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Germplasm refers to genetic resources such as seeds, tissues, and DNA sequences that are maintained for the purpose of animal and plant breeding, conservation efforts, agriculture, and other research uses. These resources may take the form of seed collections stored in seed banks, trees growing in nurseries, animal breeding lines maintained in animal breeding programs or gene banks. Germplasm collections can range from collections of wild species to elite, domesticated breeding lines that have undergone extensive human selection. Germplasm collection is important for the maintenance of biological diversity, food security, and conservation efforts. In the United States, germplasm resources are regulated by the National Genetic Resources Program (NGRP), created by the U.S. congress in 1990. In addition the web server The Germplasm Resources Information Network (GRIN) provides information about germplasms as they pertain to agriculture production. == Regulation == In the United States, germplasm resources are regulated by the National Genetic Resources Program (NGRP), created by the U.S. congress in 1990. In addition the web server The Germplasm Resources Information Network (GRIN) provides information about germplasms as they pertain to agriculture production. Specifically for plants, there is the U.S. National Plant Germplasm System (NPGS) which holds > 450,000 accessions with 10,000 species of the 85 most commonly grown crops. Many accessions held are international species, and NPGS distributes germplasm resources internationally. As genetic information moves largely online there is a transition in germplasm information from a physical location (seed banks, cryopreserving) to online platforms containing genetic sequences. In addition there are issues in the collection germplasm information and where they are shared. Historically some germplasm information had been collected in developing countries and then shared to researchers who then sell the donor country the original germplasm that they altered. There is a lack of compensation to the donor countries and
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this is an issue. == Storage methods == Effective Germplasm work includes the collection, storage, analysis, documentation, and exchange of genetic information. This information can be stored as accessions, which is DNA sequence information, or live cells/tissues that can be preserved. However, only about 5% of current germplasm resources are living samples. For live cells/tissues, germplasm resources can be stored ex situ in seed banks, botanic gardens, or through cryopreservation. Cryopreservation is the process of storing germplasm at very low temperatures, such as liquid nitrogen. This process ensures that cells do not degrade and keeps the germplasm intact. In addition, resources can be stored in situ such as the natural area the species was found. == Conservation efforts == About 10,000 years ago is when humans began to domesticate plant species for the purpose of food, seeds, and vegetation. Since then, agriculture has been a staple for human civilizations and plant breeding has allowed more genetic diversity and a more diverse gene pool. Germplasm resources allow for more genetic assets to be used and integrated for agricultural systems for plant breeding and bringing about new varieties. In addition, researchers are looking at crop wild relatives (CWRs) that could expand gene pools of crop species and provide more ability to select target traits. Furthermore, we are currently facing a biodiversity crisis event that is caused by human activities and industrialization. Many plants and animals have gone extinct due to losing their habitat, their habitat being degraded with contaminants, and climate change. Germplasm resources are a way to conserve the pre-existing biological diversity and to possibly regenerate habitats. By storing this genetic information there is data about what species are present including plants, animals, bacteria, and fungi and what a complete ecosystem in specific areas look like. == See also == Animal
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"page_id": 1512214,
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genetic resources for food and agriculture Conservation biology Cryoconservation of animal genetic resources Forest genetic resources International Treaty on Plant Genetic Resources for Food and Agriculture Plant genetic resources Seed saving Germ plasm == References == Day-Rubenstein, K and Heisey, P. 2003. Plant Genetic Resources: New Rules for International Exchange Carmen De Vicente, Maria (2005). Issues on gene flow and germplasm management. Bioversity International. ISBN 9789290436935. Archived from the original on May 3, 2008. Retrieved December 12, 2007. 63 p. Economic Research Service. Global resources and productivity: questions and answers Engels, Jan (2003). Engels, Jan; Visser, L (eds.). A Guide to Effective Management of Germplasm Collections. Bioversity International. ISBN 9789290435822. Archived from the original on May 25, 2007. 174 p. SeedQuest Primer Germplasm Resources == References == == External links == USDA-ARS Germplasm Resources Information Network (GRIN) Bioversity International Bioversity International: Germplasm Collection Bioversity International: Germplasm Databases Bioversity International: Germplasm Documentation - overview Bioversity International: Germplasm Health DAD-IS: Domestic Animal Diversity Information System
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A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules. In addition to occurring during DNA replication, trinucleotide repeat expansion can also occur during DNA repair. When a DNA trinucleotide repeat sequence is damaged, it may be repaired by processes such as homologous recombination, non-homologous end joining, mismatch repair or base excision repair. Each of these processes involves a DNA synthesis step in which strand slippage might occur leading to trinucleotide repeat expansion. The number of trinucleotide repeats appears to predict the progression, severity, and age of onset of Huntington's disease and similar trinucleotide repeat disorders. Other human diseases in which triplet repeat expansion occurs are fragile X syndrome, several spinocerebellar ataxias, myotonic dystrophy and Friedreich's ataxia. == History == The first documentation of anticipation in genetic disorders was in the 1800s.
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However, from the eyes of geneticists, this relationship was disregarded and attributed to ascertainment bias; because of this, it took almost 200 years for a link between onset of disease and trinucleotide repeats (TNR) to be acknowledged. The following findings of served as support for TNR's link to onset of disease; the detection of various repeats within these diseases demonstrated this relationship. In 1991, for fragile X syndrome, the fragile X mental retardation 1 (FMR-1) gene was found to contain a CGG expansion in its 5' untranslated region (UTR). In addition, a CAG expansion was located in X-linked spinal and bulbar muscular atrophy (SBMA) sequences. SMBA is the first "CAG / polygutamine" disease, which is a subcategory of repeat disorders. In 1992, for myotonic dystrophy type 1 (DM1), CTG expansion was found in the myotonic dystrophy protein kinase (DMPK) 3' UTR. In 1993, for Huntington's disease (HD), a longer-than-usual CAG repeat with was found in the exon 1 coding sequence. Because of these discoveries, ideas involving anticipation in disease began to develop, and curiosity formed about how the causes could be related to TNRs. After the breakthroughs, the four mechanisms for TNRs were determined, and more types of repeats were identified as well. Repeat composition and location are used to determine the mechanism of a given expansion. Onwards from 1995, it was also possible to observe the formation of hairpins in triplet repeats, which consisted of repeating CG pairs and a mismatch. During the decade after evidence that linked TNR to onset of disease was found, focus was placed on studying repeat length and dynamics on diseases, as well as investigating the mechanism behind parent-child disease inheritance. Research has shown that there is a clear inverse relationship between the length of the repeats in parents and the age of disease
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onset in children; therefore, the lengths of TNRs are used to predict age of disease onset as well as outcome in clinical diagnosis. In addition to this finding, another aspect of the diseases, the high variability of onset, was revealed. Although the onset of HD could be predicted by examining TNR length inheritance, the onset could vary up to fourfold depending on the patient, leading to the possibility of existence of age-modifying factors for disease onset; there were notable efforts in this search. Currently, CAG repeat length is considered the biggest onset age modifier for TNR diseases. Detection of TNRs was made difficult by limited technology and methods early on, and years passed before the development of sufficient ways to measure the repeats. When PCR was first attempted in the detection of TNRs, multiple band artifacts were prevalent in the results, and this made recognition of TNRs troublesome; at the time, debate centered around whether disease was brought on by smaller amounts of short expansions or a small amount of long expansions. Since then, accurate methods have been established over the years. Together, the following clinically necessary protocols have 99% accuracy in measuring TNRs. Small-pool polymerase chain reaction (SP-PCR) allows for recognition of repeat changes, and originated from the growing necessity for a method that would provide more accurate measurement of TNRs. It has been useful for examining how TNRs vary between human and mice in blood, sperm, and somatic cells. Southern blots are used to measure CGG repeats because CG-rich regions limit polymerase movement in PCR. == Overall structure == These repetitive sequences lead to instability amongst the DNA strands after reaching a certain threshold number of repeats, which can result in DNA slippage during replication. The most common and well-known triplet repeats are CAG, GCG, CTG, CGG, and
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GAA. During DNA replication, the strand being synthesized can misalign with its template strand due to the dynamic nature and flexibility of these triplet repeats. This slippage allows for the strand to find a stable intermediate amongst itself through base pairing, forming a secondary structure other than a duplex. === Location === In terms of location, these triplet repeats can be found in both coding and non-coding regions. CAG and GCN repeats, which lead to polyglutamine and polyalanine tracts respectively, are normally found in the coding regions. At the 5' untranslated region, CGG and CAG repeats are found and responsible for fragile X syndrome and spinocerebellar ataxia 12. At the 3' untranslated region, CTG repeats are found, while GAA repeats are located in the intron region. Other disease-causing repeats, but not triplet repeats, have been located in the promoter region. Once the number of repeats exceeds normal levels, Triplet Repeat Expansions (TRE) become more likely and the number of triplet repeats can typically increase to around 100 in coding regions and up to thousands in non-coding regions. This difference is due to overexpression of glutamine and alanine, which is selected against due to cell toxicity. === Intermediates === Depending on the sequence of the repeat, at least three intermediates with different secondary structures are known to form. A CGG repeat will form a G-quadruplex due to Hoogsteen base pairing, while a GAA repeat forms a triplex due to negative supercoiling. CAG, CTG, and CGG repeats form a hairpin. After the hairpin forms, the primer realigns with the 3' end of the newly synthesized strand and continues the synthesis, leading to triplet repeat expansion. The structure of the hairpin is based on a stem and a loop that contains both Watson-Crick base pairs and mismatched pairs. In CTG and CAG repeats,
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the number of nucleotides present in the loop depends on if the number of triplet repeats is odd or even. An even number of repeats forms a tetraloop structure, while an odd number leads to the formation of a triloop. == Instability == === Threshold === In trinucleotide repeat expansion there is a certain threshold or maximum amount of repeats that can occur before a sequence becomes unstable. Once this threshold is reached the repeats will start to rapidly expand causing longer and longer expansions in future generations. Once it hits this minimum allele size which is normally around 30-40 repeats, diseases and instability can be contracted, but if the number of repeats found within a sequence are below the threshold it will remain relatively stable. There is still not enough research found to understand the molecular nature that causes thresholds but researchers are continuing to study that the possibility could lie with the formation of the secondary structure when these repeats occur. It was found that diseases associated with trinucleotide repeat expansions contained secondary structures with hairpins, triplexes, and slipped-strand duplexes. These observations have led to the hypothesis that the threshold is determined by the number of repeats that must occur to stabilize the formation of these unwanted secondary structures, due to the fact that when these structures form there is an increased number of mutations that will form in the sequence resulting in more trinucleotide expansion. === Parental influence === Research suggests that there is a direct, important correlation between the sex of the parent that transmits the mutation and the degree and phenotype of disorder in the child., The degree of repeat expansion and whether or not an expansion will occur has been directly linked to the sex of the transmitting parent in both non-coding and coding
|
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trinucleotide repeat disorders. For example, research regarding the correlation between Huntington's Disease CAG trinucleotide repeat and parental transmission has found that there is a strong correlation between the two with differences in maternal and paternal transmission. Maternal transmission has been observed to only consist of an increase in repeat units of 1 while the paternal transmission is typically anywhere from 3 to 9 extra repeats. Paternal transmission is almost always responsible for large repeat transmission resulting in the early onset of Huntington's Disease while maternal transmission results in affected individuals experiencing symptom onset mirroring that of their mother., While this transmission of a trinucleotide repeat expansion is regarded to be a result of "meiotic instability", the degree to which meiosis plays a role in this process and the mechanism is not clear and numerous other processes are predicted to simultaneously play a role in this process. == Mechanisms == === Unequal homologous exchange === One proposed but highly unlikely mechanism that plays a role in trinucleotide expansion transmission occurs during meiotic or mitotic recombination. It is suggested that during these processes it is possible for a homologous repeat misalignment, commonly known for causing alpha-globin locus deletions, causes the meiotic instability of a trinucleotide repeat expansion. This process is unlikely to contribute to the transmission and presence of trinucleotide repeat expansions due to differences in expansion mechanisms. Trinucleotide repeat expansions typically favor expansions of the CAG region but, in order for the unequal homologous exchange to be a plausible suggestion, these repeats would have to go through expansion and contraction events at the same time. In addition, numerous diseases that result from transmitted trinucleotide repeat expansions, such as Fragile X syndrome, involve unstable trinucleotide repeats on the X chromosome that cannot be explained by meiotic recombination. Research has shown that although
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unequal homologous recombination is unlikely to be the sole cause of transmitted trinucleotide repeat expansions, this homologous recombination likely plays a minor role in the length of some trinucleotide repeat expansions. === DNA replication === DNA replication errors are predicted to be the main perpetrator of trinucleotide repeat expansion transmission in many predicted models due to the difficulty of Trinucleotide Repeat Expansion (TRE). TREs have been shown to occur during DNA replication in both in vitro and in vivo studies, allowing for these long tracts of triplet repeats to assemble rapidly in different mechanisms that can result in either small scale or large scale expansions. ==== Small scale expansions ==== These expansions can occur through either strand slippage or flap ligation. Okazaki fragments are a key element of the proposed error in DNA replication. It is suggested that the small size of Okazaki fragments, typically between 150 and 200 nucleotides long, makes them more likely to fall off or "slip" off the lagging strand, which creates room for trinucleotide repeats to attach to the lagging strand copy. In addition to this possibility of trinucleotide repeat expansion changes occurring due to slippage of Okazaki fragments, the ability of CG-rich trinucleotide repeat expansion sequences to form a special hairpin, toroid, and triplex DNA structures contributes to this model, suggesting error occurs during DNA replication. Hairpin structures can form as a result of the freedom of the lagging strand during DNA replication and are typically observed to form in extremely long trinucleotide repeat sequences. Research has found that this hairpin formation depends on the orientation of the trinucleotide repeats within each CAG/CTG trinucleotide strand. Strands that have duplex formation by CTG repeats in the leading strand are observed to result in extra repeats, while those without CTG repeats in the leading strand result
|
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in repeat deletions. These intermediates can pause activity of the replication fork based on their interaction with DNA polymerases through strand slippage. Contractions occur when the replication fork skips over the intermediate on the Okazaki fragment. Expansions occur when the fork reverses and restarts, which forms a chicken-foot structure. This structure results in the unstable intermediate forming on the nascent leading strand, leading to further TRE. Furthermore, this intermediate can avoid mismatch repair due to its affinity for the MSH-2-MSH3 complex, which stabilizes the hairpin instead of repairing it. In non-dividing cells, a process called flap-ligation can be responsible for TRE. 8-oxo-guanine DNA glycosylase removes a guanine and forms a nick in the sequence. The coding strand then forms a flap due to displacement, which prevents removal by an endonuclease. When the repair process finishes for either mechanism, the length of the expansion is equivalent to the number of triplet repeats involved in the formation of the hairpin intermediate. ==== Large scale expansions ==== Two mechanisms have been proposed for large scale repeats: template switching and break-induced replication. Template switching, a mechanism for large scale GAA repeats that can double the number of triplet repeats, has been proposed. GAA repeats expand when their repeat length is greater than the Okazaki fragment's length. These repeats are involved in the stalling of the replication fork as these repeats form a triplex when the 5' flap of TTC repeats fold back. Okazaki fragment synthesis continues when the template is switched to the nascent leading strand. The Okazaki fragment eventually ligates back to the 5' flap, which results in TRE. A different mechanism, based on break-induced replication, has been proposed for large scale CAG repeats and can also occur in non-dividing cells. At first, this mechanism follows the same process as the small scale
|
