scispacy_entities_extractions_and_linkers(uncleared_outputs)_.ipynb

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  "cells": [
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "view-in-github",
        "colab_type": "text"
      },
      "source": [
        "<a href=\"https://colab.research.google.com/github/WuraolaOyewusi/How-to-use-scispaCy-Entity-Linkers-for-Biomedical-Named-Entities/blob/master/scispacy_entities_extractions_and_linkers(uncleared_outputs)_.ipynb\" target=\"_parent\"><img src=\"https://colab.research.google.com/assets/colab-badge.svg\" alt=\"Open In Colab\"/></a>"
      ]
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "d1DoSlz7ZAh7",
        "colab_type": "text"
      },
      "source": [
        "###Download extracted entities dataset, run this cell if you want to go straight to entity linkage without extracting the Named Entities yourself.If you do this, you do not need to install the NER models and import them."
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "RBXisF-EYx4t",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "%%capture\n",
        "!wget https://raw.githubusercontent.com/WuraolaOyewusi/How-to-use-scispaCy-Entity-Linkers-for-Biomedical-Named-Entities/master/entities_and_label_from_4_scispacy_NER_models.csv"
      ],
      "execution_count": 1,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "jPvIMB9HlHma",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "%%capture                                                               \n",
        "!pip install scispacy\n",
        "!pip install swifter\n",
        "!pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_core_sci_sm-0.2.5.tar.gz      #scispacy medium model\n",
        "#!pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_core_sci_md-0.2.5.tar.gz      #scispacy medium model\n",
        "# !pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_ner_bc5cdr_md-0.2.5.tar.gz    #biomedical NER model trained on BC5CDR corpus\n",
        "# !pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_ner_bionlp13cg_md-0.2.5.tar.gz  #biomedical NER model trained on BIONLP13CG corpus\n",
        "# !pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_ner_craft_md-0.2.5.tar.gz    #biomedical NER model trained on CRAFT corpus\n",
        "# !pip install https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/releases/v0.2.5/en_ner_jnlpba_md-0.2.5.tar.gz     #biomedical NER model trained on JNLPBA corpus"
      ],
      "execution_count": 2,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "Yfwmr_KPnz-b",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "import spacy\n",
        "import scispacy\n",
        "import swifter\n",
        "import pandas as pd\n",
        "from spacy import displacy\n",
        "import en_core_sci_sm\n",
        "#import en_core_sci_md\n",
        "# import en_ner_bc5cdr_md\n",
        "# import en_ner_jnlpba_md\n",
        "# import en_ner_craft_md\n",
        "# import en_ner_bionlp13cg_md\n",
        "from scispacy.abbreviation import AbbreviationDetector\n",
        "from scispacy.linking import EntityLinker\n",
        "from collections import OrderedDict,Counter\n",
        "from pprint import pprint\n",
        "from tqdm import tqdm\n",
        "tqdm.pandas()"
      ],
      "execution_count": 3,
      "outputs": []
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "M7zSrtuUl6wB",
        "colab_type": "text"
      },
      "source": [
        "### The sample text here is from \n",
        "###Denison MR. CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS. In: Institute of Medicine (US) Forum on Microbial Threats; Knobler S, Mahmoud A, Lemon S, et al., editors. Learning from SARS: Preparing for the Next Disease Outbreak: Workshop Summary. Washington (DC): National Academies Press (US); 2004. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92477/"
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "Qsj-NWy1lJIO",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "sample_text= \"\"\"CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS\n",
        "Mark R. Denison, M.D.\n",
        "For coronavirus investigators, the recognition of a new coronavirus as the cause of severe acute respiratory syndrome (SARS) was certainly remarkable, yet perhaps not surprising (Baric et al., 1995). The cadre of investigators who have worked with this intriguing family of viruses over the past 30 years are familiar with many of the features of coronavirus biology, pathogenesis, and disease that manifested so dramatically in the worldwide SARS epidemic. Advances in the biology of coronaviruses have resulted in greater understanding of their capacity for adaptation to new environments, transspecies infection, and emergence of new diseases. New tools of cell and molecular biology have led to increased understanding of intracellular replication and viral cell biology, and the advent in the past five years of reverse genetic approaches to study coronaviruses has made it possible to begin to define the determinants of viral replication, transpecies adaptation, and human disease. This summary will discuss the basic life cycle and replication of the well-studied coronavirus, mouse hepatitis virus (MHV), identifying the unique characteristics of coronavirus biology and highlighting critical points where research has made significant advances, and which might represent targets for antivirals or vaccines. Areas where rapid progress has been made in SCoV research will be described. Finally, areas of need for research in coronavirus replication, genetics, and pathogenesis will be summarized.\n",
        "Coronavirus Life Cycle\n",
        "The best studied model for coronavirus replication and pathogenesis has been the group 2 murine coronavirus, mouse hepatitis virus, and much of what is known of the stages of the coronavirus life cycle has been determined in animals and in culture using this virus. Thus this discussion will focus on MHV with comparisons to SCoV and other coronaviruses. This is appropriate because bioinformatics analyses suggest that SCoV, while a distinct virus, has significant similarities in organization, putative protein functions, and replication to the group II coronaviruses, particularly within the replicase gene (Snijder et al., 2003). Excellent, detailed reviews of MHV and coronavirus replication are available elsewhere (Holmes and Lai, 1996; Lai and Cavanagh, 1997).\n",
        "The coronavirus virion is an enveloped particle containing the spike (S), membrane (M), and envelope (E) proteins. In addition, some strains of coronaviruses, but not SCoV, express a hemagglutinin protein (HE) that is also incorporated in the virion. The genome of coronaviruses is a linear, single-stranded RNA molecule of positive (mRNA) polarity, and from 28 to 32 kb in length (Bonilla et al., 1994; Drosten et al., 2003; Lee et al., 1991). Within the virion, the genome is encapsidated by multiple copies of the nucleocapsid protein (N), and has the conformation of a helical RNA/nucleocapsid structure. The S protein has been a focus of pathogenesis studies in mice because it appears to be the critical determinant of cell tropism, species specificity, host selection, cell tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and Gallagher, 1998).\n",
        "Virus replication is initiated by binding of the S protein to specific receptors on the host cell surface. For MHV, the primary receptor has been shown to be the carcino-embryonic antigen–cell adhesion molecule (CEACAM) (Dveksler et al., 1991; 1996; Holmes and Lai, 1996; Yokomuri and Lai, 1992), and for the human coronavirus, HCoV-229E, and other group 1 coronaviruses, the receptor is aminopeptidase N (Yeager et al., 1992). The precise mechanisms of entry and uncoating have yet to be defined, but likely occur by either fusion from without or viroplexis through endocytic vesicles. For wildtype MHV, entry and uncoating constitute a pH independent process that is probably direct fusion mediated by a fusion peptide in the S protein (Gallagher et al., 1991). The understanding of the region of the S1 component of coronavirus that binds to receptors was the basis for studies leading to the very recent and very rapid identification of angiotensin converting enzyme 2 (ACE 2) as a receptor for SCoV (Li et al., 2003).\n",
        "The next discrete stage in the life cycle is translation and proteolytic processing of viral replicase proteins from the input genome RNA, followed by formation of cytoplasmic replication complexes in association with cellular membranes (Denison et al., 1999; Gosert et al., 2002; Shi et al., 1999; van der Meer et al., 1999). Replication complexes are thought to be sites of all stages of viral RNA transcription and replication, and possibly assembly of nascent viral nucleocapsids. Viral assembly occurs both temporally and physically distinct from viral replication complexes in the endoplasmic-reticulum-Golgi-intermediate compartment (ERGIC), a transitional zone between late ER and Golgi (deVries et al., 1997; Klumperman et al., 1994; Krijnse-Locker et al., 1994; Rottier and Rose, 1987). Although the mechanisms by which replication products are delivered to sites of assembly remain to be determined, it has been shown that subpopulations of replicase proteins and the structural nucleocapsid (N) translocate from replication complexes to sites of assembly and may mediate the process in association with cellular membrane/protein trafficking pathways (Bost et al., 2000). Virus assembly in the ERGIC involves interactions of genome RNA, N, the membrane protein (M), and the small membrane protein (E), resulting in budding of virions into the lumen of ER/Golgi virosomes (Opstetten et al., 1995). Further maturation of virus particles occurs during movement through the Golgi, resulting in virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the virosomes to the cell surface has not been well characterized, but is presumed to occur via normal vesicle maturation and exocytic processes. The outcome is the nonlytic release of the vast majority of mature virions into the extracellular space. For MHV and several other coronaviruses that can directly fuse with cells, there is a characteristic and rapidly detectable cytopathic effect of cell-cell fusion into multinucleated syncytia. Production of infectious virus continues even after the majority of cells are fused. Syncytia were recently reported as a readout of SCoV receptor expression and cell infection (Li et al., 2003).\n",
        "Viral Replication Complex Formation and Function\n",
        "Following entry and uncoating, the 5′ most replicase gene of the input positive strand RNA genome is translated into two co-amino terminal replicase polyproteins that are co- and post-translationally processed by viral proteinases to yield 15 to 16 mature replicase proteins, as well as intermediate precursors. The nascent replicase polyproteins and intermediate precursors likely mediate the formation of viral replication complexes in the host cell cytoplasm. Interestingly, coronavirus replication requires continuous replicase gene translation and processing throughout the life cycle to maintain productive infection (Kim et al., 1995; Perlman et al., 1987; Sawicki and Sawicki, 1986). Replication complexes of MHV are associated with double-membrane vesicles (Gosert et al., 2002), and all tested MHV replicase proteins have been shown to colocalize to replication complexes at the earliest time of detection, likely both by membrane integration and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison et al., 1999; Prentice and Denison, in press; Shi et al., 1999; Sims et al., 2000; van der Meer et al., 1999). Further, replicase proteins likely mediate the process of double-membrane vesicle formation, likely by induction of cellular autophagy pathways (E. Prentice, unpublished results).\n",
        "Coronavirus replication complexes are sites for replicase gene translation and replicase polyprotein processing, and also for viral RNA synthesis. Replicase gene proteins likely mediate positive-strand, negative-strand, subgenomic, and genomic RNA synthesis, as well as processes of capping, polyadenylation, RNA unwinding, template switching during viral RNA synthesis, and discontinuous transcription and transcription attenuation. The coronavirus replicase polyproteins and mature replicase proteins represent the largest and most diverse repertoire of known and predicted distinct enzymatic functions of any positive-strand RNA virus family. Until recently, of the 15 or more mature replicase proteins, only the proteinase, RNA helicase, and RNA-dependent RNA polymerase activities had been predicted or experimentally confirmed (Brockway et al., 2003; Heusipp et al., 1997; Lee et al., 1991; Ziebuhr et al., 2000). With the advent of SARS, more extensive bioinformatics analyses have resulted in predictions of several additional functions involved in RNA processing, including methyltransferase and exonuclease activities (Snijder et al., 2003; Thiel et al., 2003). Even with inclusion of distant predicted relationships, up to eight of the replicase proteins remain without predicted or confirmed functions. In summary, it is likely that coronaviruses have exploited their genetic capacity to encode proteins in the replicase gene with distinct functions in RNA synthesis and processing, as well as proteins with specific roles in induction or modification in host cellular membrane biogenesis and trafficking, delivery of replication products to sites of assembly, and possibly virus assembly. Thus replicase translation, replicase polyprotein processing, and mature replicase proteins constitute important targets for interference with coronavirus replication, virus-cell interactions, or viral pathology.\n",
        "Coronavirus Replicase Protein Expression and Processing\n",
        "The proteinase activities for all coronaviruses include both papain-like proteinase (PLP) and picornavirus 3C-like proteinase activities that are encoded within the replicase polyproteins and mediate both cis and trans cleavage events (Ziebuhr et al., 2000). Because of the parallel evolution of the proteinases, their cleavage sites, and the hierarchical cleavage processes, the proteolytic processing of the coronavirus replicase proteins may serve as distinct regulatory and genetic elements (Ziebuhr et al., 2001). Specifically, there are both conserved and divergent regions of the replicase polyproteins by amino acid identity and similarity, with the sequences and predicted mature proteins beginning with the 3C-like proteinases through the carboxy terminus of the replicase polyprotein retaining higher identity and similarity across the predicted proteins. In contrast, the amino-terminal third of the replicase demonstrates the most variation in proteins, cleavage site locations, and the number of proteinases that mediate maturation processing. SCoV appears to have the general organization of, and similar protein sizes to, the group 2 coronaviruses such as MHV in this part of the genome (Snijder et al., 2003). However, SCoV likely uses only one PLP to mediate the cleavages, similar to the group 3 coronavirus infectious bronchitis virus (IBV). Thus this region of the replicase may experience the most variability, suggesting either the encoding of accessory functions that are flexible and tolerant of changes, or conversely group or host-specific roles that are subject to pressure for more rapid change.\n",
        "Expression of Structural and Accessory Genes\n",
        "Only the 5′ most replicase gene is translated from the input positive-strand genome RNA. The genome contains multiple other genes for the known structural proteins S, E, M, and N, as well as other genes for expression of proteins that have been labeled as “nonstructural” or “accessory” because they have been presumed to not be required for replication, and are not thought to be incorporated into virions. MHV encodes six of these genes, while SCoV encodes possibly up to 11 structural and accessory genes, which are expressed from subgenomic mRNAs (Snijder et al., 2003). Subgenomic RNA transcription occurs during minus- strand RNA synthesis by acquisition of the antileader RNA sequences from the 5′ end of the genome via homology to a transcriptional regulatory sequence (TRS, also known as an intergenic sequence), and requiring a discontinuous activity of the nascent minus-strand template and polymerase complex to acquire the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the generation of a “nested set” of subgenomic negative-strand RNAs that all contain the antileader sequences that serve as templates for similar size subgenomic mRNAs. This transcriptional strategy exposes different genes as the 5′ ORF in different mRNAs, all of which also contain the 3′ sequence downstream of the gene, including the 3′ nontranslated region of the genome.\n",
        "For MHV, genes 3, 5b, 6, and 7 encode S, E, M, and N, respectively. Genes 2, 4, and 5a are not required for replication in culture, and have been mutated to block expression, deleted, or substituted with noncoronavirus genes such as GFP (de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all coronaviruses retain these genes in various combinations in the face of presumed pressure for genetic economy and apparent lack of functions in RNA synthesis, it is presumed that these genes serve roles in modification of host cells, pathogenesis, or interactions with the immune system. SCoV encodes a larger and more complex array of these genes than MHV or other coronaviruses, which may reflect its evolution in its original animal host (Ksiazek et al., 2003; Marra et al., 2003; Snijder et al., 2003; Thiel et al., 2003). In addition, the report of a deletion within one of the accessory genes in human isolates of SCoV suggests that this may be a gene involved in host range or adaptation for replication and transmission in humans (Guan et al., 2003).\n",
        "Coronavirus Genetics\n",
        "Until recently, the genetics of coronavirus replication and pathogenesis have largely been studied using natural variants, host range mutants, passaged virus, and mutagenized viruses selected for temperature sensitivity and specific phenotypes. Classical complementation of functions made it possible to define at least eight genetic groups for MHV, with most of the complementation groups localized to the replicase gene (Stalcup et al., 1998). Taking advantage of naturally high rates of homologous RNA-RNA recombination and of host range determinants in the S protein, the development of targeted recombination has allowed more defined and detailed studies of the accessory and structural genes of MHV, transmissible gastroenteritis virus (TGEV), and feline infectious peritonitis virus (FIPV) (Haijema et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with natural variants and targeted recombination genetic studies have demonstrated that the S protein is the major determinant of host range, tropism, and pathogenesis; other genetic elements, possibly in the replicase, may influence these characteristics of different coronaviruses (Navas and Weiss, 2003). The capacity of coronaviruses to change host range, transmission, pathogenesis, and disease has been established in the laboratory using cell adaptation and virus passage (Baric et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in nature by natural variants of MHV, TGEV, and bovine coronavirus (BCoV), as well as by studies using heterologous viruses such as canine coronavirus (CcoV) to immunize cats against FIPV (Enjuanes et al., 1995; Tresnan et al., 1996). Further, targeted recombination studies have confirmed the genetic flexibility of the coronavirus genome and the ability of coronaviruses to recover wild-type replication following deletions, mutations, substitutions, and gene order rearrangements in the structural and accessory genes (de Haan et al., 2002).\n",
        "Challenges for genetic studies using natural variants and mutants, particularly in defining the precise changes responsible for altered phenotypes, has limited progress in genetic studies. Targeted recombination, while a robust system with powerful selection, has been limited to studies of the 3′ 10 kb of the MHV genome, and is limited to selection of viable recombinants. Recently, the establishment of “infectious clone” reverse genetic strategies for the coronaviruses TGEV (Transmissible Gastroenteritis Coronavirus), HCoV-229E, IBV, and MHV has made it theoretically possible to study the genetics of the entire genome and all of the structural, accessory, and replicase genes. Approaches to “infectious cloning” have included full-length cDNA clones of TGEV genome in bacterial artificial chromosomes (Gonzalez et al., 2001), recombinant vaccinia viruses containing full-length cDNA clones of HCoV-229E and IBV genomes (Casais et al., 2001; Thiel et al., 2001), and in vitro assembly strategies for TGEV, MHV, and most recently, SCoV (Yount, 2000; Yount et al., 2002, 2003).\n",
        "The in vitro assembly approach was developed to overcome the challenge of full-length cDNA cloning of the TGEV and MHV genomes, which contained “toxic” regions in the replicase gene, resulting in unstable or toxic clones in E. coli (Yount, 2000; Yount et al., 2002). Subcloning of the regions required splitting the toxic domains into separate clones. The result of this strategy was the cloning of the MHV genome into seven fragments (A through G). To recover viable virus, the following strategy is pursued: (1) cloned cDNA fragments are excised from plasmid using class 2 restriction enzymes that remove the recognition site and leave overhanging genomic sequence; (2) excised fragments are ligated (assembled) in vitro; (3) transcription of full-length genomic RNA is driven in vitro using a T7 promoter on the 5′ fragment A; (4) full-length genome RNA is electroporated into competent cells that are then plated on a monolayer of naturally permissive cells; and (5) cells are monitored for cytopathic effect or plaques, and virus is recovered from plaques or media supernatant.\n",
        "In vitro assembly has many advantages for genetic studies of such a large and complex genome RNA. First, genetic changes can be introduced and confirmed in stable small fragments without the need for a ~30kb genomic clone. Second, the cloned fragments make it possible to develop libraries of mutations that can rapidly be tested in different combinations. Furthermore, identification of putative second-site reversion mutations for deleterious introduced changes can be introduced with the original mutation to confirm their reversion potential. In combination with biochemical and cell imaging approaches, it also is possible to study highly defective or lethal mutations in electroporated cells, in order to define critical determinants of replication. The in vitro assembly approach has been used to introduce marker mutations that are silent for replication in culture (Yount et al., 2003). In addition, we have engineered mutations in the MHV replicase gene to define the requirements for polyprotein processing and to determine the role of specific replicase proteins in replication in culture and in pathogenesis in animals. Using this approach we have recovered viruses with mutations at polyprotein cleavage sites and proteinase catalytic residues, all of which have distinct phenotypes in protein processing, viral growth, and viral RNA synthesis (unpublished results). Thus, direct reverse genetic studies of the critical replicase gene functions can be performed using in vitro assembly of infectious clones.\n",
        "Advances in SCoV Research\n",
        "The rapid progress in the identification and characterization of SCoV as the etiologic agent of SARS was made possible by the fact that the virus grows well in culture, and by the foundational research in coronaviruses that has been supported by the National Institutes of Health, the Multiple Sclerosis Foundation, the U.S. Department of Agriculture, and other organizations over the past two decades. The application of knowledge concerning virus structure, genetics, receptor binding, virus entry, and viral pathogenesis has made it possible to target the spike protein for studies of SCoV replication, pathogenesis, and immune response (Xiao et al., 2003). The remarkably rapid identification of ACE 2 as a receptor for SARS has demonstrated the foundational importance of studies of other coronaviruses (Li et al., 2003). Similarly, understanding of replicase gene expression, processing, and predicted functions has identified possible targets for structure/function studies and possible therapeutic intervention. The studies of coronavirus proteinase activities, cleavage site, and structures were the basis for studies leading to the rapid determination of SCoV replicase polyprotein cleavage sites and 3CLpro crystal structure (Anand et al., 2003; Campanacci et al., 2003; Snijder et al., 2003; Thiel et al., 2003).\n",
        "Application of Reverse Genetics to Studies of SCoV\n",
        "Because of the potential for reemergence of SARS, it is important to move forward with research in diagnostics, vaccines, and therapeutics for SCoV. Experience with the development and use of reverse genetics to study other coronaviruses resulted in establishment of reverse genetics for SCoV within months of the onset of the worldwide epidemic (Yount et al., 2003). How should the understanding of other coronaviruses, the rapid advances in research with SCoV, and the development of reverse genetics for SCoV be harnesssed to achieve these goals and attack these critical questions in SCoV replication, pathogenesis, and disease? Certainly, the use of SCoV reverse genetics, along with robust tissue culture systems and emerging animal models, creates the potential to rapidly answer questions concerning: (1) determinants of virus growth in culture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and escape from biochemical and immune interference with replication; (4) determinants of virulence and pathogenesis; (5) mechanisms of genome recombination and mutation; (6) functions of and requirements for replicase, structural, and accessory proteins; and (7) development of stably attenuated viruses for use as seed stocks for inactivated vaccine or testing as live-attenuated vaccines.\n",
        "How then should these critical issues be investigated while recognizing the potential of SCoV to cause severe disease, as well as the potential for rapid spread? First, there is significant experience with other coronaviruses in attenuation of virus replication and pathogenesis, both using virus passage and by direct engineering of changes. Although coronavirus genome organization, proteins, and replication appear more tolerant of changes then previously thought, all changes of gene order, gene deletion, insertion, or mutagenesis so far reported have led to viruses impaired in replication, pathogenesis, or both. Many of the attenuating changes in MHV and other coronaviruses are conserved in SCoV and thus could be tested for likely attenuation in SCoV culture and animal models. Second, where there is clear conservation of sequences, motifs, proteins, or putative functions between SCoV and model viruses such as MHV, new or untested changes might be most rapidly analyzed under BSL2 conditions in those model viruses, and then directly applied to SARS once their phenotypes are determined. Third, all work with SCoV will be performed only under BSL3 conditions. This would also apply to chimeric viruses, whether engineered by introduction into the SCoV background, or by introducing SCoV proteins or sequences with known or predicted pathogenic consequences into other coronavirus backgrounds. Finally, it is important to develop strains of SCoV that are attenuated and stabilized against reversion and recombination, to be used as the basis for studies of other replication and pathogenesis determinants and construction of virus chimeras. Such attenuated variants would provide additional safeguards while allowing application of powerful genetic tools to the study of SCoV emergence, biology, disease, treatment, and prevention. Overall, newly invigorated programs in other human and animal coronaviruses, combined with the new research in SCoV, will shed important new light on this important virus family and perhaps lead to better understanding of the potential for resurgence of SCoV or the emergence of other coronaviruses into human populations.\"\"\""
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "gXJEXmcGyZsM",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "def display_entities(model,document):\n",
        "    \"\"\" A function that returns a tuple of displacy image of named or unnamed word entities and\n",
        "        a set of unique entities recognized based on scispacy model in use\n",
        "        Args: \n",
        "            model: A pretrained model from spaCy or ScispaCy\n",
        "            document: text data to be analysed\"\"\"\n",
        "    nlp = model.load()\n",
        "    doc = nlp(document)\n",
        "    displacy_image = displacy.render(doc, jupyter=True,style='ent')\n",
        "    entity_and_label = set([(X.text, X.label_) for X in doc.ents])\n",
        "    return  displacy_image, entity_and_label"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "Nh98GbaDyErw",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        },
        "outputId": "4670f421-68c0-4583-d915-c9bdc2c9ca97"
      },
      "source": [
        "bc5dr_entities = display_entities(en_ner_bc5cdr_md,sample_text)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "text/html": [
