Abstract: Interleukin-2 (IL-2) gene regulation was investigated in primary cultures of highly purified human peripheral blood CD28+T cells. Two discrete mechanisms for induction of T-cell proliferation could be distinguished by examining cell cycle progression and the expression of the IL-2 gene. Stimulation of cells by CD3 MoAb induced only transiently expressed, small amounts of IL-2 mRNA that was completely suppressed by cyclosporine. Costimulation of T cells with CD3 MoAb and either CD28 MoAb or PMA, but not calcium ionophore, induced a 50-100-fold increased in IL-2 gene expression and secretion. High levels of IL-2 gene expression could also be achieved by stimulation with calcium ionophore and PMA or CD28 MoAb and PMA, but not by CD28 MoAb plus calcium ionophore. IL-2 gene expression and T-cell proliferation induced by CD3 MoAb plus PMA or calcium ionophore plus PMA were completely suppressible by cyclosporine. In contrast, IL-2 gene expression and T-cell proliferation induced by CD28 MoAb ...
Read SINC-seq: correlation of transient gene expressions between nucleus and cytoplasm reflects single-cell physiology, Genome Biology on DeepDyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips.
Regulation of transforming growth factor β1 gene expression by the product of the retinoblastoma-susceptibility gene Academic Article ...
DNA actively 58-49-1 biological activity down-regulates the gene expression of LL37 in monocytes and epithelial cells. Nevertheless, due to the fact
Large search returns make our pages slow to load. Therefore, some functionality has been disabled until you refine your search to bring the number of returned assay results under TBD ...
Large search returns make our pages slow to load. Therefore, some functionality has been disabled until you refine your search to bring the number of returned assay results under TBD ...
மரபணு வெளிப்பாடு (Gene expression) என்பது மரபணுவில் இருக்கும் தகவல்கள், தொழிற்படக்கூடிய மரபணு உற்பத்திப்பொருளாக (gene product) மாற்றப்படும் செயல்முறையாகும். மரபணுவிலிருக்கும் மரபணுக் குறியீட்டுப்பகுதியில் (coding region) இருந்து இவ்வகையான மரபணு உற்பத்திப்பொருட்கள் உருவாகின்றன. மரபணு உற்பத்திப்பொருட்கள் உயிர்வேதியியல் பொருட்களாகும். பொதுவாக இந்த மரபணு உற்பத்திப் பொருட்கள் தொழிற்படும் ...
Effect of in vivo gene expression knockdown on neuroblast migration in the olfactory bulb. The RMS within the olfactory bulb (bRMS) is visible as more intensely
What is meant by gene expression? Gene expression refers to genes being turned on and producing a product. The product could be an enzyme, a structural protein, or a control molecule. Studies of gene expression typically measure the production of mRNA. Most mechanisms that control gene expression do so by controlling transcription, the synthesis of mRNA. However there are other mechanisms for controlling the rate of protein synthesis that occur downstream (between transcription and translation). Several of these are described in this animation. View the animation below, then complete the quiz to test your knowledge of the concept.. ...
Determining gene expression on a single pair of microarrays. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Genomes contain all the genetic information needed by an organism, regardless of the circumstance or environment. Generally, however, even single-cell organisms use only a fraction of their genome at any time; that is, cells generally express only a fraction of their genome at any given time. This is especially true among the individual cells that make up multicellular organisms, where cell specialization (differentiation) dictates that only certain genes be expressed in certain cells, and only at particular times during the organisms life span.. ...
Process of gene expression entails plasmid DNA or mRNA delivery to specific cells and is a technique routinely utilized in labs to study a gene of interest or a signaling pathway. Gene expression usually allows transient protein production, but in some cases stable integration into a genome and continuous protein production over time is required.
I want to show relationship between down regulation and up regulation of expression of a gene with that of patients relapse status in cancer. However, I dont have enough data to plot KM/ Survival curve. All I have is disease status and gene expression after 1 year and 3 years. I was thinking of making Box whisker plot but I have not seen box whisker showing correlation between gene expression and survival. Any suggestions how best I can show such relationship?. ...