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strand slippage mechanism until replication fork reversal. An endonuclease then cleaves the chicken-foot structure, which results in a one-ended double strand break. The CAG repeat of this broken daughter strand forms a hairpin and invades the CAG strand on the sister chromatid, which results in expansion of this repeat in a migrating D-loop DNA synthesis. This synthesis continues until it reaches the replication fork and is cleaved, which results in an expanded sister chromatid. == Disorders == === Fragile X syndrome === ==== Background ==== Fragile X syndrome is the second most common form of intellectual disability affecting 1 in 2,000-4,000 women and 1 in 4,000-8,000 men, women being twice as likely to inherit this disability due to their XX chromosomes. This disability arises from a mutation at the end of the X chromosome in the FMR1 gene (fragile X mental retardation gene) which produces a protein essential for brain development called FMRP. Individuals with fragile X syndrome experience a variety of symptoms at varying degrees that depend on gender and mutation degree such as attention deficit disorders, irritability, stimuli sensitivity, various anxiety disorders, depression, and/or aggressive behavior. Some treatments for these symptoms seen in individuals with Fragile X syndrome include SSRI's, antipsychotic medications, stimulants, folic acid, and mood stabilizers. ==== Genetic causation ==== Fragile X syndrome is caused by expansion of CGG repeats in the FMR1 gene. In males without fragile X syndrome, the CGG repeat number ranges from 53 to 200 while those affected have greater than 200 repeats of this trinucleotide sequence located at the end of the X chromosome on band Xq28.3.1. Carriers that have repeats falling within the 53 to 200 repeat range are said to have "premutation alleles", as the alleles within this range approach 200, the likelihood of expansion to a full mutation
|
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increases, and the mRNA levels are elevated five-fold. Research has shown that individuals with premutation alleles in the range of 59-69 repeats have about a 30% risk of developing full mutation and compared to those in the high range of ≥ 90 repeats. Fragile X syndrome carriers (those that fall within the premutation range) typically have unmethylated alleles, normal phenotype, and normal levels of FMR1 mRNA and FMRP protein. Fragile X syndrome men possess alleles in the full mutation range (>200 repeats) with FMRP protein levels much lower than normal and experience hypermethylation of the promoter region of the FMR1 gene. Some men with alleles in the full mutation range experience partial or no methylation which results in only slightly abnormal phenotypes due to only slight down-regulation of FMR1 gene transcription. Unmethylated and partially methylated alleles in the mutation range experience increased and normal levels of FMR1 mRNA when compared to normal controls. In contrast, when unmethylated alleles reach a repeat number of approximately 300, the transcription levels are relatively unaffected and operate at normal levels; the transcription levels of repeats greater than 300 is currently unknown. ==== Promoter silencing ==== The CGG trinucleotide repeat expansion is present within the FMR1 mRNA and its interactions are responsible for promoter silencing. The CGG trinucleotide expansion resides within the 5' untranslated region of the mRNA, which undergoes hybridization to form a complementary CGG repeat portion. The binding of this genomic repeat to the mRNA results in silencing of the promoter. Beyond this point, the mechanism of promoter silencing is unknown and still being further investigated. === Huntington's disease === ==== Background ==== Huntington's disease (HD) is a dominantly, paternally transmitted neurological disorder that affects 1 in 15,000-20,000 people in many Western populations. HD involves the basal ganglia and the cerebral cortex and
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manifests as symptoms such as cognitive, motor, and/or psychiatric impairment. ==== Causation ==== This autosomal dominant disorder results from the expansions of a trinucleotide repeat which involves CAG in exon 1 of the IT15 gene. The majority of all juvenile HD cases stem from the transmission of a high CAG trinucleotide repeat number that is a result of paternal gametogenesis. While an individual without HD has a number of CAG repeats that fall within a range between 9 and 37, an individual with HD has CAG is typically found to have repeats in a range between 37 and 102. Research has shown an inverse relationship between the number of trinucleotide repeats and age of onset, however, no relationship between trinucleotide repeat numbers and rate of HD progression and/or effected individual's body weight has been observed. Severity of functional decline has been found to be similar across a wide range of individuals with varying numbers of CAG repeats and differing ages of onset, therefore, it is suggested that the rate of disease progression is also linked to factors other than the CAG repeat such as environmental and/or genetic factors. === Myotonic dystrophy === ==== Background ==== Myotonic dystrophy is a rare muscular disorder in which numerous bodily systems are affected. There are four forms of Myotonic Dystrophy: mild phenotype and late-onset, onset in adolescence/young adulthood, early childhood featuring only learning disabilities, and a congenital form. Individuals with Myotonic Dystrophy experience severe, debilitating physical symptoms such as muscle weakness, heartbeat issues, and difficulty breathing that can be improved through treatment to maximize patients' mobility and everyday activity to alleviate some stress of their caretakers. The muscles of individuals with Myotonic Dystrophy feature an increase of type 1 fibers as well as an increased deterioration of these type 1 fibers. In addition to
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these physical ailments, individuals with Myotonic Dystrophy have been found to experience varying internalized disorders such as anxiety and mood disorders as well as cognitive delays, attention deficit disorders, autism spectrum disorders, lower IQ's, and visual-spatial difficulties. Research has shown that there is a direct correlation between expansion repeat number, IQ, and an individual's degree of visual-spatial impairment. ==== Causation ==== Myotonic dystrophy results from a (CTG)n trinucleotide repeat expansion that resides in a 3' untranslated region of a serine/threonine kinase coding transcript. This (CTG)n trinucleotide repeat is located within leukocytes; the length of the repeat and the age of the individual have been found to be directly related to disease progression and type 1 muscle fiber predominance. Age and (CTG)n length only have small correlation coefficients to disease progression, research suggests that various other factors play a role in disease progression such as changes in signal transduction pathway, somatic expression, and cell heterogeneity in (CTG)n repeats. === Friedreich's ataxia === ==== Background ==== Friedreich's ataxia is a progressive neurological disorder. Individuals experience gait and speech disturbances due to degeneration of the spinal cord and peripheral nerves. Other symptoms may include cardiac complications and diabetes. Typical age at symptom onset is 5–15, with symptoms progressively getting worse over time. ==== Causation ==== Friedreich's ataxia is an autosomal recessive disorder cause by a GAA expansion in the intron of the FXN gene. This gene codes for the protein frataxin, a mitochondrial protein involved in iron homeostasis. The mutation impairs transcription of the protein, so affected cells produce only 5-10% of the frataxin of healthy cells. This leads to iron accumulation in the mitochondria, and makes cells vulnerable to oxidative damage. Research shows that GAA repeat length is correlated with disease severity. == Point of occurrence == === Fragile X syndrome ===
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The precise timing of TNR occurrence varies by disease. Although the exact timing for FXS is not certain, research has suggested that the earliest CGG expansions for this disorder are seen in primary oocytes. It has been proposed that the repeat expansion happens in the maternal oocyte during meiotic cell cycle arrest in prophase I, however the mechanism remains nebulous. Maternally inherited premutation alleles may expand into full mutation alleles (greater than 200 repeats), resulting in decreased production of the FMR-1 gene product FMRP and causing fragile X mental retardation syndrome. For females, the large repeat expansions are based upon repair, while for males, the shortening of long repeat expansions is due to replication; therefore, their sperm lack these repeats, and paternal inheritance of long repeat expansions does not occur. Between weeks 13 and 17 of human fetal development, the large CGG repeats are shortened. === Myotonic dystrophy type 1 === Many similarities can be drawn between DM1 and FXS involving aspects of mutation. Full maternal inheritance is present within DM1, repeat expansion length is linked to maternal age and the earliest instance of expansions is seen in the two-cell stage of preimplantation embryos. There is a positive correlation between male inheritance and allele length. A study of mice found the exact timing of CTG repeat expansion to be during development of spermatogonia. In DM1 and FXS, it is hypothesized that expansion of TNRs occurs by means of multiple missteps by DNA polymerase in replication. An inability of DNA polymerase to properly move across the TNR may cause transactivation of translesion polymerases (TLPs), which will attempt to complete the replication process and overcome the block. It is understood that as the DNA polymerase fails in this way, the resulting single-stranded loops left behind in the template strand undergo deletion, affecting
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TNR length. This process leaves the potential for TNR expansions to occur. === Huntington's disease === In Huntington's disease (HD), the exact timing has not been determined; however there are a number of proposed points during germ cell development at which expansion is thought to occur. In four HD samples examined, CAG repeat expansion lengths were more variable in mature sperm than that of sperm in development in the testes, leading to the conclusion that repeat expansions had a likelihood of occurring later in sperm development. Repeat expansions have been observed to occur before the completion of meiosis in humans, specifically the first division. In germ cells undergoing differentiation, evidence suggests it is possible for expansions to generate after the completion of meiosis as well, as larger HD mutations have been found in postmeiotic cells. === Spinocerebellar ataxia type 1 === Spinocerebellar ataxia type 1 (SCA1) CAG repeats are most often passed down through paternal inheritance and similarities can be seen with HD. The tract size for offspring of mothers with these repeats does not display any degree of change. Because TNR instability is not present in young female mice, and female SCA1 patient age and instability are directly related, expansions must occur in inactive oocytes. A trend has seemed to emerge of larger expansions occurring in cells inactive in division and smaller expansions occurring in actively dividing or nondividing cells. == Therapeutics == Trinucleotide repeat expansion, is a DNA mutation that is responsible for causing any type of disorder classified as a trinucleotide repeat disorder. These disorders are progressive and affect the sequences of the human genome, frequently within the nervous system. So far the available therapeutics only have modest results at best with emphasis on the research and studying of genomic manipulation. The most advanced available therapies aim
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to target mutated gene expression by using antisense oligonucleotides (ASO) or RNA interference (RNAi) to target the messenger RNA (mRNA). While solutions for the interventions of this disease is a priority, RNAi and ASO have only reached clinical trial stages. === RNA interference (RNAi) === RNA interference is a mechanism that can be used to silence the expression of genes, RNAi is a naturally occurring process that is leveraged using synthetic small interfering RNAs (siRNAs) that are used to change the action and duration of the natural RNAi process. Another synthetic RNA is the short hairpin RNAs (shRNA) these can also be used to monitor the action and predictability of the RNAi process. RNAi begins with RNase Dicer cleaving a 21-25 nucleotide long stand of double stranded RNA substrates into small fragments. This process results in the creation of the siRNA duplexes that will be used by the complex RNA induced silencing complex (RISC). The RISC contains the antisense that will bind to complementary mRNA strands, once they are bound they are cleaved by the protein found within the RISC complex called Argonaute 2 (Ago2) between the bases 10 and 11 relative to the 5' end. Before the cleavage of the mRNA strand the double stranded antisense of the siRNA is also cleaved by the Ago2 complex, this leaves a single stranded guide within the RISC compound that will be used to find the desired mRNA strand resulting in this process to have specificity. Some problems that may occur is if the guide single strand siRNA within the RISC complex may become unstable when cleaved and begin to unwind, resulting in binding to an unfavorable mRNA strand. The perfect complementary guides for the targeted RNAs are easily recognized and will be cleaved within the RISC complex; if there is only
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partial complementary pairing between the guide strand and the targeted mRNA may cause the incorrect translation or destabilization at the target sites. === Antisense oligonucleotides === Antisense oligonucleotides (ASOs) are small strand single stranded oligodeoxynucleotides approximately 15-20 nucleic acids in length that can alter the expression of a protein. The goal of using these antisense oligonucleotides are the decrease in protein expression of a specific target usually by the inhibition of the RNase H endonuclease, as well as inhibition of the 5' cap formation or alteration of the splicing process. In the native state ASOs are rapidly digested, this requires the use of phosphorylation order for the ASO to go through the cell membranes. Despite the obvious benefits that antisense therapeutics can bring to the world with their ability to silence neural disease, there are many issues with the development of this therapy. One problem is the ASOs are highly susceptible to degradation by the nucleases within the body. This results in a high amount of chemical modification when altering the chemistry to allow for the nucleases to surpass the degradation of these synthetic nucleic acids. Native ASOs have a very short half-life even before being filtered throughout the body especially in the kidney and with the a high negative charge makes the crossing through the vascular system or membranes very difficult when trying to reach the targeted DNA or mRNA strands. With all these barriers, the chemical modifications may lead to devastating effects when being introduced into the body making each problem develop more and more side effects. The synthetic oligonucleotides are negatively charged molecules that are chemically modified in order for the molecule to regulate the gene expression within the cell. Some issues that come about this process is the toxicity and variability that can come about with
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chemical modification. The goal of the ASO is to modulate the gene expression through proteins which can be done in 2 complex ways; a)the RNase H-dependent oligonucleotides, which induce the degradation of mRNA, and (b) the steric-blocker oligonucleotides, which physically prevent or inhibit the progression of splicing or the translational machinery. The majority of investigated ASOs utilize the first mechanism with the Rnase H enzyme that hydrolyzes an RNA strand, when this enzyme is assisted using the oligonucleotides the reduction of RNA expression is efficiently reduced by 80-95% and can still inhibit expression on any region of the mRNA. == References ==
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Inflammation (from Latin: inflammatio) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin calor, dolor, rubor, tumor, and functio laesa). Inflammation is a generic response, and therefore is considered a mechanism of innate immunity, whereas adaptive immunity is specific to each pathogen. Inflammation is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. However inflammation can also have negative effects. Too much inflammation, in the form of chronic inflammation, is associated with various diseases, such as hay fever, periodontal disease, atherosclerosis, and osteoarthritis. Inflammation can be classified as acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli, and is achieved by the increased movement of plasma and leukocytes (in particular granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells in the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and involves simultaneous destruction and healing of the tissue. Inflammation has also been classified as Type 1 and Type 2 based on the type of cytokines and helper T cells (Th1 and Th2) involved. == Meaning == The earliest known reference for the term inflammation is around the early 15th century. The word
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root comes from Old French inflammation around the 14th century, which then comes from Latin inflammatio or inflammationem. Literally, the term relates to the word "flame", as the property of being "set on fire" or "to burn". The term inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response—the two components are considered together in discussion of infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation, on the other hand, describes just the body's immunovascular response, regardless of cause. But, because the two are often correlated, words ending in the suffix -itis (which means inflammation) are sometimes informally described as referring to infection: for example, the word urethritis strictly means only "urethral inflammation", but clinical health care providers usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis. However, the inflammation–infection distinction is crucial in situations in pathology and medical diagnosis that involve inflammation that is not driven by microbial invasion, such as cases of atherosclerosis, trauma, ischemia, and autoimmune diseases (including type III hypersensitivity). == Causes == == Types == === Acute === Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus. It involves a coordinated and systemic mobilization response locally of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases. Acute inflammation occurs immediately upon injury, lasting only a few days. Cytokines and chemokines promote the migration of neutrophils and macrophages to the site of inflammation. Pathogens, allergens, toxins, burns, and
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frostbite are some of the typical causes of acute inflammation. Toll-like receptors (TLRs) recognize microbial pathogens. Acute inflammation can be a defensive mechanism to protect tissues against injury. Inflammation lasting 2–6 weeks is designated subacute inflammation. ==== Cardinal signs ==== Inflammation is characterized by five cardinal signs, (the traditional names of which come from Latin): Dolor (pain) Calor (heat) Rubor (redness) Tumor (swelling) Functio laesa (loss of function) The first four (classical signs) were described by Celsus (c. 30 BC–38 AD). Pain is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings. Acute inflammation of the lung (usually in response to pneumonia) does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings. Heat and redness are due to increased blood flow at body core temperature to the inflamed site. Swelling is caused by accumulation of fluid. ===== Loss of function ===== The fifth sign, loss of function, is believed to have been added later by Galen, Thomas Sydenham or Rudolf Virchow. Examples of loss of function include pain that inhibits mobility, severe swelling that prevents movement, having a worse sense of smell during a cold, or having difficulty breathing when bronchitis is present. Loss of function has multiple causes. ==== Acute process ==== The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors (PRRs), which recognize (i.e., bind) two subclasses of molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.
