectively discover gene network structure by integrating global in vivo protein:DNA interaction data (ChIP/Array with genome-wide microarray RNA data. We test this on the yeast cell cycle transcription network, which is composed of several hundred genes with phase-specific RNA outputs. These ANNs were robust to noise in data and to a variety of perturbations. They reliably identified and ranked 10 of 12 known major cell cycle factors at the top of a set of 204, based on a sum-of-squared weights metric. Comparative analysis of motif occurrences among multiple yeast species independently confirmed relationships inferred from ANN weights analysis. ANN models can capitalize on properties of biological gene networks that other kinds of models do not. ANNs naturally take advantage of patterns of absence, as well as presence, of factor binding associated with specific expression output; they are easily subjected to in silico "mutation" to uncover biological redundancies; and they can use the full range of factor binding values. A prominent feature of cell cycle ANNs suggested an analogous property might exist in the biological network. This postulated that "network-local discrimination" occurs when regulatory connections (here between MBF and target genes are explicitly disfavored in one network module (G2, relative to others and to the class of genes outside the mitotic network. If correct, this predicts that MBF motifs will be significantly depleted from the discriminated class and that the discrimination will persist through evolution. Analysis of distantly related Schizosaccharomyces pombe confirmed this, suggesting that network-local discrimination is real and complements well-known enrichment of

  20. Current and emerging approaches to define intestinal epithelium-specific transcriptional networks

    DEFF Research Database (Denmark)

    Olsen, Anders Krûger; Boyd, Mette; Danielsen, Erik Thomas;

    2012-01-01

    Upon developmental or environmental cues, the composition of transcription factors in a transcriptional regulatory network is deeply implicated in controlling the signature of the gene expression and thereby specifies the cell- or tissue-type. Novel methods including ChIP-chip and ChIP-Seq have......, specific regulatory networks of transcription factors are activated to target specific genes, which determine the intestinal cell fate. The expanding genome-wide mapping of transcription factor binding sites and construction of transcriptional regulatory networks provide new insight into how intestinal...... been applied to analyse known transcription factors and their interacting regulatory DNA elements in the intestine. The intestine is an example of a dynamic tissue where stem cells in the crypt proliferate and undergo a differentiation process towards the villus. During this differentiation process...

  1. Current and emerging approaches to define intestinal epithelium-specific transcriptional networks

    DEFF Research Database (Denmark)

    Olsen, Anders Krüger; Boyd, Mette; Danielsen, Erik Thomas;

    2012-01-01

    applied to analyze known transcription factors and their interacting regulatory DNA elements in the intestine. The intestine is an example of a dynamic tissue where stem cells in the crypt proliferate and undergo a differentiation process toward the villus. During this differentiation process, specific......Upon developmental or environmental cues, the composition of transcription factors in a transcriptional regulatory network is deeply implicated in controlling the signature of the gene expression and thereby specifies the cell or tissue type. Novel methods including ChIP-chip and ChIP-Seq have been...... regulatory networks of transcription factors are activated to target specific genes, which determine the intestinal cell fate. The expanding genomewide mapping of transcription factor binding sites and construction of transcriptional regulatory networks provide new insight into how intestinal differentiation...

  2. Network based transcription factor analysis of regenerating axolotl limbs

    Directory of Open Access Journals (Sweden)

    Cameron Jo Ann

    2011-03-01

    Full Text Available Abstract Background Studies on amphibian limb regeneration began in the early 1700's but we still do not completely understand the cellular and molecular events of this unique process. Understanding a complex biological process such as limb regeneration is more complicated than the knowledge of the individual genes or proteins involved. Here we followed a systems biology approach in an effort to construct the networks and pathways of protein interactions involved in formation of the accumulation blastema in regenerating axolotl limbs. Results We used the human orthologs of proteins previously identified by our research team as bait to identify the transcription factor (TF pathways and networks that regulate blastema formation in amputated axolotl limbs. The five most connected factors, c-Myc, SP1, HNF4A, ESR1 and p53 regulate ~50% of the proteins in our data. Among these, c-Myc and SP1 regulate 36.2% of the proteins. c-Myc was the most highly connected TF (71 targets. Network analysis showed that TGF-β1 and fibronectin (FN lead to the activation of these TFs. We found that other TFs known to be involved in epigenetic reprogramming, such as Klf4, Oct4, and Lin28 are also connected to c-Myc and SP1. Conclusions Our study provides a systems biology approach to how different molecular entities inter-connect with each other during the formation of an accumulation blastema in regenerating axolotl limbs. This approach provides an in silico methodology to identify proteins that are not detected by experimental methods such as proteomics but are potentially important to blastema formation. We found that the TFs, c-Myc and SP1 and their target genes could potentially play a central role in limb regeneration. Systems biology has the potential to map out numerous other pathways that are crucial to blastema formation in regeneration-competent limbs, to compare these to the pathways that characterize regeneration-deficient limbs and finally, to identify stem

  3. Using Blood Informative Transcripts in Geographical Genomics: Impact of Lifestyle on Gene Expression in Fijians

    OpenAIRE

    Nath, Artika Praveeta; Arafat, Dalia; Gibson, Greg

    2012-01-01

    In previous geographical genomics studies of the impact of lifestyle on gene expression inferred from microarray analysis of peripheral blood samples, we described the complex influences of culture, ethnicity, and gender in Morocco, and of pregnancy in Brisbane. Here we describe the use of nanofluidic Fluidigm quantitative RT-PCR arrays targeted at a set of 96 transcripts that are broadly informative of the major axes of immune gene expression, to explore the population structure of transcrip...

  4. Whole Blood RNA as a Source of Transcript-Based Nutrition- and Metabolic Health-Related Biomarkers

    Science.gov (United States)

    Petrov, Petar D.; Bonet, M. Luisa; Reynés, Bárbara; Oliver, Paula; Palou, Andreu; Ribot, Joan

    2016-01-01

    Blood cells are receiving an increasing attention as an easily accessible source of transcript-based biomarkers. We studied the feasibility of using mouse whole blood RNA in this context. Several paradigms were studied: (i) metabolism-related transcripts known to be affected in rat tissues and peripheral blood mononuclear cells (PBMC) by fasting and upon the development of high fat diet (HFD)-induced overweight were assessed in whole blood RNA of fasted rats and mice and of HFD-fed mice; (ii) retinoic acid (RA)-responsive genes in tissues were assessed in whole blood RNA of control and RA-treated mice; (iii) lipid metabolism-related transcripts previously identified in PBMC as potential biomarkers of metabolic health in a rat model were assessed in whole blood in an independent model, namely retinoblastoma haploinsufficient (Rb+/-) mice. Blood was collected and stored in RNAlater® at -80°C until analysis of selected transcripts by real-time RT-PCR. Comparable changes with fasting were detected in the expression of lipid metabolism-related genes when RNA from either PBMC or whole blood of rats or mice was used. HFD-induced excess body weight and fat mass associated with expected changes in the expression of metabolism-related genes in whole blood of mice. Changes in gene expression in whole blood of RA-treated mice reproduced known transcriptional actions of RA in hepatocytes and adipocytes. Reduced expression of Fasn, Lrp1, Rxrb and Sorl1 could be validated as early biomarkers of metabolic health in young Rb+/- mice using whole blood RNA. Altogether, these results support the use of whole blood RNA in studies aimed at identifying blood transcript-based biomarkers of nutritional/metabolic status or metabolic health. Results also support reduced expression of Fasn, Lrp1, Rxrb and Sorl1 in blood cells at young age as potential biomarkers of metabolic robustness. PMID:27163124

  5. DMPD: The interferon signaling network and transcription factor C/EBP-beta. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18163952 The interferon signaling network and transcription factor C/EBP-beta. Li H... The interferon signaling network and transcription factor C/EBP-beta. PubmedID 18163952 Title The interfero...n signaling network and transcription factor C/EBP-beta. Authors Li H, Gade P, Xi

  6. Aedes aegypti midgut early trypsin is post-transcriptionally regulated by blood feeding.

    Science.gov (United States)

    Noriega, F G; Pennington, J E; Barillas-Mury, C; Wang, X Y; Wells, M A

    1996-02-01

    Early trypsin is a female-specific protease present in the Aedes aegypti midgut during the first hours after ingestion of a blood meal. Early trypsin gene expression was studied by Northern blot analysis. The early trypsin mRNA, absent in larvae, pupae and newly emerged females, reaches detectable levels at 24 h post-emergence and attains a maximum level at an adult age of 4-7 days. After the first week there is a decrease in the steady-state level of the transcript, but it remains readily detectable for up to a month after emergence. Despite the high levels of early trypsin mRNA present in the midgut of the unfed female, translation of the early trypsin mRNA occurs only after a blood or a protein meal. Early trypsin mRNA levels rapidly decrease during the first 24 h after feeding, but the steady-state level of the transcript rises again at the end of the blood digestion cycle (60 h), as the mosquito prepares for a second blood meal. PMID:8630532

  7. Altered Cerebral Blood Flow Covariance Network in Schizophrenia.

    Science.gov (United States)

    Liu, Feng; Zhuo, Chuanjun; Yu, Chunshui

    2016-01-01

    Many studies have shown abnormal cerebral blood flow (CBF) in schizophrenia; however, it remains unclear how topological properties of CBF network are altered in this disorder. Here, arterial spin labeling (ASL) MRI was employed to measure resting-state CBF in 96 schizophrenia patients and 91 healthy controls. CBF covariance network of each group was constructed by calculating across-subject CBF covariance between 90 brain regions. Graph theory was used to compare intergroup differences in global and nodal topological measures of the network. Both schizophrenia patients and healthy controls had small-world topology in CBF covariance networks, implying an optimal balance between functional segregation and integration. Compared with healthy controls, schizophrenia patients showed reduced small-worldness, normalized clustering coefficient and local efficiency of the network, suggesting a shift toward randomized network topology in schizophrenia. Furthermore, schizophrenia patients exhibited altered nodal centrality in the perceptual-, affective-, language-, and spatial-related regions, indicating functional disturbance of these systems in schizophrenia. This study demonstrated for the first time that schizophrenia patients have disrupted topological properties in CBF covariance network, which provides a new perspective (efficiency of blood flow distribution between brain regions) for understanding neural mechanisms of schizophrenia.

  8. Topological basis of signal integration in the transcriptional-regulatory network of the yeast, Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Chennubhotla Chakra

    2006-10-01

    Full Text Available Abstract Background Signal recognition and information processing is a fundamental cellular function, which in part involves comprehensive transcriptional regulatory (TR mechanisms carried out in response to complex environmental signals in the context of the cell's own internal state. However, the network topological basis of developing such integrated responses remains poorly understood. Results By studying the TR network of the yeast Saccharomyces cerevisiae we show that an intermediate layer of transcription factors naturally segregates into distinct subnetworks. In these topological units transcription factors are densely interlinked in a largely hierarchical manner and respond to external signals by utilizing a fraction of these subnets. Conclusion As transcriptional regulation represents the 'slow' component of overall information processing, the identified topology suggests a model in which successive waves of transcriptional regulation originating from distinct fractions of the TR network control robust integrated responses to complex stimuli.

  9. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    Science.gov (United States)

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. PMID:27181059

  10. Building promoter aware transcriptional regulatory networks using siRNA perturbation and deepCAGE

    DEFF Research Database (Denmark)

    Vitezic, Morana; Lassmann, Timo; Forrest, Alistair R R;

    2010-01-01

    Perturbation and time-course data sets, in combination with computational approaches, can be used to infer transcriptional regulatory networks which ultimately govern the developmental pathways and responses of cells. Here, we individually knocked down the four transcription factors PU.1, IRF8, MYB...

  11. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli

    DEFF Research Database (Denmark)

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem;

    2014-01-01

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response...... fundamental cellular processes linked to iron metabolism in order to coordinate the overall response of E. coli to iron availability....

  12. Bayesian non-negative factor analysis for reconstructing transcription factor mediated regulatory networks

    Directory of Open Access Journals (Sweden)

    Chen Yidong

    2011-10-01

    Full Text Available Abstract Background Transcriptional regulation by transcription factor (TF controls the time and abundance of mRNA transcription. Due to the limitation of current proteomics technologies, large scale measurements of protein level activities of TFs is usually infeasible, making computational reconstruction of transcriptional regulatory network a difficult task. Results We proposed here a novel Bayesian non-negative factor model for TF mediated regulatory networks. Particularly, the non-negative TF activities and sample clustering effect are modeled as the factors from a Dirichlet process mixture of rectified Gaussian distributions, and the sparse regulatory coefficients are modeled as the loadings from a sparse distribution that constrains its sparsity using knowledge from database; meantime, a Gibbs sampling solution was developed to infer the underlying network structure and the unknown TF activities simultaneously. The developed approach has been applied to simulated system and breast cancer gene expression data. Result shows that, the proposed method was able to systematically uncover TF mediated transcriptional regulatory network structure, the regulatory coefficients, the TF protein level activities and the sample clustering effect. The regulation target prediction result is highly coordinated with the prior knowledge, and sample clustering result shows superior performance over previous molecular based clustering method. Conclusions The results demonstrated the validity and effectiveness of the proposed approach in reconstructing transcriptional networks mediated by TFs through simulated systems and real data.

  13. Rh D blood group conversion using transcription activator-like effector nucleases.

    Science.gov (United States)

    Kim, Young-Hoon; Kim, Hyun O; Baek, Eun J; Kurita, Ryo; Cha, Hyuk-Jin; Nakamura, Yukio; Kim, Hyongbum

    2015-01-01

    Group O D-negative blood cells are universal donors in transfusion medicine and methods for converting other blood groups into this universal donor group have been researched. However, conversion of D-positive cells into D-negative is yet to be achieved, although conversion of group A or B cells into O cells has been reported. The Rh D blood group is determined by the RHD gene, which encodes a 12-transmembrane domain protein. Here we convert Rh D-positive erythroid progenitor cells into D-negative cells using RHD-targeting transcription activator-like effector nucleases (TALENs). After transfection of TALEN-encoding plasmids, RHD-knockout clones are obtained. Erythroid-lineage cells differentiated from these knockout erythroid progenitor cells do not agglutinate in the presence of anti-D reagents and do not express D antigen, as assessed using flow cytometry. Our programmable nuclease-induced blood group conversion opens new avenues for compatible donor cell generation in transfusion medicine. PMID:26078220

  14. Global and local architecture of the mammalian microRNA-transcription factor regulatory network.

    Directory of Open Access Journals (Sweden)

    Reut Shalgi

    2007-07-01

    Full Text Available microRNAs (miRs are small RNAs that regulate gene expression at the posttranscriptional level. It is anticipated that, in combination with transcription factors (TFs, they span a regulatory network that controls thousands of mammalian genes. Here we set out to uncover local and global architectural features of the mammalian miR regulatory network. Using evolutionarily conserved potential binding sites of miRs in human targets, and conserved binding sites of TFs in promoters, we uncovered two regulation networks. The first depicts combinatorial interactions between pairs of miRs with many shared targets. The network reveals several levels of hierarchy, whereby a few miRs interact with many other lowly connected miR partners. We revealed hundreds of "target hubs" genes, each potentially subject to massive regulation by dozens of miRs. Interestingly, many of these target hub genes are transcription regulators and they are often related to various developmental processes. The second network consists of miR-TF pairs that coregulate large sets of common targets. We discovered that the network consists of several recurring motifs. Most notably, in a significant fraction of the miR-TF coregulators the TF appears to regulate the miR, or to be regulated by the miR, forming a diversity of feed-forward loops. Together these findings provide new insights on the architecture of the combined transcriptional-post transcriptional regulatory network.

  15. Checkpoint Kinases Regulate a Global Network of Transcription Factors in Response to DNA Damage

    Directory of Open Access Journals (Sweden)

    Eric J. Jaehnig

    2013-07-01

    Full Text Available DNA damage activates checkpoint kinases that induce several downstream events, including widespread changes in transcription. However, the specific connections between the checkpoint kinases and downstream transcription factors (TFs are not well understood. Here, we integrate kinase mutant expression profiles, transcriptional regulatory interactions, and phosphoproteomics to map kinases and downstream TFs to transcriptional regulatory networks. Specifically, we investigate the role of the Saccharomyces cerevisiae checkpoint kinases (Mec1, Tel1, Chk1, Rad53, and Dun1 in the transcriptional response to DNA damage caused by methyl methanesulfonate. The result is a global kinase-TF regulatory network in which Mec1 and Tel1 signal through Rad53 to synergistically regulate the expression of more than 600 genes. This network involves at least nine TFs, many of which have Rad53-dependent phosphorylation sites, as regulators of checkpoint-kinase-dependent genes. We also identify a major DNA damage-induced transcriptional network that regulates stress response genes independently of the checkpoint kinases.

  16. Controlling for gene expression changes in transcription factor protein networks.

    Science.gov (United States)

    Banks, Charles A S; Lee, Zachary T; Boanca, Gina; Lakshminarasimhan, Mahadevan; Groppe, Brad D; Wen, Zhihui; Hattem, Gaye L; Seidel, Chris W; Florens, Laurence; Washburn, Michael P

    2014-06-01

    The development of affinity purification technologies combined with mass spectrometric analysis of purified protein mixtures has been used both to identify new protein-protein interactions and to define the subunit composition of protein complexes. Transcription factor protein interactions, however, have not been systematically analyzed using these approaches. Here, we investigated whether ectopic expression of an affinity tagged transcription factor as bait in affinity purification mass spectrometry experiments perturbs gene expression in cells, resulting in the false positive identification of bait-associated proteins when typical experimental controls are used. Using quantitative proteomics and RNA sequencing, we determined that the increase in the abundance of a set of proteins caused by overexpression of the transcription factor RelA is not sufficient for these proteins to then co-purify non-specifically and be misidentified as bait-associated proteins. Therefore, typical controls should be sufficient, and a number of different baits can be compared with a common set of controls. This is of practical interest when identifying bait interactors from a large number of different baits. As expected, we found several known RelA interactors enriched in our RelA purifications (NFκB1, NFκB2, Rel, RelB, IκBα, IκBβ, and IκBε). We also found several proteins not previously described in association with RelA, including the small mitochondrial chaperone Tim13. Using a variety of biochemical approaches, we further investigated the nature of the association between Tim13 and NFκB family transcription factors. This work therefore provides a conceptual and experimental framework for analyzing transcription factor protein interactions.

  17. Identification of identical transcript changes in liver and whole blood during acetaminophen toxicity

    Directory of Open Access Journals (Sweden)

    Liwen eZhang

    2012-09-01

    Full Text Available Abstract The ability to identify mechanisms underlying drug-induced liver injury (DILI in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a noninvasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP. In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose with similar patterns of expression in blood and liver during APAP induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only thirty eight genes were common to both the 6 and 24h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined.

  18. Physical Module Networks: an integrative approach for reconstructing transcription regulation

    OpenAIRE

    Novershtern, Noa; Regev, Aviv; Friedman, Nir

    2011-01-01

    Motivation: Deciphering the complex mechanisms by which regulatory networks control gene expression remains a major challenge. While some studies infer regulation from dependencies between the expression levels of putative regulators and their targets, others focus on measured physical interactions. Results: Here, we present Physical Module Networks, a unified framework that combines a Bayesian model describing modules of co-expressed genes and their shared regulation programs, and a phys...

  19. Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

    DEFF Research Database (Denmark)

    Zelezniak, Aleksej; Pers, Tune Hannes; Pinho Soares, Simao Pedro;

    2010-01-01

    Type 2 diabetes mellitus (T2DM) is a disorder characterized by both insulin resistance and impaired insulin secretion. Recent transcriptomics studies related to T2DM have revealed changes in expression of a large number of metabolic genes in a variety of tissues. Identification of the molecular...... mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets...... with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment...

  20. Comparative genomic reconstruction of transcriptional networks controlling central metabolism in the Shewanella genus

    Directory of Open Access Journals (Sweden)

    Kovaleva Galina

    2011-06-01

    Full Text Available Abstract Background Genome-scale prediction of gene regulation and reconstruction of transcriptional regulatory networks in bacteria is one of the critical tasks of modern genomics. The Shewanella genus is comprised of metabolically versatile gamma-proteobacteria, whose lifestyles and natural environments are substantially different from Escherichia coli and other model bacterial species. The comparative genomics approaches and computational identification of regulatory sites are useful for the in silico reconstruction of transcriptional regulatory networks in bacteria. Results To explore conservation and variations in the Shewanella transcriptional networks we analyzed the repertoire of transcription factors and performed genomics-based reconstruction and comparative analysis of regulons in 16 Shewanella genomes. The inferred regulatory network includes 82 transcription factors and their DNA binding sites, 8 riboswitches and 6 translational attenuators. Forty five regulons were newly inferred from the genome context analysis, whereas others were propagated from previously characterized regulons in the Enterobacteria and Pseudomonas spp.. Multiple variations in regulatory strategies between the Shewanella spp. and E. coli include regulon contraction and expansion (as in the case of PdhR, HexR, FadR, numerous cases of recruiting non-orthologous regulators to control equivalent pathways (e.g. PsrA for fatty acid degradation and, conversely, orthologous regulators to control distinct pathways (e.g. TyrR, ArgR, Crp. Conclusions We tentatively defined the first reference collection of ~100 transcriptional regulons in 16 Shewanella genomes. The resulting regulatory network contains ~600 regulated genes per genome that are mostly involved in metabolism of carbohydrates, amino acids, fatty acids, vitamins, metals, and stress responses. Several reconstructed regulons including NagR for N-acetylglucosamine catabolism were experimentally validated in S

  1. Computational identification of a p38SAPK regulated transcription factor network required for tumor cell quiescence

    OpenAIRE

    Adam, Alejandro P.; George, Ajish; Schewe, Denis; Bragado, Paloma; Iglesias, Bibiana V.; Ranganathan, Aparna C.; Kourtidis, Antonis; Conklin, Douglas S.; Julio A Aguirre-Ghiso

    2009-01-01

    The stress activated kinase p38 plays key roles in tumor suppression and induction of tumor cell dormancy. However, the mechanisms behind these functions remain poorly understood. Using computational tools we identified a transcription factor (TF) network regulated by p38α/β and required for human squamous carcinoma cell quiescence in vivo. We found that p38 transcriptionally regulates a core network of 46 genes that includes 16 TFs. Activation of p38 induced the expression of the TFs p53 and...

  2. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.

    Science.gov (United States)

    Fogel, Brent L; Cho, Ellen; Wahnich, Amanda; Gao, Fuying; Becherel, Olivier J; Wang, Xizhe; Fike, Francesca; Chen, Leslie; Criscuolo, Chiara; De Michele, Giuseppe; Filla, Alessandro; Collins, Abigail; Hahn, Angelika F; Gatti, Richard A; Konopka, Genevieve; Perlman, Susan; Lavin, Martin F; Geschwind, Daniel H; Coppola, Giovanni

    2014-09-15

    Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4. PMID:24760770

  3. Localizing potentially active post-transcriptional regulations in the Ewing's sarcoma gene regulatory network

    Directory of Open Access Journals (Sweden)

    Delyon Bernard

    2010-11-01

    Full Text Available Abstract Background A wide range of techniques is now available for analyzing regulatory networks. Nonetheless, most of these techniques fail to interpret large-scale transcriptional data at the post-translational level. Results We address the question of using large-scale transcriptomic observation of a system perturbation to analyze a regulatory network which contained several types of interactions - transcriptional and post-translational. Our method consisted of post-processing the outputs of an open-source tool named BioQuali - an automatic constraint-based analysis mimicking biologist's local reasoning on a large scale. The post-processing relied on differences in the behavior of the transcriptional and post-translational levels in the network. As a case study, we analyzed a network representation of the genes and proteins controlled by an oncogene in the context of Ewing's sarcoma. The analysis allowed us to pinpoint active interactions specific to this cancer. We also identified the parts of the network which were incomplete and should be submitted for further investigation. Conclusions The proposed approach is effective for the qualitative analysis of cancer networks. It allows the integrative use of experimental data of various types in order to identify the specific information that should be considered a priority in the initial - and possibly very large - experimental dataset. Iteratively, new dataset can be introduced into the analysis to improve the network representation and make it more specific.

  4. Transcriptional networks driving enhancer function in the CFTR gene.

    Science.gov (United States)

    Kerschner, Jenny L; Harris, Ann

    2012-09-01

    A critical cis-regulatory element for the CFTR (cystic fibrosis transmembrane conductance regulator) gene is located in intron 11, 100 kb distal to the promoter, with which it interacts. This sequence contains an intestine-selective enhancer and associates with enhancer signature proteins, such as p300, in addition to tissue-specific TFs (transcription factors). In the present study we identify critical TFs that are recruited to this element and demonstrate their importance in regulating CFTR expression. In vitro DNase I footprinting and EMSAs (electrophoretic mobility-shift assays) identified four cell-type-selective regions that bound TFs in vitro. ChIP (chromatin immunoprecipitation) identified FOXA1/A2 (forkhead box A1/A2), HNF1 (hepatocyte nuclear factor 1) and CDX2 (caudal-type homeobox 2) as in vivo trans-interacting factors. Mutation of their binding sites in the intron 11 core compromised its enhancer activity when measured by reporter gene assay. Moreover, siRNA (small interfering RNA)-mediated knockdown of CDX2 caused a significant reduction in endogenous CFTR transcription in intestinal cells, suggesting that this factor is critical for the maintenance of high levels of CFTR expression in these cells. The ChIP data also demonstrate that these TFs interact with multiple cis-regulatory elements across the CFTR locus, implicating a more global role in intestinal expression of the gene.

  5. Computational methods to dissect cis-regulatory transcriptional networks

    Indian Academy of Sciences (India)

    Vibha Rani

    2007-12-01

    The formation of diverse cell types from an invariant set of genes is governed by biochemical and molecular processes that regulate gene activity. A complete understanding of the regulatory mechanisms of gene expression is the major function of genomics. Computational genomics is a rapidly emerging area for deciphering the regulation of metazoan genes as well as interpreting the results of high-throughput screening. The integration of computer science with biology has expedited molecular modelling and processing of large-scale data inputs such as microarrays, analysis of genomes, transcriptomes and proteomes. Many bioinformaticians have developed various algorithms for predicting transcriptional regulatory mechanisms from the sequence, gene expression and interaction data. This review contains compiled information of various computational methods adopted to dissect gene expression pathways.

  6. Topological basis of signal integration in the transcriptional-regulatory network of the yeast, Saccharomyces cerevisiae

    OpenAIRE

    Chennubhotla Chakra; Wu Chuang; Farkas Illés J; Bahar Ivet; Oltvai Zoltán N

    2006-01-01

    Abstract Background Signal recognition and information processing is a fundamental cellular function, which in part involves comprehensive transcriptional regulatory (TR) mechanisms carried out in response to complex environmental signals in the context of the cell's own internal state. However, the network topological basis of developing such integrated responses remains poorly understood. Results By studying the TR network of the yeast Saccharomyces cerevisiae we show that an intermediate l...

  7. Combinatorial Limits of Transcription Factors and Gene Regulatory Networks in Development and Evolution

    OpenAIRE

    Werner, Eric

    2015-01-01

    Gene Regulatory Networks (GRNs) consisting of combinations of transcription factors (TFs) and their cis promoters are assumed to be sufficient to direct the development of organisms. Mutations in GRNs are assumed to be the primary drivers for the evolution of multicellular life. Here it is proven that neither of these assumptions is correct. They are inconsistent with fundamental principles of combinatorics of bounded encoded networks. It is shown there are inherent complexity and control cap...

  8. Identification of a Dynamic Core Transcriptional Network in t(8;21 AML that Regulates Differentiation Block and Self-Renewal

    Directory of Open Access Journals (Sweden)

    Anetta Ptasinska

    2014-09-01

    Full Text Available Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21, subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21 cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion. Perturbation of this equilibrium in t(8;21 cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation. Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21 is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.

  9. Coevolution within a transcriptional network by compensatory trans and cis mutations

    KAUST Repository

    Kuo, D.

    2010-10-26

    Transcriptional networks have been shown to evolve very rapidly, prompting questions as to how such changes arise and are tolerated. Recent comparisons of transcriptional networks across species have implicated variations in the cis-acting DNA sequences near genes as the main cause of divergence. What is less clear is how these changes interact with trans-acting changes occurring elsewhere in the genetic circuit. Here, we report the discovery of a system of compensatory trans and cis mutations in the yeast AP-1 transcriptional network that allows for conserved transcriptional regulation despite continued genetic change. We pinpoint a single species, the fungal pathogen Candida glabrata, in which a trans mutation has occurred very recently in a single AP-1 family member, distinguishing it from its Saccharomyces ortholog. Comparison of chromatin immunoprecipitation profiles between Candida and Saccharomyces shows that, despite their different DNA-binding domains, the AP-1 orthologs regulate a conserved block of genes. This conservation is enabled by concomitant changes in the cis-regulatory motifs upstream of each gene. Thus, both trans and cis mutations have perturbed the yeast AP-1 regulatory system in such a way as to compensate for one another. This demonstrates an example of “coevolution” between a DNA-binding transcription factor and its cis-regulatory site, reminiscent of the coevolution of protein binding partners.

  10. A network of paralogous stress response transcription factors in the human pathogen Candida glabrata.

    Directory of Open Access Journals (Sweden)

    Jawad eMerhej

    2016-05-01

    Full Text Available The yeast Candida glabrata has become the second cause of systemic candidemia in humans. However, relatively few genome-wide studies have been conducted in this organism and our knowledge of its transcriptional regulatory network is quite limited. In the present work, we combined genome-wide chromatin immunoprecipitation (ChIP-seq, transcriptome analyses and DNA binding motif predictions to describe the regulatory interactions of the seven Yap (Yeast AP1 transcription factors of C. glabrata. We described a transcriptional network containing 255 regulatory interactions and 309 potential target genes. We predicted with high confidence the preferred DNA binding sites for 5 of the 7 CgYaps and showed a strong conservation of the Yap DNA binding properties between S. cerevisiae and C. glabrata. We provided reliable functional annotation for 3 of the 7 Yaps and identified for Yap1 and Yap5 a core regulon which is conserved in S. cerevisiae, C. glabrata and C. albicans. We uncovered new roles for CgYap7 in the regulation of iron-sulfur cluster biogenesis, for CgYap1 in the regulation of heme biosynthesis and for CgYap5 in the repression of GRX4 in response to iron starvation. These transcription factors define an interconnected transcriptional network at the cross-roads between redox homeostasis, oxygen consumption and iron metabolism.

  11. Regulation of the BMP Signaling-Responsive Transcriptional Network in the Drosophila Embryo.

    Science.gov (United States)

    Deignan, Lisa; Pinheiro, Marco T; Sutcliffe, Catherine; Saunders, Abbie; Wilcockson, Scott G; Zeef, Leo A H; Donaldson, Ian J; Ashe, Hilary L

    2016-07-01

    The BMP signaling pathway has a conserved role in dorsal-ventral axis patterning during embryonic development. In Drosophila, graded BMP signaling is transduced by the Mad transcription factor and opposed by the Brinker repressor. In this study, using the Drosophila embryo as a model, we combine RNA-seq with Mad and Brinker ChIP-seq to decipher the BMP-responsive transcriptional network underpinning differentiation of the dorsal ectoderm during dorsal-ventral axis patterning. We identify multiple new BMP target genes, including positive and negative regulators of EGF signaling. Manipulation of EGF signaling levels by loss- and gain-of-function studies reveals that EGF signaling negatively regulates embryonic BMP-responsive transcription. Therefore, the BMP gene network has a self-regulating property in that it establishes a balance between its activity and that of the antagonistic EGF signaling pathway to facilitate correct patterning. In terms of BMP-dependent transcription, we identify key roles for the Zelda and Zerknüllt transcription factors in establishing the resulting expression domain, and find widespread binding of insulator proteins to the Mad and Brinker-bound genomic regions. Analysis of embryos lacking the BEAF-32 insulator protein shows reduced transcription of a peak BMP target gene and a reduction in the number of amnioserosa cells, the fate specified by peak BMP signaling. We incorporate our findings into a model for Mad-dependent activation, and discuss its relevance to BMP signal interpretation in vertebrates. PMID:27379389

  12. Numerical Simulation of Unsteady Blood Flow through Capillary Networks.

    Science.gov (United States)

    Davis, J M; Pozrikidis, C

    2011-08-01

    A numerical method is implemented for computing unsteady blood flow through a branching capillary network. The evolution of the discharge hematocrit along each capillary segment is computed by integrating in time a one-dimensional convection equation using a finite-difference method. The convection velocity is determined by the local and instantaneous effective capillary blood viscosity, while the tube to discharge hematocrit ratio is deduced from available correlations. Boundary conditions for the discharge hematocrit at divergent bifurcations arise from the partitioning law proposed by Klitzman and Johnson involving a dimensionless exponent, q≥1. When q=1, the cells are partitioned in proportion to the flow rate; as q tends to infinity, the cells are channeled into the branch with the highest flow rate. Simulations are performed for a tree-like, perfectly symmetric or randomly perturbed capillary network with m generations. When the tree involves more than a few generations, a supercritical Hopf bifurcation occurs at a critical value of q, yielding spontaneous self-sustained oscillations in the absence of external forcing. A phase diagram in the m-q plane is presented to establish conditions for unsteady flow, and the effect of various geometrical and physical parameters is examined. For a given network tree order, m, oscillations can be induced for a sufficiently high value of q by increasing the apparent intrinsic viscosity, decreasing the ratio of the vessel diameter from one generation to the next, or by decreasing the diameter of the terminal vessels. With other parameters fixed, oscillations are inhibited by increasing m. The results of the continuum model are in excellent agreement with the predictions of a discrete model where the motion of individual cells is followed from inlet to outlet.

  13. Characterizing and prototyping genetic networks with cell-free transcription-translation reactions.

    Science.gov (United States)

    Takahashi, Melissa K; Hayes, Clarmyra A; Chappell, James; Sun, Zachary Z; Murray, Richard M; Noireaux, Vincent; Lucks, Julius B

    2015-09-15

    A central goal of synthetic biology is to engineer cellular behavior by engineering synthetic gene networks for a variety of biotechnology and medical applications. The process of engineering gene networks often involves an iterative 'design-build-test' cycle, whereby the parts and connections that make up the network are built, characterized and varied until the desired network function is reached. Many advances have been made in the design and build portions of this cycle. However, the slow process of in vivo characterization of network function often limits the timescale of the testing step. Cell-free transcription-translation (TX-TL) systems offer a simple and fast alternative to performing these characterizations in cells. Here we provide an overview of a cell-free TX-TL system that utilizes the native Escherichia coli TX-TL machinery, thereby allowing a large repertoire of parts and networks to be characterized. As a way to demonstrate the utility of cell-free TX-TL, we illustrate the characterization of two genetic networks: an RNA transcriptional cascade and a protein regulated incoherent feed-forward loop. We also provide guidelines for designing TX-TL experiments to characterize new genetic networks. We end with a discussion of current and emerging applications of cell free systems.

  14. Noise Effects on Oscillator Network of Transcription Regulators

    Institute of Scientific and Technical Information of China (English)

    WANG Xian-Ju; AI Bao-Quan; LIU Guo-Tao; LIU Liang-Gang

    2002-01-01

    Based on the model describing the regulation of the PRM operator region of λ phage proposed by Jeff Hastyet al., we study the noise effects on the oscillator network. We find that the additive noise cannot change the period andthe amplitude of the relaxation oscillator, but in the multiplicative case, the period of the relaxation oscillator increasesto a constant value with the increase of the strength of noise, and the amplitude of the relaxation oscillator also showsincreases with the increase of the strength of noise. This novel results suggest that an external multiplicative noise sourcecould be used to control gene expression.

  15. Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma

    DEFF Research Database (Denmark)

    Cinegaglia, Naiara C; Andrade, Sonia Cristina S; Tokar, Tomas;

    2016-01-01

    of miR-21 expression were associated with lower patient survival (p = 0.042). We identified a regulatory network including miR-15b and miR-155, and transcription factors with prognostic value in lung cancer. Our findings may contribute to the development of treatment strategies in lung adenocarcinoma....

  16. Comparative genomic reconstruction of transcriptional networks controlling central metabolism in the Shewanella genus

    Energy Technology Data Exchange (ETDEWEB)

    Rodionov, Dmitry A.; Novichkov, Pavel; Stavrovskaya, Elena D.; Rodionova, Irina A.; Li, Xiaoqing; Kazanov, Marat D.; Ravcheev, Dmitry A.; Gerasimova, Anna V.; Kazakov, Alexey E.; Kovaleva, Galina Y.; Permina, Elizabeth A.; Laikova, Olga N.; Overbeek, Ross; Romine, Margaret F.; Fredrickson, Jim K.; Arkin, Adam P.; Dubchak, Inna; Osterman, Andrei L.; Gelfand, Mikhail S.

    2011-06-15

    Genome-scale prediction of gene regulation and reconstruction of transcriptional regulatory networks in bacteria is one of the critical tasks of modern genomics. Despite the growing number of genome-scale gene expression studies, our abilities to convert the results of these studies into accurate regulatory annotations and to project them from model to other organisms are extremely limited. The comparative genomics approaches and computational identification of regulatory sites are useful for the in silico reconstruction of transcriptional regulatory networks in bacteria. The Shewanella genus is comprised of metabolically versatile gamma-proteobacteria, whose lifestyles and natural environments are substantially different from Escherichia coli and other model bacterial species. To explore conservation and variations in the Shewanella transcriptional networks we analyzed the repertoire of transcription factors and performed genomics-based reconstruction and comparative analysis of regulons in 16 Shewanella genomes. The inferred regulatory network includes 82 transcription factors and their DNA binding sites, 8 riboswitches and 6 translational attenuators. Forty five regulons were newly inferred from the genome context analysis, whereas others were propagated from previously characterized regulons in the Enterobacteria and Pseudomonas spp.. However, even orthologous regulators with conserved DNA-binding motifs may control substantially different gene sets, revealing striking differences in regulatory strategies between the Shewanella spp. and E. coli. Multiple examples of regulatory network rewiring include regulon contraction and expansion (as in the case of PdhR, HexR, FadR), and numerous cases of recruiting non-orthologous regulators to control equivalent pathways (e.g. NagR for N-acetylglucosamine catabolism and PsrA for fatty acid degradation) and, conversely, orthologous regulators to control distinct pathways (e.g. TyrR, ArgR, Crp).

  17. Transcriptional regulation and steady-state modeling of metabolic networks

    DEFF Research Database (Denmark)

    Zelezniak, Aleksej

    become a focal point in diagnosing and treating diseases such as diabetes and cancer. Type 2 diabetes mellitus is a complex metabolic disease which is recognized as one of the largest threats to human health in the 21st century. Recent studies of gene expression levels in human tissue samples have...... indicated that multiple metabolic pathways are dys-regulated in diabetes and in individuals at risk for diabetes; which of these are primary, or central to disease pathogenesis, remains a key question. Cellular metabolic networks are highly interconnected and often tightly regulated; any perturbations...... diagnostics for type 2 diabetes and impaired glucose metabolism. In a broader context, the study provides a framework for analysis of gene expression datasets from complex heterogeneous diseases, genetic, and environmental perturbations that are reflected in and/or mediated through changes in metabolism...

  18. Integrated cellular network of transcription regulations and protein-protein interactions

    Directory of Open Access Journals (Sweden)

    Chen Bor-Sen

    2010-03-01

    Full Text Available Abstract Background With the accumulation of increasing omics data, a key goal of systems biology is to construct networks at different cellular levels to investigate cellular machinery of the cell. However, there is currently no satisfactory method to construct an integrated cellular network that combines the gene regulatory network and the signaling regulatory pathway. Results In this study, we integrated different kinds of omics data and developed a systematic method to construct the integrated cellular network based on coupling dynamic models and statistical assessments. The proposed method was applied to S. cerevisiae stress responses, elucidating the stress response mechanism of the yeast. From the resulting integrated cellular network under hyperosmotic stress, the highly connected hubs which are functionally relevant to the stress response were identified. Beyond hyperosmotic stress, the integrated network under heat shock and oxidative stress were also constructed and the crosstalks of these networks were analyzed, specifying the significance of some transcription factors to serve as the decision-making devices at the center of the bow-tie structure and the crucial role for rapid adaptation scheme to respond to stress. In addition, the predictive power of the proposed method was also demonstrated. Conclusions We successfully construct the integrated cellular network which is validated by literature evidences. The integration of transcription regulations and protein-protein interactions gives more insight into the actual biological network and is more predictive than those without integration. The method is shown to be powerful and flexible and can be used under different conditions and for different species. The coupling dynamic models of the whole integrated cellular network are very useful for theoretical analyses and for further experiments in the fields of network biology and synthetic biology.

  19. Comparative analysis of module-based versus direct methods for reverse-engineering transcriptional regulatory networks

    Directory of Open Access Journals (Sweden)

    Joshi Anagha

    2009-05-01

    Full Text Available Abstract Background A myriad of methods to reverse-engineer transcriptional regulatory networks have been developed in recent years. Direct methods directly reconstruct a network of pairwise regulatory interactions while module-based methods predict a set of regulators for modules of coexpressed genes treated as a single unit. To date, there has been no systematic comparison of the relative strengths and weaknesses of both types of methods. Results We have compared a recently developed module-based algorithm, LeMoNe (Learning Module Networks, to a mutual information based direct algorithm, CLR (Context Likelihood of Relatedness, using benchmark expression data and databases of known transcriptional regulatory interactions for Escherichia coli and Saccharomyces cerevisiae. A global comparison using recall versus precision curves hides the topologically distinct nature of the inferred networks and is not informative about the specific subtasks for which each method is most suited. Analysis of the degree distributions and a regulator specific comparison show that CLR is 'regulator-centric', making true predictions for a higher number of regulators, while LeMoNe is 'target-centric', recovering a higher number of known targets for fewer regulators, with limited overlap in the predicted interactions between both methods. Detailed biological examples in E. coli and S. cerevisiae are used to illustrate these differences and to prove that each method is able to infer parts of the network where the other fails. Biological validation of the inferred networks cautions against over-interpreting recall and precision values computed using incomplete reference networks. Conclusion Our results indicate that module-based and direct methods retrieve largely distinct parts of the underlying transcriptional regulatory networks. The choice of algorithm should therefore be based on the particular biological problem of interest and not on global metrics which cannot be

  20. Transcriptional modules related to hepatocellular carcinoma survival: coexpression network analysis.

    Science.gov (United States)

    Xu, Xinsen; Zhou, Yanyan; Miao, Runchen; Chen, Wei; Qu, Kai; Pang, Qing; Liu, Chang

    2016-06-01

    We performed weighted gene coexpression network analysis (WGCNA) to gain insights into the molecular aspects of hepatocellular carcinoma (HCC). Raw microarray datasets (including 488 samples) were downloaded from the Gene Expression Omnibus (GEO) website. Data were normalized using the RMA algorithm. We utilized the WGCNA to identify the coexpressed genes (modules) after non-specific filtering. Correlation and survival analyses were conducted using the modules, and gene ontology (GO) enrichment was applied to explore the possible mechanisms. Eight distinct modules were identified by the WGCNA. Pink and red modules were associated with liver function, whereas turquoise and black modules were inversely correlated with tumor staging. Poor outcomes were found in the low expression group in the turquoise module and in the high expression group in the red module. In addition, GO enrichment analysis suggested that inflammation, immune, virus-related, and interferon-mediated pathways were enriched in the turquoise module. Several potential biomarkers, such as cyclin-dependent kinase 1 (CDK1), topoisomerase 2α (TOP2A), and serpin peptidase inhibitor clade C (antithrombin) member 1 (SERPINC1), were also identified. In conclusion, gene signatures identified from the genome-based assays could contribute to HCC stratification. WGCNA was able to identify significant groups of genes associated with cancer prognosis. PMID:27052251

  1. TIGER: Toolbox for integrating genome-scale metabolic models, expression data, and transcriptional regulatory networks

    Directory of Open Access Journals (Sweden)

    Jensen Paul A

    2011-09-01

    Full Text Available Abstract Background Several methods have been developed for analyzing genome-scale models of metabolism and transcriptional regulation. Many of these methods, such as Flux Balance Analysis, use constrained optimization to predict relationships between metabolic flux and the genes that encode and regulate enzyme activity. Recently, mixed integer programming has been used to encode these gene-protein-reaction (GPR relationships into a single optimization problem, but these techniques are often of limited generality and lack a tool for automating the conversion of rules to a coupled regulatory/metabolic model. Results We present TIGER, a Toolbox for Integrating Genome-scale Metabolism, Expression, and Regulation. TIGER converts a series of generalized, Boolean or multilevel rules into a set of mixed integer inequalities. The package also includes implementations of existing algorithms to integrate high-throughput expression data with genome-scale models of metabolism and transcriptional regulation. We demonstrate how TIGER automates the coupling of a genome-scale metabolic model with GPR logic and models of transcriptional regulation, thereby serving as a platform for algorithm development and large-scale metabolic analysis. Additionally, we demonstrate how TIGER's algorithms can be used to identify inconsistencies and improve existing models of transcriptional regulation with examples from the reconstructed transcriptional regulatory network of Saccharomyces cerevisiae. Conclusion The TIGER package provides a consistent platform for algorithm development and extending existing genome-scale metabolic models with regulatory networks and high-throughput data.

  2. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes.

    Science.gov (United States)

    Yao, Lijing; Shen, Hui; Laird, Peter W; Farnham, Peggy J; Berman, Benjamin P

    2015-05-21

    Recent studies indicate that DNA methylation can be used to identify transcriptional enhancers, but no systematic approach has been developed for genome-wide identification and analysis of enhancers based on DNA methylation. We describe ELMER (Enhancer Linking by Methylation/Expression Relationships), an R-based tool that uses DNA methylation to identify enhancers and correlates enhancer state with expression of nearby genes to identify transcriptional targets. Transcription factor motif analysis of enhancers is coupled with expression analysis of transcription factors to infer upstream regulators. Using ELMER, we investigated more than 2,000 tumor samples from The Cancer Genome Atlas. We identified networks regulated by known cancer drivers such as GATA3 and FOXA1 (breast cancer), SOX17 and FOXA2 (endometrial cancer), and NFE2L2, SOX2, and TP63 (squamous cell lung cancer). We also identified novel networks with prognostic associations, including RUNX1 in kidney cancer. We propose ELMER as a powerful new paradigm for understanding the cis-regulatory interface between cancer-associated transcription factors and their functional target genes.

  3. Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

    Directory of Open Access Journals (Sweden)

    DeYoung Joseph

    2009-08-01

    Full Text Available Abstract Background Amyotrophic Lateral Sclerosis (ALS is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients. Results Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4% showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA was used to find disease-related networks (modules and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls and third dataset (63 patients and 63 controls, thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS. Conclusion This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.

  4. Comparative analysis of the transcription-factor gene regulatory networks of E. coli and S. cerevisiae

    Directory of Open Access Journals (Sweden)

    Santillán Moisés

    2008-01-01

    Full Text Available Abstract Background The regulatory interactions between transcription factors (TF and regulated genes (RG in a species genome can be lumped together in a single directed graph. The TF's and RG's conform the nodes of this graph, while links are drawn whenever a transcription factor regulates a gene's expression. Projections onto TF nodes can be constructed by linking every two nodes regulating a common gene. Similarly, projections onto RG nodes can be made by linking every two regulated genes sharing at least one common regulator. Recent studies of the connectivity pattern in the transcription-factor regulatory network of many organisms have revealed some interesting properties. However, the differences between TF and RG nodes have not been widely explored. Results After analysing the RG and TF projections of the transcription-factor gene regulatory networks of Escherichia coli and Saccharomyces cerevisiae, we found several common characteristic as well as some noticeable differences. To better understand these differences, we compared the properties of the E. coli and S. cerevisiae RG- and TF-projected networks with those of the corresponding projections built from randomized versions of the original bipartite networks. These last results indicate that the observed differences are mostly due to the very different ratios of TF to RG counts of the E. coli and S. cerevisiae bipartite networks, rather than to their having different connectivity patterns. Conclusion Since E. coli is a prokaryotic organism while S. cerevisiae is eukaryotic, there are important differences between them concerning processing of mRNA before translation, DNA packing, amount of junk DNA, and gene regulation. From the results in this paper we conclude that the most important effect such differences have had on the development of the corresponding transcription-factor gene regulatory networks is their very different ratios of TF to RG numbers. This ratio is more than three

  5. Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons.

    Science.gov (United States)

    Sandberg, Magnus; Flandin, Pierre; Silberberg, Shanni; Su-Feher, Linda; Price, James D; Hu, Jia Sheng; Kim, Carol; Visel, Axel; Nord, Alex S; Rubenstein, John L R

    2016-09-21

    The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants. PMID:27657450

  6. Deciphering transcriptional and metabolic networks associated with lysine metabolism during Arabidopsis seed development.

    Science.gov (United States)

    Angelovici, Ruthie; Fait, Aaron; Zhu, Xiaohong; Szymanski, Jedrzej; Feldmesser, Ester; Fernie, Alisdair R; Galili, Gad

    2009-12-01

    In order to elucidate transcriptional and metabolic networks associated with lysine (Lys) metabolism, we utilized developing Arabidopsis (Arabidopsis thaliana) seeds as a system in which Lys synthesis could be stimulated developmentally without application of chemicals and coupled this to a T-DNA insertion knockout mutation impaired in Lys catabolism. This seed-specific metabolic perturbation stimulated Lys accumulation starting from the initiation of storage reserve accumulation. Our results revealed that the response of seed metabolism to the inducible alteration of Lys metabolism was relatively minor; however, that which was observable operated in a modular manner. They also demonstrated that Lys metabolism is strongly associated with the operation of the tricarboxylic acid cycle while largely disconnected from other metabolic networks. In contrast, the inducible alteration of Lys metabolism was strongly associated with gene networks, stimulating the expression of hundreds of genes controlling anabolic processes that are associated with plant performance and vigor while suppressing a small number of genes associated with plant stress interactions. The most pronounced effect of the developmentally inducible alteration of Lys metabolism was an induction of expression of a large set of genes encoding ribosomal proteins as well as genes encoding translation initiation and elongation factors, all of which are associated with protein synthesis. With respect to metabolic regulation, the inducible alteration of Lys metabolism was primarily associated with altered expression of genes belonging to networks of amino acids and sugar metabolism. The combined data are discussed within the context of network interactions both between and within metabolic and transcriptional control systems.

  7. Unraveling the WRKY transcription factors network in Arabidopsis Thaliana by integrative approach

    Directory of Open Access Journals (Sweden)

    Mouna Choura

    2015-06-01

    Full Text Available The WRKY transcription factors superfamily are involved in diverse biological processes in plants including response to biotic and abiotic stresses and plant immunity. Protein-protein interaction network is a useful approach for understanding these complex processes. The availability of Arabidopsis Thaliana interactome offers a good opportunity to do get a global view of protein network. In this work, we have constructed the WRKY transcription factor network by combining different sources of evidence and we characterized its topological features using computational tools. We found that WRKY network is a hub-based network involving multifunctional proteins denoted as hubs such as WRKY 70, WRKY40, WRKY 53, WRKY 60, WRKY 33 and WRKY 51. Functional annotation showed seven functional modules particularly involved in biotic stress and defense responses. Furthermore, the gene ontology and pathway enrichment analysis revealed that WRKY proteins are mainly involved in plant-pathogen interaction pathways and their functions are directly related to the stress response and immune system process.

  8. Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia

    OpenAIRE

    Somasundaram, Rajesh; Prasad, Mahadesh A. J.; Ungerbäck, Jonas; Sigvardsson, Mikael

    2015-01-01

    B-lymphocyte development in the bone marrow is controlled by the coordinated action of transcription factors creating regulatory networks ensuring activation of the B-lymphoid program and silencing of alternative cell fates. This process is tightly connected to malignant transformation because B-lineage acute lymphoblastic leukemia cells display a pronounced block in differentiation resulting in the expansion of immature progenitor cells. Over the last few years, high-resolution analysis of g...

  9. Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis.

    OpenAIRE

    O'Driscoll, Lorraine

    2013-01-01

    PUBLISHED Weighted gene coexpression network analysis (WGCNA) is a powerful 'guilt-by-association'-based method to extract coexpressed groups of genes from large heterogeneous messenger RNA expression data sets. We have utilized WGCNA to identify 11 coregulated gene clusters across 2342 breast cancer samples from 13 microarray-based gene expression studies. A number of these transcriptional modules were found to be correlated to clinicopathological variables (e.g. tumor grade), survival en...

  10. GAM: a web-service for integrated transcriptional and metabolic network analysis.

    Science.gov (United States)

    Sergushichev, Alexey A; Loboda, Alexander A; Jha, Abhishek K; Vincent, Emma E; Driggers, Edward M; Jones, Russell G; Pearce, Edward J; Artyomov, Maxim N

    2016-07-01

    Novel techniques for high-throughput steady-state metabolomic profiling yield information about changes of nearly thousands of metabolites. Such metabolomic profiles, when analyzed together with transcriptional profiles, can reveal novel insights about underlying biological processes. While a number of conceptual approaches have been developed for data integration, easily accessible tools for integrated analysis of mammalian steady-state metabolomic and transcriptional data are lacking. Here we present GAM ('genes and metabolites'): a web-service for integrated network analysis of transcriptional and steady-state metabolomic data focused on identification of the most changing metabolic subnetworks between two conditions of interest. In the web-service, we have pre-assembled metabolic networks for humans, mice, Arabidopsis and yeast and adapted exact solvers for an optimal subgraph search to work in the context of these metabolic networks. The output is the most regulated metabolic subnetwork of size controlled by false discovery rate parameters. The subnetworks are then visualized online and also can be downloaded in Cytoscape format for subsequent processing. The web-service is available at: https://artyomovlab.wustl.edu/shiny/gam/. PMID:27098040

  11. Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks.

    Science.gov (United States)

    Chopin, Michaël; Seillet, Cyril; Chevrier, Stéphane; Wu, Li; Wang, Hongsheng; Morse, Herbert C; Belz, Gabrielle T; Nutt, Stephen L

    2013-12-16

    Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors-PU.1, ID2, IRF4, and IRF8-in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow-derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β-dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.

  12. Transcriptional profiling uncovers a network of cholesterol-responsive atherosclerosis target genes.

    Directory of Open Access Journals (Sweden)

    Josefin Skogsberg

    2008-03-01

    Full Text Available Despite the well-documented effects of plasma lipid lowering regimes halting atherosclerosis lesion development and reducing morbidity and mortality of coronary artery disease and stroke, the transcriptional response in the atherosclerotic lesion mediating these beneficial effects has not yet been carefully investigated. We performed transcriptional profiling at 10-week intervals in atherosclerosis-prone mice with human-like hypercholesterolemia and a genetic switch to lower plasma lipoproteins (Ldlr(-/-Apo(100/100Mttp(flox/flox Mx1-Cre. Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated that accumulation of lipid-poor macrophages reached a point that led to the rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation supported by lesion histology. Genetic lowering of plasma cholesterol (e.g., lipoproteins at this point all together prevented the formation of advanced plaques and parallel transcriptional profiling of the atherosclerotic arterial wall identified 37 cholesterol-responsive genes mediating this effect. Validation by siRNA-inhibition in macrophages incubated with acetylated-LDL revealed a network of eight cholesterol-responsive atherosclerosis genes regulating cholesterol-ester accumulation. Taken together, we have identified a network of atherosclerosis genes that in response to plasma cholesterol-lowering prevents the formation of advanced plaques. This network should be of interest for the development of novel atherosclerosis therapies.

  13. Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Zhou Qing

    2009-07-01

    Full Text Available Abstract Background Recent work has revealed that a core group of transcription factors (TFs regulates the key characteristics of embryonic stem (ES cells: pluripotency and self-renewal. Current efforts focus on identifying genes that play important roles in maintaining pluripotency and self-renewal in ES cells and aim to understand the interactions among these genes. To that end, we investigated the use of unsigned and signed network analysis to identify pluripotency and differentiation related genes. Results We show that signed networks provide a better systems level understanding of the regulatory mechanisms of ES cells than unsigned networks, using two independent murine ES cell expression data sets. Specifically, using signed weighted gene co-expression network analysis (WGCNA, we found a pluripotency module and a differentiation module, which are not identified in unsigned networks. We confirmed the importance of these modules by incorporating genome-wide TF binding data for key ES cell regulators. Interestingly, we find that the pluripotency module is enriched with genes related to DNA damage repair and mitochondrial function in addition to transcriptional regulation. Using a connectivity measure of module membership, we not only identify known regulators of ES cells but also show that Mrpl15, Msh6, Nrf1, Nup133, Ppif, Rbpj, Sh3gl2, and Zfp39, among other genes, have important roles in maintaining ES cell pluripotency and self-renewal. We also report highly significant relationships between module membership and epigenetic modifications (histone modifications and promoter CpG methylation status, which are known to play a role in controlling gene expression during ES cell self-renewal and differentiation. Conclusion Our systems biologic re-analysis of gene expression, transcription factor binding, epigenetic and gene ontology data provides a novel integrative view of ES cell biology.

  14. Virtual mutagenesis of the yeast cyclins genetic network reveals complex dynamics of transcriptional control networks.

