Statistical identification of gene association by CID in application of constructing ER regulatory network

<p>Abstract</p> <p>Background</p> <p>A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating <it>in silico </it>inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor α (ERα) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).</p> <p>Results</p> <p>The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's <it>t</it>-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.</p> <p>Conclusion</p> <p>CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.</p> <p>Availability</p> <p>the implementation of CID in R codes can be freely downloaded from <url>http://homepage.ntu.edu.tw/~lyliu/BC/</url>.</p

Investigation of molecular effects of the soy-derived phytoestrogen genistein on cardiomyocytes by proteomic analysis

2011 Fall.Includes bibliographical references.The soy-derived phytoestrogen genistein (GEN) has received attention for its potential to benefit the cardiovascular system by providing protection to cardiomyocytes against pathophysiological stresses. Although GEN is a well-known estrogen receptor (ER) agonist and a non-specific tyrosine kinase inhibitor, current understanding of the complex cellular and molecular effects of GEN in cardiomyocytes is still incomplete. The overall goal of this dissertation is to use high throughput proteomics methodologies to better understand the molecular action of GEN in cardiomyocytes and to identify proteins and pathways that respond to GEN treatment. The first study of this project focused on the concentration-dependent proteome changes in cultured HL-1 cardiomyocytes due to GEN treatments. Proteins from HL-1 cardiomyocytes treated with 1 μM and 50 μM GEN were prefractionated into hydrophilic and hydrophobic protein fractions and were analyzed by two-dimensional electrophoresis followed by protein identification using tandem mass spectrometry (MS). In total, 25 and 62 differential expressed proteins were identified in response to 1 μM and 50 μM of GEN treatment, respectively. These results suggest that 1 μM GEN enhanced the expression of heat shock proteins and anti-apoptotic proteins, while 50 μM GEN down-regulated glycolytic and antioxidant enzymes, potentially making cardiomyocytes more susceptible to energy depletion and apoptosis. The second study, employing a two-dimensional liquid chromatography and tandem MS shotgun proteomics workflow, was carried out to dissect the cellular functions changed in cardiomyocytes by ER-dependent or ER-independent actions of GEN. In this study, primary cardiomyocytes isolated from male adult SD rats were treated with 10 μM GEN without or with 10 μM ER antagonist ICI 182,780 (ERA) before proteomics comparison. A total of 14 and 15 proteins were found differentially expressed in response to the GEN, and the GEN+ERA treatment, respectively. Cellular functions such as glucose and fatty acid metabolism and cardioprotection were found to be modulated by GEN in an ER-dependent fashion, while proteins involved with steroidogenesis and estrogen signaling were identified as novel effectors of GEN via ER-independent actions. In this study, a consensus-iterative searching strategy was also developed to enhance the sensitivity of the shotgun proteomic approach. In the last study, an attempt to explore the response to a GEN stimulus in the signaling pathways, we developed a phosphopeptide enrichment method to assist the detection of protein phosphorylation in a complex peptide mixture. The quantitative performance of a sequential immobilized metal affinity chromatography (SIMAC) protocol was evaluated. We further conducted a preliminary application of this protocol in a large-scale, quantitative, label-free phosphoproteomics study to explore the alterations of protein phosphorylation patterns due to ER-independent GEN action in the SD rat cardiomyocytes. This project demonstrates the usefulness of proteomics methodologies to screen novel molecular targets influenced by GEN in cardiomyocytes. This is also the first investigation of the complex cellular impact of this soy-derived phytoestrogen in cardiomyocytes via a systems biology perspective

A Supervised Network Analysis on Gene Expression Profiles of Breast Tumors Predicts a 41-Gene Prognostic Signature of the Transcription Factor MYB

Background. MYB is predicted to be a favorable prognostic predictor in a breast cancer population. We proposed to find the inferred mechanism(s) relevant to the prognostic features of MYB via a supervised network analysis. Methods. Both coefficient of intrinsic dependence (CID) and Galton Pierson’s correlation coefficient (GPCC) were combined and designated as CIDUGPCC. It is for the univariate network analysis. Multivariate CID is for the multivariate network analysis. Other analyses using bioinformatic tools and statistical methods are included. Results. ARNT2 is predicted to be the essential gene partner of MYB. We classified four prognostic relevant gene subpools in three breast cancer cohorts as feature types I–IV. Only the probes in feature type II are the potential prognostic feature of MYB. Moreover, we further validated 41 prognosis relevant probes to be the favorable prognostic signature. Surprisingly, two additional family members of MYB are elevated to promote poor prognosis when both levels of MYB and ARNT2 decline. Both MYBL1 and MYBL2 may partially decrease the tumor suppressive activities that are predicted to be up-regulated by MYB and ARNT2. Conclusions. The major prognostic feature of MYB is predicted to be determined by the MYB subnetwork (41 probes) that is relevant across subtypes