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At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). Some of the released mediators such as bradykinin increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, to flow out of the blood vessels (extravasation) and into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function (functio laesa) is probably the result of a neurological reflex in response to pain. In addition to cell-derived mediators, several acellular biochemical cascade systems—consisting of preformed plasma proteins—act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis (e.g., burn, trauma). Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed. === Chronic === Chronic inflammation is inflammation that lasts for months or years. Macrophages, lymphocytes, and plasma cells predominate in chronic inflammation, in contrast to the neutrophils that predominate in acute inflammation. Diabetes, cardiovascular disease, allergies, and chronic obstructive pulmonary disease are examples of diseases mediated by chronic inflammation. Obesity, smoking, stress and insufficient diet are
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some of the factors that promote chronic inflammation. ==== Cardinal signs ==== Common signs and symptoms that develop during chronic inflammation are: Body pain, arthralgia, myalgia Chronic fatigue and insomnia Depression, anxiety and mood disorders Gastrointestinal complications such as constipation, diarrhea, and acid reflux Weight gain or loss Frequent infections == Vascular component == === Vasodilation and increased permeability === As defined, acute inflammation is an immunovascular response to inflammatory stimuli, which can include infection or trauma. This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid granulocytes in the acute setting). The vascular component of acute inflammation involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue. Upon contact with PAMPs, tissue macrophages and mastocytes release vasoactive amines such as histamine and serotonin, as well as eicosanoids such as prostaglandin E2 and leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release nitric oxide. These mediators vasodilate and permeabilize the blood vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (edema). This exuded tissue fluid contains various antimicrobial mediators from the plasma such as complement, lysozyme, antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded platelets, coagulants, plasmin and kinins can clot the wounded area using vitamin K-dependent mechanisms and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a fibrin lattice – as would construction scaffolding at a construction
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site – for the purpose of aiding phagocytic debridement and wound repair later on. Some of the exuded tissue fluid is also funneled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system. Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate (move) along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel. === Plasma cascade systems === The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC. The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects. The coagulation system or clotting cascade, which forms a protective protein mesh over sites of injury. The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators. === Plasma-derived mediators === * non-exhaustive list == Cellular component == The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting
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bacteria, viruses, and cellular debris. Others release enzymatic granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by granulocytes, whereas chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes. === Leukocyte extravasation === Various leukocytes, particularly neutrophils, are critically involved in the initiation and maintenance of inflammation. These cells must be able to move to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation and can be broadly divided up into a number of steps: Leukocyte margination and endothelial adhesion: The white blood cells within the vessels which are generally centrally located move peripherally towards the walls of the vessels. Activated macrophages in the tissue release cytokines such as IL-1 and TNFα, which in turn leads to production of chemokines that bind to proteoglycans forming gradient in the inflamed tissue and along the endothelial wall. Inflammatory cytokines induce the immediate expression of P-selectin on endothelial cell surfaces and P-selectin binds weakly to carbohydrate ligands on the surface of leukocytes and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines released from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands such as ICAM-1 and VCAM-1 on endothelial cells, which mediate the adhesion and further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue after signal transduction via respective G protein-coupled receptors that activates integrins on the leukocyte surface for
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firm adhesion. Such activation increases the affinity of bound integrin receptors for ICAM-1 and VCAM-1 on the endothelial cell surface, firmly binding the leukocytes to the endothelium. Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between adjacent endothelial cells. The endothelial cells retract and the leukocytes pass through the basement membrane into the surrounding tissue using adhesion molecules such as ICAM-1. Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent them from leaving the site. A variety of molecules behave as chemoattractants, for example, C3a or C5a (the anaphylatoxins), and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation. === Phagocytosis === Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue. Phagocytes express cell-surface endocytic pattern recognition receptors (PRRs) that have affinity and efficacy against non-specific microbe-associated molecular patterns (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate phagocytosis are cell wall components, including complex carbohydrates such as mannans and β-glucans, lipopolysaccharides (LPS), peptidoglycans, and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with C-type lectin receptors binding to mannans and β-glucans, and scavenger receptors binding to LPS. Upon endocytic PRR binding, actin-myosin cytoskeletal rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe. Phosphatidylinositol and Vps34-Vps15-Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular lysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. The reactive oxygen species, superoxides and hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte. Phagocytic efficacy can be enhanced by opsonization. Plasma
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derived complement C3b and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express opsonin receptors Fc receptor and complement receptor 1 (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the lysosomal elimination of the infective agent. === Cell-derived mediators === * non-exhaustive list == Morphologic patterns == Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved. Granulomatous inflammation: Characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, sarcoidosis, and syphilis. Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrin to pass through the blood vessels. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine (pseudomembranous colitis), pseudomembranous tubes can be formed. Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses. Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters exemplify this pattern of inflammation. Ulcerative inflammation: Inflammation occurring near an
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epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer. == Disorders == Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, as demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer, atherosclerosis, and ischemic heart disease. Examples of disorders associated with inflammation include: === Atherosclerosis === Atherosclerosis, formerly considered a lipid storage disorder, is now understood as a chronic inflammatory condition involving the arterial walls. Research has established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications from it. These new findings reveal links between traditional risk factors like cholesterol levels and the underlying mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to people. For instance, elevation in markers of inflammation predicts outcomes of people with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications, thus adding to prognostic information provided by traditional risk factors, such as LDL levels. Moreover, certain treatments that reduce coronary risk also limit inflammation. Notably, lipid-lowering medications such as statins have shown anti-inflammatory effects, which may contribute to their efficacy beyond just lowering LDL levels. This emerging understanding of inflammation's role in atherosclerosis has had significant clinical implications, influencing both risk stratification and therapeutic strategies. ==== Emerging treatments ==== Recent developments in the treatment of atherosclerosis have focused on addressing inflammation directly. New anti-inflammatory drugs,
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such as monoclonal antibodies targeting IL-1β, have been studied in large clinical trials, showing promising results in reducing cardiovascular events. These drugs offer a potential new avenue for treatment, particularly for patients who do not respond adequately to statins. However, concerns about long-term safety and cost remain significant barriers to widespread adoption. ==== Connection to depression ==== Inflammatory processes can be triggered by negative cognition or their consequences, such as stress, violence, or deprivation. Negative cognition may therefore contribute to inflammation, which in turn can lead to depression. A 2019 meta-analysis found that chronic inflammation is associated with a 30% increased risk of developing major depressive disorder, supporting the link between inflammation and mental health. === Allergy === An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is hay fever, which is caused by a hypersensitive response by mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis. === Myopathies === Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis. === Leukocyte defects === Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations,
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digest bacteria (Chédiak–Higashi syndrome), or produce microbicides (chronic granulomatous disease). In addition, diseases affecting the bone marrow may result in abnormal or few leukocytes. === Pharmacological === Certain drugs or exogenous chemical compounds are known to affect inflammation. Vitamin A deficiency, for example, causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatory eicosanoids. Additionally, certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. NF-κB). === Cancer === Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer. Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as NF-κB, may mediate some of the most critical effects of inflammatory stimuli on cancer cells. This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells is very likely to affect carcinogenesis. On the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism. There is some evidence from 2009 to suggest that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells. ==== Role in cancer ==== In 1863, Rudolf Virchow hypothesized that the origin of cancer was at sites of
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chronic inflammation. As of 2012, chronic inflammation was estimated to contribute to approximately 15% to 25% of human cancers. ==== Mediators and DNA damage in cancer ==== An inflammatory mediator is a messenger that acts on blood vessels and/or cells to promote an inflammatory response. Inflammatory mediators that contribute to neoplasia include prostaglandins, inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-15 and chemokines such as IL-8 and GRO-alpha. These inflammatory mediators, and others, orchestrate an environment that fosters proliferation and survival. Inflammation also causes DNA damages due to the induction of reactive oxygen species (ROS) by various intracellular inflammatory mediators. In addition, leukocytes and other phagocytic cells attracted to the site of inflammation induce DNA damages in proliferating cells through their generation of ROS and reactive nitrogen species (RNS). ROS and RNS are normally produced by these cells to fight infection. ROS, alone, cause more than 20 types of DNA damage. Oxidative DNA damages cause both mutations and epigenetic alterations. RNS also cause mutagenic DNA damages. A normal cell may undergo carcinogenesis to become a cancer cell if it is frequently subjected to DNA damage during long periods of chronic inflammation. DNA damages may cause genetic mutations due to inaccurate repair. In addition, mistakes in the DNA repair process may cause epigenetic alterations. Mutations and epigenetic alterations that are replicated and provide a selective advantage during somatic cell proliferation may be carcinogenic. Genome-wide analyses of human cancer tissues reveal that a single typical cancer cell may possess roughly 100 mutations in coding regions, 10–20 of which are "driver mutations" that contribute to cancer development. However, chronic inflammation also causes epigenetic changes such as DNA methylations, that are often more common than mutations. Typically, several hundreds to thousands of genes are methylated in a cancer cell (see DNA methylation in
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cancer). Sites of oxidative damage in chromatin can recruit complexes that contain DNA methyltransferases (DNMTs), a histone deacetylase (SIRT1), and a histone methyltransferase (EZH2), and thus induce DNA methylation. DNA methylation of a CpG island in a promoter region may cause silencing of its downstream gene (see CpG site and regulation of transcription in cancer). DNA repair genes, in particular, are frequently inactivated by methylation in various cancers (see hypermethylation of DNA repair genes in cancer). A 2018 report evaluated the relative importance of mutations and epigenetic alterations in progression to two different types of cancer. This report showed that epigenetic alterations were much more important than mutations in generating gastric cancers (associated with inflammation). However, mutations and epigenetic alterations were of roughly equal importance in generating esophageal squamous cell cancers (associated with tobacco chemicals and acetaldehyde, a product of alcohol metabolism). === HIV and AIDS === It has long been recognized that infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained inflammation and immune activation. A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency. Many now regard HIV infection not only as an evolving virus-induced immunodeficiency, but also as chronic inflammatory disease. Even after the introduction of effective antiretroviral therapy (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: SIVsm infection of its natural nonhuman primate hosts, the sooty mangabey, causes high-level viral replication but limited evidence of disease. This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental SIVsm infection of rhesus macaque produces immune activation and AIDS-like disease with
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many parallels to human HIV infection. Delineating how CD4 T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis—one of the top priorities for HIV research by the Office of AIDS Research, National Institutes of Health. Recent studies demonstrated that caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV. These are the two signature events that propel HIV disease progression to AIDS. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die. The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury. Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflammatory cytokines such as IL-1β and IL-18 can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765, which has already proven to be safe and well tolerated in phase II human clinical trials. These findings could propel development of an entirely new class of "anti-AIDS" therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting "tolerance" of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation. === Resolution === The inflammatory response must be actively terminated
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when no longer needed to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues. Mechanisms that serve to terminate inflammation include: Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. === Connection to depression === There is evidence for a link between inflammation and depression. Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression. In addition, there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode". Classical symptoms of being physically sick, such as lethargy, show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during the depressive episodes of people with bipolar disorder and drop off during remission. Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion
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of subjects positively responding to treatment. Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites. === Connection to delirium === There is evidence for a link between inflammation and delirium based on the results of a recent longitudinal study investigating CRP in COVID-19 patients. == Systemic effects == An infectious organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation, it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system. When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death. === Acute-phase proteins === Inflammation also is characterized by high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial; however, in chronic inflammation, they can contribute to amyloidosis. These proteins include C-reactive protein, serum amyloid A, and serum amyloid P, which cause a range of systemic effects including: === Leukocyte numbers === Inflammation often affects the numbers of leukocytes present in the body: Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in
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the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per microliter, but extreme cases can see it approach 100 000 cells per microliter. Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia. Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers. === Interleukins and obesity === With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems. Chronic inflammation is widely observed in obesity. Obese people commonly have many elevated markers of inflammation, including: IL-6 (Interleukin-6) Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF-α, IL-6, and CRP. Waist circumference correlates significantly with systemic inflammatory response. Loss of white adipose tissue reduces levels of inflammation markers. As of 2017 the association of systemic inflammation with insulin resistance and type 2 diabetes, and with atherosclerosis was under preliminary research, although rigorous clinical trials had not been conducted to confirm such relationships. C-reactive protein (CRP) is generated at a higher level in obese people, and may increase the risk for cardiovascular diseases. == Outcomes == The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred—and the injurious agent that is causing it. Here are the possible outcomes to inflammation: ResolutionThe complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease,
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and damaged parenchymal cells regenerate. Such is usually the outcome when limited or short-lived inflammation has occurred. FibrosisLarge amounts of tissue destruction, or damage in tissues unable to regenerate, cannot be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur. Abscess formationA cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells. Chronic inflammationIn acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release—including reactive oxygen species—are injurious to the organism's own tissues as well as invading agents. As a consequence, chronic inflammation is almost always accompanied by tissue destruction. == Examples == Inflammation is usually indicated by adding the suffix "itis", as shown below. However, some conditions, such as asthma and pneumonia, do not follow this convention. More examples are available at List of types of inflammation. == See also == == Notes == == References == == External links == Inflammation at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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A mode of toxic action is a common set of physiological and behavioral signs that characterize a type of adverse biological response. A mode of action should not be confused with mechanism of action, which refer to the biochemical processes underlying a given mode of action. Modes of toxic action are important, widely used tools in ecotoxicology and aquatic toxicology because they classify toxicants or pollutants according to their type of toxic action. There are two major types of modes of toxic action: non-specific acting toxicants and specific acting toxicants. Non-specific acting toxicants are those that produce narcosis, while specific acting toxicants are those that are non-narcotic and that produce a specific action at a specific target site. == Types == === Non-specific === Non-specific acting modes of toxic action result in narcosis; therefore, narcosis is a mode of toxic action. Narcosis is defined as a generalized depression in biological activity due to the presence of toxicant molecules in the organism. The target site and mechanism of toxic action through which narcosis affects organisms are still unclear, but there are hypotheses that support that it occurs through alterations in the cell membranes at specific sites of the membranes, such as the lipid layers or the proteins bound to the membranes. Even though continuous exposure to a narcotic toxicant can produce death, if the exposure to the toxicant is stopped, narcosis can be reversible. === Specific === Toxicants that at low concentrations modify or inhibit some biological process by binding at a specific site or molecule have a specific acting mode of toxic action. However, at high enough concentrations, toxicants with specific acting modes of toxic actions can produce narcosis that may or may not be reversible. Nevertheless, the specific action of the toxicant is always shown first because it requires
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"page_id": 39392026,
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lower concentrations. There are several specific acting modes of toxic action: Uncouplers of oxidative phosphorylation. Involves toxicants that uncouple the two processes that occur in oxidative phosphorylation: electron transfer and adenosine triphosphate (ATP) production. Acetylcholinesterase (AChE) inhibitors. AChE is an enzyme associated with nerve synapses that it’s designed to regulate nerve impulses by breaking down the neurotransmitter Acetylcholine (ACh). When toxicants bind to AChE, they inhibit the breakdown of ACh. This results in continued nerve impulses across the synapses, which eventually cause nerve system damage. Examples of AChE inhibitors are organophosphates and carbamates, which are components found in pesticides (see Acetylcholinesterase inhibitors). Irritants. These are chemicals that cause an inflammatory effect on living tissue by chemical action at the site of contact. The resulting effect of irritants is an increase in the volume of cells due to a change in size (hypertrophy) or an increase in the number of cells (hyperplasia). Examples of irritants are benzaldehyde, acrolein, zinc sulphate and chlorine. Central nervous system (CNS) seizure agents. CNS seizure agents inhibit cellular signaling by acting as receptor antagonists. They result in the inhibition of biological responses. Examples of CNS seizure agents are organochlorine pesticides. Respiratory blockers. These are toxicants that affect respiration by interfering with the electron transport chain in the mitochondria. Examples of respiratory blockers are rotenone and cyanide. == Determination == The pioneer work of identifying the major categories of modes of toxic action (see description above) was conducted by investigators from the U.S. Environmental Protection Agency (EPA) at the Duluth Laboratory using fish, reason why they named the categories as Fish Acute Toxicity Syndromes (FATS). They proposed the FATS by assessing the behavioral and physiological responses of the fish when subjected to toxicity tests, such as locomotive activities, body color, ventilation patterns, cough rate, heart rate, and
|
{
"page_id": 39392026,
"source": null,
"title": "Modes of toxic action"
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others. It has been proposed that modes of toxic action could be estimated by developing a data set of critical body residues (CBR). The CBR is the whole-body concentration of a chemical that is associated with a given adverse biological response and it is estimated using a partition coefficient and a bioconcentration factor. The whole-body residues are reasonable first approximations of the amount of chemical present at the toxic action site(s). Because different modes of toxic action generally appear to be associated with different ranges of body residues, modes of toxic action can then be separated into categories. However, it is unlikely that every chemical has the same mode of toxic action in every organism, so this variability should be considered. The effects of mixture toxicity should be considered as well, even though mixture toxicity it's generally additive, chemicals with more than one mode of toxic action may contribute to toxicity. Modeling has become a common used tool to predict modes of toxic action in the last decade. The models are based in Quantitative Structure-Activity Relationships (QSARs), which are mathematical models that relate the biological activity of molecules to their chemical structures and corresponding chemical and physicochemical properties. QSARs can then predict modes of toxic action of unknown compounds by comparing its characteristic toxicity profile and chemical structure to reference compounds with known toxicity profiles and chemical structures. Russom and colleagues were one of the first group of researchers being able to classify modes of toxic action with the use of QSARs; they classified 600 chemicals as narcotics. Even though QSARs are a useful tool for predicting modes of toxic action, chemicals having multiple modes of toxic action can obscure QSAR analyses. Therefore, these models are continuously being developed. == Applications == === Environmental risk assessment === The objective of
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"page_id": 39392026,
"source": null,
"title": "Modes of toxic action"
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environmental risk assessment is to protect the environment from adverse effects. Researchers are further developing QSAR models with the ultimate goal providing a clear insight about a mode of toxic action, but also about what the actual target site is, the concentration of the chemical at this target site, and the interaction occurring at the target site, as well as to predict the modes of toxic action in mixtures. Information on the mode of toxic action is crucial not only in understanding joint toxic effects and potential interactions between chemicals in mixtures, but also for developing assays for the evaluation of complex mixtures in the field. === Regulation === The combination of behavioral and physiological responses, CBR estimates, and chemical fate and bioaccumulation QSAR models can be a powerful regulatory tool to address pollution and toxicity in areas where effluents are discharged. == References ==
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{
"page_id": 39392026,
"source": null,
"title": "Modes of toxic action"
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Preplasmiviricota is a phylum of viruses. Its name means "precursor of certain plasmids". == Taxonomy == The phylum contains two subphyla that contain five classes. Subphyla are suffixed with -viricotina, and classes are suffixed with -viricetes. This taxonomy is shown hereafter. Subphylum: Polisuviricotina Aquintoviricetes Pharingeaviricetes Polintoviricetes Virophaviricetes Subphylum: Prepoliviricotina Tectiliviricetes == References ==
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{
"page_id": 63771427,
"source": null,
"title": "Preplasmiviricota"
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DD-Carboxypeptidase may refer to: Muramoylpentapeptide carboxypeptidase, an enzyme Zinc D-Ala-D-Ala carboxypeptidase, an enzyme DD-Transpeptidase, an enzyme
|
{
"page_id": 39260966,
"source": null,
"title": "DD-Carboxypeptidase"
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|
The Human Medicines Regulations 2012 in the United Kingdom were created, under statutory authority of the European Communities Act 1972 and the Medicines Act 1968 in 2012. The body responsible for their upkeep is the Medicines and Healthcare products Regulatory Agency. The regulations partially repealed the Medicines Act 1968 in line with EU legislation. == Amendments == In October 2020, the regulations were amended to expand the workforce eligible to administer COVID-19 vaccines, so enabling additional healthcare professionals to vaccinate the public. This was a temporary provision, but in January 2022 it was announced that this would be made permanent as would the provision for community pharmacy contractors to provide COVID-19 and flu vaccines “away from their normal registered premises”. == Regulation 174 == Regulation 174 provides an exemption to the requirement for authorisation of Regulation 46, allowing for the sale or supply of any medicinal product to be temporarily authorised by the licensing authority (MHRA) in response to the suspected or confirmed spread of pathogenic agents, toxins, chemical agents or nuclear radiation. == References == == External links == Official website
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{
"page_id": 65344295,
"source": null,
"title": "Human Medicines Regulations 2012"
}
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The MacDowell–Mansouri action (named after S. W. MacDowell and Freydoon Mansouri) is an action that is used to derive Einstein's field equations of general relativity. It can usefully be formulated in terms of Cartan geometry. == References == == Further reading == MacDowell, S. W.; Mansouri, F. (1977). "Unified geometric theory of gravity and supergravity". Phys. Rev. Lett. 38 (14): 739–742. Bibcode:1977PhRvL..38..739M. doi:10.1103/PhysRevLett.38.739. "Derek Wise on Cartan Geometry and MacDowell–Mansouri Gravity". The n-Category Café. July 7, 2007. Wise, D. (2010). “MacDowell-Mansouri gravity and Cartan geometry”. Class. Quantum Grav. 27, 155010. Reid, James A.; Wang, Charles H.-T. (2014). "Conformal holonomy in MacDowell-Mansouri gravity". J. Math. Phys. 55, 032501.