    Directory of Open Access Journals (Sweden)

    Eliska Vohradska

    Full Text Available Study of genetic networks has moved from qualitative description of interactions between regulators and regulated genes to the analysis of the interaction dynamics. This paper focuses on the analysis of dynamics of one particular network--the yeast cyclins network. Using a dedicated mathematical model of gene expression and a procedure for computation of the parameters of the model from experimental data, a complete numerical model of the dynamics of the cyclins genetic network was attained. The model allowed for performing virtual experiments on the network and observing their influence on the expression dynamics of the genes downstream in the regulatory cascade. Results show that when the network structure is more complicated, and the regulatory interactions are indirect, results of gene deletion are highly unpredictable. As a consequence of quantitative behavior of the genes and their connections within the network, causal relationship between a regulator and target gene may not be discovered by gene deletion. Without including the dynamics of the system into the network, its functional properties cannot be studied and interpreted correctly.

  15. Dissecting the expression relationships between RNA-binding proteins and their cognate targets in eukaryotic post-transcriptional regulatory networks

    Science.gov (United States)

    Nishtala, Sneha; Neelamraju, Yaseswini; Janga, Sarath Chandra

    2016-05-01

    RNA-binding proteins (RBPs) are pivotal in orchestrating several steps in the metabolism of RNA in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Here, we employed CLIP (cross-linking immunoprecipitation)-seq datasets for 60 human RBPs and RIP-ChIP (RNP immunoprecipitation-microarray) data for 69 yeast RBPs to construct a network of genome-wide RBP- target RNA interactions for each RBP. We show in humans that majority (~78%) of the RBPs are strongly associated with their target transcripts at transcript level while ~95% of the studied RBPs were also found to be strongly associated with expression levels of target transcripts when protein expression levels of RBPs were employed. At transcript level, RBP - RNA interaction data for the yeast genome, exhibited a strong association for 63% of the RBPs, confirming the association to be conserved across large phylogenetic distances. Analysis to uncover the features contributing to these associations revealed the number of target transcripts and length of the selected protein-coding transcript of an RBP at the transcript level while intensity of the CLIP signal, number of RNA-Binding domains, location of the binding site on the transcript, to be significant at the protein level. Our analysis will contribute to improved modelling and prediction of post-transcriptional networks.

  16. Phenotypic and transcriptional plasticity directed by a yeast mitogen-activated protein kinase network.

    Science.gov (United States)

    Breitkreutz, Ashton; Boucher, Lorrie; Breitkreutz, Bobby-Joe; Sultan, Mujahid; Jurisica, Igor; Tyers, Mike

    2003-11-01

    The yeast pheromone/filamentous growth MAPK pathway mediates both mating and invasive-growth responses. The interface between this MAPK module and the transcriptional machinery consists of a network of two MAPKs, Fus3 and Kss1; two regulators, Rst1 and Rst2 (a.k.a. Dig1 and Dig2); and two transcription factors, Ste12 and Tec1. Of 16 possible combinations of gene deletions in FUS3, KSS1, RST1, and RST2 in the sigma1278 background, 10 display constitutive invasive growth. Rst1 was the primary negative regulator of invasive growth, while other components either attenuated or enhanced invasive growth, depending on the genetic context. Despite activation of the invasive response by lesions at the same level in the MAPK pathway, transcriptional profiles of different invasive mutant combinations did not exhibit a unified program of gene expression. The distal MAPK regulatory network is thus capable of generating phenotypically similar invasive-growth states (an attractor) from different molecular architectures (trajectories) that can functionally compensate for one another. This systems-level robustness may also account for the observed diversity of signals that trigger invasive growth. PMID:14668360

  17. A genomic approach to identify regulatory nodes in the transcriptional network of systemic acquired resistance in plants.

    Directory of Open Access Journals (Sweden)

    Dong Wang

    2006-11-01

    Full Text Available Many biological processes are controlled by intricate networks of transcriptional regulators. With the development of microarray technology, transcriptional changes can be examined at the whole-genome level. However, such analysis often lacks information on the hierarchical relationship between components of a given system. Systemic acquired resistance (SAR is an inducible plant defense response involving a cascade of transcriptional events induced by salicylic acid through the transcription cofactor NPR1. To identify additional regulatory nodes in the SAR network, we performed microarray analysis on Arabidopsis plants expressing the NPR1-GR (glucocorticoid receptor fusion protein. Since nuclear translocation of NPR1-GR requires dexamethasone, we were able to control NPR1-dependent transcription and identify direct transcriptional targets of NPR1. We show that NPR1 directly upregulates the expression of eight WRKY transcription factor genes. This large family of 74 transcription factors has been implicated in various defense responses, but no specific WRKY factor has been placed in the SAR network. Identification of NPR1-regulated WRKY factors allowed us to perform in-depth genetic analysis on a small number of WRKY factors and test well-defined phenotypes of single and double mutants associated with NPR1. Among these WRKY factors we found both positive and negative regulators of SAR. This genomics-directed approach unambiguously positioned five WRKY factors in the complex transcriptional regulatory network of SAR. Our work not only discovered new transcription regulatory components in the signaling network of SAR but also demonstrated that functional studies of large gene families have to take into consideration sequence similarity as well as the expression patterns of the candidates.

  18. Evidence for transcript networks composed of chimeric RNAs in human cells.

    Directory of Open Access Journals (Sweden)

    Sarah Djebali

    Full Text Available The classic organization of a gene structure has followed the Jacob and Monod bacterial gene model proposed more than 50 years ago. Since then, empirical determinations of the complexity of the transcriptomes found in yeast to human has blurred the definition and physical boundaries of genes. Using multiple analysis approaches we have characterized individual gene boundaries mapping on human chromosomes 21 and 22. Analyses of the locations of the 5' and 3' transcriptional termini of 492 protein coding genes revealed that for 85% of these genes the boundaries extend beyond the current annotated termini, most often connecting with exons of transcripts from other well annotated genes. The biological and evolutionary importance of these chimeric transcripts is underscored by (1 the non-random interconnections of genes involved, (2 the greater phylogenetic depth of the genes involved in many chimeric interactions, (3 the coordination of the expression of connected genes and (4 the close in vivo and three dimensional proximity of the genomic regions being transcribed and contributing to parts of the chimeric RNAs. The non-random nature of the connection of the genes involved suggest that chimeric transcripts should not be studied in isolation, but together, as an RNA network.

  19. Regulation of Transcriptional Networks by PKC Isozymes: Identification of c-Rel as a Key Transcription Factor for PKC-Regulated Genes.

    Directory of Open Access Journals (Sweden)

    Rachana Garg

    Full Text Available Activation of protein kinase C (PKC, a family of serine-threonine kinases widely implicated in cancer progression, has major impact on gene expression. In a recent genome-wide analysis of prostate cancer cells we identified distinctive gene expression profiles controlled by individual PKC isozymes and highlighted a prominent role for PKCδ in transcriptional activation.Here we carried out a thorough bioinformatics analysis to dissect transcriptional networks controlled by PKCα, PKCδ, and PKCε, the main diacylglycerol/phorbol ester PKCs expressed in prostate cancer cells. Despite the remarkable differences in the patterns of transcriptional responsive elements (REs regulated by each PKC, we found that c-Rel represents the most frequent RE in promoters regulated by all three PKCs. In addition, promoters of PKCδ-regulated genes were particularly enriched with REs for CREB, NF-E2, RREB, SRF, Oct-1, Evi-1, and NF-κB. Most notably, by using transcription factor-specific RNAi we were able to identify subsets of PKCδ-regulated genes modulated by c-Rel and CREB. Furthermore, PKCδ-regulated genes condensed under the c-Rel transcriptional regulation display significant functional interconnections with biological processes such as angiogenesis, inflammatory response, and cell motility.Our study identified candidate transcription factors in the promoters of PKC regulated genes, in particular c-Rel was found as a key transcription factor in the control of PKCδ-regulated genes. The deconvolution of PKC-regulated transcriptional networks and their nodes may greatly help in the identification of PKC effectors and have significant therapeutics implications.

  20. Co-expression network analysis identifies transcriptional modules in the mouse liver.

    Science.gov (United States)

    Liu, Wei; Ye, Hua

    2014-10-01

    The mouse liver transcriptome has been extensively studied but little is known about the global hepatic gene network of the mouse under normal physiological conditions. Understanding this will help reveal the transcriptional organization of the liver and elucidate its functional complexity. Here, weighted gene co-expression network analysis (WGCNA) was carried out to explore gene co-expression networks using large-scale microarray data from normal mouse livers. A total of 7,203 genes were parsed into 16 gene modules associated with protein catabolism, RNA processing, muscle contraction, transcriptional regulation, oxidation reduction, sterol biosynthesis, translation, fatty acid metabolism, immune response and others. The modules were organized into higher order co-expression groups. Hub genes in each module were found to be critical for module function. In sum, the analyses revealed the gene modular map of the mouse liver under normal physiological condition. These results provide a systems-level framework to help understand the complexity of the mouse liver at the molecular level, and should be beneficial in annotating uncharacterized genes. PMID:24816893

  1. MicroRNA and transcription factor mediated regulatory network for ovarian cancer: regulatory network of ovarian cancer.

    Science.gov (United States)

    Ying, Huanchun; Lv, Jing; Ying, Tianshu; Li, Jun; Yang, Qing; Ma, Yuan

    2013-10-01

    A better understanding on the regulatory interactions of microRNA (miRNA) target genes and transcription factor (TF) target genes in ovarian cancer may be conducive for developing early diagnosis strategy. Thus, gene expression data and miRNA expression data were downloaded from The Cancer Genome Atlas in this study. Differentially expressed genes and miRNAs were selected out with t test, and Gene Ontology enrichment analysis was performed with DAVID tools. Regulatory interactions were retrieved from miRTarBase, TRED, and TRANSFAC, and then networks for miRNA target genes and TF target genes were constructed to globally present the mechanisms. As a result, a total of 1,939 differentially expressed genes were identified, and they were enriched in 28 functions, among which cell cycle was affected to the most degree. Besides, 213 differentially expressed miRNAs were identified. Two regulatory networks for miRNA target genes and TF target genes were established and then both were combined, in which E2F transcription factor 1, cyclin-dependent kinase inhibitor 1A, cyclin E1, and miR-16 were the hub genes. These genes may be potential biomarkers for ovarian cancer.

  2. Modeling the effect of transcriptional noise on switching in gene networks in a genetic bistable switch.

    Science.gov (United States)

    Chaudhury, Srabanti

    2015-06-01

    Gene regulatory networks in cells allow transitions between gene expression states under the influence of both intrinsic and extrinsic noise. Here we introduce a new theoretical method to study the dynamics of switching in a two-state gene expression model with positive feedback by explicitly accounting for the transcriptional noise. Within this theoretical framework, we employ a semi-classical path integral technique to calculate the mean switching time starting from either an active or inactive promoter state. Our analytical predictions are in good agreement with Monte Carlo simulations and experimental observations.

  3. Architecture of transcriptional regulatory circuits is knitted over the topology of bio-molecular interaction networks

    DEFF Research Database (Denmark)

    Soberano de Oliveira, Ana Paula; Patil, Kiran Raosaheb; Nielsen, Jens

    2008-01-01

    Factors, Reporter Proteins and Reporter Complexes, and use this to decipher the logic of regulatory circuits playing a key role in yeast glucose repression and human diabetes. Conclusion: Reporter Features offer the opportunity to identify regulatory hot-spots in bio-molecular interaction networks...... that are significantly affected between or across conditions. Results of the Reporter Feature analysis not only provide a snapshot of the transcriptional regulatory program but also are biologically easy to interpret and provide a powerful way to generate new hypotheses. Our Reporter Features analyses of yeast glucose...

  4. Inference of Transcriptional Network for Pluripotency in Mouse Embryonic Stem Cells

    International Nuclear Information System (INIS)

    In embryonic stem cells, various transcription factors (TFs) maintain pluripotency. To gain insights into the regulatory system controlling pluripotency, I inferred the regulatory relationships between the TFs expressed in ES cells. In this study, I applied a method based on structural equation modeling (SEM), combined with factor analysis, to 649 expression profiles of 19 TF genes measured in mouse Embryonic Stem Cells (ESCs). The factor analysis identified 19 TF genes that were regulated by several unmeasured factors. Since the known cell reprogramming TF genes (Pou5f1, Sox2 and Nanog) are regulated by different factors, each estimated factor is considered to be an input for signal transduction to control pluripotency in mouse ESCs. In the inferred network model, TF proteins were also arranged as unmeasured factors that control other TFs. The interpretation of the inferred network model revealed the regulatory mechanism for controlling pluripotency in ES cells

  5. Sox2 transcription network acts as a molecular switch to regulate properties of neural stem cells

    Institute of Scientific and Technical Information of China (English)

    Koji; Shimozaki

    2014-01-01

    Neural stem cells(NSCs) contribute to ontogeny by producing neurons at the appropriate time and location. Neurogenesis from NSCs is also involved in various biological functions in adults. Thus, NSCs continue to exert their effects throughout the lifespan of the organism. The mechanism regulating the core functional properties of NSCs is governed by intra- and extracellular signals. Among the transcription factors that serve as molecular switches, Sox2 is considered a key factor in NSCs. Sox2 forms a core network with partner factors, thereby functioning as a molecular switch. This review discusses how the network of Sox2 partner and target genes illustrates the molecular characteristics of the mechanism underlying the self-renewal and multipotency of NSCs.

  6. Transcriptional profiles of supragranular-enriched genes associate with corticocortical network architecture in the human brain.

    Science.gov (United States)

    Krienen, Fenna M; Yeo, B T Thomas; Ge, Tian; Buckner, Randy L; Sherwood, Chet C

    2016-01-26

    The human brain is patterned with disproportionately large, distributed cerebral networks that connect multiple association zones in the frontal, temporal, and parietal lobes. The expansion of the cortical surface, along with the emergence of long-range connectivity networks, may be reflected in changes to the underlying molecular architecture. Using the Allen Institute's human brain transcriptional atlas, we demonstrate that genes particularly enriched in supragranular layers of the human cerebral cortex relative to mouse distinguish major cortical classes. The topography of transcriptional expression reflects large-scale brain network organization consistent with estimates from functional connectivity MRI and anatomical tracing in nonhuman primates. Microarray expression data for genes preferentially expressed in human upper layers (II/III), but enriched only in lower layers (V/VI) of mouse, were cross-correlated to identify molecular profiles across the cerebral cortex of postmortem human brains (n = 6). Unimodal sensory and motor zones have similar molecular profiles, despite being distributed across the cortical mantle. Sensory/motor profiles were anticorrelated with paralimbic and certain distributed association network profiles. Tests of alternative gene sets did not consistently distinguish sensory and motor regions from paralimbic and association regions: (i) genes enriched in supragranular layers in both humans and mice, (ii) genes cortically enriched in humans relative to nonhuman primates, (iii) genes related to connectivity in rodents, (iv) genes associated with human and mouse connectivity, and (v) 1,454 gene sets curated from known gene ontologies. Molecular innovations of upper cortical layers may be an important component in the evolution of long-range corticocortical projections.

  7. Altered Transcriptional Control Networks with Trans-Differentiation of Isogenic Mutant KRas NSCLC Models

    Directory of Open Access Journals (Sweden)

    John A Haley

    2014-12-01

    Full Text Available BackgroundThe capacity of cancer cells to undergo epithelial mesenchymal trans-differentiation has been implicated as a factor driving metastasis, through the acquisition of enhanced migratory/invasive cell programs and the engagement of anti-apoptotic mechanisms promoting drug and radiation resistance. Our aim was to define molecular signaling changes associated with mesenchymal trans-differentiation in two KRas mutant NSCLC models. We focused on central transcription and epigenetic regulators predicted to be important for mesenchymal cell survival.Experimental designWe have modeled trans-differentiation and cancer stemness in inducible isogenic mutant KRas H358 and A549 non-small cell lung cell backgrounds. We employed large-scale quantitative phospho-proteomic, proteomic, protein-protein interaction, RNA-Seq and network function prediction approaches to dissect the molecular events associated with the establishment and maintenance of the mesenchymal state.ResultsGene set enrichment and pathway prediction indicated BMI1, KDM5B, RUNX2, MYC/MAX, NFkB, LEF1, and HIF1 target networks were significantly enriched in the trans-differentiation of H358 and A549 NSCLC models. Physical overlaps between multiple networks implicate NR4A1 as an overlapping control between TCF and NFkB pathways. Enrichment correlations also indicated marked decrease in cell cycling, which occurred early in the EMT process. RNA abundance time course studies also indicated early expression of epigenetic and chromatin regulators, including CITED4, RUNX3, CMBX1 and SIRT4. ConclusionsMultiple transcription and epigenetic pathways where altered between epithelial and mesenchymal tumor cell states, notably the polycomb repressive complex-1, HP1g and BAF/Swi-Snf. Network analysis suggests redundancy in the activation and inhibition of pathway regulators, notably factors controlling epithelial cell state.

  8. A transcription factor network controls cell migration and fate decisions in the developing zebrafish pineal complex

    Science.gov (United States)

    Clanton, Joshua A.; Dean, Benjamin J.; Gamse, Joshua T.

    2016-01-01

    The zebrafish pineal complex consists of four cell types (rod and cone photoreceptors, projection neurons and parapineal neurons) that are derived from a single pineal complex anlage. After specification, parapineal neurons migrate unilaterally away from the rest of the pineal complex whereas rods, cones and projection neurons are non-migratory. The transcription factor Tbx2b is important for both the correct number and migration of parapineal neurons. We find that two additional transcription factors, Flh and Nr2e3, negatively regulate parapineal formation. Flh induces non-migratory neuron fates and limits the extent of parapineal specification, in part by activation of Nr2e3 expression. Tbx2b is positively regulated by Flh, but opposes Flh action during specification of parapineal neurons. Loss of parapineal neuron specification in Tbx2b-deficient embryos can be partially rescued by loss of Nr2e3 or Flh function; however, parapineal migration absolutely requires Tbx2b activity. We conclude that cell specification and migration in the pineal complex are regulated by a network of at least three transcription factors. PMID:27317804

  9. Medusa structure of the gene regulatory network: dominance of transcription factors in cancer subtype classification.

    Science.gov (United States)

    Guo, Yuchun; Feng, Ying; Trivedi, Niraj S; Huang, Sui

    2011-05-01

    Gene expression profiles consisting of ten thousands of transcripts are used for clustering of tissue, such as tumors, into subtypes, often without considering the underlying reason that the distinct patterns of expression arise because of constraints in the realization of gene expression profiles imposed by the gene regulatory network. The topology of this network has been suggested to consist of a regulatory core of genes represented most prominently by transcription factors (TFs) and microRNAs, that influence the expression of other genes, and of a periphery of 'enslaved' effector genes that are regulated but not regulating. This 'medusa' architecture implies that the core genes are much stronger determinants of the realized gene expression profiles. To test this hypothesis, we examined the clustering of gene expression profiles into known tumor types to quantitatively demonstrate that TFs, and even more pronounced, microRNAs, are much stronger discriminators of tumor type specific gene expression patterns than a same number of randomly selected or metabolic genes. These findings lend support to the hypothesis of a medusa architecture and of the canalizing nature of regulation by microRNAs. They also reveal the degree of freedom for the expression of peripheral genes that are less stringently associated with a tissue type specific global gene expression profile.

  10. Dynamic transcription factor activity and networks during ErbB2 breast oncogenesis and targeted therapy.

    Science.gov (United States)

    Weiss, M S; Peñalver Bernabé, B; Shin, S; Asztalos, S; Dubbury, S J; Mui, M D; Bellis, A D; Bluver, D; Tonetti, D A; Saez-Rodriguez, J; Broadbelt, L J; Jeruss, J S; Shea, L D

    2014-12-01

    Tissue development and disease progression are multi-stage processes controlled by an evolving set of key regulatory factors, and identifying these factors necessitates a dynamic analysis spanning relevant time scales. Current omics approaches depend on incomplete biological databases to identify critical cellular processes. Herein, we present TRACER (TRanscriptional Activity CEll aRrays), which was employed to quantify the dynamic activity of numerous transcription factor (TFs) simultaneously in 3D and networks for TRACER (NTRACER), a computational algorithm that allows for cellular rewiring to establish dynamic regulatory networks based on activity of TF reporter constructs. We identified major hubs at various stages of culture associated with normal and abnormal tissue growth (i.e., ELK-1 and E2F1, respectively) and the mechanism of action for a targeted therapeutic, lapatinib, through GATA-1, which were confirmed in human ErbB2 positive breast cancer patients and human ErbB2 positive breast cancer cell lines that were either sensitive or resistant to lapatinib.

  11. Identification of the minimal connected network of transcription factors by transcriptomic and genomic data integration.

    Science.gov (United States)

    Essaghir, Ahmed

    2014-01-01

    Thanks to high-throughput experiments, biological conditions can be investigated at both the entire genomic and transcriptomic levels. In addition, protein-protein interaction (PPI) data are widely available for well-studied organisms, such as human. In this chapter, we will present an integrative approach that makes use of these data to find the PPI module involving the key regulated transcription factors shared by a number of given conditions. These conditions could be for instance different cancer types. Briefly, for the studied conditions, we need to identify commonly affected chromosomal regions subjected to copy number alterations together with the identification of differentially expressed list of genes in each condition. Transcription factor activity will be inferred from these regulated gene lists. Then, we will define TFs, for which the activity could be explained by an associative effect of both loci copy number alteration and gene expression levels of their coding genes. PPI networks could be mined, afterwards, using appropriate algorithms to find the significant module that connect those TFs together. This module could be viewed as the minimal connected network of TFs, the regulation of which is shared between the investigated conditions.

  12. Co-expression network analysis reveals transcription factors associated to cell wall biosynthesis in sugarcane.

    Science.gov (United States)

    Ferreira, Savio Siqueira; Hotta, Carlos Takeshi; Poelking, Viviane Guzzo de Carli; Leite, Debora Chaves Coelho; Buckeridge, Marcos Silveira; Loureiro, Marcelo Ehlers; Barbosa, Marcio Henrique Pereira; Carneiro, Monalisa Sampaio; Souza, Glaucia Mendes

    2016-05-01

    Sugarcane is a hybrid of Saccharum officinarum and Saccharum spontaneum, with minor contributions from other species in Saccharum and other genera. Understanding the molecular basis of cell wall metabolism in sugarcane may allow for rational changes in fiber quality and content when designing new energy crops. This work describes a comparative expression profiling of sugarcane ancestral genotypes: S. officinarum, S. spontaneum and S. robustum and a commercial hybrid: RB867515, linking gene expression to phenotypes to identify genes for sugarcane improvement. Oligoarray experiments of leaves, immature and intermediate internodes, detected 12,621 sense and 995 antisense transcripts. Amino acid metabolism was particularly evident among pathways showing natural antisense transcripts expression. For all tissues sampled, expression analysis revealed 831, 674 and 648 differentially expressed genes in S. officinarum, S. robustum and S. spontaneum, respectively, using RB867515 as reference. Expression of sugar transporters might explain sucrose differences among genotypes, but an unexpected differential expression of histones were also identified between high and low Brix° genotypes. Lignin biosynthetic genes and bioenergetics-related genes were up-regulated in the high lignin genotype, suggesting that these genes are important for S. spontaneum to allocate carbon to lignin, while S. officinarum allocates it to sucrose storage. Co-expression network analysis identified 18 transcription factors possibly related to cell wall biosynthesis while in silico analysis detected cis-elements involved in cell wall biosynthesis in their promoters. Our results provide information to elucidate regulatory networks underlying traits of interest that will allow the improvement of sugarcane for biofuel and chemicals production. PMID:26820137

  13. Identification of a nutrient-sensing transcriptional network in monocytes by using inbred rat models on a cafeteria diet

    Science.gov (United States)

    Martínez-Micaelo, Neus; González-Abuín, Noemi; Terra, Ximena; Ardévol, Ana; Pinent, Montserrat; Petretto, Enrico; Blay, Mayte

    2016-01-01

    ABSTRACT Obesity has reached pandemic levels worldwide. The current models of diet-induced obesity in rodents use predominantly high-fat based diets that do not take into account the consumption of variety of highly palatable, energy-dense foods that are prevalent in Western society. We and others have shown that the cafeteria (CAF) diet is a robust and reproducible model of human metabolic syndrome with tissue inflammation in the rat. We have previously shown that inbred rat strains such as Wistar Kyoto (WKY) and Lewis (LEW) show different susceptibilities to CAF diets with distinct metabolic and morphometric profiles. Here, we show a difference in plasma MCP-1 levels and investigate the effect of the CAF diet on peripheral blood monocyte transcriptome, as powerful stress-sensing immune cells, in WKY and LEW rats. We found that 75.5% of the differentially expressed transcripts under the CAF diet were upregulated in WKY rats and were functionally related to the activation of the immune response. Using a gene co-expression network constructed from the genes differentially expressed between CAF diet-fed LEW and WKY rats, we identified acyl-CoA synthetase short-chain family member 2 (Acss2) as a hub gene for a nutrient-sensing cluster of transcripts in monocytes. The Acss2 genomic region is significantly enriched for previously established metabolism quantitative trait loci in the rat. Notably, monocyte expression levels of Acss2 significantly correlated with plasma glucose, triglyceride, leptin and non-esterified fatty acid (NEFA) levels as well as morphometric measurements such as body weight and the total fat following feeding with the CAF diet in the rat. These results show the importance of the genetic background in nutritional genomics and identify inbred rat strains as potential models for CAF-diet-induced obesity. PMID:27483348

  14. Whole genome transcript profiling from fingerstick blood samples: a comparison and feasibility study

    OpenAIRE

    Williams Adam R; Mondala Tony S; Robison Elizabeth H; Head Steven R; Salomon Daniel R; Kurian Sunil M

    2009-01-01

    Abstract Background Whole genome gene expression profiling has revolutionized research in the past decade especially with the advent of microarrays. Recently, there have been significant improvements in whole blood RNA isolation techniques which, through stabilization of RNA at the time of sample collection, avoid bias and artifacts introduced during sample handling. Despite these improvements, current human whole blood RNA stabilization/isolation kits are limited by the requirement of a veno...

  15. A DNA-binding-site landscape and regulatory network analysis for NAC transcription factors in Arabidopsis thaliana

    DEFF Research Database (Denmark)

    Lindemose, Søren; Jensen, Michael Krogh; de Velde, Jan Van;

    2014-01-01

    Target gene identification for transcription factors is a prerequisite for the systems wide understanding of organismal behaviour. NAM-ATAF1/2-CUC2 (NAC) transcription factors are amongst the largest transcription factor families in plants, yet limited data exist from unbiased approaches to resolve...... regulatory networks of 12 NAC transcription factors. Our data offer specific single-base resolution fingerprints for most TFs studied and indicate that NAC DNA-binding specificities might be predicted from their DNA-binding domain's sequence. The developed methodology, including the application...... with the workflow associated with functional modules offer a strong resource to unravel the regulatory potential of NAC genes and that this workflow could be used to study other families of transcription factors....

  16. Transcriptional regulatory network refinement and quantification through kinetic modeling, gene expression microarray data and information theory

    Directory of Open Access Journals (Sweden)

    Tuncay Kagan

    2007-01-01

    Full Text Available Abstract Background Gene expression microarray and other multiplex data hold promise for addressing the challenges of cellular complexity, refined diagnoses and the discovery of well-targeted treatments. A new approach to the construction and quantification of transcriptional regulatory networks (TRNs is presented that integrates gene expression microarray data and cell modeling through information theory. Given a partial TRN and time series data, a probability density is constructed that is a functional of the time course of transcription factor (TF thermodynamic activities at the site of gene control, and is a function of mRNA degradation and transcription rate coefficients, and equilibrium constants for TF/gene binding. Results Our approach yields more physicochemical information that compliments the results of network structure delineation methods, and thereby can serve as an element of a comprehensive TRN discovery/quantification system. The most probable TF time courses and values of the aforementioned parameters are obtained by maximizing the probability obtained through entropy maximization. Observed time delays between mRNA expression and activity are accounted for implicitly since the time course of the activity of a TF is coupled by probability functional maximization, and is not assumed to be proportional to expression level of the mRNA type that translates into the TF. This allows one to investigate post-translational and TF activation mechanisms of gene regulation. Accuracy and robustness of the method are evaluated. A kinetic formulation is used to facilitate the analysis of phenomena with a strongly dynamical character while a physically-motivated regularization of the TF time course is found to overcome difficulties due to omnipresent noise and data sparsity that plague other methods of gene expression data analysis. An application to Escherichia coli is presented. Conclusion Multiplex time series data can be used for the

  17. PlantPAN 2.0: an update of plant promoter analysis navigator for reconstructing transcriptional regulatory networks in plants.

    Science.gov (United States)

    Chow, Chi-Nga; Zheng, Han-Qin; Wu, Nai-Yun; Chien, Chia-Hung; Huang, Hsien-Da; Lee, Tzong-Yi; Chiang-Hsieh, Yi-Fan; Hou, Ping-Fu; Yang, Tien-Yi; Chang, Wen-Chi

    2016-01-01

    Transcription factors (TFs) are sequence-specific DNA-binding proteins acting as critical regulators of gene expression. The Plant Promoter Analysis Navigator (PlantPAN; http://PlantPAN2.itps.ncku.edu.tw) provides an informative resource for detecting transcription factor binding sites (TFBSs), corresponding TFs, and other important regulatory elements (CpG islands and tandem repeats) in a promoter or a set of plant promoters. Additionally, TFBSs, CpG islands, and tandem repeats in the conserve regions between similar gene promoters are also identified. The current PlantPAN release (version 2.0) contains 16 960 TFs and 1143 TF binding site matrices among 76 plant species. In addition to updating of the annotation information, adding experimentally verified TF matrices, and making improvements in the visualization of transcriptional regulatory networks, several new features and functions are incorporated. These features include: (i) comprehensive curation of TF information (response conditions, target genes, and sequence logos of binding motifs, etc.), (ii) co-expression profiles of TFs and their target genes under various conditions, (iii) protein-protein interactions among TFs and their co-factors, (iv) TF-target networks, and (v) downstream promoter elements. Furthermore, a dynamic transcriptional regulatory network under various conditions is provided in PlantPAN 2.0. The PlantPAN 2.0 is a systematic platform for plant promoter analysis and reconstructing transcriptional regulatory networks.

  18. Whole genome transcript profiling from fingerstick blood samples: a comparison and feasibility study

    Directory of Open Access Journals (Sweden)

    Williams Adam R

    2009-12-01

    Full Text Available Abstract Background Whole genome gene expression profiling has revolutionized research in the past decade especially with the advent of microarrays. Recently, there have been significant improvements in whole blood RNA isolation techniques which, through stabilization of RNA at the time of sample collection, avoid bias and artifacts introduced during sample handling. Despite these improvements, current human whole blood RNA stabilization/isolation kits are limited by the requirement of a venous blood sample of at least 2.5 mL. While fingerstick blood collection has been used for many different assays, there has yet to be a kit developed to isolate high quality RNA for use in gene expression studies from such small human samples. The clinical and field testing advantages of obtaining reliable and reproducible gene expression data from a fingerstick are many; it is less invasive, time saving, more mobile, and eliminates the need of a trained phlebotomist. Furthermore, this method could also be employed in small animal studies, i.e. mice, where larger sample collections often require sacrificing the animal. In this study, we offer a rapid and simple method to extract sufficient amounts of high quality total RNA from approximately 70 μl of whole blood collected via a fingerstick using a modified protocol of the commercially available Qiagen PAXgene RNA Blood Kit. Results From two sets of fingerstick collections, about 70 uL whole blood collected via finger lancet and capillary tube, we recovered an average of 252.6 ng total RNA with an average RIN of 9.3. The post-amplification yields for 50 ng of total RNA averaged at 7.0 ug cDNA. The cDNA hybridized to Affymetrix HG-U133 Plus 2.0 GeneChips had an average % Present call of 52.5%. Both fingerstick collections were highly correlated with r2 values ranging from 0.94 to 0.97. Similarly both fingerstick collections were highly correlated to the venous collection with r2 values ranging from 0.88 to 0

  19. ASGR1 and ASGR2, the Genes that Encode the Asialoglycoprotein Receptor (Ashwell Receptor, Are Expressed in Peripheral Blood Monocytes and Show Interindividual Differences in Transcript Profile

    Directory of Open Access Journals (Sweden)

    Rebecca Louise Harris

    2012-01-01

    Full Text Available Background. The asialoglycoprotein receptor (ASGPR is a hepatic receptor that mediates removal of potentially hazardous glycoconjugates from blood in health and disease. The receptor comprises two proteins, asialoglycoprotein receptor 1 and 2 (ASGR1 and ASGR2, encoded by the genes ASGR1 and ASGR2. Design and Methods. Using reverse transcription amplification (RT-PCR, expression of ASGR1 and ASGR2 was investigated in human peripheral blood monocytes. Results. Monocytes were found to express ASGR1 and ASGR2 transcripts. Correctly spliced transcript variants encoding different isoforms of ASGR1 and ASGR2 were present in monocytes. The profile of transcript variants from both ASGR1 and ASGR2 differed among individuals. Transcript expression levels were compared with the hepatocyte cell line HepG2 which produces high levels of ASGPR. Monocyte transcripts were 4 to 6 orders of magnitude less than in HepG2 but nonetheless readily detectable using standard RT-PCR. The monocyte cell line THP1 gave similar results to monocytes harvested from peripheral blood, indicating it may provide a suitable model system for studying ASGPR function in this cell type. Conclusions. Monocytes transcribe and correctly process transcripts encoding the constituent proteins of the ASGPR. Monocytes may therefore represent a mobile pool of the receptor, capable of reaching sites remote from the liver.

  20. Ethylene Control of Fruit Ripening: Revisiting the Complex Network of Transcriptional Regulation.

    Science.gov (United States)

    Liu, Mingchun; Pirrello, Julien; Chervin, Christian; Roustan, Jean-Paul; Bouzayen, Mondher

    2015-12-01

    The plant hormone ethylene plays a key role in climacteric fruit ripening. Studies on components of ethylene signaling have revealed a linear transduction pathway leading to the activation of ethylene response factors. However, the means by which ethylene selects the ripening-related genes and interacts with other signaling pathways to regulate the ripening process are still to be elucidated. Using tomato (Solanum lycopersicum) as a reference species, the present review aims to revisit the mechanisms by which ethylene regulates fruit ripening by taking advantage of new tools available to perform in silico studies at the genome-wide scale, leading to a global view on the expression pattern of ethylene biosynthesis and response genes throughout ripening. Overall, it provides new insights on the transcriptional network by which this hormone coordinates the ripening process and emphasizes the interplay between ethylene and ripening-associated developmental factors and the link between epigenetic regulation and ethylene during fruit ripening.

  1. Regulatory Network of Transcription Factors in Response to Drought in Arabidopsis and Crops

    Institute of Scientific and Technical Information of China (English)

    Chen Li-miao; Li Wen-bin; Zhou Xin-an

    2012-01-01

    Drought is one of the most important environmental constraints limiting plant growth, development and crop yield. Many drought-inducible genes have been identified by molecular and genomic analyses in Arabidopsis, rice and other crops. To better understand reaction mechanism of plant to drought tolerance, we mainly focused on introducing the research of transcription factors (TFs) in signal transduction and regulatory network of gene expression conferring drought. A TF could bind multiple target genes to increase one or more kinds of stress tolerance. Sometimes, several TFs might act together with a target gene. So drought-tolerance genes or TFs might respond to high-salinity, cold or other stresses. The crosstalk of multiple stresses signal pathways is a crucial aspect of understanding stress signaling.

  2. Gene Networks in the Wild: Identifying Transcriptional Modules that Mediate Coral Resistance to Experimental Heat Stress.

    Science.gov (United States)

    Rose, Noah H; Seneca, Francois O; Palumbi, Stephen R

    2015-12-28

    Organisms respond to environmental variation partly through changes in gene expression, which underlie both homeostatic and acclimatory responses to environmental stress. In some cases, so many genes change in expression in response to different influences that understanding expression patterns for all these individual genes becomes difficult. To reduce this problem, we use a systems genetics approach to show that variation in the expression of thousands of genes of reef-building corals can be explained as variation in the expression of a small number of coexpressed "modules." Modules were often enriched for specific cellular functions and varied predictably among individuals, experimental treatments, and physiological state. We describe two transcriptional modules for which expression levels immediately after heat stress predict bleaching a day later. One of these early "bleaching modules" is enriched for sequence-specific DNA-binding proteins, particularly E26 transformation-specific (ETS)-family transcription factors. The other module is enriched for extracellular matrix proteins. These classes of bleaching response genes are clear in the modular gene expression analysis we conduct but are much more difficult to discern in single gene analyses. Furthermore, the ETS-family module shows repeated differences in expression among coral colonies grown in the same common garden environment, suggesting a heritable genetic or epigenetic basis for these expression polymorphisms. This finding suggests that these corals harbor high levels of gene-network variation, which could facilitate rapid evolution in the face of environmental change.

  3. Gene Networks in the Wild: Identifying Transcriptional Modules that Mediate Coral Resistance to Experimental Heat Stress.

    Science.gov (United States)

    Rose, Noah H; Seneca, Francois O; Palumbi, Stephen R

    2016-01-01

    Organisms respond to environmental variation partly through changes in gene expression, which underlie both homeostatic and acclimatory responses to environmental stress. In some cases, so many genes change in expression in response to different influences that understanding expression patterns for all these individual genes becomes difficult. To reduce this problem, we use a systems genetics approach to show that variation in the expression of thousands of genes of reef-building corals can be explained as variation in the expression of a small number of coexpressed "modules." Modules were often enriched for specific cellular functions and varied predictably among individuals, experimental treatments, and physiological state. We describe two transcriptional modules for which expression levels immediately after heat stress predict bleaching a day later. One of these early "bleaching modules" is enriched for sequence-specific DNA-binding proteins, particularly E26 transformation-specific (ETS)-family transcription factors. The other module is enriched for extracellular matrix proteins. These classes of bleaching response genes are clear in the modular gene expression analysis we conduct but are much more difficult to discern in single gene analyses. Furthermore, the ETS-family module shows repeated differences in expression among coral colonies grown in the same common garden environment, suggesting a heritable genetic or epigenetic basis for these expression polymorphisms. This finding suggests that these corals harbor high levels of gene-network variation, which could facilitate rapid evolution in the face of environmental change. PMID:26710855

  4. Alteration of transcriptional networks in the entorhinal cortex after maternal immune activation and adolescent cannabinoid exposure.

    Science.gov (United States)

    Hollins, Sharon L; Zavitsanou, Katerina; Walker, Frederick Rohan; Cairns, Murray J

    2016-08-01

    Maternal immune activation (MIA) and adolescent cannabinoid exposure (ACE) have both been identified as major environmental risk factors for schizophrenia. We examined the effects of these two risk factors alone, and in combination, on gene expression during late adolescence. Pregnant rats were exposed to the viral infection mimic polyriboinosinic-polyribocytidylic acid (poly I:C) on gestational day (GD) 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14days starting on postnatal day (PND) 35. Gene expression was examined in the left entorhinal cortex (EC) using mRNA microarrays. We found prenatal treatment with poly I:C alone, or HU210 alone, produced relatively minor changes in gene expression. However, following combined treatments, offspring displayed significant changes in transcription. This dramatic and persistent alteration of transcriptional networks enriched with genes involved in neurotransmission, cellular signalling and schizophrenia, was associated with a corresponding perturbation in the expression of small non-coding microRNA (miRNA). These results suggest that a combination of environmental exposures during development leads to significant genomic remodeling that disrupts maturation of the EC and its associated circuitry with important implications as the potential antecedents of memory and learning deficits in schizophrenia and other neuropsychiatric disorders. PMID:26923065

  5. Structure, function and networks of transcription factors involved in abiotic stress responses

    DEFF Research Database (Denmark)

    Lindemose, Søren; O'Shea, Charlotte; Jensen, Michael Krogh;

    2013-01-01

    Transcription factors (TFs) are master regulators of abiotic stress responses in plants. This review focuses on TFs from seven major TF families, known to play functional roles in response to abiotic stresses, including drought, high salinity, high osmolarity, temperature extremes and the phytoho......Transcription factors (TFs) are master regulators of abiotic stress responses in plants. This review focuses on TFs from seven major TF families, known to play functional roles in response to abiotic stresses, including drought, high salinity, high osmolarity, temperature extremes...... and the phytohormone ABA. Although ectopic expression of several TFs has improved abiotic stress tolerance in plants, fine-tuning of TF expression and protein levels remains a challenge to avoid crop yield loss. To further our understanding of TFs in abiotic stress responses, emerging gene regulatory networks based...... on TFs and their direct targets genes are presented. These revealed components shared between ABA-dependent and independent signaling as well as abiotic and biotic stress signaling. Protein structure analysis suggested that TFs hubs of large interactomes have extended regions with protein intrinsic...

  6. [The francophone Africa blood transfusion research network: a five-year report].

    Science.gov (United States)

    Tagny, Claude Tayou; Murphy, Edward L; Lefrère, Jean-Jacques

    2014-03-01

    There has been little blood safety research in sub-Saharan Africa, often consisting of local efforts whose findings had limited impact The "Francophone Africa Transfusion Research Network" was created in May 2007 with the objective of developing common evidence-based blood safety policies that may be adapted to each country's situation. The Group's activities to date have focused mainly on obtaining epidemiological and laboratory data on blood transfusion and on suggesting blood safety strategies, particularly in the field of TTIs. To carry out such research activities, the group works closely with the National Blood Transfusion Services (NBTS), the Regional Blood Transfusion Services (RBTS), the hospital blood banks (HBB) and collection stations. For the first 5years, four research priorities were identified: (i) descriptive studies of the characteristics of francophone African blood donors and blood centers; (ii) estimation of the residual risk of transfusion-transmitted major viral infections; (iii) an analysis of blood donor deferral strategies; and (iv) a description of TTI screening strategies and an external quality assurance system (EQAS) project. During this period, seven projects have been implemented at the national level and published and five multicenter studies were conducted and published. The present review reports the main observations and recommendations from those studies that could improve blood safety statute in Africa.

  7. Transcription factor-microRNA-target gene networks associated with ovarian cancer survival and recurrence.

    Science.gov (United States)

    Delfino, Kristin R; Rodriguez-Zas, Sandra L

    2013-01-01

    The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs), transcription factors (TFs), and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2*) were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497) were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.

  8. Transcription factor-microRNA-target gene networks associated with ovarian cancer survival and recurrence.

    Directory of Open Access Journals (Sweden)

    Kristin R Delfino

    Full Text Available The identification of reliable transcriptome biomarkers requires the simultaneous consideration of regulatory and target elements including microRNAs (miRNAs, transcription factors (TFs, and target genes. A novel approach that integrates multivariate survival analysis, feature selection, and regulatory network visualization was used to identify reliable biomarkers of ovarian cancer survival and recurrence. Expression profiles of 799 miRNAs, 17,814 TFs and target genes and cohort clinical records on 272 patients diagnosed with ovarian cancer were simultaneously considered and results were validated on an independent group of 146 patients. Three miRNAs (hsa-miR-16, hsa-miR-22*, and ebv-miR-BHRF1-2* were associated with both ovarian cancer survival and recurrence and 27 miRNAs were associated with either one hazard. Two miRNAs (hsa-miR-521 and hsa-miR-497 were cohort-dependent, while 28 were cohort-independent. This study confirmed 19 miRNAs previously associated with ovarian cancer and identified two miRNAs that have previously been associated with other cancer types. In total, the expression of 838 and 734 target genes and 12 and eight TFs were associated (FDR-adjusted P-value <0.05 with ovarian cancer survival and recurrence, respectively. Functional analysis highlighted the association between cellular and nucleotide metabolic processes and ovarian cancer. The more direct connections and higher centrality of the miRNAs, TFs and target genes in the survival network studied suggest that network-based approaches to prognosticate or predict ovarian cancer survival may be more effective than those for ovarian cancer recurrence. This study demonstrated the feasibility to infer reliable miRNA-TF-target gene networks associated with survival and recurrence of ovarian cancer based on the simultaneous analysis of co-expression profiles and consideration of the clinical characteristics of the patients.

  9. Phenotypic robustness and the assortativity signature of human transcription factor networks.

    Directory of Open Access Journals (Sweden)

    Dov A Pechenick

    2014-08-01

    Full Text Available Many developmental, physiological, and behavioral processes depend on the precise expression of genes in space and time. Such spatiotemporal gene expression phenotypes arise from the binding of sequence-specific transcription factors (TFs to DNA, and from the regulation of nearby genes that such binding causes. These nearby genes may themselves encode TFs, giving rise to a transcription factor network (TFN, wherein nodes represent TFs and directed edges denote regulatory interactions between TFs. Computational studies have linked several topological properties of TFNs - such as their degree distribution - with the robustness of a TFN's gene expression phenotype to genetic and environmental perturbation. Another important topological property is assortativity, which measures the tendency of nodes with similar numbers of edges to connect. In directed networks, assortativity comprises four distinct components that collectively form an assortativity signature. We know very little about how a TFN's assortativity signature affects the robustness of its gene expression phenotype to perturbation. While recent theoretical results suggest that increasing one specific component of a TFN's assortativity signature leads to increased phenotypic robustness, the biological context of this finding is currently limited because the assortativity signatures of real-world TFNs have not been characterized. It is therefore unclear whether these earlier theoretical findings are biologically relevant. Moreover, it is not known how the other three components of the assortativity signature contribute to the phenotypic robustness of TFNs. Here, we use publicly available DNaseI-seq data to measure the assortativity signatures of genome-wide TFNs in 41 distinct human cell and tissue types. We find that all TFNs share a common assortativity signature and that this signature confers phenotypic robustness to model TFNs. Lastly, we determine the extent to which each of the four

  10. Phenotypic robustness and the assortativity signature of human transcription factor networks.

    Science.gov (United States)

    Pechenick, Dov A; Payne, Joshua L; Moore, Jason H

    2014-08-01

    Many developmental, physiological, and behavioral processes depend on the precise expression of genes in space and time. Such spatiotemporal gene expression phenotypes arise from the binding of sequence-specific transcription factors (TFs) to DNA, and from the regulation of nearby genes that such binding causes. These nearby genes may themselves encode TFs, giving rise to a transcription factor network (TFN), wherein nodes represent TFs and directed edges denote regulatory interactions between TFs. Computational studies have linked several topological properties of TFNs - such as their degree distribution - with the robustness of a TFN's gene expression phenotype to genetic and environmental perturbation. Another important topological property is assortativity, which measures the tendency of nodes with similar numbers of edges to connect. In directed networks, assortativity comprises four distinct components that collectively form an assortativity signature. We know very little about how a TFN's assortativity signature affects the robustness of its gene expression phenotype to perturbation. While recent theoretical results suggest that increasing one specific component of a TFN's assortativity signature leads to increased phenotypic robustness, the biological context of this finding is currently limited because the assortativity signatures of real-world TFNs have not been characterized. It is therefore unclear whether these earlier theoretical findings are biologically relevant. Moreover, it is not known how the other three components of the assortativity signature contribute to the phenotypic robustness of TFNs. Here, we use publicly available DNaseI-seq data to measure the assortativity signatures of genome-wide TFNs in 41 distinct human cell and tissue types. We find that all TFNs share a common assortativity signature and that this signature confers phenotypic robustness to model TFNs. Lastly, we determine the extent to which each of the four components of the

  11. Flow of red blood cells in capillary networks

    OpenAIRE

    Couto, Ana; Teixeira, Lúcia; Leble, Vladimir; Lima, R.; Ribeiro, António E.; Dias, Ricardo

    2011-01-01

    In the present work we have studied the flow of red blood cells through a column packed with soda lime glass spheres with diameter of 337.5 micron (pore diameter 150 micron). The ratio between the average velocity of the RBCs and the average velocity of the carrying fluid (physiological saline) was close to 0.9. The RBCs migrated faster through the column than the carrying fluid mainly due to a hydrodynamic chromatographic effect.

  12. Cross-species transcriptional network analysis reveals conservation and variation in response to metal stress in cyanobacteria

    OpenAIRE

    Wang, Jiangxin; Wu, Gang; Chen, Lei; Zhang, Weiwen

    2013-01-01

    Background As one of the most dominant bacterial groups on Earth, cyanobacteria play a pivotal role in the global carbon cycling and the Earth atmosphere composition. Understanding their molecular responses to environmental perturbations has important scientific and environmental values. Since important biological processes or networks are often evolutionarily conserved, the cross-species transcriptional network analysis offers a useful strategy to decipher conserved and species-specific tran...

  13. Pleiotropy constrains the evolution of protein but not regulatory sequences in a transcription regulatory network influencing complex social behaviours

    Directory of Open Access Journals (Sweden)

    Daria eMolodtsova

    2014-12-01

    Full Text Available It is increasingly apparent that genes and networks that influence complex behaviour are evolutionary conserved, which is paradoxical considering that behaviour is labile over evolutionary timescales. How does adaptive change in behaviour arise if behaviour is controlled by conserved, pleiotropic, and likely evolutionary constrained genes? Pleiotropy and connectedness are known to constrain the general rate of protein evolution, prompting some to suggest that the evolution of complex traits, including behaviour, is fuelled by regulatory sequence evolution. However, we seldom have data on the strength of selection on mutations in coding and regulatory sequences, and this hinders our ability to study how pleiotropy influences coding and regulatory sequence evolution. Here we use population genomics to estimate the strength of selection on coding and regulatory mutations for a transcriptional regulatory network that influences complex behaviour of honey bees. We found that replacement mutations in highly connected transcription factors and target genes experience significantly stronger negative selection relative to weakly connected transcription factors and targets. Adaptively evolving proteins were significantly more likely to reside at the periphery of the regulatory network, while proteins with signs of negative selection were near the core of the network. Interestingly, connectedness and network structure had minimal influence on the strength of selection on putative regulatory sequences for both transcription factors and their targets. Our study indicates that adaptive evolution of complex behaviour can arise because of positive selection on protein-coding mutations in peripheral genes, and on regulatory sequence mutations in both transcription factors and their targets throughout the network.

  14. Dissimilatory Metabolism of Nitrogen Oxides in Bacteria:Comparative Reconstruction of Transcriptional Networks

    Energy Technology Data Exchange (ETDEWEB)

    Rodionov, Dmitry A.; Dubchak, Inna L.; Arkin, Adam P.; Alm, EricJ.; Gelfand, Mikhail S.

    2005-09-01

    result, we demonstrate considerable interconnection between various nitrogen-oxides-responsive regulatory systems for the denitrification and NO detoxification genes and evolutionary plasticity of this transcriptional network.

  15. Dissimilatory metabolism of nitrogen oxides in bacteria: comparative reconstruction of transcriptional networks.

    Directory of Open Access Journals (Sweden)

    2005-10-01

    denitrification genes. As the result, we demonstrate considerable interconnection between various nitrogen-oxides-responsive regulatory systems for the denitrification and NO detoxification genes and evolutionary plasticity of this transcriptional network.

  16. Dissimilatory metabolism of nitrogen oxides in bacteria: comparative reconstruction of transcriptional networks.

    Directory of Open Access Journals (Sweden)

    Dmitry A Rodionov

    2005-10-01

    denitrification genes. As the result, we demonstrate considerable interconnection between various nitrogen-oxides-responsive regulatory systems for the denitrification and NO detoxification genes and evolutionary plasticity of this transcriptional network.

  17. Transcriptional Regulatory Networks Activated by PI3K and ERK Transduced Growth Signals in Human Glioblastoma Cells

    Institute of Scientific and Technical Information of China (English)

    Peter M. Haverty; Zhi-Ping Weng; Ulla Hansen

    2005-01-01

    Determining how cells regulate their transcriptional response to extracellular signals is key to the understanding of complex eukaryotic systems. This study was initiated with the goals of furthering the study of mammalian transcriptional regulation and analyzing the relative benefits of related computational methodologies. One dataset available for such an analysis involved gene expression profiling of the early growth factor response to platelet derived growth factor (PDGF)in a human glioblastoma cell line; this study differentiated genes whose expression was regulated by signaling through the phosphoinositide-3-kinase (PI3K) versus the extracellular-signal regulated kinase (ERK) pathways. We have compared the inferred transcription factors from this previous study with additional predictions of regulatory transcription factors using two alternative promoter sequence analysis techniques. This comparative analysis, in which the algorithms predict overlapping,although not identical, sets of factors, argues for meticulous benchmarking of promoter sequence analysis methods to determine the positive and negative attributes that contribute to their varying results. Finally, we inferred transcriptional regulatory networks deriving from various signaling pathways using the CARRIE program suite. These networks not only included previously described transcriptional features of the response to growth signals, but also predicted new regulatory features for the propagation and modulation of the growth signal.

  18. Transcriptional profiling of the effect of lipopolysaccharide (LPS) pretreatment in blood from probiotics-treated dairy cows.

    Science.gov (United States)

    Adjei-Fremah, Sarah; Ekwemalor, Kingsley; Asiamah, Emmanuel; Ismail, Hamid; Worku, Mulumebet

    2016-12-01

    Probiotic supplements are beneficial for animal health and rumen function; and lipopolysaccharides (LPS) from gram negative bacteria have been associated with inflammatory diseases. In this study the transcriptional profile in whole blood collected from probiotics-treated cows was investigated in response to stimulation with lipopolysaccharides (LPS) in vitro. Microarray experiment was performed between LPS-treated and control samples using the Agilent one-color bovine v2 bovine (v2) 4x44K array slides. Global gene expression analysis identified 13,658 differentially expressed genes (fold change cutoff ≥ 2, P probiotics may stimulate the innate immune response of animal against parasitic and bacterial infections. We have provided a detailed description of the experimental design, microarray experiment and normalization and analysis of data which have been deposited into NCBI Gene Expression Omnibus (GEO): GSE75240. PMID:27656413

  19. Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach

    Directory of Open Access Journals (Sweden)

    Buer Jan

    2004-12-01

    Full Text Available Abstract Background Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. Results In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. Conclusion The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E

  20. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  1. Canonical pathways, networks and transcriptional factor regulation by clinical strains of Mycobacterium tuberculosis in pulmonary alveolar epithelial cells.

    Science.gov (United States)

    Mvubu, Nontobeko E; Pillay, Balakrishna; Gamieldien, Junaid; Bishai, William; Pillay, Manormoney

    2016-03-01

    Limited knowledge exists on pathways, networks and transcriptional factors regulated within epithelial cells by diverse Mycobacterium tuberculosis genotypes. This study aimed to elucidate these mechanisms induced in A549 epithelial cells by dominant clinical strains in KwaZulu-Natal, South Africa. RNA for sequencing was extracted from epithelial cells at 48 h post-infection with 5 strains at a multiplicity of infection of approximately 10:1. Bioinformatics analysis performed with the RNA-Seq Tuxedo pipeline identified differentially expressed genes. Changes in pathways, networks and transcriptional factors were identified using Ingenuity Pathway Analysis (IPA). The interferon signalling and hepatic fibrosis/hepatic stellate cell activation pathways were among the top 5 canonical pathways in all strains. Hierarchical clustering for enrichment of cholesterol biosynthesis and immune associated pathways revealed similar patterns for Beijing and Unique; F15/LAM4/KZN and F11; and, F28 and H37Rv strains, respectively. However, the induction of top scoring networks varied among the strains. Among the transcriptional factors, only EHL, IRF7, PML, STAT1, STAT2 and VDR were induced by all clinical strains. Activation of the different pathways, networks and transcriptional factors revealed in the current study may be an underlying mechanism that results in the differential host response by clinical strains of M. tuberculosis. PMID:26980499

  2. Mapping Variation in Cellular and Transcriptional Response to 1,25-Dihydroxyvitamin D3 in Peripheral Blood Mononuclear Cells.