              "<span class=\"tex2jax_ignore\"><div class=\"entities\" style=\"line-height: 2.5; direction: ltr\">\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CORONAVIRUS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " RESEARCH: \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    KEYS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " TO DIAGNOSIS, TREATMENT, AND PREVENTION OF \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              "</br>Mark R. Denison, M.D.</br>For coronavirus investigators, the recognition of a new coronavirus as the cause of severe \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    acute respiratory syndrome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ") was certainly remarkable, yet perhaps not surprising (Baric et al., 1995). The cadre of investigators who have worked with this intriguing family of viruses over the past 30 years are familiar with many of the features of coronavirus biology, pathogenesis, and disease that manifested so dramatically in the worldwide \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " epidemic. Advances in the biology of coronaviruses have resulted in greater understanding of their capacity for adaptation to new environments, transspecies \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    infection\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", and emergence of new diseases. New tools of cell and molecular biology have led to increased understanding of intracellular replication and viral cell biology, and the advent in the past five years of reverse genetic approaches to study coronaviruses has made it possible to begin to define the determinants of viral replication, transpecies adaptation, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human disease\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ". This summary will discuss the basic life cycle and replication of the well-studied coronavirus, mouse \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    hepatitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (MHV), identifying the unique characteristics of coronavirus biology and highlighting critical points where research has made significant advances, and which might represent targets for antivirals or vaccines. Areas where rapid progress has been made in SCoV research will be described. Finally, areas of need for research in coronavirus replication, genetics, and pathogenesis will be summarized.</br>Coronavirus Life Cycle</br>The best studied model for coronavirus replication and pathogenesis has been the group 2 murine coronavirus, mouse \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    hepatitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", and much of what is known of the stages of the coronavirus life cycle has been determined in animals and in culture using this virus. Thus this discussion will focus on MHV with comparisons to SCoV and other coronaviruses. This is appropriate because bioinformatics analyses suggest that SCoV, while a distinct virus, has significant similarities in organization, putative protein functions, and replication to the group II coronaviruses, particularly within the replicase gene (Snijder et al., 2003). Excellent, detailed reviews of MHV and coronavirus replication are available elsewhere (Holmes and Lai, 1996; Lai and Cavanagh, 1997).</br>The coronavirus virion is an enveloped particle containing the spike (S), membrane (M), and envelope (E) proteins. In addition, some strains of coronaviruses, but not SCoV, express a hemagglutinin protein (HE) that is also incorporated in the virion. The genome of coronaviruses is a linear, single-stranded RNA molecule of positive (mRNA) polarity, and from 28 to 32 kb in length (Bonilla et al., 1994; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Drosten\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2003; Lee et al., 1991). Within the virion, the genome is encapsidated by multiple copies of the nucleocapsid protein (N), and has the conformation of a helical RNA/nucleocapsid structure. The S protein has been a focus of pathogenesis studies in mice because it appears to be the critical determinant of cell tropism, species specificity, host selection, cell tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and Gallagher, 1998).</br>Virus replication is initiated by binding of the S protein to specific receptors on the host cell surface. For MHV, the primary receptor has been shown to be the carcino-embryonic antigen–cell adhesion molecule (CEACAM) (Dveksler et al., 1991; 1996; Holmes and Lai, 1996; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Yokomuri\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " and Lai, 1992), and for the human coronavirus, HCoV-229E, and other group 1 coronaviruses, the receptor is aminopeptidase N (Yeager et al., 1992). The precise mechanisms of entry and uncoating have yet to be defined, but likely occur by either fusion from without or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viroplexis\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " through endocytic vesicles. For wildtype MHV, entry and uncoating constitute a pH independent process that is probably direct fusion mediated by a fusion peptide in the S protein (Gallagher et al., 1991). The understanding of the region of the S1 component of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " that binds to receptors was the basis for studies leading to the very recent and very rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    angiotensin\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " converting enzyme 2 (ACE 2) as a receptor for SCoV (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Li\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2003).</br>The next discrete stage in the life cycle is translation and proteolytic processing of viral replicase proteins from the input genome RNA, followed by formation of cytoplasmic replication complexes in association with cellular membranes (Denison et al., 1999; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Gosert\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2002; Shi et al., 1999; van der \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Meer\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " et al., 1999). Replication complexes are thought to be sites of all stages of viral RNA transcription and replication, and possibly assembly of nascent viral nucleocapsids. Viral assembly occurs both temporally and physically distinct from viral replication complexes in the endoplasmic-reticulum-Golgi-intermediate compartment (ERGIC), a transitional zone between late ER and Golgi (deVries et al., 1997; Klumperman et al., 1994; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Krijnse-Locker\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " et al., 1994; Rottier and Rose, 1987). Although the mechanisms by which replication products are delivered to sites of assembly remain to be determined, it has been shown that subpopulations of replicase proteins and the structural nucleocapsid (N) translocate from replication complexes to sites of assembly and may mediate the process in association with cellular membrane/protein trafficking pathways (Bost et al., 2000). Virus assembly in the ERGIC involves interactions of genome RNA, N, the membrane protein (M), and the small membrane protein (E), resulting in budding of virions into the lumen of ER/Golgi virosomes (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Opstetten\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 1995). Further maturation of virus particles occurs during movement through the Golgi, resulting in virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the virosomes to the cell surface has not been well characterized, but is presumed to occur via normal vesicle maturation and exocytic processes. The outcome is the nonlytic release of the vast majority of mature virions into the extracellular space. For MHV and several other coronaviruses that can directly fuse with cells, there is a characteristic and rapidly detectable cytopathic effect of cell-cell fusion into multinucleated syncytia. Production of infectious virus continues even after the majority of cells are fused. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Syncytia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " were recently reported as a readout of SCoV receptor expression and cell infection (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Li\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2003).</br>Viral Replication Complex Formation and Function</br>Following entry and uncoating, the 5′ most replicase gene of the input positive strand RNA genome is translated into two co-amino terminal replicase polyproteins that are co- and post-translationally processed by viral proteinases to yield 15 to 16 mature replicase proteins, as well as intermediate precursors. The nascent replicase polyproteins and intermediate precursors likely mediate the formation of viral replication complexes in the host cell cytoplasm. Interestingly, coronavirus replication requires continuous replicase gene translation and processing throughout the life cycle to maintain \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    productive infection\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (Kim et al., 1995; Perlman et al., 1987; Sawicki and Sawicki, 1986). Replication complexes of MHV are associated with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " vesicles (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Gosert\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2002), and all tested MHV replicase proteins have been shown to colocalize to replication complexes at the earliest time of detection, likely both by membrane integration and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison et al., 1999; Prentice and Denison, in press; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Shi et al., 1999; Sims et al., 2000; van der Meer\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 1999). Further, replicase proteins likely mediate the process of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " vesicle formation, likely by induction of cellular autophagy pathways (E. Prentice, unpublished results).</br>Coronavirus replication complexes are sites for replicase gene translation and replicase polyprotein processing, and also for viral RNA synthesis. Replicase gene proteins likely mediate positive-strand, negative-strand, subgenomic, and genomic RNA synthesis, as well as processes of capping, polyadenylation, RNA unwinding, template switching during viral RNA synthesis, and discontinuous transcription and transcription attenuation. The coronavirus replicase polyproteins and mature replicase proteins represent the largest and most diverse repertoire of known and predicted distinct enzymatic functions of any positive-strand RNA virus family. Until recently, of the 15 or more mature replicase proteins, only the proteinase, RNA helicase, and RNA-dependent RNA polymerase activities had been predicted or experimentally confirmed (Brockway et al., 2003; Heusipp et al., 1997; Lee et al., 1991; Ziebuhr et al., 2000). With the advent of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", more extensive bioinformatics analyses have resulted in predictions of several additional functions involved in RNA processing, including methyltransferase and exonuclease activities (Snijder et al., 2003; Thiel et al., 2003). Even with inclusion of distant predicted relationships, up to eight of the replicase proteins remain without predicted or confirmed functions. In summary, it is likely that coronaviruses have exploited their genetic capacity to encode proteins in the replicase gene with distinct functions in RNA synthesis and processing, as well as proteins with specific roles in induction or modification in host cellular membrane biogenesis and trafficking, delivery of replication products to sites of assembly, and possibly virus assembly. Thus replicase translation, replicase polyprotein processing, and mature replicase proteins constitute important targets for interference with coronavirus replication, virus-cell interactions, or viral pathology.</br>Coronavirus Replicase Protein Expression and Processing</br>The proteinase activities for all coronaviruses include both papain-like proteinase (PLP) and picornavirus 3C-like proteinase activities that are encoded within the replicase polyproteins and mediate both cis and trans cleavage events (Ziebuhr et al., 2000). Because of the parallel evolution of the proteinases, their cleavage sites, and the hierarchical cleavage processes, the proteolytic processing of the coronavirus replicase proteins may serve as distinct regulatory and genetic elements (Ziebuhr et al., 2001). Specifically, there are both conserved and divergent regions of the replicase polyproteins by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    amino acid identity\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " and similarity, with the sequences and predicted mature proteins beginning with the 3C-like proteinases through the carboxy terminus of the replicase polyprotein retaining higher identity and similarity across the predicted proteins. In contrast, the amino-terminal third of the replicase demonstrates the most variation in proteins, cleavage site locations, and the number of proteinases that mediate maturation processing. SCoV appears to have the general organization of, and similar protein sizes to, the group 2 coronaviruses such as MHV in this part of the genome (Snijder et al., 2003). However, SCoV likely uses only one \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " to mediate the cleavages, similar to the group 3 \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus infectious bronchitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (IBV). Thus this region of the replicase may experience the most variability, suggesting either the encoding of accessory functions that are flexible and tolerant of changes, or conversely group or host-specific roles that are subject to pressure for more rapid change.</br>Expression of Structural and Accessory Genes</br>Only the 5′ most replicase gene is translated from the input positive-strand genome RNA. The genome contains multiple other genes for the known structural proteins S, E, M, and N, as well as other genes for expression of proteins that have been labeled as “nonstructural” or “accessory” because they have been presumed to not be required for replication, and are not thought to be incorporated into virions. MHV encodes six of these genes, while SCoV encodes possibly up to 11 structural and accessory genes, which are expressed from subgenomic mRNAs (Snijder et al., 2003). Subgenomic RNA transcription occurs during minus- strand RNA synthesis by acquisition of the antileader RNA sequences from the 5′ end of the genome via homology to a transcriptional regulatory sequence (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TRS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              ", also known as an intergenic sequence), and requiring a discontinuous activity of the nascent minus-strand template and polymerase complex to acquire the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the generation of a “nested set” of subgenomic negative-strand RNAs that all contain the antileader sequences that serve as templates for similar size subgenomic mRNAs. This transcriptional strategy exposes different genes as the 5′ ORF in different mRNAs, all of which also contain the 3′ sequence downstream of the gene, including the 3′ nontranslated region of the genome.</br>For MHV, genes 3, 5b, 6, and 7 encode S, E, M, and N, respectively. Genes 2, 4, and 5a are not required for replication in culture, and have been mutated to block expression, deleted, or substituted with noncoronavirus genes such as GFP (de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all coronaviruses retain these genes in various combinations in the face of presumed pressure for genetic economy and apparent lack of functions in RNA synthesis, it is presumed that these genes serve roles in modification of host cells, pathogenesis, or interactions with the immune system. SCoV encodes a larger and more complex array of these genes than MHV or other coronaviruses, which may reflect its evolution in its original animal host (Ksiazek et al., 2003; Marra et al., 2003; Snijder et al., 2003; Thiel et al., 2003). In addition, the report of a deletion within one of the accessory genes in human isolates of SCoV suggests that this may be a gene involved in host range or adaptation for replication and transmission in humans (Guan et al., 2003).</br>Coronavirus Genetics</br>Until recently, the genetics of coronavirus replication and pathogenesis have largely been studied using natural variants, host range mutants, passaged virus, and mutagenized viruses selected for temperature sensitivity and specific phenotypes. Classical complementation of functions made it possible to define at least eight genetic groups for MHV, with most of the complementation groups localized to the replicase gene (Stalcup et al., 1998). Taking advantage of naturally high rates of homologous RNA-RNA recombination and of host range determinants in the S protein, the development of targeted recombination has allowed more defined and detailed studies of the accessory and structural genes of MHV, transmissible \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gastroenteritis\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " virus (TGEV), and feline infectious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    peritonitis\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " virus (FIPV) (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Haijema\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with natural variants and targeted recombination genetic studies have demonstrated that the S protein is the major determinant of host range, tropism, and pathogenesis; other genetic elements, possibly in the replicase, may influence these characteristics of different coronaviruses (Navas and Weiss, 2003). The capacity of coronaviruses to change host range, transmission, pathogenesis, and disease has been established in the laboratory using cell adaptation and virus passage (Baric et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in nature by natural variants of MHV, TGEV, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    bovine\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " coronavirus (BCoV), as well as by studies using heterologous viruses such as canine coronavirus (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CcoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              ") to immunize cats against FIPV (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Enjuanes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 1995; Tresnan et al., 1996). Further, targeted recombination studies have confirmed the genetic flexibility of the coronavirus genome and the ability of coronaviruses to recover wild-type replication following deletions, mutations, substitutions, and gene order rearrangements in the structural and accessory genes (de Haan et al., 2002).</br>Challenges for genetic studies using natural variants and mutants, particularly in defining the precise changes responsible for altered phenotypes, has limited progress in genetic studies. Targeted recombination, while a robust system with powerful selection, has been limited to studies of the 3′ 10 kb of the MHV genome, and is limited to selection of viable recombinants. Recently, the establishment of “infectious clone” reverse genetic strategies for the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (Transmissible \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Gastroenteritis Coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              "), HCoV-229E, IBV, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " has made it theoretically possible to study the genetics of the entire genome and all of the structural, accessory, and replicase genes. Approaches to “infectious cloning” have included full-length cDNA clones of TGEV genome in bacterial artificial chromosomes (Gonzalez et al., 2001), recombinant \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vaccinia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " viruses containing full-length cDNA clones of HCoV-229E and IBV genomes (Casais et al., 2001; Thiel et al., 2001), and in vitro assembly strategies for TGEV, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", and most recently, SCoV (Yount, 2000; Yount et al., 2002, 2003).</br>The in vitro assembly approach was developed to overcome the challenge of full-length cDNA cloning of the TGEV and MHV genomes, which contained “toxic” regions in the replicase gene, resulting in unstable or toxic clones in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    E. coli\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " (Yount, 2000; Yount et al., 2002). Subcloning of the regions required splitting the toxic domains into separate clones. The result of this strategy was the cloning of the MHV genome into seven fragments (A through G). To recover viable virus, the following strategy is pursued: (1) cloned cDNA fragments are excised from plasmid using class 2 restriction enzymes that remove the recognition site and leave overhanging genomic sequence; (2) excised fragments are ligated (assembled) in vitro; (3) transcription of full-length genomic RNA is driven in vitro using a T7 promoter on the 5′ fragment A; (4) full-length genome RNA is electroporated into competent cells that are then plated on a monolayer of naturally permissive cells; and (5) cells are monitored for cytopathic effect or plaques, and virus is recovered from plaques or media supernatant.</br>In vitro assembly has many advantages for genetic studies of such a large and complex genome RNA. First, genetic changes can be introduced and confirmed in stable small fragments without the need for a ~30kb genomic clone. Second, the cloned fragments make it possible to develop libraries of mutations that can rapidly be tested in different combinations. Furthermore, identification of putative second-site reversion mutations for deleterious introduced changes can be introduced with the original mutation to confirm their reversion potential. In combination with biochemical and cell imaging approaches, it also is possible to study highly defective or lethal mutations in electroporated cells, in order to define critical determinants of replication. The in vitro assembly approach has been used to introduce marker mutations that are silent for replication in culture (Yount et al., 2003). In addition, we have engineered mutations in the MHV replicase gene to define the requirements for polyprotein processing and to determine the role of specific replicase proteins in replication in culture and in pathogenesis in animals. Using this approach we have recovered viruses with mutations at polyprotein cleavage sites and proteinase catalytic residues, all of which have distinct phenotypes in protein processing, viral growth, and viral RNA synthesis (unpublished results). Thus, direct reverse genetic studies of the critical replicase gene functions can be performed using in vitro assembly of infectious clones.</br>Advances in SCoV Research</br>The rapid progress in the identification and characterization of SCoV as the etiologic agent of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " was made possible by the fact that the virus grows well in culture, and by the foundational research in coronaviruses that has been supported by the National Institutes of Health, the Multiple Sclerosis Foundation, the U.S. Department of Agriculture, and other organizations over the past two decades. The application of knowledge concerning virus structure, genetics, receptor binding, virus entry, and viral pathogenesis has made it possible to target the spike protein for studies of SCoV replication, pathogenesis, and immune response (Xiao et al., 2003). The remarkably rapid identification of ACE 2 as a receptor for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " has demonstrated the foundational importance of studies of other coronaviruses (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Li\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEMICAL</span>\n",
              "</mark>\n",
              " et al., 2003). Similarly, understanding of replicase gene expression, processing, and predicted functions has identified possible targets for structure/function studies and possible therapeutic intervention. The studies of coronavirus proteinase activities, cleavage site, and structures were the basis for studies leading to the rapid determination of SCoV replicase polyprotein cleavage sites and 3CLpro crystal structure (Anand et al., 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Campanacci\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " et al., 2003; Snijder et al., 2003; Thiel et al., 2003).</br>Application of Reverse Genetics to Studies of SCoV</br>Because of the potential for reemergence of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", it is important to move forward with research in diagnostics, vaccines, and therapeutics for SCoV. Experience with the development and use of reverse genetics to study other coronaviruses resulted in establishment of reverse genetics for SCoV within months of the onset of the worldwide epidemic (Yount et al., 2003). How should the understanding of other coronaviruses, the rapid advances in research with SCoV, and the development of reverse genetics for SCoV be harnesssed to achieve these goals and attack these critical questions in SCoV replication, pathogenesis, and disease? Certainly, the use of SCoV reverse genetics, along with robust tissue culture systems and emerging animal models, creates the potential to rapidly answer questions concerning: (1) determinants of virus growth in culture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and escape from biochemical and immune interference with replication; (4) determinants of virulence and pathogenesis; (5) mechanisms of genome recombination and mutation; (6) functions of and requirements for replicase, structural, and accessory proteins; and (7) development of stably attenuated viruses for use as seed stocks for inactivated vaccine or testing as live-attenuated vaccines.</br>How then should these critical issues be investigated while recognizing the potential of SCoV to cause severe disease, as well as the potential for rapid spread? First, there is significant experience with other coronaviruses in attenuation of virus replication and pathogenesis, both using virus passage and by direct engineering of changes. Although coronavirus genome organization, proteins, and replication appear more tolerant of changes then previously thought, all changes of gene order, gene deletion, insertion, or mutagenesis so far reported have led to viruses impaired in replication, pathogenesis, or both. Many of the attenuating changes in MHV and other coronaviruses are conserved in SCoV and thus could be tested for likely attenuation in SCoV culture and animal models. Second, where there is clear conservation of sequences, motifs, proteins, or putative functions between SCoV and model viruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              ", new or untested changes might be most rapidly analyzed under BSL2 conditions in those model viruses, and then directly applied to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DISEASE</span>\n",
              "</mark>\n",
              " once their phenotypes are determined. Third, all work with SCoV will be performed only under BSL3 conditions. This would also apply to chimeric viruses, whether engineered by introduction into the SCoV background, or by introducing SCoV proteins or sequences with known or predicted pathogenic consequences into other coronavirus backgrounds. Finally, it is important to develop strains of SCoV that are attenuated and stabilized against reversion and recombination, to be used as the basis for studies of other replication and pathogenesis determinants and construction of virus chimeras. Such attenuated variants would provide additional safeguards while allowing application of powerful genetic tools to the study of SCoV emergence, biology, disease, treatment, and prevention. Overall, newly invigorated programs in other human and animal coronaviruses, combined with the new research in SCoV, will shed important new light on this important virus family and perhaps lead to better understanding of the potential for resurgence of SCoV or the emergence of other coronaviruses into human populations.</div></span>"
            ],
            "text/plain": [
              "<IPython.core.display.HTML object>"
            ]
          },
          "metadata": {
            "tags": []
          }
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "3gm2zsG94RTm",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        },
        "outputId": "a8bd5633-6b46-42a2-befd-c6e96df98f2b"
      },
      "source": [
        "bc5dr_entities_dataframe = pd.DataFrame(bc5dr_entities[1],columns=['Entity','Label'])  #save returned values of entities and their labels in a pandas dataframe\n",
        "bc5dr_entities_dataframe['Ner_model'] = 'bc5dr'  #include a column with constant value of NER model\n",
        "bc5dr_entities_dataframe"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>viroplexis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>productive infection</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>gastroenteritis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>hepatitis virus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>angiotensin</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>5</th>\n",
              "      <td>Enjuanes</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>6</th>\n",
              "      <td>TRS</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>7</th>\n",
              "      <td>Meer</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>8</th>\n",
              "      <td>KEYS</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>9</th>\n",
              "      <td>Campanacci</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>10</th>\n",
              "      <td>Gastroenteritis Coronavirus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>11</th>\n",
              "      <td>acute respiratory syndrome</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>12</th>\n",
              "      <td>Opstetten</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>13</th>\n",
              "      <td>coronaviruses TGEV</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>14</th>\n",
              "      <td>Yokomuri</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>15</th>\n",
              "      <td>coronavirus infectious bronchitis virus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>16</th>\n",
              "      <td>vaccinia</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>17</th>\n",
              "      <td>peritonitis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>18</th>\n",
              "      <td>E. coli</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>19</th>\n",
              "      <td>CcoV</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>20</th>\n",
              "      <td>Drosten</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>21</th>\n",
              "      <td>PLP</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>22</th>\n",
              "      <td>Haijema</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>23</th>\n",
              "      <td>Shi et al., 1999; Sims et al., 2000; van der Meer</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>24</th>\n",
              "      <td>amino acid identity</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>25</th>\n",
              "      <td>infection</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>26</th>\n",
              "      <td>CORONAVIRUS</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>27</th>\n",
              "      <td>Syncytia</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>28</th>\n",
              "      <td>Krijnse-Locker</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>29</th>\n",
              "      <td>SARS</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>30</th>\n",
              "      <td>human disease</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>31</th>\n",
              "      <td>coronavirus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>32</th>\n",
              "      <td>Gosert</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>33</th>\n",