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{
"page_id": 14684966,
"source": null,
"title": "MacDowell–Mansouri action"
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A blood culture is a medical laboratory test used to detect bacteria or fungi in a person's blood. Under normal conditions, the blood does not contain microorganisms: their presence can indicate a bloodstream infection such as bacteremia or fungemia, which in severe cases may result in sepsis. By culturing the blood, microbes can be identified and tested for resistance to antimicrobial drugs, which allows clinicians to provide an effective treatment. To perform the test, blood is drawn into bottles containing a liquid formula that enhances microbial growth, called a culture medium. Usually, two containers are collected during one draw, one of which is designed for aerobic organisms that require oxygen, and one of which is for anaerobic organisms, that do not. These two containers are referred to as a set of blood cultures. Two sets of blood cultures are sometimes collected from two different blood draw sites. If an organism only appears in one of the two sets, it is more likely to represent contamination with skin flora than a true bloodstream infection. False negative results can occur if the sample is collected after the person has received antimicrobial drugs or if the bottles are not filled with the recommended amount of blood. Some organisms do not grow well in blood cultures and require special techniques for detection. The containers are placed in an incubator for several days to allow the organisms to multiply. If microbial growth is detected, a Gram stain is conducted from the culture bottle to confirm that organisms are present and provide preliminary information about their identity. The blood is then subcultured, meaning it is streaked onto an agar plate to isolate microbial colonies for full identification and antimicrobial susceptibility testing. Because it is essential that bloodstream infections are diagnosed and treated quickly, rapid testing methods
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{
"page_id": 1250090,
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"title": "Blood culture"
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have been developed using technologies like polymerase chain reaction and MALDI-TOF MS. Procedures for culturing the blood were published as early as the mid-19th century, but these techniques were labour-intensive and bore little resemblance to contemporary methods. Detection of microbial growth involved visual examination of the culture bottles until automated blood culture systems, which monitor gases produced by microbial metabolism, were introduced in the 1970s. In developed countries, manual blood culture methods have largely been made obsolete by automated systems. == Medical uses == Blood is normally sterile. The presence of bacteria in the blood is termed bacteremia, and the presence of fungi is called fungemia. Minor damage to the skin or mucous membranes, which can occur in situations like toothbrushing or defecation, can introduce bacteria into the bloodstream, but this bacteremia is normally transient and is rarely detected in cultures because the immune system and reticuloendothelial system quickly sequester and destroy the organisms. Bacteria can enter the blood from infections such as cellulitis, UTIs and pneumonia; and infections within the vascular system, such as bacterial endocarditis or infections associated with intravenous lines, may result in a constant bacteremia. Fungemia occurs most commonly in people with poorly functioning immune systems. If bacteria or fungi are not cleared from the bloodstream, they can spread to other organs and tissues, or evoke an immune response that leads to a systemic inflammatory condition called sepsis, which can be life-threatening. When sepsis is suspected, it is necessary to draw blood cultures to identify the causative agent and provide targeted antimicrobial therapy. People who are hospitalized and have a fever, a low body temperature, a high white blood cell count or a low count of granulocytes (a category of white blood cells) commonly have cultures drawn to detect a possible bloodstream infection. Blood cultures are
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{
"page_id": 1250090,
"source": null,
"title": "Blood culture"
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used to detect bloodstream infections in febrile neutropenia, a common complication of chemotherapy in which fever occurs alongside a severely low count of neutrophils (white blood cells that defend against bacterial and fungal pathogens). Bacteremia is common in some types of infections, such as meningitis, septic arthritis and epidural abscesses, so blood cultures are indicated in these conditions. In infections less strongly associated with bacteremia, blood culture may still be indicated if the individual is at high risk of acquiring an intravascular infection or if cultures cannot be promptly obtained from the main site of infection (for example, a urine culture in pyelonephritis or a sputum culture in severe community-acquired pneumonia). Blood culture can identify an underlying microbial cause in cases of endocarditis and fever of unknown origin. The pathogens most frequently identified in blood cultures include Staphylococcus aureus, Escherichia coli and other members of the family Enterobacteriaceae, Enterococcus species, Pseudomonas aeruginosa and Candida albicans. Coagulase-negative staphylococci (CNS) are also commonly encountered, although it is often unclear whether these organisms, which constitute part of the normal skin flora, are true pathogens or merely contaminants. In blood cultures taken from newborn babies and children, CNS can indicate significant infections. The epidemiology of bloodstream infections varies with time and place; for instance, Gram-positive organisms overtook Gram-negative organisms as the predominant cause of bacteremia in the United States during the 1980s and 1990s, and rates of fungemia have greatly increased in association with a growing population of people receiving immunosuppressive treatments such as chemotherapy. Gram-negative sepsis is more common in Central and South America, Eastern Europe, and Asia than in North America and Western Europe; and in Africa, Salmonella enterica is a leading cause of bacteremia. == Procedure == === Collection === Blood cultures are typically drawn through venipuncture. Collecting the sample from
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{
"page_id": 1250090,
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"title": "Blood culture"
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an intravenous line is not recommended, as this is associated with higher contamination rates, although cultures may be collected from both venipuncture and an intravenous line to diagnose catheter-associated infections. Prior to the blood draw, the top of each collection bottle is disinfected using an alcohol swab to prevent contamination. The skin around the puncture site is then cleaned and left to dry; some protocols recommend disinfection with an alcohol-based antiseptic followed by either chlorhexidine or an iodine-based preparation, while others consider using only an alcohol-containing antiseptic to be sufficient. If blood must be drawn for other tests at the same time as a blood culture, the culture bottles are drawn first to minimize the risk of contamination. Because antimicrobial therapy can cause false negative results by inhibiting the growth of microbes, it is recommended that blood cultures are drawn before antimicrobial drugs are given, although this may be impractical in people who are critically ill. A typical blood culture collection involves drawing blood into two bottles, which together form one "culture" or "set". One bottle is designed to enhance the growth of aerobic organisms, and the other is designed to grow anaerobic organisms. In children, infection with anaerobic bacteria is uncommon, so a single aerobic bottle may be collected to minimize the amount of blood required. It is recommended that at least two sets are collected from two separate venipuncture locations. This helps to distinguish infection from contamination, as contaminants are less likely to appear in more than one set than true pathogens. Additionally, the collection of larger volumes of blood increases the likelihood that microorganisms will be detected if present. Blood culture bottles contain a growth medium, which encourages microorganisms to multiply, and an anticoagulant that prevents blood from clotting. Sodium polyanethol sulfonate (SPS) is the most commonly
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{
"page_id": 1250090,
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used anticoagulant because it does not interfere with the growth of most organisms. The exact composition of the growth medium varies, but aerobic bottles use a broth that is enriched with nutrients, such as brain-heart infusion or trypticase soy broth, and anaerobic bottles typically contain a reducing agent such as thioglycollate. The empty space in an anaerobic bottle is filled with a gas mixture that does not contain oxygen. Many commercially manufactured bottles contain a resin that absorbs antibiotics to reduce their action on the microorganisms in the sample. Bottles intended for paediatric use are designed to accommodate lower blood volumes and have additives that enhance the growth of pathogens more commonly found in children. Other specialized bottles may be used to detect fungi and mycobacteria. In low and middle income countries, pre-formulated culture bottles can be prohibitively expensive, and it may be necessary to prepare the bottles manually. It can be difficult to access the proper supplies and facilities, and in some regions, it may not be possible to perform blood cultures at all. It is important that the bottles are neither underfilled nor overfilled: underfilling can lead to false negative results as fewer organisms are present in the sample, while overfilling can inhibit microbial growth because the ratio of growth medium to blood is comparatively lower. A 1:10 to 1:5 ratio of blood to culture medium is suggested to optimize microbial growth. For routine blood cultures in adults, the Clinical and Laboratory Standards Institute (CLSI) recommends the collection of two sets of bottles from two different draws, with 20–30 mL of blood drawn in each set. In children, the amount of blood to be drawn is often based on the child's age or weight. If endocarditis is suspected, a total of six bottles may be collected. === Culturing
|
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=== After the blood is collected, the bottles are incubated at body temperature to encourage the growth of microorganisms. Bottles are usually incubated for up to five days in automated systems, although most common bloodstream pathogens are detected within 48 hours. The incubation time may be extended further if manual blood culture methods are used or if slower-growing organisms, such as certain bacteria that cause endocarditis, are suspected. In manual systems, the bottles are visually examined for indicators of microbial growth, which might include cloudiness, the production of gas, the presence of visible microbial colonies, or a change in colour from the digestion of blood, which is called hemolysis. Some manual blood culture systems indicate growth using a compartment that fills with fluid when gases are produced, or a miniature agar plate which is periodically inoculated by tipping the bottle. To ensure that positive blood cultures are not missed, a sample from the bottle is often inoculated onto an agar plate (subcultured) at the end of the incubation period regardless of whether or not indicators of growth are observed. In developed countries, manual culture methods have largely been replaced by automated systems that provide continuous computerized monitoring of the culture bottles. These systems, such as the BACTEC, BacT/ALERT and VersaTrek, consist of an incubator in which the culture bottles are continuously mixed. Growth is detected by sensors that measure the levels of gases inside the bottle—most commonly carbon dioxide—which serve as an indicator of microbial metabolism. An alarm or a visual indicator alerts the microbiologist to the presence of a positive blood culture bottle. If the bottle remains negative at the end of the incubation period, it is generally discarded without being subcultured. A technique called the lysis-centrifugation method can be used for improved isolation of slow-growing or fastidious organisms,
|
{
"page_id": 1250090,
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"title": "Blood culture"
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such as fungi, mycobacteria, and Legionella. Rather than incubating the blood in a bottle filled with growth medium, this method involves collecting blood into a tube containing an agent that destroys (lyses) red and white blood cells, then spinning the sample in a centrifuge. This process concentrates the solid contents of the sample, including microorganisms if present, into a pellet, which is used to inoculate the subculture media. While lysis-centrifugation offers greater sensitivity than conventional blood culture methods, it is prone to contamination because it requires extensive manipulation of the sample. === Identification === If growth is detected, a microbiologist will perform a Gram stain on a sample of blood from the bottle for a rapid preliminary identification of the organism. The Gram stain classifies bacteria as Gram-positive or Gram-negative and provides information about their shape—whether they are rod-shaped (referred to as bacilli), spherical (referred to as cocci), or spiral-shaped (spirochetes)—as well as their arrangement. Gram-positive cocci in clusters, for example, are typical of Staphylococcus species. Yeast and other fungi may also be identified from the Gram stain. A Gram stain identifying microbial growth from a blood culture is considered a critical result and must immediately be reported to the clinician. The Gram stain provides information about the possible identity of the organism, which assists the clinician in the selection of a more appropriate antimicrobial treatment before the full culture and sensitivity results are complete. In traditional methods, the blood is then subcultured onto agar plates to isolate the organism for further testing. The Gram stain results inform microbiologists about what types of agar plates should be used and what tests might be appropriate to identify the organism. In some cases, no organisms are seen on the Gram stain despite the culture bottle showing indicators of growth or being reported
|
{
"page_id": 1250090,
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as positive by automated instruments. This may represent a false positive result, but it is possible that organisms are present but cannot easily be visualized microscopically. Positive bottles with negative Gram stains are subcultured before being returned to the incubator, often using special culture media that promotes the growth of slow-growing organisms. It typically takes 24 to 48 hours for sufficient growth to occur on the subculture plates for definitive identification to be possible. At this point, the microbiologist will assess the appearance of the bacterial or fungal colonies and carry out tests that provide information about the metabolic and biochemical features of the organism, which permit identification to the genus or species level. For example, the catalase test can distinguish streptococci and staphylococci (two genera of Gram-positive cocci) from each other, and the coagulase test can differentiate Staphylococcus aureus, a common culprit of bloodstream infections, from the less pathogenic coagulase-negative staphylococci. Microorganisms may also be identified using automated systems, such as instruments that perform panels of biochemical tests, or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), in which microbial proteins are ionized and characterized on the basis of their mass-to-charge ratios; each microbial species exhibits a characteristic pattern of proteins when analyzed through mass spectrometry. Because bloodstream infections can be life-threatening, timely diagnosis and treatment is critical, and to this end several rapid identification methods have been developed. MALDI-TOF can be used to identify organisms directly from positive blood culture bottles after separation and concentration procedures, or from preliminary growth on the agar plate within a few hours of subculturing. Genetic methods such as polymerase chain reaction (PCR) and microarrays can identify microorganisms by detection of DNA sequences specific to certain species in blood culture samples. Several systems designed for the identification of common blood culture pathogens are
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"page_id": 1250090,
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"title": "Blood culture"
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commercially available. Some biochemical and immunologic tests can be performed directly on positive blood cultures, such as the tube coagulase test for identification of S. aureus or latex agglutination tests for Streptococcus pneumoniae, and unlike PCR and MALDI-TOF, these methods may be practical for laboratories in low and middle income countries. It is also possible to directly inoculate microbial identification panels with blood from a positive culture bottle, although this is not as reliable as testing subcultured bacteria because additives from the growth media can interfere with the results. Even faster diagnosis could be achieved through bypassing culture entirely and detecting pathogens directly from blood samples. A few direct testing systems are commercially available as of 2018, but the technology is still in its infancy. Most panels detect only a limited number of pathogens, and the sensitivity can be poor compared to conventional blood culture methods. Culturing remains necessary in order to carry out full antimicrobial sensitivity testing. === Antibiotic susceptibility testing === Antimicrobial treatment of bloodstream infections is initially empiric, meaning it is based on the clinician's suspicion about the causative agent of the disease and local patterns of antimicrobial resistance. Carrying out antibiotic susceptibility testing (AST) on pathogens isolated from a blood culture allows clinicians to provide a more targeted treatment and to discontinue broad-spectrum antibiotics, which can have undesirable side effects. In traditional AST methods, such as the disk diffusion test, pure colonies of the organism are selected from the subculture plate and used to inoculate a secondary medium. These methods require overnight incubation before results can be obtained. There are automated systems which use pre-formulated antibiotic panels, measure microbial growth automatically, and determine the sensitivity results using algorithms; some of these can provide results in as little as five hours, but others require overnight incubation as
|
{
"page_id": 1250090,
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well. Rapid administration of effective antimicrobial drugs is crucial in the treatment of sepsis, so several methods have been developed to provide faster antibiotic sensitivity results. Conventional AST methods can be carried out on young growth from the subculture plate, pellets of microorganisms obtained from concentration and purification of the positive blood culture, or directly from the culture bottle. Because direct testing methods do not isolate the organisms, they do not provide accurate results if more than one microorganism is present, although this is an infrequent occurrence in blood cultures. Another source of error is the difficulty in standardizing the amount of bacteria in the sample (the inoculum), which has a profound effect on the test results. Genetic testing can be used for rapid detection of certain antimicrobial resistance markers. Methods such as PCR and microarrays, which can be performed directly on positive blood culture samples, detect DNA sequences associated with genes that confer resistance, such as the mecA gene found in methicillin-resistant Staphylococcus aureus or the vanA and vanB genes of vancomycin-resistant enterococci. MALDI-TOF has been explored as a rapid antimicrobial sensitivity testing method; principles involve measuring microbial growth in the presence of antibiotics, identifying the breakdown of antibiotics by microbial enzymes, and detecting protein spectra associated with bacterial strains that exhibit antibiotic resistance. Some of these methods can be performed on pellets from positive blood culture bottles. However, the lack of established methodologies for AST by MALDI-TOF limits its use in clinical practice, and direct AST by MALDI-TOF, unlike genetic testing methods, had not been approved by the Food and Drug Administration as of 2018. == Limitations == Blood cultures are subject to both false positive and false negative errors. In automated culture systems, identification of positive bottles is based on the detection of gases produced by cellular
