1.
Protein Data Bank
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The Protein Data Bank is a crystallographic database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The PDB is overseen by a called the Worldwide Protein Data Bank. The PDB is a key resource in areas of structural biology, most major scientific journals, and some funding agencies, now require scientists to submit their structure data to the PDB. Many other databases use protein structures deposited in the PDB, for example, SCOP and CATH classify protein structures, while PDBsum provides a graphic overview of PDB entries using information from other sources, such as Gene ontology. By 1971, one of Meyers programs, SEARCH, enabled researchers to access information from the database to study protein structures offline. SEARCH was instrumental in enabling networking, thus marking the beginning of the PDB. Upon Hamiltons death in 1973, Tom Koeztle took over direction of the PDB for the subsequent 20 years, in January 1994, Joel Sussman of Israels Weizmann Institute of Science was appointed head of the PDB. In October 1998, the PDB was transferred to the Research Collaboratory for Structural Bioinformatics, the new director was Helen M. Berman of Rutgers University. In 2003, with the formation of the wwPDB, the PDB became an international organization, the founding members are PDBe, RCSB, and PDBj. Each of the four members of wwPDB can act as deposition, data processing, the data processing refers to the fact that wwPDB staff review and annotate each submitted entry. The data are automatically checked for plausibility. The PDB database is updated weekly, likewise, the PDB holdings list is also updated weekly. As of 14 March 2017, the breakdown of current holdings is as follows,103,514 structures in the PDB have a structure factor file,9,057 structures have an NMR restraint file. 2,826 structures in the PDB have a chemical shifts file, therefore, the final conformation of the protein is obtained, in the latter case, by solving a distance geometry problem. A few proteins are determined by cryo-electron microscopy, the significance of the structure factor files, mentioned above, is that, for PDB structures determined by X-ray diffraction that have a structure file, the electron density map may be viewed. The data of such structures is stored on the electron density server, however, since 2007, the rate of accumulation of new protein structures appears to have plateaued. The file format used by the PDB was called the PDB file format. This original format was restricted by the width of computer punch cards to 80 characters per line, around 1996, the macromolecular Crystallographic Information file format, mmCIF, which is an extension of the CIF format started to be phased in
2.
GeneCards
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GeneCards is a database of human genes that provides genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. It is being developed and maintained by the Crown Human Genome Center at the Weizmann Institute of Science and this database aims at providing a quick overview of the current available biomedical information about the searched gene, including the human genes, the encoded proteins, and the relevant diseases. The GeneCards database provides access to free Web resources about more than 7000 all known human genes that integrated from >90 data resources, such as HGNC, Ensembl, the core gene list is based on approved gene symbols published by the HUGO Gene Nomenclature Committee. The information are carefully gathered and selected from these databases by the powerful, over time, the GeneCards database has developed a suite of tools that has more specialised capability. Since 1998, the GeneCards database has been used by bioinformatics, genomics. Since the 1980s, sequence information has become abundant, many laboratories realized this. However, the information provided by the sequence databases focus on different aspect. To gather these scattered data, The Weizmann Institute of Science Crown Human Genome Centre developed a database called ‘GeneCards’ in 1997 and this database mainly deals with the human genome information, human genes, the encoded proteins’ functions, and the related diseases. At first, it includes two main features, the function to get integrated biomedical information about certain gene in ‘card’ format. Currently, the version 3 gather information from more than 90 database resources based on a consolidated gene list and it has developed a set of GeneCards suit, which are focus one more specific purposes. Nearly every 3 years life cycle, a new planning phase for subsequent revision will start, including implementation, development and semi-automated quality assurance, and deployment. Technologies used include Eclipse, Apache, Perl, XML, PHP, Propel, Java, R and MySQL. genecards. org/, annotation combinatory, Using GeneDecks, one can get a set of similar genes for a particular gene with a selected combinatorial annotation. The summary table result in ranking the different level of similarity between the genes and the probe gene. Annotation unification, Different data source often offer annotations with heterogeneous naming system, annotation unification of GeneDecks is based on the similarity in GeneCards gene-content space detection algorithms. Partner hunting, In GeneDecks’s Partner Hunter, users give a query gene, Set distillation, In Set distiller, users give a set of genes, and the system ranks attributes by their degree of sharing within a given gene set. GeneALaCart is a gene-set-orientated batch-querying engine based on the popular GeneCards database and it allows retrieval of information about multiple genes in a batch query. The GeneLoc suit member presents a human chromosome map, which is very important for designing a custom-made capture chip. GeneLoc includes further links to GeneCards, NCBIs Human Genome Sequencing, UniGene, firstly, enter what you want to search into the blank on the homepages
3.
Chromosome
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A chromosome is a DNA molecule with part or all of the genetic material of an organism. Prokaryotes usually have one single circular chromosome, whereas most eukaryotes are diploid, chromosomes in eukaryotes are composed of chromatin fiber. Chromatin fiber is made of nucleosomes, a nucleosome is a histone octamer with part of a longer DNA strand attached to and wrapped around it. Chromatin fiber, together with associated proteins is known as chromatin, chromatin is present in most cells, with a few exceptions, for example, red blood cells. Occurring only in the nucleus of cells, chromatin contains the vast majority of DNA, except for a small amount inherited maternally. Chromosomes are normally visible under a microscope only when the cell is undergoing the metaphase of cell division. Before this happens every chromosome is copied once, and the copy is joined to the original by a centromere resulting in an X-shaped structure, the original chromosome and the copy are now called sister chromatids. During metaphase, when a chromosome is in its most condensed state, in this highly condensed form chromosomes are easiest to distinguish and study. In prokaryotic cells, chromatin occurs free-floating in cytoplasm, as these cells lack organelles, the main information-carrying macromolecule is a single piece of coiled double-helix DNA, containing many genes, regulatory elements and other noncoding DNA. The DNA-bound macromolecules are proteins that serve to package the DNA, chromosomes vary widely between different organisms. Some species such as certain bacteria also contain plasmids or other extrachromosomal DNA and these are circular structures in the cytoplasm that contain cellular DNA and play a role in horizontal gene transfer. Chromosomal recombination during meiosis and subsequent sexual reproduction plays a significant role in genetic diversity. In prokaryotes and viruses, the DNA is often densely packed and organized, in the case of archaea, by homologs to eukaryotic histones, small circular genomes called plasmids are often found in bacteria and also in mitochondria and chloroplasts, reflecting their bacterial origins. Some use the term chromosome in a sense, to refer to the individualized portions of chromatin in cells. However, others use the concept in a sense, to refer to the individualized portions of chromatin during cell division. The word chromosome comes from the Greek χρῶμα and σῶμα, describing their strong staining by particular dyes, schleiden, Virchow and Bütschli were among the first scientists who recognized the structures now so familiar to everyone as chromosomes. The term was coined by von Waldeyer-Hartz, referring to the term chromatin, in a series of experiments beginning in the mid-1880s, Theodor Boveri gave the definitive demonstration that chromosomes are the vectors of heredity. His two principles were the continuity of chromosomes and the individuality of chromosomes and it is the second of these principles that was so original
4.