Identification of novel regulators of COP1-controlled morphogenesis in Arabidopsis thaliana

In Arabidopsis thaliana, COP1 is an essential element of light signal transduction acting downstream of photoreceptors and upstream of light-regulated gene expression. The COP1 protein acts as part of an E3 ligase complex to suppress photomorphogenic gene expression by ubiquitin-dependent degradation of light-regulated transcription factors. In dark-grown seedlings, the repression of photomorphogenesis involves the inhibition of hypocotyl growth, anthocyanin accumulation, expression of light-responsive genes, differentiation of etioplasts and prevention of apical hook formation. Loss of COP1 function leads to a pleiotropic phenotype comprising of constitutive photomorphogenesis in the dark and resulting in a post-germination growth arrest. The vegetative growth arrest of cop1 mutants, a possible role of COP1 concerning the cell cycle and the molecular factors regulating the nucleocytoplasmic partitioning of COP1 exemplify aspects of COP1 function and regulation that are poorly understood until now. This work aimed at the identification of regulators of COP1-controlled morphogenesis to contribute to a better dissection of the latter. In yeast two hybrid screenings (YTH) 32 new interaction candidates for COP1 were identified and a purpose oriented selection was performed. In order to select a putative regulator of COP1, all COP1 and additional DET1 interaction candidates were integrated in a network of published interactors. Out of the network and the screening results PAP2 (PRODUCTION OF ANTHOCYAN PIGMENT) was identified and selected as a putative new target. MID (= MIDGET) was selected as a putative new regulator of COP1, respectively. MID is a part of the topoisomerasis VI (TOPOVI) complex that is needed to complete more than two endocycles in plant cells. This work provides evidence for a physical interaction of MID and PAP2 with COP1. In addition, a new YTH-based domain mapping method was developed and used to identify so far unknown domains of PAP2 for the interaction with COP1 and for COP1 for the interaction with MID and TOPOVI components. Similar to cop1, mid and topoisomerase VI mutants exhibited all aspects of constitutive pohotomorphogenesis in the dark. Double mutant analysis indicated that MID is not a target of COP1. In infiltrated leaves of Nicotiana benthamina, the presence of MID is needed for COP1 to form a high number of subnuclear foci. MID and the TOPOVI were shown to be essential regulators of COP1 function probably by stabilising COP1 and thereby adding a new cell-cycle related factor to the regulation of COP1 activity. The functional relevance of the MID-COP1 interaction was proven by analysing phenotypes of the single mutants and genetic interaction. First evidence positioning MID in a SPA1 and phyA-dependent complex or pathway were obtained by the verification of the SPA1-MID interaction via BiFC, co-purification of MID with phyA and analysis of the protein stability of MID depending on light quality. Finally it was found that mid and topoVI mutants phenocopy det1-1 mutants and overexpressor lines of the C-termini of CRY1 and CRY2, possibly providing a new link to crosstalk between red and blue light mediated signaling