    Science.gov (United States)

    Kariuki, Silvia N; Maranville, Joseph C; Baxter, Shaneen S; Jeong, Choongwon; Nakagome, Shigeki; Hrusch, Cara L; Witonsky, David B; Sperling, Anne I; Di Rienzo, Anna

    2016-01-01

    The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is an important modulator of the immune system, inhibiting cellular proliferation and regulating transcription of immune response genes. In order to characterize the genetic basis of variation in the immunomodulatory effects of 1,25D, we mapped quantitative traits of 1,25D response at both the cellular and the transcriptional level. We carried out a genome-wide association scan of percent inhibition of cell proliferation (Imax) induced by 1,25D treatment of peripheral blood mononuclear cells from 88 healthy African-American individuals. Two genome-wide significant variants were identified: rs1893662 in a gene desert on chromosome 18 (p = 2.32 x 10-8) and rs6451692 on chromosome 5 (p = 2.55 x 10-8), which may influence the anti-proliferative activity of 1,25D by regulating the expression of nearby genes such as the chemokine gene, CCL28, and the translation initiation gene, PAIP1. We also identified 8 expression quantitative trait loci at a FDRvitamin D receptor binding sites near genes differentially expressed in response to 1,25D, such as FERM Domain Containing 6 (FRMD6), which plays a critical role in regulating both cell proliferation and apoptosis. Combining information from the GWAS of Imax and the response eQTL mapping enabled identification of putative Imax-associated candidate genes such as PAIP1 and the transcriptional repressor gene ZNF649. Overall, the variants identified in this study are strong candidates for immune traits and diseases linked to vitamin D, such as multiple sclerosis. PMID:27454520

  3. Global screening of potential Candida albicans biofilm-related transcription factors via network comparison

    Directory of Open Access Journals (Sweden)

    Murillo Luis A

    2010-01-01

    Full Text Available Abstract Background Candida albicans is a commonly encountered fungal pathogen in humans. The formation of biofilm is a major virulence factor in C. albicans pathogenesis and is related to antidrug resistance of this organism. Although many factors affecting biofilm have been analyzed, molecular mechanisms that regulate biofilm formation still await to be elucidated. Results In this study, from the gene regulatory network perspective, we developed an efficient computational framework, which integrates different kinds of data from genome-scale analysis, for global screening of potential transcription factors (TFs controlling C. albicans biofilm formation. S. cerevisiae information and ortholog data were used to infer the possible TF-gene regulatory associations in C. albicans. Based on TF-gene regulatory associations and gene expression profiles, a stochastic dynamic model was employed to reconstruct the gene regulatory networks of C. albicans biofilm and planktonic cells. The two networks were then compared and a score of relevance value (RV was proposed to determine and assign the quantity of correlation of each potential TF with biofilm formation. A total of twenty-three TFs are identified to be related to the biofilm formation; ten of them are previously reported by literature evidences. Conclusions The results indicate that the proposed screening method can successfully identify most known biofilm-related TFs and also identify many others that have not been previously reported. Together, this method can be employed as a pre-experiment screening approach that reveals new target genes for further characterization to understand the regulatory mechanisms in biofilm formation, which can serve as the starting point for therapeutic intervention of C. albicans infections.

  4. Dynamic transcription factor networks in epithelial-mesenchymal transition in breast cancer models.

    Science.gov (United States)

    Siletz, Anaar; Schnabel, Michael; Kniazeva, Ekaterina; Schumacher, Andrew J; Shin, Seungjin; Jeruss, Jacqueline S; Shea, Lonnie D

    2013-01-01

    The epithelial-mesenchymal transition (EMT) is a complex change in cell differentiation that allows breast carcinoma cells to acquire invasive properties. EMT involves a cascade of regulatory changes that destabilize the epithelial phenotype and allow mesenchymal features to manifest. As transcription factors (TFs) are upstream effectors of the genome-wide expression changes that result in phenotypic change, understanding the sequential changes in TF activity during EMT provides rich information on the mechanism of this process. Because molecular interactions will vary as cells progress from an epithelial to a mesenchymal differentiation program, dynamic networks are needed to capture the changing context of molecular processes. In this study we applied an emerging high-throughput, dynamic TF activity array to define TF activity network changes in three cell-based models of EMT in breast cancer based on HMLE Twist ER and MCF-7 mammary epithelial cells. The TF array distinguished conserved from model-specific TF activity changes in the three models. Time-dependent data was used to identify pairs of TF activities with significant positive or negative correlation, indicative of interdependent TF activity throughout the six-day study period. Dynamic TF activity patterns were clustered into groups of TFs that change along a time course of gene expression changes and acquisition of invasive capacity. Time-dependent TF activity data was combined with prior knowledge of TF interactions to construct dynamic models of TF activity networks as epithelial cells acquire invasive characteristics. These analyses show EMT from a unique and targetable vantage and may ultimately contribute to diagnosis and therapy.

  5. Dynamic transcription factor networks in epithelial-mesenchymal transition in breast cancer models.

    Directory of Open Access Journals (Sweden)

    Anaar Siletz

    Full Text Available The epithelial-mesenchymal transition (EMT is a complex change in cell differentiation that allows breast carcinoma cells to acquire invasive properties. EMT involves a cascade of regulatory changes that destabilize the epithelial phenotype and allow mesenchymal features to manifest. As transcription factors (TFs are upstream effectors of the genome-wide expression changes that result in phenotypic change, understanding the sequential changes in TF activity during EMT provides rich information on the mechanism of this process. Because molecular interactions will vary as cells progress from an epithelial to a mesenchymal differentiation program, dynamic networks are needed to capture the changing context of molecular processes. In this study we applied an emerging high-throughput, dynamic TF activity array to define TF activity network changes in three cell-based models of EMT in breast cancer based on HMLE Twist ER and MCF-7 mammary epithelial cells. The TF array distinguished conserved from model-specific TF activity changes in the three models. Time-dependent data was used to identify pairs of TF activities with significant positive or negative correlation, indicative of interdependent TF activity throughout the six-day study period. Dynamic TF activity patterns were clustered into groups of TFs that change along a time course of gene expression changes and acquisition of invasive capacity. Time-dependent TF activity data was combined with prior knowledge of TF interactions to construct dynamic models of TF activity networks as epithelial cells acquire invasive characteristics. These analyses show EMT from a unique and targetable vantage and may ultimately contribute to diagnosis and therapy.

  6. Altered Gene Expression in Schizophrenia: Findings from Transcriptional Signatures in Fibroblasts and Blood

    Science.gov (United States)

    Cattane, Nadia; Minelli, Alessandra; Milanesi, Elena; Maj, Carlo; Bignotti, Stefano; Bortolomasi, Marco; Chiavetto, Luisella Bocchio; Gennarelli, Massimo

    2015-01-01

    Background Whole-genome expression studies in the peripheral tissues of patients affected by schizophrenia (SCZ) can provide new insight into the molecular basis of the disorder and innovative biomarkers that may be of great utility in clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful for investigating molecular alterations in psychiatric disorders. Methods A microarray expression study was conducted comparing skin fibroblast transcriptomic profiles from 20 SCZ patients and 20 controls. All genes strongly differentially expressed were validated by real-time quantitative PCR (RT-qPCR) in fibroblasts and analyzed in a sample of peripheral blood cell (PBC) RNA from patients (n = 25) and controls (n = 22). To evaluate the specificity for SCZ, alterations in gene expression were tested in additional samples of fibroblasts and PBCs RNA from Major Depressive Disorder (MDD) (n = 16; n = 21, respectively) and Bipolar Disorder (BD) patients (n = 15; n = 20, respectively). Results Six genes (JUN, HIST2H2BE, FOSB, FOS, EGR1, TCF4) were significantly upregulated in SCZ compared to control fibroblasts. In blood, an increase in expression levels was confirmed only for EGR1, whereas JUN was downregulated; no significant differences were observed for the other genes. EGR1 upregulation was specific for SCZ compared to MDD and BD. Conclusions Our study reports the upregulation of JUN, HIST2H2BE, FOSB, FOS, EGR1 and TCF4 in the fibroblasts of SCZ patients. A significant alteration in EGR1 expression is also present in SCZ PBCs compared to controls and to MDD and BD patients, suggesting that this gene could be a specific biomarker helpful in the differential diagnosis of major psychoses. PMID:25658856

  7. Altered gene expression in schizophrenia: findings from transcriptional signatures in fibroblasts and blood.

    Directory of Open Access Journals (Sweden)

    Nadia Cattane

    Full Text Available Whole-genome expression studies in the peripheral tissues of patients affected by schizophrenia (SCZ can provide new insight into the molecular basis of the disorder and innovative biomarkers that may be of great utility in clinical practice. Recent evidence suggests that skin fibroblasts could represent a non-neural peripheral model useful for investigating molecular alterations in psychiatric disorders.A microarray expression study was conducted comparing skin fibroblast transcriptomic profiles from 20 SCZ patients and 20 controls. All genes strongly differentially expressed were validated by real-time quantitative PCR (RT-qPCR in fibroblasts and analyzed in a sample of peripheral blood cell (PBC RNA from patients (n = 25 and controls (n = 22. To evaluate the specificity for SCZ, alterations in gene expression were tested in additional samples of fibroblasts and PBCs RNA from Major Depressive Disorder (MDD (n = 16; n = 21, respectively and Bipolar Disorder (BD patients (n = 15; n = 20, respectively.Six genes (JUN, HIST2H2BE, FOSB, FOS, EGR1, TCF4 were significantly upregulated in SCZ compared to control fibroblasts. In blood, an increase in expression levels was confirmed only for EGR1, whereas JUN was downregulated; no significant differences were observed for the other genes. EGR1 upregulation was specific for SCZ compared to MDD and BD.Our study reports the upregulation of JUN, HIST2H2BE, FOSB, FOS, EGR1 and TCF4 in the fibroblasts of SCZ patients. A significant alteration in EGR1 expression is also present in SCZ PBCs compared to controls and to MDD and BD patients, suggesting that this gene could be a specific biomarker helpful in the differential diagnosis of major psychoses.

  8. An integrated approach to reconstructing genome-scale transcriptional regulatory networks.

    Science.gov (United States)

    Imam, Saheed; Noguera, Daniel R; Donohue, Timothy J

    2015-02-01

    Transcriptional regulatory networks (TRNs) program cells to dynamically alter their gene expression in response to changing internal or environmental conditions. In this study, we develop a novel workflow for generating large-scale TRN models that integrates comparative genomics data, global gene expression analyses, and intrinsic properties of transcription factors (TFs). An assessment of this workflow using benchmark datasets for the well-studied γ-proteobacterium Escherichia coli showed that it outperforms expression-based inference approaches, having a significantly larger area under the precision-recall curve. Further analysis indicated that this integrated workflow captures different aspects of the E. coli TRN than expression-based approaches, potentially making them highly complementary. We leveraged this new workflow and observations to build a large-scale TRN model for the α-Proteobacterium Rhodobacter sphaeroides that comprises 120 gene clusters, 1211 genes (including 93 TFs), 1858 predicted protein-DNA interactions and 76 DNA binding motifs. We found that ~67% of the predicted gene clusters in this TRN are enriched for functions ranging from photosynthesis or central carbon metabolism to environmental stress responses. We also found that members of many of the predicted gene clusters were consistent with prior knowledge in R. sphaeroides and/or other bacteria. Experimental validation of predictions from this R. sphaeroides TRN model showed that high precision and recall was also obtained for TFs involved in photosynthesis (PpsR), carbon metabolism (RSP_0489) and iron homeostasis (RSP_3341). In addition, this integrative approach enabled generation of TRNs with increased information content relative to R. sphaeroides TRN models built via other approaches. We also show how this approach can be used to simultaneously produce TRN models for each related organism used in the comparative genomics analysis. Our results highlight the advantages of integrating

  9. An integrated approach to reconstructing genome-scale transcriptional regulatory networks.

    Directory of Open Access Journals (Sweden)

    Saheed Imam

    2015-02-01

    Full Text Available Transcriptional regulatory networks (TRNs program cells to dynamically alter their gene expression in response to changing internal or environmental conditions. In this study, we develop a novel workflow for generating large-scale TRN models that integrates comparative genomics data, global gene expression analyses, and intrinsic properties of transcription factors (TFs. An assessment of this workflow using benchmark datasets for the well-studied γ-proteobacterium Escherichia coli showed that it outperforms expression-based inference approaches, having a significantly larger area under the precision-recall curve. Further analysis indicated that this integrated workflow captures different aspects of the E. coli TRN than expression-based approaches, potentially making them highly complementary. We leveraged this new workflow and observations to build a large-scale TRN model for the α-Proteobacterium Rhodobacter sphaeroides that comprises 120 gene clusters, 1211 genes (including 93 TFs, 1858 predicted protein-DNA interactions and 76 DNA binding motifs. We found that ~67% of the predicted gene clusters in this TRN are enriched for functions ranging from photosynthesis or central carbon metabolism to environmental stress responses. We also found that members of many of the predicted gene clusters were consistent with prior knowledge in R. sphaeroides and/or other bacteria. Experimental validation of predictions from this R. sphaeroides TRN model showed that high precision and recall was also obtained for TFs involved in photosynthesis (PpsR, carbon metabolism (RSP_0489 and iron homeostasis (RSP_3341. In addition, this integrative approach enabled generation of TRNs with increased information content relative to R. sphaeroides TRN models built via other approaches. We also show how this approach can be used to simultaneously produce TRN models for each related organism used in the comparative genomics analysis. Our results highlight the advantages

  10. The future of genome-scale modeling of yeast through integration of a transcriptional regulatory network

    DEFF Research Database (Denmark)

    Liu, Guodong; Marras, Antonio; Nielsen, Jens

    2014-01-01

    Metabolism is regulated at multiple levels in response to the changes of internal or external conditions. Transcriptional regulation plays an important role in regulating many metabolic reactions by altering the concentrations of metabolic enzymes. Thus, integration of the transcriptional regulat...

  11. Detection of some anaemia types in human blood smears using neural networks

    Science.gov (United States)

    Elsalamony, Hany A.

    2016-08-01

    The identification process based on measuring the level of haemoglobin and the classification of red blood cells using microscopic examination of blood smears is the principal way to diagnose anaemia. This paper presents a proposed algorithm for detecting some anaemia types like sickle and elliptocytosis and trying to count them with healthy ones in human red blood smears based on the circular Hough transform and some morphological tools. Some cells with unknown shapes (not platelets or white cells) also have been detected. The extracted data from the detection process has been analyzed by neural network. The experimental results have demonstrated high accuracy, and the proposed algorithm has achieved the highest detection of around 98.9% out of all the cells in 27 microscopic images. Effectiveness rates up to 100%, 98%, and 99.3% have been achieved by using neural networks for sickle, elliptocytosis and cells with unknown shapes, respectively.

  12. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed

    DEFF Research Database (Denmark)

    Giralt, Sergio; Garderet, Laurent; Durie, Brian;

    2015-01-01

    not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network, the American Society of Blood and Marrow Transplantation, and the European Society of Blood and Marrow Transplantation...

  13. Helicase-like transcription factor (Hltf regulates G2/M transition, Wt1/Gata4/Hif-1a cardiac transcription networks, and collagen biogenesis.

    Directory of Open Access Journals (Sweden)

    Rebecca A Helmer

    Full Text Available HLTF/Hltf regulates transcription, remodels chromatin, and coordinates DNA damage repair. Hltf is expressed in mouse brain and heart during embryonic and postnatal development. Silencing Hltf is semilethal. Seventy-four percent of congenic C57BL/6J Hltf knockout mice died, 75% within 12-24 hours of birth. Previous studies in neonatal (6-8 hour postpartum brain revealed silencing Hltf disrupted cell cycle progression, and attenuated DNA damage repair. An RNA-Seq snapshot of neonatal heart transcriptome showed 1,536 of 20,000 total transcripts were altered (p < 0.05 - 10 up- and 1,526 downregulated. Pathway enrichment analysis with MetaCore™ showed Hltf's regulation of the G2/M transition (p=9.726E(-15 of the cell cycle in heart is nearly identical to its role in brain. In addition, Brca1 and 12 members of the Brca1 associated genome surveillance complex are also downregulated. Activation of caspase 3 coincides with transcriptional repression of Bcl-2. Hltf loss caused downregulation of Wt1/Gata4/Hif-1a signaling cascades as well as Myh7b/miR499 transcription. Hltf-specific binding to promoters and/or regulatory regions of these genes was authenticated by ChIP-PCR. Hif-1a targets for prolyl (P4ha1, P4ha2 and lysyl (Plod2 collagen hydroxylation, PPIase enzymes (Ppid, Ppif, Ppil3 for collagen trimerization, and lysyl oxidase (Loxl2 for collagen-elastin crosslinking were downregulated. However, transcription of genes for collagens, fibronectin, Mmps and their inhibitors (Timps was unaffected. The collective downregulation of genes whose protein products control collagen biogenesis caused disorganization of the interstitial and perivascular myocardial collagen fibrillar network as viewed with picrosirius red-staining, and authenticated with spectral imaging. Wavy collagen bundles in control hearts contrasted with collagen fibers that were thin, short and disorganized in Hltf null hearts. Collagen bundles in Hltf null hearts were tangled and

  14. Mapping and Dynamics of Regulatory DNA and Transcription Factor Networks in A. thaliana

    Directory of Open Access Journals (Sweden)

    Alessandra M. Sullivan

    2014-09-01

    Full Text Available Our understanding of gene regulation in plants is constrained by our limited knowledge of plant cis-regulatory DNA and its dynamics. We mapped DNase I hypersensitive sites (DHSs in A. thaliana seedlings and used genomic footprinting to delineate ∼700,000 sites of in vivo transcription factor (TF occupancy at nucleotide resolution. We show that variation associated with 72 diverse quantitative phenotypes localizes within DHSs. TF footprints encode an extensive cis-regulatory lexicon subject to recent evolutionary pressures, and widespread TF binding within exons may have shaped codon usage patterns. The architecture of A. thaliana TF regulatory networks is strikingly similar to that of animals in spite of diverged regulatory repertoires. We analyzed regulatory landscape dynamics during heat shock and photomorphogenesis, disclosing thousands of environmentally sensitive elements and enabling mapping of key TF regulatory circuits underlying these fundamental responses. Our results provide an extensive resource for the study of A. thaliana gene regulation and functional biology.

  15. Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights.

    Science.gov (United States)

    Acquaah-Mensah, George K; Taylor, Ronald C

    2016-07-15

    Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen Brain Atlas mouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networks were learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations in mouse whole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe2l1, Egr1 and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tia1, Pdrx1, Vdac1, and Syn2). Further, Nfe2l1, Egr1 and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD. PMID:27050105

  16. Brain in situ hybridization maps as a source for reverse-engineering transcriptional regulatory networks: Alzheimer's disease insights.

    Science.gov (United States)

    Acquaah-Mensah, George K; Taylor, Ronald C

    2016-07-15

    Microarray data have been a valuable resource for identifying transcriptional regulatory relationships among genes. As an example, brain region-specific transcriptional regulatory events have the potential of providing etiological insights into Alzheimer Disease (AD). However, there is often a paucity of suitable brain-region specific expression data obtained via microarrays or other high throughput means. The Allen Brain Atlas in situ hybridization (ISH) data sets (Jones et al., 2009) represent a potentially valuable alternative source of high-throughput brain region-specific gene expression data for such purposes. In this study, Allen Brain Atlas mouse ISH data in the hippocampal fields were extracted, focusing on 508 genes relevant to neurodegeneration. Transcriptional regulatory networks were learned using three high-performing network inference algorithms. Only 17% of regulatory edges from a network reverse-engineered based on brain region-specific ISH data were also found in a network constructed upon gene expression correlations in mouse whole brain microarrays, thus showing the specificity of gene expression within brain sub-regions. Furthermore, the ISH data-based networks were used to identify instructive transcriptional regulatory relationships. Ncor2, Sp3 and Usf2 form a unique three-party regulatory motif, potentially affecting memory formation pathways. Nfe2l1, Egr1 and Usf2 emerge among regulators of genes involved in AD (e.g. Dhcr24, Aplp2, Tia1, Pdrx1, Vdac1, and Syn2). Further, Nfe2l1, Egr1 and Usf2 are sensitive to dietary factors and could be among links between dietary influences and genes in the AD etiology. Thus, this approach of harnessing brain region-specific ISH data represents a rare opportunity for gleaning unique etiological insights for diseases such as AD.

  17. High ACSL5 transcript levels associate with systemic lupus erythematosus and apoptosis in Jurkat T lymphocytes and peripheral blood cells.

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    Antonio Catalá-Rabasa

    Full Text Available BACKGROUND: Systemic lupus erythematosus (SLE is a prototypical autoimmune disease in which increased apoptosis and decreased apoptotic cells removal has been described as most relevant in the pathogenesis. Long-chain acyl-coenzyme A synthetases (ACSLs have been involved in the immunological dysfunction of mouse models of lupus-like autoimmunity and apoptosis in different in vitro cell systems. The aim of this work was to assess among the ACSL isoforms the involvement of ACSL2, ACSL4 and ACSL5 in SLE pathogenesis. FINDINGS: With this end, we determined the ACSL2, ACSL4 and ACSL5 transcript levels in peripheral blood mononuclear cells (PBMCs of 45 SLE patients and 49 healthy controls by quantitative real time-PCR (q-PCR. We found that patients with SLE had higher ACSL5 transcript levels than healthy controls [median (range, healthy controls = 16.5 (12.3-18.0 vs. SLE = 26.5 (17.8-41.7, P = 3.9×10 E-5] but no differences were found for ACSL2 and ACSL4. In in vitro experiments, ACSL5 mRNA expression was greatly increased when inducing apoptosis in Jurkat T cells and PBMCs by Phorbol-Myristate-Acetate plus Ionomycin (PMA+Io. On the other hand, short interference RNA (siRNA-mediated silencing of ACSL5 decreased induced apoptosis in Jurkat T cells up to the control levels as well as decreased mRNA expression of FAS, FASLG and TNF. CONCLUSIONS: These findings indicate that ACSL5 may play a role in the apoptosis that takes place in SLE. Our results point to ACSL5 as a potential novel functional marker of pathogenesis and a possible therapeutic target in SLE.

  18. Response of BRAF mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis

    Science.gov (United States)

    Parmenter, Tiffany J.; Kleinschmidt, Margarete; Kinross, Kathryn M.; Bond, Simon T.; Li, Jason; Kaadige, Mohan R.; Rao, Aparna; Sheppard, Karen E.; Hugo, Willy; Pupo, Gulietta M.; Pearson, Richard B.; McGee, Sean L.; Long, Georgina V.; Scolyer, Richard A.; Rizos, Helen; Lo, Roger S.; Cullinane, Carleen; Ayer, Donald E.; Ribas, Antoni; Johnstone, Ricky W.; Hicks, Rodney J.; McArthur, Grant A.

    2014-01-01

    Deregulated glucose metabolism fulfils the energetic and biosynthetic requirements for tumour growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including HIF1α, c-Myc and MondoA, drives glycolysis downstream of BRAFV600, is critical for responses to BRAF inhibition and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor-resistant melanoma cells. Thus, we provide a proof of principle for treatment of melanoma with combinations of BRAF inhibitors and glycolysis inhibitors. PMID:24469106

  19. Using graphical adaptive lasso approach to construct transcription factor and microRNA's combinatorial regulatory network in breast cancer.

    Science.gov (United States)

    Su, Naifang; Dai, Ding; Deng, Chao; Qian, Minping; Deng, Minghua

    2014-06-01

    Discovering the regulation of cancer-related gene is of great importance in cancer biology. Transcription factors and microRNAs are two kinds of crucial regulators in gene expression, and they compose a combinatorial regulatory network with their target genes. Revealing the structure of this network could improve the authors' understanding of gene regulation, and further explore the molecular pathway in cancer. In this article, the authors propose a novel approach graphical adaptive lasso (GALASSO) to construct the regulatory network in breast cancer. GALASSO use a Gaussian graphical model with adaptive lasso penalties to integrate the sequence information as well as gene expression profiles. The simulation study and the experimental profiles verify the accuracy of the authors' approach. The authors further reveal the structure of the regulatory network, and explore the role of feedforward loops in gene regulation. In addition, the authors discuss the combinatorial regulatory effect between transcription factors and microRNAs, and select miR-155 for detailed analysis of microRNA's role in cancer. The proposed GALASSO approach is an efficient method to construct the combinatorial regulatory network. It also provides a new way to integrate different data sources and could find more applications in meta-analysis problem.

  20. Detection of regulatory circuits by integrating the cellular networks of protein–protein interactions and transcription regulation

    OpenAIRE

    Yeger-Lotem, Esti; Margalit, Hanah

    2003-01-01

    The post-genomic era is marked by huge amounts of data generated by large-scale functional genomic and proteomic experiments. A major challenge is to integrate the various types of genome-scale information in order to reveal the intra- and inter- relationships between genes and proteins that constitute a living cell. Here we present a novel application of classical graph algorithms to integrate the cellular networks of protein–protein interactions and transcription regulation. We demonstrate ...

  1. Integrative transcriptome analysis identifies deregulated microRNA-transcription factor networks in lung adenocarcinoma.

    Science.gov (United States)

    Cinegaglia, Naiara C; Andrade, Sonia Cristina S; Tokar, Tomas; Pinheiro, Maísa; Severino, Fábio E; Oliveira, Rogério A; Hasimoto, Erica N; Cataneo, Daniele C; Cataneo, Antônio J M; Defaveri, Júlio; Souza, Cristiano P; Marques, Márcia M C; Carvalho, Robson F; Coutinho, Luiz L; Gross, Jefferson L; Rogatto, Silvia R; Lam, Wan L; Jurisica, Igor; Reis, Patricia P

    2016-05-17

    Herein, we aimed at identifying global transcriptome microRNA (miRNA) changes and miRNA target genes in lung adenocarcinoma. Samples were selected as training (N = 24) and independent validation (N = 34) sets. Tissues were microdissected to obtain >90% tumor or normal lung cells, subjected to miRNA transcriptome sequencing and TaqMan quantitative PCR validation. We further integrated our data with published miRNA and mRNA expression datasets across 1,491 lung adenocarcinoma and 455 normal lung samples. We identified known and novel, significantly over- and under-expressed (p ≤ 0.01 and FDR≤0.1) miRNAs in lung adenocarcinoma compared to normal lung tissue: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421, miR-181a, miR-574 and miR-1247. Validated miRNAs included let-7a-2, let-7a-3, miR-15b, miR-21, miR-155 and miR-200b; higher levels of miR-21 expression were associated with lower patient survival (p = 0.042). We identified a regulatory network including miR-15b and miR-155, and transcription factors with prognostic value in lung cancer. Our findings may contribute to the development of treatment strategies in lung adenocarcinoma.

  2. Construction of pancreatic cancer double-factor regulatory network based on chip data on the transcriptional level.

    Science.gov (United States)

    Zhao, Li-Li; Zhang, Tong; Liu, Bing-Rong; Liu, Tie-Fu; Tao, Na; Zhuang, Li-Wei

    2014-05-01

    Transcription factor (TF) and microRNA (miRNA) have been discovered playing crucial roles in cancer development. However, the effect of TFs and miRNAs in pancreatic cancer pathogenesis remains vague. We attempted to reveal the possible mechanism of pancreatic cancer based on transcription level. Using GSE16515 datasets downloaded from gene expression omnibus database, we first identified the differentially expressed genes (DEGs) in pancreatic cancer by the limma package in R. Then the DEGs were mapped into DAVID to conduct the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. TFs and miRNAs that DEGs significantly enriched were identified by Fisher's test, and then the pancreatic cancer double-factor regulatory network was constructed. In our study, total 1117 DEGs were identified and they significantly enriched in 4 KEGG pathways. A double-factor regulatory network was established, including 29 DEGs, 24 TFs, 25 miRNAs. In the network, LAMC2, BRIP1 and miR155 were identified which may be involved in pancreatic cancer development. In conclusion, the double-factor regulatory network was found to play an important role in pancreatic cancer progression and our results shed new light on the molecular mechanism of pancreatic cancer.

  3. An improved Escherichia coli strain to host gene regulatory networks involving both the AraC and LacI inducible transcription factors

    OpenAIRE

    Kogenaru, Manjunatha; Tans, Sander J

    2014-01-01

    Many of the gene regulatory networks used within the field of synthetic biology have extensively employed the AraC and LacI inducible transcription factors. However, there is no Escherichia coli strain that provides a proper background to use both transcription factors simultaneously. We have engineered an improved E. coli strain by knocking out the endogenous lacI from a strain optimal for AraC containing networks, and thoroughly characterized the strain both at molecular and functional leve...

  4. Divergent Evolution of the Transcriptional Network Controlled by Snf1-Interacting Protein Sip4 in Budding Yeasts.

    Directory of Open Access Journals (Sweden)

    Constance Mehlgarten

    Full Text Available Cellular responses to starvation are of ancient origin since nutrient limitation has always been a common challenge to the stability of living systems. Hence, signaling molecules involved in sensing or transducing information about limiting metabolites are highly conserved, whereas transcription factors and the genes they regulate have diverged. In eukaryotes the AMP-activated protein kinase (AMPK functions as a central regulator of cellular energy homeostasis. The yeast AMPK ortholog SNF1 controls the transcriptional network that counteracts carbon starvation conditions by regulating a set of transcription factors. Among those Cat8 and Sip4 have overlapping DNA-binding specificity for so-called carbon source responsive elements and induce target genes upon SNF1 activation. To analyze the evolution of the Cat8-Sip4 controlled transcriptional network we have compared the response to carbon limitation of Saccharomyces cerevisiae to that of Kluyveromyces lactis. In high glucose, S. cerevisiae displays tumor cell-like aerobic fermentation and repression of respiration (Crabtree-positive while K. lactis has a respiratory-fermentative life-style, respiration being regulated by oxygen availability (Crabtree-negative, which is typical for many yeasts and for differentiated higher cells. We demonstrate divergent evolution of the Cat8-Sip4 network and present evidence that a role of Sip4 in controlling anabolic metabolism has been lost in the Saccharomyces lineage. We find that in K. lactis, but not in S. cerevisiae, the Sip4 protein plays an essential role in C2 carbon assimilation including induction of the glyoxylate cycle and the carnitine shuttle genes. Induction of KlSIP4 gene expression by KlCat8 is essential under these growth conditions and a primary function of KlCat8. Both KlCat8 and KlSip4 are involved in the regulation of lactose metabolism in K. lactis. In chromatin-immunoprecipitation experiments we demonstrate binding of both, KlSip4 and

  5. Gene transcription profiles associated with inter-modular hubs and connection distance in human functional magnetic resonance imaging networks.

    Science.gov (United States)

    Vértes, Petra E; Rittman, Timothy; Whitaker, Kirstie J; Romero-Garcia, Rafael; Váša, František; Kitzbichler, Manfred G; Wagstyl, Konrad; Fonagy, Peter; Dolan, Raymond J; Jones, Peter B; Goodyer, Ian M; Bullmore, Edward T

    2016-10-01

    Human functional magnetic resonance imaging (fMRI) brain networks have a complex topology comprising integrative components, e.g. long-distance inter-modular edges, that are theoretically associated with higher biological cost. Here, we estimated intra-modular degree, inter-modular degree and connection distance for each of 285 cortical nodes in multi-echo fMRI data from 38 healthy adults. We used the multivariate technique of partial least squares (PLS) to reduce the dimensionality of the relationships between these three nodal network parameters and prior microarray data on regional expression of 20 737 genes. The first PLS component defined a transcriptional profile associated with high intra-modular degree and short connection distance, whereas the second PLS component was associated with high inter-modular degree and long connection distance. Nodes in superior and lateral cortex with high inter-modular degree and long connection distance had local transcriptional profiles enriched for oxidative metabolism and mitochondria, and for genes specific to supragranular layers of human cortex. In contrast, primary and secondary sensory cortical nodes in posterior cortex with high intra-modular degree and short connection distance had transcriptional profiles enriched for RNA translation and nuclear components. We conclude that, as predicted, topologically integrative hubs, mediating long-distance connections between modules, are more costly in terms of mitochondrial glucose metabolism.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574314

  6. Gene transcription profiles associated with inter-modular hubs and connection distance in human functional magnetic resonance imaging networks

    Science.gov (United States)

    Vértes, Petra E.; Rittman, Timothy; Whitaker, Kirstie J.; Romero-Garcia, Rafael; Váša, František; Wagstyl, Konrad; Fonagy, Peter; Dolan, Raymond J.; Jones, Peter B.; Goodyer, Ian M.

    2016-01-01

    Human functional magnetic resonance imaging (fMRI) brain networks have a complex topology comprising integrative components, e.g. long-distance inter-modular edges, that are theoretically associated with higher biological cost. Here, we estimated intra-modular degree, inter-modular degree and connection distance for each of 285 cortical nodes in multi-echo fMRI data from 38 healthy adults. We used the multivariate technique of partial least squares (PLS) to reduce the dimensionality of the relationships between these three nodal network parameters and prior microarray data on regional expression of 20 737 genes. The first PLS component defined a transcriptional profile associated with high intra-modular degree and short connection distance, whereas the second PLS component was associated with high inter-modular degree and long connection distance. Nodes in superior and lateral cortex with high inter-modular degree and long connection distance had local transcriptional profiles enriched for oxidative metabolism and mitochondria, and for genes specific to supragranular layers of human cortex. In contrast, primary and secondary sensory cortical nodes in posterior cortex with high intra-modular degree and short connection distance had transcriptional profiles enriched for RNA translation and nuclear components. We conclude that, as predicted, topologically integrative hubs, mediating long-distance connections between modules, are more costly in terms of mitochondrial glucose metabolism. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’. PMID:27574314

  7. Detection of Canine Distemper Virus Nucleoprotein RNA by Reverse Transcription-PCR Using Serum, Whole Blood, and Cerebrospinal Fluid from Dogs with Distemper

    OpenAIRE

    Frisk, A. L.; König, M.; Moritz, A; Baumgärtner, W.

    1999-01-01

    Reverse transcription-PCR (RT-PCR) was used to detect canine distemper virus (CDV) nucleoprotein (NP) RNA in serum, whole blood, and cerebrospinal fluid (CSF) samples from 38 dogs with clinically suspected distemper. Results were correlated to clinical findings, anti-CDV neutralizing antibody titers, postmortem findings, and demonstration of CDV NP antigen by immunohistochemistry. The specificity of the RT-PCR was ensured by amplification of RNA from various laboratory CDV strains, restrictio...

  8. Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency

    Directory of Open Access Journals (Sweden)

    Yeh Cheng-Yu

    2009-12-01

    Full Text Available Abstract Background Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. Results To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2 regulated by RUNX1 and STAT3 is correlated to the pathological stage

  9. Visualized gene network reveals the novel target transcripts Sox2 and Pax6 of neuronal development in trans-placental exposure to bisphenol A.

    Directory of Open Access Journals (Sweden)

    Chung-Wei Yang

    Full Text Available Bisphenol A (BPA is a ubiquitous endocrine disrupting chemical in our daily life, and its health effect in response to prenatal exposure is still controversial. Early-life BPA exposure may impact brain development and contribute to childhood neurological disorders. The aim of the present study was to investigate molecular target genes of neuronal development in trans-placental exposure to BPA.A meta-analysis of three public microarray datasets was performed to screen for differentially expressed genes (DEGs in exposure to BPA. The candidate genes of neuronal development were identified from gene ontology analysis in a reconstructed neuronal sub-network, and their gene expressions were determined using real-time PCR in 20 umbilical cord blood samples dichotomized into high and low BPA level groups upon the median 16.8 nM.Among 36 neuronal transcripts sorted from DAVID ontology clusters of 457 DEGs using the analysis of Bioconductor limma package, we found two neuronal genes, sex determining region Y-box 2 (Sox2 and paired box 6 (Pax6, had preferentially down-regulated expression (Bonferroni correction p-value <10(-4 and log2-transformed fold change ≤-1.2 in response to BPA exposure. Fetal cord blood samples had the obviously attenuated gene expression of Sox2 and Pax6 in high BPA group referred to low BPA group. Visualized gene network of Cytoscape analysis showed that Sox2 and Pax6 which were contributed to neural precursor cell proliferation and neuronal differentiation might be down-regulated through sonic hedgehog (Shh, vascular endothelial growth factor A (VEGFA and Notch signaling.These results indicated that trans-placental BPA exposure down-regulated gene expression of Sox2 and Pax6 potentially underlying the adverse effect on childhood neuronal development.

  10. Integrative analysis of time course microarray data and DNA sequence data via log-linear models for identifying dynamic transcriptional regulatory networks.

    Science.gov (United States)

    Choi, Hyung-Seok; Kim, Youngchul; Cho, Kwang-Hyun; Park, Taesung

    2013-01-01

    Since eukaryotic transcription is regulated by sets of Transcription Factors (TFs) having various transcriptional time delays, identification of temporal combinations of activated TFs is important to reconstruct Transcriptional Regulatory Networks (TRNs). Our methods combine time course microarray data, information on physical binding between the TFs and their targets and the regulatory sequences of genes using a log-linear model to reconstruct dynamic functional TRNs of the yeast cell cycle and human apoptosis. In conclusion, our results suggest that the proposed dynamic motif search method is more effective in reconstructing TRNs than the static motif search method.

  11. Blood pressure levels and longitudinal changes in relation to social network factors

    Directory of Open Access Journals (Sweden)

    Daniel Eriksson Sörman

    2016-04-01

    Full Text Available The aim of this study was to examine the relationship between social network variables andlevels of and longitudinal changes in blood pressure in a middle-aged/older sample. Theparticipants (50-75 years at baseline; n=1097 responded to questions concerning socialrelationships at baseline and their blood pressure (diastolic, systolic was measured. Bloodpressure levels were reassessed 5, 10, and 15 years later. Latent growth models with responses toquestions concerning social relationships as predictors and basic demographic factors (age, sex ascovariates, unexpectedly indicated that a more limited social network (no close friend, few visits,little contact with friends in other ways, not living with someone, and a composite index based onall questions was associated with significantly lower diastolic blood pressure levels. For systolicblood pressure a similar result was observed for one of the variables (lack of a close friend. Ingeneral, these effects diminished over time, as indexed by the positive relationship between severalof the social variables and slope. The results were little affected by inclusion of additionalcovariates (e.g. measures of psychological distress, smoking/alcohol habits, and BMI suggestingthat the origins of this unexpected pattern of findings must probably be sought for in other subjectrelatedfactors, such as, for example, increased help seeking. Future studies should considerqualitative aspects (e.g. feelings of loneliness, quality of social relationships in addition tostructural aspects to provide a better understanding of these associations.

  12. Network analysis of the transcriptional pattern of young and old cells of Escherichia coli during lag phase

    LENUS (Irish Health Repository)

    Pin, Carmen

    2009-11-16

    Abstract Background The aging process of bacteria in stationary phase is halted if cells are subcultured and enter lag phase and it is then followed by cellular division. Network science has been applied to analyse the transcriptional response, during lag phase, of bacterial cells starved previously in stationary phase for 1 day (young cells) and 16 days (old cells). Results A genome scale network was constructed for E. coli K-12 by connecting genes with operons, transcription and sigma factors, metabolic pathways and cell functional categories. Most of the transcriptional changes were detected immediately upon entering lag phase and were maintained throughout this period. The lag period was longer for older cells and the analysis of the transcriptome revealed different intracellular activity in young and old cells. The number of genes differentially expressed was smaller in old cells (186) than in young cells (467). Relatively, few genes (62) were up- or down-regulated in both cultures. Transcription of genes related to osmotolerance, acid resistance, oxidative stress and adaptation to other stresses was down-regulated in both young and old cells. Regarding carbohydrate metabolism, genes related to the citrate cycle were up-regulated in young cells while old cells up-regulated the Entner Doudoroff and gluconate pathways and down-regulated the pentose phosphate pathway. In both old and young cells, anaerobic respiration and fermentation pathways were down-regulated, but only young cells up-regulated aerobic respiration while there was no evidence of aerobic respiration in old cells. Numerous genes related to DNA maintenance and replication, translation, ribosomal biosynthesis and RNA processing as well as biosynthesis of the cell envelope and flagellum and several components of the chemotaxis signal transduction complex were up-regulated only in young cells. The genes for several transport proteins for iron compounds were up-regulated in both young and old cells

  13. Network analysis of the transcriptional pattern of young and old cells of Escherichia coli during lag phase

    Directory of Open Access Journals (Sweden)

    Hinton Jay CD

    2009-11-01

    Full Text Available Abstract Background The aging process of bacteria in stationary phase is halted if cells are subcultured and enter lag phase and it is then followed by cellular division. Network science has been applied to analyse the transcriptional response, during lag phase, of bacterial cells starved previously in stationary phase for 1 day (young cells and 16 days (old cells. Results A genome scale network was constructed for E. coli K-12 by connecting genes with operons, transcription and sigma factors, metabolic pathways and cell functional categories. Most of the transcriptional changes were detected immediately upon entering lag phase and were maintained throughout this period. The lag period was longer for older cells and the analysis of the transcriptome revealed different intracellular activity in young and old cells. The number of genes differentially expressed was smaller in old cells (186 than in young cells (467. Relatively, few genes (62 were up- or down-regulated in both cultures. Transcription of genes related to osmotolerance, acid resistance, oxidative stress and adaptation to other stresses was down-regulated in both young and old cells. Regarding carbohydrate metabolism, genes related to the citrate cycle were up-regulated in young cells while old cells up-regulated the Entner Doudoroff and gluconate pathways and down-regulated the pentose phosphate pathway. In both old and young cells, anaerobic respiration and fermentation pathways were down-regulated, but only young cells up-regulated aerobic respiration while there was no evidence of aerobic respiration in old cells. Numerous genes related to DNA maintenance and replication, translation, ribosomal biosynthesis and RNA processing as well as biosynthesis of the cell envelope and flagellum and several components of the chemotaxis signal transduction complex were up-regulated only in young cells. The genes for several transport proteins for iron compounds were up-regulated in both young

  14. An effective fractal-tree closure model for simulating blood flow in large arterial networks.

    Science.gov (United States)

    Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em

    2015-06-01

    The aim of the present work is to address the closure problem for hemodynamic simulations by developing a flexible and effective model that accurately distributes flow in the downstream vasculature and can stably provide a physiological pressure outflow boundary condition. To achieve this goal, we model blood flow in the sub-pixel vasculature by using a non-linear 1D model in self-similar networks of compliant arteries that mimic the structure and hierarchy of vessels in the meso-vascular regime (radii [Formula: see text]). We introduce a variable vessel length-to-radius ratio for small arteries and arterioles, while also addressing non-Newtonian blood rheology and arterial wall viscoelasticity effects in small arteries and arterioles. This methodology aims to overcome substantial cut-off radius sensitivities, typically arising in structured tree and linearized impedance models. The proposed model is not sensitive to outflow boundary conditions applied at the end points of the fractal network, and thus does not require calibration of resistance/capacitance parameters typically required for outflow conditions. The proposed model convergences to a periodic state in two cardiac cycles even when started from zero-flow initial conditions. The resulting fractal-trees typically consist of thousands to millions of arteries, posing the need for efficient parallel algorithms. To this end, we have scaled up a Discontinuous Galerkin solver that utilizes the MPI/OpenMP hybrid programming paradigm to thousands of computer cores, and can simulate blood flow in networks of millions of arterial segments at the rate of one cycle per 5 min. The proposed model has been extensively tested on a large and complex cranial network with 50 parent, patient-specific arteries and 21 outlets to which fractal trees where attached, resulting to a network of up to 4,392,484 vessels in total, and a detailed network of the arm with 276 parent arteries and 103 outlets (a total of 702,188 vessels

  15. Computational modelling of genome-wide [corrected] transcription assembly networks using a fluidics analogy.

    Directory of Open Access Journals (Sweden)

    Yousry Y Azmy

    Full Text Available Understanding how a myriad of transcription regulators work to modulate mRNA output at thousands of genes remains a fundamental challenge in molecular biology. Here we develop a computational tool to aid in assessing the plausibility of gene regulatory models derived from genome-wide expression profiling of cells mutant for transcription regulators. mRNA output is modelled as fluid flow in a pipe lattice, with assembly of the transcription machinery represented by the effect of valves. Transcriptional regulators are represented as external pressure heads that determine flow rate. Modelling mutations in regulatory proteins is achieved by adjusting valves' on/off settings. The topology of the lattice is designed by the experimentalist to resemble the expected interconnection between the modelled agents and their influence on mRNA expression. Users can compare multiple lattice configurations so as to find the one that minimizes the error with experimental data. This computational model provides a means to test the plausibility of transcription regulation models derived from large genomic data sets.

  16. Genome-wide transcriptional profiling of peripheral blood leukocytes from cattle infected with Mycobacterium bovis reveals suppression of host immune genes

    Directory of Open Access Journals (Sweden)

    Killick Kate E

    2011-12-01

    Full Text Available Abstract Background Mycobacterium bovis is the causative agent of bovine tuberculosis (BTB, a pathological infection with significant economic impact. Recent studies have highlighted the role of functional genomics to better understand the molecular mechanisms governing the host immune response to M. bovis infection. Furthermore, these studies may enable the identification of novel transcriptional markers of BTB that can augment current diagnostic tests and surveillance programmes. In the present study, we have analysed the transcriptome of peripheral blood leukocytes (PBL from eight M. bovis-infected and eight control non-infected age-matched and sex-matched Holstein-Friesian cattle using the Affymetrix® GeneChip® Bovine Genome Array with 24,072 gene probe sets representing more than 23,000 gene transcripts. Results Control and infected animals had similar mean white blood cell counts. However, the mean number of lymphocytes was significantly increased in the infected group relative to the control group (P = 0.001, while the mean number of monocytes was significantly decreased in the BTB group (P = 0.002. Hierarchical clustering analysis using gene expression data from all 5,388 detectable mRNA transcripts unambiguously partitioned the animals according to their disease status. In total, 2,960 gene transcripts were differentially expressed (DE between the infected and control animal groups (adjusted P-value threshold ≤ 0.05; with the number of gene transcripts showing decreased relative expression (1,563 exceeding those displaying increased relative expression (1,397. Systems analysis using the Ingenuity® Systems Pathway Analysis (IPA Knowledge Base revealed an over-representation of DE genes involved in the immune response functional category. More specifically, 64.5% of genes in the affects immune response subcategory displayed decreased relative expression levels in the infected animals compared to the control group. Conclusions This

  17. Modeling blood flow circulation in intracranial arterial networks: a comparative 3D/1D simulation study.

    Science.gov (United States)

    Grinberg, L; Cheever, E; Anor, T; Madsen, J R; Karniadakis, G E

    2011-01-01

    We compare results from numerical simulations of pulsatile blood flow in two patient-specific intracranial arterial networks using one-dimensional (1D) and three-dimensional (3D) models. Specifically, we focus on the pressure and flowrate distribution at different segments of the network computed by the two models. Results obtained with 1D and 3D models with rigid walls show good agreement in massflow distribution at tens of arterial junctions and also in pressure drop along the arteries. The 3D simulations with the rigid walls predict higher amplitude of the flowrate and pressure temporal oscillations than the 1D simulations with compliant walls at various segments even for small time-variations in the arterial cross-sectional areas. Sensitivity of the flow and pressure with respect to variation in the elasticity parameters is investigated with the 1D model. PMID:20661645

  18. The impact of capillary dilation on the distribution of red blood cells in artificial networks.

    Science.gov (United States)

    Schmid, Franca; Reichold, Johannes; Weber, Bruno; Jenny, Patrick

    2015-04-01

    Recent studies suggest that pericytes around capillaries are contractile and able to alter the diameter of capillaries. To investigate the effects of capillary dilation on network dynamics, we performed simulations in artificial capillary networks of different sizes and complexities. The unequal partition of hematocrit at diverging bifurcations was modeled by assuming that each red blood cell (RBC) enters the branch with the faster instantaneous flow. Network simulations with and without RBCs were performed to investigate the effect of local dilations. The results showed that the increase in flow rate due to capillary dilation was less when the effects of RBCs are included. For bifurcations with sufficient RBCs in the parent vessel and nearly equal flows in the branches, the flow rate in the dilated branch did not increase. Instead, a self-regulation of flow was observed due to accumulation of RBCs in the dilated capillary. A parametric study was performed to examine the dependence on initial capillary diameter, dilation factor, and tube hematocrit. Furthermore, the conditions needed for an efficient self-regulation mechanism are discussed. The results support the hypothesis that RBCs play a significant role for the fluid dynamics in capillary networks and that it is crucial to consider the blood flow rate and the distribution of RBCs to understand the supply of oxygen in the vasculature. Furthermore, our results suggest that capillary dilation/constriction offers the potential of being an efficient mechanism to alter the distribution of RBCs locally and hence could be important for the local regulation of oxygen delivery. PMID:25617356

  19. Signed weighted gene co-expression network analysis of transcriptional regulation in murine embryonic stem cells

    OpenAIRE

    Zhou Qing; Plath Kathrin; Fan Guoping; Mason Mike J; Horvath Steve

    2009-01-01

    Abstract Background Recent work has revealed that a core group of transcription factors (TFs) regulates the key characteristics of embryonic stem (ES) cells: pluripotency and self-renewal. Current efforts focus on identifying genes that play important roles in maintaining pluripotency and self-renewal in ES cells and aim to understand the interactions among these genes. To that end, we...

  20. The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line

    DEFF Research Database (Denmark)

    Suzuki, Harukazu; Forrest, Alistair R R; van Nimwegen, Erik;

    2009-01-01

    Using deep sequencing (deepCAGE), the FANTOM4 study measured the genome-wide dynamics of transcription-start-site usage in the human monocytic cell line THP-1 throughout a time course of growth arrest and differentiation. Modeling the expression dynamics in terms of predicted cis-regulatory sites...

  1. Complex Coordination of Cell Plasticity by a PGC-1α-controlled Transcriptional Network in Skeletal Muscle.

    Science.gov (United States)

    Kupr, Barbara; Handschin, Christoph

    2015-01-01

    Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a central regulatory nexus in the adaptation of muscle to endurance training. Intriguingly, PGC-1α integrates numerous signaling pathways and translates their activity into various transcriptional programs. This selectivity is in part controlled by differential expression of PGC-1α variants and post-translational modifications of the PGC-1α protein. PGC-1α-controlled activation of transcriptional networks subsequently enables a spatio-temporal specification and hence allows a complex coordination of changes in metabolic and contractile properties, protein synthesis and degradation rates and other features of trained muscle. In this review, we discuss recent advances in our understanding of PGC-1α-regulated skeletal muscle cell plasticity in health and disease.

  2. Complex coordination of cell plasticity by a PGC-1α-controlled transcriptional network in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Barbara eKupr

    2015-11-01

    Full Text Available Skeletal muscle cells exhibit an enormous plastic capacity in order to adapt to external stimuli. Even though our overall understanding of the molecular mechanisms that underlie phenotypic changes in skeletal muscle cells remains poor, several factors involved in the regulation and coordination of relevant transcriptional programs have been identified in recent years. For example, the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α is a central regulatory nexus in the adaptation of muscle to endurance training. Intriguingly, PGC-1α integrates numerous signaling pathways and translates their activity into various transcriptional programs. This selectivity is in part controlled by differential expression of PGC-1α variants and post-translational modifications of the PGC-1α protein. PGC-1α-controlled activation of transcriptional networks subsequently enables a spatio-temporal specification and hence allows a complex coordination of changes in metabolic and contractile properties, protein synthesis and degradation rates and other features of trained muscle. In this review, we discuss recent advances in our understanding of PGC-1α-regulated skeletal muscle cell plasticity in health and disease.

  3. Genome-Wide Mapping of Collier In Vivo Binding Sites Highlights Its Hierarchical Position in Different Transcription Regulatory Networks

    Science.gov (United States)

    Dubois, Laurence; Bataillé, Laetitia; Painset, Anaïs; Le Gras, Stéphanie; Jost, Bernard; Crozatier, Michèle; Vincent, Alain

    2015-01-01

    Collier, the single Drosophila COE (Collier/EBF/Olf-1) transcription factor, is required in several developmental processes, including head patterning and specification of muscle and neuron identity during embryogenesis. To identify direct Collier (Col) targets in different cell types, we used ChIP-seq to map Col binding sites throughout the genome, at mid-embryogenesis. In vivo Col binding peaks were associated to 415 potential direct target genes. Gene Ontology analysis revealed a strong enrichment in proteins with DNA binding and/or transcription-regulatory properties. Characterization of a selection of candidates, using transgenic CRM-reporter assays, identified direct Col targets in dorso-lateral somatic muscles and specific neuron types in the central nervous system. These data brought new evidence that Col direct control of the expression of the transcription regulators apterous and eyes-absent (eya) is critical to specifying neuronal identities. They also showed that cross-regulation between col and eya in muscle progenitor cells is required for specification of muscle identity, revealing a new parallel between the myogenic regulatory networks operating in Drosophila and vertebrates. Col regulation of eya, both in specific muscle and neuronal lineages, may illustrate one mechanism behind the evolutionary diversification of Col biological roles. PMID:26204530

  4. Genome-Wide Mapping of Collier In Vivo Binding Sites Highlights Its Hierarchical Position in Different Transcription Regulatory Networks.

    Directory of Open Access Journals (Sweden)

    Mathilde de Taffin

    Full Text Available Collier, the single Drosophila COE (Collier/EBF/Olf-1 transcription factor, is required in several developmental processes, including head patterning and specification of muscle and neuron identity during embryogenesis. To identify direct Collier (Col targets in different cell types, we used ChIP-seq to map Col binding sites throughout the genome, at mid-embryogenesis. In vivo Col binding peaks were associated to 415 potential direct target genes. Gene Ontology analysis revealed a strong enrichment in proteins with DNA binding and/or transcription-regulatory properties. Characterization of a selection of candidates, using transgenic CRM-reporter assays, identified direct Col targets in dorso-lateral somatic muscles and specific neuron types in the central nervous system. These data brought new evidence that Col direct control of the expression of the transcription regulators apterous and eyes-absent (eya is critical to specifying neuronal identities. They also showed that cross-regulation between col and eya in muscle progenitor cells is required for specification of muscle identity, revealing a new parallel between the myogenic regulatory networks operating in Drosophila and vertebrates. Col regulation of eya, both in specific muscle and neuronal lineages, may illustrate one mechanism behind the evolutionary diversification of Col biological roles.

  5. Phylogeny, Functional Annotation, and Protein Interaction Network Analyses of the Xenopus tropicalis Basic Helix-Loop-Helix Transcription Factors

    Directory of Open Access Journals (Sweden)

    Wuyi Liu

    2013-01-01

    Full Text Available The previous survey identified 70 basic helix-loop-helix (bHLH proteins, but it was proved to be incomplete, and the functional information and regulatory networks of frog bHLH transcription factors were not fully known. Therefore, we conducted an updated genome-wide survey in the Xenopus tropicalis genome project databases and identified 105 bHLH sequences. Among the retrieved 105 sequences, phylogenetic analyses revealed that 103 bHLH proteins belonged to 43 families or subfamilies with 46, 26, 11, 3, 15, and 4 members in the corresponding supergroups. Next, gene ontology (GO enrichment analyses showed 65 significant GO annotations of biological processes and molecular functions and KEGG pathways counted in frequency. To explore the functional pathways, regulatory gene networks, and/or related gene groups coding for Xenopus tropicalis bHLH proteins, the identified bHLH genes were put into the databases KOBAS and STRING to get the signaling information of pathways and protein interaction networks according to available public databases and known protein interactions. From the genome annotation and pathway analysis using KOBAS, we identified 16 pathways in the Xenopus tropicalis genome. From the STRING interaction analysis, 68 hub proteins were identified, and many hub proteins created a tight network or a functional module within the protein families.

  6. Analysis of Cryptococcus neoformans sexual development reveals rewiring of the pheromone-response network by a change in transcription factor identity.

    Science.gov (United States)

    Kruzel, Emilia K; Giles, Steven S; Hull, Christina M

    2012-06-01

    The fundamental mechanisms that control eukaryotic development include extensive regulation at the level of transcription. Gene regulatory networks, composed of transcription factors, their binding sites in DNA, and their target genes, are responsible for executing transcriptional programs. While divergence of these control networks drives species-specific gene expression that contributes to biological diversity, little is known about the mechanisms by which these networks evolve. To investigate how network evolution has occurred in fungi, we used a combination of microarray expression profiling, cis-element identification, and transcription-factor characterization during sexual development of the human fungal pathogen Cryptococcus neoformans. We first defined the major gene expression changes that occur over time throughout sexual development. Through subsequent bioinformatic and molecular genetic analyses, we identified and functionally characterized the C. neoformans pheromone-response element (PRE). We then discovered that transcriptional activation via the PRE requires direct binding of the high-mobility transcription factor Mat2, which we conclude functions as the elusive C. neoformans pheromone-response factor. This function of Mat2 distinguishes the mechanism of regulation through the PRE of C. neoformans from all other fungal systems studied to date and reveals species-specific adaptations of a fungal transcription factor that defies predictions on the basis of sequence alone. Overall, our findings reveal that pheromone-response network rewiring has occurred at the level of transcription factor identity, despite the strong conservation of upstream and downstream components, and serve as a model for how selection pressures act differently on signaling vs. gene regulatory components during eukaryotic evolution.

  7. Co-regulated transcripts associated to cooperating eSNPs define Bi-fan motifs in human gene networks.

    Directory of Open Access Journals (Sweden)

    Anat Kreimer

    2014-09-01

    Full Text Available Associations between the level of single transcripts and single corresponding genetic variants, expression single nucleotide polymorphisms (eSNPs, have been extensively studied and reported. However, most expression traits are complex, involving the cooperative action of multiple SNPs at different loci affecting multiple genes. Finding these cooperating eSNPs by exhaustive search has proven to be statistically challenging. In this paper we utilized availability of sequencing data with transcriptional profiles in the same cohorts to identify two kinds of usual suspects: eSNPs that alter coding sequences or eSNPs within the span of transcription factors (TFs. We utilize a computational framework for considering triplets, each comprised of a SNP and two associated genes. We examine pairs of triplets with such cooperating source eSNPs that are both associated with the same pair of target genes. We characterize such quartets through their genomic, topological and functional properties. We establish that this regulatory structure of cooperating quartets is frequent in real data, but is rarely observed in permutations. eSNP sources are mostly located on different chromosomes and away from their targets. In the majority of quartets, SNPs affect the expression of the two gene targets independently of one another, suggesting a mutually independent rather than a directionally dependent effect. Furthermore, the directions in which the minor allele count of the SNP affects gene expression within quartets are consistent, so that the two source eSNPs either both have the same effect on the target genes or both affect one gene in the opposite direction to the other. Same-effect eSNPs are observed more often than expected by chance. Cooperating quartets reported here in a human system might correspond to bi-fans, a known network motif of four nodes previously described in model organisms. Overall, our analysis offers insights regarding the fine motif structure

  8. Transcriptional-metabolic networks in beta-carotene-enriched potato tubers: the long and winding road to the Golden phenotype.