Chromosome 4 (human)
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Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome, chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells. Identifying genes on each chromosome is an area of genetic research. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies, in January 2017, two estimates differed by 12%, with one estimate giving 2,441 genes, and the other estimate giving 2,164 genes. The chromosome is ~191 megabases in length, in a 2012 paper, seven hundred and fifty seven protein encoding genes were identified on this chromosome. Two-hundred and eleven of these coding sequences did not have any evidence at the protein level. Two-hundred and seventy one appear to be membrane proteins, fifty-four have been classified as cancer associated proteins. k. a
5.
Locus (genetics)
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A locus in genetics is the position on a chromosome. Each chromosome carries many genes, humans estimated haploid protein coding genes are 19, 000-20,000, a variant of the similar DNA sequence located at a given locus is called an allele. The ordered list of known for a particular genome is called a gene map. Gene mapping is the process of determining the locus for a biological trait. The chromosomal locus of a gene might be written 3p22.1, here 3 means chromosome 3, p means p-arm. And 22 refers to region 2, band 2 and this is read as two two, not as twenty-two. So the entire locus is read as three P two two point one, the cytogenetic bands are counting from the centromere out toward the telomeres. A range of loci is specified in a similar way. For example, the locus of gene OCA1 may be written 11q1. 4-q2.1, meaning it is on the arm of chromosome 11. The ends of a chromosome are labeled pter and qter, a centisome is defined as 1% of a chromosome length. Chromosomal translocation Cytogenetic notation Karyotype Null allele Michael, R. Cummings, belmont, California, Brooks/Cole Overview at ornl. gov Chromosome Banding and Nomenclature from NCBI
6.
Base pair
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A base pair is a unit consisting of two nucleobases bound to each other by hydrogen bonds. They form the blocks of the DNA double helix. Dictated by specific hydrogen bonding patterns, Watson-Crick base pairs allow the DNA helix to maintain a regular helical structure that is dependent on its nucleotide sequence. The complementary nature of this structure provides a backup copy of all genetic information encoded within double-stranded DNA. Many DNA-binding proteins can recognize specific base pairing patterns that identify particular regulatory regions of genes, intramolecular base pairs can occur within single-stranded nucleic acids. The size of a gene or an organisms entire genome is often measured in base pairs because DNA is usually double-stranded. Hence, the number of base pairs is equal to the number of nucleotides in one of the strands. The haploid human genome is estimated to be about 3.2 billion bases long and to contain 20, a kilobase is a unit of measurement in molecular biology equal to 1000 base pairs of DNA or RNA. The total amount of related DNA base pairs on Earth is estimated at 5.0 x 1037, in comparison, the total mass of the biosphere has been estimated to be as much as 4 TtC. Hydrogen bonding is the interaction that underlies the base-pairing rules described above. Appropriate geometrical correspondence of hydrogen donors and acceptors allows only the right pairs to form stably. Purine-pyrimidine base pairing of AT or GC or UA results in proper duplex structure, the only other purine-pyrimidine pairings would be AC and GT and UG, these pairings are mismatches because the patterns of hydrogen donors and acceptors do not correspond. The GU pairing, with two bonds, does occur fairly often in RNA. Higher GC content results in higher melting temperatures, it is, therefore, on the converse, regions of a genome that need to separate frequently — for example, the promoter regions for often-transcribed genes — are comparatively GC-poor. GC content and melting temperature must also be taken into account when designing primers for PCR reactions, the following DNA sequences illustrate pair double-stranded patterns. By convention, the top strand is written from the 5 end to the 3 end, thus and this is due to their isosteric chemistry. One common mutagenic base analog is 5-bromouracil, which resembles thymine, most intercalators are large polyaromatic compounds and are known or suspected carcinogens. Examples include ethidium bromide and acridine, an unnatural base pair is a designed subunit of DNA which is created in a laboratory and does not occur in nature
7.
Homology (biology)
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In biology, homology is the existence of shared ancestry between a pair of structures, or genes, in different taxa. Evolutionary biology explains homologous structures adapted to different purposes as the result of descent with modification from a common ancestor, examples include the legs of a centipede, the maxillary palp and labial palp of an insect, and the spinous processes of successive vertebrae in a vertebral column. Sequence homology between protein or DNA sequences is defined in terms of shared ancestry. Two segments of DNA can have shared ancestry because of either an event or a duplication event. Homology among proteins or DNA is inferred from their sequence similarity, significant similarity is strong evidence that two sequences are related by divergent evolution from a common ancestor. Alignments of multiple sequences are used to discover the homologous regions, the word homology, coined in about 1656, derives from the Greek ὁμόλογος homologos from ὁμός homos same and λόγος logos relation. Homology is the relationship between biological structures or sequences that are derived from a common ancestor, for example, many insects possess two pairs of flying wings. In beetles, the first pair of wings has evolved into a pair of hard wing covers, the same major forearm bones are found in fossils of lobe-finned fish such as Eusthenopteron. The opposite of homologous organs are analogous organs which do similar jobs in two taxa that were not present in their last common ancestor but rather evolved separately. For example, the wings of insects and birds evolved independently in widely separated groups, similarly, the wings of a sycamore maple seed and the wings of a bird are analogous but not homologous, as they develop from quite different structures. A structure can be homologous at one level, but only analogous at another, for example, in the pterosaurs, the wing involves both the forelimb and the hindlimb. Analogy is called homoplasy in cladistics, and convergent or parallel evolution in evolutionary biology, specialised terms are used in taxonomic research. Primary homology is that initially conjectured by a researcher based on similar structure or anatomical connections, secondary homology is implied by parsimony analysis, where a character that only occurs once on a tree is taken to be homologous. As implied in this definition, many cladists consider homology to be synonymous with synapomorphy, homologies provide the fundamental basis for all biological classification, although some may be highly counter-intuitive. The homologies between these have been discovered by comparing genes in evolutionary developmental biology, among insects, the stinger of the female honey bee is a modified ovipositor, homologous with ovipositors in other insects such as the Orthoptera, Hemiptera, and those Hymenoptera without stingers. The three small bones in the ear of mammals including humans, the malleus, incus. The malleus and incus develop in the embryo from structures that form jaw bones in lizards, both lines of evidence show that these bones are homologous, sharing a common ancestor. Among the many homologies in mammal reproductive systems, ovaries and testicles are homologous, in many plants, defensive or storage structures are made by modifications of the development of primary leaves, stems, and roots
8.