Mining a stroke knowledge graph from literature

From Springer Nature via Jisc Publications RouterHistory: collection 2021-05, received 2021-06-13, accepted 2021-07-06, registration 2021-07-09, pub-electronic 2021-07-29, online 2021-07-29Publication status: PublishedFunder: National High-level Personnel for Defense Technology Program; Grant(s): (2017-JCJQ-ZQ-013), and NSF 61902405Funder: the national key r&d project by ministry of science and technology of china; Grant(s): 2018YFB1003203Funder: the open fund from the State Key Laboratory of High Performance Computing; Grant(s): No. 201901-11Funder: National Science Foundation of China; Grant(s): U1811462Abstract: Background: Stroke has an acute onset and a high mortality rate, making it one of the most fatal diseases worldwide. Its underlying biology and treatments have been widely studied both in the “Western” biomedicine and the Traditional Chinese Medicine (TCM). However, these two approaches are often studied and reported in insolation, both in the literature and associated databases. Results: To aid research in finding effective prevention methods and treatments, we integrated knowledge from the literature and a number of databases (e.g. CID, TCMID, ETCM). We employed a suite of biomedical text mining (i.e. named-entity) approaches to identify mentions of genes, diseases, drugs, chemicals, symptoms, Chinese herbs and patent medicines, etc. in a large set of stroke papers from both biomedical and TCM domains. Then, using a combination of a rule-based approach with a pre-trained BioBERT model, we extracted and classified links and relationships among stroke-related entities as expressed in the literature. We construct StrokeKG, a knowledge graph includes almost 46 k nodes of nine types, and 157 k links of 30 types, connecting diseases, genes, symptoms, drugs, pathways, herbs, chemical, ingredients and patent medicine. Conclusions: Our Stroke-KG can provide practical and reliable stroke-related knowledge to help with stroke-related research like exploring new directions for stroke research and ideas for drug repurposing and discovery. We make StrokeKG freely available at http://114.115.208.144:7474/browser/ (Please click "Connect" directly) and the source structured data for stroke at https://github.com/yangxi1016/Strok

Phytochemical Omics in Medicinal Plants

Medicinal plants are used to treat diseases and provide health benefits, and their applications are increasing around the world. A huge array of phytochemicals have been identified from medicinal plants, belonging to carotenoids, flavonoids, lignans, and phenolic acids, and so on, with a wide range of biological activities. In order to explore our knowledge of phytochemicals with the assistance of modern molecular tools and high-throughput technologies, this book collects recent innovative original research and review articles on subtopics of mechanistic insights into bioactivities, treatment of diseases, profiling, extraction and identification, and biotechnology

From Phenotype to Genotype: Discovery of New Molecular Primary Immunodeficiencies

Since the 1950s, the investigation of genetic causes of primary immunodeficiencies has fundamentally shaped our understanding of the immune system, and that fountain of knowledge has continued to expand explosively as we enter the genomic era with the dawn of CRISPR and personalized medicine. In this work, I describe four new monogenetic causes of primary immunodeficiency (PID) and a novel gene that may be associated with common variable immunodeficiency (CVID). The index cases were initially identified from two large PID cohorts – one based at the National Institutes of Health (NIH) in the United States and the other based at University of Cambridge in the United Kingdom. Eight individuals from four different kindreds were identified to have IL2RB deficiency due to three different loss of function IL2RB mutations, leading to either significant truncation of protein, reduced surface expression, or decreased IL-2 binding affinity. These patients all presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, and cytomegalovirus disease and had loss of regulatory T cells and “adaptive” natural killer cells. Another consanguineous kindred in the NIH cohort was found to have infantile inflammatory bowel disease associated with a rare homozygous IL37 mutation. Functional validation using cell lines and induced pluripotent stem cells (iPSCs) revealed a failure of the mutant IL-37 to be secreted extracellularly or translocated to the nucleus causing an inability to suppress pro-inflammatory cytokine production. Using a combination of whole genome sequencing and genome wide association studies to analyze the UK cohort of predominantly antibody-deficient patients, we identified PTPN2 and SOCS1 haploinsufficiency due to a combination of common and rare variants as genetic causes of CVID. These patients had loss of TC-PTP and SOCS1 protein as well as hyper-phosphorylation of STAT1. This dissertation closes with a tantalizing description of a kindred with four CVID patients with either homozygous recessive or compound heterozygous mutations in a poorly characterized gene TTC21A. Preliminary primary B cell CRISPR experiments and CRISPR knock-in mouse studies are so far inconclusive. The work presented here adds to the compendium of PID discoveries and provides insight into well-understood signaling pathways like IL-2, IL-1beta and interferon-gamma as well as attempts to elucidate the role of enigmatic genes like IL-37 and TTC21A using iPSCs and CRISPR technologies.NIH Oxford-Cambridge Scholarship, Cambridge Trus

Sex-steroids and social network in relation to Staphylococcus aureus nasal carriage