|
{
"page_id": 1250090,
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metabolism, so samples with high numbers of white blood cells may be reported as positive when no bacteria are present. Inspection of the growth curve produced by the instrument can help to distinguish between true and false positive cultures, but Gram staining and subculturing are still necessary for any sample that is flagged as positive. Blood cultures can become contaminated with microorganisms from the skin or the environment, which multiply inside the culture bottle, giving the false impression that those organisms are present in the blood. Contamination of blood cultures can lead to unnecessary antibiotic treatment and longer hospital stays. The frequency of contamination can be reduced by following established protocols for blood culture collection, but it cannot be eliminated; for instance, bacteria can survive in deeper layers of the skin even after meticulous disinfection of the blood draw site. The CLSI defines an acceptable contamination rate as no greater than 3% of all blood cultures. The frequency of contamination varies widely between institutions and between different departments in the same hospital; studies have found rates ranging from 0.8 to 12.5 percent. When faced with a positive blood culture result, clinicians must decide whether the finding represents contamination or genuine infection. Some organisms, such as S. aureus or Streptococcus pneumoniae, are usually considered to be pathogenic when detected in a blood culture, while others are more likely to represent contamination with skin flora; but even common skin organisms such as coagulase-negative staphylococci can cause bloodstream infections under certain conditions. When such organisms are present, interpretation of the culture result involves taking into account the person's clinical condition and whether or not multiple cultures are positive for the same organism. False negatives may be caused by drawing blood cultures after the person has received antibiotics or collecting an insufficient amount of
|
{
"page_id": 1250090,
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blood. The volume of blood drawn is considered the most important variable in ensuring that pathogens are detected: the more blood that is collected, the more pathogens are recovered. However, if the amount of blood collected far exceeds the recommended volume, bacterial growth may be inhibited by natural inhibitors present in the blood and an inadequate amount of growth medium in the bottle. Over-filling of blood culture bottles may also contribute to iatrogenic anemia. Not all pathogens are easily detected by conventional blood culture methods. Particularly fastidious organisms, such as Brucella and Mycobacterium species, may require prolonged incubation times or special culture media. Some organisms are exceedingly difficult to culture or do not grow in culture at all, so serology testing or molecular methods such as PCR are preferred if infection with these organisms is suspected. == History == Early blood culture methods were labour-intensive. One of the first known procedures, published in 1869, recommended that leeches be used to collect blood from the patient. A microbiology textbook from 1911 noted that decontamination of the draw site and equipment could take over an hour, and that due to a lack of effective methods for preserving blood, the cultures would sometimes have to be prepared at the patient's bedside. In addition to subculturing the broth, some protocols specified that the blood be mixed with melted agar and the mixture poured into a petri dish. In 1915, a blood culture collection system consisting of glass vacuum tubes containing glucose broth and an anticoagulant was described. Robert James Valentine Pulvertaft published a seminal work on blood cultures in 1930, specifying—among other insights—an optimal blood-to-broth ratio of 1:5, which is still accepted today. The use of SPS as an anticoagulant and preservative was introduced in the 1930s and 40s and resolved some of the
|
{
"page_id": 1250090,
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logistical issues with earlier methods. From the 1940s through the 1980s, a great deal of research was carried out on broth formulations and additives, with the goal of creating a growth medium that could accommodate all common bloodstream pathogens. In 1947, M.R. Castañeda invented a "biphasic" culture bottle for the identification of Brucella species, which contained both broth and an agar slant, allowing the agar to be easily subcultured from the broth; this was a precursor of some contemporary systems for manual blood cultures. E.G. Scott in 1951 published a protocol described as "the advent of the modern blood culture set". Scott's method involved inoculating blood into two rubber-sealed glass bottles; one for aerobes and one for anaerobes. The aerobic bottle contained trypticase soy broth and an agar slant, and the anaerobic bottle contained thioglycollate broth. The lysis-centrifugation method was introduced in 1917 by Mildred Clough, but it was rarely used in clinical practice until commercial systems were developed in the mid-1970s. Automated blood culture systems first became available in the 1970s. The earliest of these—the BACTEC systems, produced by Johnston Laboratories (now Becton Dickinson)—used culture broths containing nutrients labelled with radioactive isotopes. Microbes that fed on these substrates would produce radioactive carbon dioxide, and growth could be detected by monitoring its concentration. Before this technique was applied to blood cultures, it had been proposed by NASA as a method for detecting life on Mars. Throughout the 1970s and 80s several manufacturers attempted to detect microbial growth by measuring changes in the electrical conductivity of the culture medium, but none of these methods were commercially successful. A major issue with the early BACTEC systems was that they produced radioactive waste, which required special disposal procedures, so in 1984 a new generation of BACTEC instruments was released that used spectrophotometry to
|
{
"page_id": 1250090,
"source": null,
"title": "Blood culture"
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detect CO2. The BacT/ALERT system, which indirectly detects production of CO2 by measuring the decrease in the medium's pH, was approved for use in the US in 1991. Unlike the BACTEC systems available at the time, the BacT/ALERT did not require a needle to be introduced into the bottle for sampling; this reduced the frequency of contamination and made it the first system to provide truly continuous monitoring of blood cultures. This non-invasive measurement method was adopted in 1992 by the BACTEC 9000 series, which used fluorescent indicators to detect pH changes. The Difco ESP, a direct predecessor of the contemporary VersaTREK system which detects gas production by measuring pressure changes, was also first approved in 1992. By 1996, an international study found that 55% of 466 laboratories surveyed were using the BACTEC or BacT/ALERT systems, with other automated systems accounting for 10% of the total. == Notes == == References == === Bibliography ===
|
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"page_id": 1250090,
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"title": "Blood culture"
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Autopoiesis and Cognition: The Realization of the Living is a cybernetic work in systems theory and the philosophy of biology by Humberto Maturana and Francisco Varela. It was first published under the title De Maquinas y Seres Vivos (English: 'On Machines and Living Beings') in 1972 in Chile by Editorial Universitaria S.A., with a second edition published in 1980 by the D. Reidel Publishing Company, Dordrecht, Holland, and a third edition published in 1991 by Springer. This work defines and explores the concept of autopoiesis, or 'self-creation' in biological systems in an effort to address cognition and autonomy in living systems. Autopoiesis was a core text for the field of second-order cybernetics, which often dealt with themes of self-reference and feedback loops. The book is the 42nd volume in the series Boston Studies in the Philosophy of Science. == Reception == Autopoiesis and Cognition was most widely read as a work of systems theory. Reviews of the work praise it as an effort by scientists to bring their science to bear while crafting a phenomenology of biology, and addressing such important questions as the basis of life and cognition. However, reviewers also point out inconsistencies in the formal argument that Maturana and Varela are attempting to make. Reviewer M.G. writes in The Review of Metaphysics (v. 35, 1981),It seems to me that the authors' claim to be able to say what is cognition by means of a biological cognition collapses on itself. The notion of autopoiesis defines a phenomenological domain which then excludes all descriptions irrelevant to the autopoietic unity. This is a patent circularity.The concepts introduced by the work were quite divisive, and a debate over their validity has continued since their introduction, in fields such as biology, sociology, organizational management, and systems theory. == Influence == === Sociology
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"title": "Autopoiesis and Cognition: The Realization of the Living"
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=== Sociologist and social systems theorist Niklas Luhmann adapted the ideas from Autopoiesis to describe social systems, as did cyberneticist Stafford Beer. === Biology === The influence of Autopoiesis in mainstream biology was limited. Autopoiesis is not commonly used as the criterion for life. However, its basic principles are seen as features of the functions of biological organisms. Sir Paul Nurse, for example states 'living entities ... construct their own metabolism, and use it to maintain themselves, grow, and reproduce'. == References ==
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Trophoblast glycoprotein, also known as TPBG, 5T4, Wnt-Activated Inhibitory Factor 1 or WAIF1, is a human protein encoded by a TPBG gene. TPBG is an antagonist of Wnt/β-catenin signalling pathway. == Clinical significance == 5T4 is an antigen expressed in a number of carcinomas. It is an N-glycosylated transmembrane 72 kDa glycoprotein containing eight leucine-rich repeats. 5T4 is often referred to as an oncofetal antigen due to its expression in foetal trophoblast (where it was first discovered) or trophoblast glycoprotein (TPBG). 5T4 is found in tumors including the colorectal, ovarian, and gastric. Its expression is used as a prognostic aid in these cases. It has very limited expression in normal tissue but is widespread in malignant tumours throughout their development. One study found that 5T4 was present in 85% of a cohort of 72 colorectal carcinomas and in 81% of a cohort of 27 gastric carcinomas. Its confined expression appears to give 5T4 the potential to be a target for T cells in cancer immunotherapy. There has been extensive research into its role in antibody-directed immunotherapy through the use of the high-affinity murine monoclonal antibody, mAb5T4, to deliver response modifiers (such as staphylococcus aureus superantigen) accurately to a tumor. 5T4 is also the target of the cancer vaccine TroVax which is in clinical trials for the treatment of a range of different solid tumour types. == Interactions == TPBG has been shown to interact with GIPC1. == References == == Further reading ==
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Mercury is a chemical element; it has symbol Hg and atomic number 80. It is commonly known as quicksilver. A heavy, silvery d-block element, mercury is the only metallic element that is known to be liquid at standard temperature and pressure; the only other element that is liquid under these conditions is the halogen bromine, though metals such as caesium, gallium, and rubidium melt just above room temperature. Mercury occurs in deposits throughout the world mostly as cinnabar (mercuric sulfide). The red pigment vermilion is obtained by grinding natural cinnabar or synthetic mercuric sulfide. Exposure to mercury and mercury-containing organic compounds is toxic to the nervous system, immune system and kidneys of humans and other animals; mercury poisoning can result from exposure to water-soluble forms of mercury (such as mercuric chloride or methylmercury) either directly or through mechanisms of biomagnification. Mercury is used in thermometers, barometers, manometers, sphygmomanometers, float valves, mercury switches, mercury relays, fluorescent lamps and other devices, although concerns about the element's toxicity have led to the phasing out of such mercury-containing instruments. It remains in use in scientific research applications and in amalgam for dental restoration in some locales. It is also used in fluorescent lighting. Electricity passed through mercury vapor in a fluorescent lamp produces short-wave ultraviolet light, which then causes the phosphor in the tube to fluoresce, making visible light. == Properties == === Physical properties === Mercury is a heavy, silvery-white metal that is liquid at room temperature. Compared to other metals, it is a poor conductor of heat, but a fair conductor of electricity. It has a melting point of −38.83 °C and a boiling point of 356.73 °C, both the lowest of any stable metal, although preliminary experiments on copernicium and flerovium have indicated that they have even lower boiling points. This
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effect is due to lanthanide contraction and relativistic contraction reducing the orbit radius of the outermost electrons, and thus weakening the metallic bonding in mercury. Upon freezing, the volume of mercury decreases by 3.59% and its density changes from 13.69 g/cm3 when liquid to 14.184 g/cm3 when solid. The coefficient of volume expansion is 181.59 × 10−6 at 0 °C, 181.71 × 10−6 at 20 °C and 182.50 × 10−6 at 100 °C (per °C). Solid mercury is malleable and ductile, and can be cut with a knife. Table of thermal and physical properties of liquid mercury: === Chemical properties === Mercury does not react with most acids, such as dilute sulfuric acid, although oxidizing acids such as concentrated sulfuric acid and nitric acid or aqua regia dissolve it to give sulfate, nitrate, and chloride. Like silver, mercury reacts with atmospheric hydrogen sulfide. Mercury reacts with solid sulfur flakes, which are used in mercury spill kits to absorb mercury (spill kits also use activated carbon and powdered zinc). ==== Amalgams ==== Mercury dissolves many metals such as gold and silver to form amalgams. Iron is an exception, and iron flasks have traditionally been used to transport the material. Several other first row transition metals with the exception of manganese, copper and zinc are also resistant in forming amalgams. Other elements that do not readily form amalgams with mercury include platinum. Sodium amalgam is a common reducing agent in organic synthesis, and is also used in high-pressure sodium lamps. Mercury readily combines with aluminium to form a mercury-aluminium amalgam when the two pure metals come into contact. Since the amalgam destroys the aluminium oxide layer which protects metallic aluminium from oxidizing in-depth (as in iron rusting), even small amounts of mercury can seriously corrode aluminium. For this reason, mercury is not
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allowed aboard an aircraft under most circumstances because of the risk of it forming an amalgam with exposed aluminium parts in the aircraft. Mercury embrittlement is the most common type of liquid metal embrittlement, as mercury is a natural component of some hydrocarbon reservoirs and will come into contact with petroleum processing equipment under normal conditions. === Isotopes === There are seven stable isotopes of mercury, with 202Hg being the most abundant (29.86%). The longest-lived radioisotopes are 194Hg with a half-life of 444 years, and 203Hg with a half-life of 46.612 days. Most of the remaining radioisotopes have half-lives that are less than a day. 206Hg occurs naturally in tiny traces as an intermediate decay product of 238U. 199Hg and 201Hg are the most often studied NMR-active nuclei, having spins of 1⁄2 and 3⁄2 respectively. == Etymology == Hg is the modern chemical symbol for mercury. It is an abbreviation of hydrargyrum, a romanized form of the ancient Greek name for mercury, ὑδράργυρος (hydrargyros). Hydrargyrum ( hy-DRAR-jər-əm) has also been used in English, though the term is now dated. Hydrargyros is a Greek compound word meaning 'water-silver', from ὑδρ- (hydr-), the root of ὕδωρ (hydor) 'water', and ἄργυρος (argyros) 'silver'. Like the English name quicksilver ('living-silver'), this name was due to mercury's liquid and shiny properties. The modern English name mercury comes from the planet Mercury. In medieval alchemy, the seven known metals—quicksilver, gold, silver, copper, iron, lead, and tin—were associated with the seven planets. Quicksilver was associated with the fastest planet, which had been named after the Roman god Mercury, who was associated with speed and mobility. The astrological symbol for the planet became one of the alchemical symbols for the metal, and Mercury became an alternative name for the metal. Mercury is the only metal for which the
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alchemical planetary name survives, as it was decided it was preferable to quicksilver as a chemical name. == History == Mercury was found in Egyptian tombs that date from 1500 BC; cinnabar, the most common natural source of mercury, has been in use since the Neolithic Age. In China and Tibet, mercury use was thought to prolong life, heal fractures, and maintain generally good health, although it is now known that exposure to mercury vapor leads to serious adverse health effects. The first emperor of a unified China, Qín Shǐ Huáng Dì—allegedly buried in a tomb that contained rivers of flowing mercury on a model of the land he ruled, representative of the rivers of China—was reportedly killed by drinking a mercury and powdered jade mixture formulated by Qin alchemists intended as an elixir of immortality. Khumarawayh ibn Ahmad ibn Tulun, the second Tulunid ruler of Egypt (r. 884–896), known for his extravagance and profligacy, reportedly built a basin filled with mercury, on which he would lie on top of air-filled cushions and be rocked to sleep. In November 2014 "large quantities" of mercury were discovered in a chamber 60 feet below the 1800-year-old pyramid known as the Temple of the Feathered Serpent, the third-largest pyramid of Teotihuacan, Mexico, along with "jade statues, jaguar remains, a box filled with carved shells and rubber balls". In Lamanai, once a major city of the Maya civilization, a pool of mercury was found under a marker in a Mesoamerican ballcourt. Aristotle recounts that Daedalus made a wooden statue of Aphrodite move by pouring quicksilver in its interior. In Greek mythology Daedalus gave the appearance of voice in his statues using quicksilver. The ancient Greeks used cinnabar (mercury sulfide) in ointments; the ancient Egyptians and the Romans used it in cosmetics. By 500 BC
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mercury was used to make amalgams (Medieval Latin amalgama, "alloy of mercury") with other metals. Alchemists thought of mercury as the First Matter from which all metals were formed. They believed that different metals could be produced by varying the quality and quantity of sulfur contained within the mercury. The purest of these was gold, and mercury was called for in attempts at the transmutation of base (or impure) metals into gold, which was the goal of many alchemists. The mines in Almadén (Spain), Monte Amiata (Italy), and Idrija (now Slovenia) dominated mercury production from the opening of the mine in Almadén 2500 years ago, until new deposits were found at the end of the 19th century. Beginning in 1558, with the invention of the patio process to extract silver from ore using mercury, mercury became an essential resource in the economy of Spain and its American colonies. Mercury was used to extract silver from the lucrative mines in New Spain and Peru. Initially, the Spanish Crown's mines in Almadén in Southern Spain supplied all the mercury for the colonies. Mercury deposits were discovered in the New World, and more than 100,000 tons of mercury were mined from the region of Huancavelica, Peru, over the course of three centuries following the discovery of deposits there in 1563. In 1786 the main mine at Huancavelica suffered a sudden collapse that killed over 100 persons and greatly reduced the mine's output. Through the legalization of scavanging known as pallaqueo mercury production rose again peaking in 1794–1796. The French Revolutionary Wars disrupted European mercury supply to Spanish America leading to an increasing reliance for the mines in present-day Peru and Bolivia on mercury from Huancavelica but this mines production was clearly by 1799 not enough to supply the demand in the Andean mines.