Entrez
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The name Entrez was chosen to reflect the spirit of welcoming the public to search the content available from the NLM. Entrez Global Query is a search and retrieval system that provides access to all databases simultaneously with a single query string. Entrez can efficiently retrieve related sequences, structures, and references, the Entrez system can provide views of gene and protein sequences and chromosome maps. Some textbooks are available online through the Entrez system. The Entrez front page provides, by default, access to the global query, all databases indexed by Entrez can be searched via a single query string, supporting boolean operators and search term tags to limit parts of the search statement to particular fields. This returns a unified results page, that shows the number of hits for the search in each of the databases, Entrez also provides a similar interface for searching each particular database and for refining search results. The Limits feature allows the user to narrow a search a web forms interface, the History feature gives a numbered list of recently performed queries. Results of previous queries can be referred to by number and combined via boolean operators, search results can be saved temporarily in a Clipboard. Users with a MyNCBI account can save queries indefinitely and also choose to have updates with new search results e-mailed for saved queries of most databases and it is widely used in the field of biotechnology as a reference tool for students and professionals alike. Entrez searches the following databases, PubMed, biomedical literature citations and abstracts, including Medline - articles from journals, in addition to using the search engine forms to query the data in Entrez, NCBI provides the Entrez Programming Utilities for more direct access to query results. The eUtils are accessed by posting specially formed URLs to the NCBI server, there was also an eUtils SOAP interface which was terminated on July 2015. In 1991, entrez was introduced in CD form, in 1993, a client-server version of the software provided connectivity with the internet. In 1994, NCBI established a website, and Entrez was a part of initial release. In 2001, Entrez bookshelf was released and in 2003, the Entrez Gene database was developed, Entrez search engine form Entrez Help
9.
Ensembl genome database project
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Ensembl is one of several well known genome browsers for the retrieval of genomic information. Similar databases and browsers are found at NCBI and the University of California, the human genome consists of three billion base pairs, which code for approximately 20, 000–25,000 genes. However the genome alone is of use, unless the locations. One option is manual annotation, whereby a team of scientists tries to locate genes using experimental data from scientific journals, however this is a slow, painstaking task. The alternative, known as automated annotation, is to use the power of computers to do the complex pattern-matching of protein to DNA. In the Ensembl project, sequence data are fed into the gene annotation system which creates a set of predicted gene locations and saves them in a MySQL database for subsequent analysis, Ensembl makes these data freely accessible to the world research community. All the data and code produced by the Ensembl project is available to download, in addition, the Ensembl website provides computer-generated visual displays of much of the data. Over time the project has expanded to additional species as well as a wider range of genomic data, including genetic variations. Central to the Ensembl concept is the ability to automatically generate graphical views of the alignment of genes and these are shown as data tracks, and individual tracks can be turned on and off, allowing the user to customise the display to suit their research interests. The interface also enables the user to zoom in to a region or move along the genome in either direction, the graphics are complemented by tabular displays, and in many cases data can be exported directly from the page in a variety of standard file formats such as FASTA. Externally produced data can also be added to the display, either via a DAS server on the internet, or by uploading a file in one of the supported formats, such as BAM, BED. Graphics are generated using a suite of custom Perl modules based on GD, in addition to its website, Ensembl provides a Perl API that models biological objects such as genes and proteins, allowing simple scripts to be written to retrieve data of interest. The same API is used internally by the web interface to display the data and it is divided in sections like the core API, the compara API, the variation API, and the functional genomics API. The Ensembl website provides information on how to install and use the API. This software can be used to access the public MySQL database, the users could even choose to retrieve data from the MySQL with direct SQL queries, but this requires an extensive knowledge of the current database schema. Large datasets can be retrieved using the BioMart data-mining tool and it provides a web interface for downloading datasets using complex queries. Last, there is an FTP server which can be used to download entire MySQL databases as some selected data sets in other formats. The annotated genomes include most fully sequenced vertebrates and selected model organisms, all of them are eukaryotes, there are no prokaryotes
10.
UniProt
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UniProt is a freely accessible database of protein sequence and functional information, many entries being derived from genome sequencing projects. It contains an amount of information about the biological function of proteins derived from the research literature. The UniProt consortium comprises the European Bioinformatics Institute, the Swiss Institute of Bioinformatics, EBI, located at the Wellcome Trust Genome Campus in Hinxton, UK, hosts a large resource of bioinformatics databases and services. SIB, located in Geneva, Switzerland, maintains the ExPASy servers that are a resource for proteomics tools. In 2002, EBI, SIB, and PIR joined forces as the UniProt consortium, each consortium member is heavily involved in protein database maintenance and annotation. Until recently, EBI and SIB together produced the Swiss-Prot and TrEMBL databases and these databases coexisted with differing protein sequence coverage and annotation priorities. Swiss-Prot aimed to provide reliable protein sequences associated with a level of annotation. Recognizing that sequence data were being generated at a pace exceeding Swiss-Prots ability to keep up, meanwhile, PIR maintained the PIR-PSD and related databases, including iProClass, a database of protein sequences and curated families. The consortium members pooled their resources and expertise, and launched UniProt in December 2003. UniProt provides four core databases, UniProtKB, UniParc, UniRef, UniProt Knowledgebase is a protein database partially curated by experts, consisting of two sections, UniProtKB/Swiss-Prot and UniProtKB/TrEMBL. As of 19 March 2014, release 2014_03 of UniProtKB/Swiss-Prot contains 542,782 sequence entries, UniProtKB/Swiss-Prot is a manually annotated, non-redundant protein sequence database. It combines information extracted from literature and biocurator-evaluated computational analysis. The aim of UniProtKB/Swiss-Prot is to all known relevant information about a particular protein. Annotation is regularly reviewed to keep up with current scientific findings, the manual annotation of an entry involves detailed analysis of the protein sequence and of the scientific literature. Sequences from the gene and the same species are merged into the same database entry. Differences between sequences are identified, and their cause documented, a range of sequence analysis tools is used in the annotation of UniProtKB/Swiss-Prot entries. Computer-predictions are manually evaluated, and relevant results selected for inclusion in the entry and these predictions include post-translational modifications, transmembrane domains and topology, signal peptides, domain identification, and protein family classification. Relevant publications are identified by searching databases such as PubMed, the full text of each paper is read, and information is extracted and added to the entry
11.
PubMed
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
12.
Wikidata
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Wikidata is a collaboratively edited knowledge base operated by the Wikimedia Foundation. It is intended to provide a source of data which can be used by Wikimedia projects such as Wikipedia. This is similar to the way Wikimedia Commons provides storage for files and access to those files for all Wikimedia projects. Wikidata is powered by the software Wikibase, Wikidata is a document-oriented database, focused on items. Each item represents a topic and is identified by a number, prefixed with the letter Q—for example. This enables the basic information required to identify the topic the item covers to be translated without favouring any language, information is added to items by creating statements. Statements take the form of pairs, with each statement consisting of a property. The creation of the project was funded by donations from the Allen Institute for Artificial Intelligence, the Gordon and Betty Moore Foundation, at this time, only the first phase was available. Historically, a Wikipedia article would include a list of links, being links to articles on the same topic in other editions of Wikipedia. Initially, Wikidata was a repository of interlanguage links. No Wikipedia language editions were able to access Wikidata, so they needed to continue to maintain their own lists of interlanguage links, on 14 January 2013, the Hungarian Wikipedia became the first to enable the provision of interlanguage links via Wikidata. This functionality was extended to the Hebrew and Italian Wikipedias on 30 January, to the English Wikipedia on 13 February, on 23 September 2013, phase 1 went live on Wikimedia Commons. The first aspects of the second phase were deployed on 4 February 2013, the values were initially limited to two data types, with more data types to follow later. The first new type, string, was deployed on 6 March, the ability of the various language editions of Wikipedia to access data added to Wikidata as part of phase two was rolled out progressively between 27 March and 25 April 2013. On 16 September 2015, Wikidata began allowing so-called arbitrary access, for example, in the past the article about Berlin you could not access data about Germany, but with arbitrary access it could. On 27 April 2016 arbitrary access was activated on Wikimedia Commons, phase 3 will involve database querying and the creation of lists based on data stored on Wikidata. As of October 2016 two tools for querying Wikidata were available, AutoList and PetScan, additionally to a public SPARQL endpoint, there is concern that the project is being influenced by lobbying companies, PR professionals and search engine optimizers. As of December 2015, according to Wikimedia statistics, half of the information in Wikidata is unsourced, another 30% is labeled as having come from Wikipedia, but with no indication as to which article
13.