    Science.gov (United States)

    Diretto, Gianfranco; Al-Babili, Salim; Tavazza, Raffaela; Scossa, Federico; Papacchioli, Velia; Migliore, Melania; Beyer, Peter; Giuliano, Giovanni

    2010-10-01

    Vitamin A deficiency is a public health problem in a large number of countries. Biofortification of major staple crops (wheat [Triticum aestivum], rice [Oryza sativa], maize [Zea mays], and potato [Solanum tuberosum]) with β-carotene has the potential to alleviate this nutritional problem. Previously, we engineered transgenic "Golden" potato tubers overexpressing three bacterial genes for β-carotene synthesis (CrtB, CrtI, and CrtY, encoding phytoene synthase, phytoene desaturase, and lycopene β-cyclase, respectively) and accumulating the highest amount of β-carotene in the four aforementioned crops. Here, we report the systematic quantitation of carotenoid metabolites and transcripts in 24 lines carrying six different transgene combinations under the control of the 35S and Patatin (Pat) promoters. Low levels of B-I expression are sufficient for interfering with leaf carotenogenesis, but not for β-carotene accumulation in tubers and calli, which requires high expression levels of all three genes under the control of the Pat promoter. Tubers expressing the B-I transgenes show large perturbations in the transcription of endogenous carotenoid genes, with only minor changes in carotenoid content, while the opposite phenotype (low levels of transcriptional perturbation and high carotenoid levels) is observed in Golden (Y-B-I) tubers. We used hierarchical clustering and pairwise correlation analysis, together with a new method for network correlation analysis, developed for this purpose, to assess the perturbations in transcript and metabolite levels in transgenic leaves and tubers. Through a "guilt-by-profiling" approach, we identified several endogenous genes for carotenoid biosynthesis likely to play a key regulatory role in Golden tubers, which are candidates for manipulations aimed at the further optimization of tuber carotenoid content. PMID:20671108

  9. A Novel Analytical Approach to Pulsatile Blood Flow in the Arterial Network.

    Science.gov (United States)

    Flores, Joaquín; Alastruey, Jordi; Corvera Poiré, Eugenia

    2016-10-01

    Haemodynamic simulations using one-dimensional (1-D) computational models exhibit many of the features of the systemic circulation under normal and diseased conditions. We propose a novel linear 1-D dynamical theory of blood flow in networks of flexible vessels that is based on a generalized Darcy's model and for which a full analytical solution exists in frequency domain. We assess the accuracy of this formulation in a series of benchmark test cases for which computational 1-D and 3-D solutions are available. Accordingly, we calculate blood flow and pressure waves, and velocity profiles in the human common carotid artery, upper thoracic aorta, aortic bifurcation, and a 20-artery model of the aorta and its larger branches. Our analytical solution is in good agreement with the available solutions and reproduces the main features of pulse waveforms in networks of large arteries under normal physiological conditions. Our model reduces computational time and provides a new approach for studying arterial pulse wave mechanics; e.g.,  the analyticity of our model allows for a direct identification of the role played by physical properties of the cardiovascular system on the pressure waves.

  10. Grasses use an alternatively wired bHLH transcription factor network to establish stomatal identity.

    Science.gov (United States)

    Raissig, Michael T; Abrash, Emily; Bettadapur, Akhila; Vogel, John P; Bergmann, Dominique C

    2016-07-19

    Stomata, epidermal valves facilitating plant-atmosphere gas exchange, represent a powerful model for understanding cell fate and pattern in plants. Core basic helix-loop-helix (bHLH) transcription factors regulating stomatal development were identified in Arabidopsis, but this dicot's developmental pattern and stomatal morphology represent only one of many possibilities in nature. Here, using unbiased forward genetic screens, followed by analysis of reporters and engineered mutants, we show that stomatal initiation in the grass Brachypodium distachyon uses orthologs of stomatal regulators known from Arabidopsis but that the function and behavior of individual genes, the relationships among genes, and the regulation of their protein products have diverged. Our results highlight ways in which a kernel of conserved genes may be alternatively wired to produce diversity in patterning and morphology and suggest that the stomatal transcription factor module is a prime target for breeding or genome modification to improve plant productivity. PMID:27382177

  11. Grasses use an alternatively wired bHLH transcription factor network to establish stomatal identity

    Science.gov (United States)

    Raissig, Michael T.; Abrash, Emily; Bettadapur, Akhila; Bergmann, Dominique C.

    2016-01-01

    Stomata, epidermal valves facilitating plant–atmosphere gas exchange, represent a powerful model for understanding cell fate and pattern in plants. Core basic helix–loop–helix (bHLH) transcription factors regulating stomatal development were identified in Arabidopsis, but this dicot’s developmental pattern and stomatal morphology represent only one of many possibilities in nature. Here, using unbiased forward genetic screens, followed by analysis of reporters and engineered mutants, we show that stomatal initiation in the grass Brachypodium distachyon uses orthologs of stomatal regulators known from Arabidopsis but that the function and behavior of individual genes, the relationships among genes, and the regulation of their protein products have diverged. Our results highlight ways in which a kernel of conserved genes may be alternatively wired to produce diversity in patterning and morphology and suggest that the stomatal transcription factor module is a prime target for breeding or genome modification to improve plant productivity. PMID:27382177

  12. Unexpected complexity of the reef-building coral Acropora millepora transcription factor network.

    KAUST Repository

    Ryu, Taewoo

    2011-04-28

    Coral reefs are disturbed on a global scale by environmental changes including rising sea surface temperatures and ocean acidification. Little is known about how corals respond or adapt to these environmental changes especially at the molecular level. This is mostly because of the paucity of genome-wide studies on corals and the application of systems approaches that incorporate the latter. Like in any other organism, the response of corals to stress is tightly controlled by the coordinated interplay of many transcription factors.

  13. Reconstructing Generalized Logical Networks of Transcriptional Regulation in Mouse Brain from Temporal Gene Expression Data

    Directory of Open Access Journals (Sweden)

    Lodowski Kerrie H

    2009-01-01

    Full Text Available Gene expression time course data can be used not only to detect differentially expressed genes but also to find temporal associations among genes. The problem of reconstructing generalized logical networks to account for temporal dependencies among genes and environmental stimuli from transcriptomic data is addressed. A network reconstruction algorithm was developed that uses statistical significance as a criterion for network selection to avoid false-positive interactions arising from pure chance. The multinomial hypothesis testing-based network reconstruction allows for explicit specification of the false-positive rate, unique from all extant network inference algorithms. The method is superior to dynamic Bayesian network modeling in a simulation study. Temporal gene expression data from the brains of alcohol-treated mice in an analysis of the molecular response to alcohol are used for modeling. Genes from major neuronal pathways are identified as putative components of the alcohol response mechanism. Nine of these genes have associations with alcohol reported in literature. Several other potentially relevant genes, compatible with independent results from literature mining, may play a role in the response to alcohol. Additional, previously unknown gene interactions were discovered that, subject to biological verification, may offer new clues in the search for the elusive molecular mechanisms of alcoholism.

  14. Transcriptional infidelity promotes heritable phenotypic change in a bistable gene network.

    Directory of Open Access Journals (Sweden)

    Alasdair J E Gordon

    2009-02-01

    Full Text Available Bistable epigenetic switches are fundamental for cell fate determination in unicellular and multicellular organisms. Regulatory proteins associated with bistable switches are often present in low numbers and subject to molecular noise. It is becoming clear that noise in gene expression can influence cell fate. Although the origins and consequences of noise have been studied, the stochastic and transient nature of RNA errors during transcription has not been considered in the origin or modeling of noise nor has the capacity for such transient errors in information transfer to generate heritable phenotypic change been discussed. We used a classic bistable memory module to monitor and capture transient RNA errors: the lac operon of Escherichia coli comprises an autocatalytic positive feedback loop producing a heritable all-or-none epigenetic switch that is sensitive to molecular noise. Using single-cell analysis, we show that the frequency of epigenetic switching from one expression state to the other is increased when the fidelity of RNA transcription is decreased due to error-prone RNA polymerases or to the absence of auxiliary RNA fidelity factors GreA and GreB (functional analogues of eukaryotic TFIIS. Therefore, transcription infidelity contributes to molecular noise and can effect heritable phenotypic change in genetically identical cells in the same environment. Whereas DNA errors allow genetic space to be explored, RNA errors may allow epigenetic or expression space to be sampled. Thus, RNA infidelity should also be considered in the heritable origin of altered or aberrant cell behaviour.

  15. Binding Sites in the EFG1 Promoter for Transcription Factors in a Proposed Regulatory Network: A Functional Analysis in the White and Opaque Phases of Candida albicans

    Science.gov (United States)

    Pujol, Claude; Srikantha, Thyagarajan; Park, Yang-Nim; Daniels, Karla J.; Soll, David R.

    2016-01-01

    In Candida albicans the transcription factor Efg1, which is differentially expressed in the white phase of the white-opaque transition, is essential for expression of the white phenotype. It is one of six transcription factors included in a proposed interactive transcription network regulating white-opaque switching and maintenance of the alternative phenotypes. Ten sites were identified in the EFG1 promoter that differentially bind one or more of the network transcription factors in the white and/or opaque phase. To explore the functionality of these binding sites in the differential expression of EFG1, we generated targeted deletions of each of the 10 binding sites, combinatorial deletions, and regional deletions using a Renilla reniformis luciferase reporter system. Individually targeted deletion of only four of the 10 sites had minor effects consistent with differential expression of EFG1, and only in the opaque phase. Alternative explanations are considered. PMID:27172219

  16. The Plasmodium falciparum var gene transcription strategy at the onset of blood stage infection in a human volunteer

    DEFF Research Database (Denmark)

    Wang, Christian W; Hermsen, Cornelus C; Sauerwein, Robert W;

    2009-01-01

    The var genes encode a family of adhesion receptor proteins, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which profoundly influence malaria pathogenesis. Only a single var gene is transcribed and one PfEMP1 expressed per P.falciparum parasite. Here we present the in vivo...... transcript distribution of var genes in a P. falciparum-infected non-immune individual and show that the initial expression of PfEMP1 is based on a strategy that allows all or most variants of PfEMP1s to be expressed by the parasite population at the onset of the blood stage infection....

  17. BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis

    DEFF Research Database (Denmark)

    Bagger, Frederik Otzen; Sasivarevic, Damir; Hadi Sohi, Sina;

    2016-01-01

    largely inaccessible. Current databases provide information about gene-expression but fail to answer key questions regarding co-regulation, genetic programs or effect on patient survival. To address these shortcomings, we present BloodSpot (www.bloodspot.eu), which includes and greatly extends our...... the relationship between different cell types in the database. The database now includes 23 high-quality curated data sets relevant to normal and malignant blood formation and, in addition, we have assembled and built a unique integrated data set, BloodPool. Bloodpool contains more than 2000 samples assembled from...

  18. Blood pressure long term regulation: A neural network model of the set point development

    Directory of Open Access Journals (Sweden)

    Frías Bruno

    2011-06-01

    Full Text Available Abstract Background The notion of the nucleus tractus solitarius (NTS as a comparator evaluating the error signal between its rostral neural structures (RNS and the cardiovascular receptor afferents into it has been recently presented. From this perspective, stress can cause hypertension via set point changes, so offering an answer to an old question. Even though the local blood flow to tissues is influenced by circulating vasoactive hormones and also by local factors, there is yet significant sympathetic control. It is well established that the state of maturation of sympathetic innervation of blood vessels at birth varies across animal species and it takes place mostly during the postnatal period. During ontogeny, chemoreceptors are functional; they discharge when the partial pressures of oxygen and carbon dioxide in the arterial blood are not normal. Methods The model is a simple biological plausible adaptative neural network to simulate the development of the sympathetic nervous control. It is hypothesized that during ontogeny, from the RNS afferents to the NTS, the optimal level of each sympathetic efferent discharge is learned through the chemoreceptors' feedback. Its mean discharge leads to normal oxygen and carbon dioxide levels in each tissue. Thus, the sympathetic efferent discharge sets at the optimal level if, despite maximal drift, the local blood flow is compensated for by autoregulation. Such optimal level produces minimum chemoreceptor output, which must be maintained by the nervous system. Since blood flow is controlled by arterial blood pressure, the long-term mean level is stabilized to regulate oxygen and carbon dioxide levels. After development, the cardiopulmonary reflexes play an important role in controlling efferent sympathetic nerve activity to the kidneys and modulating sodium and water excretion. Results Starting from fixed RNS afferents to the NTS and random synaptic weight values, the sympathetic efferents converged

  19. Reconstructing Generalized Logical Networks of Transcriptional Regulation in Mouse Brain from Temporal Gene Expression Data

    Energy Technology Data Exchange (ETDEWEB)

    Song, Mingzhou (Joe) [New Mexico State University, Las Cruces; Lewis, Chris K. [New Mexico State University, Las Cruces; Lance, Eric [New Mexico State University, Las Cruces; Chesler, Elissa J [ORNL; Kirova, Roumyana [Bristol-Myers Squibb Pharmaceutical Research & Development, NJ; Langston, Michael A [University of Tennessee, Knoxville (UTK); Bergeson, Susan [Texas Tech University, Lubbock

    2009-01-01

    The problem of reconstructing generalized logical networks to account for temporal dependencies among genes and environmental stimuli from high-throughput transcriptomic data is addressed. A network reconstruction algorithm was developed that uses the statistical significance as a criterion for network selection to avoid false-positive interactions arising from pure chance. Using temporal gene expression data collected from the brains of alcohol-treated mice in an analysis of the molecular response to alcohol, this algorithm identified genes from a major neuronal pathway as putative components of the alcohol response mechanism. Three of these genes have known associations with alcohol in the literature. Several other potentially relevant genes, highlighted and agreeing with independent results from literature mining, may play a role in the response to alcohol. Additional, previously-unknown gene interactions were discovered that, subject to biological verification, may offer new clues in the search for the elusive molecular mechanisms of alcoholism.

  20. The transcriptional regulatory network of Corynebacterium jeikeium K411 and its interaction with metabolic routes contributing to human body odor formation.

    Science.gov (United States)

    Barzantny, Helena; Schröder, Jasmin; Strotmeier, Jasmin; Fredrich, Eugenie; Brune, Iris; Tauch, Andreas

    2012-06-15

    Lipophilic corynebacteria are involved in the generation of volatile odorous products in the process of human body odor formation by degrading skin lipids and specific odor precursors. Therefore, these bacteria represent appropriate model systems for the cosmetic industry to examine axillary malodor formation on the molecular level. To understand the transcriptional control of metabolic pathways involved in this process, the transcriptional regulatory network of the lipophilic axilla isolate Corynebacterium jeikeium K411 was reconstructed from the complete genome sequence. This bioinformatic approach detected a gene-regulatory repertoire of 83 candidate proteins, including 56 DNA-binding transcriptional regulators, nine two-component systems, nine sigma factors, and nine regulators with diverse physiological functions. Furthermore, a cross-genome comparison among selected corynebacterial species of the taxonomic cluster 3 revealed a common gene-regulatory repertoire of 44 transcriptional regulators, including the MarR-like regulator Jk0257, which is exclusively encoded in the genomes of this taxonomical subline. The current network reconstruction comprises 48 transcriptional regulators and 674 gene-regulatory interactions that were assigned to five interconnected functional modules. Most genes involved in lipid degradation are under the combined control of the global cAMP-sensing transcriptional regulator GlxR and the LuxR-family regulator RamA, probably reflecting the essential role of lipid degradation in C. jeikeium. This study provides the first genome-scale in silico analysis of the transcriptional regulation of metabolism in a lipophilic bacterium involved in the formation of human body odor.

  1. The Interferon Signaling Network and Transcription Factor C/EBP-β

    Institute of Scientific and Technical Information of China (English)

    Hui Li; Padmaja Gade; Weihua Xiao; Dhan V.Kalvakolanu

    2007-01-01

    Cytoines like interferons (IFNs) play a central role in regulating innate and specific immunities against the pathogens and neoplastic cells. A number of signaling pathways are induced in response to IFN in various cells.One classic mechanism employed by IFNs is the JAK-STAT signaling pathway for inducing cellular responses.Here we describe the non-STAT pathways that participate in IFN-induced responses. In particular, we will focus on the role played by transcription factor C/EBP-β in mediating these responses.

  2. Concerted spatial-frequency and polarization-phase filtering of laser images of polycrystalline networks of blood plasma smears

    Science.gov (United States)

    Ushenko, Yu A.

    2012-11-01

    The complex technique of concerted polarization-phase and spatial-frequency filtering of blood plasma laser images is suggested. The possibility of obtaining the coordinate distributions of phases of linearly and circularly birefringent protein networks of blood plasma separately is presented. The statistical (moments of the first to fourth orders) and scale self-similar (logarithmic dependences of power spectra) structure of phase maps of different types of birefringence of blood plasma of two groups of patients-healthy people (donors) and those suffering from rectal cancer-is investigated. The diagnostically sensitive parameters of a pathological change of the birefringence of blood plasma polycrystalline networks are determined. The effectiveness of this technique for detecting change in birefringence in the smears of other biological fluids in diagnosing the appearance of cholelithiasis (bile), operative differentiation of the acute and gangrenous appendicitis (exudate), and differentiation of inflammatory diseases of joints (synovial fluid) is shown.

  3. A Multiparameter Network Reveals Extensive Divergence between C. elegans bHLH Transcription Factors

    DEFF Research Database (Denmark)

    Grove, C.; De Masi, Federico; Newburger, Daniel;

    2009-01-01

    and in other complex multicellular organisms, including humans. Cross-species comparisons of integrated networks may provide further insights into molecular features underlying protein family evolution. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data....

  4. A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency

    Science.gov (United States)

    Artyomov, Maxim; Meissner, Alex; Chakraborty, Arup

    2010-03-01

    Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. This is because of epigenetic differences; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward -- i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by transfecting certain transcription factors into differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine, but it is inefficient. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.

  5. Gatekeeper of pluripotency: A common Oct4 transcriptional network operates in mouse eggs and embryonic stem cells

    Directory of Open Access Journals (Sweden)

    Redi Carlo A

    2011-07-01

    Full Text Available Abstract Background Oct4 is a key factor of an expanded transcriptional network (Oct4-TN that governs pluripotency and self-renewal in embryonic stem cells (ESCs and in the inner cell mass from which ESCs are derived. A pending question is whether the establishment of the Oct4-TN initiates during oogenesis or after fertilisation. To this regard, recent evidence has shown that Oct4 controls a poorly known Oct4-TN central to the acquisition of the mouse egg developmental competence. The aim of this study was to investigate the identity and extension of this maternal Oct4-TN, as much as whether its presence is circumscribed to the egg or maintained beyond fertilisation. Results By comparing the genome-wide transcriptional profile of developmentally competent eggs that express the OCT4 protein to that of developmentally incompetent eggs in which OCT4 is down-regulated, we unveiled a maternal Oct4-TN of 182 genes. Eighty of these transcripts escape post-fertilisation degradation and represent the maternal Oct4-TN inheritance that is passed on to the 2-cell embryo. Most of these 80 genes are expressed in cancer cells and 37 are notable companions of the Oct4 transcriptome in ESCs. Conclusions These results provide, for the first time, a developmental link between eggs, early preimplantation embryos and ESCs, indicating that the molecular signature that characterises the ESCs identity is rooted in oogenesis. Also, they contribute a useful resource to further study the mechanisms of Oct4 function and regulation during the maternal-to-embryo transition and to explore the link between the regulation of pluripotency and the acquisition of de-differentiation in cancer cells.

  6. Output targets and transcriptional regulation by a cyclic dimeric GMP-responsive circuit in the Vibrio parahaemolyticus Scr network.

    Science.gov (United States)

    Ferreira, Rosana B R; Chodur, Daniel M; Antunes, Luis Caetano M; Trimble, Michael J; McCarter, Linda L

    2012-03-01

    The Vibrio parahaemolyticus Scr system modulates decisions pertinent to surface colonization by affecting the cellular level of cyclic dimeric GMP (c-di-GMP). In this work, we explore the scope and mechanism of this regulation. Transcriptome comparison of ΔscrABC and wild-type strains revealed expression differences with respect to ∼100 genes. Elevated c-di-GMP repressed genes in the surface-sensing regulon, including those encoding the lateral flagellar and type III secretion systems and N-acetylglucosamine-binding protein GpbA while inducing genes encoding other cell surface molecules and capsular polysaccharide. The transcription of a few regulatory genes was also affected, and the role of one was characterized. Mutations in cpsQ suppressed the sticky phenotype of scr mutants. cpsQ encodes one of four V. parahaemolyticus homologs in the CsgD/VpsT family, members of which have been implicated in c-di-GMP signaling. Here, we demonstrate that CpsQ is a c-di-GMP-binding protein. By using a combination of mutant and reporter analyses, CpsQ was found to be the direct, positive regulator of cpsA transcription. This c-di-GMP-responsive regulatory circuit could be reconstituted in Escherichia coli, where a low level of this nucleotide diminished the stability of CpsQ. The molecular interplay of additional known cps regulators was defined by establishing that CpsS, another CsgD family member, repressed cpsR, and the transcription factor CpsR activated cpsQ. Thus, we are developing a connectivity map of the Scr decision-making network with respect to its wiring and output strategies for colonizing surfaces and interaction with hosts; in doing so, we have isolated and reproduced a c-di-GMP-sensitive regulatory module in the circuit.

  7. Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress

    KAUST Repository

    Yun, Kil-Young

    2010-01-25

    Background: The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10C), an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach.Results: Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters.Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters.Conclusion: Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries. 2010 Yun et al; licensee BioMed Central Ltd.

  8. NUMERICAL SIMULATION OF HEMODYNAMICS IN THE HOST BLOOD VESSEL AND MICROVASCULAR NETWORK GENERATED FROM TUMOR-INDUCED ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    ZHAO Gai-ping; WU Jie; XU Shi-xiong; COLLINS M.W.; JIANG Yu-ping; WANG Jian

    2006-01-01

    Numerical simulation of hemodynamics under the combined effects of both the host blood vessel and the microvascular network,which is based on a 2-D tumor inside and outside vascular network generated from a discrete mathematical model of tumor-induced angiogenesis, is performed systemically. And a "microvascular network-transport across microvascular network-flow in interstitium" model is developed to study the flow in solid tumor. Simulations are carried out to examine the effects of the variations of the inlet Reynolds number in the host blood vessel, the hydraulic conductivity of the microvascular wall, and interstitial hydraulic conductivity coefficient on the fluid flow in tumor microcirculation. The results are consistent with data obtained in terms of physiology. These results may provide some theoretical references and the bases for further clinical experimental research.

  9. A Risk Based Neural Network Approach for Predictive Modeling of Blood Glucose Dynamics.

    Science.gov (United States)

    Frandes, Mirela; Timar, Bogdan; Lungeanu, Diana

    2016-01-01

    For type 1 diabetes patients, maintaining the blood glucose (BG) at normal values is a challenging task due to e.g. variable insulin reactions, diets, lifestyles, emotional conditions, etc. Hyperglycemic and hypoglycemic events can generate various complications (e.g. diabetic ketoacidosis, retinopathy, neuropathy, etc.), so predicting BG values in time is of great importance for diabetes self-management. Herein, we propose a non-linear autoregressive neural network approach, based on the minimal dataset available from a continuous glucose monitoring (CGM) sensor, with an integrated measure of intra-patient BG variability. The method kept the balance between accuracy and complexity, allowing a fast response with no additional effort or discomfort for the patient. PMID:27577449

  10. Optical blood pressure estimation with photoplethysmography and FFT-based neural networks.

    Science.gov (United States)

    Xing, Xiaoman; Sun, Mingshan

    2016-08-01

    We introduce and validate a beat-to-beat optical blood pressure (BP) estimation paradigm using only photoplethysmogram (PPG) signal from finger tips. The scheme determines subject-specific contribution to PPG signal and removes most of its influence by proper normalization. Key features such as amplitudes and phases of cardiac components were extracted by a fast Fourier transform and were used to train an artificial neural network, which was then used to estimate BP from PPG. Validation was done on 69 patients from the MIMIC II database plus 23 volunteers. All estimations showed a good correlation with the reference values. This method is fast and robust, and can potentially be used to perform pulse wave analysis in addition to BP estimation. PMID:27570693

  11. A transcriptional network associated with natural variation in Drosophila aggressive behavior

    OpenAIRE

    Edwards, Alexis C.; Ayroles, Julien F.; STONE, ERIC A.; Carbone, Mary Anna; Lyman, Richard F.; Mackay, Trudy FC

    2009-01-01

    Background Aggressive behavior is an important component of fitness in most animals. Aggressive behavior is genetically complex, with natural variation attributable to multiple segregating loci with allelic effects that are sensitive to the physical and social environment. However, we know little about the genes and genetic networks affecting natural variation in aggressive behavior. Populations of Drosophila melanogaster harbor quantitative genetic variation in aggressive behavior, providing...

  12. Blood Perfusion in Microfluidic Models of Pulmonary Capillary Networks: Role of Geometry and Hematocrit

    Science.gov (United States)

    Stauber, Hagit; Waisman, Dan; Sznitman, Josue; Technion-IIT Team; Department of Neonatology Carmel Medical Center; Faculty of Medicine-Technion IIT Collaboration

    2015-11-01

    Microfluidic platforms are increasingly used to study blood microflows at true physiological scale due to their ability to overcome manufacturing obstacle of complex anatomical morphologies, such as the organ-specific architectures of the microcirculation. In the present work, we utilize microfluidic platforms to devise in vitro models of the underlying pulmonary capillary networks (PCN), where capillary lengths and diameters are similar to the size of RBCs (~ 5-10 μm). To better understand flow characteristics and dispersion of red blood cells (RBCs) in PCNs, we have designed microfluidic models of alveolar capillary beds inspired by the seminal ``sheet flow'' model of Fung and Sobin (1969). Our microfluidic PCNs feature confined arrays of staggered pillars with diameters of ~ 5,7 and 10 μm, mimicking the dense structure of pulmonary capillary meshes. The devices are perfused with suspensions of RBCs at varying hematocrit levels under different flow rates. Whole-field velocity patterns using micro-PIV and single-cell tracking using PTV are obtained with fluorescently-labelled RBCs and discussed. Our experiments deliver a real-scale quantitative description of RBC perfusion characteristics across the pulmonary capillary microcirculation.

  13. Single image correlation for blood flow mapping in complex vessel networks

    Science.gov (United States)

    Chirico, Giuseppe; Sironi, Laura; Bouzin, Margaux; D'Alfonso, Laura; Collini, Maddalena; Ceffa, Nicolo'G.; Marquezin, Cassia

    2015-05-01

    Microcirculation plays a key role in the maintenance and hemodynamics of tissues and organs also due to its extensive interaction with the immune system. A critical limitation of state-of-the-art clinical techniques to characterize the blood flow is their lack of the spatial resolution required to scale down to individual capillaries. On the other hand the study of the blood flow through auto- or cross-correlation methods fail to correlate the flow speed values with the morphological details required to describe an intricate network of capillaries. Here we propose to use a newly developed technique (FLICS, FLow Image Correlation Spectroscopy) that, by employing a single raster-scanned xy-image acquired in vivo by confocal or multi-photon excitation fluorescence microscopy, allows the quantitative measurement of the blood flow velocity in the whole vessel pattern within the field of view, while simultaneously maintaining the morphological information on the immobile structures of the explored circulatory system. Fluorescent flowing objects produce diagonal lines in the raster-scanned image superimposed to static morphological details. The flow velocity is obtained by computing the Cross Correlation Function (CCF) of the intensity fluctuations detected in pairs of columns of the image. The whole analytical dependence of the CCFs on the flow speed amplitude and the flow direction has been reported recently. We report here the derivation of approximated analytical relations that allows to use the CCF peak lag time and the corresponding CCF value, to directly estimate the flow speed amplitude and the flow direction. The validation has been performed on Zebrafish embryos for which the flow direction was changed systematically by rotating the embryos on the microscope stage. The results indicate that also from the CCF peak lag time it is possible to recover the flow speed amplitude within 13% of uncertainty (overestimation) in a wide range of angles between the flow and

  14. Loss of variation of state detected in soybean metabolic and human myelomonocytic leukaemia cell transcriptional networks under external stimuli

    KAUST Repository

    Sakata, Katsumi

    2016-10-24

    Soybean (Glycine max) is sensitive to flooding stress, and flood damage at the seedling stage is a barrier to growth. We constructed two mathematical models of the soybean metabolic network, a control model and a flooded model, from metabolic profiles in soybean plants. We simulated the metabolic profiles with perturbations before and after the flooding stimulus using the two models. We measured the variation of state that the system could maintain from a state–space description of the simulated profiles. The results showed a loss of variation of state during the flooding response in the soybean plants. Loss of variation of state was also observed in a human myelomonocytic leukaemia cell transcriptional network in response to a phorbol-ester stimulus. Thus, we detected a loss of variation of state under external stimuli in two biological systems, regardless of the regulation and stimulus types. Our results suggest that a loss of robustness may occur concurrently with the loss of variation of state in biological systems. We describe the possible applications of the quantity of variation of state in plant genetic engineering and cell biology. Finally, we present a hypothetical “external stimulus-induced information loss” model of biological systems.

  15. Transcriptional Profiling of Whole Blood Identifies a Unique 5-Gene Signature for Myelofibrosis and Imminent Myelofibrosis Transformation

    DEFF Research Database (Denmark)

    Hasselbalch, Hans Carl; Skov, Vibe; Stauffer Larsen, Thomas;

    2014-01-01

    selectively and highly deregulated in myelofibrosis patients. Gene expression microarray studies have been performed on whole blood from 69 patients with myeloproliferative neoplasms. Amongst the top-20 of the most upregulated genes in PMF compared to controls, we identified 5 genes (DEFA4, ELA2, OLFM4, CTSG...

  16. Network motif-based identification of transcription factor-target gene relationships by integrating multi-source biological data

    Directory of Open Access Journals (Sweden)

    de los Reyes Benildo G

    2008-04-01

    Full Text Available Abstract Background Integrating data from multiple global assays and curated databases is essential to understand the spatio-temporal interactions within cells. Different experiments measure cellular processes at various widths and depths, while databases contain biological information based on established facts or published data. Integrating these complementary datasets helps infer a mutually consistent transcriptional regulatory network (TRN with strong similarity to the structure of the underlying genetic regulatory modules. Decomposing the TRN into a small set of recurring regulatory patterns, called network motifs (NM, facilitates the inference. Identifying NMs defined by specific transcription factors (TF establishes the framework structure of a TRN and allows the inference of TF-target gene relationship. This paper introduces a computational framework for utilizing data from multiple sources to infer TF-target gene relationships on the basis of NMs. The data include time course gene expression profiles, genome-wide location analysis data, binding sequence data, and gene ontology (GO information. Results The proposed computational framework was tested using gene expression data associated with cell cycle progression in yeast. Among 800 cell cycle related genes, 85 were identified as candidate TFs and classified into four previously defined NMs. The NMs for a subset of TFs are obtained from literature. Support vector machine (SVM classifiers were used to estimate NMs for the remaining TFs. The potential downstream target genes for the TFs were clustered into 34 biologically significant groups. The relationships between TFs and potential target gene clusters were examined by training recurrent neural networks whose topologies mimic the NMs to which the TFs are classified. The identified relationships between TFs and gene clusters were evaluated using the following biological validation and statistical analyses: (1 Gene set enrichment

  17. Supra-optimal expression of the cold-regulated OsMyb4 transcription factor in transgenic rice changes the complexity of transcriptional network with major effects on stress tolerance and panicle development

    KAUST Repository

    Park, Myoungryoul

    2010-09-28

    The R2R3-type OsMyb4 transcription factor of rice has been shown to play a role in the regulation of osmotic adjustment in heterologous overexpression studies. However, the exact composition and organization of its underlying transcriptional network has not been established to be a robust tool for stress tolerance enhancement by regulon engineering. OsMyb4 network was dissected based on commonalities between the global chilling stress transcriptome and the transcriptome configured by OsMyb4 overexpression. OsMyb4 controls a hierarchical network comprised of several regulatory sub-clusters associated with cellular defense and rescue, metabolism and development. It regulates target genes either directly or indirectly through intermediary MYB, ERF, bZIP, NAC, ARF and CCAAT-HAP transcription factors. Regulatory sub-clusters have different combinations of MYB-like, GCC-box-like, ERD1-box-like, ABRE-like, G-box-like, as1/ocs/TGA-like, AuxRE-like, gibberellic acid response element (GARE)-like and JAre-like cis-elements. Cold-dependent network activity enhanced cellular antioxidant capacity through radical scavenging mechanisms and increased activities of phenylpropanoid and isoprenoid metabolic processes involving various abscisic acid (ABA), jasmonic acid (JA), salicylic acid (SA), ethylene and reactive oxygen species (ROS) responsive genes. OsMyb4 network is independent of drought response element binding protein/C-repeat binding factor (DREB/CBF) and its sub-regulons operate with possible co-regulators including nuclear factor-Y. Because of its upstream position in the network hierarchy, OsMyb4 functions quantitatively and pleiotrophically. Supra-optimal expression causes misexpression of alternative targets with costly trade-offs to panicle development. © 2010 Blackwell Publishing Ltd.

  18. Evaluation of microphthalmia associated transcription factor (MITF expression in peripheral blood of a population with malign melanoma and control population and cell lines

    Directory of Open Access Journals (Sweden)

    Nelson Rangel

    2009-03-01

    Full Text Available Background: The incidence of malign melanoma tumours has increased more rapidly than any other type of cancer; this has intensified the searching for tools that facilitate early detection of melanoma. Microphthalmia associated transcription factor (MITF is currently known as being a master melanocyte regulator. The article analyses MITF gene expression in peripheral blood of individuals suffering from melanoma, compared to people without any type of cancer and some cell lines.Materials and methods: Thirty one samples of peripheral blood were used: 19 from patients having melanoma and 12 from healthy people. Then RNA was extracted from these samples. MITF and housekeeping genes (b2M and GAPDH expression levels were then quantified by real-time PCR. Five cell lines were also used to determine the MITF expression.Results: MITF gene expression could be observed in all individuals, though no statistical significant differences were found among expression levels in the groups studied (p=0.09. Even so, MITF expression in the group of patients suffering from melanoma was much more variable than that observed in the group of cancer-free people. Expression was detected in the cell line AGS (gastric adenocarcinoma, not yet described.Conclusions: MITF gene expression levels were detected in the peripheral blood from both people suffering from melanoma and people without any type of cancer. However, variability in the number of molecules in MITF gene expression was observed in people with melanoma, this suggests the presence of tumour cells in circulation.

  19. The DtxR protein acting as dual transcriptional regulator directs a global regulatory network involved in iron metabolism of Corynebacterium glutamicum

    Directory of Open Access Journals (Sweden)

    Hüser Andrea T

    2006-02-01

    Full Text Available Abstract Background The knowledge about complete bacterial genome sequences opens the way to reconstruct the qualitative topology and global connectivity of transcriptional regulatory networks. Since iron is essential for a variety of cellular processes but also poses problems in biological systems due to its high toxicity, bacteria have evolved complex transcriptional regulatory networks to achieve an effective iron homeostasis. Here, we apply a combination of transcriptomics, bioinformatics, in vitro assays, and comparative genomics to decipher the regulatory network of the iron-dependent transcriptional regulator DtxR of Corynebacterium glutamicum. Results A deletion of the dtxR gene of C. glutamicum ATCC 13032 led to the mutant strain C. glutamicum IB2103 that was able to grow in minimal medium only under low-iron conditions. By performing genome-wide DNA microarray hybridizations, differentially expressed genes involved in iron metabolism of C. glutamicum were detected in the dtxR mutant. Bioinformatics analysis of the genome sequence identified a common 19-bp motif within the upstream region of 31 genes, whose differential expression in C. glutamicum IB2103 was verified by real-time reverse transcription PCR. Binding of a His-tagged DtxR protein to oligonucleotides containing the 19-bp motifs was demonstrated in vitro by DNA band shift assays. At least 64 genes encoding a variety of physiological functions in iron transport and utilization, in central carbohydrate metabolism and in transcriptional regulation are controlled directly by the DtxR protein. A comparison with the bioinformatically predicted networks of C. efficiens, C. diphtheriae and C. jeikeium identified evolutionary conserved elements of the DtxR network. Conclusion This work adds considerably to our currrent understanding of the transcriptional regulatory network of C. glutamicum genes that are controlled by DtxR. The DtxR protein has a major role in controlling the

  20. Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation.

    Science.gov (United States)

    Gagnon, Louis; Smith, Amy F; Boas, David A; Devor, Anna; Secomb, Timothy W; Sakadžić, Sava

    2016-01-01

    Oxygen is delivered to brain tissue by a dense network of microvessels, which actively control cerebral blood flow (CBF) through vasodilation and contraction in response to changing levels of neural activity. Understanding these network-level processes is immediately relevant for (1) interpretation of functional Magnetic Resonance Imaging (fMRI) signals, and (2) investigation of neurological diseases in which a deterioration of neurovascular and neuro-metabolic physiology contributes to motor and cognitive decline. Experimental data on the structure, flow and oxygen levels of microvascular networks are needed, together with theoretical methods to integrate this information and predict physiologically relevant properties that are not directly measurable. Recent progress in optical imaging technologies for high-resolution in vivo measurement of the cerebral microvascular architecture, blood flow, and oxygenation enables construction of detailed computational models of cerebral hemodynamics and oxygen transport based on realistic three-dimensional microvascular networks. In this article, we review state-of-the-art optical microscopy technologies for quantitative in vivo imaging of cerebral microvascular structure, blood flow and oxygenation, and theoretical methods that utilize such data to generate spatially resolved models for blood flow and oxygen transport. These "bottom-up" models are essential for the understanding of the processes governing brain oxygenation in normal and disease states and for eventual translation of the lessons learned from animal studies to humans. PMID:27630556

  1. Modeling of Cerebral Oxygen Transport Based on In vivo Microscopic Imaging of Microvascular Network Structure, Blood Flow, and Oxygenation

    Science.gov (United States)

    Gagnon, Louis; Smith, Amy F.; Boas, David A.; Devor, Anna; Secomb, Timothy W.; Sakadžić, Sava

    2016-01-01

    Oxygen is delivered to brain tissue by a dense network of microvessels, which actively control cerebral blood flow (CBF) through vasodilation and contraction in response to changing levels of neural activity. Understanding these network-level processes is immediately relevant for (1) interpretation of functional Magnetic Resonance Imaging (fMRI) signals, and (2) investigation of neurological diseases in which a deterioration of neurovascular and neuro-metabolic physiology contributes to motor and cognitive decline. Experimental data on the structure, flow and oxygen levels of microvascular networks are needed, together with theoretical methods to integrate this information and predict physiologically relevant properties that are not directly measurable. Recent progress in optical imaging technologies for high-resolution in vivo measurement of the cerebral microvascular architecture, blood flow, and oxygenation enables construction of detailed computational models of cerebral hemodynamics and oxygen transport based on realistic three-dimensional microvascular networks. In this article, we review state-of-the-art optical microscopy technologies for quantitative in vivo imaging of cerebral microvascular structure, blood flow and oxygenation, and theoretical methods that utilize such data to generate spatially resolved models for blood flow and oxygen transport. These “bottom-up” models are essential for the understanding of the processes governing brain oxygenation in normal and disease states and for eventual translation of the lessons learned from animal studies to humans.

  2. Measurement and modeling of transcriptional noise in the cell cycle regulatory network.

    Science.gov (United States)

    Ball, David A; Adames, Neil R; Reischmann, Nadine; Barik, Debashis; Franck, Christopher T; Tyson, John J; Peccoud, Jean

    2013-10-01

    Fifty years of genetic and molecular experiments have revealed a wealth of molecular interactions involved in the control of cell division. In light of the complexity of this control system, mathematical modeling has proved useful in analyzing biochemical hypotheses that can be tested experimentally. Stochastic modeling has been especially useful in understanding the intrinsic variability of cell cycle events, but stochastic modeling has been hampered by a lack of reliable data on the absolute numbers of mRNA molecules per cell for cell cycle control genes. To fill this void, we used fluorescence in situ hybridization (FISH) to collect single molecule mRNA data for 16 cell cycle regulators in budding yeast, Saccharomyces cerevisiae. From statistical distributions of single-cell mRNA counts, we are able to extract the periodicity, timing, and magnitude of transcript abundance during the cell cycle. We used these parameters to improve a stochastic model of the cell cycle to better reflect the variability of molecular and phenotypic data on cell cycle progression in budding yeast.

  3. Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms.

    Directory of Open Access Journals (Sweden)

    Alan E Bilsland

    2014-02-01

    Full Text Available Cancer cells depend on transcription of telomerase reverse transcriptase (TERT. Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3'-oxime (BIO predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several

  4. Tissue-specific regulatory network extractor (TS-REX): a database and software resource for the tissue and cell type-specific investigation of transcription factor-gene networks.

    Science.gov (United States)

    Colecchia, Federico; Kottwitz, Denise; Wagner, Mandy; Pfenninger, Cosima V; Thiel, Gerald; Tamm, Ingo; Peterson, Carsten; Nuber, Ulrike A

    2009-06-01

    The prediction of transcription factor binding sites in genomic sequences is in principle very useful to identify upstream regulatory factors. However, when applying this concept to genomes of multicellular organisms such as mammals, one has to deal with a large number of false positive predictions since many transcription factor genes are only expressed in specific tissues or cell types. We developed TS-REX, a database/software system that supports the analysis of tissue and cell type-specific transcription factor-gene networks based on expressed sequence tag abundance of transcription factor-encoding genes in UniGene EST libraries. The use of expression levels of transcription factor-encoding genes according to hierarchical anatomical classifications covering different tissues and cell types makes it possible to filter out irrelevant binding site predictions and to identify candidates of potential functional importance for further experimental testing. TS-REX covers ESTs from H. sapiens and M. musculus, and allows the characterization of both presence and specificity of transcription factors in user-specified tissues or cell types. The software allows users to interactively visualize transcription factor-gene networks, as well as to export data for further processing. TS-REX was applied to predict regulators of Polycomb group genes in six human tumor tissues and in human embryonic stem cells. PMID:19443447

  5. Transcriptional activity of telomerase complex in CD34- stem cells of cord blood in dependence of preparation time.

    Directory of Open Access Journals (Sweden)

    M Bojdys-Szyndlar

    2009-12-01

    Full Text Available The aim of the study was to determine whether the expression of telomerase subunits encoding genes changes during the process of cord blood preparation. It should establish if the commonly accepted 24 hours time interval in stem cells kriopreservation procedure significantly influences their immortalization and so decreases the "quality" of cord blood stem cells. Investigation includes 69 women. Spontaneous labour was the inclusion condition. The material was collected at birth after clamping of umbilical cord by direct vasopuncture. CD34- cells were extracted from cord blood (MACS, Miltenyi Biotec; Bisley, Surrey, UK. The expression profile of telomerase activators and inhibitors encoding genes was determined using HG_U133A oligonucleotide microarray (Affymetrix. We used a real-time quantitative RT-PCR assay to quantify the telomerase TERT, hTR and TP1 subunits mRNA copy numbers in CD34- cells in 0, 6, 12 and 24 hours after cord blood collection. We observed significant decrease of numbers of copies of TERTA+B mRNA within the successive hours of observation. Significant decrease of numbers of TERTA mRNA copies was confirmed after 24 hours. However, we observed significant increase of numbers of copies of TERTB mRNA after 6 hours of observation. Similar level was maintained during another 6h. The significantly lower number of copies of TERTB mRNA was observed after 24h. We also observed significant increase of number of copies of TERT mRNA after 6 hours. Number of copies of TERT mRNA significantly decreased after another 6h, remaining, however, on a higher then initial one. The significant lower number of copies of TERT mRNA was observed 24h after delivery. The possible explanation of those results is discussed in the paper.

  6. A network of interdependent molecular interactions describes a higher order Nrd1-Nab3 complex involved in yeast transcription termination.

    Science.gov (United States)

    Loya, Travis J; O'Rourke, Thomas W; Degtyareva, Natalya; Reines, Daniel

    2013-11-22

    Nab3 and Nrd1 are yeast heterogeneous nuclear ribonucleoprotein (hnRNP)-like proteins that heterodimerize and bind RNA. Genetic and biochemical evidence reveals that they are integral to the termination of transcription of short non-coding RNAs by RNA polymerase II. Here we define a Nab3 mutation (nab3Δ134) that removes an essential part of the protein's C terminus but nevertheless can rescue, in trans, the phenotype resulting from a mutation in the RNA recognition motif of Nab3. This low complexity region of Nab3 appears intrinsically unstructured and can form a hydrogel in vitro. These data support a model in which multiple Nrd1-Nab3 heterodimers polymerize onto substrate RNA to effect termination, allowing complementation of one mutant Nab3 molecule by another lacking a different function. The self-association property of Nab3 adds to the previously documented interactions between these hnRNP-like proteins, RNA polymerase II, and the nascent transcript, leading to a network of nucleoprotein interactions that define a higher order Nrd1-Nab3 complex. This was underscored from the synthetic phenotypes of yeast strains with pairwise combinations of Nrd1 and Nab3 mutations known to affect their distinct biochemical activities. The mutations included a Nab3 self-association defect, a Nab3-Nrd1 heterodimerization defect, a Nrd1-polymerase II binding defect, and an Nab3-RNA recognition motif mutation. Although no single mutation was lethal, cells with any two mutations were not viable for four such pairings, and a fifth displayed a synthetic growth defect. These data strengthen the idea that a multiplicity of interactions is needed to assemble a higher order Nrd1-Nab3 complex that coats specific nascent RNAs in preparation for termination. PMID:24100036

  7. Quantitative classification of HbA1C and blood glucose level for diabetes diagnosis using neural networks

    International Nuclear Information System (INIS)

    In this study, artificial neural network structures were used for the quantitative classification of Haemoglobin A1C and blood glucose level for diabetes diagnosis as a non-invasive measurement technique. The neural network structures make inferences from the relationship between the palm perspiration and blood data values. For this purpose, feed forward multilayer, Elman, and radial basis neural network structures were used. The quartz crystal microbalance type and humidity sensors were used for the detection of palm perspiration rates. Total 297 volunteer's data is used in this study. Three quarters of the data was used to train the neural networks. The remaining data were used as test data. The best results for the quantitative classification were obtained from the feed forward NN structure for the detection of the glucose and HbA1C level quantities. And, the performances of all neural networks for the HbA1C value were better than the performances of these neural networks for the glucose level.

  8. The B-MYB transcriptional network guides cell cycle progression and fate decisions to sustain self-renewal and the identity of pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Ming Zhan

    Full Text Available Embryonic stem cells (ESCs are pluripotent and have unlimited self-renewal capacity. Although pluripotency and differentiation have been examined extensively, the mechanisms responsible for self-renewal are poorly understood and are believed to involve an unusual cell cycle, epigenetic regulators and pluripotency-promoting transcription factors. Here we show that B-MYB, a cell cycle regulated phosphoprotein and transcription factor critical to the formation of inner cell mass, is central to the transcriptional and co-regulatory networks that sustain normal cell cycle progression and self-renewal properties of ESCs. Phenotypically, B-MYB is robustly expressed in ESCs and induced pluripotent stem cells (iPSCs, and it is present predominantly in a hypo-phosphorylated state. Knockdown of B-MYB results in functional cell cycle abnormalities that involve S, G2 and M phases, and reduced expression of critical cell cycle regulators like ccnb1 and plk1. By conducting gene expression profiling on control and B-MYB deficient cells, ChIP-chip experiments, and integrative computational analyses, we unraveled a highly complex B-MYB-mediated transcriptional network that guides ESC self-renewal. The network encompasses critical regulators of all cell cycle phases and epigenetic regulators, pluripotency transcription factors, and differentiation determinants. B-MYB along with E2F1 and c-MYC preferentially co-regulate cell cycle target genes. B-MYB also co-targets genes regulated by OCT4, SOX2 and NANOG that are significantly associated with stem cell differentiation, embryonic development, and epigenetic control. Moreover, loss of B-MYB leads to a breakdown of the transcriptional hierarchy present in ESCs. These results coupled with functional studies demonstrate that B-MYB not only controls and accelerates cell cycle progression in ESCs it contributes to fate decisions and maintenance of pluripotent stem cell identity.

  9. Fractals and fractal dimension of systems of blood vessels: An analogy between artery trees, river networks, and urban hierarchies

    CERN Document Server

    Chen, Yanguang

    2015-01-01

    An analogy between the fractal nature of networks of arteries and that of systems of rivers has been drawn in the previous works. However, the deep structure of the hierarchy of blood vessels has not yet been revealed. This paper is devoted to researching the fractals, allometric scaling, and hierarchy of blood vessels. By analogy with Horton-Strahler's laws of river composition, three exponential laws have been put forward. These exponential laws can be reconstructed and transformed into three linear scaling laws, which can be named composition laws of blood vessels network. From these linear scaling laws it follows a set of power laws, including the three-parameter Zipf's law on the rank-size distribution of blood vessel length and the allometric scaling law on the length-diameter relationship of blood vessels in different orders. The models are applied to the observed data on human beings and animals early given by other researchers, and an interesting finding is that human bodies more conform to natural r...

  10. Gene transcript analysis blood values correlate with {sup 68}Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Kidd, M.; Modlin, I.M.; Drozdov, I. [Wren Laboratories, Branford, CT (United States); Prasad, V. [Charite University Hospital, Department of Nuclear Medicine, Berlin (Germany); Severi, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Ambrosini, V. [S. Orsola-Malpighi University Hospital, Nuclear Medicine, Bologna (Italy); Kwekkeboom, D.J.; Krenning, E.P. [Erasmus Medical Center Rotterdam, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [Zentralklinik Bad Berka, THERANOSTICS Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)

    2015-08-15

    Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between {sup 68}Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive {sup 68}Ga-SSA PET: data set 1 ({sup 68}Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 ({sup 68}Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUV{sub max}), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUV{sub max} measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ{sup 2} = 20.1, p < 2.5 x 10{sup -6}). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUV{sub max} (R {sup 2} = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUV{sub max}. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUV{sub max} [ROC-derived AUC (R {sup 2} = 0.7, p < 0.05)]. No statistical relationship was identified

  11. Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status

    International Nuclear Information System (INIS)

    Precise determination of neuroendocrine tumor (NET) disease status and response to therapy remains a rate-limiting concern for disease management. This reflects limitations in biomarker specificity and resolution capacity of imaging. In order to evaluate biomarker precision and identify if combinatorial blood molecular markers and imaging could provide added diagnostic value, we assessed the concordance between 68Ga-somatostatin analog (SSA) positron emission tomography (PET), circulating NET gene transcripts (NETest), chromogranin A (CgA), and Ki-67 in NETs. We utilized two independent patient groups with positive 68Ga-SSA PET: data set 1 (68Ga-SSA PETs undertaken for peptide receptor radionuclide therapy (PRRT), as primary or salvage treatment, n = 27) and data set 2 (68Ga-SSA PETs performed in patients referred for initial disease staging or restaging after various therapies, n = 22). We examined the maximum standardized uptake value (SUVmax), circulating gene transcripts, CgA levels, and baseline Ki-67. Regression analyses, generalized linear modeling, and receiver-operating characteristic (ROC) analyses were undertaken to determine the strength of the relationships. SUVmax measured in two centers were mathematically evaluated (regression modeling) and determined to be comparable. Of 49 patients, 47 (96 %) exhibited a positive NETest. Twenty-six (54 %) had elevated CgA (χ2 = 20.1, p < 2.5 x 10-6). The majority (78 %) had Ki-67 < 20 %. Gene transcript scores were predictive of imaging with >95 % concordance and significantly correlated with SUVmax (R 2 = 0.31, root-mean-square error = 9.4). The genes MORF4L2 and somatostatin receptors SSTR1, 3, and 5 exhibited the highest correlation with SUVmax. Progressive disease was identified by elevated levels of a quotient of MORF4L2 expression and SUVmax [ROC-derived AUC (R 2 = 0.7, p < 0.05)]. No statistical relationship was identified between CgA and Ki-67 and no relationship with imaging parameters was evident. 68Ga

  12. 酵母转录调控协作网络的分析%Analysis of Transcriptional Regulation Collaboration Networks in Saccharomy cescerevisiae

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Collaboration networks have proven informative when used to describe various kinds of human relationships. Similar strategy could be used in the transcriptional regulatory network. A collaboration network of target genes (TGs) was constructed based on common transcription factors (TFs), and similarly, a smaller network of transcription factors was constructed based on their common target genes. After clustering the target gene collaboration networks, genes in the same cluster were often enriched for one or more GO terms. The results also showed that genes with specific GO terms tend to share similar regulatory mechanisms. It indicates that in a collaboration network approach the relatively simple "regulatory mechanism" measure used here was able to extract considerable biologically relevant information. Moreover, a definition of anomaly used before in a bipartite graph analysis method was applied into the collaboration networks analysis. And the correlation between the anomalies and the essential genes was discovered. In a conclusion,a collaboration network approach may be a valuable supplement to other analyses of transcriptional networks.%协作网通常被用于描述各种社会关系,相似的概念也可以应用到转录调控网络的研究中.针对被调控基因共享转录因子的相似性,可以建立一个被调控基因协作网,同样,根据转录因子调控基因的相似性可以建立一个相对较小的转录因子协作网.对被调控基因协作网的聚类研究发现,大部分的类都显著地富集一个或者多个GO功能注释.进一步的结果分析发现某些GO注释的基因更倾向于共享相似的调控机制.这表明,在协作网中,相对简单的调控机制相似性能捕捉生物功能相关的信息.并且,将在二部图分析中使用的概念--"异常点"引入到协作网的分析中,发现协作网的异常点和致死基因有相关性.综上所述,协作网的方法是分析转录调控网络的一个有用的补充.

  13. Transcriptional profiling of whole blood identifies a unique 5-gene signature for myelofibrosis and imminent myelofibrosis transformation.

    Directory of Open Access Journals (Sweden)

    Hans Carl Hasselbalch

    Full Text Available Identifying a distinct gene signature for myelofibrosis may yield novel information of the genes, which are responsible for progression of essential thrombocythemia and polycythemia vera towards myelofibrosis. We aimed at identifying a simple gene signature - composed of a few genes - which were selectively and highly deregulated in myelofibrosis patients. Gene expression microarray studies have been performed on whole blood from 69 patients with myeloproliferative neoplasms. Amongst the top-20 of the most upregulated genes in PMF compared to controls, we identified 5 genes (DEFA4, ELA2, OLFM4, CTSG, and AZU1, which were highly significantly deregulated in PMF only. None of these genes were significantly regulated in ET and PV patients. However, hierarchical cluster analysis showed that these genes were also highly expressed in a subset of patients with ET (n = 1 and PV (n = 4 transforming towards myelofibrosis and/or being featured by an aggressive phenotype. We have identified a simple 5-gene signature, which is uniquely and highly significantly deregulated in patients in transitional stages of ET and PV towards myelofibrosis and in patients with PMF only. Some of these genes are considered to be responsible for the derangement of bone marrow stroma in myelofibrosis. Accordingly, this gene-signature may reflect key processes in the pathogenesis and pathophysiology of myelofibrosis development.

  14. Simulation of one-dimensional blood flow in networks of human vessels using a novel TVD scheme.

    Science.gov (United States)

    Huang, P G; Muller, L O

    2015-05-01

    An extension of a total variation diminishing (TVD) scheme to solve one-dimensional (1D) blood flow for human circulation is proposed. This method is simple as it involves only a few modifications to existing shock-capturing TVD schemes. We have applied the method to a wide range of test cases including a complete simulation of the human vascular network. Excellent solutions have been demonstrated for problems involving varying and discontinuous mechanical properties of blood vessels. For 1D network simulations, the method has been shown to agree well with the reported computational results. Finally, the method has been demonstrated to compare favorably with in vivo experiments set up to study the impact of circle of Willis anomalies on flow patterns in the cerebral arterial system. PMID:25529823

  15. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate.