Gene expression is the process by which genetic information is used to produce proteins, essential for cells to function properly. It takes place in two steps (first the transcription, then the translation), considered to be two independent processes until now. Today, microbiologists provide additional evidence that they are intrinsically related and that a protein complex called Ccr4-Not plays a key role in gene expression by acting as a messenger between the nucleus and the cytoplasm.
Gene Expression Macro Version 1.1 Instructions Rev B 1 Bio-Rad Gene Expression Macro Users Guide 2004 Bio-Rad Laboratories Table of Contents: Introduction Opening
Hi All,. I want examine different gene expression for different treatment by using qRT-PCR , i will not do any sequencing or assembly . First RNA will be extract and then my question is How can i choose the candidate genes before run PCR ??? Then i can design the primer for the candidate and run PCR.. I hope if someone can explain and suggest methods for chose the candidate ... Thanks. ...
Is a useful technique for acquiring the gene expression pattern of a number of selected genes due to its high sensitivity, specificity and broad quantification
FRAMINGHAM, Mass.--Genzyme Molecular Oncology here and Bayer have inked an agreement that will allow Bayer the use of Genzyme Molecular Oncologys patented Serial Analysis of Gene Expression (SAGE) technology. Bayer will utilize SAGE to identify genes that may have import
This detailed volume provides a toolbox for designing constructs, tackling expression and solubility issues, handling membrane proteins and protein complexes, and exploring innovative engineering of E
Once upon a time, it was rare to meet someone who took an interest in their genealogy beyond the desire to know why people in that old family photo looked the way they did or wondered what had led up to the portrait for which they sat decades or centuries before.
The answer, though, is differences in gene expression in a cell. Clones have identical DNA, but the way the DNA is transcribed to RNA, and the way the RNA is translated to making a protein, can be specific to the cell. There are epigenetic factors - basically, chemicals that adhere to certain parts of the genome - that dictate NOT whether the DNA is there, but how often the DNA is read to make RNA and how efficiently that is made into functional proteins. Think about a fertilized egg. It divides into two cells, then 4 cells, then 8 cells, then 16 cells, then 32 cells, etc. Every time the cell divides, it has to make a perfect copy of its DNA. The cell machinery isnt always perfect and little changes in DNA can occur. Also, those chemicals that can affect gene expression can get added or subtracted as cells divide. Many of them, however, are passed on to the daughter cells. Thats how identical cells can have different levels of gene expression, and how people and horses and dogs with identical ...
There are comments on PubPeer for publication: Integrated functional, gene expression and genomic analysis for the identification of cancer targets (2009)
Akhilesh Bajpai, Sravanthi Davuluri and Acharya KK* (*Correspondence: [email protected]), A comparative account of gene expression resources, feature-validations and application-based categorizations; In: Startbioinfo; 12 Oct 2011, http://www.startbioinfo.com/gene-expression/ ...
An embedded and charset-unspecified text was scrubbed... Name: not available URL: ,https://stat.ethz.ch/pipermail/bioconductor/attachments/20120423/2ea69f12/attachment.pl ...
An expression system refers to the factors that work together to yield a particular gene product such as a protein, ribozyme or RNA particle.
Bioengineers have demonstrated that simultaneous control over transcription and translation in cells can achieve the most stringent control of gene expression
Effect of mannan-oligosaccharides (MOS) supplementation onperformance, immunity and HSP70 gene expression in broilerchicken during hot-dry summer
I am fascinated by a fundamental question in biology; How is regulation of gene expression as a response to external stimulus achieved? My laboratory
Chapter 18 Regulation of Gene Expression Gene Regulation Is Necessary By switching genes off when they are not needed, cells can prevent resources from being wasted. There should be natural selection
EPFL chemists have uncovered the first steps in the process of gene expression by showing how the protein Rap1 pries open the tightly wound, compacted structure of DNA in the cell to gain access to specific genes.
Im just not quite sure the answer to this. When we talk about epigenetics and gene expression, does it not matter if we have snps or not? For...
A new study presents the first analysis of the pilot dataset from the Genotype-Tissue Expression (GTEx) project, which investigates how our underlying DNA regulates gene expression.