Protein
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Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, a linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide, short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides, or sometimes oligopeptides. The individual amino acid residues are bonded together by peptide bonds, the sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the code specifies 20 standard amino acids, however. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors, proteins can also work together to achieve a particular function, and they often associate to form stable protein complexes. Once formed, proteins only exist for a period of time and are then degraded and recycled by the cells machinery through the process of protein turnover. A proteins lifespan is measured in terms of its half-life and covers a wide range and they can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal and or misfolded proteins are degraded more rapidly due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms, many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism. Proteins also have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized, digestion breaks the proteins down for use in the metabolism. Methods commonly used to study structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance. Most proteins consist of linear polymers built from series of up to 20 different L-α-amino acids, all proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, and a variable side chain are bonded. Only proline differs from this structure as it contains an unusual ring to the N-end amine group. The amino acids in a chain are linked by peptide bonds. Once linked in the chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen. The peptide bond has two forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are roughly coplanar
14.
Gene
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A gene is a locus of DNA which is made up of nucleotides and is the molecular unit of heredity. The transmission of genes to an offspring is the basis of the inheritance of phenotypic traits. These genes make up different DNA sequences called genotypes, genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions, genes can acquire mutations in their sequence, leading to different variants, known as alleles, in the population. These alleles encode slightly different versions of a protein, which cause different phenotypical traits, usage of the term having a gene typically refers to containing a different allele of the same, shared gene. Genes evolve due to natural selection or survival of the fittest of the alleles, the concept of a gene continues to be refined as new phenomena are discovered. For example, regulatory regions of a gene can be far removed from its coding regions, some viruses store their genome in RNA instead of DNA and some gene products are functional non-coding RNAs. The existence of discrete inheritable units was first suggested by Gregor Mendel, from 1857 to 1864, in Brno, he studied inheritance patterns in 8000 common edible pea plants, tracking distinct traits from parent to offspring. He described these mathematically as 2n combinations where n is the number of differing characteristics in the original peas, although he did not use the term gene, he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured the distinction between genotype and phenotype, charles Darwin developed a theory of inheritance he termed pangenesis, from Greek pan and genesis / genos. Darwin used the term gemmule to describe hypothetical particles that would mix during reproduction, de Vries called these units pangenes, after Darwins 1868 pangenesis theory. In 1909 the Danish botanist Wilhelm Johannsen shortened the name to gene, advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid was shown to be the repository of genetic information by experiments in the 1940s to 1950s. In the early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities, indivisible by recombination, collectively, this body of research established the central dogma of molecular biology, which states that proteins are translated from RNA, which is transcribed from DNA. This dogma has since shown to have exceptions, such as reverse transcription in retroviruses. The modern study of genetics at the level of DNA is known as molecular genetics, in 1972, Walter Fiers and his team at the University of Ghent were the first to determine the sequence of a gene, the gene for Bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing, an automated version of the Sanger method was used in early phases of the Human Genome Project. The theories developed in the 1930s and 1940s to integrate molecular genetics with Darwinian evolution are called the evolutionary synthesis
15.
Complement system
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It is part of the innate immune system, which is not adaptable and does not change over the course of an individuals lifetime. It can be recruited and brought into action by the immune system. The complement system consists of a number of proteins found in the blood, in general synthesized by the liver. When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines, over 30 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 10% of the fraction of blood serum. Three biochemical pathways activate the complement system, the complement pathway, the alternative complement pathway. In 1888, George Nuttall found that blood serum had mild killing activity against the bacterium that causes anthrax. The killing activity disappeared when he heated the blood, in 1891, Hans Ernst August Buchner, noting the same property of blood in his experiments, named the killing property alexin, which means to ward off in Greek. By 1884, several laboratories had demonstrated that serum from guinea pigs that had recovered from cholera killed the cholera bacterium in vitro, heating the serum destroyed its killing activity. Nevertheless, the serum, when injected into guinea pigs exposed to the cholera bacteria. In 1899, Paul Ehrlich renamed the heat-sensitive component complement, Ehrlich introduced the term complement as part of his larger theory of the immune system. According to this theory, the system consists of cells that have specific receptors on their surface to recognize antigens. Upon immunisation with an antigen, more of these receptors are formed, Ehrlich, therefore, named this heat-labile component complement, because it is something in the blood that complements the cells of the immune system. Ehrlich believed that each antigen-specific amboceptor has its own specific complement, in the early 20th century, this controversy was resolved when it became understood that complement can act in combination with specific antibodies, or on its own in a non-specific way. Complement triggers the immune functions, Phagocytosis – by opsonizing antigens. But significant amounts are produced by tissue macrophages, blood monocytes. The three pathways of activation all generate homologous variants of the protease C3-convertase, the mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies. In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage, C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization
16.
Guinea pig
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The guinea pig, cavy or domestic guinea pig, or cuy for livestock breeds, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family Suidae, recent studies applying molecular markers, in addition to studying the skull and skeletal morphology of current and mummified animals, revealed that the ancestor is most likely Cavia tschudii. Since the 1960s, efforts have made to increase consumption of the animal outside South America. In Western societies, the guinea pig has enjoyed widespread popularity as a household pet since its introduction by European traders in the 16th century. Their docile nature, friendly, even affectionate responsiveness to handling and feeding, biological experimentation on guinea pigs has been carried out since the 17th century. They are still used in research, primarily as models for medical conditions such as juvenile diabetes, tuberculosis, scurvy. The guinea pig was first domesticated as early as 5000 BC for food by tribes in the Andean region of South America, statues dating from circa 500 BC to 500 AD that depict guinea pigs have been unearthed in archaeological digs in Peru and Ecuador. The Moche people of ancient Peru worshipped animals and often depicted the guinea pig in their art, from about 1200 AD to the Spanish conquest in 1532, selective breeding resulted in many varieties of domestic guinea pigs, which form the basis for some of the modern domestic breeds. They continue to be a source in the region, many households in the Andean highlands raise the animal. Folklore traditions involving guinea pigs are numerous, they are exchanged as gifts, used in social and religious ceremonies. They also play a role in healing rituals by folk doctors, or curanderos, who use the animals to diagnose diseases such as jaundice, rheumatism, arthritis. They are rubbed against the bodies of the sick, and are seen as a supernatural medium, black guinea pigs are considered especially useful for diagnoses. The animal also may be cut open and its entrails examined to determine whether the cure was effective and these methods are widely accepted in many parts of the Andes, where Western medicine is either unavailable or distrusted. Spanish, Dutch, and English traders brought guinea pigs to Europe, the guinea pig was first described in the West in 1554 by the Swiss naturalist Conrad Gessner. Its binomial scientific name was first used by Erxleben in 1777, it is an amalgam of Pallas generic designation, the scientific name of the common species is Cavia porcellus, with porcellus being Latin for little pig. Cavia is New Latin, it is derived from cabiai, the name in the language of the Galibi tribes once native to French Guiana. Cabiai may be an adaptation of the Portuguese çavia, which is derived from the Tupi word saujá. Guinea pigs are called quwi or jaca in Quechua and cuy or cuyo in the Spanish of Ecuador, Peru, and Bolivia
17.