              "      <td>bovine</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>34</th>\n",
              "      <td>Li</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>35</th>\n",
              "      <td>double-membrane</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>36</th>\n",
              "      <td>MHV</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "                                               Entity     Label Ner_model\n",
              "0                                          viroplexis   DISEASE     bc5dr\n",
              "1                                productive infection   DISEASE     bc5dr\n",
              "2                                     gastroenteritis   DISEASE     bc5dr\n",
              "3                                     hepatitis virus   DISEASE     bc5dr\n",
              "4                                         angiotensin  CHEMICAL     bc5dr\n",
              "5                                            Enjuanes  CHEMICAL     bc5dr\n",
              "6                                                 TRS  CHEMICAL     bc5dr\n",
              "7                                                Meer   DISEASE     bc5dr\n",
              "8                                                KEYS  CHEMICAL     bc5dr\n",
              "9                                          Campanacci   DISEASE     bc5dr\n",
              "10                        Gastroenteritis Coronavirus   DISEASE     bc5dr\n",
              "11                         acute respiratory syndrome   DISEASE     bc5dr\n",
              "12                                          Opstetten  CHEMICAL     bc5dr\n",
              "13                                 coronaviruses TGEV   DISEASE     bc5dr\n",
              "14                                           Yokomuri  CHEMICAL     bc5dr\n",
              "15            coronavirus infectious bronchitis virus   DISEASE     bc5dr\n",
              "16                                           vaccinia   DISEASE     bc5dr\n",
              "17                                        peritonitis   DISEASE     bc5dr\n",
              "18                                            E. coli   DISEASE     bc5dr\n",
              "19                                               CcoV  CHEMICAL     bc5dr\n",
              "20                                            Drosten  CHEMICAL     bc5dr\n",
              "21                                                PLP  CHEMICAL     bc5dr\n",
              "22                                            Haijema  CHEMICAL     bc5dr\n",
              "23  Shi et al., 1999; Sims et al., 2000; van der Meer  CHEMICAL     bc5dr\n",
              "24                                amino acid identity  CHEMICAL     bc5dr\n",
              "25                                          infection   DISEASE     bc5dr\n",
              "26                                        CORONAVIRUS   DISEASE     bc5dr\n",
              "27                                           Syncytia  CHEMICAL     bc5dr\n",
              "28                                     Krijnse-Locker   DISEASE     bc5dr\n",
              "29                                               SARS   DISEASE     bc5dr\n",
              "30                                      human disease   DISEASE     bc5dr\n",
              "31                                        coronavirus   DISEASE     bc5dr\n",
              "32                                             Gosert  CHEMICAL     bc5dr\n",
              "33                                             bovine  CHEMICAL     bc5dr\n",
              "34                                                 Li  CHEMICAL     bc5dr\n",
              "35                                    double-membrane  CHEMICAL     bc5dr\n",
              "36                                                MHV   DISEASE     bc5dr"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 7
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "JR8ZWV7PyRTH",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        },
        "outputId": "78884746-bd30-4b37-94eb-995317a6dc9e"
      },
      "source": [
        "bionlp13cg_entities = display_entities(en_ner_bionlp13cg_md,sample_text)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "text/html": [
              "<span class=\"tex2jax_ignore\"><div class=\"entities\" style=\"line-height: 2.5; direction: ltr\">CORONAVIRUS RESEARCH: \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    KEYS\n",
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              "</mark>\n",
              " TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS</br>Mark R. Denison, M.D.</br>For coronavirus investigators, the recognition of a new \n",
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              "</mark>\n",
              " as the cause of severe acute respiratory syndrome (SARS) was certainly remarkable, yet perhaps not surprising (Baric et al., 1995). The cadre of investigators who have worked with this intriguing family of viruses over the past 30 years are familiar with many of the features of \n",
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              "</mark>\n",
              " biology, pathogenesis, and disease that manifested so dramatically in the worldwide SARS epidemic. Advances in the biology of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
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              "</mark>\n",
              " have resulted in greater understanding of their capacity for adaptation to new environments, transspecies infection, and emergence of new diseases. New tools of \n",
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              "    cell\n",
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              "</mark>\n",
              " and molecular biology have led to increased understanding of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intracellular\n",
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              "</mark>\n",
              " replication and \n",
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              "    viral cell\n",
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              "</mark>\n",
              " biology, and the advent in the past five years of reverse genetic approaches to study \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
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              "</mark>\n",
              " has made it possible to begin to define the determinants of viral replication, transpecies adaptation, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
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              "</mark>\n",
              " disease. This summary will discuss the basic life cycle and replication of the well-studied coronavirus, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mouse hepatitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              "), identifying the unique characteristics of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
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              "</mark>\n",
              " biology and highlighting critical points where research has made significant advances, and which might represent targets for antivirals or vaccines. Areas where rapid progress has been made in SCoV research will be described. Finally, areas of need for research in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
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              "</mark>\n",
              " replication, genetics, and pathogenesis will be summarized.</br>Coronavirus Life Cycle</br>The best studied model for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
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              "</mark>\n",
              " replication and pathogenesis has been the group 2 \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    murine coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mouse hepatitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and much of what is known of the stages of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
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              "</mark>\n",
              " life cycle has been determined in animals and in culture using this virus. Thus this discussion will focus on \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " with comparisons to SCoV and other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
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              "</mark>\n",
              ". This is appropriate because bioinformatics analyses suggest that SCoV, while a distinct virus, has significant similarities in organization, putative protein functions, and replication to the group II coronaviruses, particularly within the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
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              "</mark>\n",
              " gene (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003). Excellent, detailed reviews of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " replication are available elsewhere (Holmes and Lai, 1996; Lai and Cavanagh, 1997).</br>The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " virion is an enveloped particle containing the spike (S), \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " (M), and envelope (E) proteins. In addition, some strains of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", but not SCoV, express a hemagglutinin protein (HE) that is also incorporated in the virion. The genome of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " is a linear, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    single-stranded RNA molecule\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " of positive (mRNA) polarity, and from 28 to 32 kb in length (Bonilla et al., 1994; Drosten et al., 2003; Lee et al., 1991). Within the virion, the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " is encapsidated by multiple copies of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    nucleocapsid protein (N)\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ", and has the conformation of a helical RNA/nucleocapsid structure. The S protein has been a focus of pathogenesis studies in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mice\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " because it appears to be the critical determinant of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " tropism, species specificity, host selection, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and Gallagher, 1998).</br>Virus replication is initiated by binding of the S protein to specific receptors on the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host cell surface\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ". For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", the primary receptor has been shown to be the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    carcino-embryonic antigen–cell adhesion molecule\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CEACAM\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ") (Dveksler et al., 1991; 1996; Holmes and Lai, 1996; Yokomuri and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Lai, 1992\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              "), and for the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    HCoV-229E\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and other group 1 coronaviruses, the receptor is \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    aminopeptidase N\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (Yeager et al., 1992). The precise mechanisms of entry and uncoating have yet to be defined, but likely occur by either fusion from without or viroplexis through \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    endocytic vesicles\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              ". For wildtype \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", entry and uncoating constitute a pH independent process that is probably direct fusion mediated by a fusion peptide in the S protein (Gallagher et al., 1991). The understanding of the region of the S1 component of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " that binds to receptors was the basis for studies leading to the very recent and very rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    angiotensin converting enzyme 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ACE 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ") as a receptor for SCoV (Li et al., 2003).</br>The next discrete stage in the life cycle is translation and proteolytic processing of viral replicase proteins from the input genome RNA, followed by formation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cytoplasmic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " replication complexes in association with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular membranes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " (Denison et al., 1999; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Gosert\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " et al., 2002; Shi et al., 1999; van der Meer et al., 1999). Replication complexes are thought to be sites of all stages of viral RNA transcription and replication, and possibly assembly of nascent viral nucleocapsids. Viral assembly occurs both temporally and physically distinct from viral replication complexes in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    endoplasmic-reticulum-Golgi-intermediate compartment\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ERGIC\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              "), a transitional zone between late \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ER\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " (deVries et al., 1997; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Klumperman\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " et al., 1994; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Krijnse-Locker\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " et al., 1994; Rottier and Rose, 1987). Although the mechanisms by which replication products are delivered to sites of assembly remain to be determined, it has been shown that subpopulations of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteins and the structural nucleocapsid (N) translocate from replication complexes to sites of assembly and may mediate the process in association with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " membrane/protein trafficking pathways (Bost et al., 2000). Virus assembly in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ERGIC\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " involves interactions of genome RNA, N, the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane protein (M\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              "), and the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    small membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " protein (E), resulting in budding of virions into the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    lumen\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ER/Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " virosomes (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Opstetten\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " et al., 1995). Further maturation of virus particles occurs during movement through the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              ", resulting in virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the virosomes to the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell surface\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " has not been well characterized, but is presumed to occur via normal vesicle maturation and exocytic processes. The outcome is the nonlytic release of the vast majority of mature virions into the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    extracellular space\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              ". For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and several other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " that can directly fuse with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ", there is a characteristic and rapidly detectable cytopathic effect of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell-cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " fusion into multinucleated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    syncytia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ". Production of infectious virus continues even after the majority of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " are fused. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Syncytia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " were recently reported as a readout of SCoV receptor expression and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " infection (Li et al., 2003).</br>Viral Replication Complex Formation and Function</br>Following entry and uncoating, the 5′ most \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene of the input positive \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    strand\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " RNA genome is translated into two \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    co-amino terminal replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " polyproteins that are co- and post-translationally processed by viral proteinases to yield 15 to 16 mature \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteins, as well as intermediate precursors. The nascent replicase polyproteins and intermediate precursors likely mediate the formation of viral replication complexes in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host cell cytoplasm\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ". Interestingly, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " replication requires continuous replicase gene translation and processing throughout the life cycle to maintain productive infection (Kim et al., 1995; Perlman et al., 1987; Sawicki and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Sawicki, 1986\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              "). Replication complexes of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " are associated with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane vesicles\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Gosert\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " et al., 2002), and all tested \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " proteins have been shown to colocalize to replication complexes at the earliest time of detection, likely both by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " integration and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison et al., 1999; Prentice and Denison, in press; Shi et al., 1999; Sims et al., 2000; van der Meer et al., 1999). Further, replicase proteins likely mediate the process of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane vesicle\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " formation, likely by induction of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " autophagy pathways (E. Prentice, unpublished results).</br>Coronavirus replication complexes are sites for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene translation and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " polyprotein processing, and also for viral RNA synthesis. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Replicase gene proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " likely mediate positive-strand, negative-strand, subgenomic, and genomic RNA synthesis, as well as processes of capping, polyadenylation, RNA unwinding, template switching during viral RNA synthesis, and discontinuous transcription and transcription attenuation. The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " polyproteins and mature replicase proteins represent the largest and most diverse repertoire of known and predicted distinct enzymatic functions of any \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    positive-strand RNA virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " family. Until recently, of the 15 or more mature \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteins, only the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ", RNA helicase, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA-dependent RNA polymerase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " activities had been predicted or experimentally confirmed (Brockway et al., 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Heusipp et al., 1997\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              "; Lee et al., 1991; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " et al., 2000). With the advent of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", more extensive bioinformatics analyses have resulted in predictions of several additional functions involved in RNA processing, including methyltransferase and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    exonuclease\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " activities (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Thiel\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " et al., 2003). Even with inclusion of distant predicted relationships, up to eight of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteins remain without predicted or confirmed functions. In summary, it is likely that \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " have exploited their genetic capacity to encode proteins in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene with distinct functions in RNA synthesis and processing, as well as proteins with specific roles in induction or modification in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host cellular membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " biogenesis and trafficking, delivery of replication products to sites of assembly, and possibly virus assembly. Thus replicase translation, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " polyprotein processing, and mature replicase proteins constitute important targets for interference with coronavirus replication, virus-cell interactions, or viral pathology.</br>Coronavirus Replicase Protein Expression and Processing</br>The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " activities for all \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " include both \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    papain-like proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ") and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    picornavirus 3C-like proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " activities that are encoded within the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " polyproteins and mediate both cis and trans cleavage events (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " et al., 2000). Because of the parallel evolution of the proteinases, their cleavage sites, and the hierarchical cleavage processes, the proteolytic processing of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " proteins may serve as distinct regulatory and genetic elements (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " et al., 2001). Specifically, there are both conserved and divergent regions of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " polyproteins by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    amino acid\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SIMPLE_CHEMICAL</span>\n",
              "</mark>\n",
              " identity and similarity, with the sequences and predicted mature proteins beginning with the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3C-like\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteinases through the carboxy terminus of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " polyprotein retaining higher identity and similarity across the predicted proteins. In contrast, the amino-terminal third of the replicase demonstrates the most variation in proteins, cleavage site locations, and the number of proteinases that mediate maturation processing. SCoV appears to have the general organization of, and similar protein sizes to, the group 2 coronaviruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " in this part of the genome (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003). However, SCoV likely uses only one \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SIMPLE_CHEMICAL</span>\n",
              "</mark>\n",
              " to mediate the cleavages, similar to the group 3 coronavirus infectious bronchitis virus (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    IBV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              "). Thus this region of the replicase may experience the most variability, suggesting either the encoding of accessory functions that are flexible and tolerant of changes, or conversely group or host-specific roles that are subject to pressure for more rapid change.</br>Expression of Structural and Accessory Genes</br>Only the 5′ most \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene is translated from the input \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    positive-strand genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ". The genome contains multiple other genes for the known structural proteins S, E, M, and N, as well as other genes for expression of proteins that have been labeled as “nonstructural” or “accessory” because they have been presumed to not be required for replication, and are not thought to be incorporated into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ". \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " encodes six of these genes, while SCoV encodes possibly up to 11 structural and accessory genes, which are expressed from subgenomic mRNAs (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003). Subgenomic RNA transcription occurs during minus- \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    strand\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " RNA synthesis by acquisition of the antileader RNA sequences from the 5′ end of the genome via homology to a transcriptional regulatory sequence (TRS, also known as an intergenic sequence), and requiring a discontinuous activity of the nascent minus-strand template and polymerase complex to acquire the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the generation of a “nested set” of subgenomic negative-strand RNAs that all contain the antileader sequences that serve as templates for similar size subgenomic mRNAs. This transcriptional strategy exposes different genes as the 5′ ORF in different mRNAs, all of which also contain the 3′ sequence downstream of the gene, including the 3′ nontranslated region of the genome.</br>For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", genes 3, 5b, 6, and 7 encode S, E, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    M\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ", and N, respectively. Genes 2, 4, and 5a are not required for replication in culture, and have been mutated to block expression, deleted, or substituted with noncoronavirus genes such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    GFP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " (de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all coronaviruses retain these genes in various combinations in the face of presumed pressure for genetic economy and apparent lack of functions in RNA synthesis, it is presumed that these genes serve roles in modification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ", pathogenesis, or interactions with the immune system. SCoV encodes a larger and more complex array of these genes than \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " or other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", which may reflect its evolution in its original animal host (Ksiazek et al., 2003; Marra et al., 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Thiel\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " et al., 2003). In addition, the report of a deletion within one of the accessory genes in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " isolates of SCoV suggests that this may be a gene involved in host range or adaptation for replication and transmission in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    humans\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (Guan et al., 2003).</br>Coronavirus Genetics</br>Until recently, the genetics of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " replication and pathogenesis have largely been studied using natural variants, host range mutants, passaged virus, and mutagenized viruses selected for temperature sensitivity and specific phenotypes. Classical complementation of functions made it possible to define at least eight genetic groups for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", with most of the complementation groups localized to the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene (Stalcup et al., 1998). Taking advantage of naturally high rates of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    homologous RNA-RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " recombination and of host range determinants in the S protein, the development of targeted recombination has allowed more defined and detailed studies of the accessory and structural genes of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", transmissible gastroenteritis virus (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              "), and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    feline infectious peritonitis virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    FIPV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ") (Haijema et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with natural variants and targeted recombination genetic studies have demonstrated that the S protein is the major determinant of host range, tropism, and pathogenesis; other genetic elements, possibly in the replicase, may influence these characteristics of different \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (Navas and Weiss, 2003). The capacity of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " to change host range, transmission, pathogenesis, and disease has been established in the laboratory using \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " adaptation and virus passage (Baric et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in nature by natural variants of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    bovine coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    BCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              "), as well as by studies using heterologous viruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    canine coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CcoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ") to immunize \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cats\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " against \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    FIPV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Enjuanes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " et al., 1995; Tresnan et al., 1996). Further, targeted recombination studies have confirmed the genetic flexibility of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genome and the ability of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " to recover wild-type replication following deletions, mutations, substitutions, and gene order rearrangements in the structural and accessory genes (de Haan et al., 2002).</br>Challenges for genetic studies using natural variants and mutants, particularly in defining the precise changes responsible for altered phenotypes, has limited progress in genetic studies. Targeted recombination, while a robust system with powerful selection, has been limited to studies of the 3′ 10 kb of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genome, and is limited to selection of viable recombinants. Recently, the establishment of “infectious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              "” reverse genetic strategies for the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (Transmissible Gastroenteritis Coronavirus), \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    HCoV-229E\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    IBV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " has made it theoretically possible to study the genetics of the entire genome and all of the structural, accessory, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " genes. Approaches to “infectious cloning” have included full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genome in bacterial artificial \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    chromosomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " (Gonzalez et al., 2001), recombinant vaccinia viruses containing full-length cDNA clones of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    HCoV-229E\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    IBV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genomes (Casais et al., 2001; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Thiel\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " et al., 2001), and in vitro assembly strategies for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and most recently, SCoV (Yount, 2000; Yount et al., 2002, 2003).</br>The in vitro assembly approach was developed to overcome the challenge of full-length cDNA cloning of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genomes, which contained “toxic” regions in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene, resulting in unstable or toxic \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    E. coli\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (Yount, 2000; Yount et al., 2002). Subcloning of the regions required splitting the toxic domains into separate \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ". The result of this strategy was the cloning of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " genome into seven fragments (A through G). To recover viable virus, the following strategy is pursued: (1) cloned cDNA fragments are excised from plasmid using class 2 restriction enzymes that remove the recognition site and leave overhanging genomic sequence; (2) excised fragments are ligated (assembled) in vitro; (3) transcription of full-length genomic RNA is driven in vitro using a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    T7\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " promoter on the 5′ fragment A; (4) full-length genome RNA is electroporated into competent \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " that are then plated on a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    monolayer\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " of naturally permissive \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              "; and (5) cells are monitored for cytopathic effect or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    plaques\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TISSUE</span>\n",