    Directory of Open Access Journals (Sweden)

    Jatin Narula

    2010-05-01

    Full Text Available Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

  16. The Blood Quality Monitoring Network System's Role in the Safety of Blood Transfusion%血液质量监测网络体系在输血安全中的作用

    Institute of Scientific and Technical Information of China (English)

    胡秀兰; 田志彬; 李忠杰; 玄红霞; 陈书芳

    2013-01-01

    目的探寻建立血站血液质量监测网络体系,确保血液质量与安全。方法对献血者献血前的血液标本进行初筛,对采血场所、关键原辅材料、关键设备进行质量控制,同时加强采后血液的质量监测以及各供血库的监测。结果比较质量监测网络体系建立前后血液质量情况,发现血液质量监测网络体系建立后血液质量有明显提高。结论建立完整有效、安全的血液质量监测网络体系,对血液的采集、检验、保存、运送和使用等多个环节进行血液质量监测,监控血液"从血管到血管"的全过程,确保献血者、用血者身体健康和生命安全。%Objective To explore the establishment of a blood bank blood quality monitoring network system to ensure the quality and safety of blood. Methods for screening blood donors before blood samples, blood col ection establishments, the key raw materials, key equipment for quality control quality, while strengthening the postharvest quality monitoring of blood as wel as monitoring for blood banks. Results the comparative quality monitoring network system to establish the quality of blood before and after situation, significantly improved blood quality monitoring network system to establish the quality of blood. Conclusions to establish a complete and ef ective, safe blood quality monitoring network system for blood col ection, testing, preservation, transportation and use of other aspects of the blood quality monitoring, monitoring of blood"from the blood vessels to the blood vessels,"the whole process to ensure donors with blood by the health and safety of life.

  17. Functional and gene network analyses of transcriptional signatures characterizing pre-weaned bovine mammary parenchyma or fat pad uncovered novel inter-tissue signaling networks during development

    Directory of Open Access Journals (Sweden)

    Lewin Harris A

    2010-05-01

    Full Text Available Abstract Background The neonatal bovine mammary fat pad (MFP surrounding the mammary parenchyma (PAR is thought to exert proliferative effects on the PAR through secretion of local modulators of growth induced by systemic hormones. We used bioinformatics to characterize transcriptomics differences between PAR and MFP from ~65 d old Holstein heifers. Data were mined to uncover potential crosstalk through the analyses of signaling molecules preferentially expressed in one tissue relative to the other. Results Over 9,000 differentially expressed genes (DEG; False discovery rate ≤ 0.05 were found of which 1,478 had a ≥1.5-fold difference between PAR and MFP. Within the DEG highly-expressed in PAR vs. MFP (n = 736 we noted significant enrichment of functions related to cell cycle, structural organization, signaling, and DNA/RNA metabolism. Only actin cytoskeletal signaling was significant among canonical pathways. DEG more highly-expressed in MFP vs. PAR (n = 742 belong to lipid metabolism, signaling, cell movement, and immune-related functions. Canonical pathways associated with metabolism and signaling, particularly immune- and metabolism-related were significantly-enriched. Network analysis uncovered a central role of MYC, TP53, and CTNNB1 in controlling expression of DEG highly-expressed in PAR vs. MFP. Similar analysis suggested a central role for PPARG, KLF2, EGR2, and EPAS1 in regulating expression of more highly-expressed DEG in MFP vs. PAR. Gene network analyses revealed putative inter-tissue crosstalk between cytokines and growth factors preferentially expressed in one tissue (e.g., ANGPTL1, SPP1, IL1B in PAR vs. MFP; ADIPOQ, IL13, FGF2, LEP in MFP vs. PAR with DEG preferentially expressed in the other tissue, particularly transcription factors or pathways (e.g., MYC, TP53, and actin cytoskeletal signaling in PAR vs. MFP; PPARG and LXR/RXR Signaling in MFP vs. PAR. Conclusions Functional analyses underscored a reciprocal influence in

  18. Transforming growth factor beta-1 and interleukin-17 gene transcription in peripheral blood mononuclear cells and the human response to infection.

    LENUS (Irish Health Repository)

    White, Mary

    2012-02-01

    INTRODUCTION: The occurrence of severe sepsis may be associated with deficient pro-inflammatory cytokine production. Transforming growth factor beta-1 (TGFbeta-1) predominantly inhibits inflammation and may simultaneously promote IL-17 production. Interleukin-17 (IL-17) is a recently described pro-inflammatory cytokine, which may be important in auto-immunity and infection. We investigated the hypothesis that the onset of sepsis is related to differential TGFbeta-1 and IL-17 gene expression. METHODS: A prospective observational study in a mixed intensive care unit (ICU) and hospital wards in a university hospital. Patients (59) with severe sepsis; 15 patients with gram-negative bacteraemia but without critical illness and 10 healthy controls were assayed for TGFbeta-1, IL-17a, IL-17f, IL-6 and IL-1beta mRNA in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR and serum protein levels by ELISA. RESULTS: TGFbeta-1 mRNA levels are reduced in patients with bacteraemia and sepsis compared with controls (p=0.02). IL-6 mRNA levels were reduced in bacteraemic patients compared with septic patients and controls (p=0.008). IL-1beta mRNA levels were similar in all groups, IL-17a and IL-17f mRNA levels are not detectable in peripheral blood mononuclear cells. IL-6 protein levels were greater in patients with sepsis than bacteraemic and control patients (p<0.0001). Activated TGFbeta-1 and IL-17 protein levels were similar in all groups. IL-1beta protein was not detectable in the majority of patients. CONCLUSIONS: Down regulation of TGFbeta-1 gene transcription was related to the occurrence of infection but not the onset of sepsis. Interleukin-17 production in PBMC may not be significant in the human host response to infection.

  19. Construction and analysis of regulatory genetic networks in cervical cancer based on involved microRNAs, target genes, transcription factors and host genes.

    Science.gov (United States)

    Wang, Ning; Xu, Zhiwen; Wang, Kunhao; Zhu, Minghui; Li, Yang

    2014-04-01

    Over recent years, genes and microRNA (miRNA/miR) have been considered as key biological factors in human carcinogenesis. During cancer development, genes may act as multiple identities, including target genes of miRNA, transcription factors and host genes. The present study concentrated on the regulatory networks consisting of the biological factors involved in cervical cancer in order to investigate their features and affect on this specific pathology. Numerous raw data was collected and organized into purposeful structures, and adaptive procedures were defined for application to the prepared data. The networks were therefore built with the factors as basic components according to their interacting associations. The networks were constructed at three levels of interdependency, including a differentially-expressed network, a related network and a global network. Comparisons and analyses were made at a systematic level rather than from an isolated gene or miRNA. Critical hubs were extracted in the core networks and notable features were discussed, including self-adaption feedback regulation. The present study expounds the pathogenesis from a novel point of view and is proposed to provide inspiration for further investigation and therapy.

  20. Entropic elasticity of end adsorbed polymer chains: The spectrin network of red blood cells as C*-gel

    Science.gov (United States)

    Everaers, Ralf; Graham, Ian S.; Zuckermann, Martin J.; Sackmann, Erich

    1996-03-01

    We use Monte Carlo methods to investigate the end-to-end distance distribution and entropic elasticity of self-avoiding walks in a three-dimensional half-space with both ends adsorbed on the limiting surface. The obtained distributions are well described by the Redner-des Cloizeaux (RdC) ansatz q(x)=Cxθ exp(-(Kx)t), x being the rescaled length. Using the recent solution of the junction affine model for networks of RdC springs we apply the results to the cytoskeleton of the red blood cell (RBC), a two-dimensional network of spectrin molecules which is attached to the inner surface of the erythrocyte membrane. The shear moduli predicted for a noninteracting surface are in close agreement with simulation results by Boal for a bead-spring model of the spectrin network. Moreover, we calculate stress-strain relations for finite deformations. In particular for a network which is fully adsorbed on the bilayer we find a strongly nonlinear elastic response. Our results suggest that the elastic properties of RBCs cannot be obtained within the usual Gaussian models and depend sensitively on the degree of adsorption of the spectrin network.

  1. Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling

    Directory of Open Access Journals (Sweden)

    Craigon Marie

    2009-08-01

    Full Text Available Abstract Background Interferons (IFNs are potent antiviral cytokines capable of reprogramming the macrophage phenotype through the induction of interferon-stimulated genes (ISGs. Here we have used targeted RNA interference to suppress the expression of a number of key genes associated with IFN signalling in murine macrophages prior to stimulation with interferon-gamma. Genome-wide changes in transcript abundance caused by siRNA activity were measured using exon-level microarrays in the presence or absence of IFNγ. Results Transfection of murine bone-marrow derived macrophages (BMDMs with a non-targeting (control siRNA and 11 sequence-specific siRNAs was performed using a cationic lipid transfection reagent (Lipofectamine2000 prior to stimulation with IFNγ. Total RNA was harvested from cells and gene expression measured on Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. Network-based analysis of these data revealed six siRNAs to cause a marked shift in the macrophage transcriptome in the presence or absence IFNγ. These six siRNAs targeted the Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2 transcripts. The perturbation of the transcriptome by the six siRNAs was highly similar in each case and affected the expression of over 600 downstream transcripts. Regulated transcripts were clustered based on co-expression into five major groups corresponding to transcriptional networks associated with the type I and II IFN response, cell cycle regulation, and NF-KB signalling. In addition we have observed a significant non-specific immune stimulation of cells transfected with siRNA using Lipofectamine2000, suggesting use of this reagent in BMDMs, even at low concentrations, is enough to induce a type I IFN response. Conclusion Our results provide evidence that the type I IFN response in murine BMDMs is dependent on Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2, and that siRNAs targeted to these genes results in perturbation of key transcriptional networks associated

  2. Overexpression of E2F mRNAs associated with gastric cancer progression identified by the transcription factor and miRNA co-regulatory network analysis.

    Science.gov (United States)

    Zhang, XiaoTian; Ni, ZhaoHui; Duan, ZiPeng; Xin, ZhuoYuan; Wang, HuaiDong; Tan, JiaYi; Wang, GuoQing; Li, Fan

    2015-01-01

    Gene expression is regulated at the transcription and translation levels; thus, both transcription factors (TFs) and microRNAs (miRNA) play roles in regulation of gene expression. This study profiled differentially expressed mRNAs and miRNAs in gastric cancer tissues to construct a TF and miRNA co-regulatory network in order to identify altered genes in gastric cancer progression. A total of 70 cases gastric cancer and paired adjacent normal tissues were subjected to cDNA and miRNA microarray analyses. We obtained 887 up-regulated and 93 down-regulated genes and 41 down-regulated and 4 up-regulated miRNAs in gastric cancer tissues. Using the Transcriptional Regulatory Element Database, we obtained 105 genes that are regulated by the E2F family of genes and using Targetscan, miRanda, miRDB and miRWalk tools, we predicted potential targeting genes of these 45 miRNAs. We then built up the E2F-related TF and miRNA co-regulatory gene network and identified 9 hub-genes. Furthermore, we found that levels of E2F1, 2, 3, 4, 5, and 7 mRNAs associated with gastric cancer cell invasion capacity, and has associated with tumor differentiation. These data showed Overexpression of E2F mRNAs associated with gastric cancer progression.

  3. Assessment of performance of professionals in immunohematology proficiency tests of the public blood bank network of the state of Minas Gerais

    OpenAIRE

    Stela Brener; Ângela Melgaço Ferreira; Ricardo Vilas Freire de Carvalho; Marcele Cunha Ribeiro do Valle; Helio Moraes-Souza

    2012-01-01

    BACKGROUND: Despite significant advances, the practice of blood transfusion is still a complex process and subject to risks. Factors that influence the safety of blood transfusion include technical skill and knowledge in hemotherapy mainly obtained by the qualification and training of teams. OBJECTIVE: This study aimed to investigate the relationship between professional categories working in transfusion services of the public blood bank network in the State of Minas Gerais and their performa...

  4. Detection of Tumor Cell-Specific mRNA in the Peripheral Blood of Patients with Breast Cancer — Evaluation of Several Markers with Real-Time Reverse Transcription-PCR

    Directory of Open Access Journals (Sweden)

    Ulrich Andergassen

    2013-01-01

    Full Text Available It is widely known that cells from epithelial tumors, e.g., breast cancer, detach from their primary tissue and enter blood circulation. We show that the presence of circulating tumor cells (CTCs in samples of patients with primary and metastatic breast cancer can be detected with an array of selected tumor-marker-genes by reverse transcription real-time PCR. The focus of the presented work is on detecting differences in gene expression between healthy individuals and adjuvant and metastatic breast cancer patients, not an accurate quantification of these differences. Therefore, total RNA was isolated from blood samples of healthy donors and patients with primary or metastatic breast cancer after enrichment of mononuclear cells by density gradient centrifugation. After reverse transcription real-time PCR was carried out with a set of marker genes (BCSP, CK8, Her2, MGL, CK18, CK19. B2M and GAPDH were used as reference genes. Blood samples from patients with metastatic disease revealed increased cytokine gene levels in comparison to normal blood samples. Detection of a single gene was not sufficient to detect CTCs by reverse transcription real-time PCR. Markers used here were selected based on a recent study detecting cancer cells on different protein levels. The combination of such a marker array leads to higher and more specific discovery rates, predominantly in metastatic patients. Identification of CTCs by PCR methods may lead to better diagnosis and prognosis and could help to choose an adequate therapy.

  5. Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression

    NARCIS (Netherlands)

    G. Denecker (Geertrui); A.M. Vandamme (Anne Mieke); E. Akay (Ela); D. Koludrovic (D.); J. Taminau (J.); K. Lemeire (K.); A. Gheldof (A.); B. de Craene (B.); M. van Gele (M.); L. Brochez (L.); G.M. Udupi (G.); S.M. Rafferty; B. Balint (B.); W.M. Gallagher (W.); M.A.I. Ghanem (Mazen); D. Huylebroeck (Danny); K. Haigh (Katharina); J.J. van den Oord (Joost); L. Larue; I. Davidson (Irwin); J.-C. Marine (J.); G. Berx (Geert)

    2014-01-01

    textabstractDeregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as

  6. Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin

    Energy Technology Data Exchange (ETDEWEB)

    Larkin, Andrew [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Department of Statistics, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Siddens, Lisbeth K. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Krueger, Sharon K. [Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Tilton, Susan C.; Waters, Katrina M. [Superfund Research Center, Oregon State University (United States); Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Williams, David E., E-mail: david.williams@oregonstate.edu [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Linus Pauling Institute, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Baird, William M. [Department of Environmental and Molecular Toxicology, Oregon State University (United States); Superfund Research Center, Oregon State University (United States); Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States)

    2013-03-01

    Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave-one-out cross-validation. Predictions were within 1 log{sub 2} fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights. - Highlights: ► Tested a model to predict PAH mixture-mediated changes in Cyp1b1 expression ► Quantitative predictions in agreement with microarrays for Cyp1b1 induction ► Unexpected difference in expression between DBC and other treatments predicted ► Model predictions

  7. The testosterone-dependent and independent transcriptional networks in the hypothalamus of Gpr54 and Kiss1 knockout male mice are not fully equivalent

    Directory of Open Access Journals (Sweden)

    Sutcliffe Margaret

    2011-04-01

    Full Text Available Abstract Background Humans and mice with loss of function mutations in GPR54 (KISS1R or kisspeptin do not progress through puberty, caused by a failure to release GnRH. The transcriptional networks regulated by these proteins in the hypothalamus have yet to be explored by genome-wide methods. Results We show here, using 1 million exon mouse arrays (Exon 1.0 Affymetrix and quantitative polymerase chain reaction (QPCR validation to analyse microdissected hypothalamic tissue from Gpr54 and Kiss1 knockout mice, the extent of transcriptional regulation in the hypothalamus. The sensitivity to detect important transcript differences in microdissected RNA was confirmed by the observation of counter-regulation of Kiss1 expression in Gpr54 knockouts and confirmed by immunohistochemistry (IHC. Since Gpr54 and Kiss1 knockout animals are effectively pre-pubertal with low testosterone (T levels, we also determined which of the validated transcripts were T-responsive and which varied according to genotype alone. We observed four types of transcriptional regulation (i genotype only dependent regulation, (ii T only dependent regulation, (iii genotype and T-dependent regulation with interaction between these variables, (iv genotype and T-dependent regulation with no interaction between these variables. The results implicate for the first time several transcription factors (e.g. Npas4, Esr2, proteases (Klk1b22, and the orphan 10-transmembrane transporter TMEM144 in the biology of GPR54/kisspeptin function in the hypothalamus. We show for the neuronal activity regulated transcription factor NPAS4, that distinct protein over-expression is seen in the hypothalamus and hippocampus in Gpr54 knockout mice. This links for the first time the hypothalamic-gonadal axis with this important regulator of inhibitory synapse formation. Similarly we confirm TMEM144 up-regulation in the hypothalamus by RNA in situ hybridization and western blot. Conclusions Taken together, global

  8. Prediction of air-to-blood partition coefficients of volatile organic compounds using genetic algorithm and artificial neural network

    Energy Technology Data Exchange (ETDEWEB)

    Konoz, Elahe [Department of Chemistry, Central Tehran Branch, Islamic Azad University, Tehran (Iran, Islamic Republic of); Golmohammadi, Hassan [Department of Chemistry, Mazandaran University, Babolsar (Iran, Islamic Republic of)], E-mail: hassan.gol@gmail.com

    2008-07-07

    An artificial neural network (ANN) was constructed and trained for the prediction of air-to-blood partition coefficients of volatile organic compounds. The inputs of this neural network are theoretically derived descriptors that were chosen by genetic algorithm (GA) and multiple linear regression (MLR) features selection techniques. These descriptors are: R maximal autocorrelation of lag 1 weighted by atomic Sanderson electronegativities (R1E+), electron density on the most negative atom in molecule (EDNA), maximum partial charge for C atom (MXPCC), surface weighted charge partial surface area (WNSA1), fractional charge partial surface area (FNSA2) and atomic charge weighted partial positive surface area (PPSA3). The standard errors of training, test and validation sets for the ANN model are 0.095, 0.148 and 0.120, respectively. Result obtained showed that nonlinear model can simulate the relationship between structural descriptors and the partition coefficients of the molecules in data set accurately.

  9. Transcription profile of DNA repair genes and micro RNA in resting human peripheral blood mono nuclear cells exposed to gamma radiation

    International Nuclear Information System (INIS)

    Human genome is constantly under various genotoxic agents including ionizing radiation which may exert multiple cellular and molecular consequences. Ionizing radiation induces a spectrum of DNA damages in human cells that results in activation of various DNA repair pathways to maintain the integrity of the genome. Radiation induced DNA damage response may lead to alteration in expression of gene, protein and microRNA profile in human cells. miRNA are small, non-coding, ssRNA of 20-22 nucleotide in length and regulate gene expression at post-transcriptional level. In the present study, attempts have been made to study the gene expression pattern of selected DNA repair genes and miRNA in resting human peripheral blood mono nuclear cells (PBMC) exposed to gamma radiation. Venous blood samples were collected from 10 volunteers. PBMC were separated and exposed to gamma radiation between 0.1 Gy to 2.0 Gy at a dose rate of 1.0 Gy/min. Total RNA was isolated at 0 h and 4 h post irradiation. Expression profile of p53, ATM (DNA Damage Response), ERCC3, hRad23A, hRad23B (Nucleotide Excision Repair), hMSH2, hMSH6 and hMLH1 (Mis-Match Repair) and miRNA (miR-16, miR-21, miR24 and miR-155) which are known to regulate expression of DNA repair genes was analyzed by real time quantitative PCR. Our results showed significant (P < 0.05) up regulation of p53 at higher doses (1.0 Gy and 2.0 Gy), whereas hRad23A and MLH1 showed significant increase in expression across the doses at 4 h post irradiation. Interestingly, the expression profile of miR155 showed significant (P<0.05) up regulation at 4 h post irradiation across all the doses. The significant up regulation of p53, hRad23A and hMLH1 at mRNA level and significant up regulation of miR-155 perhaps indicates an active role of these genes and miRNA in radiation induced DNA damage and its response in gamma irradiated human PBMC. (author)

  10. Studies on functional network of transcriptional coactivator CBP; Tensha jono inshi CBP no kinoteki nettowaku ni kansuru kenkyu

    Energy Technology Data Exchange (ETDEWEB)

    Fukamizu, Akiyoshi [University of Tsukuba, Ibaraki (Japan). Institute of Applied BIochemistry

    1999-12-16

    CBP/p 300 is a multidomain transcriptional cofactor which acts in junction with other factors to regulate transcription. To elucidate the domain function of CBP, we fused its dissected fragments to Gal 4 DNA-binding domain and transfected the deletion mutants into several cell lines. First, we found that the minimal transactivation domain (MTD) at the N-terminal portion maps to between 344-451 aa, and shows activity in a cell-type dependent manner. Second, by means of the yeast two hybrid screening using CBP fragments as baits, we cloned hypoxia-inducible factor (HIF) 1{alpha}, Stat 2, and hepatocyte nuclear factor 4 (HNF 4) cDNAs. These results suggested a functional role of MTD located at the CBP/p 300 N-terminal region in connecting to transcriptional factors and a physiological significance of complexes formed in response to a variety of extracellular stimuli to the nucleus. (author)

  11. Mapping mammalian cell-type-specific transcriptional regulatory networks using KD-CAGE and ChIP-seq data in the TC-YIK cell line.

    Directory of Open Access Journals (Sweden)

    Marina eLizio

    2015-11-01

    Full Text Available Mammals are composed of hundreds of different cell types with specialized functions. Each of these cellular phenotypes are controlled by different combinations of transcription factors. Using a human non islet cell insulinoma cell line (TC-YIK which expresses insulin and the majority of known pancreatic beta cell specific genes as an example, we describe a general approach to identify key cell-type-specific transcription factors (TFs and their direct and indirect targets. By ranking all human TFs by their level of enriched expression in TC-YIK relative to a broad collection of samples (FANTOM5, we confirmed known key regulators of pancreatic function and development. Systematic siRNA mediated perturbation of these TFs followed by qRT-PCR revealed their interconnections with NEUROD1 at the top of the regulation hierarchy and its depletion drastically reducing insulin levels. For 15 of the TF knock-downs (KD, we then used Cap Analysis of Gene Expression (CAGE to identify thousands of their targets genome-wide (KD-CAGE. The data confirm NEUROD1 as a key positive regulator in the transcriptional regulatory network (TRN, and ISL1 and PROX1 as antagonists. As a complimentary approach we used ChIP-seq on four of these factors to identify NEUROD1, LMX1A, PAX6 and RFX6 binding sites in the human genome. Examining the overlap between genes perturbed in the KD-CAGE experiments and genes with a ChIP-seq peak within 1kb of their promoter, we identified direct transcriptional targets of these TFs. Integration of KD-CAGE and ChIP-seq data shows that both NEUROD1 and LMX1A work as the main transcriptional activators. In the core TRN (i.e. TF-TF only, NEUROD1 directly transcriptionally activates the pancreatic TFs HSF4, INSM1, MLXIPL, MYT1, NKX6-3, ONECUT2, PAX4, PROX1, RFX6, ST18, DACH1 and SHOX2, while LMX1A directly transcriptionally activates DACH1, SHOX2, PAX6 and PDX1. Analysis of these complementary datasets suggests the need for caution in interpreting

  12. Artificial neural networks to evaluate the boron concentration decreasing profile in Blood-BPA samples of BNCT patients

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Reiriz, Alejandro, E-mail: garciareiriz@gmail.com [Department of Analytical Chemistry, Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario, Rosario Institute of Chemistry (IQUIR-CONICET), Suipacha 531, Rosario S2002LRK (Argentina); Magallanes, Jorge [Comision Nacional de Energia Atomica, Av. Gral. Paz 1499, San Martin, B1650KNA, Buenos Aires (Argentina); Zupan, Jure [National Institute of Chemistry, Hajdrihova 19, SLO-1000 Ljubljana, Eslovenia (Slovenia); Liberman, Sara [Comision Nacional de Energia Atomica, Av. Gral. Paz 1499, San Martin, B1650KNA, Buenos Aires (Argentina)

    2011-12-15

    For the prediction of decay concentration profiles of the p-boronophenylalanine (BPA) in blood during BNCT treatment, a method is suggested based on Kohonen neural networks. The results of a model trained with the concentration profiles from the literature are described. The prediction of the model was validated by the leave-one-out method. Its robustness shows that it is mostly independent on small variations. The ability to fit retrospective experimental data shows an uncertainty lower than the two compartment model used previously. - Highlights: Black-Right-Pointing-Pointer We predicted decaying concentration profiles of BPA in blood during BNCT therapy. Black-Right-Pointing-Pointer Is suggested a method based on Kohonen neural networks. Black-Right-Pointing-Pointer The results show that it is very robust and mostly independent of small variations. Black-Right-Pointing-Pointer It has a better ability to fit retrospective experimental data. Black-Right-Pointing-Pointer The model could be progressively improved by adding new data to the training matrix.

  13. Polarization-dependent laser autofluorescence of the polycrystalline networks of blood plasma films in the task of liver pathology differentiation.

    Science.gov (United States)

    Prysyazhnyuk, V P; Ushenko, Yu A; Dubolazov, A V; Ushenko, A G; Ushenko, V A

    2016-04-20

    Current research presents the results of the investigation of diagnostic efficiency of laser polarization autofluorescence for the set of endogenous fluorophores of blood plasma polycrystalline films in two spectral regions (0.5-0.53 μm and 0.63-0.67 μm) under the excitation of laser radiation with a wavelength of 0.405 μm. A model of generalized optical anisotropy of protein networks of blood plasma polycrystalline films is proposed for the purpose of defining laser autofluorescence processes. Both phase (linear birefringence and optical activity) and amplitude (linear and circular dichroisms) anisotropies have been considered. Interconnections between the optimal condition of probing beam polarization state and the efficiency of induction laser autofluorescence have been found. Statistical analysis of coordinate distributions of laser polarization autofluorescence intensities is suggested by means of determination of the quantitative criteria (statistical moments of the 1st-4th orders). The efficiency of laser polarization autofluorescence of polycrystalline networks in the task of differentiation of nonalcoholic fatty liver disease and chronic hepatitis of human liver has been analyzed. PMID:27140117

  14. Histidine switch controlling pH-dependent protein folding and DNA binding in a transcription factor at the core of synthetic network devices.

    Science.gov (United States)

    Deochand, D K; Perera, I C; Crochet, R B; Gilbert, N C; Newcomer, M E; Grove, A

    2016-07-19

    Therapeutic strategies have been reported that depend on synthetic network devices in which a urate-sensing transcriptional regulator detects pathological levels of urate and triggers production or release of urate oxidase. The transcription factor involved, HucR, is a member of the multiple antibiotic resistance (MarR) protein family. We show that protonation of stacked histidine residues at the pivot point of long helices that form the scaffold of the dimer interface leads to reversible formation of a molten globule state and significantly attenuated DNA binding at physiological temperatures. We also show that binding of urate to symmetrical sites in each protein lobe is communicated via the dimer interface. This is the first demonstration of regulation of a MarR family transcription factor by pH-dependent interconversion between a molten globule and a compact folded state. Our data further suggest that HucR may be utilized in synthetic devices that depend on detection of pH changes. PMID:27282811

  15. A co-expression network analysis reveals lncRNA abnormalities in peripheral blood in early-onset schizophrenia.

    Science.gov (United States)

    Ren, Yan; Cui, Yuehua; Li, Xinrong; Wang, Binhong; Na, Long; Shi, Junyan; Wang, Liang; Qiu, Lixia; Zhang, Kerang; Liu, Guifen; Xu, Yong

    2015-12-01

    Long non-coding RNAs (lncRNAs) are emerging as important regulators of gene expression and disease processes especially in neuropsychiatric disorders. To explore the potential regulatory roles of lncRNAs in schizophrenia, we performed an integrated co-expression network analysis on lncRNA and mRNA microarray profiles generated from the peripheral blood samples in 19 drug-naïve first-episode early-onset schizophrenia (EOS) patients and 18 demographically matched typically developing controls (TDCs). Using weighted gene co-expression network analysis (WGCNA), we showed that the lncRNAs were organized into co-expressed modules, and two lncRNA modules were associated with EOS. The mRNA networks were constructed and three disease-associated modules were identified. Gene Ontology (GO) analysis indicated that the mRNAs were highly enriched for mitochondrion and related biological processes. Moreover, our results revealed a significant correlation between lncRNAs and mRNAs using the canonical correlation analysis (CCA). Our results suggest that the convergent lncRNA alteration may be involved in the etiologies of EOS, and mitochondrial dysfunction participates in the pathological process of the disease. Our findings may shed light on the pathogenesis of schizophrenia and facilitate future diagnosis and therapeutic strategies. PMID:25967042

  16. Determination of Blood Glucose Concentration by Using Wavelet Transform and Neural Networks

    Directory of Open Access Journals (Sweden)

    Vajravelu Ashok

    2013-03-01

    Full Text Available Background: Early and non-invasive determination of blood glucose level is of great importance. We aimed to present a new technique to accurately infer the blood glucose concentration in peripheral blood flow using non-invasive optical monitoring system.Methods: The data for the research were obtained from 900 individuals. Of them, 750 people had diabetes mellitus (DM. The system was designed using a helium neon laser source of 632.8 nm wavelength with 5mW power, photo detectors and digital storage oscilloscope. The laser beam was directed through a single optical fiber to the index finger and the scattered beams were collected by the photo detectors placed circumferentially to the transmitting fiber. The received signals were filtered using band pass filter and finally sent to a digital storage oscilloscope. These signals were then decomposed into approximation and detail coefficients using modified Haar Wavelet Transform. Back propagation neural and radial basis functions were employed for the prediction of blood glucose concentration.Results: The data of 450 patients were randomly used for training, 225 for testing and the rest for validation. The data showed that outputs from radial basis function were nearer to the clinical value. Significant variations could be seen from signals obtained from patients with DM and those without DM.Conclusion: The proposed non-invasive optical glucose monitoring system is able to predict the glucose concentration by proving that there is a definite variation in hematological distribution between patients with DM and those without DM.

  17. Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2

    OpenAIRE

    Fogel, Brent L.; Cho, Ellen; Wahnich, Amanda; Gao, Fuying; Becherel, Olivier J.; Wang, Xizhe; Fike, Francesca; Chen, Leslie; Criscuolo, Chiara; De Michele, Giuseppe; Filla, Alessandro; Collins, Abigail; Hahn, Angelika F.; Gatti, Richard A.; Konopka, Genevieve

    2014-01-01

    Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and ...

  18. Multi-tissue analysis of co-expression networks by higher-order generalized singular value decomposition identifies functionally coherent transcriptional modules.

    Directory of Open Access Journals (Sweden)

    Xiaolin Xiao

    2014-01-01

    Full Text Available Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states. Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based and humans (mRNA-sequencing-based and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi

  19. Blood transcriptomic markers for major depression: from animal models to clinical settings.

    Science.gov (United States)

    Redei, Eva E; Mehta, Neha S

    2015-05-01

    Depression is a heterogeneous disorder and, similar to other spectrum disorders, its manifestation varies by age of onset, severity, comorbidity, treatment responsiveness, and other factors. A laboratory blood test based on specific biomarkers for major depressive disorder (MDD) and its subgroups could increase diagnostic accuracy and expedite the initiation of treatment. We identified candidate blood biomarkers by examining genome-wide expression differences in the blood of animal models representing both the genetic and environmental/stress etiologies of depression. Human orthologs of the resulting transcript panel were tested in pilot studies. Transcript abundance of 11 blood markers differentiated adolescent subjects with early-onset MDD from adolescents with no disorder (ND). A set of partly overlapping transcripts distinguished adolescent patients who had comorbid anxiety disorders from those with only MDD. In adults, blood levels of nine transcripts discerned subjects with MDD from ND controls. Even though cognitive behavioral therapy (CBT) resulted in remission of some patients, the levels of three transcripts consistently signaled prior MDD status. A coexpression network of transcripts seems to predict responsiveness to CBT. Thus, our approach can be developed into clinically valid diagnostic panels of blood transcripts for different manifestations of MDD, potentially reducing diagnostic heterogeneity and advancing individualized treatment strategies.

  20. Identification of a regulation network in response to cadmium toxicity using blood clam Tegillarca granosa as model

    Science.gov (United States)

    Bao, Yongbo; Liu, Xiao; Zhang, Weiwei; Cao, Jianping; Li, Wei; Li, Chenghua; Lin, Zhihua

    2016-01-01

    Clam, a filter-feeding lamellibranch mollusk, is capable to accumulate high levels of trace metals and has therefore become a model for investigation the mechanism of heavy metal toxification. In this study, the effects of cadmium were characterized in the gills of Tegillarca granosa during a 96-hour exposure course using integrated metabolomic and proteomic approaches. Neurotoxicity and disturbances in energy metabolism were implicated according to the metabolic responses after Cd exposure, and eventually affected the osmotic function of gill tissue. Proteomic analysis showed that oxidative stress, calcium-binding and sulfur-compound metabolism proteins were key factors responding to Cd challenge. A knowledge-based network regulation model was constructed with both metabolic and proteomic data. The model suggests that Cd stimulation mainly inhibits a core regulation network that is associated with histone function, ribosome processing and tight junctions, with the hub proteins actin, gamma 1 and Calmodulin 1. Moreover, myosin complex inhibition causes abnormal tight junctions and is linked to the irregular synthesis of amino acids. For the first time, this study provides insight into the proteomic and metabolomic changes caused by Cd in the blood clam T. granosa and suggests a potential toxicological pathway for Cd. PMID:27760991

  1. Investigations of Escherichia coli promoter sequences with artificial neural networks: new signals discovered upstream of the transcriptional startpoint

    DEFF Research Database (Denmark)

    Pedersen, Anders Gorm; Engelbrecht, Jacob

    1995-01-01

    We present a novel method for using the learning ability of a neural network as a measure of information in local regions of input data. Using the method to analyze Escherichia coli promoters, we discover all previously described signals, and furthermore find new signals that are regularly spaced...

  2. The transcriptional regulatory network in the drought response and its crosstalk in abiotic stress responses including drought, cold and heat

    Directory of Open Access Journals (Sweden)

    Kazuo eNakashima

    2014-05-01

    Full Text Available Drought negatively impacts plant growth and the productivity of crops around the world. Understanding the molecular mechanisms in the drought response is important for improvement of drought tolerance using molecular techniques. In plants, abscisic acid (ABA is accumulated under osmotic stress conditions caused by drought, and has a key role in stress responses and tolerance. Comprehensive molecular analyses have shown that ABA regulates the expression of many genes under osmotic stress conditions, and the ABA-responsive element (ABRE is the major cis-element for ABA-responsive gene expression. Transcription factors (TFs are master regulators of gene expression. ABRE-binding protein (AREB and ABRE-binding factor (ABF TFs control gene expression in an ABA-dependent manner. SNF1-related protein kinases 2, group A 2C-type protein phosphatases, and ABA receptors were shown to control the ABA signaling pathway. ABA-independent signaling pathways such as dehydration-responsive element-binding protein (DREB TFs and NAC TFs are also involved in stress responses including drought, heat and cold. Recent studies have suggested that there are interactions between the major ABA signaling pathway and other signaling factors in stress responses. The important roles of these transcription factors in crosstalk among abiotic stress responses will be discussed. Control of ABA or stress signaling factor expression can improve tolerance to environmental stresses. Recent studies using crops have shown that stress-specific overexpression of TFs improves drought tolerance and grain yield compared with controls in the field.

  3. Pax9 regulates a molecular network involving Bmp4, Fgf10, Shh signaling and the Osr2 transcription factor to control palate morphogenesis.

    Science.gov (United States)

    Zhou, Jing; Gao, Yang; Lan, Yu; Jia, Shihai; Jiang, Rulang

    2013-12-01

    Cleft palate is one of the most common birth defects in humans. Whereas gene knockout studies in mice have shown that both the Osr2 and Pax9 transcription factors are essential regulators of palatogenesis, little is known about the molecular mechanisms involving these transcription factors in palate development. We report here that Pax9 plays a crucial role in patterning the anterior-posterior axis and outgrowth of the developing palatal shelves. We found that tissue-specific deletion of Pax9 in the palatal mesenchyme affected Shh expression in palatal epithelial cells, indicating that Pax9 plays a crucial role in the mesenchyme-epithelium interactions during palate development. We found that expression of the Bmp4, Fgf10, Msx1 and Osr2 genes is significantly downregulated in the developing palatal mesenchyme in Pax9 mutant embryos. Remarkably, restoration of Osr2 expression in the early palatal mesenchyme through a Pax9(Osr2KI) allele rescued posterior palate morphogenesis in the absence of Pax9 protein function. Our data indicate that Pax9 regulates a molecular network involving the Bmp4, Fgf10, Shh and Osr2 pathways to control palatal shelf patterning and morphogenesis.

  4. A Dual-Function Transcription Factor, AtYY1, Is a Novel Negative Regulator of the Arabidopsis ABA Response Network.

    Science.gov (United States)

    Li, Tian; Wu, Xiu-Yun; Li, Hui; Song, Jian-Hui; Liu, Jin-Yuan

    2016-05-01

    Abscisic acid (ABA) plays crucial roles in plant growth and development, as well as in response to various environmental stresses. To date, many regulatory genes involved in the ABA response network have been identified; however, their roles have remained to be fully elucidated. In this study, we identified AtYY1, an Arabidopsis homolog of the mammalian C2H2 zinc-finger transcription factor Yin Yang 1 (YY1), as a novel negative regulator of the ABA response. AtYY1 is a dual-function transcription factor with both repression and activation domains. The expression of AtYY1 was induced by ABA and stress conditions including high salt and dehydration. The yy1 mutant was more sensitive to ABA and NaCl than the wild-type, while overexpressing AtYY1 plants were less sensitive. AtYY1 loss also enhanced ABA-induced stomatal closing and drought resistance. Moreover, AtYY1 can bind the ABA REPRESSOR1 (ABR1) promoter and directly upregulate ABR1 expression, as well as negatively regulate ABA- and salt-responsive gene expression. Additional analysis indicated that ABA INSENSITIVE4 (ABI4) might positively regulate AtYY1 expression and that ABR1 can antagonize this regulation. Our findings provide direct evidence that AtYY1 is a novel negative regulator of the ABA response network and that the ABI4-AtYY1-ABR1 regulatory pathway may fine-tune ABA-responsive gene expression in Arabidopsis. PMID:26961720

  5. Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

    OpenAIRE

    Tian, Yuan; Voineagu, Irina; Paşca, Sergiu P; Won, Hyejung; Chandran, Vijayendran; Horvath, Steve; Dolmetsch, Ricardo E.; Geschwind, Daniel H.

    2014-01-01

    Background Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Cav1.2. Methods T...

  6. Gene network analyses of first service conception in Brangus heifers: use of genome and trait associations, hypothalamic-transcriptome information, and transcription factors.

    Science.gov (United States)

    Fortes, M R S; Snelling, W M; Reverter, A; Nagaraj, S H; Lehnert, S A; Hawken, R J; DeAtley, K L; Peters, S O; Silver, G A; Rincon, G; Medrano, J F; Islas-Trejo, A; Thomas, M G

    2012-09-01

    Measures of heifer fertility are economically relevant traits for beef production systems and knowledge of candidate genes could be incorporated into future genomic selection strategies. Ten traits related to growth and fertility were measured in 890 Brangus heifers (3/8 Brahman × 5/8 Angus, from 67 sires). These traits were: BW and hip height adjusted to 205 and 365 d of age, postweaning ADG, yearling assessment of carcass traits (i.e., back fat thickness, intramuscular fat, and LM area), as well as heifer pregnancy and first service conception (FSC). These fertility traits were collected from controlled breeding seasons initiated with estrous synchronization and AI targeting heifers to calve by 24 mo of age. The BovineSNP50 BeadChip was used to ascertain 53,692 SNP genotypes for ∼802 heifers. Associations of genotypes and phenotypes were performed and SNP effects were estimated for each trait. Minimally associated SNP (P < 0.05) and their effects across the 10 traits formed the basis for an association weight matrix and its derived gene network related to FSC (57.3% success and heritability = 0.06 ± 0.05). These analyses yielded 1,555 important SNP, which inferred genes linked by 113,873 correlations within a network. Specifically, 1,386 SNP were nodes and the 5,132 strongest correlations (|r| ≥ 0.90) were edges. The network was filtered with genes queried from a transcriptome resource created from deep sequencing of RNA (i.e., RNA-Seq) from the hypothalamus of a prepubertal and a postpubertal Brangus heifer. The remaining hypothalamic-influenced network contained 978 genes connected by 2,560 edges or predicted gene interactions. This hypothalamic gene network was enriched with genes involved in axon guidance, which is a pathway known to influence pulsatile release of LHRH. There were 5 transcription factors with 21 or more connections: ZMAT3, STAT6, RFX4, PLAGL1, and NR6A1 for FSC. The SNP that identified these genes were intragenic and were on chromosomes

  7. The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) database and analysis pipeline for arterial spin labeling MRI data.

    Science.gov (United States)

    Shin, David D; Ozyurt, I Burak; Liu, Thomas T

    2013-01-01

    Arterial spin labeling (ASL) is a magnetic resonance imaging technique that provides a non-invasive and quantitative measure of cerebral blood flow (CBF). After more than a decade of active research, ASL is now emerging as a robust and reliable CBF measurement technique with increased availability and ease of use. There is a growing number of research and clinical sites using ASL for neuroscience research and clinical care. In this paper, we present an online CBF Database and Analysis Pipeline, collectively called the Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN) that allows researchers to upload and share ASL and clinical data. In addition to serving the role as a central data repository, the CBFBIRN provides a streamlined data processing infrastructure for CBF quantification and group analysis, which has the potential to accelerate the discovery of new scientific and clinical knowledge. All capabilities and features built into the CBFBIRN are accessed online using a web browser through a secure login. In this work, we begin with a general description of the CBFBIRN system data model and its architecture, then devote the remainder of the paper to the CBFBIRN capabilities. The latter part of our work is divided into two processing modules: (1) Data Upload and CBF Quantification Module; (2) Group Analysis Module that supports three types of analysis commonly used in neuroscience research. To date, the CBFBIRN hosts CBF maps and associated clinical data from more than 1,300 individual subjects. The data have been contributed by more than 20 different research studies, investigating the effect of various conditions on CBF including Alzheimer's, schizophrenia, bipolar disorder, depression, traumatic brain injury, HIV, caffeine usage, and methamphetamine abuse. Several example results, generated by the CBFBIRN processing modules, are presented. We conclude with the lessons learned during implementation and deployment of the CBFBIRN and our

  8. Gene network analyses of first service conception in Brangus heifers: use of genome and trait associations, hypothalamic-transcriptome information, and transcription factors.

    Science.gov (United States)

    Fortes, M R S; Snelling, W M; Reverter, A; Nagaraj, S H; Lehnert, S A; Hawken, R J; DeAtley, K L; Peters, S O; Silver, G A; Rincon, G; Medrano, J F; Islas-Trejo, A; Thomas, M G

    2012-09-01

    Measures of heifer fertility are economically relevant traits for beef production systems and knowledge of candidate genes could be incorporated into future genomic selection strategies. Ten traits related to growth and fertility were measured in 890 Brangus heifers (3/8 Brahman × 5/8 Angus, from 67 sires). These traits were: BW and hip height adjusted to 205 and 365 d of age, postweaning ADG, yearling assessment of carcass traits (i.e., back fat thickness, intramuscular fat, and LM area), as well as heifer pregnancy and first service conception (FSC). These fertility traits were collected from controlled breeding seasons initiated with estrous synchronization and AI targeting heifers to calve by 24 mo of age. The BovineSNP50 BeadChip was used to ascertain 53,692 SNP genotypes for ∼802 heifers. Associations of genotypes and phenotypes were performed and SNP effects were estimated for each trait. Minimally associated SNP (P Brangus heifer. The remaining hypothalamic-influenced network contained 978 genes connected by 2,560 edges or predicted gene interactions. This hypothalamic gene network was enriched with genes involved in axon guidance, which is a pathway known to influence pulsatile release of LHRH. There were 5 transcription factors with 21 or more connections: ZMAT3, STAT6, RFX4, PLAGL1, and NR6A1 for FSC. The SNP that identified these genes were intragenic and were on chromosomes 1, 5, 9, and 11. Chromosome 5 harbored both STAT6 and RFX4. The large number of interactions and genes observed with network analyses of multiple sources of genomic data (i.e., GWAS and RNA-Seq) support the concept of FSC being a polygenic trait. PMID:22739780

  9. Community structure analysis of transcriptional networks reveals distinct molecular pathways for early- and late-onset temporal lobe epilepsy with childhood febrile seizures.

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Moreira-Filho

    Full Text Available Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS constitute an initial precipitating insult (IPI commonly associated with mesial temporal lobe epilepsy (MTLE. FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E or late (L disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i the visualization and analysis of differentially expressed (DE and complete (CO - all valid GO annotated transcripts - GCNs for the E and L groups; ii the study of interactions between all the system's constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure-related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less

  10. A Provincial Information Networking Blood Overall Design%A省血站信息联网总体方案设计

    Institute of Scientific and Technical Information of China (English)

    陈为营

    2015-01-01

    This paper focuses on the blood bank information A province overall program connections online design, the main contents include design principles, design objectives, the program features general requirements, the performance of the overall program requirements and network architecture design. Through 4:00 Blood framework for networking solutions are introduced, through research and design of this article, ready to start the next step of the blood bank information networking management information system design and development, and ultimately for the province's blood bank information management A work in the past.%文章主要对A省的血站信息进行网上连接的总体方案进行设计,介绍的主要内容包括方案设计原则、方案设计目标、方案功能总体要求、方案性能总体要求、网络结构设计等。文章通过4点对血站方案的联网框架进行介绍,经过研究和方案设计,下一步准备入手对血站信息联网管理的信息系统进行设计和开发,最终用于A省的血站信息管理工作中来。

  11. Blood Glucose Prediction Using Artificial Neural Networks Trained with the AIDA Diabetes Simulator: A Proof-of-Concept Pilot Study

    Directory of Open Access Journals (Sweden)

    Gavin Robertson

    2011-01-01

    Full Text Available Diabetes mellitus is a major, and increasing, global problem. However, it has been shown that, through good management of blood glucose levels (BGLs, the associated and costly complications can be reduced significantly. In this pilot study, Elman recurrent artificial neural networks (ANNs were used to make BGL predictions based on a history of BGLs, meal intake, and insulin injections. Twenty-eight datasets (from a single case scenario were compiled from the freeware mathematical diabetes simulator, AIDA. It was found that the most accurate predictions were made during the nocturnal period of the 24 hour daily cycle. The accuracy of the nocturnal predictions was measured as the root mean square error over five test days (RMSE5 day not used during ANN training. For BGL predictions of up to 1 hour a RMSE5 day of (±SD 0.15±0.04 mmol/L was observed. For BGL predictions up to 10 hours, a RMSE5  day of (±SD 0.14±0.16 mmol/L was observed. Future research will investigate a wider range of AIDA case scenarios, real-patient data, and data relating to other factors influencing BGLs. ANN paradigms based on real-time recurrent learning will also be explored to accommodate dynamic physiology in diabetes.

  12. Deciphering transcriptional networks that govern Coffea arabica seed development using combined cDNA array and real-time RT-PCR approaches.

    Science.gov (United States)

    Salmona, Jordi; Dussert, Stéphane; Descroix, Frédéric; de Kochko, Alexandre; Bertrand, Benoît; Joët, Thierry

    2008-01-01

    Due to its economic importance, Coffea arabica is becoming the subject of increasing genomic research and, in particular, the genes involved in the final chemical composition of the bean and the sensorial quality of the coffee beverage. The aim of the present study was to decipher the transcriptional networks that govern the development of the C. arabica seed, a model for non-orthodox albuminous seeds of tropical origin. For this purpose, we developed a transcriptomic approach combining two techniques: targeted cDNA arrays, containing 266 selected candidate gene sequences, and real-time RT-PCR on a large subset of 111 genes. The combination of the two techniques allowed us to limit detection of false positives and to reveal the advantages of using large real-time RT-PCR screening. Multivariate analysis was conducted on both datasets and results were broadly convergent. First, principle component analysis (PCA) revealed a dramatic re-programming of the transcriptional machinery between early cell division and elongation, storage and maturation phases. Second, hierarchical clustering analysis (HCA) led to the identification of 11 distinct patterns of gene expression during seed development as well as to the detection of genes expressed at specific developmental stages that can be used as functional markers of phenological changes. In addition, this study led to the description of gene expression profiles for quality-related genes, most of them formerly uncharacterised in Coffea. Their involvement in storage compound synthesis and accumulation during endosperm development and final metabolic re-adjustments during maturation is discussed. PMID:18026845

  13. The Human Blood Metabolome-Transcriptome Interface.

    Directory of Open Access Journals (Sweden)

    Jörg Bartel

    2015-06-01

    Full Text Available Biological systems consist of multiple organizational levels all densely interacting with each other to ensure function and flexibility of the system. Simultaneous analysis of cross-sectional multi-omics data from large population studies is a powerful tool to comprehensively characterize the underlying molecular mechanisms on a physiological scale. In this study, we systematically analyzed the relationship between fasting serum metabolomics and whole blood transcriptomics data from 712 individuals of the German KORA F4 cohort. Correlation-based analysis identified 1,109 significant associations between 522 transcripts and 114 metabolites summarized in an integrated network, the 'human blood metabolome-transcriptome interface' (BMTI. Bidirectional causality analysis using Mendelian randomization did not yield any statistically significant causal associations between transcripts and metabolites. A knowledge-based interpretation and integration with a genome-scale human metabolic reconstruction revealed systematic signatures of signaling, transport and metabolic processes, i.e. metabolic reactions mainly belonging to lipid, energy and amino acid metabolism. Moreover, the construction of a network based on functional categories illustrated the cross-talk between the biological layers at a pathway level. Using a transcription factor binding site enrichment analysis, this pathway cross-talk was further confirmed at a regulatory level. Finally, we demonstrated how the constructed networks can be used to gain novel insights into molecular mechanisms associated to intermediate clinical traits. Overall, our results demonstrate the utility of a multi-omics integrative approach to understand the molecular mechanisms underlying both normal physiology and disease.

  14. Transcriptional networks associated with the immune system are disrupted by organochlorine pesticides in largemouth bass (Micropterus salmoides) ovary.

    Science.gov (United States)

    Martyniuk, Christopher J; Doperalski, Nicholas J; Feswick, April; Prucha, Melinda S; Kroll, Kevin J; Barber, David S; Denslow, Nancy D

    2016-08-01

    Largemouth bass (Micropterus salmoides) inhabiting Lake Apopka, Florida are exposed to high levels of persistent organochlorine pesticides (OCPs) and dietary uptake is a significant route of exposure for these apex predators. The objectives of this study were to determine the dietary effects of two organochlorine pesticides (p, p'-dichlorodiphenyldichloroethylene; p, p' DDE and methoxychlor; MXC) on the reproductive axis of largemouth bass. Reproductive bass (late vitellogenesis) were fed one of the following diets: control pellets, 125ppm p, p'-DDE, or 10ppm MXC (mg/kg) for 84days. Due to the fact that both p,p' DDE and MXC have anti-androgenic properties, the anti-androgenic pharmaceutical flutamide was fed to a fourth group of largemouth bass (750ppm). Following a 3 month exposure, fish incorporated p,p' DDE and MXC into both muscle and ovary tissue, with the ovary incorporating 3 times more organochlorine pesticides compared to muscle. Endpoints assessed were those related to reproduction due to previous studies demonstrating that these pesticides impact the reproductive axis and we hypothesized that a dietary exposure would result in impaired reproduction. However, oocyte distribution, gonadosomatic index, plasma vitellogenin, and plasma sex steroids (17β-estradiol, E2 and testosterone, T) were not different between control animals and contaminant-fed largemouth bass. Moreover, neither p, p' DDE nor MXC affected E2 or T production in ex vivo oocyte cultures from chemical-fed largemouth bass. However, both pesticides did interfere with the normal upregulation of androgen receptor that is observed in response to human chorionic gonadotropin in ex vivo cultures, an observation that may be related to their anti-androgenic properties. Transcriptomics profiling in the ovary revealed that gene networks related to cell processes such as leukocyte cell adhesion, ossification, platelet function and inhibition, xenobiotic metabolism, fibrinolysis, and thermoregulation

  15. Transcriptional networks associated with the immune system are disrupted by organochlorine pesticides in largemouth bass (Micropterus salmoides) ovary.

    Science.gov (United States)

    Martyniuk, Christopher J; Doperalski, Nicholas J; Feswick, April; Prucha, Melinda S; Kroll, Kevin J; Barber, David S; Denslow, Nancy D

    2016-08-01

    Largemouth bass (Micropterus salmoides) inhabiting Lake Apopka, Florida are exposed to high levels of persistent organochlorine pesticides (OCPs) and dietary uptake is a significant route of exposure for these apex predators. The objectives of this study were to determine the dietary effects of two organochlorine pesticides (p, p'-dichlorodiphenyldichloroethylene; p, p' DDE and methoxychlor; MXC) on the reproductive axis of largemouth bass. Reproductive bass (late vitellogenesis) were fed one of the following diets: control pellets, 125ppm p, p'-DDE, or 10ppm MXC (mg/kg) for 84days. Due to the fact that both p,p' DDE and MXC have anti-androgenic properties, the anti-androgenic pharmaceutical flutamide was fed to a fourth group of largemouth bass (750ppm). Following a 3 month exposure, fish incorporated p,p' DDE and MXC into both muscle and ovary tissue, with the ovary incorporating 3 times more organochlorine pesticides compared to muscle. Endpoints assessed were those related to reproduction due to previous studies demonstrating that these pesticides impact the reproductive axis and we hypothesized that a dietary exposure would result in impaired reproduction. However, oocyte distribution, gonadosomatic index, plasma vitellogenin, and plasma sex steroids (17β-estradiol, E2 and testosterone, T) were not different between control animals and contaminant-fed largemouth bass. Moreover, neither p, p' DDE nor MXC affected E2 or T production in ex vivo oocyte cultures from chemical-fed largemouth bass. However, both pesticides did interfere with the normal upregulation of androgen receptor that is observed in response to human chorionic gonadotropin in ex vivo cultures, an observation that may be related to their anti-androgenic properties. Transcriptomics profiling in the ovary revealed that gene networks related to cell processes such as leukocyte cell adhesion, ossification, platelet function and inhibition, xenobiotic metabolism, fibrinolysis, and thermoregulation

  16. Considering the effect of stem-loop reverse transcription and real-time PCR analysis of blood and saliva specific microRNA markers upon mixed body fluid stains.

    Science.gov (United States)

    Uchimoto, Mari L; Beasley, Emma; Coult, Natalie; Omelia, Emma J; World, Damian; Williams, Graham

    2013-07-01

    Forensic RNA analysis is gathering pace with reports of messenger RNA analysis being used in case work, and with microRNA being increasingly researched. Such techniques address a fundamental issue in body fluid identification, namely increased specificity over existing chemical tests, and the incorporation of additional body fluids such as vaginal material. The use of RNA analysis will be of particular value to sex offences, where there can be a mixture of multiple body fluids from different people. The aim of this study was to determine whether microRNA based body fluid identification tests can be applied to mixed body fluid samples. Blood and saliva were acquired from volunteers and underwent total RNA extraction. Mixed samples were prepared using a range of ratios from 1:1 to 10:1. Each mixed sample then underwent a blood-saliva differentiation test developed in-house, which includes stem-loop reverse transcription and real-time PCR analysis. Aliquots following mixture preparation also underwent standard STR analysis, utilising Quantiplex and Next Generation Multiplex kits. Data relating to the development of an in-house blood-saliva differentiation test is presented, in which it has been demonstrated that such a test has a lower limit of detection than the enzymatic equivalent. It has been shown that not only is it possible to determine the presence of more than one body fluid, it is also possible to determine the major body fluid contributor as well as the minor contributor.

  17. RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors

    DEFF Research Database (Denmark)

    Thompson, Nancy; Gésina, Emilie; Scheinert, Peter;

    2012-01-01

    those factors, PTF1a, a basic helix-loop-helix (bHLH) transcription factor which controls pancreas exocrine cell differentiation, maintenance, and functionality, is also needed for the early specification of pancreas progenitors. We used RNA profiling and chromatin immunoprecipitation (ChIP) sequencing...... promoted by PTF1a. These proteins, most of which were previously shown to be necessary for pancreas bud maintenance or formation, form a transcription factor network that allows the maintenance of pancreas progenitors. In addition, we identify Bmp7, Nr5a2, RhoV, and P2rx1 as new targets of PTF1a in...

  18. The Journey of a Transcription Factor

    DEFF Research Database (Denmark)

    Pireyre, Marie

    Plants have developed astonishing networks regulating their metabolism to adapt to their environment. The complexity of these networks is illustrated by the expansion of families of regulators such as transcription factors in the plant kingdom. Transcription factors specifically impact...... transcriptional networks by integrating exogenous and endogenous stimuli and regulating gene expression accordingly. Regulation of transcription factors and their activation is thus highly important to modulate the transcriptional programs and increase fitness of the plant in a given environment. Plant metabolism...... MYBs to activate transcription of GLS biosynthetic genes. A lot is known about transcriptional regulation of these nine GLS regulators. This thesis aimed at identifying regulatory mechanisms at the protein level, allowing rapid and specific regulation of transcription factors using GLS as a model...