Blood plasma
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Blood plasma is a straw coloured liquid component of blood that normally holds the blood cells in whole blood in suspension, this makes plasma the extracellular matrix of blood cells. It makes up about 55% of the total blood volume. It is the fluid part of extracellular fluid. It is mostly water, and contains dissolved proteins, glucose, clotting factors, electrolytes, hormones, carbon dioxide, Plasma also serves as the protein reserve of the human body. It plays a role in an intravascular osmotic effect that keeps electrolytes in balanced form and protects the body from infection. Blood plasma is prepared by spinning a tube of fresh blood containing an anticoagulant in a centrifuge until the blood fall to the bottom of the tube. The blood plasma is then poured or drawn off, Blood plasma has a density of approximately 1025 kg/m3, or 1.025 g/ml. Blood serum is blood plasma without clotting factors, in other words, plasmapheresis is a medical therapy that involves blood plasma extraction, treatment, and reintegration. Fresh frozen plasma is on the WHO Model List of Essential Medicines, Blood plasma volume may be expanded by or drained to extravascular fluid when there are changes in Starling forces across capillary walls. For example, when blood pressure drops in circulatory shock, Starling forces drive fluid into the interstitium, standing still for a prolonged period will cause an increase in transcapillary hydrostatic pressure. As a result, approximately 12% of blood plasma volume will cross into the extravascular compartment and this causes an increase in hematocrit, serum total protein, blood viscosity and, as a result of increased concentration of coagulation factors, it causes orthostatic hypercoagulability. The use of plasma as a substitute for whole blood and for transfusion purposes was proposed in March 1918, in the correspondence columns of the British Medical Journal. Dried plasmas in powder or strips of material format were developed, prior to the United States involvement in the war, liquid plasma and whole blood were used. The Blood for Britain program during the early 1940s was quite successful based on Charles Drews contribution, a large project began in August 1940 to collect blood in New York City hospitals for the export of plasma to Britain. Drew was appointed supervisor of the Plasma for Britain project. His notable contribution at this time was to transform the test tube methods of many blood researchers into the first successful mass production techniques. Nonetheless, the decision was made to develop a dried plasma package for the forces as it would reduce breakage and make the transportation, packaging. The resulting dried plasma package came in two tin cans containing 400 cc bottles, one bottle contained enough distilled water to reconstitute the dried plasma contained within the other bottle
18.
Glycoprotein
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Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification and this process is known as glycosylation. Secreted extracellular proteins are often glycosylated, in proteins that have segments extending extracellularly, the extracellular segments are also often glycosylated. Glycoproteins are also often important integral membrane proteins, where they play a role in cell–cell interactions and it is important to distinguish endoplasmic reticulum-based glycosylation of the secretory system without reversible cytosolic-nuclear glycosylation. In contrast, classical secretory glycosylation can be structurally essential, for example, inhibition of asparagine-linked, i. e. N-linked, glycosylation can prevent glycoprotein folding and full inhibition can be toxic to an individual cell. In contrast, perturbation of terminal processing, which occurs in the Golgi apparatus, is dispensable for isolated cells but can lead to human disease, a famous example of this latter effect is the ABO blood system. There are several types of glycosylation, although the first two are the most common, in N-glycosylation, sugars are attached to nitrogen, typically on the amide side-chain of asparagine. In O-glycosylation, sugars are attached to oxygen, typically on serine or threonine, in P-glycosylation, sugars are attached to phosphorus on a phosphoserine. In C-glycosylation, sugars are attached directly to carbon, such as in the addition of mannose to tryptophan, in glypiation, a GPI glycolipid is attached to the C-terminus of a polypeptide, serving as a membrane anchor. Monosaccharides commonly found in eukaryotic glycoproteins include, The sugar group can assist in protein folding or improve proteins stability, one example of glycoproteins found in the body is mucins, which are secreted in the mucus of the respiratory and digestive tracts. The sugars when attached to give them considerable water-holding capacity. Glycoproteins are important for blood cell recognition, especially in mammals. Examples of glycoproteins in the system are, molecules such as antibodies. Molecules of the major histocompatibility complex, which are expressed on the surface of cells, sialyl Lewis X antigen on the surface of leukocytes. H antigen of the ABO blood compatibility antigens, other examples of glycoproteins include, glycoprotein IIb/IIIa, an integrin found on platelets that is required for normal platelet aggregation and adherence to the endothelium. Components of the zona pellucida, which surrounds the oocyte, and is important for sperm-egg interaction, structural glycoproteins, which occur in connective tissue. These help bind together the fibers, cells, and ground substance of connective tissue and they may also help components of the tissue bind to inorganic substances, such as calcium in bone. Glycoprotein-41 and glycoprotein-120 are HIV viral coat proteins, soluble glycoproteins often show a high viscosity, for example, in egg white and blood plasma
19.
Disulfide
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In chemistry, a disulfide refers to a functional group with the structure R–S–S–R. The linkage is called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. The connection is a persulfide, in analogy to its congener, peroxide, in inorganic chemistry disulfide usually refers to the corresponding anion S2−2, for example in disulfur dichloride. The disulfide bonds are strong, with a bond dissociation energy of 60 kcal/mol. However, being about 40% weaker than C–C and C–H bonds, rotation about the S–S axis is subject to a low barrier. Disulfides show a preference for dihedral angles approaching 90°. When the angle approaches 0° or 180°, then the disulfide is a significantly better oxidant, disulfides where the two R groups are the same are called symmetric, examples being diphenyl disulfide and dimethyl disulfide. When the two R groups are not identical, the compound is said to be an asymmetric or mixed disulfide, by comparison, the standard reduction potential for ferrodoxins is about −430 mV. Disulfide bonds are formed from the oxidation of sulfhydryl groups. The transformation is depicted as follows,2 RSH ⇌ RS–SR +2 H+ +2 e− A variety of oxidants promote this reaction including air, such reactions are thought to proceed via sulfenic acid intermediates. In the laboratory, iodine in the presence of base is employed to oxidize thiols to disulfides. Several metals, such as copper and iron complexes affect this reaction, the alkylation of alkali metal di- and polysulfides gives disulfides. Thiokol polymers arise when sodium polysulfide is treated with an alkyl dihalide, in the converse reaction, carbanionic reagents react with elemental sulfur to afford mixtures of the thioether, disulfide, and higher polysulfides. These reactions are often unselective but can be optimized for specific applications, many specialized methods have been developed for forming disulfides, usually for applications in organic synthesis. A variety of reductants can be used, furthermore, it is often not needed to remove TCEP before modification of protein thiols. In organic synthesis, hydride agents are employed for scission of disulfides. The original disulfide bond is broken, and its other sulfur atom is released as a new thiolate, meanwhile, a new disulfide bond forms between the attacking thiolate and the original sulfur atom. Thiolates, not thiols, attack disulfide bonds, hence, thiol–disulfide exchange is inhibited at low pH where the protonated thiol form is favored relative to the deprotonated thiolate form
20.
