Gene regulation and systems biology最新文献

{"title":"Pathway-Based Analysis of the Liver Response to Intravenous Methylprednisolone Administration in Rats: Acute Versus Chronic Dosing.","authors":"Alison Acevedo, Ana Berthel, Debra DuBois, Richard R Almon, William J Jusko, Ioannis P Androulakis","doi":"10.1177/1177625019840282","DOIUrl":"10.1177/1177625019840282","url":null,"abstract":"<p><p>Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficult; multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared using a model-based assessment of pathway dynamics, extending the principles of pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The model-based approach enabled us to hypothesize on the likely emergence (or disappearance) of indirect dosing-dependent regulatory interactions, pointing to likely mechanistic implications of dosing of MPL transcriptional regulation. Both acute and chronic MPL administration induced a strong core of activity within pathway families including the following: lipid metabolism, amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, regulation of essential organelles, and xenobiotic metabolism pathway families. Pathway activities alter between acute and chronic dosing, indicating that MPL response is dosing dependent. Furthermore, because multiple pathway activities are dominant within a single pathway, we observe that pathways cannot be defined by a single response. Instead, pathways are defined by multiple, complex, and temporally related activities corresponding to different subgroups of genes within each pathway.</p>","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5a/3f/10.1177_1177625019840282.PMC6466473.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37183573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal and Spatial Differential Expression of Glutamate Receptor Genes in the Brain of Down Syndrome","authors":"A. Ortiz, Mailyn Alejandra Bedoya Saldarriaga, Julio César Montoya Villegas, F. García-Vallejo","doi":"10.5772/INTECHOPEN.82446","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82446","url":null,"abstract":"Studying the dysregulation of expression of glutamate receptors is crucial to better understand the mechanisms associated with cognitive disabilities in Down syndrome (DS) patients. By using data of microarray experiments previously deposited in GEO Dataset, we studied the expression of 26 glutamate receptor genes in DS brain samples since prenatal to adult age in several brain structures. Overall, our results showed a complexity in the expression of the genes which were depen-dent mainly on the brain structure analyzed; especially, the hippocampus showed a different expression pattern. While in the general brain analysis the overexpressed genes were GRIN3A and GRIN2C, higher expression levels of GRM1, GRID2, and GRIK1 gene receptors were recorded in hippocampus. Our results suggest that the glutamatergic system in association with other neurotransmitter systems in the human brain would associate with glutamatergic receptor alterations to bring upon synaptic changes and cognitive deficits in DS models.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83313420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introductory Chapter: Gene Regulation, an RNA Network-Dependent Architecture","authors":"P. Behzadi, Lernik Issakhanian","doi":"10.5772/INTECHOPEN.84535","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.84535","url":null,"abstract":"Genetics is known as an old and ancient science that its origination goes back to at least 7000 years ago. Iranians are one of the earliest pioneers in genetics from ancient world. The brilliant Iranian (Persian) literature epic of Shahnameh edited by the Iranian shining star literate “Abolqasem Ferdowsi Toosi” is an invaluable evidence to prove this claim. By the time and progression in biology, the superamazing molecule of DNA was discovered. Today, we know that the unique molecule of DNA involves the genetic and vital data within its bases as constitutional structures of nucleotides. Both eukaryotic and prokaryotic chromosomes are made up of DNA molecules. In addition to DNAs, the role and importance of RNAs are not lesser than DNAs [1]. In 1953, the interesting structure of DNA molecule with anti-parallel doublehelix architecture was recognized by Watson and Crick. In 1958, the hypothesis of central dogma of molecular biology was published by Crick in which he described the translation of genetic language located on DNA into amino acid sequences of protein by the transient molecule of RNA (mainly messenger RNA (mRNA)). The primitive biological characteristics of mRNA were recognized in 1961, while these properties regarding ribosomal RNA (rRNA) and transfer RNA (tRNA) molecules were determined in the 1950s [2].","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75548199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-based Evaluation of Gene Expression Changes in Response to <i>Leishmania</i> Infection.","authors":"Brendan D Stamper,&nbsp;Madison Davis,&nbsp;Sean Scott-Collins,&nbsp;Julie Tran,&nbsp;Caryn Ton,&nbsp;Agapi Simidyan,&nbsp;Sigrid C