Staphylococcus aureus (S. aureus) is a human pathogen that can colonize skin and mucosa. Nasal carriage is associated with increased risk of autoinfection and transmission and it is therefore important to identify possible targets for prevention of carriage. Sex and age are the most important risk factors for S. aureus carriage, and hypotheses about sex-steroids as major host determinants have therefore emerged. We investigated if hormonal contraceptives and endogenous sex-steroids were associated with S. aureus carriage. We studied the transmission of S. aureus carriage in social networks and examined if known host risk factors for carriage were associated with social contact, indicating potential confounding or indirect transmission. We used data from the cross-sectional health surveys Fit Futures 1&2 and the sixth Tromsø Study. Females taking combination hormonal contraceptives (containing both estrogen and progestin) had doubled odds of nasal carriage compared to non-users. Users of progestin-only contraceptives had half the odds of nasal carriage compared to non-users. An increase in endogenous testosterone in women gave reduced odds of S. aureus nasal carriage. We found similar associations in adult men, but data were inconclusive. We demonstrate transmission of S. aureus and specific S. aureus genotypes in a social network of youths. We found higher risk of transmission with female friendships, while male friendships had no influence on transmission, although men were more frequent carriers. Use of alcohol more than twice a month, normal BMI, and moderate/high physical activity were associated with transmission. The results suggest that both exogenous and endogenous sex-steroid exposures are relevant in carriage of S. aureus. We show for the first time that the male predominance in carriage is determined by sex-specific predisposing host characteristics as S. aureus social transmission is less frequent than in females. We need more prospective studies to clarify causal relationships and targets for prevention.Gule stafylokokker er en viktig årsak til alvorlige infeksjoner hos mennesker. Bærere av gule stafylokokker har økt risiko for infeksjon og smitte. Det er derfor avgjørende å øke kunnskapen om bærerskap for å kunne identifisere mulige strategier for forebygging av infeksjon og smitte. Fra tidligere studier vet vi at kjønn og alder er bestemmende for bærerskap. Dette har fremmet hypoteser om at kjønnshormoner kan være viktige determinanter. Vi undersøkte om hormonell prevensjon og nivå av kroppens egne kjønnshormoner har betydning for bærerskap av gule stafylokokker. Vi studerte også spredning av bakterien i sosiale nettverk og undersøkte om kjente risikofaktorer for bærerskap var assosiert med sosial kontakt. Vi brukte data fra tverrsnittstudiene Fit Futures 1&2 og den sjette Tromsøundersøkelsen. Resultatene viser at bruk av hormonell prevensjon som inneholder østrogen og progestin, ga dobbel odds for bærerskap sammenlignet med ikke-bruk. Bruk av hormonell prevensjon som bare inneholdt progestin halverte oddsen sammenlignet med ikke-bruk. Høyere nivå av serum testosteron hos voksne kvinner ga redusert odds for bærerskap. Vi fant også lignende assosiasjoner hos menn, men dataene var inkonklusive. Analysene våre viser at bærerskap av gule stafylokokker og spesifikke genotyper smitter i sosiale nettverk blant ungdom. Det var høyere risiko for smitte hos kvinner, mens mannlig kjønn ikke påvirket smitten selv om prevalensen var høyre hos menn. Bruk av alkohol mer enn to ganger i måneden, normal BMI og moderat/høy fysisk aktivitet var assosiert med høyere risiko for overføring av bakterien. Resultatene tyder på at kjønnshormoner er svært relevant når det kommer til bærerskap av gule stafylokokker. Vi viser at sosial kontakt er viktigere for spredning av gule stafylokokker innad blant kvinner enn blant menn. Den høyere forekomsten av bærerskap hos menn er derfor i stor grad uttrykk for iboende vertsfaktorer. Vi trenger flere prospektive studier for å avklare årsakssammenhenger og mål for forebygging

The Human Body as a Super Network: Digital Methods to Analyze the Propagation of Aging

Biological aging is a complex process involving multiple biological processes. These can be understood theoretically though considering them as individual networks—e.g., epigenetic networks, cell-cell networks (such as astroglial networks), and population genetics. Mathematical modeling allows the combination of such networks so that they may be studied in unison, to better understand how the so-called “seven pillars of aging” combine and to generate hypothesis for treating aging as a condition at relatively early biological ages. In this review, we consider how recent progression in mathematical modeling can be utilized to investigate aging, particularly in, but not exclusive to, the context of degenerative neuronal disease. We also consider how the latest techniques for generating biomarker models for disease prediction, such as longitudinal analysis and parenclitic analysis can be applied to as both biomarker platforms for aging, as well as to better understand the inescapable condition. This review is written by a highly diverse and multi-disciplinary team of scientists from across the globe and calls for greater collaboration between diverse fields of research