Protein dimer
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In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules such as proteins or nucleic acids. It is a structure of a protein. A homodimer is formed by two identical molecules, a heterodimer is formed by two different macromolecules. Most dimers in biochemistry are not connected by covalent bonds, an example of a non-covalent heterodimer is the enzyme reverse transcriptase, which is composed of two different amino acid chains. An exception is dimers that are linked by disulfide bridges such as the homodimeric protein NEMO, some proteins contain specialized domains to ensure dimerization
21.
Protein domain
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A protein domain is a conserved part of a given protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact structure and often can be independently stable. Many proteins consist of structural domains. One domain may appear in a variety of different proteins, molecular evolution uses domains as building blocks and these may be recombined in different arrangements to create proteins with different functions. Domains vary in length from between about 25 amino acids up to 500 amino acids in length, the shortest domains such as zinc fingers are stabilized by metal ions or disulfide bridges. Domains often form functional units, such as the calcium-binding EF hand domain of calmodulin, because they are independently stable, domains can be swapped by genetic engineering between one protein and another to make chimeric proteins. The concept of the domain was first proposed in 1973 by Wetlaufer after X-ray crystallographic studies of hen lysozyme and papain, Wetlaufer defined domains as stable units of protein structure that could fold autonomously. In the past domains have been described as units of, compact structure function and evolution folding, each definition is valid and will often overlap, i. e. a compact structural domain that is found amongst diverse proteins is likely to fold independently within its structural environment. Nature often brings several domains together to form multidomain and multifunctional proteins with a vast number of possibilities, in a multidomain protein, each domain may fulfill its own function independently, or in a concerted manner with its neighbours. An appropriate example is pyruvate kinase, an enzyme that plays an important role in regulating the flux from fructose-1. It contains an all-β nucleotide binding domain, a binding domain. Each domain in this protein occurs in diverse sets of protein families, the central α/β-barrel substrate binding domain is one of the most common enzyme folds. It is seen in different enzyme families catalysing completely unrelated reactions. The α/β-barrel is commonly called the TIM barrel named after triose phosphate isomerase and it is currently classified into 26 homologous families in the CATH domain database. The TIM barrel is formed from a sequence of β-α-β motifs closed by the first and last strand hydrogen bonding together, there is debate about the evolutionary origin of this domain. One study has suggested that a single ancestral enzyme could have diverged into several families, the TIM-barrel in pyruvate kinase is discontinuous, meaning that more than one segment of the polypeptide is required to form the domain. This is likely to be the result of the insertion of one domain into another during the proteins evolution and it has been shown from known structures that about a quarter of structural domains are discontinuous. The inserted β-barrel regulatory domain is continuous, made up of a stretch of polypeptide
22.
Factor H
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Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large, soluble glycoprotein that circulates in human plasma, Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt different conformations with lower or higher activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification, the molecule is made up of 20 complement control protein modules connected to one another by short linkers and arranged in an extended head to tail fashion. The CCP modules are numbered from 1-20, CCPs 1-4 and CCPs 19-20 engage with C3b while CCPs 7 and CCPs 19-20 bind to GAGs and sialic acid. To date atomic structures have been determined for CCPs 1-3, CCP5, CCP7, CCPs 10-11 and CCPs 11-12, CCPs 12-13, CCP15, CCP16, CCPs 15-16, CCPs 18-20, and CCPs 19-20. The atomic structure for CCPs 6-8 bound to the GAG mimic sucrose octasulfate, CCPs 1-4 in complex with C3b, although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution. Due to the role that factor H plays in the regulation of complement. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections, underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms in factor H often result in pathologies, moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence. Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. This SNP, located in CCP module 7 of factor H, has shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease. Alterations in the immune response are involved in pathogenesis of many disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the complement pathway in patients with schizophrenia. It was found that rs800292 SNP was positively associated with stroke, haemolytic uraemic syndrome is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease, has been linked to mutations in genes of the complement system. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin and C3d binding. Given the central role of factor H in protecting cells from complement and this recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence
23.
Serine protease
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Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site. They are found ubiquitously in both eukaryotes and prokaryotes, Serine proteases fall into two broad categories based on their structure, chymotrypsin-like or subtilisin-like. In humans, they are responsible for coordinating various physiological functions, including digestion, immune response, the MEROPS protease classification system counts 16 superfamilies each containing many families. Each superfamily uses the catalytic triad or dyad in a different protein fold, the majority belong to the S1 family of the PA clan of proteases. For superfamilies, P = superfamily containing a mixture of nucleophile class families, within each superfamily, families are designated by their catalytic nucleophile. Families of Serine proteases Serine proteases are characterised by a distinctive structure and these enzymes can be further categorised based on their substrate specificity as either trypsin-like, chymotrypsin-like or elastase-like. Trypsin-like proteases cleave peptide bonds following a positively charged amino acid and this specificity is driven by the residue which lies at the base of the enzymes S1 pocket. The S1 pocket of chymotrypsin-like enzymes is more hydrophobic than in trypsin-like proteases and this results in a specificity for medium to large sized hydrophobic residues, such as tyrosine, phenylalanine and tryptophan. These include thrombin, tissue activating plasminogen and plasmin and they have been found to have roles in coagulation and digestion as well as in the pathophysiology of neurodegenerative disorders such as Alzheimers and Parkinsons induced dementia. Elastase-like proteases have a much smaller S1 cleft than either trypsin- or chymotrypsin-like proteases, consequently, residues such as alanine, glycine and valine tend to be preferred. Subtilisin is a protease in prokaryotes. Subtilisin is evolutionarily unrelated to the chymotrypsin-clan, but shares the same catalytic mechanism utilising a catalytic triad and this is the classic example used to illustrate convergent evolution, since the same mechanism evolved twice independently during evolution. The main player in the mechanism in the serine proteases is the catalytic triad. The triad is located in the site of the enzyme, where catalysis occurs. The triad is a structure consisting of three amino acids, His 57, Ser 195 and Asp 102. These three key amino acids play an essential role in the cleaving ability of the proteases. While the amino acid members of the triad are located far from one another on the sequence of the protein, due to folding, in the event of catalysis, an ordered mechanism occurs in which several intermediates are generated. The catalysis of the cleavage can be seen as a ping-pong catalysis, in which a substrate binds, a product is released, another substrate binds
24.