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Spain abolished the royal mercury monopoly in 1813. Mercury poisoning in the mines left many people disabled through the early modern period but mercury itself was not the chief cause of deaths in the mines. The patio process and later pan amalgamation process continued to create great demand for mercury to treat silver ores until the late 19th century. == Occurrence == Mercury is an extremely rare element in Earth's crust; it has an average crustal abundance by mass of only 0.08 parts per million (ppm) and is the 66th most abundant element in the Earth's crust. Because it does not blend geochemically with those elements that constitute the majority of the crustal mass, mercury ores can be extraordinarily concentrated considering the element's abundance in ordinary rock. The richest mercury ores contain up to 2.5% mercury by mass, and even the leanest concentrated deposits are at least 0.1% mercury (12,000 times average crustal abundance). It is found either as a native metal (rare) or in cinnabar, metacinnabar, sphalerite, corderoite, livingstonite and other minerals, with cinnabar (HgS) being the most common ore. Mercury ores often occur in hot springs or other volcanic regions. Former mines in Italy, the United States and Mexico, which once produced a large proportion of the world supply, have now been completely mined out or, in the case of Slovenia (Idrija) and Spain (Almadén), shut down due to the fall of the price of mercury. Nevada's McDermitt Mine, the last mercury mine in the United States, closed in 1992. The price of mercury has been highly volatile over the years and in 2006 was $650 per 76-pound (34.46 kg) flask. Mercury is extracted by heating cinnabar in a current of air and condensing the vapor. The equation for this extraction is: HgS + O2 → Hg +
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SO2 In 2020, China was the top producer of mercury, providing 88% of the world output (2200 out of 2500 tonnes), followed by Tajikistan (178 t), Russia (50 t) and Mexico (32 t). Because of the high toxicity of mercury, both the mining of cinnabar and refining for mercury are hazardous and historic causes of mercury poisoning. In China, prison labor was used by a private mining company as recently as the 1950s to develop new cinnabar mines. Thousands of prisoners were used by the Luo Xi mining company to establish new tunnels. Worker health in functioning mines is at high risk. A newspaper claimed that an unidentified European Union directive calling for energy-efficient lightbulbs to be made mandatory by 2012 encouraged China to re-open cinnabar mines to obtain the mercury required for CFL bulb manufacture. Environmental dangers have been a concern, particularly in the southern cities of Foshan and Guangzhou, and in Guizhou province in the southwest. Abandoned mercury mine processing sites often contain very hazardous waste piles of roasted cinnabar calcines. Water run-off from such sites is a recognized source of ecological damage. Former mercury mines may be suited for constructive re-use; for example, in 1976 Santa Clara County, California purchased the historic Almaden Quicksilver Mine and created a county park on the site, after conducting extensive safety and environmental analysis of the property. == Chemistry == All known mercury compounds exhibit one of two positive oxidation states: I and II. Experiments have failed to unequivocally demonstrate any higher oxidation states: both the claimed 1976 electrosynthesis of an unstable Hg(III) species and 2007 cryogenic isolation of HgF4 have disputed interpretations and remain difficult (if not impossible) to reproduce. === Compounds of mercury(I) === Unlike its lighter neighbors, cadmium and zinc, mercury usually forms simple stable compounds with metal-metal
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bonds. Most mercury(I) compounds are diamagnetic and feature the dimeric cation, Hg2+2. Stable derivatives include the chloride and nitrate. In aqueous solution of a mercury(I) salt, slight disproportion of Hg2+2 into Hg and Hg2+ results in >0.5% of dissolved mercury existing as Hg2+. In these solutions, complexation of the Hg2+ with addition of ligands such as cyanide causes disproportionation to go to completion, with all Hg2+2 precipitating as elemental mercury and insoluble mercury(II) compounds (e.g. mercury(II) cyanide if cyanide is used as the ligand). Mercury(I) chloride, a colorless solid also known as calomel, is really the compound with the formula Hg2Cl2, with the connectivity Cl-Hg-Hg-Cl. It reacts with chlorine to give mercury(II) chloride, which resists further oxidation. Mercury(I) hydride, a colorless gas, has the formula HgH, containing no Hg-Hg bond; however, the gas has only ever been observed as isolated molecules. Indicative of its tendency to bond to itself, mercury forms mercury polycations, which consist of linear chains of mercury centers, capped with a positive charge. One example is Hg3(AsF6)2 containing the Hg2+3 cation. === Compounds of mercury(II) === Mercury(II) is the most common oxidation state and is the main one in nature as well. All four mercuric halides are known and have been demonstrated to form linear coordination geometry, despite mercury's tendency to form tetrahedral molecular geometry with other ligands. This behavior is similar to the Ag+ ion. The best known mercury halide is mercury(II) chloride, an easily sublimating white solid. Mercury(II) oxide, the main oxide of mercury, arises when the metal is exposed to air for long periods at elevated temperatures. It reverts to the elements upon heating near 400 °C, as was demonstrated by Joseph Priestley in an early synthesis of pure oxygen. Hydroxides of mercury are poorly characterized, as attempted isolation studies of mercury(II) hydroxide have
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yielded mercury oxide instead. Being a soft metal, mercury forms very stable derivatives with the heavier chalcogens. Preeminent is mercury(II) sulfide, HgS, which occurs in nature as the ore cinnabar and is the brilliant pigment vermilion. Like ZnS, HgS crystallizes in two forms, the reddish cubic form and the black zinc blende form. The latter sometimes occurs naturally as metacinnabar. Mercury(II) selenide (HgSe) and mercury(II) telluride (HgTe) are known, these as well as various derivatives, e.g. mercury cadmium telluride and mercury zinc telluride being semiconductors useful as infrared detector materials. Mercury(II) salts form a variety of complex derivatives with ammonia. These include Millon's base (Hg2N+), the one-dimensional polymer (salts of HgNH+2)n), and "fusible white precipitate" or [Hg(NH3)2]Cl2. Known as Nessler's reagent, potassium tetraiodomercurate(II) (K2HgI4) is still occasionally used to test for ammonia owing to its tendency to form the deeply colored iodide salt of Millon's base. Mercury fulminate is a detonator widely used in explosives. === Organomercury compounds === Organic mercury compounds are historically important but are of little industrial value in the western world. Mercury(II) salts are a rare example of simple metal complexes that react directly with aromatic rings. Organomercury compounds are always divalent and usually two-coordinate and linear geometry. Unlike organocadmium and organozinc compounds, organomercury compounds do not react with water. They usually have the formula HgR2, which are often volatile, or HgRX, which are often solids, where R is aryl or alkyl and X is usually halide or acetate. Methylmercury, a generic term for compounds with the formula CH3HgX, is a dangerous family of compounds that are often found in polluted water. They arise by a process known as biomethylation. == Applications == Mercury is used primarily for the manufacture of industrial chemicals or for electrical and electronic applications. It is used in some liquid-in-glass thermometers,
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especially those used to measure high temperatures. A still increasing amount is used as gaseous mercury in fluorescent lamps, while most of the other applications are slowly being phased out due to health and safety regulations. In some applications, mercury is replaced with less toxic but considerably more expensive Galinstan alloy. === Medicine === ==== Historical and folk ==== Mercury and its compounds have been used in medicine, although they are much less common today than they once were, now that the toxic effects of mercury and its compounds are more widely understood. An example of the early therapeutic application of mercury was published in 1787 by James Lind. The first edition of The Merck Manuals (1899) featured many then-medically relevant mercuric compounds, such as mercury-ammonium chloride, yellow mercury proto-iodide, calomel, and mercuric chloride, among others. Mercury in the form of one of its common ores, cinnabar, is used in various traditional medicines, especially in traditional Chinese medicine. Review of its safety has found that cinnabar can lead to significant mercury intoxication when heated, consumed in overdose, or taken long term, and can have adverse effects at therapeutic doses, though effects from therapeutic doses are typically reversible. Although this form of mercury appears to be less toxic than other forms, its use in traditional Chinese medicine has not yet been justified, as the therapeutic basis for the use of cinnabar is not clear. Mercury(I) chloride (also known as calomel or mercurous chloride) has been used in traditional medicine as a diuretic, topical disinfectant, and laxative. Mercury(II) chloride (also known as mercuric chloride or corrosive sublimate) was once used to treat syphilis (along with other mercury compounds), although it is so toxic that sometimes the symptoms of its toxicity were confused with those of the syphilis it was believed to treat.
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It is also used as a disinfectant. Blue mass, a pill or syrup in which mercury is the main ingredient, was prescribed throughout the 19th century for numerous conditions including constipation, depression, child-bearing and toothaches. In the early 20th century, mercury was administered to children yearly as a laxative and dewormer, and it was used in teething powders for infants. The mercury-containing organohalide merbromin (sometimes sold as Mercurochrome) is still widely used but has been banned in some countries, such as the U.S. ==== Contemporary ==== Mercury is an ingredient in dental amalgams. Thiomersal (called Thimerosal in the United States) is an organic compound used as a preservative in vaccines, although this use is in decline. Although it was widely speculated that this mercury-based preservative could cause or trigger autism in children, no evidence supports any such link. Nevertheless, thiomersal has been removed from, or reduced to trace amounts in, all U.S. vaccines recommended for children 6 years of age and under, with the exception of the inactivated influenza vaccine. Merbromin (Mercurochrome), another mercury compound, is a topical antiseptic used for minor cuts and scrapes in some countries. Today, the use of mercury in medicine has greatly declined in all respects, especially in developed countries. Mercury is still used in some diuretics, although substitutes such as thiazides now exist for most therapeutic uses. In 2003, mercury compounds were found in some over-the-counter drugs, including topical antiseptics, stimulant laxatives, diaper-rash ointment, eye drops, and nasal sprays. The FDA has "inadequate data to establish general recognition of the safety and effectiveness" of the mercury ingredients in these products. === Production of chlorine and caustic soda === Chlorine is produced from sodium chloride (common salt, NaCl) using electrolysis to separate metallic sodium from chlorine gas. Usually salt is dissolved in water to produce
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a brine. By-products of any such chloralkali process are hydrogen (H2) and sodium hydroxide (NaOH), which is commonly called caustic soda or lye. By far the largest use of mercury in the late 20th century was in the mercury cell process (also called the Castner-Kellner process) where metallic sodium is formed as an amalgam at a cathode made from mercury; this sodium is then reacted with water to produce sodium hydroxide. Many of the industrial mercury releases of the 20th century came from this process, although modern plants claim to be safe in this regard. From the 1960s onward, the majority of industrial plants moved away from mercury cell processes towards diaphragm cell technologies to produce chlorine, though 11% of the chlorine made in the United States was still produced with the mercury cell method as of 2005. === Laboratory uses === ==== Thermometers ==== Thermometers containing mercury were invented in the early 18th century by Daniel Gabriel Fahrenheit, though earlier attempts at making temperature-measuring instruments filled with quicksilver had been described in the 1650s.: 23 Fahrenheit's mercury thermometer was based on an earlier design that used alcohol rather than mercury; the mercury thermometer was significantly more accurate than those using alcohol. From the early 21st century onwards, the use of mercury thermometers has been declining, and mercury-containing instruments have been banned in many jurisdictions following the 1998 Protocol on Heavy Metals. Modern alternatives to mercury thermometers include resistance thermometers, thermocouples, and thermistor sensors that output to a digital display. ==== Mirrors ==== Some transit telescopes use a basin of mercury to form a flat and absolutely horizontal mirror, useful in determining an absolute vertical or perpendicular reference. Concave horizontal parabolic mirrors may be formed by rotating liquid mercury on a disk, the parabolic form of the liquid thus formed
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reflecting and focusing incident light. Such liquid-mirror telescopes are cheaper than conventional large mirror telescopes by up to a factor of 100, but the mirror cannot be tilted and always points straight up. ==== Electrochemistry ==== Liquid mercury is part of a popular secondary reference electrode (called the calomel electrode) in electrochemistry as an alternative to the standard hydrogen electrode. The calomel electrode is used to work out the electrode potential of half cells. The triple point of mercury, −38.8344 °C, is a fixed point used as a temperature standard for the International Temperature Scale (ITS-90). ==== Polarography and crystallography ==== In polarography, both the dropping mercury electrode and the hanging mercury drop electrode use elemental mercury. This use allows a new uncontaminated electrode to be available for each measurement or each new experiment. Mercury-containing compounds are also of use in the field of structural biology. Mercuric compounds such as mercury(II) chloride or potassium tetraiodomercurate(II) can be added to protein crystals in an effort to create heavy atom derivatives that can be used to solve the phase problem in X-ray crystallography via isomorphous replacement or anomalous scattering methods. === Niche uses === Gaseous mercury is used in mercury-vapor lamps and some "neon sign" type advertising signs and fluorescent lamps. Those low-pressure lamps emit very spectrally narrow lines, which are traditionally used in optical spectroscopy for calibration of spectral position. Commercial calibration lamps are sold for this purpose; reflecting a fluorescent ceiling light into a spectrometer is a common calibration practice. Gaseous mercury is also found in some electron tubes, including ignitrons, thyratrons, and mercury arc rectifiers. It is also used in specialist medical care lamps for skin tanning and disinfection. Gaseous mercury is added to cold cathode argon-filled lamps to increase the ionization and electrical conductivity. An argon-filled lamp without
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mercury will have dull spots and will fail to light correctly. Lighting containing mercury can be bombarded/oven pumped only once. When added to neon filled tubes, inconsistent red and blue spots are produced in the light emissions until the initial burning-in process is completed; eventually it will light a consistent dull off-blue color. The Deep Space Atomic Clock (DSAC) under development by the Jet Propulsion Laboratory utilises mercury in a linear ion-trap-based clock. The novel use of mercury permits the creation of compact atomic clocks with low energy requirements ideal for space probes and Mars missions. ==== Skin whitening ==== Mercury is effective as an active ingredient in skin whitening compounds used to depigment skin. The Minamata Convention on Mercury limits the concentration of mercury in such whiteners to 1 part per million. However, as of 2022, many commercially sold whitener products continue to exceed that limit, and are considered toxic. === Firearms === Mercury(II) fulminate is a primary explosive, which has mainly been used as a primer of a cartridge in firearms throughout the 19th and 20th centuries. === Mining === Mercury is used in illegal gold mining to help separate gold particles from a mixture of sand or gravel and water. Small gold particles may form mercury-gold amalgam and therefore increase the gold recovery rates. The use of mercury causes a severe pollution problem in places such as Ghana. === Historic uses === Many historic applications made use of the peculiar physical properties of mercury, especially as a dense liquid and a liquid metal: Quantities of liquid mercury ranging from 90 to 600 grams (3.2 to 21.2 oz) have been recovered from elite Maya tombs (100–700 AD) or ritual caches at six sites. This mercury may have been used in bowls as mirrors for divinatory purposes. Five of
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these date to the Classic Period of Maya civilization (c. 250–900) but one example predated this. In Islamic Spain, it was used for filling decorative pools. Later, the American artist Alexander Calder built a mercury fountain for the Spanish Pavilion at the 1937 World Exhibition in Paris. The fountain is now on display at the Fundació Joan Miró in Barcelona. The Fresnel lenses of old lighthouses used to float and rotate in a bath of mercury which acted like a bearing. Mercury sphygmomanometers, barometers, diffusion pumps, coulometers, and many other laboratory instruments took advantage of mercury's properties as a very dense, opaque liquid with a nearly linear thermal expansion. As an electrically conductive liquid, it was used in mercury switches (including home mercury light switches installed prior to 1970), tilt switches used in old fire detectors and in some home thermostats. Owing to its acoustic properties, mercury was used as the propagation medium in delay-line memory devices used in early digital computers of the mid-20th century, such as the SEAC computer. In 1911, Heike Kamerlingh Onnes discovered superconductivity through the cooling of mercury below 4 kelvin shortly after the discovery and production of liquid helium. Its superconductive properties were later determined to be unusual compared to other later-discovered superconductors, such as the more popular niobium alloys. Experimental mercury vapor turbines were installed to increase the efficiency of fossil-fuel electrical power plants. The South Meadow power plant in Hartford, CT employed mercury as its working fluid, in a binary configuration with a secondary water circuit, for a number of years starting in the late 1920s in a drive to improve plant efficiency. Several other plants were built, including the Schiller Station in Portsmouth, NH, which went online in 1950. The idea did not catch on industry-wide due to the weight and