Genotyping & gene expression full services from Eurofins Genomics . Wide range of platforms and assays available ** Call +49 8092 8289-0
Telencephalic and diencephalic gene expression in the fgf16 morphants.The expression of emx1 (A, B), tbr1 (C, D), dlx2 (E, F), pax6a (G, H), and shh (I, J) in w
This function will fit smooth spline curves for the gene expression dynamics along pseudotime in a gene-wise manner and return the corresponding response matrix. This function is build on other functions (fit_models and responseMatrix) and used in calILRs and calABCs functions
You need to make cDNA with random hexamers or oligo dT, then amplify the gene with specific primers after that by PCR. In my experience there isnt a whole lot of difference between random hexamers or oligo dT. They seem to work equally as well for cDNA generation.. Lately, I have been using the Invitrogen SuperScript III kit with random hexamers to amplify my cDNAs. Works great.. Rb. ...
We have previously shown that the intramuscular injection of naked plasmid DNA enables foreign gene expression in muscle. Further studies showed that the intravascular delivery of naked plasmid DNA enables high levels of expression not only in muscle but also in hepatocytes. For the liver, this tech …
BACKGROUND: Although, systematic analysis of gene annotation is a powerful tool for interpreting gene expression data, it sometimes is blurred by incomplete gene annotation, missing expression response of key genes and secondary gene expression responses. These shortcomings may be partially circumvented by instead matching gene expression signatures to signatures of other experiments. FINDINGS: To facilitate this we present the Functional Association Response by Overlap (FARO) server, that match input signatures to a compendium of 242 gene expression signatures, extracted from more than 1700 Arabidopsis microarray experiments. CONCLUSIONS: Hereby we present a publicly available tool for robust characterization of Arabidopsis gene expression experiments which can point to similar experimental factors in other experiments. The server is available at http://www.cbs.dtu.dk/services/faro ...
CG000170_TechNote_BiologicalandTechnicalVariationinSingleCell3GeneExpressionExperiments_RevA_.pdf. Technical Note - Biological & Technical Variation in Single Cell Gene Expression Experiments. The Chromium Single Cell 3′ v2 Reagent Kits protocol (Document CG00052) produces Single Cell 3′ short-read sequencer compatible libraries. Technical and biological variation may be present in the experiment design, and may impact data interpretation. Potential sources of technical variation include running a sample on two separate microfluidic chips or at different well positions on the same chip, and or technical variation introduced by sequencing libraries on separate Illumina flowcells or sequencing lanes. This Technical Note examines the potential sources of technical and biological variation and their effects on single cell gene expression. These factors need to be considered when designing an experiment to minimize bias and generate reliable single cell gene expression data.. FOR USE WITH. ...
Researchers use DNA microarrays, or gene chips, to distinguish among different types of tissues based on the expression patterns of thousands of genes. A new study says the technology can be modified to profile more tissue samples simultaneously and with greater efficiency. The innovation is called an array of arrays. Gene expression profiles are typically obtained one at a time by hybridizing a single tissue sample to a single array on an individual glass slide. The integrated device described in the study is a glass wafer that includes 49 individual oligonucleotide arrays arranged as a 7 × 7 array of arrays. David J. Lockhart and colleagues at the Genomics Institute of the Novartis Research Foundation, in San Diego, California, developed a way to hybridize many tissue samples to multiple arrays on a single glass slide, or wafer. Using this and other modifications, they completed a study of gene expression in ovarian cancer in a single experiment. This was done in a fraction of the time and ...
Background Despite sharing the same genes, identical twins demonstrate substantial variability in behavioral traits and in their risk for disease. Epigenetic factors-DNA and chromatin modifications that affect levels of gene expression without affecting the DNA sequence-are thought to be important in establishing this variability. Epigenetically-mediated differences in the levels of gene expression that are associated with individual variability traditionally are thought to occur only in a gene-specific manner. We challenge this idea by exploring the large-scale organizational patterns of gene expression in an epigenetic model of behavioral variability. Methodology/Findings To study the effects of epigenetic influences on behavioral variability, we examine gene expression in genetically identical mice. Using a novel approach to microarray analysis, we show that variability in the large-scale organization of gene expression levels, rather than differences in the expression levels of specific genes, is
Quantitative gene expression analysis aims to define the gene expression patterns determining cell behavior. So far, these assessments can only be performed at the population level. Therefore, they determine the average gene expression within a population, overlooking possible cell-to-cell heterogeneity that could lead to different cell behaviors/cell fates. Understanding individual cell behavior requires multiple gene expression analyses of single cells, and may be fundamental for the understanding of all types of biological events and/or differentiation processes. We here describe a new reverse transcription-polymerase chain reaction (RT-PCR) approach allowing the simultaneous quantification of the expression of 20 genes in the same single cell. This method has broad application, in different species and any type of gene combination. RT efficiency is evaluated. Uniform and maximized amplification conditions for all genes are provided. Abundance relationships are maintained, allowing the ...