Roberts","doi":"10.1177/1177625019828350","DOIUrl":"https://doi.org/10.1177/1177625019828350","url":null,"abstract":"<p><p>Since the development of high-density microarray technology in the late 1990s, global host gene expression changes in response to various stimuli have been extensively studied. More than a dozen peer-reviewed publications have investigated the effect of <i>Leishmania</i> infection in various models since 2001. This review covers the transcriptional changes in macrophage models induced by various <i>Leishmania</i> species and summarizes the resulting impact these studies have on our understanding of the host response to leishmaniasis in vitro. Characterization of the similarities and differences between various model systems will not only further our understanding of <i>Leishmania</i>-induced changes to macrophage gene expression but also identify potential therapeutic targets in the future.</p>","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625019828350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36988380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Activation by the Cytokine-Driven Transcription Factor STAT1","authors":"R. Nast, Julia Staab, T. Meyer","doi":"10.5772/INTECHOPEN.82699","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82699","url":null,"abstract":"Signal transducers and activators of transcription (STATs) are a family of cytokine-regulated transcription factors, which serve the dual role of external signal transduction and transcriptional activation. The founding member of this family, STAT1, is involved in a plethora of cellular processes, including interferon-dependent upregulation of various effector mechanisms in immune and non-immune cells to control bacterial, fungal and parasitic infections. In this chapter, we discuss the principles of STAT1-driven gene expression and focus on the clinical phenotypes of various human STAT1 mutations. In particular, we highlight the significance of sequence-specific DNA binding and intact nucleocytoplasmic shuttling for full transcriptional activation of interferon-driven target genes.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81303225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reviewer List","authors":"A. Elsalam, A. Adams, Murray Agirbasli, M. Akar, Nejat Akin, Muharram Akın, Melike Aksu, Emrullah Kokalj, N. Kostić, Jelena Kovač, Mirjana Kubisz, Peter Kukula, Krzysztof Kulkarni, Bipin Kulkarni, Roshni Kurtoglu, M. Lackner","doi":"10.1177/2516865719829635","DOIUrl":"https://doi.org/10.1177/2516865719829635","url":null,"abstract":"List of Reviewer present in this pdf.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/2516865719829635","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41905087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct E2F-Mediated Transcriptional Mechanisms in Cell Proliferation, Endoreplication and Apoptosis","authors":"H. Komori, R. Iwanaga, A. Bradford, Keigo Araki, K. Ohtani","doi":"10.5772/INTECHOPEN.82448","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.82448","url":null,"abstract":"E2F and DP family proteins are evolutionally conserved transcription factors among higher eukaryotes. E2F and DP proteins typically form a heterodimeric complex, which controls cell proliferation by regulating expression of growth-related genes. In addition, E2F family proteins have roles in various cellular events that require the expression of context-specific genes. E2F proteins use distinct mechanisms to regulate context-specific genes in different circumstances. The primary goal of this chapter is to compare three distinct mechanisms of mammalian E2F-mediated transcriptional regulation that control cell proliferation, endoreplication and apoptosis. Briefly, E2F7 and E2F8 control endoreplication by suppressing the expression of their target genes. They do not require DP or pRb. In control of apoptosis, E2F1 regulates the expression of the tumor suppressor gene Arf by binding to a non-canonical E2F binding site, within the Arf promoter, in a DP-independent manner. Furthermore, we examine the functions of E2F and DP in Drosophila melanogaster (fruit fly) to identify those mechanisms of E2F-mediated transcriptional regulation that have been evolutionarily conserved. The detailed mechanisms of how E2F protein regulates the expression of context-specific target genes will be instrumental in understanding how a single family of transcription factor regulates diverse pleiotropic cellular processes in an organism.","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91297516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic Impacts of Rumen Epithelium Induced by Butyrate Infusion in Dairy Cattle in Dry Period.","authors":"Ransom L Baldwin,&nbsp;Robert W Li,&nbsp;Yankai Jia,&nbsp;Cong-Jun Li","doi":"10.1177/1177625018774798","DOIUrl":"https://doi.org/10.1177/1177625018774798","url":null,"abstract":"<p><p>The purpose of this study was to evaluate the effects of butyrate infusion on rumen epithelial transcriptome. Next-generation sequencing (NGS) and bioinformatics are used to accelerate our understanding of regulation in rumen epithelial transcriptome of cattle in the dry period induced by butyrate infusion at the