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toxicity of mercury, as well as the advent of supercritical steam plants in later years. Similarly, liquid mercury was used as a coolant for some nuclear reactors; however, sodium is proposed for reactors cooled with liquid metal, because the high density of mercury requires much more energy to circulate as coolant. Mercury was a propellant for early ion engines in electric space propulsion systems. Advantages were mercury's high molecular weight, low ionization energy, low dual-ionization energy, high liquid density and liquid storability at room temperature. Disadvantages were concerns regarding environmental impact associated with ground testing and concerns about eventual cooling and condensation of some of the propellant on the spacecraft in long-duration operations. The first spaceflight to use electric propulsion was a mercury-fueled ion thruster developed at NASA Glenn Research Center and flown on the Space Electric Rocket Test "SERT-1" spacecraft launched by NASA at its Wallops Flight Facility in 1964. The SERT-1 flight was followed up by the SERT-2 flight in 1970. Mercury and caesium were preferred propellants for ion engines until Hughes Research Laboratory performed studies finding xenon gas to be a suitable replacement. Xenon is now the preferred propellant for ion engines, as it has a high molecular weight, little or no reactivity due to its noble gas nature, and high liquid density under mild cryogenic storage. Other applications made use of the chemical properties of mercury: The mercury battery is a non-rechargeable electrochemical battery, a primary cell, that was common in the middle of the 20th century. It was used in a wide variety of applications and was available in various sizes, particularly button sizes. Its constant voltage output and long shelf life gave it a niche use for camera light meters and hearing aids. The mercury cell was effectively banned in most countries in the
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1990s due to concerns about the mercury contaminating landfills. Mercury was used for preserving wood, developing daguerreotypes, silvering mirrors, anti-fouling paints, herbicides, interior latex paint, handheld maze games, cleaning, and road leveling devices in cars. Mercury compounds have been used in antiseptics, laxatives, antidepressants, and in antisyphilitics. Mercury has been replaced with safer compounds in most, if not all, of these applications. It was allegedly used by allied spies to sabotage Luftwaffe planes: a mercury paste was applied to bare aluminium, causing the metal to rapidly corrode; this would cause structural failures. Mercury was once used as a gun barrel bore cleaner. From the mid-18th to the mid-19th centuries, a process called "carroting" was used in the making of felt hats. Animal skins were rinsed in an orange solution (the term "carroting" arose from this color) of the mercury compound mercuric nitrate, Hg(NO3)2. This process separated the fur from the pelt and matted it together. This solution and the vapors it produced were highly toxic. The United States Public Health Service banned the use of mercury in the felt industry in December 1941. The psychological symptoms associated with mercury poisoning inspired the phrase "mad as a hatter". Lewis Carroll's "Mad Hatter" in his book Alice's Adventures in Wonderland was a play on words based on the older phrase, but the character himself does not exhibit symptoms of mercury poisoning. Historically, mercury was used extensively in hydraulic gold mining (see #Mining. Large-scale use of mercury stopped in the 1960s. However, mercury is still used in small scale, often clandestine, gold prospecting. It is estimated that 45,000 metric tons of mercury used in California for placer mining have not been recovered. Mercury was also used in silver mining to extract the metal from ore through the patio process. == Toxicity and safety
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== Due to its physical properties and relative chemical inertness, liquid mercury is absorbed very poorly through intact skin and the gastrointestinal tract. Mercury vapor is the primary hazard of elemental mercury. As a result, containers of mercury are securely sealed to avoid spills and evaporation. Heating of mercury, or of compounds of mercury that may decompose when heated, should be carried out with adequate ventilation in order to minimize exposure to mercury vapor. The most toxic forms of mercury are its organic compounds, such as dimethylmercury and methylmercury. Mercury can cause both chronic and acute poisoning. === Releases in the environment === Preindustrial deposition rates of mercury from the atmosphere may be about 4 ng per 1 L of ice deposited. Volcanic eruptions and related natural sources are responsible for approximately half of atmospheric mercury emissions. Atmospheric mercury contamination in outdoor urban air at the start of the 21st century was measured at 0.01–0.02 μg/m3. A 2001 study measured mercury levels in 12 indoor sites chosen to represent a cross-section of building types, locations and ages in the New York area. This study found mercury concentrations significantly elevated over outdoor concentrations, at a range of 0.0065 – 0.523 μg/m3. The average was 0.069 μg/m3. Half of mercury emissions are attributed to mankind. The sources can be divided into the following estimated percentages: 65% from stationary combustion, of which coal-fired power plants are the largest aggregate source (40% of U.S. mercury emissions in 1999). This includes power plants fueled with gas where the mercury has not been removed. Emissions from coal combustion are between one and two orders of magnitude higher than emissions from oil combustion, depending on the country. 11% from gold production. The three largest point sources for mercury emissions in the U.S. are the three largest gold
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mines. Hydrogeochemical release of mercury from gold-mine tailings has been accounted as a significant source of atmospheric mercury in eastern Canada. 6.8% from non-ferrous metal production, typically smelters. 6.4% from cement production. 3.0% from waste disposal, including municipal and hazardous waste, crematoria, and sewage sludge incineration. 3.0% from caustic soda production. 1.4% from pig iron and steel production. 1.1% from mercury production, mainly for batteries. 2.0% from other sources. The above percentages are estimates of the global human-caused mercury emissions in 2000, excluding biomass burning, an important source in some regions. A serious industrial disaster was the dumping of waste mercury compounds into Minamata Bay, Japan, between 1932 and 1968. It is estimated that over 3,000 people suffered various deformities, severe mercury poisoning symptoms or death from what became known as Minamata disease. China is estimated to produce 50% of mercury emissions, most of which result from production of vinyl chloride. Mercury also enters into the environment through the improper disposal of mercury-containing products. Due to health concerns, toxics use reduction efforts are cutting back or eliminating mercury in such products. For example, the amount of mercury sold in thermostats in the United States decreased from 14.5 tons in 2004 to 3.9 tons in 2007. The tobacco plant readily absorbs and accumulates heavy metals such as mercury from the surrounding soil into its leaves. These are subsequently inhaled during tobacco smoking. While mercury is a constituent of tobacco smoke, studies have largely failed to discover a significant correlation between smoking and mercury uptake by humans compared to sources such as occupational exposure, fish consumption, and amalgam tooth fillings. A less well-known source of mercury is the burning of joss paper, which is a common tradition practiced in Asia, including China, Vietnam, Hong Kong, Thailand, Taiwan and Malaysia. ==== Spill cleanup
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==== Mercury spills pose an immediate threat to people handling the material, in addition to being an environmental hazard if the material is not contained properly. This is of particular concern for visible mercury, or mercury in liquid state, as its unusual appearance and behavior for a metal makes it an attractive nuisance to the uninformed. Procedures have been developed to contain mercury spills, as well as recommendations on appropriate responses based on the conditions of a spill. Tracking liquid mercury away from the site of a spill is a major concern in liquid mercury spills; regulations emphasize containment of the visible mercury as the first course of action, followed by monitoring of mercury vapors and vapor cleanup. Several products are sold as mercury spill adsorbents, ranging from metal salts to polymers and zeolites. === Sediment contamination === Sediments within large urban-industrial estuaries act as an important sink for point source and diffuse mercury pollution within catchments. A 2015 study of foreshore sediments from the Thames estuary measured total mercury at 0.01 to 12.07 mg/kg with mean of 2.10 mg/kg and median of 0.85 mg/kg (n = 351). The highest mercury concentrations were shown to occur in and around the city of London in association with fine grain muds and high total organic carbon content. The strong affinity of mercury for carbon rich sediments has also been observed in salt marsh sediments of the River Mersey, with a mean concentration of 2 mg/kg, up to 5 mg/kg. These concentrations are far higher than those in the salt marsh river creek sediments of New Jersey and mangroves of Southern China, which exhibit low mercury concentrations of about 0.2 mg/kg. === Occupational exposure === Due to the health effects of mercury exposure, industrial and commercial uses are regulated in many countries. The
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World Health Organization, OSHA, and NIOSH all treat mercury as an occupational hazard; both OSHA and NIOSH, among other regulatory agencies, have established specific occupational exposure limits on the element and its derivative compounds in liquid and vapor form. Environmental releases and disposal of mercury are regulated in the U.S. primarily by the United States Environmental Protection Agency. === Fish === Fish and shellfish have a natural tendency to concentrate mercury in their bodies, often in the form of methylmercury, a highly toxic organic compound of mercury. Species of fish that are high on the food chain, such as shark, swordfish, king mackerel, bluefin tuna, albacore tuna, and tilefish contain higher concentrations of mercury than others. Because mercury and methylmercury are fat soluble, they primarily accumulate in the viscera, although they are also found throughout the muscle tissue. Mercury presence in fish muscles can be studied using non-lethal muscle biopsies. Mercury present in prey fish accumulates in the predator that consumes them. Since fish are less efficient at depurating than accumulating methylmercury, methylmercury concentrations in the fish tissue increase over time. Thus species that are high on the food chain amass body burdens of mercury that can be ten times higher than the species they consume. This process is called biomagnification. Mercury poisoning happened this way in Minamata, Japan, now called Minamata disease. In the Lower Amazon, mercury contamination in fish is driven by anthropogenic activities such as gold mining and deforestation, which release mercury into aquatic ecosystems. Studies report mercury concentrations in fish muscle tissue ranging from 0.01 to 0.67 μg/g, with carnivorous species like Plagioscion squamosissimus showing higher levels due to biomagnification, sometimes exceeding the World Health Organization's safety threshold of 0.5 μg/g. Local communities relying on fish as a dietary staple face potential health risks from mercury
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exposure. Mercury levels in aquatic species, including fish and shrimp (Macrobrachium amazonicum), indicate broader environmental contamination, particularly near mining areas. === Cosmetics === Some facial creams contain dangerous levels of mercury. Most contain comparatively non-toxic inorganic mercury, but products containing highly toxic organic mercury have been encountered. New York City residents have been found to be exposed to significant levels of inorganic mercury compounds through the use of skin care products. === Effects and symptoms of mercury poisoning === Toxic effects include damage to the brain, kidneys and lungs. Mercury poisoning can result in several diseases, including acrodynia (pink disease), Hunter-Russell syndrome, and Minamata disease. Symptoms typically include sensory impairment (vision, hearing, speech), disturbed sensation and a lack of coordination. The type and degree of symptoms exhibited depend upon the individual toxin, the dose, and the method and duration of exposure. Case–control studies have shown effects such as tremors, impaired cognitive skills, and sleep disturbance in workers with chronic exposure to mercury vapor even at low concentrations in the range 0.7–42 μg/m3. A study has shown that acute exposure (4–8 hours) to calculated elemental mercury levels of 1.1 to 44 mg/m3 resulted in chest pain, dyspnea, cough, hemoptysis, impairment of pulmonary function, and evidence of interstitial pneumonitis. Acute exposure to mercury vapor has been shown to result in profound central nervous system effects, including psychotic reactions characterized by delirium, hallucinations, and suicidal tendency. Occupational exposure has resulted in broad-ranging functional disturbance, including erethism, irritability, excitability, excessive shyness, and insomnia. With continuing exposure, a fine tremor develops and may escalate to violent muscular spasms. Tremor initially involves the hands and later spreads to the eyelids, lips, and tongue. Long-term, low-level exposure has been associated with more subtle symptoms of erethism, including fatigue, irritability, loss of memory, vivid dreams and depression. ===
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Treatment === Research on the treatment of mercury poisoning is limited. Currently available drugs for acute mercurial poisoning include chelators N-acetyl-D,L-penicillamine (NAP), British Anti-Lewisite (BAL), 2,3-dimercapto-1-propanesulfonic acid (DMPS), and dimercaptosuccinic acid (DMSA). In one small study including 11 construction workers exposed to elemental mercury, patients were treated with DMSA and NAP. Chelation therapy with both drugs resulted in the mobilization of a small fraction of the total estimated body mercury. DMSA was able to increase the excretion of mercury to a greater extent than NAP. == Regulations == === International === 140 countries agreed in the Minamata Convention on Mercury by the United Nations Environment Programme (UNEP) to prevent mercury vapor emissions. The convention was signed on 10 October 2013. === United States === In the United States, the Environmental Protection Agency is charged with regulating and managing mercury contamination. Several laws give the EPA this authority, including the Clean Air Act, the Clean Water Act, the Resource Conservation and Recovery Act, and the Safe Drinking Water Act. Additionally, the Mercury-Containing and Rechargeable Battery Management Act, passed in 1996, phases out the use of mercury in batteries, and provides for the efficient and cost-effective disposal of many types of used batteries. North America contributed approximately 11% of the total global anthropogenic mercury emissions in 1995. The United States Clean Air Act, passed in 1990, put mercury on a list of toxic pollutants that need to be controlled to the greatest possible extent. Thus, industries that release high concentrations of mercury into the environment agreed to install maximum achievable control technologies (MACT). In March 2005, the EPA promulgated a regulation that added power plants to the list of sources that should be controlled and instituted a national cap and trade system. States were given until November 2006 to impose stricter controls,
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but after a legal challenge from several states, the regulations were struck down by a federal appeals court on 8 February 2008. The rule was deemed not sufficient to protect the health of persons living near coal-fired power plants, given the negative effects documented in the EPA Study Report to Congress of 1998. However newer data published in 2015 showed that after introduction of the stricter controls mercury declined sharply, indicating that the Clean Air Act had its intended impact. The EPA announced new rules for coal-fired power plants on 22 December 2011. Cement kilns that burn hazardous waste are held to a looser standard than are standard hazardous waste incinerators in the United States, and as a result are a disproportionate source of mercury pollution. === European Union === In the European Union, the directive on the Restriction of the Use of Certain Hazardous Substances in Electrical and Electronic Equipment (see RoHS) bans mercury from certain electrical and electronic products, and limits the amount of mercury in other products to less than 1000 ppm. There are restrictions for mercury concentration in packaging (the limit is 100 ppm for sum of mercury, lead, hexavalent chromium and cadmium) and batteries (the limit is 5 ppm). In July 2007, the European Union also banned mercury in non-electrical measuring devices, such as thermometers and barometers. The ban applies to new devices only, and contains exemptions for the health care sector and a two-year grace period for manufacturers of barometers. === Scandinavia === Norway enacted a total ban on the use of mercury in the manufacturing and import/export of mercury products, effective 1 January 2008. In 2002, several lakes in Norway were found to have a poor state of mercury pollution, with an excess of 1 μg/g of mercury in their sediment. In 2008,
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Norway's Minister of Environment Development Erik Solheim said: "Mercury is among the most dangerous environmental toxins. Satisfactory alternatives to Hg in products are available, and it is therefore fitting to induce a ban." Products containing mercury were banned in Sweden in 2009, while elemental mercury has been banned from manufacture and use in all but a few applications (such as certain energy-saving light sources and amalgam dental fillings) in Denmark since 2008. == See also == COLEX process (isotopic separation) Mercury pollution in the ocean Red mercury == Notes == == References == == Further reading == Johnston, Andrew Scott (15 September 2013). Mercury and the Making of California: Mining, Landscape, and Race, 1840–1890. TotalBoox, TBX. University Press of Colorado. ISBN 978-1-4571-8399-7. OCLC 969039240. == External links == Chemistry in its element podcast (MP3) from the Royal Society of Chemistry's Chemistry World: Mercury Mercury at The Periodic Table of Videos (University of Nottingham) Centers for Disease Control and Prevention – Mercury Topic EPA fish consumption guidelines Hg 80 Mercury Material Safety Data Sheet – Mercury ICSC 0056 Stopping Pollution: Mercury – Oceana Natural Resources Defense Council (NRDC): Mercury Contamination in Fish guide – NRDC NLM Hazardous Substances Databank – Mercury BBC – Earth News – Mercury "turns" wetland birds such as ibises homosexual Changing Patterns in the Use, Recycling, and Material Substitution of Mercury in the United States United States Geological Survey Thermodynamical data on liquid mercury. "Mercury (element)" . Encyclopædia Britannica (11th ed.). 1911.
