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Gene Regulation and Systems Biology

Brendan D Stamper, Madison Davis, Sean Scott-Collins, Julie Tran, Caryn Ton, Agapi Simidyan, Sigrid C Roberts
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 Leishmania infection in various models since 2001. This review covers the transcriptional changes in macrophage models induced by various Leishmania species and summarizes the resulting impact these studies have on our understanding of the host response to leishmaniasis in vitro...
2019: Gene Regulation and Systems Biology
Ransom L Baldwin, Robert W Li, Yankai Jia, Cong-Jun Li
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...
2018: Gene Regulation and Systems Biology
Sean T McQuade, Ruth E Abrams, Jeffrey S Barrett, Benedetto Piccoli, Karim Azer
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...
2017: Gene Regulation and Systems Biology
Jeffrey E Ming, Ruth E Abrams, Derek W Bartlett, Mengdi Tao, Tu Nguyen, Howard Surks, Katherine Kudrycki, Ananth Kadambi, Christina M Friedrich, Nassim Djebli, Britta Goebel, Alex Koszycki, Meera Varshnaya, Joseph Elassal, Poulabi Banerjee, William J Sasiela, Michael J Reed, Jeffrey S Barrett, Karim Azer
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...
2017: Gene Regulation and Systems Biology
Samuel Sheehy, Borhane Annabi
Signal-transducing functions driven by the cytoplasmic domain of membrane type-1 matrix metalloproteinase (MT1-MMP) are believed to regulate many inflammation-associated cancer cell functions including migration, proliferation, and survival. Aside from upregulation of the inflammation biomarker cyclooxygenase-2 (COX-2) expression, MT1-MMP's role in relaying intracellular signals triggered by extracellular pro-inflammatory cues remains poorly understood. Here, we triggered inflammation in HT1080 fibrosarcoma cells with phorbol-12-myristate-13-acetate (PMA), an inducer of COX-2 and of MT1-MMP...
2017: Gene Regulation and Systems Biology
Tianfeng Tan, Richard Man Kit Yu, Rudolf Shiu Sun Wu, Richard Yuen Chong Kong
Hypoxia is an important environmental stressor leading to endocrine disruption and reproductive impairment in fish. Although the hypoxia-inducible factor 1 (HIF-1) is known to regulate the transcription of various genes mediating oxygen homeostasis, its role in modulating steroidogenesis-related gene expression remains poorly understood. In this study, the regulatory effect of HIF-1 on the expression of 9 steroidogenic enzyme genes was investigated in zebrafish embryos using a "gain-of-function and loss-of-function" approach...
2017: Gene Regulation and Systems Biology
Lisl Km Shoda, Christina Battista, Scott Q Siler, David S Pisetsky, Paul B Watkins, Brett A Howell
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration...
2017: Gene Regulation and Systems Biology
Jing Nie, Debra C DuBois, Bai Xue, William J Jusko, Richard R Almon
In the present report, we examined the responses of diabetic Goto-Kakizaki (GK) rats and control Wistar-Kyoto (WKY) rats fed either a standard chow or high-fat diet (HFD) from weaning to 20 weeks of age. This comparison included gene expression profiling of skeletal muscle using Affymetrix gene array chips. The expression profiling is interpreted within the context of a wide array of physiological measurements. Genes whose expressions are different between the 2 strains regardless of diet, as well as genes that differ between strains only with HFD, were identified...
2017: Gene Regulation and Systems Biology
Seul-A Bae, Ioannis P Androulakis
The feeding and fasting cycles are strong behavioral signals that entrain biological rhythms of the periphery. The feeding rhythms synchronize the activities of the metabolic organs, such as liver, synergistically with the light/dark cycle primarily entraining the suprachiasmatic nucleus. The likely phase misalignment between the feeding rhythms and the light/dark cycles appears to induce circadian disruptions leading to multiple physiological abnormalities motivating the need to investigate the mechanisms behind joint light-feeding circadian entrainment of peripheral tissues...
2017: Gene Regulation and Systems Biology
James A Bynum, Xinyu Wang, Salomon A Stavchansky, Phillip D Bowman
1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), a synthetic derivative of oleanolic acid that exhibits antioxidant and anti-inflammatory activity in several animal and in vitro models, has been shown to be beneficial if given after injury. Although induction of heme oxygenase 1 appears to be a major effector of cytoprotection, the mechanism by which the overall effect is mediated is largely unknown. This study evaluated temporal gene expression profiles to better characterize the early transcriptional events and their relationship to the dynamics of the cytoprotective response in human umbilical vein endothelial cells (HUVEC) to CDDO-Im...