Gene Expression Analysis Market-[By Technology (DNA Microarray, Real-Time PCR, Next Generation Sequencing), By Consumables (DNA chips, Reagents), By Services (Gene Profiling, Bioinformatics, Data Analysis Software) & Applications]-Global Forecast to 2018. The global gene expression analysis market is witnessing a significant growth and will continue to do so in the next five years. The factors contributing to this growth are increased funding scenario worldwide, increased government involvement, developments in research for diseases like cancer, and the use of gene expression in drug discovery and personalized medicine. The Asian region is projected to have the highest growth rate with growth hinged at China, India, and Japan. Apart from Asia, countries such as Turkey, Brazil, and South Africa too have a high projected growth.. In the Asian region, China is the genomic leader. China has cultivated a favorable condition to support gene expression analysis growth. From its humble beginning in 1999 ...
The most comprehensive gene expression qPCR assay selection in the industry- helping you achieve highly sensitive and specific detection from your research.. TaqMan Gene Expression Assays are probe and primer sets based on 5 nuclease chemistry using TaqMan MGB (minor groove binder) probes, the most quantitative gene expression technology available.. ...
Gene Expression Analysis can provide an ideal blend of high-level analysis and granular detail when studying a biological system. We know that the RNA levels of an organisms genes not only determine the systems overall status, but also the functioning of the many molecular pathways in the organism. We also know that activity in these pathways can make or break a commercial product or production process. Lets see how Time-Series Gene Expression Analysis can address these challenges.. The key is to is to look at the dynamics in gene expression, this means studying the ways in which gene expression changes during a biological process. As the price of RNA-seq data has come down, it has become very feasible to analyze time series RNA-seq data from organisms in commercial biological products and industrial production processes. The focus then is on deploying tools and expertise to use the information contained in the tens of thousands of data points that these time series experiments produce, to ...
It is gene expression that defines a cells identity. Science, Sciences Science of Aging Knowledge Environment (SAGE KE), and Sciences STKE focus attention on the highly dynamic nature of gene expression. Mechanisms governing selective gene expression in multigene families, as well as those by which cis- and trans-acting factors contribute to regulation of gene expression, are topics under discussion. In addition, new methodologies allow researchers to gain insight into gene expression at the level of single cells and provide a glimpse at the real-time interactions among proteins and DNA.. ...
Inflammation involves timed gene expression, suggesting that the fine-tuned onset, amplitude, and termination of expression of hundreds of genes is of critical importance to organismal homeostasis. Recent study of post-transcriptional regulation of inflammatory gene expression led to the suggestion of a regulatory role for pre-mRNA splicing. Here, using a hybrid capture approach to purify incompletely spliced, chromatin-associated pre-mRNAs, we use deep sequencing to study pre-mRNA splicing of the NF-kB transcriptome. By freezing transcription and examining subsequent splicing of complete transcripts, we find many introns splice tens to hundreds of times slower than average. In many cases, this is attributable to poor splice donor sequences that are evolutionarily conserved. When these introns were altered by ~2 base pairs to yield stronger splice donors, gene expression levels increased markedly for several genes in the context of a reporter system. We propose that such splice sites represent a ...
The Gene Expression Metasignatures (GEMS) analysis tool was developed to allow researchers to determine a weighted consensus across multiple datasets for the regulation of a gene by acute (0-4 h) or chronic (24 h) treatment with 17beta-estradiol in MCF-7 cells. GEMS was retired in November 2012. In its place we have developed a broader, large-scale differential gene expression tool for the nuclear receptor signaling research community, Transcriptomine. Transcriptomine collates omics-scale differential gene expression studies across the nuclear receptor and coregulator signaling field into a single analysis tool, allowing researchers to detect patterns across multiple datasets. A large number of 17beta-estradiol MCF-7 datasets have been uploaded to the database, including all those originally in GEMS. These can currently be viewed as individual fold changes.. ...