              "</mark>\n",
              ", and virus is recovered from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    plaques\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TISSUE</span>\n",
              "</mark>\n",
              " or media supernatant.</br>In vitro assembly has many advantages for genetic studies of such a large and complex genome RNA. First, genetic changes can be introduced and confirmed in stable small fragments without the need for a ~30kb genomic \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ". Second, the cloned fragments make it possible to develop libraries of mutations that can rapidly be tested in different combinations. Furthermore, identification of putative second-site reversion mutations for deleterious introduced changes can be introduced with the original mutation to confirm their reversion potential. In combination with biochemical and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              " imaging approaches, it also is possible to study highly defective or lethal mutations in electroporated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ", in order to define critical determinants of replication. The in vitro assembly approach has been used to introduce marker mutations that are silent for replication in culture (Yount et al., 2003). In addition, we have engineered mutations in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " gene to define the requirements for polyprotein processing and to determine the role of specific \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " proteins in replication in culture and in pathogenesis in animals. Using this approach we have recovered viruses with mutations at polyprotein cleavage sites and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase catalytic residues\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              ", all of which have distinct phenotypes in protein processing, viral growth, and viral RNA synthesis (unpublished results). Thus, direct reverse genetic studies of the critical \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene functions can be performed using in vitro assembly of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    infectious clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL</span>\n",
              "</mark>\n",
              ".</br>Advances in SCoV Research</br>The rapid progress in the identification and characterization of SCoV as the etiologic agent of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " was made possible by the fact that the virus grows well in culture, and by the foundational research in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " that has been supported by the National Institutes of Health, the Multiple Sclerosis Foundation, the U.S. Department of Agriculture, and other organizations over the past two decades. The application of knowledge concerning virus structure, genetics, receptor binding, virus entry, and viral pathogenesis has made it possible to target the spike protein for studies of SCoV replication, pathogenesis, and immune response (Xiao et al., 2003). The remarkably rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ACE 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " as a receptor for SARS has demonstrated the foundational importance of studies of other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Li et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003). Similarly, understanding of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GENE_OR_GENE_PRODUCT</span>\n",
              "</mark>\n",
              " gene expression, processing, and predicted functions has identified possible targets for structure/function studies and possible therapeutic intervention. The studies of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " activities, cleavage site, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    structures\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TISSUE</span>\n",
              "</mark>\n",
              " were the basis for studies leading to the rapid determination of SCoV replicase polyprotein cleavage sites and 3CLpro crystal structure (Anand et al., 2003; Campanacci et al., 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Snijder et al.,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " 2003; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Thiel\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " et al., 2003).</br>Application of Reverse Genetics to Studies of SCoV</br>Because of the potential for reemergence of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", it is important to move forward with research in diagnostics, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vaccines\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", and therapeutics for SCoV. Experience with the development and use of reverse genetics to study other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " resulted in establishment of reverse genetics for SCoV within months of the onset of the worldwide epidemic (Yount et al., 2003). How should the understanding of other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", the rapid advances in research with SCoV, and the development of reverse genetics for SCoV be harnesssed to achieve these goals and attack these critical questions in SCoV replication, pathogenesis, and disease? Certainly, the use of SCoV reverse genetics, along with robust \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    tissue\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TISSUE</span>\n",
              "</mark>\n",
              " culture systems and emerging animal models, creates the potential to rapidly answer questions concerning: (1) determinants of virus growth in culture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and escape from biochemical and immune interference with replication; (4) determinants of virulence and pathogenesis; (5) mechanisms of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              " recombination and mutation; (6) functions of and requirements for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELLULAR_COMPONENT</span>\n",
              "</mark>\n",
              ", structural, and accessory proteins; and (7) development of stably attenuated viruses for use as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    seed stocks\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM_SUBSTANCE</span>\n",
              "</mark>\n",
              " for inactivated vaccine or testing as live-attenuated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vaccines\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ".</br>How then should these critical issues be investigated while recognizing the potential of SCoV to cause severe disease, as well as the potential for rapid spread? First, there is significant experience with other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " in attenuation of virus replication and pathogenesis, both using virus passage and by direct engineering of changes. Although coronavirus genome organization, proteins, and replication appear more tolerant of changes then previously thought, all changes of gene order, gene deletion, insertion, or mutagenesis so far reported have led to viruses impaired in replication, pathogenesis, or both. Many of the attenuating changes in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " are conserved in SCoV and thus could be tested for likely attenuation in SCoV culture and animal models. Second, where there is clear conservation of sequences, motifs, proteins, or putative functions between SCoV and model viruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", new or untested changes might be most rapidly analyzed under BSL2 conditions in those model viruses, and then directly applied to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SARS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " once their phenotypes are determined. Third, all work with SCoV will be performed only under BSL3 conditions. This would also apply to chimeric viruses, whether engineered by introduction into the SCoV background, or by introducing SCoV proteins or sequences with known or predicted pathogenic consequences into other coronavirus backgrounds. Finally, it is important to develop strains of SCoV that are attenuated and stabilized against reversion and recombination, to be used as the basis for studies of other replication and pathogenesis determinants and construction of virus chimeras. Such attenuated variants would provide additional safeguards while allowing application of powerful genetic tools to the study of SCoV emergence, biology, disease, treatment, and prevention. Overall, newly invigorated programs in other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " and animal \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              ", combined with the new research in SCoV, will shed important new light on this important virus family and perhaps lead to better understanding of the potential for resurgence of SCoV or the emergence of other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronaviruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">ORGANISM</span>\n",
              "</mark>\n",
              " populations.</div></span>"
            ],
            "text/plain": [
              "<IPython.core.display.HTML object>"
            ]
          },
          "metadata": {
            "tags": []
          }
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "qx0xyYrSylN9",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 391
        },
        "outputId": "21965a2d-8180-4fca-d140-b962836b1cdb"
      },
      "source": [
        "bionlp13cg_entities_dataframe = pd.DataFrame(bionlp13cg_entities[1],columns=['Entity','Label']) #save returned values of entities and their labels in a pandas dataframe\n",
        "bionlp13cg_entities_dataframe['Ner_model'] = 'bionlp13cg'  #include a column with constant value of NER model\n",
        "bionlp13cg_entities_dataframe"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
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              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>ER/Golgi</td>\n",
              "      <td>CELLULAR_COMPONENT</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>coronaviruses TGEV</td>\n",
              "      <td>ORGANISM</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>endoplasmic-reticulum-Golgi-intermediate compa...</td>\n",
              "      <td>GENE_OR_GENE_PRODUCT</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>human</td>\n",
              "      <td>ORGANISM</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>GFP</td>\n",
              "      <td>GENE_OR_GENE_PRODUCT</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>...</th>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>103</th>\n",
              "      <td>MHV</td>\n",
              "      <td>ORGANISM</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>104</th>\n",
              "      <td>aminopeptidase N</td>\n",
              "      <td>GENE_OR_GENE_PRODUCT</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>105</th>\n",
              "      <td>Syncytia</td>\n",
              "      <td>CELL</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>106</th>\n",
              "      <td>intracellular</td>\n",
              "      <td>IMMATERIAL_ANATOMICAL_ENTITY</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>107</th>\n",
              "      <td>HCoV-229E</td>\n",
              "      <td>ORGANISM</td>\n",
              "      <td>bionlp13cg</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "<p>108 rows × 3 columns</p>\n",
              "</div>"
            ],
            "text/plain": [
              "                                                Entity  ...   Ner_model\n",
              "0                                             ER/Golgi  ...  bionlp13cg\n",
              "1                                   coronaviruses TGEV  ...  bionlp13cg\n",
              "2    endoplasmic-reticulum-Golgi-intermediate compa...  ...  bionlp13cg\n",
              "3                                                human  ...  bionlp13cg\n",
              "4                                                  GFP  ...  bionlp13cg\n",
              "..                                                 ...  ...         ...\n",
              "103                                                MHV  ...  bionlp13cg\n",
              "104                                   aminopeptidase N  ...  bionlp13cg\n",
              "105                                           Syncytia  ...  bionlp13cg\n",
              "106                                      intracellular  ...  bionlp13cg\n",
              "107                                          HCoV-229E  ...  bionlp13cg\n",
              "\n",
              "[108 rows x 3 columns]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 9
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "kntdryjY6fCr",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        },
        "outputId": "38d45459-db98-45f4-ecda-275780b9d7d5"
      },
      "source": [
        "craft_entities = display_entities(en_ner_craft_md,sample_text)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "text/html": [
              "<span class=\"tex2jax_ignore\"><div class=\"entities\" style=\"line-height: 2.5; direction: ltr\">CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS</br>Mark R. Denison, M.D.</br>For coronavirus investigators, the recognition of a new coronavirus as the cause of severe acute respiratory syndrome (SARS) was certainly remarkable, yet perhaps not surprising (Baric et al., 1995). The cadre of investigators who have worked with this intriguing family of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " over the past 30 years are familiar with many of the features of coronavirus biology, pathogenesis, and disease that manifested so dramatically in the worldwide SARS epidemic. Advances in the biology of coronaviruses have resulted in greater understanding of their capacity for adaptation to new environments, transspecies infection, and emergence of new diseases. New tools of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    molecular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " biology have led to increased understanding of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intracellular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " replication and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " biology, and the advent in the past five years of reverse \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " approaches to study coronaviruses has made it possible to begin to define the determinants of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication, transpecies adaptation, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " disease. This summary will discuss the basic life cycle and replication of the well-studied coronavirus, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mouse\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " hepatitis \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " (MHV), identifying the unique characteristics of coronavirus biology and highlighting critical points where research has made significant advances, and which might represent targets for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    antivirals\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " or vaccines. Areas where rapid progress has been made in SCoV research will be described. Finally, areas of need for research in coronavirus replication, genetics, and pathogenesis will be summarized.</br>Coronavirus Life Cycle</br>The best studied model for coronavirus replication and pathogenesis has been the group 2 \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    murine\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " coronavirus, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mouse\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " hepatitis \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", and much of what is known of the stages of the coronavirus life cycle has been determined in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animals\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " and in culture using this \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ". Thus this discussion will focus on MHV with comparisons to SCoV and other coronaviruses. This is appropriate because bioinformatics analyses suggest that SCoV, while a distinct \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", has significant similarities in organization, putative \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " functions, and replication to the group II coronaviruses, particularly within the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (Snijder et al., 2003). Excellent, detailed reviews of MHV and coronavirus replication are available elsewhere (Holmes and Lai, 1996; Lai and Cavanagh, 1997).</br>The coronavirus \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " is an enveloped particle containing the spike (S), \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (M), and envelope (E) \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ". In addition, some strains of coronaviruses, but not SCoV, express a hemagglutinin \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " (HE) that is also incorporated in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ". The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of coronaviruses is a linear, single-stranded \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " molecule of positive (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mRNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ") polarity, and from 28 to 32 kb in length (Bonilla et al., 1994; Drosten et al., 2003; Lee et al., 1991). Within the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ", the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " is encapsidated by multiple copies of the nucleocapsid \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " (N), and has the conformation of a helical RNA/nucleocapsid structure. The S \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " has been a focus of pathogenesis studies in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mice\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " because it appears to be the critical determinant of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " tropism, species specificity, host selection, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and Gallagher, 1998).</br>\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication is initiated by binding of the S \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " to specific receptors on the host \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell surface\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ". For MHV, the primary receptor has been shown to be the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    carcino-embryonic antigen–cell adhesion molecule\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " (CEACAM) (Dveksler et al., 1991; 1996; Holmes and Lai, 1996; Yokomuri and Lai, 1992), and for the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " coronavirus, HCoV-229E, and other group 1 coronaviruses, the receptor is aminopeptidase N (Yeager et al., 1992). The precise mechanisms of entry and uncoating have yet to be defined, but likely occur by either fusion from without or viroplexis through \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    endocytic vesicles\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ". For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    wildtype MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", entry and uncoating constitute a pH independent process that is probably direct fusion mediated by a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    fusion peptide\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in the S \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " (Gallagher et al., 1991). The understanding of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    region\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the S1 component of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " that binds to receptors was the basis for studies leading to the very recent and very rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    angiotensin converting enzyme 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " (ACE 2) as a receptor for SCoV (Li et al., 2003).</br>The next discrete stage in the life cycle is translation and proteolytic processing of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " from the input \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", followed by formation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cytoplasmic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " in association with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular membranes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " (Denison et al., 1999; Gosert et al., 2002; Shi et al., 1999; van der Meer et al., 1999). Replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " are thought to be \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of all stages of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " transcription and replication, and possibly assembly of nascent \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral nucleocapsids\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ". \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " assembly occurs both temporally and physically distinct from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " in the endoplasmic-reticulum-Golgi-intermediate compartment (ERGIC), a transitional zone between late \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ER\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (deVries et al., 1997; Klumperman et al., 1994; Krijnse-Locker et al., 1994; Rottier and Rose, 1987). Although the mechanisms by which replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    products\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " are delivered to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of assembly remain to be determined, it has been shown that subpopulations of replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " and the structural nucleocapsid (N) translocate from replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of assembly and may mediate the process in association with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " membrane/protein trafficking pathways (Bost et al., 2000). Virus assembly in the ERGIC involves interactions of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", N, the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (M), and the small \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (E), resulting in budding of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " into the lumen of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ER/Golgi virosomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (Opstetten et al., 1995). Further maturation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " particles occurs during movement through the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ", resulting in virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the virosomes to the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell surface\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " has not been well characterized, but is presumed to occur via normal \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vesicle\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " maturation and exocytic processes. The outcome is the nonlytic release of the vast majority of mature \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " into the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    extracellular space\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              ". For MHV and several other coronaviruses that can directly fuse with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ", there is a characteristic and rapidly detectable cytopathic effect of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell-cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " fusion into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    multinucleated syncytia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ". Production of infectious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " continues even after the majority of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " are fused. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Syncytia\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " were recently reported as a readout of SCoV receptor expression and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " infection (Li et al., 2003).</br>\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " Replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Complex\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " Formation and Function</br>Following entry and uncoating, the 5′ most replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the input positive \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    strand RNA genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " is translated into two \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    co-amino terminal replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " that are \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    co-\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " and post-translationally processed by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " proteinases to yield 15 to 16 mature replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", as well as intermediate precursors. The nascent replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and intermediate precursors likely mediate the formation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " in the host \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell cytoplasm\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ". Interestingly, coronavirus replication requires continuous replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " translation and processing throughout the life cycle to maintain productive infection (Kim et al., 1995; Perlman et al., 1987; Sawicki and Sawicki, 1986). Replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " of MHV are associated with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane vesicles\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (Gosert et al., 2002), and all tested \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " have been shown to colocalize to replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " at the earliest time of detection, likely both by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane integration\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison et al., 1999; Prentice and Denison, in press; Shi et al., 1999; Sims et al., 2000; van der Meer et al., 1999). Further, replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " likely mediate the process of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    double-membrane vesicle\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " formation, likely by induction of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " autophagy pathways (E. Prentice, unpublished results).