  19. Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

    Directory of Open Access Journals (Sweden)

    Yansheng Geng

    Full Text Available Hepatitis E virus (HEV is endemic worldwide and a major cause of acute liver disease in developing countries. However, the molecular mechanisms of liver pathology and clinical disease are not well understood for HEV infection. Open reading frame 3 (ORF3 of HEV encodes a small phosphoprotein, which is assumed to be involved in liver pathology and clinical disease. In this study, the interactions between the HEV ORF3 protein and human proteins were investigated using a stringent, high-throughput yeast two-hybrid (Y2H analysis. Thirty two proteins were shown to interact with genotype 1 ORF3, 28 of which have not been reported previously. These novel interactions were evaluated by coimmunoprecipitation of protein complexes from transfected cells. We found also that the ORF3 proteins of genotype 4 and rabbit HEV interacted with all of the human proteins identified by the genotype 1 ORF3 protein. However, the putative ORF3 protein derived from avian HEV did not interact with the majority of these human proteins. The identified proteins were used to infer an overall interaction map linking the ORF3 protein with components of the host cellular networks. Analysis of this interaction map, based on functional annotation with the Gene Ontology features and KEGG pathways, revealed an enrichment of host proteins involved in complement coagulation, cellular iron ion homeostasis and oxidative stress. Additional canonical pathway analysis highlighted the enriched biological pathways relevant to blood coagulation and hemostasis. Consideration of the clinical manifestations of hepatitis E reported previously and the results of biological analysis from this study suggests that the ORF3 protein is likely to lead to an imbalance of coagulation and fibrinolysis by interacting with host proteins and triggering the corresponding pathological processes. These results suggest critical approaches to further study of the pathogenesis of the HEV ORF3 protein.

  20. ETS transcription factors in hematopoietic stem cell development.

    Science.gov (United States)

    Ciau-Uitz, Aldo; Wang, Lu; Patient, Roger; Liu, Feng

    2013-12-01

    Hematopoietic stem cells (HSCs) are essential for the maintenance of the hematopoietic system. However, these cells cannot be maintained or created in vitro, and very little is known about their generation during embryogenesis. Many transcription factors and signaling pathways play essential roles at various stages of HSC development. Members of the ETS ('E twenty-six') family of transcription factors are recognized as key regulators within the gene regulatory networks governing hematopoiesis, including the ontogeny of HSCs. Remarkably, although all ETS transcription factors bind the same DNA consensus sequence and overlapping tissue expression is observed, individual ETS transcription factors play unique roles in the development of HSCs. Also, these transcription factors are recurrently used throughout development and their functions are context-dependent, increasing the challenge of studying their mechanism of action. Critically, ETS factors also play roles under pathological conditions, such as leukemia and, therefore, deciphering their mechanism of action will not only enhance our knowledge of normal hematopoiesis, but also inform protocols for their creation in vitro from pluripotent stem cells and the design of new therapeutic approaches for the treatment of malignant blood cell diseases. In this review, we summarize the key findings on the roles of ETS transcription factors in HSC development and discuss novel mechanisms by which they could control hematopoiesis.

  1. Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression.

    Directory of Open Access Journals (Sweden)

    Hans Carl Hasselbalch

    Full Text Available The Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocythemia (ET, polycythemia vera (PV, and myelofibrosis (MF (MPNs - have recently been shown to be associated with chronic inflammation, oxidative stress and accumulation of reactive oxygen species (ROS. Using whole blood transcriptional profiling, we report that several oxidative stress and anti-oxidative stress genes are significantly deregulated in MPNs. Among the twenty most up- and downregulated genes, ATOX1, DEFB122, GPX8, PRDX2, PRDX6, PTGS1, and SEPP1 were progressively upregulated from ET over PV to PMF, whereas AKR1B1, CYBA, SIRT2, TTN, and UCP2 were progressively downregulated in ET, PV and PMF (all FDR <0.05. The gene Nrf2, encoding the transcription factor nuclear factor erythroid 2-related factor 2 (NFE2L2 or Nrf2 was significantly downregulated in all MPNs. Nrf2 has a key role in the regulation of the oxidative stress response and modulates both migration and retention of hematopoietic stem cells (HSCs in their niche. The patogenetic importance of Nrf2 depletion in the context of expansion of the hematopoietic progenitor pool in MPNs is discussed with particular focus upon the implications of concomitant downregulation of Nrf2 and CXCR4 for stem cell mobilization.

  2. Transcription of piano music with deep learning

    OpenAIRE

    Jug, Jan

    2015-01-01

    Transcription of music is a complex process of transcribing an audio recording into a symbolic notation. The goal of this thesis was to examine transcription of piano music with deep learning, for which three models of deep neural networks were implemented: multilayer perceptron, convolutional neural network and deep belief network. Through the use of deep belief network, unsupervised pretraining for automatic extraction of musical features from audio signals was also tested. Learning of thes...

  3. Identification of differentially expressed transcripts and pathways in blood one week and six months following implant of left ventricular assist devices.

    Directory of Open Access Journals (Sweden)

    Adam Mitchell

    Full Text Available INTRODUCTION: Continuous-flow left ventricular assist devices (LVADs are an established therapy for patients with end-stage heart failure. The short- and long-term impact of these devices on peripheral blood gene expression has not been characterized, and may provide insight into the molecular pathways mediated in response to left ventricular remodeling and an improvement in overall systemic circulation. We performed RNA sequencing to identify genes and pathways influenced by these devices. METHODS: RNA was extracted from blood of 9 heart failure patients (8 male prior to LVAD implantation, and at 7 and 180 days postoperatively. Libraries were sequenced on an Illumina HiSeq2000 and sequences mapped to the human Ensembl GRCh37.67 genome assembly. RESULTS: A specific set of genes involved in regulating cellular immune response, antigen presentation, and T cell activation and survival were down-regulated 7 days after LVAD placement. 6 months following LVAD placement, the expression levels of these genes were significantly increased; yet importantly, remained significantly lower than age and sex-matched samples from healthy controls. CONCLUSIONS: In summary, this genomic analysis identified a significant decrease in the expression of genes that promote a healthy immune response in patients with heart failure that was partially restored 6 months following LVAD implant.

  4. Increased P-35, EBI3 Transcripts and Other Treg Markers in Peripheral Blood Mononuclear Cells of Breast Cancer Patients with Different clinical Stages

    Directory of Open Access Journals (Sweden)

    Maryam Hamidinia

    2015-06-01

    Full Text Available Purpose: Currently, cancer as a major problem around the world threatens human health and has a high incidence in developing countries. Many reports have indicated that patients suffering from cancer demonstrate decreased antitumor immune responses as well as a high prevalence of T regulatory population. It has been reported that Foxp3+Tregs exert suppression by cell contact-dependent mechanisms which are mediated by soluble factors such as immunosuppressive cytokines like IL-10, TGF-​B and IL-35. Consequently there is a great need to identify prognostic and diagnostic biomarkers of regulatory T cells for vaccine and drug development. Methods: In this study IL-10, TGF-B, IL-35 and Foxp3 mRNA gene expression has been measured in peripheral blood of 40 breast cancer patients and 40 normal age-matched women using quantitative real-time PCR (qRT-PCR method with Master Mix reaction containing SYBER Green. GAPDH gene was used as housekeeping gene. Results: Our data demonstrated a significant up-regulation of IL-10, TGF-​B, P35, EBI3 and Foxp3 gene expression in patients’ peripheral blood compared to normal healthy controls (p<0.05. Conclusion: The data suggests that the immune system is suppressed in breast cancer patients, which may be due to elevated Treg cells population. These results may be useful for diagnostic or therapeutic purposes. However it may require more investigations

  5. CluGene: A Bioinformatics Framework for the Identification of Co-Localized, Co-Expressed and Co-Regulated Genes Aimed at the Investigation of Transcriptional Regulatory Networks from High-Throughput Expression Data.

    Directory of Open Access Journals (Sweden)

    Tania Dottorini

    Full Text Available The full understanding of the mechanisms underlying transcriptional regulatory networks requires unravelling of complex causal relationships. Genome high-throughput technologies produce a huge amount of information pertaining gene expression and regulation; however, the complexity of the available data is often overwhelming and tools are needed to extract and organize the relevant information. This work starts from the assumption that the observation of co-occurrent events (in particular co-localization, co-expression and co-regulation may provide a powerful starting point to begin unravelling transcriptional regulatory networks. Co-expressed genes often imply shared functional pathways; co-expressed and functionally related genes are often co-localized, too; moreover, co-expressed and co-localized genes are also potential targets for co-regulation; finally, co-regulation seems more frequent for genes mapped to proximal chromosome regions. Despite the recognized importance of analysing co-occurrent events, no bioinformatics solution allowing the simultaneous analysis of co-expression, co-localization and co-regulation is currently available. Our work resulted in developing and valuating CluGene, a software providing tools to analyze multiple types of co-occurrences within a single interactive environment allowing the interactive investigation of combined co-expression, co-localization and co-regulation of genes. The use of CluGene will enhance the power of testing hypothesis and experimental approaches aimed at unravelling transcriptional regulatory networks. The software is freely available at http://bioinfolab.unipg.it/.

  6. The identification of transcription factors expressed in the notochord of Ciona intestinalis adds new potential players to the Brachyury gene regulatory network

    OpenAIRE

    Diana S José-Edwards; Kerner, Pierre; Kugler, Jamie E.; Deng, Wei; Jiang, Di; Di Gregorio, Anna

    2011-01-01

    The notochord is the distinctive characteristic of chordates; however, the knowledge of the complement of transcription factors governing the development of this structure is still incomplete. Here we present the expression patterns of seven transcription factor genes detected in the notochord of the ascidian Ciona intestinalis at various stages of embryonic development. Four of these transcription factors, Fos-a, NFAT5, AFF and Klf15, have not been directly associated with the notochord in p...

  7. Recovery of Unrelated Donors of Peripheral Blood Stem Cells versus Recovery of Unrelated Donors of Bone Marrow: A Prespecified Analysis from the Phase III Blood and Marrow Transplant Clinical Trials Network Protocol 0201.

    Science.gov (United States)

    Burns, Linda J; Logan, Brent R; Chitphakdithai, Pintip; Miller, John P; Drexler, Rebecca; Spellman, Stephen; Switzer, Galen E; Wingard, John R; Anasetti, Claudio; Confer, Dennis L

    2016-06-01

    We report a comparison of time to recovery, side effects, and change in blood counts from baseline to after donation from unrelated donors who participated in the Blood and Marrow Transplant Clinical Trials Network phase III randomized, multicenter trial (0201) in which donor-recipient pairs were randomized to either peripheral blood stem cell (PBSC) or bone marrow (BM) donation. Of the entire cohort, 262 donated PBSC and 264 donated BM; 372 (71%) donors were from domestic and 154 (29%) were from international centers (145 German and 9 Canadian). PBSC donors recovered in less time, with a median time to recovery of 1 week compared with 2.3 weeks for BM donors. The number of donors reporting full recovery was significantly greater for donors of PBSC than of BM at 1, 2, and 3 weeks and 3 months after donation. Multivariate analysis showed that PBSC donors were more likely to recover at any time after donation compared with BM donors (hazard ratio, 2.08; 95% confidence interval [CI], 1.73 to 2.50; P ratio, 1.13; 95% CI, .74 to 1.74; P = .556). Blood counts were affected by product donated, with greater mean change from baseline to after donation for white blood cells, neutrophils, mononuclear cells, and platelets in PBSC donors whereas BM donors experienced a greater mean change in hemoglobin. This analysis provided an enhanced understanding of donor events as product donated was independent of physician bias or donor preference. PMID:27013014

  8. Significance of Establishment of Cord Blood Bank and Its Information Networking Management on Cord Blood Stem Cell Transplantation%脐带血库的建立及其信息网络化管理对脐带血干细胞移植的意义

    Institute of Scientific and Technical Information of China (English)

    刘婷

    2011-01-01

    目的:探讨如何建立脐带血(UCB)库、UCB库信息网络化管理策略及对UCB干细胞移植的意义.方法:通过建立UCB库及UCB库的信息网络化管理,使UCB库在UCB干细胞移植中发挥尽可能大的作用.结果:建立起来的血库切实可行,UCB库信息网络化管理最大限度地发挥了UCB在UCB干细胞移植中的作用.结论:UCB库的建立及其信息网络化管理对UCB干细胞移植意义重大,可最大限度地发挥UCB库的作用.%[ Objective ] To explore how to establish a cord blood bank, information networking management strategies of cord blood bank and its significance on cord blood stem cell transplantation. [ Methods ] In order to make the cord blood bank plays its full role in cord blood stem cell transplantation, the cord blood bank was established and the information networking management was carried out. [ Results]The blood bank is feasible, and umbilical cord blood gets the maximum use in cord blood stem cell transplantation by implementation of information networking management of cord blood bank. [ Conclusion] The establishment of cord blood bank and its information networking management has a great significance on cord blood stem cell transplantation, which can get a maximum effect of cord blood bank.

  9. Over-expression of Oct4 and Sox2 transcription factors enhances differentiation of human umbilical cord blood cells in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Guseva, Daria [Kazan State Medical University, Kazan, Republic of Tatarstan (Russian Federation); Hannover Medical School, Hannover (Germany); Rizvanov, Albert A.; Salafutdinov, Ilnur I.; Kudryashova, Nezhdana V. [Kazan Federal University, Kazan, Republic of Tatarstan (Russian Federation); Palotás, András, E-mail: palotas@asklepios-med.eu [Kazan Federal University, Kazan, Republic of Tatarstan (Russian Federation); Asklepios-Med (Private Medical Practice and Research Center), Szeged (Hungary); Islamov, Rustem R., E-mail: islamru@yahoo.com [Kazan State Medical University, Kazan, Republic of Tatarstan (Russian Federation)

    2014-09-05

    Highlights: • Gene and cell-based therapies comprise innovative aspects of regenerative medicine. • Genetically modified hUCB-MCs enhanced differentiation of cells in a mouse model of ALS. • Stem cells successfully transformed into micro-glial and endothelial lines in spinal cords. • Over-expressing oct4 and sox2 also induced production of neural marker PGP9.5. • Formation of new nerve cells, secreting trophic factors and neo-vascularisation could improve symptoms in ALS. - Abstract: Gene and cell-based therapies comprise innovative aspects of regenerative medicine. Even though stem cells represent a highly potential therapeutic strategy, their wide-spread exploitation is marred by ethical concerns, potential for malignant transformation and a plethora of other technical issues, largely restricting their use to experimental studies. Utilizing genetically modified human umbilical cord blood mono-nuclear cells (hUCB-MCs), this communication reports enhanced differentiation of transplants in a mouse model of amyotrophic lateral sclerosis (ALS). Over-expressing Oct4 and Sox2 induced production of neural marker PGP9.5, as well as transformation of hUCB-MCs into micro-glial and endothelial lines in ALS spinal cords. In addition to producing new nerve cells, providing degenerated areas with trophic factors and neo-vascularisation might prevent and even reverse progressive loss of moto-neurons and skeletal muscle paralysis.

  10. Over-expression of Oct4 and Sox2 transcription factors enhances differentiation of human umbilical cord blood cells in vivo

    International Nuclear Information System (INIS)

    Highlights: • Gene and cell-based therapies comprise innovative aspects of regenerative medicine. • Genetically modified hUCB-MCs enhanced differentiation of cells in a mouse model of ALS. • Stem cells successfully transformed into micro-glial and endothelial lines in spinal cords. • Over-expressing oct4 and sox2 also induced production of neural marker PGP9.5. • Formation of new nerve cells, secreting trophic factors and neo-vascularisation could improve symptoms in ALS. - Abstract: Gene and cell-based therapies comprise innovative aspects of regenerative medicine. Even though stem cells represent a highly potential therapeutic strategy, their wide-spread exploitation is marred by ethical concerns, potential for malignant transformation and a plethora of other technical issues, largely restricting their use to experimental studies. Utilizing genetically modified human umbilical cord blood mono-nuclear cells (hUCB-MCs), this communication reports enhanced differentiation of transplants in a mouse model of amyotrophic lateral sclerosis (ALS). Over-expressing Oct4 and Sox2 induced production of neural marker PGP9.5, as well as transformation of hUCB-MCs into micro-glial and endothelial lines in ALS spinal cords. In addition to producing new nerve cells, providing degenerated areas with trophic factors and neo-vascularisation might prevent and even reverse progressive loss of moto-neurons and skeletal muscle paralysis

  11. Time series analysis of benzo[a]pyrene-induced transcriptome changes suggests that a network of transcription factors regulates the effects on functional gene sets

    NARCIS (Netherlands)

    Delft, J.H.M. van; Mathijs, K.; Staal, Y.C.M.; Herwijnen, M.H.M. van; Brauers, K.J.J.; Boorsma, A.; Kleinjans, J.C.S.

    2010-01-01

    Chemical carcinogens may cause a multitude of effects inside cells, thereby affecting transcript levels of genes by direct activation of transcription factors (TF) or indirectly through the formation of DNA damage. As the temporal profiles of these responses may be profoundly different, examining ti

  12. Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in> Escherichia coli K-12 MG1655

    DEFF Research Database (Denmark)

    Seo, Sang Woo; Kim, Donghyuk; Szubin, Richard;

    2015-01-01

    Three transcription factors (TFs), OxyR, SoxR, and SoxS, play a critical role in transcriptional regulation of the defense system for oxidative stress in bacteria. However, their full genome-wide regulatory potential is unknown. Here, we perform a genome-scale reconstruction of the OxyR, SoxR, an...

  13. Investigating transcription reinitiation through in vitro approaches.

    Science.gov (United States)

    Dieci, Giorgio; Fermi, Beatrice; Bosio, Maria Cristina

    2014-01-01

    By influencing the number of RNA molecules repeatedly synthesized from the same gene, the control of transcription reinitiation has the potential to shape the transcriptome. Transcription reinitiation mechanisms have been mainly addressed in vitro, through approaches based on both crude and reconstituted systems. These studies support the notion that transcription reinitiation and its regulation rely on dedicated networks of molecular interactions within transcription machineries. At the same time, comparison with in vivo transcription rates suggests that additional mechanisms, factors and conditions must exist in the nucleus, whose biochemical elucidation is a fascinating challenge for future in vitro transcription studies.

  14. [Two vital transcriptional factors Oct-4 and Nanog to keep the pluripotency and self-renewal of stem cells and related regulation network].

    Science.gov (United States)

    Zhou, Yi-Ye; Zeng, Fan-Yi

    2008-05-01

    Oct-4 and Nanog are two critical transcriptional factors to keep pluripotency and self-renewal of stem cells in vivo and in vitro, and they usually express only in pluripotent cells and not in differentiated cells. They bind to the regulatory regions of targeted gene and often interact with other transcriptional factors and extracellular signal path components, such as Sox-2, FoxD3, LIF and BMP in specific tissues or developmental stages. So that all of these constitute a transcriptional crosstalk, and finally determine the cells destiny: keeping pluripotency or turning to differentiation. PMID:18487140

  15. A transcriptional regulatory network of Bacillus pumilus predicted by comparative genomcis methods%利用比较基因组学方法预测短小芽孢杆菌转录调控网络

    Institute of Scientific and Technical Information of China (English)

    桂俊鸿; 李校; 赵培虎; 刘震; 王海燕; 张义正

    2012-01-01

    To explore the gene transcriptional regulatory relations of Bacillus pumilus, a candidate tran-scriptional regulatory network of B. Pumilus has been predicted by searching the homologous transcription factors (TFs) and the homologous regulated genes from Bacillus subtilis genome. The positional weight matrix(PWM) of transcription factor binding sites(TFBSs) was used to scan the whole B. Pumilus genome in order to verify the candidate transcriptional regulatory networks. Finally, a more complete transcriptional regulatory networks had been constructed by integrating with other B. Pumilus TFs and regulated genes. The network consist of 195 TFs and 1201 regulated genes. The result showed that, in bacteria, with the data set of the closely related model species which has a long history of experimental research, it is feasible to predict the transcriptional regulatory network by using comparative genomics methods. The study provided a feasible approach for exploring gene regulatory networks of the organism which lacks large-scale gene expression microarray data.%为探讨短小芽孢杆菌(Bacillus pumilus)的基因调控关系,通过在其亲缘关系最近的模式菌——枯草芽孢杆菌(Bacillus subtilis)中寻找同源转录因子及其调控基因的方式,预测出B.pumilus的候选转录调控网络;并利用转录因子绑定位点的位置权重矩阵(Positional Weight Matrix)在B.pumilus全基因组的基因上游区域扫描motif的方式来验证候选转录调控网络;最后再整合其他B.pumilus专属的调控数据,最终形成一个较完备的B.pumilus基因转录调控网络(包含195个转录因子和1201个受控基因).上述结果表明,在细菌中,利用比较基因组学的方法,以一个被广泛研究的模式生物所积累的基因转录调控关系数据为基础,推测出亲缘关系较近的其他物种的基因调控网络,其结果是可靠的,为探索一些尚不具备大规模基因表达芯片数据的物种的基因调

  16. Blood Clots

    Science.gov (United States)

    ... Index A-Z Blood Clots Blood clots are semi-solid masses of blood that can be stationary (thrombosis) ... treated? What are blood clots? Blood clots are semi-solid masses of blood. Normally, blood flows freely through ...

  17. Dissection of the Oncogenic MYCN Transcriptional Network Reveals a Large Set of Clinically Relevant Cell Cycle Genes as Drivers of Neuroblastoma Tumorigenesis

    NARCIS (Netherlands)

    D.M. Murphy; P.G. Buckley; K. Bryan; K.M. Watters; J. Koster; P. van Sluis; J. Molenaar; R. Versteeg; R.L. Stallings

    2011-01-01

    Amplification of the oncogenic transcription factor MYCN plays a major role in the pathogenesis of several pediatric cancers, including neuroblastoma, medulloblastoma, and rhabodomyosarcoma. For neuroblastoma, MYCN amplification is the most powerful genetic predictor of poor patient survival, yet th

  18. MRA Images Identification of the Artery Blood Vessel of the Knee with SOM LVQ Neural Networks as Auxiliary.

    Science.gov (United States)

    Huang, Hung-Chun; Chien, Chia-Hung; Shih, Ting-Fang; Chong, Fok-Ching

    2005-01-01

    The ways of angiography are divided into two kinds at present: the invasive type and the non invasive type. Because the magnetic resonance angiography (MRA) has advantages of the non invasive type, thus people can accept MRA more easily. Presently, to diagnoses for the initial stage triage of the blood vessel on clinic by MRA mostly. We to be allowed to see clearly that the shape of lower limb artery which like the dendrite and the blood vessel is thick from the trunk to the thin branch, also we can see the narrow embolism and the blocked place through MRA. This study is aiming at the image of artery of blood vessel by MRA assay, and is attempting to use two-dimensional structure of SOM and LVQ to make out topologies for the shape of artery of blood vessel. We expect that MRA could be useful tools for earlier on the quick triage and auxiliary diagnosis of doctors. By actual examples truly prove that patients after peripheral arterial occlusive disease (PAOD) treatment can diagnose effectively, shorten the time of patients waiting for reports and improve the whole efficiency of the medical treatment system.

  19. 基于BP网络的血液气味识别模型的建立%Identification of blood odors based on BP artificial neural network

    Institute of Scientific and Technical Information of China (English)

    龙成生; 王辛; 单军; 吴德华; 宋珍华

    2012-01-01

    以血液气味样品的气相色谱质谱分析结果为基础,建立了一个基于BP人工神经网络的血液气味识别模型,并利用Matlab计算平台对此模型进行了优化、训练和测试.此模型的网络结构为9×13×1,隐含层传递函数为tansig,输出层传递函数为logsig,训练函数为trainrp.优化后的模型对血液样品的正确识别率为100%.%This paper proposed an identification model for blood odors based on Back Propagation Artificial Neural Network. The features were extracted from the data of blood samples which were analyzed by means of Gas Chromatography-Mass Spectrometer. Matlab was used to optimize the model, which then was trained and tested using human and animal blood odor samples. The architecture of the model was 9 × 13 × 1, the transfer functions of the hidden layer and the output layer were tansig and logsig, respectively, the train function was trainrp. The optimized model correctly identified the train and test samples with the accuracy of 100%.

  20. Networking

    OpenAIRE

    Rauno Lindholm, Daniel; Boisen Devantier, Lykke; Nyborg, Karoline Lykke; Høgsbro, Andreas; de Fries, Louise Skovlund

    2016-01-01

    The purpose of this project was to examine what influencing factor that has had an impact on the presumed increasement of the use of networking among academics on the labour market and how it is expressed. On the basis of the influence from globalization on the labour market it can be concluded that the globalization has transformed the labour market into a market based on the organization of networks. In this new organization there is a greater emphasis on employees having social...

  1. Engineering a Dual-Layer Chitosan-Lactide Hydrogel To Create Endothelial Cell Aggregate-Induced Microvascular Networks In Vitro and Increase Blood Perfusion In Vivo.

    Science.gov (United States)

    Kim, Sungwoo; Kawai, Toshiyuki; Wang, Derek; Yang, Yunzhi

    2016-08-01

    Here, we report the use of chemically cross-linked and photo-cross-linked hydrogels to engineer human umbilical vein endothelial cell (HUVEC) aggregate-induced microvascular networks to increase blood perfusion in vivo. First, we studied the effect of chemically cross-linked and photo-cross-linked chitosan-lactide hydrogels on stiffness, degradation rates, and HUVEC behaviors. The photo-cross-linked hydrogel was relatively stiff (E = ∼15 kPa) and possessed more compact networks, denser surface texture, and lower enzymatic degradation rates than the relatively soft, chemically cross-linked hydrogel (E = ∼2 kPa). While both hydrogels exhibited nontoxicity, the soft chemically cross-linked hydrogels expedited the formation of cell aggregates compared to the photo-cross-linked hydrogels. Cells on the less stiff, chemically cross-linked hydrogels expressed more matrix metalloproteinase (MMP) activity than the stiffer, photo-cross-linked hydrogel. This difference in MMP activity resulted in a more dramatic decrease in mechanical stiffness after 3 days of incubation for the chemically cross-linked hydrogel, as compared to the photo-cross-linked one. After determining the physical and biological properties of each hydrogel, we accordingly engineered a dual-layer hydrogel construct consisting of the relatively soft, chemically cross-linked hydrogel layer for HUVEC encapsulation, and the relatively stiff, acellular, photo-cross-linked hydrogel for retention of cell-laden microvasculature above. This dual-layer hydrogel construct enabled a lasting HUVEC aggregate-induced microvascular network due to the combination of stable substrate, enriched cell adhesion molecules, and extracellular matrix proteins. We tested the dual-layer hydrogel construct in a mouse model of hind-limb ischemia, where the HUVEC aggregate-induced microvascular networks significantly enhanced blood perfusion rate to ischemic legs and decreased tissue necrosis compared with both no treatment and

  2. Cerebral blood flow in posterior cortical nodes of the default mode network decreases with task engagement but remains higher than in most brain regions.

    Science.gov (United States)

    Pfefferbaum, Adolf; Chanraud, Sandra; Pitel, Anne-Lise; Müller-Oehring, Eva; Shankaranarayanan, Ajit; Alsop, David C; Rohlfing, Torsten; Sullivan, Edith V

    2011-01-01

    Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic "default mode network" and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.

  3. Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks

    Directory of Open Access Journals (Sweden)

    Chris R. Evelyn

    2016-05-01

    Full Text Available Metastasis is the major cause of cancer deaths and control of gene transcription has emerged as a critical contributing factor. RhoA- and RhoC-induced gene transcription via the actin-regulated transcriptional co-activator megakaryocytic leukemia (MKL and serum response factor (SRF drive metastasis in breast cancer and melanoma. We recently identified a compound, CCG-1423, which blocks Rho/MKL/SRF-mediated transcription and inhibits PC-3 prostate cancer cell invasion. Here, we undertook a genome-wide expression study in PC-3 cells to explore the mechanism and function of this compound. There was significant overlap in the genes modulated by CCG-1423 and Latrunculin B (Lat B, which blocks the Rho/MKL/SRF pathway by preventing actin polymerization. In contrast, the general transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (DRB showed a markedly different pattern. Effects of CCG-1423 and Lat B on gene expression correlated with literature studies of MKL knock-down. Gene sets involved in DNA synthesis and repair, G1/S transition, and apoptosis were modulated by CCG-1423. It also upregulated genes involved in endoplasmic reticulum stress. Targets of the known Rho target transcription factor family E2F and genes related to melanoma progression and metastasis were strongly suppressed by CCG-1423. These results confirm the ability of our compound to inhibit expression of numerous Rho/MKL-dependent genes and show effects on stress pathways as well. This suggests a novel approach to targeting aggressive cancers and metastasis.

  4. Small-Molecule Inhibition of Rho/MKL/SRF Transcription in Prostate Cancer Cells: Modulation of Cell Cycle, ER Stress, and Metastasis Gene Networks.

    Science.gov (United States)

    Evelyn, Chris R; Lisabeth, Erika M; Wade, Susan M; Haak, Andrew J; Johnson, Craig N; Lawlor, Elizabeth R; Neubig, Richard R

    2016-05-28

    Metastasis is the major cause of cancer deaths and control of gene transcription has emerged as a critical contributing factor. RhoA- and RhoC-induced gene transcription via the actin-regulated transcriptional co-activator megakaryocytic leukemia (MKL) and serum response factor (SRF) drive metastasis in breast cancer and melanoma. We recently identified a compound, CCG-1423, which blocks Rho/MKL/SRF-mediated transcription and inhibits PC-3 prostate cancer cell invasion. Here, we undertook a genome-wide expression study in PC-3 cells to explore the mechanism and function of this compound. There was significant overlap in the genes modulated by CCG-1423 and Latrunculin B (Lat B), which blocks the Rho/MKL/SRF pathway by preventing actin polymerization. In contrast, the general transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosyl-1H-benzimidazole (DRB) showed a markedly different pattern. Effects of CCG-1423 and Lat B on gene expression correlated with literature studies of MKL knock-down. Gene sets involved in DNA synthesis and repair, G1/S transition, and apoptosis were modulated by CCG-1423. It also upregulated genes involved in endoplasmic reticulum stress. Targets of the known Rho target transcription factor family E2F and genes related to melanoma progression and metastasis were strongly suppressed by CCG-1423. These results confirm the ability of our compound to inhibit expression of numerous Rho/MKL-dependent genes and show effects on stress pathways as well. This suggests a novel approach to targeting aggressive cancers and metastasis.

  5. Postpartal immunometabolic gene network expression and function in blood neutrophils are altered in response to prepartal energy intake and postpartal intramammary inflammatory challenge.

    Science.gov (United States)

    Moyes, K M; Graugnard, D E; Khan, M J; Mukesh, M; Loor, J J

    2014-01-01

    The effect of over-feeding energy prepartum on blood polymorphonuclear neutrophil (PMN) response remains unclear. Cows fed controlled (CON; 1.34Mcal/kg of dry matter) or excess energy (OVE; 1.62Mcal/kg dry matter) during the dry period (~45d before expected calving date) received an intramammary (IM) challenge with Escherichia coli lipopolysaccharide (LPS) during the postpartal period to determine the effects of IM LPS and prepartal diet on the expression of key genes associated with immunometabolic response in blood PMN. Feed intake and daily milk yield were recorded throughout the study period. At 7d in milk (DIM), all cows received LPS (200µg) into 1 rear mammary quarter. Blood PMN were isolated at 7, 14, and 30 DIM, as well as before (0h) and after (12h) IM LPS challenge for gene expression analysis using quantitative real time PCR. Phagocytosis capabilities in vitro were assessed at 7, 14, and 30 DIM. Data were analyzed using the MIXED procedure of SAS with repeated measures. No differences in feed intake and milk yield were observed between OVE- and CON-fed cows. As expected, IM LPS challenge altered the expression of genes associated with the immune response (e.g., 1.9- and 1.8-fold for SELL and TLR2, respectively), metabolism (e.g., 1.8- and -1.8-fold for LDHA and SLC2A1, respectively), and transcription (e.g., 1.1- and 1.7-fold for NCOR1 and PPARD, respectively). At 12h postchallenge, an upregulation of TLR2 (1.8-fold), HIF1A (1.9-fold), and NFKB1 (1.5-fold) was observed for OVE rather than CON. At 7 DIM, S100A9 tended (2.2-fold) to be upregulated for OVE rather than CON. At 14 DIM, OVE resulted in lower PMN phagocytosis and an upregulation of NCOR2 (1.6-fold) and RXRA (1.9-fold) compared with CON-fed cows. At 30 DIM, an upregulation of MPO (3.5-fold) and PLA2G4A (1.5-fold) and a tendency for RXRA (1.7-fold) was observed for OVE- rather than CON-fed cows. Our results suggest that IM LPS challenge altered gene expression associated with metabolism in PMN

  6. Detection of dengue virus RNA in blood clots by multiplex nested reverse transcription-PCR%多重套式RT-PCR检测患者凝血块中登革病毒RNA

    Institute of Scientific and Technical Information of China (English)

    张拥军; 黄萌; 翁育伟; 郑友限; 王金章

    2012-01-01

    目的 建立简便、灵敏、适合于全部血清型登革病毒核酸检测的多重套式RT- PCR体系,检测临床样品中登革病毒RNA,作为实验室辅助诊断的依据.方法 利用登革病毒标准株核酸,建立多重RT- PCR检测方法.提取患者凝血块总RNA,分别用一步法RT- PCR及多重套式RT PCR检测.结果 通过对检测体系进行优化,多重RT- PCR能够同时检测4种血清型登革病毒核酸.采用多重套式RT- PCR方法,从8例登革热患者凝血块中有4例检测到病毒RNA,而其它核酸检测方法仅检出1例阳性.结论 多重套式RT-PCR的方法能够从临床凝血块样品中检测到登革病毒核酸,并同时进行血清学分型,简化了登革病毒核酸检测步骤,有利于对临床样品开展病毒核酸检测.%Dengue is the most common vector borne viral disease of humans globally.Detection of viral RNA from suspected patient specimens is rapid,specific and confirmative in laboratory diagnosis of dengue infections during the acute phase.In this study,a multiplex nested reverse transcription PCR (RT-PCR) system was established for clinical specimens.While other nucleic acid amplification tests showed relatively low sensitivity,the multiplex nested RT PCR assay detected 4 cases among blood clots from 8 serologically confirmed dengue patients.These results suggested that blood clots of dengue patients could be used in laboratory diagnosis,and that the multiplex nested RT PCR assay,which simplified the detection procedure,could facilitate viral RNA detection of specimens in clinical laboratories.

  7. A pathway-specific microarray analysis highlights the complex and co-ordinated transcriptional networks of the developing grain of field-grown barley

    DEFF Research Database (Denmark)

    Hansen, Michael; Friis, Carsten; Bowra, Steve;

    2009-01-01

    The aim of the study was to describe the molecular and biochemical interactions associated with amino acid biosynthesis and storage protein accumulation in the developing grains of field-grown barley. Our strategy was to analyse the transcription of genes associated with the biosynthesis of stora...

  8. Assessment of performance of professionals in immunohematology proficiency tests of the public blood bank network of the state of Minas Gerais

    Directory of Open Access Journals (Sweden)

    Stela Brener

    2012-01-01

    Full Text Available BACKGROUND: Despite significant advances, the practice of blood transfusion is still a complex process and subject to risks. Factors that influence the safety of blood transfusion include technical skill and knowledge in hemotherapy mainly obtained by the qualification and training of teams. OBJECTIVE: This study aimed to investigate the relationship between professional categories working in transfusion services of the public blood bank network in the State of Minas Gerais and their performance in proficiency tests. METHODS: This was an observational cross-sectional study (2007-2008 performed using a specific instrument, based on evidence and the results of immunohematology proficiency tests as mandated by law. RESULTS: The error rates in ABO and RhD phenotyping, irregular antibody screening and cross-matching were 12.5%, 9.6%, 43.8% and 20.1%, respectively. When considering the number of tests performed, the error rates were 4.6%, 4.2%, 26.7% and 11.0%, respectively. The error rates varied for different professional categories: biochemists, biologists and biomedical scientists (65.0%, clinical pathology technicians (44.1% and laboratory assistants, nursing technicians and assistant nurses (74.6%. A statistically significant difference was observed when the accuracy of clinical pathology technicians was compared with those of other professionals with only high school education (p-value < 0.001. This was not seen for professionals with university degrees (p-value = 0.293. CONCLUSION: These results reinforce the need to invest in training, improvement of educational programs, new teaching methods and tools for periodic evaluations, contributing to increase transfusion safety and improve hemotherapy in Brazil.

  9. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report

    Science.gov (United States)

    Breen, M S; Uhlmann, A; Nday, C M; Glatt, S J; Mitt, M; Metsalpu, A; Stein, D J; Illing, N

    2016-01-01

    The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and

  10. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report.

    Science.gov (United States)

    Breen, M S; Uhlmann, A; Nday, C M; Glatt, S J; Mitt, M; Metsalpu, A; Stein, D J; Illing, N

    2016-01-01

    The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and

  11. Blood transfusions

    Science.gov (United States)

    ... called homologous blood donation. Many communities have a blood bank at which any healthy person can donate blood. ... need to arrange with your hospital or local blood bank before your surgery to have directed donor blood. ...

  12. Epidemic microclusters of blood-culture proven sepsis in very-low-birth weight infants: experience of the German Neonatal Network.

    Directory of Open Access Journals (Sweden)

    Christoph Härtel

    Full Text Available INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6% infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age occurred in 203/2110 (9.6% VLBW infants. In 182/235 (77.4% late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01. Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83% and 43/235 (18.5% late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days. First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in

  13. Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655

    Directory of Open Access Journals (Sweden)

    Sang Woo Seo

    2015-08-01

    Full Text Available Three transcription factors (TFs, OxyR, SoxR, and SoxS, play a critical role in transcriptional regulation of the defense system for oxidative stress in bacteria. However, their full genome-wide regulatory potential is unknown. Here, we perform a genome-scale reconstruction of the OxyR, SoxR, and SoxS regulons in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 68 genes in 51 transcription units (TUs belong to these regulons. Among them, 48 genes showed more than 2-fold changes in expression level under single-TF-knockout conditions. This reconstruction expands the genome-wide roles of these factors to include direct activation of genes related to amino acid biosynthesis (methionine and aromatic amino acids, cell wall synthesis (lipid A biosynthesis and peptidoglycan growth, and divalent metal ion transport (Mn2+, Zn2+, and Mg2+. Investigating the co-regulation of these genes with other stress-response TFs reveals that they are independently regulated by stress-specific TFs.

  14. In Silico Analysis of Gene Expression Network Components Underlying Pigmentation Phenotypes in the Python Identified Evolutionarily Conserved Clusters of Transcription Factor Binding Sites

    Science.gov (United States)

    2016-01-01

    Color variation provides the opportunity to investigate the genetic basis of evolution and selection. Reptiles are less studied than mammals. Comparative genomics approaches allow for knowledge gained in one species to be leveraged for use in another species. We describe a comparative vertebrate analysis of conserved regulatory modules in pythons aimed at assessing bioinformatics evidence that transcription factors important in mammalian pigmentation phenotypes may also be important in python pigmentation phenotypes. We identified 23 python orthologs of mammalian genes associated with variation in coat color phenotypes for which we assessed the extent of pairwise protein sequence identity between pythons and mouse, dog, horse, cow, chicken, anole lizard, and garter snake. We next identified a set of melanocyte/pigment associated transcription factors (CREB, FOXD3, LEF-1, MITF, POU3F2, and USF-1) that exhibit relatively conserved sequence similarity within their DNA binding regions across species based on orthologous alignments across multiple species. Finally, we identified 27 evolutionarily conserved clusters of transcription factor binding sites within ~200-nucleotide intervals of the 1500-nucleotide upstream regions of AIM1, DCT, MC1R, MITF, MLANA, OA1, PMEL, RAB27A, and TYR from Python bivittatus. Our results provide insight into pigment phenotypes in pythons. PMID:27698666

  15. Network-Based Biomarkers for Cold Coagulation Blood Stasis Syndrome and the Therapeutic Effects of Shaofu Zhuyu Decoction in Rats

    Directory of Open Access Journals (Sweden)

    Shulan Su

    2013-01-01

    Full Text Available In this study, the reverse docking methodology was applied to predict the action targets and pathways of Shaofu Zhuyu decoction (SFZYD bioactive ingredients. Furthermore, Traditional Chinese Medicine (TCM cold coagulation blood stasis (CCBS syndrome was induced in female Sprague-Dawley rats with an ice-water bath and epinephrine, and SFZYD was used to treat CCBS syndrome. A metabolomic approach was used to evaluate changes in the metabolic profiles and to analyze the pharmacological mechanism of SFZYD actions. Twenty-three potential protein targets and 15 pathways were discovered, respectively; among these, pathways are associated with inflammation and immunological stress, hormone metabolism, coagulation function, and glycometabolism. There were also changes in the levels of endogenous metabolites of LysoPCs and glucuronides. Twenty endogenous metabolites were identified. Furthermore, the relative quantities of 6 endogenous metabolites in the plasma and 5 in the urine were significantly affected by SFZYD (P<0.05. The pharmacological mechanism of SFZYD was partially associated with glycerophospholipid metabolism and pentose and glucuronate interconversions. In conclusion, our findings demonstrated that TCM CCBS pattern induced by ice water and epinephrine was complex and related to multiple metabolic pathways. SFZYD did regulate the TCM CCBS by multitargets, and biomarkers and SFZYD should be used for the clinical treatment of CCBS syndrome.

  16. The Cerebral Blood Flow Biomedical Informatics Research Network (CBFBIRN Database and Analysis Pipeline for Arterial Spin Labeling MRI Data

    Directory of Open Access Journals (Sweden)

    David D. Shin

    2013-10-01

    Full Text Available Arterial spin labeling (ASL is a MRI technique that provides a noninvasive and quantitative measure of cerebral blood flow (CBF. After more than a decade of active research, ASL is now emerging as a robust and reliable CBF measurement technique with increased availability and ease of use. There is a growing number of research and clinical sites using ASL for neuroscience research and clinical care. In this paper, we present an online CBF Database and Analysis Pipeline, collectively called the CBFBIRN that allows researchers to upload and share ASL and clinical data. In addition to serving the role as a central data repository, the CBFBIRN provides a streamlined data processing infrastructure for CBF quantification and group analysis, which has the potential to accelerate the discovery of new scientific and clinical knowledge. All capabilities and features built into the CBFBIRN are accessed online using a web browser through a secure login. In this work, we begin with a general description of the CBFBIRN system data model and its architecture, then devote the remainder of the paper to the CBFBIRN capabilities. The latter part of our work is divided into two processing modules: 1 Data Upload and CBF Quantification Module; 2 Group Analysis Module that supports three types of analysis commonly used in neuroscience research. To date, the CBFBIRN hosts CBF maps and associated clinical data from more than 1300 individual subjects. The data have been contributed by more than 20 different research studies, investigating the effect of various conditions on CBF including Alzheimer’s, schizophrenia, bipolar disorder, depression, traumatic brain injury, HIV, caffeine usage and Methamphetamine abuse. Several example results, generated by the CBFBIRN processing modules, are presented. We conclude with the lessons learned during implementation and deployment of the CBFBIRN and our experience in promoting data sharing.

  17. Theta-burst stimulation of hippocampal slices induces network-level calcium oscillations and activates analogous gene transcription to spatial learning.

    Directory of Open Access Journals (Sweden)

    Graham K Sheridan

    Full Text Available Over four decades ago, it was discovered that high-frequency stimulation of the dentate gyrus induces long-term potentiation (LTP of synaptic transmission. LTP is believed to underlie how we process and code external stimuli before converting it to salient information that we store as 'memories'. It has been shown that rats performing spatial learning tasks display theta-frequency (3-12 Hz hippocampal neural activity. Moreover, administering theta-burst stimulation (TBS to hippocampal slices can induce LTP. TBS triggers a sustained rise in intracellular calcium [Ca2+]i in neurons leading to new protein synthesis important for LTP maintenance. In this study, we measured TBS-induced [Ca2+]i oscillations in thousands of cells at increasing distances from the source of stimulation. Following TBS, a calcium wave propagates radially with an average speed of 5.2 µm/s and triggers multiple and regular [Ca2+]i oscillations in the hippocampus. Interestingly, the number and frequency of [Ca2+]i fluctuations post-TBS increased with respect to distance from the electrode. During the post-tetanic phase, 18% of cells exhibited 3 peaks in [Ca2+]i with a frequency of 17 mHz, whereas 2.3% of cells distributed further from the electrode displayed 8 [Ca2+]i oscillations at 33 mHz. We suggest that these observed [Ca2+]i oscillations could lead to activation of transcription factors involved in synaptic plasticity. In particular, the transcription factor, NF-κB, has been implicated in memory formation and is up-regulated after LTP induction. We measured increased activation of NF-κB 30 min post-TBS in CA1 pyramidal cells and also observed similar temporal up-regulation of NF-κB levels in CA1 neurons following water maze training in rats. Therefore, TBS of hippocampal slice cultures in vitro can mimic the cell type-specific up-regulations in activated NF-κB following spatial learning in vivo. This indicates that TBS may induce similar transcriptional changes to

  18. Blood culture

    Science.gov (United States)

    Culture - blood ... A blood sample is needed . The site where blood will be drawn is first cleaned with an antiseptic such ... organism from the skin getting into (contaminating) the blood sample and causing a false-positive result (see ...

  19. Blood Thinners

    Science.gov (United States)

    If you have some kinds of heart or blood vessel disease, or if you have poor blood flow to your brain, your doctor may recommend that you take a blood thinner. Blood thinners reduce the risk of heart ...

  20. Blood Basics

    Science.gov (United States)

    ... Patient Group Links Advocacy Toolkit Home For Patients Blood Basics Blood is a specialized body fluid. It ... about 9 pints. Jump To: The Components of Blood and Their Importance Many people have undergone blood ...

  1. Blood pressure

    Science.gov (United States)

    ... the walls of the arteries is called blood pressure. Blood pressure is measured both as the heart contracts, which ... as it relaxes, which is called diastole. Normal blood pressure is considered to be a systolic blood pressure ...

  2. Dissection of the oncogenic MYCN transcriptional network reveals a large set of clinically relevant cell cycle genes as drivers of neuroblastoma tumorigenesis.

    Science.gov (United States)

    Murphy, Derek M; Buckley, Patrick G; Bryan, Kenneth; Watters, Karen M; Koster, Jan; van Sluis, Peter; Molenaar, Jan; Versteeg, Rogier; Stallings, Raymond L

    2011-06-01

    Amplification of the oncogenic transcription factor MYCN plays a major role in the pathogenesis of several pediatric cancers, including neuroblastoma, medulloblastoma, and rhabodomyosarcoma. For neuroblastoma, MYCN amplification is the most powerful genetic predictor of poor patient survival, yet the mechanism by which MYCN drives tumorigenesis is only partially understood. To gain an insight into the distribution of MYCN binding and to identify clinically relevant MYCN target genes, we performed an integrated analysis of MYCN ChIP-chip and mRNA expression using the MYCN repressible SHEP-21N neuroblastoma cell line. We hypothesized that genes exclusively MYCN bound in SHEP-21N cells over-expressing MYCN would be enriched for direct targets which contribute to the process of disease progression. Integrated analysis revealed that MYCN drives tumorigenesis predominantly as a positive regulator of target gene transcription. A high proportion of genes (24%) that are MYCN bound and up-regulated in the SHEP-21N model are significantly associated with poor overall patient survival (OS) in a set of 88 tumors. In contrast, the proportion of genes down-regulated when bound by MYCN in the SHEP-21N model and which are significantly associated with poor overall patient survival when under-expressed in primary tumors was significantly lower (5%). Gene ontology analysis determined a highly statistically significant enrichment for cell cycle related genes within the over-expressed MYCN target group which were also associated with poor OS. We conclude that the over-expression of MYCN leads to aberrant binding and over-expression of genes associated with cell cycle regulation which are significantly correlated with poor OS and MYCN amplification.

  3. Transcriptional Landscape of Cardiomyocyte Maturation

    Directory of Open Access Journals (Sweden)

    Hideki Uosaki

    2015-11-01

    Full Text Available Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM differentiation. However, control of the CM maturation that is subsequently required to generate adult myocytes remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs, which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent-stem-cell-derived CMs mature early in culture but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.

  4. Advances in Research of Transcriptional Regulatory Network in Response to Cold Stress in Plants%植物应答低温胁迫的转录调控网络研究进展

    Institute of Scientific and Technical Information of China (English)

    刘辉; 李德军; 邓治

    2014-01-01

    温度的变化。同时, ICE1的表达还受JAZ1/4的负调控和ERF2的正调控。除CBF依赖的低温应答信号途径外,一些转录因子则通过不依赖于CBF的途径调控植物低温应答,如JERF3、MYB2/4/96/3R-2、WRKY19/21/76、NAC1/2及SAP1/8等。植物低温应答转录调控网络为通过转基因技术提高农作物抗寒性提供了理论基础。转基因结果表明,AtCBF1-AtCBF3、AtICE1、AtCCA1α、TaCBF14/15、TaNAC2、TaWRKY19、VrCBF1/4、MdCIbHLH1、PtrbHLH、OsMYB2、GmNAC20、JERF3及ZFP182等转录因子在植物抗寒遗传改良中具有潜在的应用价值。此外,文章还探讨了此领域研究中存在的主要问题及今后研究的重点,以期为进一步解析植物适应低温胁迫的分子机制提供参考。%Cold stress seriously influences plant growth, development, and crop yield. In order to survive, plants have evolved complex and high-efficiency regulatory networks to respond and adapt to cold stress. Among these regulatory networks, transcriptional regulation plays crucial roles. Transcription factors can regulate a set of genes by binding to cis-acting regulatory elements in the promoter regions, and play crucial roles in abiotic stress-responsive transcriptional regulatory network in plants. In this review, the authors comprehensively summarized the transcription factors involved in regulating plant response to cold stress, including AP2/ERF (APETALA2/ethylene responsive factor), MYB (myeloblastosis), bHLH (basic helix-loop-helix), NAC (NAM, ATAF1, ATAF2 and CUC2), ZFP (zinc finger protein), WRKY, VOZ (vascular plant one zinc-finger protein), CAMTA (calmodulin-binding transcription activator), and EIN3 (ethylene-insensitive 3). Their structure characteristics were simply summarized, while their functions and regulatory mechanisms were emphatically introduced. Based on the relationships among transcription factors, a transcriptional regulatory network diagram of plant response to cold stress was draw. In this network

  5. Deciphering transcriptional regulations coordinating the response to environmental changes

    OpenAIRE

    Acuña, Vicente; Aravena, Andrés; Guziolowski, Carito; Eveillard, Damien; Siegel, Anne; Maass, Alejandro

    2016-01-01

    Background Gene co-expression evidenced as a response to environmental changes has shown that transcriptional activity is coordinated, which pinpoints the role of transcriptional regulatory networks (TRNs). Nevertheless, the prediction of TRNs based on the affinity of transcription factors (TFs) with binding sites (BSs) generally produces an over-estimation of the observable TF/BS relations within the network and therefore many of the predicted relations are spurious. Results We present Lomba...

  6. Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells

    DEFF Research Database (Denmark)

    Ortis, Fernanda; Naamane, Najib; Flamez, Daisy;

    2010-01-01

    OBJECTIVE: Cytokines contribute to pancreatic beta-cell death in type 1 diabetes. This effect is mediated by complex gene networks that remain to be characterized. We presently utilized array analysis to define the global expression pattern of genes, including spliced variants, modified...... of genes involved in the maintenance of beta-cell phenotype and growth/regeneration. Cytokines induced hypoxia-inducible factor-alpha, which in this context has a proapoptotic role. Cytokines also modified the expression of >20 genes involved in RNA splicing, and exon array analysis showed cytokine......-induced changes in alternative splicing of >50% of the cytokine-modified genes. CONCLUSIONS: The present study doubles the number of known genes expressed in primary beta-cells, modified or not by cytokines, and indicates the biological role for several novel cytokine-modified pathways in beta-cells. It also...

  7. A Systems Biology-Based Approach to Uncovering the Molecular Mechanisms Underlying the Effects of Dragon's Blood Tablet in Colitis, Involving the Integration of Chemical Analysis, ADME Prediction, and Network Pharmacology

    OpenAIRE

    Haiyu Xu; Yanqiong Zhang; Yun Lei; Xiumei Gao; Huaqiang Zhai; Na Lin; Shihuan Tang; Rixin Liang; Yan Ma; Defeng Li; Yi Zhang; Guangrong Zhu; Hongjun Yang; Luqi Huang

    2014-01-01

    Traditional Chinese medicine (TCM) is one of the oldest East Asian medical systems. The present study adopted a systems biology-based approach to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of dragon's blood (DB) tablets for the treatment of colitis. This study integrated chemical analysis, prediction of absorption, distribution, metabolism, and excretion (ADME), and network pharmacology. Firstly, a rapid, reliable, and accurate ult...

  8. Prevalence of optimal treatment regimens in patients with apparent treatment-resistant hypertension based on office blood pressure in a community-based practice network.

    Science.gov (United States)

    Egan, Brent M; Zhao, Yumin; Li, Jiexiang; Brzezinski, W Adam; Todoran, Thomas M; Brook, Robert D; Calhoun, David A

    2013-10-01

    Hypertensive patients with clinical blood pressure (BP) uncontrolled on ≥3 antihypertensive medications (ie, apparent treatment-resistant hypertension [aTRH]) comprise ≈28% to 30% of all uncontrolled patients in the United States. However, the proportion receiving these medications in optimal doses is unknown; aTRH is used because treatment adherence and measurement artifacts were not available in electronic record data from our >200 community-based clinics Outpatient Quality Improvement Network. This study sought to define the proportion of uncontrolled hypertensives with aTRH on optimal regimens and clinical factors associated with optimal therapy. During 2007-2010, 468 877 hypertensive patients met inclusion criteria. BP hypertension doses). Among 468 877 hypertensives, 147 635 (31.5%) were uncontrolled; among uncontrolled hypertensives, 44 684 were prescribed ≥3 BP medications (30.3%), of whom 22 189 (15.0%) were prescribed optimal therapy. Clinical factors independently associated with optimal BP therapy included black race (odds ratio, 1.40 [95% confidence interval, 1.32-1.49]), chronic kidney disease (1.31 [1.25-1.38]), diabetes mellitus (1.30 [1.24-1.37]), and coronary heart disease risk equivalent status (1.29 [1.14-1.46]). Clinicians more often prescribe optimal therapy for aTRH when cardiovascular risk is greater and treatment goals lower. Approximately 1 in 7 of all uncontrolled hypertensives and 1 in 2 with uncontrolled aTRH are prescribed ≥3 BP medications in optimal regimens. Prescribing more optimal pharmacotherapy for uncontrolled hypertensives including aTRH, confirmed with out-of-office BP, could improve hypertension control.

  9. Networks in Cell Biology

    Science.gov (United States)

    Buchanan, Mark; Caldarelli, Guido; De Los Rios, Paolo; Rao, Francesco; Vendruscolo, Michele

    2010-05-01

    Introduction; 1. Network views of the cell Paolo De Los Rios and Michele Vendruscolo; 2. Transcriptional regulatory networks Sarath Chandra Janga and M. Madan Babu; 3. Transcription factors and gene regulatory networks Matteo Brilli, Elissa Calistri and Pietro Lió; 4. Experimental methods for protein interaction identification Peter Uetz, Björn Titz, Seesandra V. Rajagopala and Gerard Cagney; 5. Modeling protein interaction networks Francesco Rao; 6. Dynamics and evolution of metabolic networks Daniel Segré; 7. Hierarchical modularity in biological networks: the case of metabolic networks Erzsébet Ravasz Regan; 8. Signalling networks Gian Paolo Rossini; Appendix 1. Complex networks: from local to global properties D. Garlaschelli and G. Caldarelli; Appendix 2. Modelling the local structure of networks D. Garlaschelli and G. Caldarelli; Appendix 3. Higher-order topological properties S. Ahnert, T. Fink and G. Caldarelli; Appendix 4. Elementary mathematical concepts A. Gabrielli and G. Caldarelli; References.

  10. Transcriptional networks of TCP transcription factors in Arabidopsis development

    NARCIS (Netherlands)

    Danisman, S.D.

    2011-01-01

    Leaves are a plant’s main organs of photosynthesis and hence the development of this organ is under strict control. The different phases of leaf development are under the control of both endogenous and exogenous influences. In this work we were interested in a particular class of

  11. Blood Types

    Science.gov (United States)

    ... How Can I Help a Friend Who Cuts? Blood Types KidsHealth > For Teens > Blood Types Print A A ... or straight hair instead of curly. ...Make Eight Blood Types The different markers that can be found in ...

  12. Heritable change caused by transient transcription errors.

    Directory of Open Access Journals (Sweden)

    Alasdair J E Gordon

    2013-06-01

    Full Text Available Transmission of cellular identity relies on the faithful transfer of information from the mother to the daughter cell. This process includes accurate replication of the DNA, but also the correct propagation of regulatory programs responsible for cellular identity. Errors in DNA replication (mutations and protein conformation (prions can trigger stable phenotypic changes and cause human disease, yet the ability of transient transcriptional errors to produce heritable phenotypic change ('epimutations' remains an open question. Here, we demonstrate that transcriptional errors made specifically in the mRNA encoding a transcription factor can promote heritable phenotypic change by reprogramming a transcriptional network, without altering DNA. We have harnessed the classical bistable switch in the lac operon, a memory-module, to capture the consequences of transient transcription errors in living Escherichia coli cells. We engineered an error-prone transcription sequence (A9 run in the gene encoding the lac repressor and show that this 'slippery' sequence directly increases epigenetic switching, not mutation in the cell population. Therefore, one altered transcript within a multi-generational series of many error-free transcripts can cause long-term phenotypic consequences. Thus, like DNA mutations, transcriptional epimutations can instigate heritable changes that increase phenotypic diversity, which drives both evolution and disease.