Gene expression is the process by which genetic instructions are used to synthesise gene products. Measuring this gene expression is a key element in the study of life sciences. For example, understanding the level of gene expression in a cell, tissue or organism can provide valuable information in terms of identifying viral infection, determining cancer susceptibility or testing whether a bacteria is resistant to penicillin.
The primary goal of the study is to measure in the intact human heart, the alterations in gene expression over time that are associated with reverse remodeling in response to β-blockade. The second goal is to investigate the signaling mechanisms which in turn are responsible for these changes in gene expression, and the third goal is to determine the relationship between intrinsic systolic dysfunction and remodeling of the left ventricle. This will be accomplished by measuring ventricular size, function, and gene expression in myocardial tissue samples obtained by percutaneous biopsy prior to initiation of β-blockade and at 3 and 12 months after start of therapy. The specific Aims and Hypotheses to be tested are:. ...
The edge package implements methods for carrying out differential expression analyses of genome-wide gene expression studies. Significance testing using the optimal discovery procedure and generalized likelihood ratio tests (equivalent to F-tests and t-tests) are implemented for general study designs. Special functions are available to facilitate the analysis of common study designs, including time course experiments. Other packages such as snm, sva, and qvalue are integrated in edge to provide a wide range of tools for gene expression analysis.
Relative gene expression analysis requires precise, powerful and cutting edge technology called Real Time PCR, that is being utilized today by many research laboratories around the world.
Weight Loss, Gene Expression and Excretion. Losing weight is NOT about counting calories because not all calories (foods we eat) are created equally. A calorie consumed is different than a calorie of energy that you burn off through exercise because of a concept called gene expression. The foods you eat affect your bodys ability to alter gene expression. There are two basic types of genes: constitutional and inducible. Constitutional genes encode DNA and RNA messages that are expressed in a constant fashion and are not generally modified by environmental or lifestyle choices. Inducible genes, however, are sensitive to toxins, nutritional influences, and the environment and can be up-regulated or down regulated in their expression. These inducible genes play a large role in the aging process and in the livers ability handle detoxification and excretion.. Our genetic inheritance also plays a large role in how vulnerable we are to age-related diseases via the inducible gene system. A good ...
Seker, H. (2004) A Multi-Fuzzy Filtering Approach to Reliable Gene Expression Profile Analysis. Proceedings of the 2004 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology, October 2004, pp. 37-40 ...
View Notes - Gene Expression from BIOL 101 at UNC. Gene Expression/Test 3 Tuesday, March 03, 2009 9:30 AM 1. Helicase molecule o Protein made on ribosome o In cytoplasm. Sometime cell needs sometime
An important new study has revealed the clearest picture yet of precisely how much measurement variation influences gene expression profiles of breast cancer.
Gene expression can be quantitatively analyzed by hybridizing fluor-tagged mRNA to targets on a cDNA micro- array. Comparison of expression levels arising from co- hybridized samples is achieved by taking ratios of average expression levels for individual genes. The present paper concerns image processing to automatically segment digitized micro-arrays and measure median gene expression levees across cDNA target sites. The main difficulty arises from determination of the target site when signal intensity is low. Segmentation must be accomplished for target sites that can possess highly unstable geometry and consist of a relatively small number of pixels. Segmentation must also be computationally efficient. The present paper proposes a nonparametric statistical method that separates target site from local background using the Mann-Whitney test ...
Jurasek JV, Raposa LB, Gubicskóné Kisbenedek A et al.. Táplálkozástudományi és Dietetikai Intézet, Pécsi Tudományegyetem, Egészségtudományi Kar Pécs.. Orvosi hetilap. Mar 2017.. Nowadays, the food industry more often uses different type of additives during the food production.Our aim was to examine the monosodium-glutamates effect (in animal experiment) on DNA-methyltransferases in gene expression patterns of mRNA levels.In the investigation we used 24 (n=24) CD1 type female mice. The animals were fed with different equivalent human doses of the tested substance. After autopsy, mRNA was isolated from different tissues (lung, liver, kidney, spleen). DNMT1, DNMT3A and DNMT3B levels were determined by Quantitative Real-Time PCR.DNMT1 significantly suppressed the gene expression in all the three treated groups ( ...