</br>\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " are \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " for replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " translation and replicase polyprotein processing, and also for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " synthesis. Replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " likely mediate \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    positive-strand\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    negative-strand\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    subgenomic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genomic RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " synthesis, as well as processes of capping, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyadenylation\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " unwinding, template switching during \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " synthesis, and discontinuous transcription and transcription attenuation. The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " and mature replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " represent the largest and most diverse repertoire of known and predicted distinct \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    enzymatic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " functions of any positive-strand \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " family. Until recently, of the 15 or more mature replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", only the proteinase, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " helicase, and RNA-dependent \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " polymerase activities had been predicted or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    experimentally\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " confirmed (Brockway et al., 2003; Heusipp et al., 1997; Lee et al., 1991; \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " et al., 2000). With the advent of SARS, more extensive bioinformatics analyses have resulted in predictions of several additional functions involved in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " processing, including methyltransferase and exonuclease activities (Snijder et al., 2003; Thiel et al., 2003). Even with inclusion of distant \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    predicted\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " relationships, up to eight of the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " remain without predicted or confirmed functions. In summary, it is likely that coronaviruses have exploited their \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " capacity to encode \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " in the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " with distinct functions in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " synthesis and processing, as well as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " with specific roles in induction or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    modification\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in host \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cellular membrane\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " biogenesis and trafficking, delivery of replication \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    products\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of assembly, and possibly \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " assembly. Thus replicase translation, replicase polyprotein processing, and mature replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " constitute important targets for interference with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus-cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " interactions, or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " pathology.</br>Coronavirus Replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " Expression and Processing</br>The proteinase activities for all coronaviruses include both papain-like proteinase (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              ") and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    picornavirus 3C-like proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " activities that are encoded within the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and mediate both \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cis\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " and trans cleavage events (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " et al., 2000). Because of the parallel evolution of the proteinases, their cleavage \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and the hierarchical cleavage processes, the proteolytic processing of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " may serve as distinct regulatory and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic elements\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Ziebuhr\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " et al., 2001). Specifically, there are both \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    conserved\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and divergent \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    regions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    amino acid\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " identity and similarity, with the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sequences\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and predicted mature \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " beginning with the 3C-like proteinases through the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    carboxy terminus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyprotein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " retaining higher identity and similarity across the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    predicted proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". In contrast, the amino-terminal third of the replicase demonstrates the most variation in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cleavage site locations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and the number of proteinases that mediate maturation processing. SCoV appears to have the general organization of, and similar \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " sizes to, the group 2 coronaviruses such as MHV in this part of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (Snijder et al., 2003). However, SCoV likely uses only one \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " to mediate the cleavages, similar to the group 3 coronavirus infectious bronchitis \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " (IBV). Thus this \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    region\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the replicase may experience the most variability, suggesting either the encoding of accessory functions that are flexible and tolerant of changes, or conversely group or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host-specific\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " roles that are subject to pressure for more rapid change.</br>Expression of Structural and Accessory \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              "</br>Only the 5′ most replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " is translated from the input \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    positive-strand genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " contains multiple other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " for the known structural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " S, E, M, and N, as well as other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " for expression of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " that have been labeled as “nonstructural” or “accessory” because they have been presumed to not be required for replication, and are not thought to be incorporated into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ". MHV encodes six of these \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", while SCoV encodes possibly up to 11 structural and accessory \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", which are expressed from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    subgenomic mRNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (Snijder et al., 2003). Subgenomic \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " transcription occurs during minus- \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    strand RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " synthesis by acquisition of the antileader \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA sequences\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " from the 5′ end of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " via \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    homology\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " to a transcriptional \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    regulatory sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (TRS, also known as an \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intergenic sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              "), and requiring a discontinuous activity of the nascent minus-strand template and polymerase complex to acquire the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the generation of a “nested set” of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    subgenomic negative-strand RNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " that all contain the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    antileader sequences\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " that serve as templates for similar size \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    subgenomic mRNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". This transcriptional strategy exposes different \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " as the 5′ \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ORF\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in different \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mRNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", all of which also contain the 3′ \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " downstream of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", including the 3′ \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    nontranslated region\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ".</br>For MHV, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " 3, 5b, 6, and 7 encode S, E, M, and N, respectively. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " 2, 4, and 5a are not required for replication in culture, and have been \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutated\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " to block expression, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    deleted\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", or substituted with noncoronavirus \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " such as GFP (de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all coronaviruses retain these \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in various combinations in the face of presumed pressure for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " economy and apparent lack of functions in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " synthesis, it is presumed that these \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " serve roles in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    modification\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of host \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ", pathogenesis, or interactions with the immune system. SCoV encodes a larger and more complex array of these \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " than MHV or other coronaviruses, which may reflect its evolution in its original \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animal\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " host (Ksiazek et al., 2003; Marra et al., 2003; Snijder et al., 2003; Thiel et al., 2003). In addition, the report of a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    deletion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " within one of the accessory \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " isolates of SCoV suggests that this may be a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " involved in host range or adaptation for replication and transmission in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    humans\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " (Guan et al., 2003).</br>Coronavirus Genetics</br>Until recently, the genetics of coronavirus replication and pathogenesis have largely been studied using natural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    variants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", host range \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", passaged \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", and mutagenized \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " selected for temperature sensitivity and specific phenotypes. Classical complementation of functions made it possible to define at least eight \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " groups for MHV, with most of the complementation groups localized to the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (Stalcup et al., 1998). Taking advantage of naturally high rates of homologous RNA-RNA recombination and of host range determinants in the S \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", the development of targeted recombination has allowed more defined and detailed studies of the accessory and structural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of MHV, transmissible gastroenteritis \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " (TGEV), and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    feline\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " infectious peritonitis \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " (FIPV) (Haijema et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with natural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    variants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and targeted recombination \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " studies have demonstrated that the S \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " is the major determinant of host range, tropism, and pathogenesis; other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic elements\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", possibly in the replicase, may influence these characteristics of different coronaviruses (Navas and Weiss, 2003). The capacity of coronaviruses to change host range, transmission, pathogenesis, and disease has been established in the laboratory using \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " adaptation and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " passage (Baric et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in nature by natural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    variants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of MHV, TGEV, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    bovine\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " coronavirus (BCoV), as well as by studies using heterologous \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    canine\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " coronavirus (CcoV) to immunize \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cats\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " against FIPV (Enjuanes et al., 1995; Tresnan et al., 1996). Further, targeted recombination studies have confirmed the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " flexibility of the coronavirus \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and the ability of coronaviruses to recover \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    wild-type\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " replication following \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    deletions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    substitutions\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " order rearrangements in the structural and accessory \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (de Haan et al., 2002).</br>Challenges for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " studies using natural \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    variants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", particularly in defining the precise changes responsible for altered phenotypes, has limited progress in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " studies. Targeted recombination, while a robust system with powerful selection, has been limited to studies of the 3′ 10 kb of the MHV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and is limited to selection of viable recombinants. Recently, the establishment of “infectious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              "” reverse \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " strategies for the coronaviruses TGEV (Transmissible Gastroenteritis Coronavirus), HCoV-229E, IBV, and MHV has made it theoretically possible to study the genetics of the entire \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and all of the structural, accessory, and replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". Approaches to “infectious cloning” have included full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of TGEV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    bacterial\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " artificial \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    chromosomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GO</span>\n",
              "</mark>\n",
              " (Gonzalez et al., 2001), recombinant \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vaccinia viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " containing full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of HCoV-229E and IBV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (Casais et al., 2001; Thiel et al., 2001), and in vitro assembly strategies for TGEV, MHV, and most recently, SCoV (Yount, 2000; Yount et al., 2002, 2003).</br>The in vitro assembly approach was developed to overcome the challenge of full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " cloning of the TGEV and MHV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", which contained “\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    toxic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              "” regions in the replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", resulting in unstable or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    toxic clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " in E. coli (Yount, 2000; Yount et al., 2002). Subcloning of the regions required splitting the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    toxic domains\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " into separate \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". The result of this strategy was the cloning of the MHV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " into seven \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " (A through G). To recover viable \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", the following strategy is pursued: (1) cloned \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " are excised from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    plasmid\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " using class 2 restriction \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    enzymes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " that \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    remove\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    recognition site\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and leave \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    overhanging genomic sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              "; (2) \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    excised fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " are ligated (assembled) in vitro; (3) transcription of full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genomic RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " is driven in vitro using a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    T7 promoter\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " on the 5′ \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    fragment\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " A; (4) full-length \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " is electroporated into competent \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " that are then plated on a monolayer of naturally permissive \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              "; and (5) \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " are monitored for cytopathic effect or plaques, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " is recovered from plaques or media supernatant.</br>In vitro assembly has many advantages for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " studies of such a large and complex \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". First, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " changes can be introduced and confirmed in stable small \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " without the need for a ~30kb \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genomic clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ". Second, the cloned \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " make it possible to develop libraries of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " that can rapidly be tested in different combinations. Furthermore, identification of putative second-site reversion \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " for deleterious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    introduced\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " changes can be \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    introduced\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " with the original \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutation\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " to confirm their reversion potential. In combination with biochemical and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cell\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              " imaging approaches, it also is possible to study highly defective or lethal \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in electroporated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CL</span>\n",
              "</mark>\n",
              ", in order to define critical determinants of replication. The in vitro assembly approach has been used to introduce marker \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " that are silent for replication in culture (Yount et al., 2003). In addition, we have engineered \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " to define the requirements for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyprotein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " processing and to determine the role of specific replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " in replication in culture and in pathogenesis in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animals\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ". Using this approach we have recovered \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " at \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polyprotein cleavage sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " and proteinase catalytic \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    residues\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", all of which have distinct phenotypes in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " processing, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " growth, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " synthesis (unpublished results). Thus, direct reverse \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " studies of the critical replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " functions can be performed using in vitro assembly of infectious \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ".</br>Advances in SCoV Research</br>The rapid progress in the identification and characterization of SCoV as the etiologic agent of SARS was made possible by the fact that the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " grows well in culture, and by the foundational research in coronaviruses that has been supported by the National Institutes of Health, the Multiple Sclerosis Foundation, the U.S. Department of Agriculture, and other organizations over the past two decades. The application of knowledge concerning \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " structure, genetics, receptor binding, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " entry, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " pathogenesis has made it possible to target the spike \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " for studies of SCoV replication, pathogenesis, and immune response (Xiao et al., 2003). The remarkably rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ACE 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " as a receptor for SARS has demonstrated the foundational importance of studies of other coronaviruses (Li et al., 2003). Similarly, understanding of replicase \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " expression, processing, and predicted functions has identified possible targets for structure/function studies and possible therapeutic intervention. The studies of coronavirus proteinase activities, cleavage \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    site\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", and structures were the basis for studies leading to the rapid determination of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV replicase polyprotein cleavage sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">GGP</span>\n",
              "</mark>\n",
              " and 3CLpro crystal structure (Anand et al., 2003; Campanacci et al., 2003; Snijder et al., 2003; Thiel et al., 2003).</br>Application of Reverse Genetics to Studies of SCoV</br>Because of the potential for reemergence of SARS, it is important to move forward with research in diagnostics, vaccines, and therapeutics for SCoV. Experience with the development and use of reverse genetics to study other coronaviruses resulted in establishment of reverse genetics for SCoV within months of the onset of the worldwide epidemic (Yount et al., 2003). How should the understanding of other coronaviruses, the rapid advances in research with SCoV, and the development of reverse genetics for SCoV be harnesssed to achieve these goals and attack these critical questions in SCoV replication, pathogenesis, and disease? Certainly, the use of SCoV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    reverse\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " genetics, along with robust tissue culture systems and emerging \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animal\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " models, creates the potential to rapidly answer questions concerning: (1) determinants of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " growth in culture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and escape from biochemical and immune interference with replication; (4) determinants of virulence and pathogenesis; (5) mechanisms of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " recombination and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutation\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              "; (6) functions of and requirements for replicase, structural, and accessory \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              "; and (7) development of stably attenuated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " for use as seed stocks for inactivated vaccine or testing as live-attenuated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    vaccines\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ".</br>How then should these critical issues be investigated while recognizing the potential of SCoV to cause severe disease, as well as the potential for rapid spread? First, there is significant experience with other coronaviruses in attenuation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " replication and pathogenesis, both using \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " passage and by direct engineering of changes. Although coronavirus \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " organization, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", and replication appear more tolerant of changes then previously thought, all changes of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " order, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    gene deletion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    insertion\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mutagenesis\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " so far reported have led to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " impaired in replication, pathogenesis, or both. Many of the attenuating changes in MHV and other coronaviruses are conserved in SCoV and thus could be tested for likely attenuation in SCoV culture and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animal\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " models. Second, where there is clear \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    conservation\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sequences\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    motifs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              ", or putative functions between SCoV and model \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " such as MHV, new or untested changes might be most rapidly analyzed under BSL2 conditions in those model \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", and then directly applied to SARS once their phenotypes are determined. Third, all work with SCoV will be performed only under BSL3 conditions. This would also apply to chimeric \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viruses\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              ", whether engineered by introduction into the SCoV background, or by introducing SCoV \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CHEBI</span>\n",