  13. Immunoelectrophoresis - blood

    Science.gov (United States)

    IEP - serum; Immunoglobulin electrophoresis - blood; Gamma globulin electrophoresis; Serum immunoglobulin electrophoresis ... A blood sample is needed. For information on how this is done, see: Venipuncture

  14. Transcriptional Profiling and miRNA-Target Network Analysis Identify Potential Biomarkers for Efficacy Evaluation of Fuzheng-Huayu Formula-Treated Hepatitis B Caused Liver Cirrhosis

    Science.gov (United States)

    Chen, Qilong; Wu, Feizhen; Wang, Mei; Dong, Shu; Liu, Yamin; Lu, Yiyu; Song, Yanan; Zhou, Qianmei; Liu, Ping; Luo, Yunquan; Su, Shibing

    2016-01-01

    Fuzheng-Huayu (FZHY) formula has been found to have a satisfactory effect on hepatitis B-caused cirrhosis (HBC) treatment. However, the efficacy evaluation of FZHY is often challenging. In this study, a randomized, double-blind and placebo-controlled trial was used to evaluate the therapeutic efficacy of FZHY in HBC treatment. In the trial, 35 medical indexes were detected, and 14 indexes had a statistically-significant difference before compared to after the trial. Importantly, the Child-Pugh score also demonstrated FZHY having therapeutic efficacy. Furthermore, the microRNA (miRNA) profiles of 12 serum samples were detected in FZHY groups, and 112 differential-expressed (DE) miRNAs were determined. Using predicted miRNA targets, 13 kernel miRNAs were identified from the established miRNA-target network. Subsequently, quantitative Real-time Polymerase Chain Reaction (qRT-PCR) was used to validate the expression level of 13 identified miRNAs in the trials. The results showed that nine miRNAs have a statistically-significant difference before compared to after FZHY treatment. By means of a logistic regression model, a miRNA panel with hsa-miR-18a-5p, -326, -1182 and -193b-5p was established, and it can clearly improve the accuracy of the efficacy evaluation of FZHY. This study suggested that the particular miRNAs can act as potential biomarkers and obviously increase the diagnostic accuracy for drug evaluation in HBC treatment progression. PMID:27271613

  15. Our evolving knowledge of the transcriptional landscape.

    Science.gov (United States)

    Hume, David A

    2008-01-01

    The development of a genome-scale approach to identification of the 5' ends of capped mRNAs (CAGE) has given new insights into many aspects of mammalian RNApolII transcription control. They include the identification of the minimal initiator motif, the different types of proximal promoter architecture, the promoters of noncoding RNAs, the transcription of retrotransposons, and the extensive impact of alternative promoters on the proteome. CAGE also offers applications as a form of expression profiling that measures promoter use, allowing more precise development of transcriptional network models.

  16. NAC transcription factors: structurally distinct, functionally diverse

    DEFF Research Database (Denmark)

    Olsen, Addie Nina; Ernst, Heidi A; Leggio, Leila Lo;

    2005-01-01

    NAC proteins constitute one of the largest families of plant-specific transcription factors, and the family is present in a wide range of land plants. Here, we summarize the biological and molecular functions of the NAC family, paying particular attention to the intricate regulation of NAC protein...... level and localization, and to the first indications of NAC participation in transcription factor networks. The recent determination of the DNA and protein binding NAC domain structure offers insight into the molecular functions of the protein family. Research into NAC transcription factors has...

  17. Treatment of Obstructive Sleep Apnea Alters Cancer-associated Transcriptional Signatures in Circulating Leukocytes

    Science.gov (United States)

    Gharib, Sina A.; Seiger, Ashley N.; Hayes, Amanda L.; Mehra, Reena; Patel, Sanjay R.

    2014-01-01

    Rationale: Obstructive sleep apnea (OSA) has been associated with a number of chronic disorders that may improve with effective therapy. However, the molecular pathways affected by continuous positive airway pressure (CPAP) treatment are largely unknown. We sought to assess the system-wide consequences of CPAP therapy by transcriptionally profiling peripheral blood leukocytes (PBLs). Methods: Subjects in whom severe OSA was diagnosed were treated with CPAP, and whole-genome expression measurement of PBLs was performed at baseline and following therapy. We used gene set enrichment analysis (GSEA) to identify pathways that were differentially enriched. Network analysis was then applied to highlight key drivers of processes influenced by CPAP. Results: Eighteen subjects with significant OSA underwent CPAP therapy and microarray analysis of their PBLs. Treatment with CPAP improved apnea-hypopnea index (AHI), daytime sleepiness, and blood pressure, but did not affect anthropometric measures. GSEA revealed a number of enriched gene sets, many of which were involved in neoplastic processes and displayed downregulated expression patterns in response to CPAP. Network analysis identified several densely connected genes that are important modulators of cancer and tumor growth. Conclusions: Effective therapy of OSA with CPAP is associated with alterations in circulating leukocyte gene expression. Functional enrichment and network analyses highlighted transcriptional suppression in cancer-related pathways, suggesting potentially novel mechanisms linking OSA with neoplastic signatures. Citation: Gharib SA; Seiger AN; Hayes AL; Mehra R; Patel SR. Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes. SLEEP 2014;37(4):709-714. PMID:24688164

  18. ETS transcription factors in embryonic vascular development.

    Science.gov (United States)

    Craig, Michael P; Sumanas, Saulius

    2016-07-01

    At least thirteen ETS-domain transcription factors are expressed during embryonic hematopoietic or vascular development and potentially function in the formation and maintenance of the embryonic vasculature or blood lineages. This review summarizes our current understanding of the specific roles played by ETS factors in vasculogenesis and angiogenesis and the implications of functional redundancies between them.

  19. Genome-wide association study of white blood cell count in 16,388 African Americans: the continental origins and genetic epidemiology network (COGENT.

    Directory of Open Access Journals (Sweden)

    Alexander P Reiner

    2011-06-01

    Full Text Available Total white blood cell (WBC and neutrophil counts are lower among individuals of African descent due to the common African-derived "null" variant of the Duffy Antigen Receptor for Chemokines (DARC gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22 associated with WBC in African Americans (P<2.5×10(-8. The lead SNP (rs9131 on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261 on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter

  20. Virtual blood bank

    Directory of Open Access Journals (Sweden)

    Kit Fai Wong

    2011-01-01

    Full Text Available Virtual blood bank is the computer-controlled, electronically linked information management system that allows online ordering and real-time, remote delivery of blood for transfusion. It connects the site of testing to the point of care at a remote site in a real-time fashion with networked computers thus maintaining the integrity of immunohematology test results. It has taken the advantages of information and communication technologies to ensure the accuracy of patient, specimen and blood component identification and to enhance personnel traceability and system security. The built-in logics and process constraints in the design of the virtual blood bank can guide the selection of appropriate blood and minimize transfusion risk. The quality of blood inventory is ascertained and monitored, and an audit trail for critical procedures in the transfusion process is provided by the paperless system. Thus, the virtual blood bank can help ensure that the right patient receives the right amount of the right blood component at the right time.

  1. Artificial blood

    Directory of Open Access Journals (Sweden)

    Sarkar Suman

    2008-01-01

    Full Text Available Artificial blood is a product made to act as a substitute for red blood cells. While true blood serves many different functions, artificial blood is designed for the sole purpose of transporting oxygen and carbon dioxide throughout the body. Depending on the type of artificial blood, it can be produced in different ways using synthetic production, chemical isolation, or recombinant biochemical technology. Development of the first blood substitutes dates back to the early 1600s, and the search for the ideal blood substitute continues. Various manufacturers have products in clinical trials; however, no truly safe and effective artificial blood product is currently marketed. It is anticipated that when an artificial blood product is available, it will have annual sales of over $7.6 billion in the United States alone.

  2. Blood smear

    Science.gov (United States)

    ... osmotic fragility ) Deficiency of an enzyme called lecithin cholesterol acyl transferase Abnormalities of hemoglobin , the protein in ... sickle and Pappenheimer Red blood cells, target cells Formed elements of blood References Bain BJ. The peripheral ...

  3. Gene expression profiling of cultured human NF1 heterozygous (NF1+/-) melanocytes reveals downregulation of a transcriptional cis-regulatory network mediating activation of the melanocyte-specific dopachrome tautomerase (DCT) gene.

    Science.gov (United States)

    Boucneau, Joachim; De Schepper, Sofie; Vuylsteke, Marnik; Van Hummelen, Paul; Naeyaert, Jean-Marie; Lambert, Jo

    2005-08-01

    One of the major primary features of the neurocutaneous genetic disorder Neurofibromatosis type 1 are the hyperpigmentary café-au-lait macules where disregulation of melanocyte biology is supposed to play a key etiopathogenic role. To gain better insight into the possible role of the tumor suppressor gene NF1, a transcriptomic microarray analysis was performed on human NF1 heterozygous (NF1+/-) melanocytes of a Neurofibromatosis type 1 patient and NF1 wild type (NF1+/+) melanocytes of a healthy control patient, both cultured from normally pigmented skin and hyperpigmented lesional café-au-lait skin. From the magnitude of gene effects, we found that gene expression was affected most strongly by genotype and less so by lesional type. A total of 137 genes had a significant twofold or more up- (72) or downregulated (65) expression in NF1+/- melanocytes compared with NF1+/+ melanocytes. Melanocytes cultured from hyperpigmented café-au-lait skin showed 37 upregulated genes whereas only 14 were downregulated compared with normal skin melanocytes. In addition, significant genotype xlesional type interactions were observed for 465 genes. Differentially expressed genes were mainly involved in regulating cell proliferation and cell adhesion. A high number of transcription factor genes, among which a specific subset important in melanocyte lineage development, were downregulated in the cis-regulatory network governing the activation of the melanocyte-specific dopachrome tautomerase (DCT) gene. Although the results presented have been obtained with a restricted number of patients (one NF1 patient and one control) and using cDNA microarrays that may limit their interpretation, the data nevertheless addresses for the first time the effect of a heterozygous NF1 gene on the expression of the human melanocyte transcriptome and has generated several interesting candidate genes helpful in elucidating the etiopathology of café-au-lait macules in NF1 patients.

  4. Comparison of Transcription Factor Binding Site Models

    KAUST Repository

    Bhuyan, Sharifulislam

    2012-05-01

    Modeling of transcription factor binding sites (TFBSs) and TFBS prediction on genomic sequences are important steps to elucidate transcription regulatory mechanism. Dependency of transcription regulation on a great number of factors such as chemical specificity, molecular structure, genomic and epigenetic characteristics, long distance interaction, makes this a challenging problem. Different experimental procedures generate evidence that DNA-binding domains of transcription factors show considerable DNA sequence specificity. Probabilistic modeling of TFBSs has been moderately successful in identifying patterns from a family of sequences. In this study, we compare performances of different probabilistic models and try to estimate their efficacy over experimental TFBSs data. We build a pipeline to calculate sensitivity and specificity from aligned TFBS sequences for several probabilistic models, such as Markov chains, hidden Markov models, Bayesian networks. Our work, containing relevant statistics and evaluation for the models, can help researchers to choose the most appropriate model for the problem at hand.

  5. Transcriptional control of spermatogonial maintenance and differentiation.

    Science.gov (United States)

    Song, Hye-Won; Wilkinson, Miles F

    2014-06-01

    Spermatogenesis is a multistep process that generates millions of spermatozoa per day in mammals. A key to this process is the spermatogonial stem cell (SSC), which has the dual property of continually renewing and undergoing differentiation into a spermatogonial progenitor that expands and further differentiates. In this review, we will focus on how these proliferative and early differentiation steps in mammalian male germ cells are controlled by transcription factors. Most of the transcription factors that have so far been identified as promoting SSC self-renewal (BCL6B, BRACHYURY, ETV5, ID4, LHX1, and POU3F1) are upregulated by glial cell line-derived neurotrophic factor (GDNF). Since GDNF is crucial for promoting SSC self-renewal, this suggests that these transcription factors are responsible for coordinating the action of GDNF in SSCs. Other transcription factors that promote SSC self-renewal are expressed independently of GDNF (FOXO1, PLZF, POU5F1, and TAF4B) and thus may act in non-GDNF pathways to promote SSC cell growth or survival. Several transcription factors have been identified that promote spermatogonial differentiation (DMRT1, NGN3, SOHLH1, SOHLH2, SOX3, and STAT3); some of these may influence the decision of an SSC to commit to differentiate while others may promote later spermatogonial differentiation steps. Many of these transcription factors regulate each other and act on common targets, suggesting they integrate to form complex transcriptional networks in self-renewing and differentiating spermatogonia.

  6. Direct analysis of blood serum by total reflection X-ray fluorescence spectrometry and application of an artificial neural network approach for cancer diagnosis*1

    Science.gov (United States)

    Hernández-Caraballo, Edwin A.; Marcó-Parra, Lué M.

    2003-12-01

    Iron, copper, zinc and selenium were determined directly in serum samples from healthy individuals ( n=33) and cancer patients ( n=27) by total reflection X-ray fluorescence spectrometry using the Compton peak as internal standard [L.M. Marcó P. et al., Spectrochim. Acta Part B 54 (1999) 1469-1480]. The standardized concentrations of these elements were used as input data for two-layer artificial neural networks trained with the generalized delta rule in order to classify such individuals according to their health status. Various artificial neural networks, comprising a linear function in the input layer, a hyperbolic tangent function in the hidden layer and a sigmoid function in the output layer, were evaluated for such a purpose. Of the networks studied, the (4:4:1) gave the highest estimation (98%) and prediction rates (94%). The latter demonstrates the potential of the total reflection X-ray fluorescence spectrometry/artificial neural network approach in clinical chemistry.

  7. Cord Blood

    Directory of Open Access Journals (Sweden)

    Saeed Abroun

    2014-05-01

    Full Text Available   Stem cells are naïve or master cells. This means they can transform into special 200 cell types as needed by body, and each of these cells has just one function. Stem cells are found in many parts of the human body, although some sources have richer concentrations than others. Some excellent sources of stem cells, such as bone marrow, peripheral blood, cord blood, other tissue stem cells and human embryos, which last one are controversial and their use can be illegal in some countries. Cord blood is a sample of blood taken from a newborn baby's umbilical cord. It is a rich source of stem cells, umbilical cord blood and tissue are collected from material that normally has no use following a child’s birth. Umbilical cord blood and tissue cells are rich sources of stem cells, which have been used in the treatment of over 80 diseases including leukemia, lymphoma and anemia as bone marrow stem cell potency.  The most common disease category has been leukemia. The next largest group is inherited diseases. Patients with lymphoma, myelodysplasia and severe aplastic anemia have also been successfully transplanted with cord blood. Cord blood is obtained by syringing out the placenta through the umbilical cord at the time of childbirth, after the cord has been detached from the newborn. Collecting stem cells from umbilical blood and tissue is ethical, pain-free, safe and simple. When they are needed to treat your child later in life, there will be no rejection or incompatibility issues, as the procedure will be using their own cells. In contrast, stem cells from donors do have these potential problems. By consider about cord blood potency, cord blood banks (familial or public were established. In IRAN, four cord blood banks has activity, Shariati BMT center cord blood bank, Royan familial cord blood banks, Royan public cord blood banks and Iranian Blood Transfusion Organ cord blood banks. Despite 50,000 sample which storage in these banks, but the

  8. Navigating the transcriptional roadmap regulating plant secondary cell wall deposition

    Directory of Open Access Journals (Sweden)

    Steven Grant Hussey

    2013-08-01

    Full Text Available The current status of lignocellulosic biomass as an invaluable resource in industry, agriculture and health has spurred increased interest in understanding the transcriptional regulation of secondary cell wall (SCW biosynthesis. The last decade of research has revealed an extensive network of NAC, MYB and other families of transcription factors regulating Arabidopsis SCW biosynthesis, and numerous studies have explored SCW-related transcription factors in other dicots and monocots. Whilst the general structure of the Arabidopsis network has been a topic of several reviews, they have not comprehensively represented the detailed protein-DNA and protein-protein interactions described in the literature, and an understanding of network dynamics and functionality has not yet been achieved for SCW formation. Furthermore the methodologies employed in studies of SCW transcriptional regulation have not received much attention, especially in the case of non-model organisms. In this review, we have reconstructed the most exhaustive literature-based network representations to date of SCW transcriptional regulation in Arabidopsis. We include a manipulable Cytoscape representation of the Arabidopsis SCW transcriptional network to aid in future studies, along with a list of supporting literature for each documented interaction. Amongst other topics, we discuss the various components of the network, its evolutionary conservation in plants, putative modules and dynamic mechanisms that may influence network function, and the approaches that have been employed in network inference. Future research should aim to better understand network function and its response to dynamic perturbations, whilst the development and application of genome-wide approaches such as ChIP-seq and systems genetics are in progress for the study of SCW transcriptional regulation in non-model organisms.

  9. Morphology of nuclear transcription.

    Science.gov (United States)

    Weipoltshammer, Klara; Schöfer, Christian

    2016-04-01

    Gene expression control is a fundamental determinant of cellular life with transcription being the most important step. The spatial nuclear arrangement of the transcription process driven by RNA polymerases II and III is nonrandomly organized in foci, which is believed to add another regulatory layer on gene expression control. RNA polymerase I transcription takes place within a specialized organelle, the nucleolus. Transcription of ribosomal RNA directly responds to metabolic requirements, which in turn is reflected in the architecture of nucleoli. It differs from that of the other polymerases with respect to the gene template organization, transcription rate, and epigenetic expression control, whereas other features are shared like the formation of DNA loops bringing genes and components of the transcription machinery in close proximity. In recent years, significant advances have been made in the understanding of the structural prerequisites of nuclear transcription, of the arrangement in the nuclear volume, and of the dynamics of these entities. Here, we compare ribosomal RNA and mRNA transcription side by side and review the current understanding focusing on structural aspects of transcription foci, of their constituents, and of the dynamical behavior of these components with respect to foci formation, disassembly, and cell cycle. PMID:26847177

  10. A Nonnatural Transcriptional Coactivator

    Science.gov (United States)

    Nyanguile, Origene; Uesugi, Motonari; Austin, David J.; Verdine, Gregory L.

    1997-12-01

    In eukaryotes, sequence-specific DNA-binding proteins activate gene expression by recruiting the transcriptional apparatus and chromatin remodeling proteins to the promoter through protein-protein contacts. In many instances, the connection between DNA-binding proteins and the transcriptional apparatus is established through the intermediacy of adapter proteins known as coactivators. Here we describe synthetic molecules with low molecular weight that act as transcriptional coactivators. We demonstrate that a completely nonnatural activation domain in one such molecule is capable of stimulating transcription in vitro and in vivo. The present strategy provides a means of gaining external control over gene activation through intervention using small molecules.

  11. Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells.

    Science.gov (United States)

    Lafarge, S; Hamzeh-Cognasse, H; Richard, Y; Pozzetto, B; Cogné, M; Cognasse, F; Garraud, O

    2011-11-01

    The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces.

  12. Blood / Money

    OpenAIRE

    Strong, Thomas

    1997-01-01

    Marilyn Strathern has argued that "nature" in Euro-American culture has appeared as constraint; it has figured the givens of existence on which human artifice is seen to construct "society" or "culture."(5) Among those givens is the notion that human beings are naturally individuals. And blood, too, images individuality: "The very thought of blood, individual blood, touches the deepest feelings in man about life and death" ([RIchard Titmuss] 16.) Transfusion medicine, then, draws on a series ...

  13. Transcriptome and network changes in climbers at extreme altitudes.

    Directory of Open Access Journals (Sweden)

    Fang Chen

    Full Text Available Extreme altitude can induce a range of cellular and systemic responses. Although it is known that hypoxia underlies the major changes and that the physiological responses include hemodynamic changes and erythropoiesis, the molecular mechanisms and signaling pathways mediating such changes are largely unknown. To obtain a more complete picture of the transcriptional regulatory landscape and networks involved in extreme altitude response, we followed four climbers on an expedition up Mount Xixiabangma (8,012 m, and collected blood samples at four stages during the climb for mRNA and miRNA expression assays. By analyzing dynamic changes of gene networks in response to extreme altitudes, we uncovered a highly modular network with 7 modules of various functions that changed in response to extreme altitudes. The erythrocyte differentiation module is the most prominently up-regulated, reflecting increased erythrocyte differentiation from hematopoietic stem cells, probably at the expense of differentiation into other cell lineages. These changes are accompanied by coordinated down-regulation of general translation. Network topology and flow analyses also uncovered regulators known to modulate hypoxia responses and erythrocyte development, as well as unknown regulators, such as the OCT4 gene, an important regulator in stem cells and assumed to only function in stem cells. We predicted computationally and validated experimentally that increased OCT4 expression at extreme altitude can directly elevate the expression of hemoglobin genes. Our approach established a new framework for analyzing the transcriptional regulatory network from a very limited number of samples.

  14. The transcriptional landscape

    DEFF Research Database (Denmark)

    Nielsen, Henrik

    2011-01-01

    The application of new and less biased methods to study the transcriptional output from genomes, such as tiling arrays and deep sequencing, has revealed that most of the genome is transcribed and that there is substantial overlap of transcripts derived from the two strands of DNA. In protein codi...

  15. The Transcription Factor Encyclopedia

    DEFF Research Database (Denmark)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I;

    2012-01-01

    ABSTRACT: Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130...

  16. Understanding Blood Counts

    Science.gov (United States)

    ... Lab and Imaging Tests Understanding Blood Counts Understanding Blood Counts Understanding Blood Counts SHARE: Print Glossary Blood cell counts give ... your blood that's occupied by red cells. Normal Blood Counts Normal blood counts fall within a range ...

  17. NAC Transcription Factors in Stress Responses and Senescence

    DEFF Research Database (Denmark)

    O'Shea, Charlotte

    of these studies have also revealed emerging gene regulatory networks and protein-protein interaction networks. However, structural studies relating structure to function are lagging behind. Structure-function analysis of the NAC transcription factors has therefore been the main focus of this PhD thesis....... A systematic analysis has been performed of protein intrinsic disorder (ID), referring to the lack of a fixed tertiary structure, in NAC transcription factors. The transcription regulatory domains (TRDs) from six phylogenetically representative Arabidopsis thaliana NAC transcription factors have a similarly......RF is a functional hotspot for both transcriptional activity and interaction with the cellular hub protein Radical Induced Cell Death1 (RCD1). Specific amino acid residues essential for the interaction were identified. These studies and structural analysis suggested that RCD1-ANAC046 complex formation does...

  18. A gene co-expression network in whole blood of schizophrenia patients is independent of antipsychotic-use and enriched for brain-expressed genes

    DEFF Research Database (Denmark)

    de Jong, Simone; Boks, Marco P M; Fuller, Tova F;

    2012-01-01

    of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co......-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One...... of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in...

  19. Blood donation

    CERN Multimedia

    GS Department

    2009-01-01

    A blood donation is organised by the Cantonal Hospital of Geneva On Thursday 19 March 2009 from 9 a.m. to 5 p.m. CERN RESTAURANT 2 Number of donations during the last blood donations :135 donors in July 2008 122 donors in November 2008 Let’s do better in 2009 !!! Give 30 minutes of your time to save lives...

  20. BLOOD DONATION

    CERN Document Server

    SC Unit

    2008-01-01

    A blood donation, organized by EFS (Etablissement Français du Sang) of Annemasse will take place On Wednesday 12 November 2008, from 8:30 to 16:00, at CERN Restaurant 2 If possible, please, bring your blood group Card.

  1. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

    Science.gov (United States)

    Niederwieser, D; Baldomero, H; Szer, J; Gratwohl, M; Aljurf, M; Atsuta, Y; Bouzas, L F; Confer, D; Greinix, H; Horowitz, M; Iida, M; Lipton, J; Mohty, M; Novitzky, N; Nunez, J; Passweg, J; Pasquini, M C; Kodera, Y; Apperley, J; Seber, A; Gratwohl, A

    2016-06-01

    Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation. PMID:26901703

  2. Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

    Science.gov (United States)

    Niederwieser, D; Baldomero, H; Szer, J; Gratwohl, M; Aljurf, M; Atsuta, Y; Bouzas, L F; Confer, D; Greinix, H; Horowitz, M; Iida, M; Lipton, J; Mohty, M; Novitzky, N; Nunez, J; Passweg, J; Pasquini, M C; Kodera, Y; Apperley, J; Seber, A; Gratwohl, A

    2016-06-01

    Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

  3. Transcriptional Regulation of Pyruvate Dehydrogenase Kinase

    OpenAIRE

    Ji Yun Jeong; Nam Ho Jeoung; Keun-Gyu Park; In-Kyu Lee

    2012-01-01

    The pyruvate dehydrogenase complex (PDC) activity is crucial to maintains blood glucose and ATP levels, which largely depends on the phosphorylation status by pyruvate dehydrogenase kinase (PDK) isoenzymes. Although it has been reported that PDC is phosphorylated and inactivated by PDK2 and PDK4 in metabolically active tissues including liver, skeletal muscle, heart, and kidney during starvation and diabetes, the precise mechanisms by which expression of PDK2 and PDK4 are transcriptionally re...

  4. Tainted blood

    DEFF Research Database (Denmark)

    Deleuran, Ida; Sheikh, Zainab Afshan; Hoeyer, Klaus

    2015-01-01

    study of the historical rise and current workings of safety practices in the Danish blood system. Here, we identify a strong focus on contamination in order to avoid 'tainted blood', at the expense of working with risks that could be avoided through enhanced blood monitoring practices. Of further...... significance to this focus are the social dynamics found at the heart of safety practices aimed at avoiding contamination. We argue that such dynamics need more attention, in order to achieve good health outcomes in transfusion medicine. Thus, we conclude that, to ensure continuously safe blood systems, we...... need to move beyond the bifurcation of the social and medical aspects of blood supply as two separate issues and approach social dynamics as key medical safety questions....

  5. Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers.

    Science.gov (United States)

    Pramparo, Tiziano; Lombardo, Michael V; Campbell, Kathleen; Barnes, Cynthia Carter; Marinero, Steven; Solso, Stephanie; Young, Julia; Mayo, Maisi; Dale, Anders; Ahrens-Barbeau, Clelia; Murray, Sarah S; Lopez, Linda; Lewis, Nathan; Pierce, Karen; Courchesne, Eric

    2015-12-01

    Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment. PMID:26668231

  6. Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers.

    Science.gov (United States)

    Pramparo, Tiziano; Lombardo, Michael V; Campbell, Kathleen; Barnes, Cynthia Carter; Marinero, Steven; Solso, Stephanie; Young, Julia; Mayo, Maisi; Dale, Anders; Ahrens-Barbeau, Clelia; Murray, Sarah S; Lopez, Linda; Lewis, Nathan; Pierce, Karen; Courchesne, Eric

    2015-12-14

    Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.

  7. 牛病毒性腹泻病毒感染牛外周血单核细胞对CD80和CD86 mRNA转录的影响%Effects of bovine viral diarrhea viruses in vitro on transcription of CD80 and CD86 mRNA in bovine peripheral blood mononuclear cells

    Institute of Scientific and Technical Information of China (English)

    韩猛立; 黄新; 钟发刚

    2012-01-01

    The clinically healthy Holstein bovine tested negative for bovine viral diarrhea virus(BVDV) in peripheral blood mononuclear cells(PBMC) were infected with noncytopathic(NCP) and cytopathic(CP) BVDV.The changes levels of mRNA of CD80 and CD86 genes were analyzed using a real-time fluorescent quantitative PCR(real-time FQ-PCR).The results showed that the transcription of CD80 mRNA exhibited two transcription high at 4 h(P0.05) and 12,24 h(P0.01) post-inoculation(PI),and CD86 mRNA reached the highest level at 6 h(P0.05)PI in NCP BVDV-infected PBMC;then the mRNAs transcriptions of CD80 peaked at 24 h(P0.05)and CD86 peaked at 6 h(P0.05) in CP BVDV-infected PBMC with signifficant differences compared to that of the other PI.While the transcription on CD80 mRNAs witnessed more kinetic changes,it indicats NCP and CP BVDV could significantly supress the transcription of CD80-CD86 genes early during the infection,and the situation might weaken the antigen presentation of PBMC in the inoculated bovine.%用非致细胞病变(noncytopathic,NCP)和致细胞病变(cytopathic,CP)型牛病毒性腹泻病毒(BVDV)感染临床健康BVDV检测阴性的荷斯坦奶牛外周血单核细胞(PBMC),利用实时荧光定量PCR技术对感染后共刺激分子CD80和CD86mRNA转录水平的变化进行定量分析。结果表明,在NCP型BVDV感染牛PBMC后CD80在4h(P〈0.05)和12,24h(P〈0.01)出现2次转录高峰,CD86在6h(P〈0.05)出现转录高峰;CP型BVDV感染后,CD80在24h(P〈0.05)出现转录高峰,CD86在6h(P〈0.05)出现转录高峰。尽管CD80在NCP型BVDV感染后呈现较复杂的动态变化,但结果提示NCP型和CP型BVDV感染均可导致牛PBMC的共刺激分子CD80和CD86基因转录在感染早期明显受到抑制,PBMC的抗原呈递能力受到影响。

  8. Transcription factor CTCF and mammalian genome organization

    Directory of Open Access Journals (Sweden)

    Kotova E. S.

    2014-07-01

    Full Text Available The CTCF transcription factor is thought to be one of the main participants in various gene regulatory networks including transcription activation and repression, formation of independently functioning chromatin domains, regulation of imprinting etc. Sequencing of human and other genomes opened up a possibility to ascertain the genomic distribution of CTCF binding sites and to identify CTCF-dependent cis-regulatory elements, including insulators. In the review, we summarized recent data on CTCF functioning within a framework of the chromatin loop domain hypothesis of large-scale regulation of the genome activity. Its fundamental properties allow CTCF to serve as a transcription factor, an insulator protein and a dispersed genome-wide demarcation tool able to recruit various factors that emerge in response to diverse external and internal signals, and thus to exert its signal-specific function(s.

  9. How salicylic acid takes transcriptional control over jasmonic acid signaling

    Directory of Open Access Journals (Sweden)

    Lotte eCaarls

    2015-03-01

    Full Text Available Transcriptional regulation is a central process in plant immunity. The induction or repression of defense genes is orchestrated by signaling networks that are directed by plant hormones of which salicylic acid (SA and jasmonic acid (JA are the major players. Extensive cross-communication between the hormone signaling pathways allows for fine tuning of transcriptional programs, determining resistance to invaders and trade-offs with plant development. Here, we give an overview of how SA can control transcriptional reprogramming of JA-induced genes in Arabidopsis thaliana. SA can influence activity and/or localization of transcriptional regulators by post-translational modifications of transcription factors and co-regulators. SA-induced redox changes, mediated by thioredoxins and glutaredoxins, modify transcriptional regulators that are involved in suppression of JA-dependent genes, such as NPR1 and TGA transcription factors, which affects their localization or DNA binding activity. Furthermore, SA can mediate sequestering of JA-responsive transcription factors away from their target genes by stalling them in the cytosol or in complexes with repressor proteins in the nucleus. SA also affects JA-induced transcription by inducing degradation of transcription factors with an activating role in JA signaling, as was shown for the ERF transcription factor ORA59. Additionally, SA can induce negative regulators, among which WRKY transcription factors, that can directly or indirectly inhibit JA-responsive gene expression. Finally, at the DNA level, modification of histones by SA-dependent factors can result in repression of JA-responsive genes. These diverse and complex regulatory mechanisms affect important signaling hubs in the integration of hormone signaling networks. Some pathogens have evolved effectors that highjack hormone crosstalk mechanisms for their own good, which are described in this review as well.

  10. The transcriptional regulation of pluripotency

    Institute of Scientific and Technical Information of China (English)

    Jia-Chi Yeo; Huck-Hui Ng

    2013-01-01

    The defining features of embryonic stem cells (ESCs) are their self-renewing and pluripotent capacities.Indeed,the ability to give rise into all cell types within the organism not only allows ESCs to function as an ideal in vitro tool to study embryonic development,but also offers great therapeutic potential within the field of regenerative medicine.However,it is also this same remarkable developmental plasticity that makes the efficient control of ESC differentiation into the desired cell type very difficult.Therefore,in order to harness ESCs for clinical applications,a detailed understanding of the molecular and cellular mechanisms controlling ESC pluripotency and lineage commitment is necessary.In this respect,through a variety of transcriptomic approaches,ESC pluripotency has been found to be regulated by a system of ESC-associated transcription factors; and the external signalling environment also acts as a key factor in modulating the ESC transcriptome.Here in this review,we summarize our current understanding of the transcriptional regulatory network in ESCs,discuss how the control of various signalling pathways could influence pluripotency,and provide a future outlook of ESC research.

  11. Moving blood.

    Science.gov (United States)

    Pelis, K

    1997-01-01

    Our internationally acclaimed journalist Sanguinia has returned safely from her historic assignment. Travelling from Homeric Greece to British Romanticism, she was witness to blood drinking, letting, bathing, and transfusion. In this report, she explores connections between the symbolic and the sadistic; the mythic and the medical--all in an effort to appreciate the layered meanings our culture has given to the movement of blood between our bodies. PMID:9407636

  12. Biology of Blood

    Science.gov (United States)

    ... Mail Facebook TwitterTitle Google+ LinkedIn Home Blood Disorders Biology of Blood Overview of Blood Medical Dictionary Also ... Version. DOCTORS: Click here for the Professional Version Biology of Blood Overview of Blood Components of Blood ...

  13. Blood donation before surgery

    Science.gov (United States)

    ... type of donor blood. Many communities have a blood bank where healthy people can donate blood. This blood ... need to arrange with your hospital or local blood bank before your surgery to have directed donor blood. ...

  14. Blood Clotting and Pregnancy

    Medline Plus

    Full Text Available ... Blood Basics Blood Disorders Anemia Bleeding Disorders Blood Cancers Blood Clots Blood Clotting and Pregnancy Clots and ... Increased maternal age Other medical illness (e.g., cancer, infection) back to top How are Blood Clots ...

  15. Catecholamine blood test

    Science.gov (United States)

    Norepinephrine -- blood; Epinephrine -- blood; Adrenalin -- blood; Dopamine -- blood ... A blood sample is needed. ... the test. This is especially true if both blood and urine catecholamines are to be measured. You ...

  16. Blood (For Parents)

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Blood KidsHealth > For Parents > Blood Print A A A ... about the mysterious, life-sustaining fluid called blood. Blood Basics Two types of blood vessels carry blood ...

  17. Blood Facts and Statistics

    Science.gov (United States)

    ... About Blood > Blood Facts and Statistics Printable Version Blood Facts and Statistics Facts about blood needs Facts ... about American Red Cross Blood Services Facts about blood needs Every two seconds someone in the U.S. ...

  18. Subgroup-specific intrinsic disorder profiles of arabidopsis NAC transcription factors

    DEFF Research Database (Denmark)

    Stender, Emil G.; O'Shea, Charlotte; Skriver, Karen

    2015-01-01

    Protein intrinsic disorder (ID), referring to the lack of a fixed tertiary structure, is significant in signaling and transcription. We recently characterized ID in 6 phylogenetically representative Arabidopsis thaliana NAC transcription factors. Their transcription regulatory domains are mostly.......g. transcriptional activation and interactions. Based on our analysis, we suggest that ID profiling of regulatory proteins in general can be used to guide identification of interaction partners of network proteins....

  19. Analysis of protein interaction networks related to core transcription factors target genes in embryonic stem cells%胚胎干细胞核心转录因子靶基因集蛋白互作网络特征分析

    Institute of Scientific and Technical Information of China (English)

    左长清; 汪宗桂; 吴铁; 崔燎

    2011-01-01

    BACKGROUND: It is sufficient to reprogram somatic cells, through transduction of some core transcription factors, into pluripotent stem cells (iPS) that exhibit the essential characteristics of embryonic stem (ES) cells. At present, the complex mechanism is not yet fully understood.OBJECTIVE: To study the protein interaction networks related to core transcription factors target genes in embryonic stem cells and to obtain regulatory mechanism controlled "stemness".METHODS: Non-redundant protein interaction data (NRPD) were obtained after removal of redundant data in BioGRID database.Protein interaction pairs, formed by the target genes, were extracted by perl program and the largest continuous protein interaction networks were obtained through searching NRPD using breadth-first search algorithm. At the same time, 1 000 random networks were analyzed and compared. At last, network visualization was analyzed through the Cytoscape software and network characteristics were explained using complex scale-free network model of Barabasi-Albert.RESULTS AND CONCLUSION : More protein interaction pairs and larger continuous protein network, statistically significant difference compared with random genes, were formed by core transcription factor target genes. The continuous protein network is scale-free characteristics of complex networks. This study has suggested that target genes may regulate synergistically "stemness" characteristics of embryonic stem cells through close interaction and forming a network module.%背景:外源性核心转录因子导入终末分化细胞能产生具有与胚胎干细胞特性相似的诱导多潜能干细胞,其复杂机制目前尚未完全阐明.目的:分析核心转录因子靶基因集蛋白互作网络特征,获得其影响"干性"特征的调控机制.方法:去除BioGRID数据库中的冗余数据,获得非冗余蛋白互作数据库.perl程序搜索靶基因集组成的蛋白互作对,广度优先算法搜索非冗余蛋白互作数

  20. Prediction of capillary gas chromatographic retention times of fatty acid methyl esters in human blood using MLR, PLS and back-propagation artificial neural networks.

    Science.gov (United States)

    Gupta, Vinod Kumar; Khani, Hadi; Ahmadi-Roudi, Behzad; Mirakhorli, Shima; Fereyduni, Ehsan; Agarwal, Shilpi

    2011-01-15

    Quantitative structure-retention relationship (QSRR) models correlating the retention times of fatty acid methyl esters in high resolution capillary gas chromatography and their structures were developed based on non-linear and linear modeling methods. Genetic algorithm (GA) was used for the selection of the variables that resulted in the best-fitted models. Gravitational index (G2), number of cis double bond (NcDB) and number of trans double bond (NtDB) were selected among a large number of descriptors. The selected descriptors were considered as inputs for artificial neural networks (ANNs) with three different weights update functions including Levenberg-Marquardt backpropagation network (LM-ANN), BFGS (Broyden, Fletcher, Goldfarb, and Shanno) quasi-Newton backpropagation (BFG-ANN) and conjugate gradient backpropagation with Polak-Ribiére updates (CGP-ANN). Computational result indicates that the LM-ANN method has better predictive power than the other methods. The model was also tested successfully for external validation criteria. Standard error for the training set using LM-ANN was SE=0.932 with correlation coefficient R=0.996. For the prediction and validation sets, standard error was SE=0.645 and SE=0.445 and correlation coefficient was R=0.999 and R=0.999, respectively. The accuracy of 3-2-1 LM-ANN model was illustrated using leave multiple out-cross validations (LMO-CVs) and Y-randomization.

  1. Directed network modules

    CERN Document Server

    Pálla, G; Farkas, I J; Pollner, P; Vicsek, T; Derenyi, Imre; Farkas, Illes J.; Palla, Gergely; Pollner, Peter; Vicsek, Tamas

    2007-01-01

    A search technique locating network modules, i.e., internally densely connected groups of nodes in directed networks is introduced by extending the Clique Percolation Method originally proposed for undirected networks. After giving a suitable definition for directed modules we investigate their percolation transition in the Erdos-Renyi graph both analytically and numerically. We also analyse four real-world directed networks, including Google's own webpages, an email network, a word association graph and the transcriptional regulatory network of the yeast Saccharomyces cerevisiae. The obtained directed modules are validated by additional information available for the nodes. We find that directed modules of real-world graphs inherently overlap and the investigated networks can be classified into two major groups in terms of the overlaps between the modules. Accordingly, in the word-association network and among Google's webpages the overlaps are likely to contain in-hubs, whereas the modules in the email and t...

  2. Managing your blood sugar

    Science.gov (United States)

    Hyperglycemia - control; Hypoglycemia - control; Diabetes - blood sugar control; Blood glucose - managing ... Know how to: Recognize and treat low blood sugar (hypoglycemia) Recognize and treat high blood sugar (hyperglycemia) ...

  3. Transcriptional regulation of the operon encoding stress-responsive ECF sigma factor SigH and its anti-sigma factor RshA, and control of its regulatory network in Corynebacterium glutamicum

    Directory of Open Access Journals (Sweden)

    Busche Tobias

    2012-09-01

    Full Text Available Abstract Background The expression of genes in Corynebacterium glutamicum, a Gram-positive non-pathogenic bacterium used mainly for the industrial production of amino acids, is regulated by seven different sigma factors of RNA polymerase, including the stress-responsive ECF-sigma factor SigH. The sigH gene is located in a gene cluster together with the rshA gene, putatively encoding an anti-sigma factor. The aim of this study was to analyze the transcriptional regulation of the sigH and rshA gene cluster and the effects of RshA on the SigH regulon, in order to refine the model describing the role of SigH and RshA during stress response. Results Transcription analyses revealed that the sigH gene and rshA gene are cotranscribed from four sigH housekeeping promoters in C. glutamicum. In addition, a SigH-controlled rshA promoter was found to only drive the transcription of the rshA gene. To test the role of the putative anti-sigma factor gene rshA under normal growth conditions, a C. glutamicum rshA deletion strain was constructed and used for genome-wide transcription profiling with DNA microarrays. In total, 83 genes organized in 61 putative transcriptional units, including those previously detected using sigH mutant strains, exhibited increased transcript levels in the rshA deletion mutant compared to its parental strain. The genes encoding proteins related to disulphide stress response, heat stress proteins, components of the SOS-response to DNA damage and proteasome components were the most markedly upregulated gene groups. Altogether six SigH-dependent promoters upstream of the identified genes were determined by primer extension and a refined consensus promoter consisting of 45 original promoter sequences was constructed. Conclusions The rshA gene codes for an anti-sigma factor controlling the function of the stress-responsive sigma factor SigH in C. glutamicum. Transcription of rshA from a SigH-dependent promoter may serve to quickly

  4. 基于矩阵分解技术的系统性红斑狼疮转录调控网络构建%The Construction of a Transcriptional Regulatory Network of Systemic Lupus Erythematosus Based on the Matrix Decomposition Techniques

    Institute of Scientific and Technical Information of China (English)

    孔薇; 张帅; 牟晓阳

    2016-01-01

    Using biclustering method to improve the effectiveness of extraction of characteristic genes from systemic lupus erythematosus (SLE) gene expression data .To predict the activities of transcriptional factors (TFs) and their regulatory influences on target genes during SLE course ,to construct a SLE‐related transcriptional regulatory network and to discover SLE‐related biological processes by matrix decomposi‐tion techniques .Bicluster method ,FastICA ,was applied to SLE gene expression data to extract 800 charac‐teristic genes .Then ,by integrating the prior biological information of transcriptional regulation ,significant TFs and their target genes were extracted .Based on that ,NCA was applied to determine the activities of TFs and their regulatory influences on target genes ,and the transcriptional regulatory network of SLE was constructed .The transcriptional regulatory network consisting of 9 significantly changed TFs and their reg‐ulated 47 target genes was constructed .Combining with molecular biological analysis we found that the changes of the TFs activities had evident influences on target genes between normal and SLE samples , which was consistent with the pathological features of SLE .The methods applied here using matrix decom‐position technique have effectively extracted characteristic genes and constructed a transcriptional regulato‐ry network of SLE ,and biological processes closely related to inflammatory response and immune system could be discovered .Our methods would provide a novel method for uncovering the pathogenesis of SLE and designing the corresponding biological experiments .%利用双向聚类方法提高系统性红斑狼疮(systemic lupus erythematosus ,SLE)基因表达数据特征基因提取的有效性;预测SLE患病过程中转录因子活性以及对靶基因的调控强度变化,构建和挖掘与SLE发病密切相关的转录调控网络及其生物过程。利用FastICA方法进行双向

  5. Niche adaptation by expansion and reprogramming of general transcription factors

    OpenAIRE

    Turkarslan, Serdar; Reiss, David J; Gibbins, Goodwin; Su, Wan Lin; Pan, Min; Bare, J Christopher; Plaisier, Christopher L.; Baliga, Nitin S

    2011-01-01

    The evolutionary success of an organism depends on its ability to continually adapt to changes in the patterns of constant, periodic, and transient challenges within its environment. This process of ‘niche adaptation' requires reprogramming of the organism's environmental response networks by reorganizing interactions among diverse parts including environmental sensors, signal transducers, and transcriptional and post-transcriptional regulators. Gene duplications have been discovered to be on...

  6. Classifying transcription factor targets and discovering relevant biological features

    OpenAIRE

    DeLisi Charles; Kon Mark; Holloway Dustin T

    2008-01-01

    Abstract Background An important goal in post-genomic research is discovering the network of interactions between transcription factors (TFs) and the genes they regulate. We have previously reported the development of a supervised-learning approach to TF target identification, and used it to predict targets of 104 transcription factors in yeast. We now include a new sequence conservation measure, expand our predictions to include 59 new TFs, introduce a web-server, and implement an improved r...

  7. The transcription factor encyclopedia.

    Science.gov (United States)

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

  8. DNA Topoisomerases in Transcription

    DEFF Research Database (Denmark)

    Rødgaard, Morten Terpager

    2015-01-01

    This Ph.D. thesis summarizes the main results of my studies on the interplay between DNA topoisomerases and transcription. The work was performed from 2011 to 2015 at Aarhus University in the Laboratory of Genome Research, and was supervised by associate professor Anni H. Andersen. Most of the ex......This Ph.D. thesis summarizes the main results of my studies on the interplay between DNA topoisomerases and transcription. The work was performed from 2011 to 2015 at Aarhus University in the Laboratory of Genome Research, and was supervised by associate professor Anni H. Andersen. Most...

  9. Synthetic Biology Platform for Sensing and Integrating Endogenous Transcriptional Inputs in Mammalian Cells.

    Science.gov (United States)

    Angelici, Bartolomeo; Mailand, Erik; Haefliger, Benjamin; Benenson, Yaakov

    2016-08-30

    One of the goals of synthetic biology is to develop programmable artificial gene networks that can transduce multiple endogenous molecular cues to precisely control cell behavior. Realizing this vision requires interfacing natural molecular inputs with synthetic components that generate functional molecular outputs. Interfacing synthetic circuits with endogenous mammalian transcription factors has been particularly difficult. Here, we describe a systematic approach that enables integration and transduction of multiple mammalian transcription factor inputs by a synthetic network. The approach is facilitated by a proportional amplifier sensor based on synergistic positive autoregulation. The circuits efficiently transduce endogenous transcription factor levels into RNAi, transcriptional transactivation, and site-specific recombination. They also enable AND logic between pairs of arbitrary transcription factors. The results establish a framework for developing synthetic gene networks that interface with cellular processes through transcriptional regulators. PMID:27545896

  10. Blood Transfusion

    Science.gov (United States)

    ... to infections including those we develop from our vaccinations (such as poliovirus antibodies, which are made by ... the Transfusion Medicine Unit, Blood Bank, and Stem Cell Storage Facility University of Rochester Medical ... and health educators who are available by phone Monday through Friday, 9 am to 9 pm ( ...

  11. Screening Driving Transcription Factors in the Processing of Gastric Cancer

    Directory of Open Access Journals (Sweden)

    Guangzhong Xu

    2016-01-01

    Full Text Available Background. Construction of the transcriptional regulatory network can provide additional clues on the regulatory mechanisms and therapeutic applications in gastric cancer. Methods. Gene expression profiles of gastric cancer were downloaded from GEO database for integrated analysis. All of DEGs were analyzed by GO enrichment and KEGG pathway enrichment. Transcription factors were further identified and then a global transcriptional regulatory network was constructed. Results. By integrated analysis of the six eligible datasets (340 cases and 43 controls, a bunch of 2327 DEGs were identified, including 2100 upregulated and 227 downregulated DEGs. Functional enrichment analysis of DEGs showed that digestion was a significantly enriched GO term for biological process. Moreover, there were two important enriched KEGG pathways: cell cycle and homologous recombination. Furthermore, a total of 70 differentially expressed TFs were identified and the transcriptional regulatory network was constructed, which consisted of 566 TF-target interactions. The top ten TFs regulating most downstream target genes were BRCA1, ARID3A, EHF, SOX10, ZNF263, FOXL1, FEV, GATA3, FOXC1, and FOXD1. Most of them were involved in the carcinogenesis of gastric cancer. Conclusion. The transcriptional regulatory network can help researchers to further clarify the underlying regulatory mechanisms of gastric cancer tumorigenesis.

  12. Bayesian Music Transcription

    NARCIS (Netherlands)

    Cemgil, A.T.

    2004-01-01

    Music transcription refers to extraction of a human readable and interpretable description from a recording of a music performance. The final goal is to implement a program that can automatically infer a musical notation that lists the pitch levels of notes and corresponding score positions in any a

  13. Automatic Music Transcription

    Science.gov (United States)

    Klapuri, Anssi; Virtanen, Tuomas

    Written musical notation describes music in a symbolic form that is suitable for performing a piece using the available musical instruments. Traditionally, musical notation indicates the pitch, target instrument, timing, and duration of each sound to be played. The aim of music transcription either by humans or by a machine is to infer these musical parameters, given only the acoustic recording of a performance.

  14. Blood Culture (For Parents)

    Science.gov (United States)

    ... KidsHealth in the Classroom What Other Parents Are Reading Upsetting News Reports? What to Say Vaccines: Which ... BMP) Blood Test: Complete Blood Count Basic Blood Chemistry Tests Getting a Blood Test (Video) Blood Test: ...

  15. Blood Clotting and Pregnancy

    Medline Plus

    Full Text Available ... For Patients Blood Disorders Blood Clots Blood Clotting & Pregnancy If you are pregnant, or you have just ... The risk of developing a blood clot during pregnancy is increased by the following: Previous blood clots ...

  16. Blood Count Tests

    Science.gov (United States)

    Your blood contains red blood cells (RBC), white blood cells (WBC), and platelets. Blood count tests measure the number and types of cells in your blood. This helps doctors check on your overall health. ...

  17. Blood pressure measurement

    Science.gov (United States)

    Diastolic blood pressure; Systolic blood pressure; Blood pressure reading; Measuring blood pressure ... or your health care provider will wrap the blood pressure cuff snugly around your upper arm. The ...

  18. Blood Transfusions (For Teens)

    Science.gov (United States)

    ... How Can I Help a Friend Who Cuts? Blood Transfusions KidsHealth > For Teens > Blood Transfusions Print A ... United States get blood transfusions. A Bit About Blood As blood moves throughout the body, it carries ...

  19. High Blood Pressure (Hypertension)

    Science.gov (United States)

    ... your doctor prescribes it, medicine. What Is Blood Pressure? Blood pressure is the force of blood flow inside ... Will I Know if I Have High Blood Pressure? High blood pressure is a silent problem — you won't ...

  20. Blood Pressure Quiz

    Science.gov (United States)

    ... page please turn Javascript on. Feature: High Blood Pressure Blood Pressure Quiz Past Issues / Fall 2011 Table of Contents ... About High Blood Pressure / Treatment: Types of Blood Pressure Medications / Blood Pressure Quiz Fall 2011 Issue: Volume 6 Number ...

  1. Hypertension (High Blood Pressure)

    Science.gov (United States)

    ... right away. continue How Do Doctors Measure Blood Pressure? Blood pressure readings are fast and painless. Blood pressure ... same age, height, and gender have lower blood pressure. Blood pressure between 90% and 95% of the normal ...

  2. The de novo formation of a vascular network, in warm-blooded embryos, occurs via a self-assembly process that spans multiple length and time scales

    Science.gov (United States)

    Little, Charles D.

    2007-03-01

    Taking advantage of wide-field, time-lapse microscopy we examined the assembly of vascular polygonal networks in whole bird embryos and in explanted embryonic mouse tissue (allantois). Primary vasculogenesis assembly steps range from cellular (1-10 μm) to tissue (100μm-1mm) level events: Individual vascular endothelial cells extend protrusions and move with respect to the extracellular matrix/surrounding tissue. Consequently, long-range, tissue-level, deformations directly influence the vascular pattern. Experimental perturbation of endothelial-specific cell-cell adhesions (VE-cadherin), during mouse vasculogenesis, permitted dissection of the cellular motion required for sprout formation. In particular, cells are shown to move actively onto vascular cords that are subject to strain via tissue deformations. Based on the empirical data we propose a simple model of preferential migration along stretched cells. Numerical simulations reveal that the model evolves into a quasi-stationary pattern containing linear segments, which interconnect above a critical volume fraction. In the quasi-stationary state the generation of new branches offsets the coarsening driven by surface tension. In agreement with empirical data, the characteristic size of the resulting polygonal pattern is density-independent within a wide range of volume fractions. These data underscore the potential of combining physical studies with experimental embryology as a means of studying complex morphogenetic systems. In collaboration with Brenda J. Rongish^1, Andr'as Czir'ok^1,2, Erica D. Perryn^1, Cheng Cui^1, and Evan A. Zamir^1 ^1Department of Anatomy and Cell Biology, the University of Kansas Medical Center, Kansas City, KS ^2Department of Biological Physics, E"otv"os Lor'and University, Budapest, Hungary.

  3. Electroencephalography reveals lower regional blood perfusion and atrophy of the temporoparietal network associated with memory deficits and hippocampal volume reduction in mild cognitive impairment due to Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Moretti DV

    2015-02-01

    Full Text Available Davide Vito MorettiNational Institute for the research and cure of Alzheimer’s disease, S. John of God, Fatebenefratelli, Brescia, Italy Background: An increased electroencephalographic (EEG upper/lower alpha power ratio has been associated with less regional blood perfusion, atrophy of the temporoparietal region of the brain, and reduction of hippocampal volume in subjects affected by mild cognitive impairment due to Alzheimer’s disease as compared with subjects who do not develop the disease. Moreover, EEG theta frequency activity is quite different in these groups. This study investigated the correlation between biomarkers and memory performance.Methods: EEG α3/α2 power ratio and cortical thickness were computed in 74 adult subjects with prodromal Alzheimer’s disease. Twenty of these subjects also underwent assessment of blood perfusion by single-photon emission computed tomography (SPECT. Pearson’s r was used to assess the correlation between cortical thinning, brain perfusion, and memory impairment.Results: In the higher α3/α2 frequency power ratio group, greater cortical atrophy and lower regional perfusion in the temporoparietal cortex was correlated with an increase in EEG theta frequency. Memory impairment was more pronounced in the magnetic resonance imaging group and SPECT groups.Conclusion: A high EEG upper/low alpha power ratio was associated with cortical thinning and less perfusion in the temporoparietal area. Moreover, atrophy and less regional perfusion were significantly correlated with memory impairment in subjects with prodromal Alzheimer’s disease. The EEG upper/lower alpha frequency power ratio could be useful for identifying individuals at risk for progression to Alzheimer’s dementia and may be of value in the clinical context.Keywords: electroencephalography, perfusion, atrophy, temporoparietal network, memory deficits, hippocampal volume, mild cognitive impairment, Alzheimer’s disease

  4. Transcription Dynamics in Living Cells.

    Science.gov (United States)

    Lenstra, Tineke L; Rodriguez, Joseph; Chen, Huimin; Larson, Daniel R

    2016-07-01

    The transcription cycle can be roughly divided into three stages: initiation, elongation, and termination. Understanding the molecular events that regulate all these stages requires a dynamic view of the underlying processes. The development of techniques to visualize and quantify transcription in single living cells has been essential in revealing the transcription kinetics. They have revealed that (a) transcription is heterogeneous between cells and (b) transcription can be discontinuous within a cell. In this review, we discuss the progress in our quantitative understanding of transcription dynamics in living cells, focusing on all parts of the transcription cycle. We present the techniques allowing for single-cell transcription measurements, review evidence from different organisms, and discuss how these experiments have broadened our mechanistic understanding of transcription regulation.