level of the whole transcriptome. Butyrate, as an essential element of nutrients, is a histone deacetylase (HDAC) inhibitor that can alter histone acetylation and methylation, and plays a prominent role in regulating genomic activities influencing rumen nutrition utilization and function. Ruminal infusion of butyrate was following 0-hour sampling (baseline controls) and continued for 168 hours at a rate of 5.0 L/day of a 2.5 M solution as a continuous infusion. Following the 168-hour infusion, the infusion was stopped, and cows were maintained on the basal lactation ration for an additional 168 hours for sampling. Rumen epithelial samples were serially collected via biopsy through rumen fistulae at 0-, 24-, 72-, and 168-hour (D1, D3, D7) and 168-hour post-infusion (D14). In comparison with pre-infusion at 0 hours, a total of 3513 genes were identified to be impacted in the rumen epithelium by butyrate infusion at least once at different sampling time points at a stringent cutoff of false discovery rate (FDR) < 0.01. The maximal effect of butyrate was observed at day 7. Among these impacted genes, 117 genes were responsive consistently from day 1 to day 14, and another 42 genes were lasting through day 7. Temporal effects induced by butyrate infusion indicate that the transcriptomic alterations are very dynamic. Gene ontology (GO) enrichment analysis revealed that in the early stage of rumen butyrate infusion (on day 1 and day 3 of butyrate infusion), the transcriptomic effects in the rumen epithelium were involved with mitotic cell cycle process, cell cycle process, and regulation of cell cycle. Bioinformatic analysis of cellular functions, canonical pathways, and upstream regulator of impacted genes underlie the potential mechanisms of butyrate-induced gene expression regulation in rumen epithelium. The introduction of transcriptomic and bioinformatic technologies to study nutrigenomics in the farm animal presented a new prospect to study multiple levels of biological information to better apprehend the whole animal response to nutrition, physiological state, and their interactions. The nutrigenomics approach may eventually lead to more precise management of utilization of feed resources in a more effective approach.</p>","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625018774798","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36118366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linear-In-Flux-Expressions Methodology: Toward a Robust Mathematical Framework for Quantitative Systems Pharmacology Simulators.","authors":"Sean T McQuade,&nbsp;Ruth E Abrams,&nbsp;Jeffrey S Barrett,&nbsp;Benedetto Piccoli,&nbsp;Karim Azer","doi":"10.1177/1177625017711414","DOIUrl":"https://doi.org/10.1177/1177625017711414","url":null,"abstract":"<p><p>Quantitative Systems Pharmacology (QSP) modeling is increasingly used as a quantitative tool for advancing mechanistic hypotheses on the mechanism of action of a drug, and its pharmacological effect in relevant disease phenotypes, to enable linking the right drug to the right patient. Application of QSP models relies on creation of virtual populations for simulating scenarios of interest. Creation of virtual populations requires 2 important steps, namely, identification of a subset of model parameters that can be associated with a phenotype of disease and development of a sampling strategy from identified distributions of these parameters. We improve on existing sampling methodologies by providing a means of representing the structural relationship across model parameters and describing propagation of variability in the model. This gives a robust, systematic method for creating a virtual population. We have developed the Linear-In-Flux-Expressions (LIFE) method to simulate variability in patient pharmacokinetics and pharmacodynamics using relationships between parameters at baseline to create a virtual population. We demonstrate the importance of this methodology on a model of cholesterol metabolism. The LIFE methodology brings us a step closer toward improved QSP simulators through enhanced capture of the observed variability in drug and disease clinical data.</p>","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017711414","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35949817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics.","authors":"Jeffrey E Ming,&nbsp;Ruth E Abrams,&nbsp;Derek W Bartlett,&nbsp;Mengdi Tao,&nbsp;Tu Nguyen,&nbsp;Howard Surks,&nbsp;Katherine Kudrycki,&nbsp;Ananth Kadambi,&nbsp;Christina M Friedrich,&nbsp;Nassim Djebli,&nbsp;Britta Goebel,&nbsp;Alex Koszycki,&nbsp;Meera Varshnaya,&nbsp;Joseph Elassal,&nbsp;Poulabi Banerjee,&nbsp;William J Sasiela,&nbsp;Michael J Reed,&nbsp;Jeffrey S Barrett,&nbsp;Karim Azer","doi":"10.1177/1177625017710941","DOIUrl":"https://doi.org/10.1177/1177625017710941","url":null,"abstract":"<p><p>Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease.</p>","PeriodicalId":73138,"journal":{"name":"Gene regulation and systems biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/1177625017710941","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35317591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}