              "</mark>\n",
              " or \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    sequences\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " with known or predicted pathogenic consequences into other coronavirus backgrounds. Finally, it is important to develop strains of SCoV that are attenuated and stabilized against reversion and recombination, to be used as the basis for studies of other replication and pathogenesis determinants and construction of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " chimeras. Such attenuated \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    variants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " would provide additional safeguards while allowing application of powerful \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genetic\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">SO</span>\n",
              "</mark>\n",
              " tools to the study of SCoV emergence, biology, disease, treatment, and prevention. Overall, newly invigorated programs in other \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    animal\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " coronaviruses, combined with the new research in SCoV, will shed important new light on this important \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " family and perhaps lead to better understanding of the potential for resurgence of SCoV or the emergence of other coronaviruses into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">TAXON</span>\n",
              "</mark>\n",
              " populations.</div></span>"
            ],
            "text/plain": [
              "<IPython.core.display.HTML object>"
            ]
          },
          "metadata": {
            "tags": []
          }
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "CY0U65S27NzX",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 391
        },
        "outputId": "a8796ed2-6be8-44ea-8e2b-f73022bbf017"
      },
      "source": [
        "craft_entities_dataframe = pd.DataFrame(craft_entities[1],columns=['Entity','Label'])  #save returned values of entities and their labels in a pandas dataframe\n",
        "craft_entities_dataframe['Ner_model'] = 'craft' #include a column with constant value of NER model\n",
        "craft_entities_dataframe"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
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              "\n",
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              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
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              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>cells</td>\n",
              "      <td>CL</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>overhanging genomic sequence</td>\n",
              "      <td>SO</td>\n",
              "      <td>craft</td>\n",
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              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>gene deletion</td>\n",
              "      <td>SO</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>wild-type</td>\n",
              "      <td>SO</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>ORF</td>\n",
              "      <td>SO</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>...</th>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>156</th>\n",
              "      <td>virus-cell</td>\n",
              "      <td>GO</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>157</th>\n",
              "      <td>cell cytoplasm</td>\n",
              "      <td>CL</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>158</th>\n",
              "      <td>toxic domains</td>\n",
              "      <td>CHEBI</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>159</th>\n",
              "      <td>virions</td>\n",
              "      <td>CL</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>160</th>\n",
              "      <td>cis</td>\n",
              "      <td>CHEBI</td>\n",
              "      <td>craft</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "<p>161 rows × 3 columns</p>\n",
              "</div>"
            ],
            "text/plain": [
              "                           Entity  Label Ner_model\n",
              "0                           cells     CL     craft\n",
              "1    overhanging genomic sequence     SO     craft\n",
              "2                   gene deletion     SO     craft\n",
              "3                       wild-type     SO     craft\n",
              "4                             ORF     SO     craft\n",
              "..                            ...    ...       ...\n",
              "156                    virus-cell     GO     craft\n",
              "157                cell cytoplasm     CL     craft\n",
              "158                 toxic domains  CHEBI     craft\n",
              "159                       virions     CL     craft\n",
              "160                           cis  CHEBI     craft\n",
              "\n",
              "[161 rows x 3 columns]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 12
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "srLAGPsu7Yvl",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 1000
        },
        "outputId": "22ba72ac-fed0-48dd-b4bf-d6853d082b40"
      },
      "source": [
        "jnlpba_entities = display_entities(en_ner_jnlpba_md,sample_text)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "text/html": [
              "<span class=\"tex2jax_ignore\"><div class=\"entities\" style=\"line-height: 2.5; direction: ltr\">CORONAVIRUS RESEARCH: KEYS TO DIAGNOSIS, TREATMENT, AND PREVENTION OF SARS</br>Mark R. Denison, M.D.</br>For coronavirus investigators, the recognition of a new coronavirus as the cause of severe acute respiratory syndrome (SARS) was certainly remarkable, yet perhaps not surprising (Baric et al., 1995). The cadre of investigators who have worked with this intriguing family of viruses over the past 30 years are familiar with many of the features of coronavirus biology, pathogenesis, and disease that manifested so dramatically in the worldwide SARS epidemic. Advances in the biology of coronaviruses have resulted in greater understanding of their capacity for adaptation to new environments, transspecies infection, and emergence of new diseases. New tools of cell and molecular biology have led to increased understanding of intracellular replication and viral cell biology, and the advent in the past five years of reverse genetic approaches to study coronaviruses has made it possible to begin to define the determinants of viral replication, transpecies adaptation, and human disease. This summary will discuss the basic life cycle and replication of the well-studied coronavirus, mouse hepatitis virus (MHV), identifying the unique characteristics of coronavirus biology and highlighting critical points where research has made significant advances, and which might represent targets for antivirals or vaccines. Areas where rapid progress has been made in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " research will be described. Finally, areas of need for research in coronavirus replication, genetics, and pathogenesis will be summarized.</br>Coronavirus Life Cycle</br>The best studied model for coronavirus replication and pathogenesis has been the group 2 murine coronavirus, mouse hepatitis virus, and much of what is known of the stages of the coronavirus life cycle has been determined in animals and in culture using this virus. Thus this discussion will focus on \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " with comparisons to \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and other coronaviruses. This is appropriate because bioinformatics analyses suggest that \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", while a distinct virus, has significant similarities in organization, putative protein functions, and replication to the group II coronaviruses, particularly within the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (Snijder et al., 2003). Excellent, detailed reviews of MHV and coronavirus replication are available elsewhere (Holmes and Lai, 1996; Lai and Cavanagh, 1997).</br>The coronavirus virion is an enveloped particle containing the spike (S), membrane (M), and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    envelope (E) proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ". In addition, some strains of coronaviruses, but not \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", express a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    hemagglutinin protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (HE) that is also incorporated in the virion. The genome of coronaviruses is a linear, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    single-stranded RNA molecule\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " of positive (mRNA) polarity, and from 28 to 32 kb in length (Bonilla et al., 1994; Drosten et al., 2003; Lee et al., 1991). Within the virion, the genome is encapsidated by multiple copies of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    nucleocapsid protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    N\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              "), and has the conformation of a helical RNA/nucleocapsid structure. The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " has been a focus of pathogenesis studies in mice because it appears to be the critical determinant of cell tropism, species specificity, host selection, cell tropism, and disease (Navas and Weiss, 2003; Navas et al., 2001; Rao and Gallagher, 1998).</br>Virus replication is initiated by binding of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to specific receptors on the host cell surface. For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    primary receptor\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " has been shown to be the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    carcino-embryonic antigen–cell adhesion molecule\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CEACAM\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ") (Dveksler et al., 1991; 1996; Holmes and Lai, 1996; Yokomuri and Lai, 1992), and for the human coronavirus, HCoV-229E, and other group 1 coronaviruses, the receptor is aminopeptidase N (Yeager et al., 1992). The precise mechanisms of entry and uncoating have yet to be defined, but likely occur by either fusion from without or viroplexis through endocytic vesicles. For wildtype MHV, entry and uncoating constitute a pH independent process that is probably direct fusion mediated by a fusion peptide in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (Gallagher et al., 1991). The understanding of the region of the S1 component of coronavirus that binds to receptors was the basis for studies leading to the very recent and very rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    angiotensin converting enzyme 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ACE 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ") as a receptor for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (Li et al., 2003).</br>The next discrete stage in the life cycle is translation and proteolytic processing of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " from the input genome RNA, followed by formation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cytoplasmic replication complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " in association with cellular membranes (Denison et al., 1999; Gosert et al., 2002; Shi et al., 1999; van der Meer et al., 1999). Replication complexes are thought to be sites of all stages of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " transcription and replication, and possibly assembly of nascent viral nucleocapsids. Viral assembly occurs both temporally and physically distinct from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral replication complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " in the endoplasmic-reticulum-Golgi-intermediate compartment (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ERGIC\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              "), a transitional zone between late \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ER\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Golgi\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    deVries\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " et al., 1997; Klumperman et al., 1994; Krijnse-Locker et al., 1994; Rottier and Rose, 1987). Although the mechanisms by which replication products are delivered to sites of assembly remain to be determined, it has been shown that subpopulations of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and the structural nucleocapsid (N) translocate from replication complexes to sites of assembly and may mediate the process in association with cellular membrane/protein trafficking pathways (Bost et al., 2000). Virus assembly in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ERGIC\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " involves interactions of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    genome RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    N\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    membrane protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (M), and the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    small membrane protein (E)\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", resulting in budding of virions into the lumen of ER/Golgi virosomes (Opstetten et al., 1995). Further maturation of virus particles occurs during movement through the Golgi, resulting in virosomes filled with mature particles (Salamuera et al., 1999). Trafficking of the virosomes to the cell surface has not been well characterized, but is presumed to occur via normal vesicle maturation and exocytic processes. The outcome is the nonlytic release of the vast majority of mature virions into the extracellular space. For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and several other coronaviruses that can directly fuse with cells, there is a characteristic and rapidly detectable cytopathic effect of cell-cell fusion into multinucleated syncytia. Production of infectious virus continues even after the majority of cells are fused. Syncytia were recently reported as a readout of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV receptor\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " expression and cell infection (Li et al., 2003).</br>Viral Replication Complex Formation and Function</br>Following entry and uncoating, the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    5′ most replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of the input positive strand RNA genome is translated into two \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    co-amino terminal replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " that are co- and post-translationally processed by \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral proteinases\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to yield 15 to 16 mature replicase proteins, as well as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intermediate precursors\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              ". The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    nascent replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intermediate precursors\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              " likely mediate the formation of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral replication complexes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " in the host cell cytoplasm. Interestingly, coronavirus replication requires continuous replicase gene translation and processing throughout the life cycle to maintain productive infection (Kim et al., 1995; Perlman et al., 1987; Sawicki and Sawicki, 1986). Replication complexes of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " are associated with double-membrane vesicles (Gosert et al., 2002), and all tested \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " have been shown to colocalize to replication complexes at the earliest time of detection, likely both by membrane integration and by protein-protein and protein-RNA interactions (Bost et al., 2000; Denison et al., 1999; Prentice and Denison, in press; Shi et al., 1999; Sims et al., 2000; van der Meer et al., 1999). Further, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " likely mediate the process of double-membrane vesicle formation, likely by induction of cellular autophagy pathways (E. Prentice, unpublished results).</br>Coronavirus replication complexes are sites for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " translation and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyprotein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " processing, and also for viral RNA synthesis. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Replicase gene proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " likely mediate positive-strand, negative-strand, subgenomic, and genomic RNA synthesis, as well as processes of capping, polyadenylation, RNA unwinding, template switching during \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    viral RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " synthesis, and discontinuous transcription and transcription attenuation. The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mature replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " represent the largest and most diverse repertoire of known and predicted distinct enzymatic functions of any \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    positive-strand RNA virus family\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ". Until recently, of the 15 or more \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mature replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", only the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA helicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    RNA-dependent RNA polymerase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " activities had been predicted or experimentally confirmed (Brockway et al., 2003; Heusipp et al., 1997; Lee et al., 1991; Ziebuhr et al., 2000). With the advent of SARS, more extensive bioinformatics analyses have resulted in predictions of several additional functions involved in RNA processing, including \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    methyltransferase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    exonuclease\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " activities (Snijder et al., 2003; Thiel et al., 2003). Even with inclusion of distant predicted relationships, up to eight of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " remain without predicted or confirmed functions. In summary, it is likely that coronaviruses have exploited their genetic capacity to encode proteins in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " with distinct functions in RNA synthesis and processing, as well as proteins with specific roles in induction or modification in host cellular membrane biogenesis and trafficking, delivery of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replication products\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to sites of assembly, and possibly virus assembly. Thus \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " translation, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyprotein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " processing, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mature replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " constitute important targets for interference with coronavirus replication, virus-cell interactions, or viral pathology.</br>Coronavirus Replicase Protein Expression and Processing</br>The \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " activities for all coronaviruses include both \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    papain-like proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ") and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    picornavirus 3C-like proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " activities that are encoded within the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and mediate both cis and trans cleavage events (Ziebuhr et al., 2000). Because of the parallel evolution of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinases\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", their cleavage sites, and the hierarchical cleavage processes, the proteolytic processing of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " may serve as distinct \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    regulatory and genetic elements\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (Ziebuhr et al., 2001). Specifically, there are both conserved and divergent regions of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyproteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " by amino acid identity and similarity, with the sequences and predicted mature proteins beginning with the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3C-like proteinases\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " through the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    carboxy terminus\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase polyprotein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " retaining higher identity and similarity across the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    predicted proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ". In contrast, the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    amino-terminal third\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " demonstrates the most variation in proteins, cleavage site locations, and the number of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinases\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " that mediate maturation processing. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " appears to have the general organization of, and similar protein sizes to, the group 2 coronaviruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " in this part of the genome (Snijder et al., 2003). However, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " likely uses only one \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    PLP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to mediate the cleavages, similar to the group 3 coronavirus infectious bronchitis virus (IBV). Thus this region of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " may experience the most variability, suggesting either the encoding of accessory functions that are flexible and tolerant of changes, or conversely group or host-specific roles that are subject to pressure for more rapid change.</br>Expression of Structural and Accessory Genes</br>Only the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    5′ most replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " is translated from the input positive-strand genome RNA. The genome contains multiple other genes for the known \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    structural proteins S, E, M,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    N\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", as well as other genes for expression of proteins that have been labeled as “nonstructural” or “accessory” because they have been presumed to not be required for replication, and are not thought to be incorporated into virions. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " encodes six of these genes, while \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " encodes possibly up to 11 structural and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    accessory genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", which are expressed from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    subgenomic mRNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " (Snijder et al., 2003). \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    Subgenomic RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " transcription occurs during \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    minus- strand RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " synthesis by acquisition of the antileader RNA sequences from the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    5′ end\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of the genome via homology to a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    transcriptional regulatory sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TRS\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", also known as an \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    intergenic sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              "), and requiring a discontinuous activity of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    nascent minus-strand template\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    polymerase complex\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to acquire the leader (Sawicki and Sawicki, 1998). The outcome of transcription is the generation of a “nested set” of subgenomic negative-strand RNAs that all contain the antileader sequences that serve as templates for similar size subgenomic mRNAs. This transcriptional strategy exposes different genes as the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    5′ ORF\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " in different \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    mRNAs\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              ", all of which also contain the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3′ sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " downstream of the gene, including the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3′ nontranslated region\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of the genome.</br>For \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV, genes 3\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", 5b, 6, and 7 encode \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S, E, M,\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and N, respectively. Genes 2, 4, and 5a are not required for replication in culture, and have been mutated to block expression, deleted, or substituted with noncoronavirus genes such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    GFP\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (de Haan et al., 2002; Ortego et al., 2003; Sarma et al., 2002). Because all coronaviruses retain these genes in various combinations in the face of presumed pressure for genetic economy and apparent lack of functions in RNA synthesis, it is presumed that these genes serve roles in modification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    host cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              ", pathogenesis, or interactions with the immune system. \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " encodes a larger and more complex array of these genes than \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " or other coronaviruses, which may reflect its evolution in its original animal host (Ksiazek et al., 2003; Marra et al., 2003; Snijder et al., 2003; Thiel et al., 2003). In addition, the report of a deletion within one of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    accessory genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " in human isolates of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " suggests that this may be a gene involved in host range or adaptation for replication and transmission in humans (Guan et al., 2003).</br>Coronavirus Genetics</br>Until recently, the genetics of coronavirus replication and pathogenesis have largely been studied using natural variants, host range mutants, passaged virus, and mutagenized viruses selected for temperature sensitivity and specific phenotypes. Classical complementation of functions made it possible to define at least eight genetic groups for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", with most of the complementation groups localized to the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (Stalcup et al., 1998). Taking advantage of naturally high rates of homologous RNA-RNA recombination and of host range determinants in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", the development of targeted recombination has allowed more defined and detailed studies of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    accessory and structural genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", transmissible gastroenteritis virus (TGEV), and feline infectious peritonitis virus (FIPV) (Haijema et al., 2003; Kuo et al., 2000; Masters et al., 1994). Studies with natural variants and targeted recombination genetic studies have demonstrated that the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    S protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " is the major determinant of host range, tropism, and pathogenesis; other genetic elements, possibly in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", may influence these characteristics of different coronaviruses (Navas and Weiss, 2003). The capacity of coronaviruses to change host range, transmission, pathogenesis, and disease has been established in the laboratory using cell adaptation and virus passage (Baric et al., 1997, 1999; Chen and Baric, 1995, 1996), and has been demonstrated in nature by natural variants of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", TGEV, and bovine coronavirus (BCoV), as well as by studies using heterologous viruses such as canine coronavirus (\n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    CcoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ") to immunize cats against FIPV (Enjuanes et al., 1995; Tresnan et al., 1996). Further, targeted recombination studies have confirmed the genetic flexibility of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " and the ability of coronaviruses to recover wild-type replication following deletions, mutations, substitutions, and gene order rearrangements in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    structural and accessory genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (de Haan et al., 2002).</br>Challenges for genetic studies using \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    natural variants and mutants\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", particularly in defining the precise changes responsible for altered phenotypes, has limited progress in genetic studies. Targeted recombination, while a robust system with powerful selection, has been limited to studies of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3′ 10 kb\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", and is limited to selection of viable recombinants. Recently, the establishment of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    “infectious clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              "” reverse genetic strategies for the coronaviruses TGEV (Transmissible Gastroenteritis Coronavirus), HCoV-229E, IBV, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " has made it theoretically possible to study the genetics of the entire genome and all of the structural, accessory, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase genes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ". Approaches to “infectious cloning” have included \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    full-length cDNA clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    bacterial artificial chromosomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (Gonzalez et al., 2001), recombinant vaccinia viruses containing \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    full-length cDNA clones\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    HCoV-229E and IBV genomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " (Casais et al., 2001; Thiel et al., 2001), and in vitro assembly strategies for TGEV, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", and most recently, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (Yount, 2000; Yount et al., 2002, 2003).</br>The in vitro assembly approach was developed to overcome the challenge of full-length cDNA cloning of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    TGEV and MHV genomes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", which contained “toxic” regions in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", resulting in unstable or toxic clones in E. coli (Yount, 2000; Yount et al., 2002). Subcloning of the regions required splitting the toxic domains into separate clones. The result of this strategy was the cloning of the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV genome\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " into seven fragments (A through G). To recover viable virus, the following strategy is pursued: (1) cloned \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cDNA fragments\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " are excised from \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    plasmid\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " using \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    class 2 restriction enzymes\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " that remove the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    recognition site\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " and leave \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    overhanging genomic sequence\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              "; (2) excised fragments are ligated (assembled) in vitro; (3) transcription of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    full-length genomic RNA\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">RNA</span>\n",