  5. 乳腺癌组织学分级下目标基因提取及转录调控网络构建%Aimed genes' extraction and construction of transcription regulatory network under different grading levels of breast cancer

    Institute of Scientific and Technical Information of China (English)

    孔薇; 李海燕; 牟晓阳; 杨旸

    2014-01-01

    目的乳腺癌类型和分级多样性导致其预后差别显著,探寻乳腺癌不同分级情况下的基因表达差异及调控关系能够为乳腺癌致病机制的发现提供重要依据。方法对不同分级下的乳腺癌基因表达数据利用快速独立成分分析( FastICA)方法提取特征基因,并结合人类蛋白质相互作用( PPI)数据选取目标基因。在此基础上,结合转录因子对靶基因调控的先验信息,利用网络成分分析( NCA)方法对与乳腺癌发病有密切关系的转录因子及其靶基因构建转录调控网络。结果筛选出的基因经过数据库验证与乳腺癌相关的占48.15%,构建的调控网络发现了多个转录因子及靶基因在不同分级情况下的活性变化趋势。结论 FastICA算法结合PPI数据提取目标基因的方法较为有效,通过NCA算法构建的转录调控网络为研究乳腺癌发生发展机制提供了新的方法。%Objective The diversities of breast cancer types and grading levels lead to distinct difference for breast cancer prognosis. Studying the gene difference expression and regulatory relationship among genes under different grading levels of breast cancer could provide an important basis for finding breast cancer pathogenesis. MethodsUsing fast independent component analysis ( FastICA ) method to extract feature genes of gene expression data of breast cancer, and then selected the aimed genes by combining with human protein-protein interaction data ( PPI) . On this basis, introducing prior information which described regulatory relationships about how transcription factors regulated their target genes, we continued to analize transcription factors and their target genes, which were closely associated with the incidence of breast cancer, by using network components analysis method ( NCA) , and then constructed a transcriptional regulatory network. Results Selected aimed gene which was closely associated with breast cancer is

  6. Effects of bovine viral diarrhea viruses in vitro on transcription of interferon-al- pha, beta, gamma mRNA in bovine peripheral blood mononuclear cells%牛病毒性腹泻病毒感染牛外周血单核细胞对IFN-α、β、γmRNA转录的影响

    Institute of Scientific and Technical Information of China (English)

    韩猛立; 黄新; 钟发刚

    2012-01-01

    The study was done to survery the interferon-alpha, beta and gamma mRNA transcription profiles of bovine viral diarrfea viruse(BVDV) infection,and to investigate the host-BVDV interaction. The clinically healthy Holstein cows tested negative for bovine viral diarrhea virus(BVDV) in peripheral blood mononuclear cells(PBMC) were in- fected with noncytopathic(NCP) and cytopathic(NCP) BVDV. The mRNA levels of IFN-α,β and γ genes were ana lyzed using a reaPtime fluorescent quantitative PCR(reaPtime FQ-PCR). The results indicated that the transcription of I type(IFN-α,β) mRNA showed a different increasing levels (P〈0.01) ,after infected CP- and NCP BVDV in PBMC;only IFN-α decreased at 4,12 h(P〈0. 05) after infected CP-BVDV. And IFN-γ was increased throughout the infection process of CP and NCP BVDV in PBMC (P〈0. 05). The transcription levels of IFN mRNA were in- creased when two biotype of BVDV infected in PBMC.%为了解牛病毒性腹泻病毒(BVDV)感染对干扰素(IFN)mRNA转录时相的影响,探讨宿主-病毒之间的相互关系,用非致细胞病变(noncytopathic,NCP)和致细胞病变(cytopathic,CP)型BVDV感染临床健康BVDV检测阴性的荷斯坦奶牛外周血单核细胞(PBMC),利用实时荧光定量PCR技术对感染后IFN-α、β、γmRNA转录水平的变化进行定量分析。结果表明,CP型和NCP型BVDV感染PBMC后,Ⅰ型IFN(IFN-α、β)均呈现出不同程度的转录水平上调,且差异极显著(P〈0.01);只有IFN-α在CP型BVDV感染后4,12h(P〈0.5)出现转录下调。IFN-γ在整个感染过程中均呈现出不同程度的转录水平上调,且差异显著(P〈0.05)。这表明2种生物型BVDV感染可引起PBMC中IFN mRNA转录水平升高。

  7. Directed network modules

    International Nuclear Information System (INIS)

    A search technique locating network modules, i.e. internally densely connected groups of nodes in directed networks is introduced by extending the clique percolation method originally proposed for undirected networks. After giving a suitable definition for directed modules we investigate their percolation transition in the Erdos-Renyi graph both analytically and numerically. We also analyse four real-world directed networks, including Google's own web-pages, an email network, a word association graph and the transcriptional regulatory network of the yeast Saccharomyces cerevisiae. The obtained directed modules are validated by additional information available for the nodes. We find that directed modules of real-world graphs inherently overlap and the investigated networks can be classified into two major groups in terms of the overlaps between the modules. Accordingly, in the word-association network and Google's web-pages, overlaps are likely to contain in-hubs, whereas the modules in the email and transcriptional regulatory network tend to overlap via out-hubs

  8. Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets.

    Science.gov (United States)

    Fazlollahi, Mina; Muroff, Ivor; Lee, Eunjee; Causton, Helen C; Bussemaker, Harmen J

    2016-03-29

    Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

  9. Single-cell analyses of regulatory network perturbations using enhancer-targeting TALEs suggest novel roles for PU.1 during haematopoietic specification.

    Science.gov (United States)

    Wilkinson, Adam C; Kawata, Viviane K S; Schütte, Judith; Gao, Xuefei; Antoniou, Stella; Baumann, Claudia; Woodhouse, Steven; Hannah, Rebecca; Tanaka, Yosuke; Swiers, Gemma; Moignard, Victoria; Fisher, Jasmin; Hidetoshi, Shimauchi; Tijssen, Marloes R; de Bruijn, Marella F T R; Liu, Pentao; Göttgens, Berthold

    2014-10-01

    Transcription factors (TFs) act within wider regulatory networks to control cell identity and fate. Numerous TFs, including Scl (Tal1) and PU.1 (Spi1), are known regulators of developmental and adult haematopoiesis, but how they act within wider TF networks is still poorly understood. Transcription activator-like effectors (TALEs) are a novel class of genetic tool based on the modular DNA-binding domains of Xanthomonas TAL proteins, which enable DNA sequence-specific targeting and the manipulation of endogenous gene expression. Here, we report TALEs engineered to target the PU.1-14kb and Scl+40kb transcriptional enhancers as efficient new tools to perturb the expression of these key haematopoietic TFs. We confirmed the efficiency of these TALEs at the single-cell level using high-throughput RT-qPCR, which also allowed us to assess the consequences of both PU.1 activation and repression on wider TF networks during developmental haematopoiesis. Combined with comprehensive cellular assays, these experiments uncovered novel roles for PU.1 during early haematopoietic specification. Finally, transgenic mouse studies confirmed that the PU.1-14kb element is active at sites of definitive haematopoiesis in vivo and PU.1 is detectable in haemogenic endothelium and early committing blood cells. We therefore establish TALEs as powerful new tools to study the functionality of transcriptional networks that control developmental processes such as early haematopoiesis.

  10. 血细胞形态双语教学网络资源库的建立与应用%Construction and application of network bilingual teaching resource database of blood cell morphology

    Institute of Scientific and Technical Information of China (English)

    王忠英; 邓小燕; 嘉红云; 林桢; 黄式文; 吴晓蔓

    2011-01-01

    Morphological examination of blood cells is an important part of the hematology examination course. In order to enrich teaching resources, network of bilingual education resource was established and put into application by the Department of Hematology in Guangzhou Medical College. The repository improved teaching quality of cell morphology, and played a role in training personnel of hematology examination with solid basic skills.%血细胞形态学检验是血液学检验课程的重要内容。为了丰富血细胞形态学教学资源,广州医学院血液学检验教研室建立了血细胞形态双语教学网络资源库,并投入应用。该资源库提高了细胞形态教学质量,为培养具有扎实基本功的血液学检验人才发挥了应有的作用。

  11. SNFing HIV transcription

    Directory of Open Access Journals (Sweden)

    Bukrinsky Michael

    2006-08-01

    Full Text Available Abstract The SWI/SNF chromatin remodeling complex is an essential regulator of transcription of cellular genes. HIV-1 infection induces exit of a core component of SWI/SNF, Ini1, into the cytoplasm and its association with the viral pre-integration complex. Several recent papers published in EMBO Journal, Journal of Biological Chemistry, and Retrovirology provide new information regarding possible functions of Ini1 and SWI/SNF in HIV life cycle. It appears that Ini1 has an inhibitory effect on pre-integration steps of HIV replication, but also contributes to stimulation of Tat-mediated transcription. This stimulation involves displacement of the nucleosome positioned at the HIV promoter.

  12. The post-transcriptional operon

    DEFF Research Database (Denmark)

    Tenenbaum, Scott A.; Christiansen, Jan; Nielsen, Henrik

    2011-01-01

    A post-transcriptional operon is a set of monocistronic mRNAs encoding functionally related proteins that are co-regulated by a group of RNA-binding proteins and/or small non-coding RNAs so that protein expression is coordinated at the post-transcriptional level. The post-transcriptional operon m...

  13. A Genome-Scale Resource for the Functional Characterization of Arabidopsis Transcription Factors

    Directory of Open Access Journals (Sweden)

    Jose L. Pruneda-Paz

    2014-07-01

    Full Text Available Extensive transcriptional networks play major roles in cellular and organismal functions. Transcript levels are in part determined by the combinatorial and overlapping functions of multiple transcription factors (TFs bound to gene promoters. Thus, TF-promoter interactions provide the basic molecular wiring of transcriptional regulatory networks. In plants, discovery of the functional roles of TFs is limited by an increased complexity of network circuitry due to a significant expansion of TF families. Here, we present the construction of a comprehensive collection of Arabidopsis TFs clones created to provide a versatile resource for uncovering TF biological functions. We leveraged this collection by implementing a high-throughput DNA binding assay and identified direct regulators of a key clock gene (CCA1 that provide molecular links between different signaling modules and the circadian clock. The resources introduced in this work will significantly contribute to a better understanding of the transcriptional regulatory landscape of plant genomes.

  14. Classical swine fever virus detection: results of a real-time reverse transcription polymerase chain reaction ring trial conducted in the framework of the European network of excellence for epizootic disease diagnosis and control

    DEFF Research Database (Denmark)

    Hoffmann, Bernd; Blome, Sandra; Bonilauri, Paolo;

    2011-01-01

    The current study reports on a real-time reverse transcription polymerase chain reaction (real-time RT-PCR) ring trial for the detection of Classical swine fever virus (CSFV) genomic RNA undertaken by 10 European laboratories. All laboratories were asked to use their routine in-house real-time RT-PCR...... and specificity values. Nevertheless, some in-house systems had unspecific reactions or suboptimal sensitivity with only a single CSFV genotype. Follow-up actions involved either improvement of suboptimal assays or replacement of specific laboratory assays with the FLI protocol, with or without modifications....... In conclusion, the ring trial showed reliability of classical swine fever diagnosis on an international level and helped to optimize CSFV-specific RT-PCR diagnostics....

  15. Ubiquitin and proteasomes in transcription.

    Science.gov (United States)

    Geng, Fuqiang; Wenzel, Sabine; Tansey, William P

    2012-01-01

    Regulation of gene transcription is vitally important for the maintenance of normal cellular homeostasis. Failure to correctly regulate gene expression, or to deal with problems that arise during the transcription process, can lead to cellular catastrophe and disease. One of the ways cells cope with the challenges of transcription is by making extensive use of the proteolytic and nonproteolytic activities of the ubiquitin-proteasome system (UPS). Here, we review recent evidence showing deep mechanistic connections between the transcription and ubiquitin-proteasome systems. Our goal is to leave the reader with a sense that just about every step in transcription-from transcription initiation through to export of mRNA from the nucleus-is influenced by the UPS and that all major arms of the system--from the first step in ubiquitin (Ub) conjugation through to the proteasome-are recruited into transcriptional processes to provide regulation, directionality, and deconstructive power. PMID:22404630

  16. Eliminating Cancer Stem Cells in CML with Combination Transcriptional Therapy.

    Science.gov (United States)

    Carvajal, Luis A; Steidl, Ulrich

    2016-07-01

    Leukemia stem cells (LSCs) are resistant to current therapies used to treat chronic myeloid leukemia (CML). Abraham et al. (2016) have identified a molecular network critical for CML LSC survival and propose that simultaneously targeting two of their major transcriptional regulators, p53 and c-Myc, may facilitate their eradication. PMID:27392220

  17. Transcription Factors Exhibit Differential Conservation in Bacteria with Reduced Genomes.

    Science.gov (United States)

    Galán-Vásquez, Edgardo; Sánchez-Osorio, Ismael; Martínez-Antonio, Agustino

    2016-01-01

    The description of transcriptional regulatory networks has been pivotal in the understanding of operating principles under which organisms respond and adapt to varying conditions. While the study of the topology and dynamics of these networks has been the subject of considerable work, the investigation of the evolution of their topology, as a result of the adaptation of organisms to different environmental conditions, has received little attention. In this work, we study the evolution of transcriptional regulatory networks in bacteria from a genome reduction perspective, which manifests itself as the loss of genes at different degrees. We used the transcriptional regulatory network of Escherichia coli as a reference to compare 113 smaller, phylogenetically-related γ-proteobacteria, including 19 genomes of symbionts. We found that the type of regulatory action exerted by transcription factors, as genomes get progressively smaller, correlates well with their degree of conservation, with dual regulators being more conserved than repressors and activators in conditions of extreme reduction. In addition, we found that the preponderant conservation of dual regulators might be due to their role as both global regulators and nucleoid-associated proteins. We summarize our results in a conceptual model of how each TF type is gradually lost as genomes become smaller and give a rationale for the order in which this phenomenon occurs.

  18. Transcription Factors Exhibit Differential Conservation in Bacteria with Reduced Genomes.

    Directory of Open Access Journals (Sweden)

    Edgardo Galán-Vásquez

    Full Text Available The description of transcriptional regulatory networks has been pivotal in the understanding of operating principles under which organisms respond and adapt to varying conditions. While the study of the topology and dynamics of these networks has been the subject of considerable work, the investigation of the evolution of their topology, as a result of the adaptation of organisms to different environmental conditions, has received little attention. In this work, we study the evolution of transcriptional regulatory networks in bacteria from a genome reduction perspective, which manifests itself as the loss of genes at different degrees. We used the transcriptional regulatory network of Escherichia coli as a reference to compare 113 smaller, phylogenetically-related γ-proteobacteria, including 19 genomes of symbionts. We found that the type of regulatory action exerted by transcription factors, as genomes get progressively smaller, correlates well with their degree of conservation, with dual regulators being more conserved than repressors and activators in conditions of extreme reduction. In addition, we found that the preponderant conservation of dual regulators might be due to their role as both global regulators and nucleoid-associated proteins. We summarize our results in a conceptual model of how each TF type is gradually lost as genomes become smaller and give a rationale for the order in which this phenomenon occurs.

  19. Transcription Factors Exhibit Differential Conservation in Bacteria with Reduced Genomes.

    Science.gov (United States)

    Galán-Vásquez, Edgardo; Sánchez-Osorio, Ismael; Martínez-Antonio, Agustino

    2016-01-01

    The description of transcriptional regulatory networks has been pivotal in the understanding of operating principles under which organisms respond and adapt to varying conditions. While the study of the topology and dynamics of these networks has been the subject of considerable work, the investigation of the evolution of their topology, as a result of the adaptation of organisms to different environmental conditions, has received little attention. In this work, we study the evolution of transcriptional regulatory networks in bacteria from a genome reduction perspective, which manifests itself as the loss of genes at different degrees. We used the transcriptional regulatory network of Escherichia coli as a reference to compare 113 smaller, phylogenetically-related γ-proteobacteria, including 19 genomes of symbionts. We found that the type of regulatory action exerted by transcription factors, as genomes get progressively smaller, correlates well with their degree of conservation, with dual regulators being more conserved than repressors and activators in conditions of extreme reduction. In addition, we found that the preponderant conservation of dual regulators might be due to their role as both global regulators and nucleoid-associated proteins. We summarize our results in a conceptual model of how each TF type is gradually lost as genomes become smaller and give a rationale for the order in which this phenomenon occurs. PMID:26766575

  20. Non-equilibrium hyperbolic transport in transcriptional regulation.

    Directory of Open Access Journals (Sweden)

    Enrique Hernández-Lemus

    Full Text Available In this work we studied memory and irreversible transport phenomena in a non-equilibrium thermodynamical model for genomic transcriptional regulation. Transcriptional regulation possess an extremely complex phenomenology, and it is, of course, of foremost importance in organismal cell development and in the pathogenesis of complex diseases. A better understanding of the way in which these processes occur is mandatory to optimize the construction of gene regulatory networks, but also to connect these networks with multi-scale phenomena (e.g. metabolism, signalling pathways, etc. under an integrative Systems Biology-like vision. In this paper we analyzed three simple mechanisms of genetic stimulation: an instant pulse, a periodic biochemical signal and a saturation process with sigmoidal kinetics and from these we derived the system's thermodynamical response, in the form of, for example, anomalous transcriptional bursts.

  1. Blood Clotting and Pregnancy

    Medline Plus

    Full Text Available ... 6, 2016, San Diego, CA Abstracts Registration Housing Travel Information Government Concierge View all meetings Publications Blood ... Blood Clots Blood Clotting and Pregnancy Clots and Travel DVT Myths vs. Facts Blood Detectives Find a ...

  2. Where to Donate Blood

    Science.gov (United States)

    ... zip code using the Blood Bank Locator below: Blood Bank Locator City: State/Province: ZIP Code: Country: Show ... safety and care. The Association sets standards for blood banks and transfusion services, and accredits member blood banks ...

  3. High blood pressure

    Science.gov (United States)

    ... you are at risk for: Bleeding from the aorta, the large blood vessel that supplies blood to ... tests Blood pressure check Blood pressure References American Diabetes Association. Standards of medical care in diabetes-2015 ...

  4. Lead levels - blood

    Science.gov (United States)

    Blood lead levels ... A blood sample is needed. Most of the time blood is drawn from a vein located on the inside ... may be used to puncture the skin. The blood collects in a small glass tube called a ...

  5. Types of Blood Donations

    Science.gov (United States)

    ... Double Red Cell Plasma Platelets Red Cells What blood donation type is best for me? **If you do not ... blood type, a whole blood donation is recommended** Blood Donation Types: Volunteer Donations The standard or most common type ...

  6. Blood Type Game

    Science.gov (United States)

    ... Donor Community > Games > Blood Type Game Printable Version Blood Type Game This feature requires version 6 or later ... many points as possible by matching the appropriate blood type of a donor to the blood type of ...

  7. Blood Transfusion and Donation

    Science.gov (United States)

    ... in the United States receive life-saving blood transfusions. During a transfusion, you receive whole blood or parts of blood ... liver failure or a severe infection. Most blood transfusions go very smoothly. Some infectious agents, such as ...

  8. Blood Transfusion (For Parents)

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Blood Transfusions KidsHealth > For Parents > Blood Transfusions Print A ... and help put your child at ease. About Blood Transfusions Blood is like the body's transportation system. ...

  9. Understanding Blood Pressure Readings

    Science.gov (United States)

    ... What is the AHA recommendation for healthy blood pressure? This blood pressure chart reflects categories defined by the American ... unusually low blood pressure readings. How is high blood pressure diagnosed? Your healthcare providers will want to get ...

  10. Blood Clotting and Pregnancy

    Medline Plus

    Full Text Available ... Housing Travel Information Government Concierge View all meetings Publications Blood Current Issue First Edition Abstracts Blood Advances ... reflect the most recent scientific research View all publications For Patients Blood Basics Blood Disorders Anemia Bleeding ...

  11. A Framework for a Smart Social Blood Donation System Based on Mobile Cloud Computing

    OpenAIRE

    Mostafa, Almetwally M.; Youssef, Ahmed E.; Alshorbagy, Gamal

    2014-01-01

    Blood Donation and Blood Transfusion Services (BTS) are crucial for saving people lives. Recently, worldwide efforts have been undertaken to utilize social media and smartphone applications to make the blood donation process more convenient, offer additional services, and create communities around blood donation centers. Blood banks suffer frequent shortage of blood; hence, advertisements are frequently seen on social networks urging healthy individuals to donate blood for patients who urgent...

  12. The impact of statins for the network between blood coagulation and inflammation in sepsis%他汀类调脂药物对脓毒症凝血-炎症网络的影响

    Institute of Scientific and Technical Information of China (English)

    黎永琳; 周红

    2014-01-01

    Sepsis is a systemic inflammatory response syndrome by infection , which can develop into severe sepsis or sepsis shock.The case fatality rate is still 30%~70%, although with the evolutive anti-inflective therapy and multi-organ support therapy.It was found that lipid metabolism was chaotic in sepsis in some recent studies. Stains are known for reducing blood lipid and improving the atherosclerosis, but they are also noted by improving inflammation, coagulation,endothelial function and so on in sepsis.This paper will introduce the impact of statins for the network between blood coagulation and inflammation in sepsis.%目的脓毒症是由于感染引起的全身系统性炎症反应,可发展为严重脓毒症和感染性休克。尽管抗感染治疗和器官功能支持技术取得了长足的进步,脓毒症的病死率仍高达30%~70%。近年来的研究表明,脓毒症发生时,脂质代谢同样发生紊乱。他汀类药物因为其能有效地降低血脂,改善动脉粥样硬化情况而被大家所认识。随着对该药物的进一步研究发现,他汀类药物降脂以外的作用越来越受到重视,如改善内皮功能、抑制血管炎症、改善凝血功能、减少血栓形成和改善总体血管功能等。本文就目前他汀类药物治疗脓毒症时抗炎、抗凝影响的研究做一简述。

  13. Deciphering Transcriptional Regulation

    DEFF Research Database (Denmark)

    Valen, Eivind

    in different cell types. This thesis presents several methods for analysis and description of promoters. We focus particularly the binding sites of TFs and computational methods for locating these. We contribute to the ¿eld by compiling a database of binding preferences for TFs which can be used for site...... published providing an unbiased overview of the transcription start site (TSS) usage in a tissue. We have paired this method with high-throughput sequencing technology to produce a library of unprecedented depth (DeepCAGE) for the mouse hippocampus. We investigated this in detail and focused particularly...

  14. MORPHEUS, a webtool for transcription factor binding analysis using position weight matrices with dependency

    OpenAIRE

    Eugenio Gómez Minguet; Stéphane Segard; Céline Charavay; François Parcy

    2015-01-01

    Transcriptional networks are central to any biological process and changes affecting transcription factors or their binding sites in the genome are a key factor driving evolution. As more organisms are being sequenced, tools are needed to easily predict transcription factor binding sites (TFBS) presence and affinity from mere inspection of genomic sequences. Although many TFBS discovery algorithms exist, tools for using the DNA binding models they generate are relatively scarce and their use ...

  15. Transcriptional responses and regulations to deficient phosphorus in plants

    Institute of Scientific and Technical Information of China (English)

    Jinxiang BAO; Shuhua ZHANG; Wenjing LU; Chengjin GUO; Juntao GU; Kai XIAO

    2009-01-01

    Significant progress has been made over the past several years in the understanding of phosphorus (Pi)-starvation responses in plants and their regulation. The transcriptional changes that occur in response to Pi starvation are beginning to be revealed, although much is left to understand about their significance. In this paper, the recent progresses on the gene expression changes under deficient-Pi, cis-regulatory elements involved in response to deficient-Pi, the transcriptional control of Pi-starvation responses in eukaryotes, transcription factors involved in response to Pi-starvation, the role of MicroRNA on regulation of phosphate homeostasis, and phosphate sensing and signal transduction in plants have been summarized. The purpose of this review is to provide some basis for further elucidation of the transcriptional responses and regulations, and the networks of Pi sensing and signal transduction under deficient-Pi in plants in the future.

  16. Types of Blood Transfusions

    Science.gov (United States)

    ... Home » Health Information for the Public » Health Topics » Blood Transfusion » Types of Blood Transfusions Explore Blood Transfusion What Is... ... Share this page from the NHLBI on Twitter. Types of Blood Transfusions Blood is transfused either as whole blood ( ...

  17. Cord blood testing

    Science.gov (United States)

    ... to evaluate the oxygen, carbon dioxide, and pH levels) Blood sugar level Blood type and Rh Complete blood count ( ... means you have a blood infection (septicemia). High levels of blood sugar (glucose) in the cord blood may be found ...

  18. Leukocyte transcript alterations in West-African girls following a booster vaccination with diphtheria-tetanus-pertussis vaccine

    DEFF Research Database (Denmark)

    Orntoft, Nikolaj W; Thorsen, Kasper; Benn, Christine S;

    2013-01-01

    Background. Observational studies from low-income countries have shown that the vaccination against diphtheria, tetanus and pertussis (DTP) is associated with excess female mortality due to infectious diseases. Methods. To investigate possible changes in gene expression after DTP vaccination, we...... identified a group of nine comparable West African girls, from a biobank of 356 children, who were due to receive DTP booster vaccine at age 18 months. As a pilot experiment we extracted RNA from blood samples before, and 6 weeks after, vaccination to analyze the coding transcriptome in leukocytes using...... expression microarrays, and ended up with information from eight girls. The data was further analyzed using dedicated array pathway and network software. We aimed to study whether DTP vaccination introduced a systematic alteration in the immune system in girls. Results. We found very few transcripts to alter...

  19. An Improved Systematic Approach to Predicting Transcription Factor Target Genes Using Support Vector Machine

    OpenAIRE

    Song Cui; Eunseog Youn; Joohyun Lee; Maas, Stephan J.

    2014-01-01

    Biological prediction of transcription factor binding sites and their corresponding transcription factor target genes (TFTGs) makes great contribution to understanding the gene regulatory networks. However, these approaches are based on laborious and time-consuming biological experiments. Numerous computational approaches have shown great potential to circumvent laborious biological methods. However, the majority of these algorithms provide limited performances and fail to consider the struct...

  20. eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci

    DEFF Research Database (Denmark)

    Mousavi, Kambiz; Zare, Hossein; Dell'orso, Stefania;

    2013-01-01

    Transcription factors and DNA regulatory binding motifs are fundamental components of the gene regulatory network. Here, by using genome-wide binding profiling, we show extensive occupancy of transcription factors of myogenesis (MyoD and Myogenin) at extragenic enhancer regions coinciding with RNA...

  1. Application of follow-up service network platform In blood glucose management of diabetics%网络平台随访服务模式在糖尿病患者血糖管理中的应用

    Institute of Scientific and Technical Information of China (English)

    王秀丽; 李萍; 侯铭

    2012-01-01

    Objective To investigate the implementation of health management of diabetics through follow-up service network platform,and analyze the effect of this model on blood glucose level and behavior of diabetics.Methods 114 cases of diabetics were divided into two groups by random number table method:the control group ( n =56),which received traditional follow-up service,and the experimental group ( n =58 ),which received follow-up services through network platform.Before the intervention and 3 months after the intervention,the two groups were evaluated by diabetics-specific quality of life scale,diabetes knowledge questionnaire and self-management questionnaire.Biochemical parameters of the patients were also observed,including fasting blood glucose (FPG),2h postprandial blood glucose (PG2h) and glycosylated hemoglobin (HbA1c).Results Before the intervention there were no significant differences between the two groups in terms of the blood glucose,lipid metabolism and scores of specific quality of life (P > 0.05).After 3 months,the scores of the experimental group in three latitudes of specific quality of life,namely psychological latitude ( - 1.34 ± 2.128 ),social latitude ( - 2.38 ± 1.554 ),treatment latitude (2.86 ± 1.701 ),were all lower than the scores of the control group [ ( - 2.11 + 1.765 ),( - 1.46 + 1.078 ),( 2.09±1.431 ),respectively ].The differences were statistically significant (t =-3.233,-3.663,2.621,respectively,P <0.05 ).The biochemical parameters of the experimental group,namely level of FPG [ (6.8 ± 2.0) mmol/L],PG2h [ ( 10.0 ±3.1 ) mmol/L]and HbA1c [(6.9± 1.2)%] all decreased compared with the control group [(8.7 ±3.1)mmol/L,(12.6 ±4.9)mmol/L,(7.9 t2.6)% ; respectively],and the differences were statistically significant (t =-2.56,-3.67,- 3.17,respectively; P < 0.05 ).Average cognitive score ( 6.50 ± 5.083 ) and behavior score ( - 2.05 ± 1.932 )of the experimental group were higher than those of the control group [ ( 4.62 ± 3

  2. Transcription initiation complex structures elucidate DNA opening.

    Science.gov (United States)

    Plaschka, C; Hantsche, M; Dienemann, C; Burzinski, C; Plitzko, J; Cramer, P

    2016-05-19

    Transcription of eukaryotic protein-coding genes begins with assembly of the RNA polymerase (Pol) II initiation complex and promoter DNA opening. Here we report cryo-electron microscopy (cryo-EM) structures of yeast initiation complexes containing closed and open DNA at resolutions of 8.8 Å and 3.6 Å, respectively. DNA is positioned and retained over the Pol II cleft by a network of interactions between the TATA-box-binding protein TBP and transcription factors TFIIA, TFIIB, TFIIE, and TFIIF. DNA opening occurs around the tip of the Pol II clamp and the TFIIE 'extended winged helix' domain, and can occur in the absence of TFIIH. Loading of the DNA template strand into the active centre may be facilitated by movements of obstructing protein elements triggered by allosteric binding of the TFIIE 'E-ribbon' domain. The results suggest a unified model for transcription initiation with a key event, the trapping of open promoter DNA by extended protein-protein and protein-DNA contacts.

  3. Adaptive evolution of transcription factor binding sites

    Directory of Open Access Journals (Sweden)

    Berg Johannes

    2004-10-01

    Full Text Available Abstract Background The regulation of a gene depends on the binding of transcription factors to specific sites located in the regulatory region of the gene. The generation of these binding sites and of cooperativity between them are essential building blocks in the evolution of complex regulatory networks. We study a theoretical model for the sequence evolution of binding sites by point mutations. The approach is based on biophysical models for the binding of transcription factors to DNA. Hence we derive empirically grounded fitness landscapes, which enter a population genetics model including mutations, genetic drift, and selection. Results We show that the selection for factor binding generically leads to specific correlations between nucleotide frequencies at different positions of a binding site. We demonstrate the possibility of rapid adaptive evolution generating a new binding site for a given transcription factor by point mutations. The evolutionary time required is estimated in terms of the neutral (background mutation rate, the selection coefficient, and the effective population size. Conclusions The efficiency of binding site formation is seen to depend on two joint conditions: the binding site motif must be short enough and the promoter region must be long enough. These constraints on promoter architecture are indeed seen in eukaryotic systems. Furthermore, we analyse the adaptive evolution of genetic switches and of signal integration through binding cooperativity between different sites. Experimental tests of this picture involving the statistics of polymorphisms and phylogenies of sites are discussed.

  4. Model-based redesign of global transcription regulation

    Science.gov (United States)

    Carrera, Javier; Rodrigo, Guillermo; Jaramillo, Alfonso

    2009-01-01

    Synthetic biology aims to the design or redesign of biological systems. In particular, one possible goal could be the rewiring of the transcription regulation network by exchanging the endogenous promoters. To achieve this objective, we have adapted current methods to the inference of a model based on ordinary differential equations that is able to predict the network response after a major change in its topology. Our procedure utilizes microarray data for training. We have experimentally validated our inferred global regulatory model in Escherichia coli by predicting transcriptomic profiles under new perturbations. We have also tested our methodology in silico by providing accurate predictions of the underlying networks from expression data generated with artificial genomes. In addition, we have shown the predictive power of our methodology by obtaining the gene profile in experimental redesigns of the E. coli genome, where rewiring the transcriptional network by means of knockouts of master regulators or by upregulating transcription factors controlled by different promoters. Our approach is compatible with most network inference methods, allowing to explore computationally future genome-wide redesign experiments in synthetic biology. PMID:19188257

  5. An Atlas of Combinatorial Transcriptional Regulation in Mouse and Man

    KAUST Repository

    Ravasi, Timothy

    2010-03-01

    Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.

  6. Nucleocytoplasmic shuttling of transcription factors

    DEFF Research Database (Denmark)

    Cartwright, P; Helin, K

    2000-01-01

    To elicit the transcriptional response following intra- or extracellular stimuli, the signals need to be transmitted to their site of action within the nucleus. The nucleocytoplasmic shuttling of transcription factors is a mechanism mediating this process. The activation and inactivation...... of the transcriptional response is essential for cells to progress through the cell cycle in a normal manner. The involvement of cytoplasmic and nuclear accessory molecules, and the general nuclear membrane transport components, are essential for this process. Although nuclear import and export for different...... transcription factor families are regulated by similar mechanisms, there are several differences that allow for the specific activation of each transcription factor. This review discusses the general import and export pathways found to be common amongst many different transcription factors, and highlights...

  7. Transcriptional Silencing of Retroviral Vectors

    DEFF Research Database (Denmark)

    Lund, Anders Henrik; Duch, M.; Pedersen, F.S.

    1996-01-01

    . Extinction of long-term vector expression has been observed after implantation of transduced hematopoietic cells as well as fibroblasts, myoblasts and hepatocytes. Here we review the influence of vector structure, integration site and cell type on transcriptional silencing. While down-regulation of proviral...... transcription is known from a number of cellular and animal models, major insight has been gained from studies in the germ line and embryonal cells of the mouse. Key elements for the transfer and expression of retroviral vectors, such as the viral transcriptional enhancer and the binding site for the t......RNA primer for reverse transcription may have a major influence on transcriptional silencing. Alterations of these elements of the vector backbone as well as the use of internal promoter elements from housekeeping genes may contribute to reduce transcriptional silencing. The use of cell culture and animal...

  8. Autologous blood donation

    OpenAIRE

    Goodnough, Lawrence T

    2004-01-01

    Although preoperative autologous blood donation is employed in elective surgery, this is declining because of the increasingly safe allogeneic blood supply. However, it continues to be used because of the public's perception of allogeneic blood risks and increasing blood shortages. Patients may donate a unit of blood (450 ± 45 ml) as often as twice weekly, up to 72 hours before surgery. Preoperative autologous blood is most beneficial in procedures that cause significant blood loss. It has be...

  9. Initiation of HIV Reverse Transcription

    Directory of Open Access Journals (Sweden)

    Roland Marquet

    2010-01-01

    Full Text Available Reverse transcription of retroviral genomes into double stranded DNA is a key event for viral replication. The very first stage of HIV reverse transcription, the initiation step, involves viral and cellular partners that are selectively packaged into the viral particle, leading to an RNA/protein complex with very specific structural and functional features, some of which being, in the case of HIV-1, linked to particular isolates. Recent understanding of the tight spatio-temporal regulation of reverse transcription and its importance for viral infectivity further points toward reverse transcription and potentially its initiation step as an important drug target.

  10. Superfamilies of Evolved and Designed Networks

    Science.gov (United States)

    Milo, Ron; Itzkovitz, Shalev; Kashtan, Nadav; Levitt, Reuven; Shen-Orr, Shai; Ayzenshtat, Inbal; Sheffer, Michal; Alon, Uri

    2004-03-01

    Complex biological, technological, and sociological networks can be of very different sizes and connectivities, making it difficult to compare their structures. Here we present an approach to systematically study similarity in the local structure of networks, based on the significance profile (SP) of small subgraphs in the network compared to randomized networks. We find several superfamilies of previously unrelated networks with very similar SPs. One superfamily, including transcription networks of microorganisms, represents ``rate-limited'' information-processing networks strongly constrained by the response time of their components. A distinct superfamily includes protein signaling, developmental genetic networks, and neuronal wiring. Additional superfamilies include power grids, protein-structure networks and geometric networks, World Wide Web links and social networks, and word-adjacency networks from different languages.

  11. Medications and Blood Pressure

    Science.gov (United States)

    ... Blood Pressure Tools & Resources Stroke More Medications and Blood Pressure Updated:Jul 6,2016 When your blood pressure ... was last reviewed on 08/04/2014. High Blood Pressure • Home • About High Blood Pressure (HBP) • Why HBP ...

  12. Longitudinal evaluation of leukocyte transcripts in killer whales (Orcinus Orca).

    Science.gov (United States)

    Sitt, Tatjana; Bowen, Lizabeth; Lee, Chia-Shan; Blanchard, Myra T; McBain, James; Dold, Christopher; Stott, Jeffrey L

    2016-07-01

    Early identification of illness and/or presence of environmental and/or social stressors in free-ranging and domestic cetaceans is a priority for marine mammal health care professionals. Incorporation of leukocyte gene transcript analysis into the diagnostic tool kit has the potential to augment classical diagnostics based upon ease of sample storage and shipment, inducible nature and well-defined roles of transcription and associated downstream actions. Development of biomarkers that could serve to identify "insults" and potentially differentiate disease etiology would be of great diagnostic value. To this end, a modest number of peripheral blood leukocyte gene transcripts were selected for application to a domestic killer whale population with a focus on broad representation of inducible immunologically relevant genes. Normalized leukocyte transcript values, longitudinally acquired from 232 blood samples derived from 26 clinically healthy whales, were not visibly influenced temporally nor by sex or the specific Park in which they resided. Stability in leukocyte transcript number during periods of health enhances their potential use in diagnostics through identification of outliers. Transcript levels of two cytokine genes, IL-4 and IL-17, were highly variable within the group as compared to the other transcripts. IL-4 transcripts were typically absent. Analysis of transcript levels on the other genes of interest, on an individual animal basis, identified more outliers than were visible when analyzed in the context of the entire population. The majority of outliers (9 samples) were low, though elevated transcripts were identified for IL-17 from 2 animals and one each for Cox-2 and IL-10. The low number of outliers was not unexpected as sample selection was intentionally directed towards animals that were clinically healthy at the time of collection. Outliers may reflect animals experiencing subclinical disease that is transient and self-limiting. The immunologic

  13. Longitudinal evaluation of leukocyte transcripts in killer whales (Orcinus Orca)

    Science.gov (United States)

    Sitt, Tatjana; Bowen, Lizabeth; Lee, Chia-Shan; Blanchard, Myra; McBain, James; Dold, Christopher; Stott, Jeffrey L.

    2016-01-01

    Early identification of illness and/or presence of environmental and/or social stressors in free-ranging and domestic cetaceans is a priority for marine mammal health care professionals. Incorporation of leukocyte gene transcript analysis into the diagnostic tool kit has the potential to augment classical diagnostics based upon ease of sample storage and shipment, inducible nature and well-defined roles of transcription and associated downstream actions. Development of biomarkers that could serve to identify “insults” and potentially differentiate disease etiology would be of great diagnostic value. To this end, a modest number of peripheral blood leukocyte gene transcripts were selected for application to a domestic killer whale population with a focus on broad representation of inducible immunologically relevant genes. Normalized leukocyte transcript values, longitudinally acquired from 232 blood samples derived from 26 clinically healthy whales, were not visibly influenced temporally nor by sex or the specific Park in which they resided. Stability in leukocyte transcript number during periods of health enhances their potential use in diagnostics through identification of outliers. Transcript levels of two cytokine genes, IL-4 and IL-17, were highly variable within the group as compared to the other transcripts. IL-4 transcripts were typically absent. Analysis of transcript levels on the other genes of interest, on an individual animal basis, identified more outliers than were visible when analyzed in the context of the entire population. The majority of outliers (9 samples) were low, though elevated transcripts were identified for IL-17 from 2 animals and one each for Cox-2 and IL-10. The low number of outliers was not unexpected as sample selection was intentionally directed towards animals that were clinically healthy at the time of collection. Outliers may reflect animals experiencing subclinical disease that is transient and self-limiting. The

  14. Peripheral blood RNA gene expression profiling in illicit methcathinone users reveals effect on immune system

    Directory of Open Access Journals (Sweden)

    Katrin eSikk

    2011-08-01

    Full Text Available Methcathinone (ephedrone is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese, or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We analyzed whole genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data was analyzed by Bayesian modelling and functional annotation. In order to verify the genechip results we performed quantitative real-time (RT PCR in selected genes. 326 out of analyzed 28,869 genes showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative RT-PCR confirmed differential expression for the most of selected genes. Functional annotation and network analysis indicated that most of the genes were related to activation immunological disease, cellular movement and cardiovascular disease gene network (enrichment score 42. As HIV and HCV infections were confounding factors, we performed additional stratification of patients. A similar functional activation of the immunological disease pathway was evident when we compared patients according to the injection status (past versus current users, balanced for HIV and HCV infection. However, this difference was not large therefore the major effect was related to the HIV status of the patients. Mn-methcathinone abusers have blood transcriptional patterns mostly caused by their HIV and HCV infections.

  15. Age gene expression and coexpression progressive signatures in peripheral blood leukocytes.

    Science.gov (United States)

    Irizar, Haritz; Goñi, Joaquín; Alzualde, Ainhoa; Castillo-Triviño, Tamara; Olascoaga, Javier; Lopez de Munain, Adolfo; Otaegui, David

    2015-12-01

    Both cellular senescence and organismic aging are known to be dynamic processes that start early in life and progress constantly during the whole life of the individual. In this work, with the objective of identifying signatures of age-related progressive change at the transcriptomic level, we have performed a whole-genome gene expression analysis of peripheral blood leukocytes in a group of healthy individuals with ages ranging from 14 to 93 years. A set of genes with progressively changing gene expression (either increase or decrease with age) has been identified and contextualized in a coexpression network. A modularity analysis has been performed on this network and biological-term and pathway enrichment analyses have been used for biological interpretation of each module. In summary, the results of the present work reveal the existence of a transcriptomic component that shows progressive expression changes associated to age in peripheral blood leukocytes, highlighting both the dynamic nature of the process and the need to complement young vs. elder studies with longitudinal studies that include middle aged individuals. From the transcriptional point of view, immunosenescence seems to be occurring from a relatively early age, at least from the late 20s/early 30s, and the 49-56 year old age-range appears to be critical. In general, the genes that, according to our results, show progressive expression changes with aging are involved in pathogenic/cellular processes that have classically been linked to aging in humans: cancer, immune processes and cellular growth vs. maintenance.

  16. Blood vessels, circulation and blood pressure.

    Science.gov (United States)

    Hendry, Charles; Farley, Alistair; McLafferty, Ella

    This article, which forms part of the life sciences series, describes the vessels of the body's blood and lymphatic circulatory systems. Blood pressure and its regulatory systems are examined. The causes and management of hypertension are also explored. It is important that nurses and other healthcare professionals understand the various mechanisms involved in the regulation of blood pressure to prevent high blood pressure or ameliorate its damaging consequences.

  17. Mutational robustness of gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Aalt D J van Dijk

    Full Text Available Mutational robustness of gene regulatory networks refers to their ability to generate constant biological output upon mutations that change network structure. Such networks contain regulatory interactions (transcription factor-target gene interactions but often also protein-protein interactions between transcription factors. Using computational modeling, we study factors that influence robustness and we infer several network properties governing it. These include the type of mutation, i.e. whether a regulatory interaction or a protein-protein interaction is mutated, and in the case of mutation of a regulatory interaction, the sign of the interaction (activating vs. repressive. In addition, we analyze the effect of combinations of mutations and we compare networks containing monomeric with those containing dimeric transcription factors. Our results are consistent with available data on biological networks, for example based on evolutionary conservation of network features. As a novel and remarkable property, we predict that networks are more robust against mutations in monomer than in dimer transcription factors, a prediction for which analysis of conservation of DNA binding residues in monomeric vs. dimeric transcription factors provides indirect evidence.

  18. A semi-supervised method for predicting transcription factor-gene interactions in Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Jason Ernst

    2008-03-01

    Full Text Available While Escherichia coli has one of the most comprehensive datasets of experimentally verified transcriptional regulatory interactions of any organism, it is still far from complete. This presents a problem when trying to combine gene expression and regulatory interactions to model transcriptional regulatory networks. Using the available regulatory interactions to predict new interactions may lead to better coverage and more accurate models. Here, we develop SEREND (SEmi-supervised REgulatory Network Discoverer, a semi-supervised learning method that uses a curated database of verified transcriptional factor-gene interactions, DNA sequence binding motifs, and a compendium of gene expression data in order to make thousands of new predictions about transcription factor-gene interactions, including whether the transcription factor activates or represses the gene. Using genome-wide binding datasets for several transcription factors, we demonstrate that our semi-supervised classification strategy improves the prediction of targets for a given transcription factor. To further demonstrate the utility of our inferred interactions, we generated a new microarray gene expression dataset for the aerobic to anaerobic shift response in E. coli. We used our inferred interactions with the verified interactions to reconstruct a dynamic regulatory network for this response. The network reconstructed when using our inferred interactions was better able to correctly identify known regulators and suggested additional activators and repressors as having important roles during the aerobic-anaerobic shift interface.

  19. Learning Networks, Networked Learning

    NARCIS (Netherlands)

    Sloep, Peter; Berlanga, Adriana

    2010-01-01

    Sloep, P. B., & Berlanga, A. J. (2011). Learning Networks, Networked Learning [Redes de Aprendizaje, Aprendizaje en Red]. Comunicar, XIX(37), 55-63. Retrieved from http://dx.doi.org/10.3916/C37-2011-02-05

  20. Learning Networks, Networked Learning

    NARCIS (Netherlands)

    Sloep, Peter

    2011-01-01

    Sloep, P. B. (2011). Learning Networks, Networked Learning. Presentation at Annual Assembly of the European Society for the Systemic Innovation of Education - ESSIE. May, 27, 2011, Leuven, Belgium: Open University in the Netherlands.

  1. Reduced-Intensity Conditioning with Fludarabine, Cyclophosphamide, and High-Dose Rituximab for Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma: A Phase Two Multicenter Trial from the Blood and Marrow Transplant Clinical Trials Network.

    Science.gov (United States)

    Laport, Ginna G; Wu, Juan; Logan, Brent; Bachanova, Veronika; Hosing, Chitra; Fenske, Timothy; Longo, Walter; Devine, Steven M; Nademanee, Auayporn; Gersten, Iris; Horowitz, Mary; Lazarus, Hillard M; Riches, Marcie L

    2016-08-01

    Allogeneic (allo) hematopoietic cell transplantation (HCT) can induce long-term remissions in chemosensitive relapsed follicular lymphoma (FL). The Blood and Marrow Transplant Clinical Trials Network conducted a multicenter phase 2 trial to examine the efficacy of alloHCT using reduced-intensity conditioning with rituximab (RTX) in multiply relapsed, chemosensitive FL. The primary endpoint was 2-year progression-free survival (PFS). The conditioning regimen consisted of fludarabine, cyclophosphamide, and high-dose RTX (FCR), in which 3 of the 4 doses of RTX were administered at a dose of 1 gm/m(2). Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus and methotrexate. Sixty-five patients were enrolled and 62 were evaluable. Median age was 55 years (range, 29 to 74). This group was heavily pretreated: 77% had received ≥ 3 prior regimens, 32% had received ≥ 5 prior regimens, and 11% had received prior autologous HCT. Donors were HLA-matched siblings (n = 33) or HLA-matched unrelated adults (n = 29). No graft failures occurred. The overall response rate after HCT was 94% with 90% in complete remission (CR), including 24 patients not in CR before alloHCT. With a median follow-up of 47 months (range, 30 to 73), 3-year PFS and overall survival rates were 71% (95% confidence interval, 58% to 81%) and 82% (95% confidence interval, 70% to 90%), respectively. Three-year cumulative incidences of relapse/progression and nonrelapse mortality were 13% and 16%, respectively. Two-year cumulative incidences of grades 2 to 4 and grades 3 or 4 acute GVHD were 27% and 10%, respectively, and extensive chronic GVHD incidence was 55%. Serum RTX concentrations peaked at day +28 and remained detectable as late as 1 year in 59% of patients with available data. In conclusion, alloHCT with FCR conditioning confers high CR rates, a low incidence of relapse/progression, and excellent survival probabilities in heavily pretreated FL patients. PMID:27118571

  2. Structural basis of transcription activation.

    Science.gov (United States)

    Feng, Yu; Zhang, Yu; Ebright, Richard H

    2016-06-10

    Class II transcription activators function by binding to a DNA site overlapping a core promoter and stimulating isomerization of an initial RNA polymerase (RNAP)-promoter closed complex into a catalytically competent RNAP-promoter open complex. Here, we report a 4.4 angstrom crystal structure of an intact bacterial class II transcription activation complex. The structure comprises Thermus thermophilus transcription activator protein TTHB099 (TAP) [homolog of Escherichia coli catabolite activator protein (CAP)], T. thermophilus RNAP σ(A) holoenzyme, a class II TAP-dependent promoter, and a ribotetranucleotide primer. The structure reveals the interactions between RNAP holoenzyme and DNA responsible for transcription initiation and reveals the interactions between TAP and RNAP holoenzyme responsible for transcription activation. The structure indicates that TAP stimulates isomerization through simple, adhesive, stabilizing protein-protein interactions with RNAP holoenzyme. PMID:27284196

  3. Regulatory hotspots in the malaria parasite genome dictate transcriptional variation.

    Directory of Open Access Journals (Sweden)

    Joseph M Gonzales

    2008-09-01

    Full Text Available The determinants of transcriptional regulation in malaria parasites remain elusive. The presence of a well-characterized gene expression cascade shared by different Plasmodium falciparum strains could imply that transcriptional regulation and its natural variation do not contribute significantly to the evolution of parasite drug resistance. To clarify the role of transcriptional variation as a source of stain-specific diversity in the most deadly malaria species and to find genetic loci that dictate variations in gene expression, we examined genome-wide expression level polymorphisms (ELPs in a genetic cross between phenotypically distinct parasite clones. Significant variation in gene expression is observed through direct co-hybridizations of RNA from different P. falciparum clones. Nearly 18% of genes were regulated by a significant expression quantitative trait locus. The genetic determinants of most of these ELPs resided in hotspots that are physically distant from their targets. The most prominent regulatory locus, influencing 269 transcripts, coincided with a Chromosome 5 amplification event carrying the drug resistance gene, pfmdr1, and 13 other genes. Drug selection pressure in the Dd2 parental clone lineage led not only to a copy number change in the pfmdr1 gene but also to an increased copy number of putative neighboring regulatory factors that, in turn, broadly influence the transcriptional network. Previously unrecognized transcriptional variation, controlled by polymorphic regulatory genes and possibly master regulators within large copy number variants, contributes to sweeping phenotypic evolution in drug-resistant malaria parasites.

  4. Transcriptional Regulation of the p16 Tumor Suppressor Gene.

    Science.gov (United States)

    Kotake, Yojiro; Naemura, Madoka; Murasaki, Chihiro; Inoue, Yasutoshi; Okamoto, Haruna

    2015-08-01

    The p16 tumor suppressor gene encodes a specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 and is found altered in a wide range of human cancers. p16 plays a pivotal role in tumor suppressor networks through inducing cellular senescence that acts as a barrier to cellular transformation by oncogenic signals. p16 protein is relatively stable and its expression is primary regulated by transcriptional control. Polycomb group (PcG) proteins associate with the p16 locus in a long non-coding RNA, ANRIL-dependent manner, leading to repression of p16 transcription. YB1, a transcription factor, also represses the p16 transcription through direct association with its promoter region. Conversely, the transcription factors Ets1/2 and histone H3K4 methyltransferase MLL1 directly bind to the p16 locus and mediate p16 induction during replicative and premature senescence. In the present review, we discuss the molecular mechanisms by which these factors regulate p16 transcription.

  5. High Blood Pressure

    Science.gov (United States)

    ... normal blood pressure 140/90 or higher is high blood pressure Between 120 and 139 for the top number, ... prehypertension. Prehypertension means you may end up with high blood pressure, unless you take steps to prevent it. High ...

  6. Low Blood Glucose (Hypoglycemia)

    Science.gov (United States)

    ... Other Dental Problems Diabetic Eye Disease Low Blood Glucose (Hypoglycemia) What is hypoglycemia? Hypoglycemia, also called low ... actions can also help prevent hypoglycemia: Check blood glucose levels Knowing your blood glucose level can help ...

  7. Blood Clotting and Pregnancy

    Science.gov (United States)

    ... The risk of developing a blood clot during pregnancy is increased by the following: Previous blood clots A genetic predisposition to blood clots Obesity Prolonged immobility (e.g., bedrest, long distance travel) Multiple ...

  8. CEA blood test

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    Carcinoembryonic antigen blood test ... A blood sample is needed . ... When the needle is inserted to draw blood, some people feel moderate pain. Others feel only a prick or stinging sensation. Afterward, there may be some throbbing or a slight bruise. ...

  9. Ketones blood test

    Science.gov (United States)

    ... Ketones - serum; Nitroprusside test; Ketone bodies - serum; Ketones - blood ... A blood sample is needed. ... When the needle is inserted to draw blood, some people feel slight ... there may be some throbbing or a slight bruise. This soon ...

  10. Magnesium blood test

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    Magnesium - blood ... A blood sample is needed. ... When the needle is inserted to draw blood, some people feel slight pain. Others feel a prick or stinging. Afterward, there may be some throbbing or a slight bruise. This soon ...

  11. Hyperglycemia (High Blood Glucose)

    Medline Plus

    Full Text Available ... Blood Pressure Physical Activity High Blood Glucose My Health Advisor Tools To Know Your Risk Alert Day ... DKA (Ketoacidosis) & Ketones Kidney Disease (Nephropathy) Gastroparesis Mental Health Step On Up Treatment & Care Blood Glucose Testing ...

  12. Blood Type Puzzle.

    Science.gov (United States)

    Kelly, Janet

    1997-01-01

    Presents a blood type puzzle that provides a visual, hands-on mechanism by which students can examine blood group reactions. Offers students an opportunity to construct their own knowledge about blood types. (JRH)

  13. High blood pressure - infants

    Science.gov (United States)

    National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics . ...

  14. What Is Blood?

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    ... Our Member Blood Centers Our Partners What is blood? PUBLICATIONS EDUCATION PRESS ROOM BLOG CAREERS CONTACT ABC ... for patients who need it. One unit of blood can be separated into the following components: Nearly ...

  15. High Blood Pressure Facts

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    ... Heart Disease Cholesterol Salt Million Hearts® WISEWOMAN High Blood Pressure Facts Recommend on Facebook Tweet Share Compartir ... facts about high blood pressure [PDF-255K] . High Blood Pressure in the United States About 70 million ...

  16. Blood Clotting and Pregnancy

    Medline Plus

    Full Text Available ... back to top How are Blood Clots in Pregnant Women Treated? Typically, blood clots are treated with ... you think you have one. If you are pregnant and have concerns about blood clots, talk with ...

  17. Hyperglycemia (High Blood Glucose)

    Medline Plus

    Full Text Available ... symptoms include the following: High blood glucose High levels of sugar in the urine Frequent urination Increased ... you should check and what your blood glucose levels should be. Checking your blood and then treating ...

  18. High Blood Pressure

    Science.gov (United States)

    ... pressure and should be taken seriously. Over time, consistently high blood pressure weakens and damages ... of landmark NIH blood pressure study confirm that lower blood pressure target can reduce ...

  19. Money for Blood and Markets for Blood.

    Science.gov (United States)

    Derpmann, Simon; Quante, Michael

    2015-12-01

    Ontario's Bill 178 proposing a Voluntary Blood Donations Act declares the offer or acceptance of payment for the donation of blood a legal offence and makes it subject to penalty. The bill reinvigorates a fundamental debate about the ethical problems associated with the payment of money for blood. Scarcity of blood donors is a recurring problem in most health systems, and monetary remuneration of the willingness to donate blood is regularly discussed--and sometimes practiced--as a means to overcome scarcity in blood. However, making blood an object of economic exchange has long aroused ethical concerns that often refer to the specific meaning of blood. From the perspective of a modern understanding of money as a metric of economic value, the exchange of money for blood--shed or given--is seen as ethically troubling, because it appears to imply a commensurability of the value of human life and economic wealth. In this paper, we begin with a general taxonomy of the types of arguments that speak in favour or against compensating donors for giving blood. We then describe the context in which the discussion about payment for blood arises, and of the specific aims and concerns that are brought forward in this context. This is used to reconstruct the normative background that supports the rejection of payment for blood as it is envisaged in Bill 178 and the aims of the proposal. We then argue that while a payment indeed changes the nature of a blood donation in an ethically considerable way, we do not believe that decisive arguments against the monetary remuneration of blood donations can be substantiated, at least not independently of assuming specific societal circumstances. Thus it may be possible to establish a stable and safe blood supply through just gratification while at the same time taking strong provisions against social disconnection, injustice, exploitation or heteronomy.

  20. Transcriptional programs controlling perinatal lung maturation.

    Directory of Open Access Journals (Sweden)

    Yan Xu

    Full Text Available The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS and Broncho-Pulmonary Dysplasia (BPD, which are leading causes of mortality and morbidity in preterm infants. Mechanisms synchronizing gestational length and lung maturation remain to be elucidated. In this study, we designed a genome-wide mRNA expression time-course study from E15.5 to Postnatal Day 0 (PN0 using lung RNAs from C57BL/6J (B6 and A/J mice that differ in gestational length by ∼30 hr (B6transcriptional networks controlling lung maturation. We identified both temporal and strain dependent gene expression patterns during lung maturation. For time dependent changes, cell adhesion, vasculature development, and lipid metabolism/transport were major bioprocesses induced during the saccular stage of lung development at E16.5-E17.5. CEBPA, PPARG, VEGFA, CAV1 and CDH1 were found to be key signaling and transcriptional regulators of these processes. Innate defense/immune responses were induced at later gestational ages (E18.5-20.5, STAT1, AP1, and EGFR being important regulators of these responses. Expression of RNAs associated with the cell cycle and chromatin assembly was repressed during prenatal lung maturation and was regulated by FOXM1, PLK1, chromobox, and high mobility group families of transcription factors. Strain dependent lung mRNA expression differences peaked at E18.5. At this time, mRNAs regulating surfactant and innate immunity were more abundantly expressed in lungs of B6 (short gestation than in A/J (long gestation mice, while expression of genes involved in chromatin assembly and histone modification were expressed at lower levels in B6 than in A/J mice. The present study systemically mapped key regulators