Catalytic triad
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A catalytic triad refers to the three amino acid residues that function together at the centre of the active site of some hydrolase and transferase enzymes. An Acid-Base-Nucleophile triad is a motif for generating a nucleophilic residue for covalent catalysis. The nucleophile is most commonly a serine or cysteine amino acid, as well as divergent evolution of function, catalytic triads show some of the best examples of convergent evolution. Chemical constraints on catalysis have led to the same solution independently evolving in at least 23 separate superfamilies. Their mechanism of action is one of the best studied in biochemistry. The enzymes trypsin and chymotrypsin were first purified in the 1930s, a serine in each of trypsin and chymotrypsin was identified as the catalytic nucleophile in the 1950s. The structure of chymotrypsin was solved by X-ray crystallography in the 1960s, other proteases were sequenced and aligned to reveal a family of related proteases, now called the S1 family. Simultaneously, the structures of the evolutionarily unrelated papain and subtilisin proteases were found to contain analogous triads, the charge-relay mechanism for the activation of the nucleophile by the other triad members was proposed in the late 1960s. As more protease structures were solved by X-ray crystallography in the 1970s and 80s, understanding how chemical constraints on evolution led to the convergence of so many enzyme families on the same triad geometries has developed in the 2010s. The massive body of work on the charge-relay, covalent catalysis used by catalytic triads has led to the mechanism being the best characterised in all of biochemistry. Enzymes that contain an catalytic triad use it for one of two types, either to split a substrate or to transfer one portion of a substrate over to a second substrate. Triads are an inter-dependent set of residues in the site of an enzyme. These triad residues act together to make the nucleophile member highly reactive, catalytic triads perform covalent catalysis using a residue as a nucleophile. The reactivity of the residue is increased by the functional groups of the other triad members. The nucleophile is polarised and oriented by the base, which is itself bound, catalysis is performed in two stages. First, the nucleophile attacks the carbonyl carbon and forces the carbonyl oxygen to accept an electron. The build-up of negative charge on this intermediate is stabilized by an oxanion hole within the active site. The intermediate then collapses back to a carbonyl, ejecting the first half of the substrate, the ejection of this first leaving group is often aided by donation of a proton by the base
25.
Asparagine
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Asparagine, encoded by the codons AAU and AAC, is an α-amino acid that is used in the biosynthesis of proteins. It contains a group, an α-carboxylic acid group. It is non-essential in humans, meaning the body can synthesize it, a reaction between asparagine and reducing sugars or other source of carbonyls produces acrylamide in food when heated to sufficient temperature. These products occur in baked goods such as French fries, potato chips, asparagine was first isolated in 1806 in a crystalline form by French chemists Louis Nicolas Vauquelin and Pierre Jean Robiquet from asparagus juice, in which it is abundant, hence the chosen name. It was the first amino acid to be isolated and its role can be thought as capping the hydrogen bond interactions that would otherwise be satisfied by the polypeptide backbone. Glutamines, with a methylene group, have more conformational entropy. Asparagine also provides key sites for N-linked glycosylation, modification of the chain with the addition of carbohydrate chains. Typically, a tree can solely be added to an asparagine residue if the latter is flanked on the C side by X-serine or X-threonine. Asparagine is not essential for humans, which means that it can be synthesized from central metabolic pathway intermediates and is not required in the diet, oxaloacetate is converted to aspartate using a transaminase enzyme. The enzyme transfers the amino group from glutamate to oxaloacetate producing α-ketoglutarate and aspartate, the enzyme asparagine synthetase produces asparagine, AMP, glutamate, and pyrophosphate from aspartate, glutamine, and ATP. In the asparagine synthetase reaction, ATP is used to activate aspartate, glutamine donates an ammonium group, which reacts with β-aspartyl-AMP to form asparagine and free AMP. Asparagine usually enters the citric acid cycle in humans as oxaloacetate, in bacteria, the degradation of asparagine leads to the production of oxaloacetate which is the molecule which combines with citrate in the citric acid cycle. Asparagine is hydrolyzed to aspartate by asparaginase, aspartate then undergoes transamination to form glutamate and oxaloacetate from alpha-ketoglutarate. Asparagine is required for development and function of the brain and it also plays an important role in the synthesis of ammonia. The addition of N-acetylglucosamine to asparagine is performed by enzymes in the endoplasmic reticulum. This glycosylation is important both for structure and protein function. GMD MS Spectrum Why Asparagus Makes Your Pee Stink
26.
Crystal structure
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In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the nature of the constituent particles to form symmetric patterns that repeat along the principal directions of three-dimensional space in matter. The smallest group of particles in the material that constitutes the pattern is the unit cell of the structure. The unit cell completely defines the symmetry and structure of the crystal lattice. The repeating patterns are said to be located at the points of the Bravais lattice, the lengths of the principal axes, or edges, of the unit cell and the angles between them are the lattice constants, also called lattice parameters. The symmetry properties of the crystal are described by the concept of space groups, all possible symmetric arrangements of particles in three-dimensional space may be described by the 230 space groups. The crystal structure and symmetry play a role in determining many physical properties, such as cleavage, electronic band structure. The crystal structure of a material can be described in terms of its unit cell, the unit cell is a box containing one or more atoms arranged in three dimensions. The unit cells stacked in three-dimensional space describe the arrangement of atoms of the crystal. Commonly, atomic positions are represented in terms of fractional coordinates, the atom positions within the unit cell can be calculated through application of symmetry operations to the asymmetric unit. The asymmetric unit refers to the smallest possible occupation of space within the unit cell and this does not, however imply that the entirety of the asymmetric unit must lie within the boundaries of the unit cell. Symmetric transformations of atom positions are calculated from the group of the crystal structure. Vectors and planes in a lattice are described by the three-value Miller index notation. It uses the indices ℓ, m, and n as directional parameters, which are separated by 90°, by definition, the syntax denotes a plane that intercepts the three points a1/ℓ, a2/m, and a3/n, or some multiple thereof. That is, the Miller indices are proportional to the inverses of the intercepts of the plane with the unit cell, if one or more of the indices is zero, it means that the planes do not intersect that axis. A plane containing a coordinate axis is translated so that it no longer contains that axis before its Miller indices are determined, the Miller indices for a plane are integers with no common factors. Negative indices are indicated with horizontal bars, as in, in an orthogonal coordinate system for a cubic cell, the Miller indices of a plane are the Cartesian components of a vector normal to the plane. Likewise, the planes are geometric planes linking nodes
27.