              "</mark>\n",
              " is driven in vitro using a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    T7 promoter\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " on the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    5′ fragment A\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              "; (4) full-length genome RNA is electroporated into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    competent cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              " that are then plated on a monolayer of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    naturally permissive cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              "; and (5) cells are monitored for cytopathic effect or plaques, and virus is recovered from plaques or media supernatant.</br>In vitro assembly has many advantages for genetic studies of such a large and complex genome RNA. First, genetic changes can be introduced and confirmed in stable small fragments without the need for a \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ~30kb genomic clone\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ". Second, the cloned fragments make it possible to develop libraries of mutations that can rapidly be tested in different combinations. Furthermore, identification of putative second-site reversion mutations for deleterious introduced changes can be introduced with the original mutation to confirm their reversion potential. In combination with biochemical and cell imaging approaches, it also is possible to study highly defective or lethal mutations in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    electroporated cells\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              ", in order to define critical determinants of replication. The in vitro assembly approach has been used to introduce marker mutations that are silent for replication in culture (Yount et al., 2003). In addition, we have engineered mutations in the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " to define the requirements for polyprotein processing and to determine the role of specific \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " in replication in culture and in pathogenesis in animals. Using this approach we have recovered viruses with mutations at polyprotein cleavage sites and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    proteinase catalytic residues\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", all of which have distinct phenotypes in protein processing, viral growth, and viral RNA synthesis (unpublished results). Thus, direct reverse genetic studies of the critical \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " functions can be performed using in vitro assembly of infectious clones.</br>Advances in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " Research</br>The rapid progress in the identification and characterization of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " as the etiologic agent of SARS was made possible by the fact that the virus grows well in culture, and by the foundational research in coronaviruses that has been supported by the National Institutes of Health, the Multiple Sclerosis Foundation, the U.S. Department of Agriculture, and other organizations over the past two decades. The application of knowledge concerning virus structure, genetics, receptor binding, virus entry, and viral pathogenesis has made it possible to target the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    spike protein\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " for studies of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " replication, pathogenesis, and immune response (Xiao et al., 2003). The remarkably rapid identification of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    ACE 2\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " as a receptor for SARS has demonstrated the foundational importance of studies of other coronaviruses (Li et al., 2003). Similarly, understanding of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase gene\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              " expression, processing, and predicted functions has identified possible targets for structure/function studies and possible therapeutic intervention. The studies of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    coronavirus proteinase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " activities, \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    cleavage site\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">DNA</span>\n",
              "</mark>\n",
              ", and structures were the basis for studies leading to the rapid determination of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV replicase polyprotein cleavage sites\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    3CLpro crystal structure\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " (Anand et al., 2003; Campanacci et al., 2003; Snijder et al., 2003; Thiel et al., 2003).</br>Application of Reverse Genetics to Studies of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              "Because of the potential for reemergence of SARS, it is important to move forward with research in diagnostics, vaccines, and therapeutics for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV.\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " Experience with the development and use of reverse genetics to study other coronaviruses resulted in establishment of reverse genetics for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " within months of the onset of the worldwide epidemic (Yount et al., 2003). How should the understanding of other coronaviruses, the rapid advances in research with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", and the development of reverse genetics for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " be harnesssed to achieve these goals and attack these critical questions in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " replication, pathogenesis, and disease? Certainly, the use of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " reverse genetics, along with robust tissue culture systems and emerging animal models, creates the potential to rapidly answer questions concerning: (1) determinants of virus growth in culture; (2) potential mechanisms of transpecies adaptation; (3) sensitivity to and escape from biochemical and immune interference with replication; (4) determinants of virulence and pathogenesis; (5) mechanisms of genome recombination and mutation; (6) functions of and requirements for \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    replicase\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", structural, and \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    accessory proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              "; and (7) development of stably attenuated viruses for use as seed stocks for inactivated vaccine or testing as live-attenuated vaccines.</br>How then should these critical issues be investigated while recognizing the potential of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " to cause severe disease, as well as the potential for rapid spread? First, there is significant experience with other coronaviruses in attenuation of virus replication and pathogenesis, both using virus passage and by direct engineering of changes. Although coronavirus genome organization, proteins, and replication appear more tolerant of changes then previously thought, all changes of gene order, gene deletion, insertion, or mutagenesis so far reported have led to viruses impaired in replication, pathogenesis, or both. Many of the attenuating changes in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and other coronaviruses are conserved in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and thus could be tested for likely attenuation in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV culture\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_LINE</span>\n",
              "</mark>\n",
              " and animal models. Second, where there is clear conservation of sequences, motifs, proteins, or putative functions between \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and model viruses such as \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    MHV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", new or untested changes might be most rapidly analyzed under BSL2 conditions in those model viruses, and then directly applied to SARS once their phenotypes are determined. Third, all work with \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " will be performed only under BSL3 conditions. This would also apply to chimeric viruses, whether engineered by introduction into the \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " background, or by introducing \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV proteins\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " or sequences with known or predicted pathogenic consequences into other coronavirus backgrounds. Finally, it is important to develop strains of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " that are attenuated and stabilized against reversion and recombination, to be used as the basis for studies of other replication and pathogenesis determinants and construction of virus chimeras. Such attenuated variants would provide additional safeguards while allowing application of powerful genetic tools to the study of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " emergence, biology, disease, treatment, and prevention. Overall, newly invigorated programs in other human and animal coronaviruses, combined with the new research in \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              ", will shed important new light on this important \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    virus family\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " and perhaps lead to better understanding of the potential for resurgence of \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    SCoV\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">PROTEIN</span>\n",
              "</mark>\n",
              " or the emergence of other coronaviruses into \n",
              "<mark class=\"entity\" style=\"background: #ddd; padding: 0.45em 0.6em; margin: 0 0.25em; line-height: 1; border-radius: 0.35em;\">\n",
              "    human populations\n",
              "    <span style=\"font-size: 0.8em; font-weight: bold; line-height: 1; border-radius: 0.35em; text-transform: uppercase; vertical-align: middle; margin-left: 0.5rem\">CELL_TYPE</span>\n",
              "</mark>\n",
              ".</div></span>"
            ],
            "text/plain": [
              "<IPython.core.display.HTML object>"
            ]
          },
          "metadata": {
            "tags": []
          }
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "5raJie4E7uka",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 391
        },
        "outputId": "af42cafc-6f64-4068-8f31-636f7b108d84"
      },
      "source": [
        "jnlpa_entities_dataframe = pd.DataFrame(jnlpba_entities[1],columns=['Entity','Label']) #save returned values of entities and their labels in a pandas dataframe\n",
        "jnlpa_entities_dataframe['Ner_model'] = 'jnlpa' # include a column with constant value of NER model\n",
        "jnlpa_entities_dataframe"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>TGEV and MHV genomes</td>\n",
              "      <td>DNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>carboxy terminus</td>\n",
              "      <td>PROTEIN</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>minus- strand RNA</td>\n",
              "      <td>RNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>bacterial artificial chromosomes</td>\n",
              "      <td>DNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>3′ nontranslated region</td>\n",
              "      <td>DNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>...</th>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "      <td>...</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>111</th>\n",
              "      <td>spike protein</td>\n",
              "      <td>PROTEIN</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>112</th>\n",
              "      <td>cDNA fragments</td>\n",
              "      <td>DNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>113</th>\n",
              "      <td>regulatory and genetic elements</td>\n",
              "      <td>DNA</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>114</th>\n",
              "      <td>MHV</td>\n",
              "      <td>PROTEIN</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>115</th>\n",
              "      <td>MHV replicase proteins</td>\n",
              "      <td>PROTEIN</td>\n",
              "      <td>jnlpa</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "<p>116 rows × 3 columns</p>\n",
              "</div>"
            ],
            "text/plain": [
              "                               Entity    Label Ner_model\n",
              "0                TGEV and MHV genomes      DNA     jnlpa\n",
              "1                    carboxy terminus  PROTEIN     jnlpa\n",
              "2                   minus- strand RNA      RNA     jnlpa\n",
              "3    bacterial artificial chromosomes      DNA     jnlpa\n",
              "4             3′ nontranslated region      DNA     jnlpa\n",
              "..                                ...      ...       ...\n",
              "111                     spike protein  PROTEIN     jnlpa\n",
              "112                    cDNA fragments      DNA     jnlpa\n",
              "113   regulatory and genetic elements      DNA     jnlpa\n",
              "114                               MHV  PROTEIN     jnlpa\n",
              "115            MHV replicase proteins  PROTEIN     jnlpa\n",
              "\n",
              "[116 rows x 3 columns]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 14
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "T9UqOgw275Yg",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 180
        },
        "outputId": "6ce39c47-216f-4d6e-e539-d6714d2294d0"
      },
      "source": [
        "entities_and_label_from_4_NER_model_dataframe = pd.concat([bc5dr_entities_dataframe,bionlp13cg_entities_dataframe,craft_entities_dataframe,jnlpa_entities_dataframe])\n",
        "#Concatenate all pandas dataframe into one.\n",
        "entities_and_label_from_4_NER_model_dataframe.to_csv('entities_and_label_from_4_scispacy_NER_models.csv', index=False) #Save dataframe to csv\n",
        "entities_and_label_from_4_NER_model_dataframe.info()"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "stream",
          "text": [
            "<class 'pandas.core.frame.DataFrame'>\n",
            "Int64Index: 422 entries, 0 to 115\n",
            "Data columns (total 3 columns):\n",
            " #   Column     Non-Null Count  Dtype \n",
            "---  ------     --------------  ----- \n",
            " 0   Entity     422 non-null    object\n",
            " 1   Label      422 non-null    object\n",
            " 2   Ner_model  422 non-null    object\n",
            "dtypes: object(3)\n",
            "memory usage: 13.2+ KB\n"
          ],
          "name": "stdout"
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "PmTLIRWDIGvi",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "#Load pre extracted dataset into pandas\n",
        "entities_and_label_from_4_NER_model_dataframe = pd.read_csv('/content/entities_and_label_from_4_scispacy_NER_models.csv')"
      ],
      "execution_count": 22,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "PEWKIrElMGk0",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 191
        },
        "outputId": "629a6338-3725-4bb7-f528-dd4aa7f94312"
      },
      "source": [
        "#pd.options.display.max_colwidth = 1000      #increase display width of the pandas dataframe\n",
        "entities_and_label_from_4_NER_model_dataframe.head() "
      ],
      "execution_count": 23,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>viroplexis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>productive infection</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>gastroenteritis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>hepatitis virus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>angiotensin</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "                 Entity     Label Ner_model\n",
              "0            viroplexis   DISEASE     bc5dr\n",
              "1  productive infection   DISEASE     bc5dr\n",
              "2       gastroenteritis   DISEASE     bc5dr\n",
              "3       hepatitis virus   DISEASE     bc5dr\n",
              "4           angiotensin  CHEMICAL     bc5dr"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 23
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "fv4fPUkna8NQ",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "def entity_linker(linker_name,document):\n",
        "    \"\"\" A function that accepts the name of a scispacy knowledge base and documents and returns the entity link details\"\"\"\n",
        "    linker = EntityLinker(k = 10,max_entities_per_mention = 2, name=linker_name)  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "    nlp = en_core_sci_sm.load()\n",
        "    nlp.add_pipe(linker)\n",
        "    doc = nlp(document)\n",
        "    try:\n",
        "        entity = doc.ents[0]\n",
        "    except IndexError:\n",
        "        entity = 'Nan'\n",
        "    entity_details = []\n",
        "    entity_details.append(entity)\n",
        "    try:\n",
        "        for linker_ent in entity._.kb_ents:\n",
        "            Concept_Id, Score = linker_ent\n",
        "            entity_details.append('Entity_Matching_Score :{}'.format(Score))\n",
        "            entity_details.append(linker.kb.cui_to_entity[linker_ent[0]])\n",
        "    except AttributeError:\n",
        "        pass\n",
        "    return entity_details"
      ],
      "execution_count": 7,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "Cbvv3BeOWVL3",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        ""
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "markdown",
      "metadata": {
        "id": "Ecb0XT6XQjG2",
        "colab_type": "text"
      },
      "source": [
        "###Test the entity_linker function with the 4 sciSpacy knowledge bases \"umls\",\"mesh\",\"go\",\"hpo\". The function will return 2 entities and their scores as it relates to the Knowledge base. As at the time of this writing the \"rxnorm\" knowledge base returned KeyError, I will investigate further on why this is happening"
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "ULPjZ5orDkBZ",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "test1 = 'fever'"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "KLAHiv9zG_Jy",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 508
        },
        "outputId": "c8713594-5dbc-497e-9378-6d02f2dbca6e"
      },
      "source": [
        "entity_linker('umls',test1)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "stream",
          "text": [
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls/tfidf_vectors_sparse.npz not found in cache, downloading to /tmp/tmpbs40dloe\n",
            "Finished download, copying /tmp/tmpbs40dloe to cache at /root/.scispacy/datasets/b7aadedb8a0dc19e86aca4e866e8767a419889c39f92f96e9458ee264bc13783.d670f5df5e7ad62f30ba05df2f48cafc6058117f2e352385f289872ac8c95028.tfidf_vectors_sparse.npz\n",
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls/nmslib_index.bin not found in cache, downloading to /tmp/tmpgp4bzxbf\n",
            "Finished download, copying /tmp/tmpgp4bzxbf to cache at /root/.scispacy/datasets/dda67f3ef5951cfedf2de7de7b3561d45ce9e8ed92346cc196310a76b15fe0b6.fdebf628ed43f2d0fba4f250d97a57ddcb36b183308702481009f67c5d771465.nmslib_index.bin\n",
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls/tfidf_vectorizer.joblib not found in cache, downloading to /tmp/tmp50x32sb9\n",
            "Finished download, copying /tmp/tmp50x32sb9 to cache at /root/.scispacy/datasets/2d16de7bdaeca09492930b4065e44c63c649377e583a60baedc48b21160e6ffe.d22e20f8a82d5590c728adb94b7cf2d9bc3c953bfb63e06e356fd8b13d7b4d77.tfidf_vectorizer.joblib\n"
          ],
          "name": "stdout"
        },
        {
          "output_type": "stream",
          "text": [
            "/usr/local/lib/python3.6/dist-packages/sklearn/base.py:318: UserWarning: Trying to unpickle estimator TfidfTransformer from version 0.20.3 when using version 0.22.2.post1. This might lead to breaking code or invalid results. Use at your own risk.\n",
            "  UserWarning)\n",
            "/usr/local/lib/python3.6/dist-packages/sklearn/base.py:318: UserWarning: Trying to unpickle estimator TfidfVectorizer from version 0.20.3 when using version 0.22.2.post1. This might lead to breaking code or invalid results. Use at your own risk.\n",
            "  UserWarning)\n"
          ],
          "name": "stderr"
        },
        {
          "output_type": "stream",
          "text": [
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls/concept_aliases.json not found in cache, downloading to /tmp/tmpqle0ngjw\n",
            "Finished download, copying /tmp/tmpqle0ngjw to cache at /root/.scispacy/datasets/d485a39692e39f93339abf6102c3336dda07d84d8ae46a03d55079b54cad1137.a65425f2cddfa1f741a17c18fc68797f5434547425e30bbe236dea0dcb7a9389.concept_aliases.json\n",
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls_2020_aa_cat0129.jsonl not found in cache, downloading to /tmp/tmpsjoz7zd2\n",
            "Finished download, copying /tmp/tmpsjoz7zd2 to cache at /root/.scispacy/datasets/cf6297e16bc34e731db62e18b99603d440223279d6574e101d610ab5c713b265.1b0c2eaa35a3a31246741feac4b0255581214437fb86cd941018283668d461b0.umls_2020_aa_cat0129.jsonl\n",
            "https://s3-us-west-2.amazonaws.com/ai2-s2-scispacy/data/umls_semantic_type_tree.tsv not found in cache, downloading to /tmp/tmpw8oxgnu2\n",
            "Finished download, copying /tmp/tmpw8oxgnu2 to cache at /root/.scispacy/datasets/21a1012c532c3a431d60895c509f5b4d45b0f8966c4178b892190a302b21836f.330707f4efe774134872b9f77f0e3208c1d30f50800b3b39a6b8ec21d9adf1b7.umls_semantic_type_tree.tsv\n"
          ],
          "name": "stdout"
        },
        {
          "output_type": "execute_result",
          "data": {
            "text/plain": [
              "[fever,\n",
              " 'Entity_Matching_Score :1.0',\n",
              " CUI: C0424755, Name: Fever symptoms (finding)\n",
              "Definition: None\n",
              "TUI(s): T033\n",
              "Aliases: (total: 6): \n",
              "\t Fever symptoms (finding), Fever, Fever symptoms, symptoms fever, fever symptoms, fever symptom,\n",
              " 'Entity_Matching_Score :1.0',\n",
              " CUI: C4552740, Name: Fever, CTCAE\n",
              "Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal.\n",
              "TUI(s): T033\n",
              "Aliases: (total: 2): \n",
              "\t Fever, CTCAE, Fever]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 9
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "CNQRN9tGDoAl",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 228
        },
        "outputId": "5d161894-045f-4fd0-f2f0-e9fa1d00aac3"
      },
      "source": [
        "entity_linker('go',test1)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/plain": [
              "[fever,\n",
              " 'Entity_Matching_Score :0.8655633330345154',\n",
              " CUI: C2245278, Name: positive regulation of fever generation\n",
              "Definition: Any process that activates or increases the frequency, rate, or extent of fever generation. [GOC:add]\n",
              "TUI(s): T040\n",
              "Aliases: (total: 4): \n",
              "\t positive regulation of pyrexia, upregulation of fever, up regulation of fever, up-regulation of fever,\n",
              " 'Entity_Matching_Score :0.8369923233985901',\n",
              " CUI: C2245274, Name: negative regulation of fever generation\n",
              "Definition: Any process that stops, prevents, or reduces the rate or extent of fever generation. [GOC:add, GOC:dph, GOC:tb]\n",
              "TUI(s): T040\n",
              "Aliases: (total: 4): \n",
              "\t negative regulation of pyrexia, down regulation of fever, down-regulation of fever, downregulation of fever]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 40
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "yGdep4utF8pB",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 228
        },
        "outputId": "1778950b-c52f-403a-b8e6-26b8309fdb08"
      },
      "source": [
        "entity_linker('hpo',test1)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/plain": [
              "[fever,\n",
              " 'Entity_Matching_Score :1.0',\n",
              " CUI: C0015967, Name: Fever\n",
              "Definition: An abnormal elevation of body temperature, usually as a result of a pathologic process.\n",
              "TUI(s): T184\n",
              "Aliases: (total: 3): \n",
              "\t Fever, Hyperthermia, Pyrexia,\n",
              " 'Entity_Matching_Score :0.8298224806785583',\n",
              " CUI: C0018621, Name: Hay fever\n",
              "Definition: Allergic rhinitis caused by outdoor allergens.\n",
              "TUI(s): T047\n",
              "Aliases: (total: 3): \n",
              "\t Seasonal allergy, Seasonal allergy, Hayfever]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 72
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "jkC4TEEpF_xk",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 411
        },
        "outputId": "d7558c88-5f4c-4d89-806a-df59a93446d0"
      },
      "source": [
        "entity_linker('mesh',test1)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "stream",
          "text": [
            "https://ai2-s2-scispacy.s3-us-west-2.amazonaws.com/data/mesh_linking_model/tfidf_vectors_sparse.npz not found in cache, downloading to /tmp/tmpj5xgyxeg\n",
            "Finished download, copying /tmp/tmpj5xgyxeg to cache at /root/.scispacy/datasets/b28c5ae2b3052b66e3df4d9e8082fd6138060d0369555a603bf103facbc8a175.cdcb8550ec06b33ef35938f3ffb30ca58f6082bc649ce9c8069d041eb33c22b6.tfidf_vectors_sparse.npz\n",
            "https://ai2-s2-scispacy.s3-us-west-2.amazonaws.com/data/mesh_linking_model/nmslib_index.bin not found in cache, downloading to /tmp/tmp2aszg8qx\n",
            "Finished download, copying /tmp/tmp2aszg8qx to cache at /root/.scispacy/datasets/6812e57b9f4b0e14d6f9974a745e136fb47b5c2a2d955635a4d13675f6add07d.62b9b370bfb8c9433ba8fb69c1fb83405116079c4f741698b8159319d01833c0.nmslib_index.bin\n",
            "https://ai2-s2-scispacy.s3-us-west-2.amazonaws.com/data/mesh_linking_model/tfidf_vectorizer.joblib not found in cache, downloading to /tmp/tmp1wu3x5id\n",
            "Finished download, copying /tmp/tmp1wu3x5id to cache at /root/.scispacy/datasets/418d053aba7875dd273cbad2b63ccebdd7ceeb923355172d1dc581ec780c8b13.5473393740d5e23a46590babbdd7a98603d6a22476c1ecbca3faf50b07e1fa71.tfidf_vectorizer.joblib\n",