Learn what gene expression measures, what techniques can be used, and what questions quantification of gene expression can answer for scientists and medical professionals.
We demonstrate here that SMART PCR-amplified cDNAs arrayed on a nylon membrane are suitable for high-throughput tissue expression profiling when starting biological materials are limited. We show that SMART cDNA accurately reflects gene expression patterns found in total RNA by comparing the express …
The ability of cells to control the expression of genes is important for cell survival. Nutrients can alter the gene expression that controls levels of bioactive proteins. Herbs alter gene activity in various ways. Gene transcription, the most important, is the initial step in gene expression. The pregnane X receptor (PXR receptor) is the target […]. View Post ...
Utilize species-agnostic, lipid-based tagging compatible with cells or nuclei to load up to 12 samples onto one GEM well. Click here to learn more ...
TimesVector is a triclustering tool for clustering time-series data that comprises multiple conditions, or phenotypes. It identifies gene clusters that exhibit distinctly similar or different gene expression patterns among the comparing sample conditions. For example, for a time-series data set of five different strains of yeast, each data sampled at 3 time points, TimesVector will search for gene clusters where a specific strain shows a distinctively different gene expression pattern from the others.. As an example result, 33 genes in cluster 25 were significantly induced at day 5 (D5) during fermentation, only in the DV10 yeast strain (data from GSE11651) ...
The secretory protein Reg3γ (also known as PAP III) is expressed in several tissues, and its expression is induced in various injuries and inflammatory conditions in gastrointestinal tract (Iovanna et al. 1992; Ogawa et al. 2003), skeletal muscle (Klasan et al. 2014) as well as in central and peripheral nervous system (Namikawa et al. 2005, 2006; Ampo et al. 2009; Kawahara et al. 2011; Klasan et al. 2014). However, almost nothing is known about cardiac Reg3γ gene expression, although increased Reg3γ expression has been repeatedly identified in cardiac gene expression profiling screens (Rysä et al. 2005; Tenhunen et al. 2006a; Watanabe et al. 2008; Liu et al. 2009). In this study, we are first to characterize the expression and regulation of Reg3γ in the heart. We found that Reg3γ gene expression is rapidly up‐regulated by post‐MI remodeling and Ang II in the adult rat heart in vivo. We showed that losartan treatment reduced left ventricular Reg3γ gene expression levels activated by ...
The general goal of the technique is similar to the DNA microarray. However, SAGE is a sequence-based sampling technique. Observations are not based on hybridization, which result in more qualitative, digital values. In addition, the mRNA sequences do not need to be known a priori, so genes or gene variants which are not known can be discovered. Microarray experiments are much cheaper to perform, so large-scale studies do not typically use SAGE. Quantifying gene expressions is more exact in SAGE because it involves directly counting the number of transcripts whereas spot intensities in microarrays fall in non-discrete gradients and are prone to background noise. ...
Renal Tissue Thawed for 30 Minutes Is Still Suitable for Gene Expression Analysis. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
BioXpedias Technologies for Gene Expression Profiling offers RNA analyses of samples, using technologies that are time-, cost-, and sample-effective.
Gene expression analysis market will surpass more than US$ 4,500 million revenues towards the end of the forecast period, 2017-2022.
Gene editing with the TUNR system allows you to obtain intermediates with high, medium and low reduction of gene expression with the same targeting quality as for knock-out.
OK...so my notice earlier was an early April fools joke. Anyway, I apologize to Ron Edgar of the Gene Expression Omnibus, as a concerned reader emailed him. Ill try to think of something more innocuous next time. I should have just made up a fake organization ...
Learn how to prepare RNA for gene expression analysis from cultured cells in 7 minutes. The Cells-to-CT 1-Step TaqMan Kit is a simple, quick alternative to traditional RNA extraction.
The RNAscope® and BaseScope™ ISH assays can both be applied as methods to detect gene expression with morphological context in a multitude of mouse models.