C3 (complement)
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Complement component 3, often simply called C3, is a protein of the immune system. It plays a role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3, C3 plays a central role in the activation of complement system. Its activation is required for classical and alternative complement activation pathways. People with C3 deficiency are susceptible to bacterial infection, one form of C3-convertase, also known as C4b2a, is formed by a heterodimer of activated forms of C4 and C2. It catalyzes the cleavage of C3 into C3a and C3b. C3a is an anaphylotoxin and the precursor of some such as ASP. Factor I can cleave C3b into C3c and C3d, the latter of which plays a role in enhancing B cell responses, in the alternative complement pathway, C3 is cleaved by C3bBb, another form of C3-convertase composed of activated forms of C3 and factor B. Once C3 is activated to C3b, it exposes a reactive thioester that allows the peptide to covalently attach to any surface that can provide a nucleophile such as an amine or a hydroxyl group. Activated C3 can then interact with factor B, Factor B is then activated by factor D, to form Bb. The resultant complex, C3bBb, is called the alternative pathway C3 convertase, first, the proteolytic component of the convertase, Bb, is removed by complement regulatory proteins having decay-accelerating factor activity. Next, C3b is broken down progressively to first iC3b, then C3c + C3dg, Factor I is the protease that performs these cuts but it requires the help of another protein to supply cofactor activity. Several crystallographic structures of C3 have been determined and reveal that this protein contains 13 domains, levels of C3 in the blood may be measured to support or refute a particular medical diagnosis. Complement component 3 has been shown to interact with Factor H. Deficiencies in C3 lead to generic infections, usually fatal to the newborn
28.
Complement factor B
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Complement factor B is a protein that in humans is encoded by the CFB gene. This gene encodes complement factor B, a component of the pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide, upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a protease that associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation and this gene localizes to the major histocompatibility complex class III region on chromosome 6. This cluster includes several genes involved in regulation of the immune reaction, the polyadenylation site of this gene is 421 bp from the 5 end of the gene for complement component 2
29.
Complement factor H
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Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large, soluble glycoprotein that circulates in human plasma, Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt different conformations with lower or higher activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification, the molecule is made up of 20 complement control protein modules connected to one another by short linkers and arranged in an extended head to tail fashion. The CCP modules are numbered from 1-20, CCPs 1-4 and CCPs 19-20 engage with C3b while CCPs 7 and CCPs 19-20 bind to GAGs and sialic acid. To date atomic structures have been determined for CCPs 1-3, CCP5, CCP7, CCPs 10-11 and CCPs 11-12, CCPs 12-13, CCP15, CCP16, CCPs 15-16, CCPs 18-20, and CCPs 19-20. The atomic structure for CCPs 6-8 bound to the GAG mimic sucrose octasulfate, CCPs 1-4 in complex with C3b, although an atomic resolution structure for intact factor H has not yet been determined, low resolution techniques indicate that it may be bent back in solution. Due to the role that factor H plays in the regulation of complement. Overactive factor H may result in reduced complement activity on pathogenic cells - increasing susceptibility to microbial infections, underactive factor H may result in increased complement activity on healthy host cells - resulting in autoimmune diseases. It is not surprising therefore that mutations or single nucleotide polymorphisms in factor H often result in pathologies, moreover, the complement inhibitory activities of factor H, and other complement regulators, are often used by pathogens to increase virulence. Recently it was discovered that about 35% of individuals carry an at-risk Single Nucleotide Polymorphism in one or both copies of their factor H gene. This SNP, located in CCP module 7 of factor H, has shown to affect the interaction between factor H and heparin indicating a causal relationship between the SNP and disease. Alterations in the immune response are involved in pathogenesis of many disorders including schizophrenia. Recent studies indicated alterations in the complement system, including hyperactivation of the complement pathway in patients with schizophrenia. It was found that rs800292 SNP was positively associated with stroke, haemolytic uraemic syndrome is a disease associated with microangiopathic haemolytic anemia, thrombocytopenia and acute renal failure. A rare subset of this disease, has been linked to mutations in genes of the complement system. These factor H mutations tend to congregate towards the C-terminus of factor H—a region responsible for discriminating self from non-self—and have been shown to disrupt heparin and C3d binding. Given the central role of factor H in protecting cells from complement and this recruitment of factor H by pathogens provides significant resistance to complement attack, and therefore increased virulence
30.
Properdin
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Properdin or Factor P is the only known positive regulator of complement activation that stabilizes the alternative pathway convertases. It is found in the serum of more complex animals. Properdin is a globulin protein composed of multiple identical protein subunits with a separate ligand-binding site. Native properdin occurs in head-to-tail dimers, trimers and tetramers in the fixed ratio 22,52,28 and it is known that it participates in some specific immune responses. It plays a part in inflammation as well as the engulfing of pathogens by phagocytes. In addition it is known to help to neutralize some viruses, the properdin promotes the association of C3b with Factor B and provides a focal point for the assembly of C3bBb on a surface. It binds to preformed alternative pathway C3-convertases, properdin also inhibits the Factor H – mediated cleavage of C3b by Factor I. The alternative pathway is not dependent on antibodies, properdin was discovered in 1954 by Dr. Louis Pillemer of the Institute of Pathology. Properdin deficiency is a rare X-linked disease in which properdin is deficient, affected individuals are susceptible to fulminant meningococcal disease. Properdin at the US National Library of Medicine Medical Subject Headings
31.
Immunoglobulin G
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Immunoglobulin G is a type of antibody. Each IgG has two binding sites. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in the circulation, IgG molecules are created and released by plasma B cells. Antibodies are major components of humoral immunity, IgG is the main type of antibody found in blood and extracellular fluid allowing it to control infection of body tissues. By binding many kinds of such as viruses, bacteria. IgG is also associated with type II and type III hypersensitivity reactions, IgG antibodies are generated following class switching and maturation of the antibody response and thus participate predominantly in the secondary immune response. IgG is secreted as a monomer that is small in size allowing it to easily perfuse tissues and it is the only isotype that has receptors to facilitate passage through the human placenta, thereby providing protection to the fetus in utero. Along with IgA secreted in the breast milk, residual IgG absorbed through the placenta provides the neonate with humoral immunity before its own immune system develops, colostrum contains a high percentage of IgG, especially bovine colostrum. In individuals with prior immunity to a pathogen, IgG appears about 24–48 hours after antigenic stimulation and this repertoire of immunoglobulins is crucial for the newborns who are very sensitive to infections above all for the respiratory and digestive systems. IgG are also involved in the regulation of allergic reactions, in the Alternative pathway antigens form complexes with IgG, which then cross-link macrophage FcγRIII and stimulates only PAF release. IgG antibodies can prevent IgE mediated anaphylaxis by intercepting a specific antigen before it binds to mast cell –associated IgE, consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but can mediate systemic anaphylaxis induced by larger quantities. IgG antibodies are large molecules of about 150 kDa made of four peptide chains and it contains two identical class γ heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to other and to a light chain each by disulfide bonds. The resulting tetramer has two halves, which together form the Y-like shape. Each end of the fork contains an identical antigen binding site, the various regions and domains of a typical IgG are depicted in the figure to the left. The Fc regions of IgGs bear a highly conserved N-glycosylation site, the N-glycans attached to this site are predominantly core-fucosylated diantennary structures of the complex type. In addition, small amounts of these N-glycans also bear bisecting GlcNAc and α-2, there are four IgG subclasses in humans, named in order of their abundance in serum. Note, IgG affinity to Fc receptors on phagocytic cells is specific to species from which the antibody comes as well as the class
32.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
. PMID 8613545.