2017: Gene Regulation and Systems Biology
Shadia Zaman, Sirarat Sarntivijai, Darrell R Abernethy
Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases...
2017: Gene Regulation and Systems Biology
Rosario Lombardo, Corrado Priami
A main source of failures in systems projects (including systems pharmacology) is poor communication level and different expectations among the stakeholders. A common and not ambiguous language that is naturally comprehensible by all the involved players is a boost to success. We present bStyle, a modeling tool that adopts a graphical language close enough to cartoons to be a common media to exchange ideas and data and that it is at the same time formal enough to enable modeling, analysis, and dynamic simulations of a system...
2017: Gene Regulation and Systems Biology
Richard J Allen, Cynthia J Musante
Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes...
2017: Gene Regulation and Systems Biology
Mudra Choudhury, Stephen A Ramsey
We describe a novel computational approach to identify transcription factors (TFs) that are candidate regulators in a human cell type of interest. Our approach involves integrating cell type-specific expression quantitative trait locus (eQTL) data and TF data from chromatin immunoprecipitation-to-tag-sequencing (ChIP-seq) experiments in cell lines. To test the method, we used eQTL data from human monocytes in order to screen for TFs. Using a list of known monocyte-regulating TFs, we tested the hypothesis that the binding sites of cell type-specific TF regulators would be concentrated in the vicinity of monocyte eQTLs...
2016: Gene Regulation and Systems Biology
Justyna Szostak, Florian Martin, Marja Talikka, Manuel C Peitsch, Julia Hoeng
The cellular and molecular mechanisms behind the process of atherosclerotic plaque destabilization are complex, and molecular data from aortic plaques are difficult to interpret. Biological network models may overcome these difficulties and precisely quantify the molecular mechanisms impacted during disease progression. The atherosclerosis plaque destabilization biological network model was constructed with the semiautomated curation pipeline, BELIEF. Cellular and molecular mechanisms promoting plaque destabilization or rupture were captured in the network model...
2016: Gene Regulation and Systems Biology
Anu Chacko, Donald R Staines, Samantha C Johnston, Sonya M Marshall-Gradisnik
BACKGROUND: The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME...
2016: Gene Regulation and Systems Biology
Phoebe Zapanta Trio, Satoru Fujisaki, Shunsuke Tanigawa, Ayami Hisanaga, Kozue Sakao, De-Xing Hou
6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC), 6-(methylthio)hexyl isothiocyanate (6-MTITC), and 4-(methylsulfinyl)butyl isothiocyanate (4-MSITC) are isothiocyanate (ITC) bioactive compounds from Japanese Wasabi. Previous in vivo studies highlighted the neuroprotective potential of ITCs since ITCs enhance the production of antioxidant-related enzymes. Thus, in this present study, a genome-wide DNA microarray analysis was designed to profile gene expression changes in a neuron cell line, IMR-32, stimulated by these ITCs...
2016: Gene Regulation and Systems Biology
Wendell Vilas-Boas, Camylla V B Figueiredo, Thassila N Pitanga, Magda O S Carvalho, Rayra P Santiago, Sânzio S Santana, Caroline C Guarda, Angela M D Zanette, Bruno A V Cerqueira, Marilda S Gonçalves
Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS -786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM-1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS)...
2016: Gene Regulation and Systems Biology
Aishwarya Alex Namasivayam, Alejandro Ferreiro Morales, Ángela María Fajardo Lacave, Aravind Tallam, Borislav Simovic, David Garrido Alfaro, Dheeraj Reddy Bobbili, Florian Martin, Ganna Androsova, Irina Shvydchenko, Jennifer Park, Jorge Val Calvo, Julia Hoeng, Manuel C Peitsch, Manuel González Vélez Racero, Maria Biryukov, Marja Talikka, Modesto Berraquero Pérez, Neha Rohatgi, Noberto Díaz-Díaz, Rajesh Mandarapu, Rubén Amián Ruiz, Sergey Davidyan, Shaman Narayanasamy, Stéphanie Boué, Svetlana Guryanova, Susana Martínez Arbas, Swapna Menon, Yang Xiang
Biological network models offer a framework for understanding disease by describing the relationships between the mechanisms involved in the regulation of biological processes. Crowdsourcing can efficiently gather feedback from a wide audience with varying expertise. In the Network Verification Challenge, scientists verified and enhanced a set of 46 biological networks relevant to lung and chronic obstructive pulmonary disease. The networks were built using Biological Expression Language and contain detailed information for each node and edge, including supporting evidence from the literature...
2016: Gene Regulation and Systems Biology
T K Huth, E W Brenu, D R Staines, S M Marshall-Gradisnik
Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated. The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs)...
2016: Gene Regulation and Systems Biology
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