            "https://ai2-s2-scispacy.s3-us-west-2.amazonaws.com/data/mesh_linking_model/concept_aliases.json not found in cache, downloading to /tmp/tmps2yyz05s\n",
            "Finished download, copying /tmp/tmps2yyz05s to cache at /root/.scispacy/datasets/ee3f06eff5008dc3a2f9e52df6128f32ac832c0026a9a677bbe7a2d8f253ca43.1b70562d4cd41b4b8657534ae5abd2a8ee5641e9a11e92b9c172165a3ae6a5c2.concept_aliases.json\n",
            "https://ai2-s2-scispacy.s3-us-west-2.amazonaws.com/data/mesh_2020.jsonl not found in cache, downloading to /tmp/tmpsodq9pnw\n",
            "Finished download, copying /tmp/tmpsodq9pnw to cache at /root/.scispacy/datasets/e3d47cc15aee0d5dfbaff226e071e35bcb731ad8a752f91bbda8b8dd4b2acc67.aa95b0492040d1386799638de559a625798ede06bc23e9b77166500fab9903d0.mesh_2020.jsonl\n"
          ],
          "name": "stdout"
        },
        {
          "output_type": "execute_result",
          "data": {
            "text/plain": [
              "[fever,\n",
              " 'Entity_Matching_Score :1.0',\n",
              " CUI: D005334, Name: Fever\n",
              "Definition: An abnormal elevation of body temperature, usually as a result of a pathologic process.\n",
              "TUI(s): \n",
              "Aliases: (total: 3): \n",
              "\t Hyperthermia, Fever, Pyrexia,\n",
              " 'Entity_Matching_Score :0.8281346559524536',\n",
              " CUI: D006255, Name: Rhinitis, Allergic, Seasonal\n",
              "Definition: Allergic rhinitis that occurs at the same time every year. It is characterized by acute CONJUNCTIVITIS with lacrimation and ITCHING, and regarded as an allergic condition triggered by specific ALLERGENS.\n",
              "TUI(s): \n",
              "Aliases: (total: 6): \n",
              "\t Seasonal Allergic Rhinitis, Rhinitis, Allergic, Seasonal, Hay Fever, Hayfever, Pollen Allergy, Pollinosis]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 15
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "KGDemdKNRnIm",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 296
        },
        "outputId": "4be98e8f-225e-4a67-db15-a2bbdcd573ab"
      },
      "source": [
        "entity_linker('rxnorm',test1)"
      ],
      "execution_count": null,
      "outputs": [
        {
          "output_type": "error",
          "ename": "KeyError",
          "evalue": "ignored",
          "traceback": [
            "\u001b[0;31m---------------------------------------------------------------------------\u001b[0m",
            "\u001b[0;31mKeyError\u001b[0m                                  Traceback (most recent call last)",
            "\u001b[0;32m<ipython-input-11-d04a7bafee1e>\u001b[0m in \u001b[0;36m<module>\u001b[0;34m()\u001b[0m\n\u001b[0;32m----> 1\u001b[0;31m \u001b[0mentity_linker\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0;34m'rxnorm'\u001b[0m\u001b[0;34m,\u001b[0m\u001b[0mtest1\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0m",
            "\u001b[0;32m<ipython-input-7-ec5009b884ea>\u001b[0m in \u001b[0;36mentity_linker\u001b[0;34m(linker_name, document)\u001b[0m\n\u001b[1;32m      3\u001b[0m     \u001b[0mnlp\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0men_core_sci_sm\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mload\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m      4\u001b[0m     \u001b[0mnlp\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0madd_pipe\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mlinker_call\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0;32m----> 5\u001b[0;31m     \u001b[0mdoc\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mnlp\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mdocument\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0m\u001b[1;32m      6\u001b[0m     \u001b[0mentity\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mdoc\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0ments\u001b[0m\u001b[0;34m[\u001b[0m\u001b[0;36m0\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m      7\u001b[0m     \u001b[0mentity_details\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0;34m[\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n",
            "\u001b[0;32m/usr/local/lib/python3.6/dist-packages/spacy/language.py\u001b[0m in \u001b[0;36m__call__\u001b[0;34m(self, text, disable, component_cfg)\u001b[0m\n\u001b[1;32m    447\u001b[0m             \u001b[0;32mif\u001b[0m \u001b[0;32mnot\u001b[0m \u001b[0mhasattr\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mproc\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0;34m\"__call__\"\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m:\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    448\u001b[0m                 \u001b[0;32mraise\u001b[0m \u001b[0mValueError\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mErrors\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mE003\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mformat\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mcomponent\u001b[0m\u001b[0;34m=\u001b[0m\u001b[0mtype\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mproc\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mname\u001b[0m\u001b[0;34m=\u001b[0m\u001b[0mname\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0;32m--> 449\u001b[0;31m             \u001b[0mdoc\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mproc\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mdoc\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0;34m**\u001b[0m\u001b[0mcomponent_cfg\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mget\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mname\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0;34m{\u001b[0m\u001b[0;34m}\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0m\u001b[1;32m    450\u001b[0m             \u001b[0;32mif\u001b[0m \u001b[0mdoc\u001b[0m \u001b[0;32mis\u001b[0m \u001b[0;32mNone\u001b[0m\u001b[0;34m:\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    451\u001b[0m                 \u001b[0;32mraise\u001b[0m \u001b[0mValueError\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mErrors\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mE005\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mformat\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mname\u001b[0m\u001b[0;34m=\u001b[0m\u001b[0mname\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n",
            "\u001b[0;32m/usr/local/lib/python3.6/dist-packages/scispacy/linking.py\u001b[0m in \u001b[0;36m__call__\u001b[0;34m(self, doc)\u001b[0m\n\u001b[1;32m    102\u001b[0m \u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    103\u001b[0m         \u001b[0mmention_strings\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0;34m[\u001b[0m\u001b[0mx\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mtext\u001b[0m \u001b[0;32mfor\u001b[0m \u001b[0mx\u001b[0m \u001b[0;32min\u001b[0m \u001b[0mmentions\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0;32m--> 104\u001b[0;31m         \u001b[0mbatch_candidates\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mself\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mcandidate_generator\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mmention_strings\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mself\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mk\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0m\u001b[1;32m    105\u001b[0m \u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    106\u001b[0m         \u001b[0;32mfor\u001b[0m \u001b[0mmention\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mcandidates\u001b[0m \u001b[0;32min\u001b[0m \u001b[0mzip\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mdoc\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0ments\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mbatch_candidates\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m:\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n",
            "\u001b[0;32m/usr/local/lib/python3.6/dist-packages/scispacy/candidate_generation.py\u001b[0m in \u001b[0;36m__call__\u001b[0;34m(self, mention_texts, k)\u001b[0m\n\u001b[1;32m    342\u001b[0m             \u001b[0;32mfor\u001b[0m \u001b[0mneighbor_index\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mdistance\u001b[0m \u001b[0;32min\u001b[0m \u001b[0mzip\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mneighbors\u001b[0m\u001b[0;34m,\u001b[0m \u001b[0mdistances\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m:\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    343\u001b[0m                 \u001b[0mmention\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mself\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mann_concept_aliases_list\u001b[0m\u001b[0;34m[\u001b[0m\u001b[0mneighbor_index\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0;32m--> 344\u001b[0;31m                 \u001b[0mconcepts_for_mention\u001b[0m \u001b[0;34m=\u001b[0m \u001b[0mself\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mkb\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0malias_to_cuis\u001b[0m\u001b[0;34m[\u001b[0m\u001b[0mmention\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[0m\u001b[1;32m    345\u001b[0m                 \u001b[0;32mfor\u001b[0m \u001b[0mconcept_id\u001b[0m \u001b[0;32min\u001b[0m \u001b[0mconcepts_for_mention\u001b[0m\u001b[0;34m:\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n\u001b[1;32m    346\u001b[0m                     \u001b[0mconcept_to_mentions\u001b[0m\u001b[0;34m[\u001b[0m\u001b[0mconcept_id\u001b[0m\u001b[0;34m]\u001b[0m\u001b[0;34m.\u001b[0m\u001b[0mappend\u001b[0m\u001b[0;34m(\u001b[0m\u001b[0mmention\u001b[0m\u001b[0;34m)\u001b[0m\u001b[0;34m\u001b[0m\u001b[0;34m\u001b[0m\u001b[0m\n",
            "\u001b[0;31mKeyError\u001b[0m: 'Feverall'"
          ]
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "wz0cNhDhXVk3",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "linker = EntityLinker(k = 10,max_entities_per_mention = 2, name='umls')  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "nlp = en_core_sci_sm.load()\n",
        "nlp.add_pipe(linker)\n",
        "def umls_entity_linker(document):\n",
        "    \"\"\" A function that accepts and document and returns the entity link details\"\"\"\n",
        "    #linker = EntityLinker(k = 10,max_entities_per_mention = 2, name=linker_name)  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "    #nlp = en_core_sci_sm.load()\n",
        "    #nlp.add_pipe(linker)\n",
        "    doc = nlp(document)\n",
        "    try:\n",
        "        entity = doc.ents[0]\n",
        "    except IndexError:\n",
        "        entity = 'Nan'\n",
        "    entity_details = []\n",
        "    entity_details.append(entity)\n",
        "    try:\n",
        "        for linker_ent in entity._.kb_ents:\n",
        "            Concept_Id, Score = linker_ent\n",
        "            entity_details.append('Entity_Matching_Score :{}'.format(Score))\n",
        "            entity_details.append(linker.kb.cui_to_entity[linker_ent[0]])\n",
        "    except AttributeError:\n",
        "        pass\n",
        "    return entity_details"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "BMox9XvtXcER",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "linker = EntityLinker(k = 10,max_entities_per_mention = 2, name='mesh')  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "nlp = en_core_sci_sm.load()\n",
        "nlp.add_pipe(linker)\n",
        "def mesh_entity_linker(document):\n",
        "    \"\"\" A function that accepts the name of a scispacy knowledge base and documents and returns the entity link details\"\"\"\n",
        "    #linker = EntityLinker(k = 10,max_entities_per_mention = 2, name=linker_name)  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "    #nlp = en_core_sci_sm.load()\n",
        "    #nlp.add_pipe(linker)\n",
        "    doc = nlp(document)\n",
        "    try:\n",
        "        entity = doc.ents[0]\n",
        "    except IndexError:\n",
        "        entity = 'Nan'\n",
        "    entity_details = []\n",
        "    entity_details.append(entity)\n",
        "    try:\n",
        "        for linker_ent in entity._.kb_ents:\n",
        "            Concept_Id, Score = linker_ent\n",
        "            entity_details.append('Entity_Matching_Score :{}'.format(Score))\n",
        "            entity_details.append(linker.kb.cui_to_entity[linker_ent[0]])\n",
        "    except AttributeError:\n",
        "        pass\n",
        "    return entity_details"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "OgjHY5ZVWsno",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "linker = EntityLinker(k = 10,max_entities_per_mention = 2, name='go')  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "nlp = en_core_sci_sm.load()\n",
        "nlp.add_pipe(linker)\n",
        "def go_entity_linker(document):\n",
        "    \"\"\" A function that accepts the name of a scispacy knowledge base and documents and returns the entity link details\"\"\"\n",
        "    #linker = EntityLinker(k = 10,max_entities_per_mention = 2, name=linker_name)  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "    #nlp = en_core_sci_sm.load()\n",
        "    #nlp.add_pipe(linker)\n",
        "    doc = nlp(document)\n",
        "    try:\n",
        "        entity = doc.ents[0]\n",
        "    except IndexError:\n",
        "        entity = 'Nan'\n",
        "    entity_details = []\n",
        "    entity_details.append(entity)\n",
        "    try:\n",
        "        for linker_ent in entity._.kb_ents:\n",
        "            Concept_Id, Score = linker_ent\n",
        "            entity_details.append('Entity_Matching_Score :{}'.format(Score))\n",
        "            entity_details.append(linker.kb.cui_to_entity[linker_ent[0]])\n",
        "    except AttributeError:\n",
        "        pass\n",
        "    return entity_details"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "elUyfllnXzlc",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        "linker = EntityLinker(k = 10,max_entities_per_mention = 2, name='hpo')  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "nlp = en_core_sci_sm.load()\n",
        "nlp.add_pipe(linker)\n",
        "def hpo_entity_linker(document):\n",
        "    \"\"\" A function that accepts the name of a scispacy knowledge base and documents and returns the entity link details\"\"\"\n",
        "    #linker = EntityLinker(k = 10,max_entities_per_mention = 2, name=linker_name)  #parameters are tunable,so it can be set to return more than 2 entity matches\n",
        "    #nlp = en_core_sci_sm.load()\n",
        "    #nlp.add_pipe(linker)\n",
        "    doc = nlp(document)\n",
        "    try:\n",
        "        entity = doc.ents[0]\n",
        "    except IndexError:\n",
        "        entity = 'Nan'\n",
        "    entity_details = []\n",
        "    entity_details.append(entity)\n",
        "    try:\n",
        "        for linker_ent in entity._.kb_ents:\n",
        "            Concept_Id, Score = linker_ent\n",
        "            entity_details.append('Entity_Matching_Score :{}'.format(Score))\n",
        "            entity_details.append(linker.kb.cui_to_entity[linker_ent[0]])\n",
        "    except AttributeError:\n",
        "        pass\n",
        "    return entity_details"
      ],
      "execution_count": null,
      "outputs": []
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "avMAgX9hRbZO",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 65,
          "referenced_widgets": [
            "7752ade7dc8e4b4b8fca6e9f40630ec8",
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            "7eee4cb5d7154547a837d4ab030f64f9",
            "c95fd212dffd4cac856cf369dc1c9777",
            "436ed2e698254b119092128a278eda74",
            "b655631768a64a7088ae1eb153b4c401",
            "d40fec26599946818f9eb85f9693c59e"
          ]
        },
        "outputId": "47732b50-7a85-47e0-9791-d081276b46e7"
      },
      "source": [
        "entities_and_label_from_4_NER_model_dataframe['umls_output'] = entities_and_label_from_4_NER_model_dataframe['Entity'].swifter.apply(lambda x : umls_entity_linker(x))"
      ],
      "execution_count": 26,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "application/vnd.jupyter.widget-view+json": {
              "model_id": "7752ade7dc8e4b4b8fca6e9f40630ec8",
              "version_minor": 0,
              "version_major": 2
            },
            "text/plain": [
              "HBox(children=(FloatProgress(value=0.0, description='Pandas Apply', max=422.0, style=ProgressStyle(description…"
            ]
          },
          "metadata": {
            "tags": []
          }
        },
        {
          "output_type": "stream",
          "text": [
            "\n"
          ],
          "name": "stdout"
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "1jYNzLBsCHYK",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 65,
          "referenced_widgets": [
            "486f96e0c4154518a5e0a93c8d8570a3",
            "009de111b3da467ea317adc0c332db0c",
            "ace11008cab745e38463577a77345877",
            "137c7a6042f44eea956afcdab9c4eaf6",
            "267e1852612b4b08a3147975f336df64",
            "da88d85e476a4cc285a39298fa6cfabe",
            "99e29d69d38948099f9d7a725b490ec1",
            "774d60d2c32243d9a7954b1ac00472bb"
          ]
        },
        "outputId": "e2a1b498-4b39-465e-eef3-3ad2322c177f"
      },
      "source": [
        "entities_and_label_from_4_NER_model_dataframe['mesh_output'] = entities_and_label_from_4_NER_model_dataframe['Entity'].swifter.apply(lambda x : mesh_entity_linker(x))"
      ],
      "execution_count": 27,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "application/vnd.jupyter.widget-view+json": {
              "model_id": "486f96e0c4154518a5e0a93c8d8570a3",
              "version_minor": 0,
              "version_major": 2
            },
            "text/plain": [
              "HBox(children=(FloatProgress(value=0.0, description='Pandas Apply', max=422.0, style=ProgressStyle(description…"
            ]
          },
          "metadata": {
            "tags": []
          }
        },
        {
          "output_type": "stream",
          "text": [
            "\n"
          ],
          "name": "stdout"
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "nGMon8d3XWpX",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 65,
          "referenced_widgets": [
            "dbccdb277e3144afa42c52a96a4f6bfe",
            "ec385f5e1a1c4e4e88f3656aa483ca12",
            "78903bfb00d240f09b01cb91557b4a20",
            "370293c5154247febefcf1415cb5d57a",
            "e30d744077a04da5bf19fdbff02a3e00",
            "c39d3ef103114b3ca5c1643cdb084de2",
            "fb23de1bef524f70bd19254922e47d56",
            "bf746811e2d24eb18c8fa56ff1df07c4"
          ]
        },
        "outputId": "ee511bd3-10c0-4b21-b2bd-27a4a473cabf"
      },
      "source": [
        "entities_and_label_from_4_NER_model_dataframe['go_output'] = entities_and_label_from_4_NER_model_dataframe['Entity'].swifter.apply(lambda x : go_entity_linker(x))"
      ],
      "execution_count": 25,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "application/vnd.jupyter.widget-view+json": {
              "model_id": "dbccdb277e3144afa42c52a96a4f6bfe",
              "version_minor": 0,
              "version_major": 2
            },
            "text/plain": [
              "HBox(children=(FloatProgress(value=0.0, description='Pandas Apply', max=422.0, style=ProgressStyle(description…"
            ]
          },
          "metadata": {
            "tags": []
          }
        },
        {
          "output_type": "stream",
          "text": [
            "\n"
          ],
          "name": "stdout"
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "_gH_yzGoXcDX",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 65,
          "referenced_widgets": [
            "8c765511ed10490aa2b1e062b80a0bc9",
            "6da92d7350e94b59a0cc7bbb94ac9711",
            "bce3b2d825854c8bbf17ddeef352d133",
            "67f3fba998f64d69bb23164f0ef6e9cd",
            "1a79e621e0654c4c89ce45bb8b64aa29",
            "830793c0b8a241b1a504326f9250f4d5",
            "6d19615e7ab04091af648729506d9955",
            "2122d51771694ea185b53e91223e7ccc"
          ]
        },
        "outputId": "484a96af-c67e-4149-ca4e-6892d99b61c2"
      },
      "source": [
        "entities_and_label_from_4_NER_model_dataframe['hpo_output'] = entities_and_label_from_4_NER_model_dataframe['Entity'].swifter.apply(lambda x : hpo_entity_linker(x))"
      ],
      "execution_count": 28,
      "outputs": [
        {
          "output_type": "display_data",
          "data": {
            "application/vnd.jupyter.widget-view+json": {
              "model_id": "8c765511ed10490aa2b1e062b80a0bc9",
              "version_minor": 0,
              "version_major": 2
            },
            "text/plain": [
              "HBox(children=(FloatProgress(value=0.0, description='Pandas Apply', max=422.0, style=ProgressStyle(description…"
            ]
          },
          "metadata": {
            "tags": []
          }
        },
        {
          "output_type": "stream",
          "text": [
            "\n"
          ],
          "name": "stdout"
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "C5WhHzl_ZjpF",
        "colab_type": "code",
        "colab": {
          "base_uri": "https://localhost:8080/",
          "height": 565
        },
        "outputId": "2ada208a-998c-4b90-da64-ce497ceb5bfb"
      },
      "source": [
        "pd.options.display.max_colwidth = 1000      #increase display width of the pandas dataframe\n",
        "entities_and_label_from_4_NER_model_dataframe.head()"
      ],
      "execution_count": 29,
      "outputs": [
        {
          "output_type": "execute_result",
          "data": {
            "text/html": [
              "<div>\n",
              "<style scoped>\n",
              "    .dataframe tbody tr th:only-of-type {\n",
              "        vertical-align: middle;\n",
              "    }\n",
              "\n",
              "    .dataframe tbody tr th {\n",
              "        vertical-align: top;\n",
              "    }\n",
              "\n",
              "    .dataframe thead th {\n",
              "        text-align: right;\n",
              "    }\n",
              "</style>\n",
              "<table border=\"1\" class=\"dataframe\">\n",
              "  <thead>\n",
              "    <tr style=\"text-align: right;\">\n",
              "      <th></th>\n",
              "      <th>Entity</th>\n",
              "      <th>Label</th>\n",
              "      <th>Ner_model</th>\n",
              "      <th>go_output</th>\n",
              "      <th>umls_output</th>\n",
              "      <th>mesh_output</th>\n",
              "      <th>hpo_output</th>\n",
              "    </tr>\n",
              "  </thead>\n",
              "  <tbody>\n",
              "    <tr>\n",
              "      <th>0</th>\n",
              "      <td>viroplexis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "      <td>[Nan]</td>\n",
              "      <td>[Nan]</td>\n",
              "      <td>[Nan]</td>\n",
              "      <td>[Nan]</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>1</th>\n",
              "      <td>productive infection</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "      <td>[(productive, infection)]</td>\n",
              "      <td>[(productive, infection)]</td>\n",
              "      <td>[(productive, infection)]</td>\n",
              "      <td>[(productive, infection)]</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>2</th>\n",
              "      <td>gastroenteritis</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "      <td>[(gastroenteritis), Entity_Matching_Score :0.8153096437454224, (C3808828, Recurrent gastroenteritis, [], [T033], Increased susceptibility to gastroenteritis, an infectious inflammationof the stomach and small intestines manifested by signs and symptoms such as diarheas and abdominal pain, as manifested by recurrent episodes of gastroenteritis. []), Entity_Matching_Score :0.7275374531745911, (C1262481, Eosinophilic gastroenteritis, [Gastrointestinal eosinophilia, Eosinophilic gastrointestinal disease, GI eosinophilia, Eosinophilic enteritis], [T047], Gastroenteritis that is characterized by eosinophilic infiltration.)]</td>\n",
              "      <td>[(gastroenteritis), Entity_Matching_Score :0.8153096437454224, (C3808828, Recurrent gastroenteritis, [], [T033], Increased susceptibility to gastroenteritis, an infectious inflammationof the stomach and small intestines manifested by signs and symptoms such as diarheas and abdominal pain, as manifested by recurrent episodes of gastroenteritis. []), Entity_Matching_Score :0.7275374531745911, (C1262481, Eosinophilic gastroenteritis, [Gastrointestinal eosinophilia, Eosinophilic gastrointestinal disease, GI eosinophilia, Eosinophilic enteritis], [T047], Gastroenteritis that is characterized by eosinophilic infiltration.)]</td>\n",
              "      <td>[(gastroenteritis), Entity_Matching_Score :0.8153096437454224, (C3808828, Recurrent gastroenteritis, [], [T033], Increased susceptibility to gastroenteritis, an infectious inflammationof the stomach and small intestines manifested by signs and symptoms such as diarheas and abdominal pain, as manifested by recurrent episodes of gastroenteritis. []), Entity_Matching_Score :0.7275374531745911, (C1262481, Eosinophilic gastroenteritis, [Gastrointestinal eosinophilia, Eosinophilic gastrointestinal disease, GI eosinophilia, Eosinophilic enteritis], [T047], Gastroenteritis that is characterized by eosinophilic infiltration.)]</td>\n",
              "      <td>[(gastroenteritis), Entity_Matching_Score :0.8153096437454224, (C3808828, Recurrent gastroenteritis, [], [T033], Increased susceptibility to gastroenteritis, an infectious inflammationof the stomach and small intestines manifested by signs and symptoms such as diarheas and abdominal pain, as manifested by recurrent episodes of gastroenteritis. []), Entity_Matching_Score :0.7275374531745911, (C1262481, Eosinophilic gastroenteritis, [Gastrointestinal eosinophilia, Eosinophilic gastrointestinal disease, GI eosinophilia, Eosinophilic enteritis], [T047], Gastroenteritis that is characterized by eosinophilic infiltration.)]</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>3</th>\n",
              "      <td>hepatitis virus</td>\n",
              "      <td>DISEASE</td>\n",
              "      <td>bc5dr</td>\n",
              "      <td>[(hepatitis, virus), Entity_Matching_Score :0.7850497961044312, (C0042721, Viral hepatitis, [], [T047], An acute or chronic inflammation of the liver parenchyma caused by viruses. Representative examples include hepatitis A, B, and C, cytomegalovirus hepatitis, and herpes simplex hepatitis.), Entity_Matching_Score :0.7254184484481812, (C0019158, Hepatitis, [Liver inflammation], [T047], INFLAMMATION of the LIVER.)]</td>\n",
              "      <td>[(hepatitis, virus), Entity_Matching_Score :0.7850497961044312, (C0042721, Viral hepatitis, [], [T047], An acute or chronic inflammation of the liver parenchyma caused by viruses. Representative examples include hepatitis A, B, and C, cytomegalovirus hepatitis, and herpes simplex hepatitis.), Entity_Matching_Score :0.7254184484481812, (C0019158, Hepatitis, [Liver inflammation], [T047], INFLAMMATION of the LIVER.)]</td>\n",
              "      <td>[(hepatitis, virus), Entity_Matching_Score :0.7850497961044312, (C0042721, Viral hepatitis, [], [T047], An acute or chronic inflammation of the liver parenchyma caused by viruses. Representative examples include hepatitis A, B, and C, cytomegalovirus hepatitis, and herpes simplex hepatitis.), Entity_Matching_Score :0.7254184484481812, (C0019158, Hepatitis, [Liver inflammation], [T047], INFLAMMATION of the LIVER.)]</td>\n",
              "      <td>[(hepatitis, virus), Entity_Matching_Score :0.7850497961044312, (C0042721, Viral hepatitis, [], [T047], An acute or chronic inflammation of the liver parenchyma caused by viruses. Representative examples include hepatitis A, B, and C, cytomegalovirus hepatitis, and herpes simplex hepatitis.), Entity_Matching_Score :0.7254184484481812, (C0019158, Hepatitis, [Liver inflammation], [T047], INFLAMMATION of the LIVER.)]</td>\n",
              "    </tr>\n",
              "    <tr>\n",
              "      <th>4</th>\n",
              "      <td>angiotensin</td>\n",
              "      <td>CHEMICAL</td>\n",
              "      <td>bc5dr</td>\n",
              "      <td>[(angiotensin)]</td>\n",
              "      <td>[(angiotensin)]</td>\n",
              "      <td>[(angiotensin)]</td>\n",
              "      <td>[(angiotensin)]</td>\n",
              "    </tr>\n",
              "  </tbody>\n",
              "</table>\n",
              "</div>"
            ],
            "text/plain": [
              "                 Entity  ...                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         hpo_output\n",
              "0            viroplexis  ...                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              [Nan]\n",
              "1  productive infection  ...                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          [(productive, infection)]\n",
              "2       gastroenteritis  ...  [(gastroenteritis), Entity_Matching_Score :0.8153096437454224, (C3808828, Recurrent gastroenteritis, [], [T033], Increased susceptibility to gastroenteritis, an infectious inflammationof the stomach and small intestines manifested by signs and symptoms such as diarheas and abdominal pain, as manifested by recurrent episodes of gastroenteritis. []), Entity_Matching_Score :0.7275374531745911, (C1262481, Eosinophilic gastroenteritis, [Gastrointestinal eosinophilia, Eosinophilic gastrointestinal disease, GI eosinophilia, Eosinophilic enteritis], [T047], Gastroenteritis that is characterized by eosinophilic infiltration.)]\n",
              "3       hepatitis virus  ...                                                                                                                                                                                                                  [(hepatitis, virus), Entity_Matching_Score :0.7850497961044312, (C0042721, Viral hepatitis, [], [T047], An acute or chronic inflammation of the liver parenchyma caused by viruses. Representative examples include hepatitis A, B, and C, cytomegalovirus hepatitis, and herpes simplex hepatitis.), Entity_Matching_Score :0.7254184484481812, (C0019158, Hepatitis, [Liver inflammation], [T047], INFLAMMATION of the LIVER.)]\n",
              "4           angiotensin  ...                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    [(angiotensin)]\n",
              "\n",
              "[5 rows x 7 columns]"
            ]
          },
          "metadata": {
            "tags": []
          },
          "execution_count": 29
        }
      ]
    },
    {
      "cell_type": "code",
      "metadata": {
        "id": "o-ubDR8AhVEC",
        "colab_type": "code",
        "colab": {}
      },
      "source": [
        ""
      ],
      "execution_count": null,
      "outputs": []
    }
  ]
}