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In linear algebra, the Gram matrix (or Gramian matrix, Gramian) of a set of vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} in an inner product space is the Hermitian matrix of inner products, whose entries are given by the inner product G i j = ⟨ v i , v j ⟩ {\displaystyle G_{ij}=\left\langle v_{i},v_{j}\right\rangle } . If the vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} are the columns of matrix X {\displaystyle X} then the Gram matrix is X † X {\displaystyle X^{\dagger }X} in the general case that the vector coordinates are complex numbers, which simplifies to X ⊤ X {\displaystyle X^{\top }X} for the case that the vector coordinates are real numbers. An important application is to compute linear independence: a set of vectors are linearly independent if and only if the Gram determinant (the determinant of the Gram matrix) is non-zero. It is named after Jørgen Pedersen Gram. == Examples == For finite-dimensional real vectors in R n {\displaystyle \mathbb {R} ^{n}} with the usual Euclidean dot product, the Gram matrix is G = V ⊤ V {\displaystyle G=V^{\top }V} , where V {\displaystyle V} is a matrix whose columns are the vectors v k {\displaystyle v_{k}} and V ⊤ {\displaystyle V^{\top }} is its transpose whose rows are the vectors v k ⊤ {\displaystyle v_{k}^{\top }} . For complex vectors in C n {\displaystyle \mathbb {C} ^{n}} , G = V † V {\displaystyle G=V^{\dagger }V} , where V † {\displaystyle V^{\dagger }} is the conjugate transpose of V {\displaystyle V} . Given square-integrable functions { ℓ i ( ⋅ ) , i = 1 , … , n } {\displaystyle \{\ell _{i}(\cdot ),\,i=1,\dots ,n\}} on the interval [ t 0 , t f ] {\displaystyle \left[t_{0},t_{f}\right]}
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, the Gram matrix G = [ G i j ] {\displaystyle G=\left[G_{ij}\right]} is: G i j = ∫ t 0 t f ℓ i ∗ ( τ ) ℓ j ( τ ) d τ . {\displaystyle G_{ij}=\int _{t_{0}}^{t_{f}}\ell _{i}^{*}(\tau )\ell _{j}(\tau )\,d\tau .} where ℓ i ∗ ( τ ) {\displaystyle \ell _{i}^{*}(\tau )} is the complex conjugate of ℓ i ( τ ) {\displaystyle \ell _{i}(\tau )} . For any bilinear form B {\displaystyle B} on a finite-dimensional vector space over any field we can define a Gram matrix G {\displaystyle G} attached to a set of vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} by G i j = B ( v i , v j ) {\displaystyle G_{ij}=B\left(v_{i},v_{j}\right)} . The matrix will be symmetric if the bilinear form B {\displaystyle B} is symmetric. === Applications === In Riemannian geometry, given an embedded k {\displaystyle k} -dimensional Riemannian manifold M ⊂ R n {\displaystyle M\subset \mathbb {R} ^{n}} and a parametrization ϕ : U → M {\displaystyle \phi :U\to M} for ( x 1 , … , x k ) ∈ U ⊂ R k {\displaystyle (x_{1},\ldots ,x_{k})\in U\subset \mathbb {R} ^{k}} , the volume form ω {\displaystyle \omega } on M {\displaystyle M} induced by the embedding may be computed using the Gramian of the coordinate tangent vectors: ω = det G d x 1 ⋯ d x k , G = [ ⟨ ∂ ϕ ∂ x i , ∂ ϕ ∂ x j ⟩ ] . {\displaystyle \omega ={\sqrt {\det G}}\ dx_{1}\cdots dx_{k},\quad G=\left[\left\langle {\frac {\partial \phi }{\partial x_{i}}},{\frac {\partial \phi }{\partial x_{j}}}\right\rangle \right].} This generalizes the classical surface integral of a parametrized surface ϕ : U → S ⊂ R 3 {\displaystyle \phi :U\to S\subset \mathbb {R} ^{3}} for
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( x , y ) ∈ U ⊂ R 2 {\displaystyle (x,y)\in U\subset \mathbb {R} ^{2}} : ∫ S f d A = ∬ U f ( ϕ ( x , y ) ) | ∂ ϕ ∂ x × ∂ ϕ ∂ y | d x d y . {\displaystyle \int _{S}f\ dA=\iint _{U}f(\phi (x,y))\,\left|{\frac {\partial \phi }{\partial x}}\,{\times }\,{\frac {\partial \phi }{\partial y}}\right|\,dx\,dy.} If the vectors are centered random variables, the Gramian is approximately proportional to the covariance matrix, with the scaling determined by the number of elements in the vector. In quantum chemistry, the Gram matrix of a set of basis vectors is the overlap matrix. In control theory (or more generally systems theory), the controllability Gramian and observability Gramian determine properties of a linear system. Gramian matrices arise in covariance structure model fitting (see e.g., Jamshidian and Bentler, 1993, Applied Psychological Measurement, Volume 18, pp. 79–94). In the finite element method, the Gram matrix arises from approximating a function from a finite dimensional space; the Gram matrix entries are then the inner products of the basis functions of the finite dimensional subspace. In machine learning, kernel functions are often represented as Gram matrices. (Also see kernel PCA) Since the Gram matrix over the reals is a symmetric matrix, it is diagonalizable and its eigenvalues are non-negative. The diagonalization of the Gram matrix is the singular value decomposition. == Properties == === Positive-semidefiniteness === The Gram matrix is symmetric in the case the inner product is real-valued; it is Hermitian in the general, complex case by definition of an inner product. The Gram matrix is positive semidefinite, and every positive semidefinite matrix is the Gramian matrix for some set of vectors. The fact that the Gramian matrix is positive-semidefinite can be seen from the following simple derivation:
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x † G x = ∑ i , j x i ∗ x j ⟨ v i , v j ⟩ = ∑ i , j ⟨ x i v i , x j v j ⟩ = ⟨ ∑ i x i v i , ∑ j x j v j ⟩ = ‖ ∑ i x i v i ‖ 2 ≥ 0. {\displaystyle x^{\dagger }\mathbf {G} x=\sum _{i,j}x_{i}^{*}x_{j}\left\langle v_{i},v_{j}\right\rangle =\sum _{i,j}\left\langle x_{i}v_{i},x_{j}v_{j}\right\rangle ={\biggl \langle }\sum _{i}x_{i}v_{i},\sum _{j}x_{j}v_{j}{\biggr \rangle }={\biggl \|}\sum _{i}x_{i}v_{i}{\biggr \|}^{2}\geq 0.} The first equality follows from the definition of matrix multiplication, the second and third from the bi-linearity of the inner-product, and the last from the positive definiteness of the inner product. Note that this also shows that the Gramian matrix is positive definite if and only if the vectors v i {\displaystyle v_{i}} are linearly independent (that is, ∑ i x i v i ≠ 0 {\textstyle \sum _{i}x_{i}v_{i}\neq 0} for all x {\displaystyle x} ). === Finding a vector realization === Given any positive semidefinite matrix M {\displaystyle M} , one can decompose it as: M = B † B {\displaystyle M=B^{\dagger }B} , where B † {\displaystyle B^{\dagger }} is the conjugate transpose of B {\displaystyle B} (or M = B T B {\displaystyle M=B^{\textsf {T}}B} in the real case). Here B {\displaystyle B} is a k × n {\displaystyle k\times n} matrix, where k {\displaystyle k} is the rank of M {\displaystyle M} . Various ways to obtain such a decomposition include computing the Cholesky decomposition or taking the non-negative square root of M {\displaystyle M} . The columns b ( 1 ) , … , b ( n ) {\displaystyle b^{(1)},\dots ,b^{(n)}} of B {\displaystyle B} can be seen as n vectors in C k {\displaystyle \mathbb {C} ^{k}} (or
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k-dimensional Euclidean space R k {\displaystyle \mathbb {R} ^{k}} , in the real case). Then M i j = b ( i ) ⋅ b ( j ) {\displaystyle M_{ij}=b^{(i)}\cdot b^{(j)}} where the dot product a ⋅ b = ∑ ℓ = 1 k a ℓ ∗ b ℓ {\textstyle a\cdot b=\sum _{\ell =1}^{k}a_{\ell }^{*}b_{\ell }} is the usual inner product on C k {\displaystyle \mathbb {C} ^{k}} . Thus a Hermitian matrix M {\displaystyle M} is positive semidefinite if and only if it is the Gram matrix of some vectors b ( 1 ) , … , b ( n ) {\displaystyle b^{(1)},\dots ,b^{(n)}} . Such vectors are called a vector realization of M {\displaystyle M} . The infinite-dimensional analog of this statement is Mercer's theorem. === Uniqueness of vector realizations === If M {\displaystyle M} is the Gram matrix of vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} in R k {\displaystyle \mathbb {R} ^{k}} then applying any rotation or reflection of R k {\displaystyle \mathbb {R} ^{k}} (any orthogonal transformation, that is, any Euclidean isometry preserving 0) to the sequence of vectors results in the same Gram matrix. That is, for any k × k {\displaystyle k\times k} orthogonal matrix Q {\displaystyle Q} , the Gram matrix of Q v 1 , … , Q v n {\displaystyle Qv_{1},\dots ,Qv_{n}} is also M {\displaystyle M} . This is the only way in which two real vector realizations of M {\displaystyle M} can differ: the vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} are unique up to orthogonal transformations. In other words, the dot products v i ⋅ v j {\displaystyle v_{i}\cdot v_{j}} and w i ⋅ w j {\displaystyle w_{i}\cdot w_{j}} are equal if and only if some rigid transformation of
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R k {\displaystyle \mathbb {R} ^{k}} transforms the vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} to w 1 , … , w n {\displaystyle w_{1},\dots ,w_{n}} and 0 to 0. The same holds in the complex case, with unitary transformations in place of orthogonal ones. That is, if the Gram matrix of vectors v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} is equal to the Gram matrix of vectors w 1 , … , w n {\displaystyle w_{1},\dots ,w_{n}} in C k {\displaystyle \mathbb {C} ^{k}} then there is a unitary k × k {\displaystyle k\times k} matrix U {\displaystyle U} (meaning U † U = I {\displaystyle U^{\dagger }U=I} ) such that v i = U w i {\displaystyle v_{i}=Uw_{i}} for i = 1 , … , n {\displaystyle i=1,\dots ,n} . === Other properties === Because G = G † {\displaystyle G=G^{\dagger }} , it is necessarily the case that G {\displaystyle G} and G † {\displaystyle G^{\dagger }} commute. That is, a real or complex Gram matrix G {\displaystyle G} is also a normal matrix. The Gram matrix of any orthonormal basis is the identity matrix. Equivalently, the Gram matrix of the rows or the columns of a real rotation matrix is the identity matrix. Likewise, the Gram matrix of the rows or columns of a unitary matrix is the identity matrix. The rank of the Gram matrix of vectors in R k {\displaystyle \mathbb {R} ^{k}} or C k {\displaystyle \mathbb {C} ^{k}} equals the dimension of the space spanned by these vectors. == Gram determinant == The Gram determinant or Gramian is the determinant of the Gram matrix: | G ( v 1 , … , v n ) | = | ⟨ v 1 , v 1 ⟩
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⟨ v 1 , v 2 ⟩ … ⟨ v 1 , v n ⟩ ⟨ v 2 , v 1 ⟩ ⟨ v 2 , v 2 ⟩ … ⟨ v 2 , v n ⟩ ⋮ ⋮ ⋱ ⋮ ⟨ v n , v 1 ⟩ ⟨ v n , v 2 ⟩ … ⟨ v n , v n ⟩ | . {\displaystyle {\bigl |}G(v_{1},\dots ,v_{n}){\bigr |}={\begin{vmatrix}\langle v_{1},v_{1}\rangle &\langle v_{1},v_{2}\rangle &\dots &\langle v_{1},v_{n}\rangle \\\langle v_{2},v_{1}\rangle &\langle v_{2},v_{2}\rangle &\dots &\langle v_{2},v_{n}\rangle \\\vdots &\vdots &\ddots &\vdots \\\langle v_{n},v_{1}\rangle &\langle v_{n},v_{2}\rangle &\dots &\langle v_{n},v_{n}\rangle \end{vmatrix}}.} If v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} are vectors in R m {\displaystyle \mathbb {R} ^{m}} then it is the square of the n-dimensional volume of the parallelotope formed by the vectors. In particular, the vectors are linearly independent if and only if the parallelotope has nonzero n-dimensional volume, if and only if Gram determinant is nonzero, if and only if the Gram matrix is nonsingular. When n > m the determinant and volume are zero. When n = m, this reduces to the standard theorem that the absolute value of the determinant of n n-dimensional vectors is the n-dimensional volume. The volume of the simplex formed by the vectors is Volume(parallelotope) / n!. When v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} are linearly independent, the distance between a point x {\displaystyle x} and the linear span of v 1 , … , v n {\displaystyle v_{1},\dots ,v_{n}} is | G ( x , v 1 , … , v n ) | | G ( v 1 , … , v n ) | {\displaystyle {\sqrt {\frac {|G(x,v_{1},\dots ,v_{n})|}{|G(v_{1},\dots ,v_{n})|}}}} . Consider the moment problem: given c 1 , … , c n ∈ C {\displaystyle c_{1},\dots
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,c_{n}\in \mathbb {C} } , find a vector v {\displaystyle v} such that ⟨ v , v i ⟩ = c i {\textstyle \left\langle v,v_{i}\right\rangle =c_{i}} , for all 1 ⩽ i ⩽ n {\textstyle 1\leqslant i\leqslant n} . There exists a unique solution with minimal norm:: 38 v = − 1 G ( v 1 , v 2 , … , v n ) det [ 0 c 1 c 2 ⋯ c n v 1 ⟨ v 1 , v 1 ⟩ ⟨ v 1 , v 2 ⟩ ⋯ ⟨ v 1 , v n ⟩ v 2 ⟨ v 2 , v 1 ⟩ ⟨ v 2 , v 2 ⟩ ⋯ ⟨ v 2 , v n ⟩ ⋮ ⋮ ⋮ ⋱ ⋮ v n ⟨ v n , v 1 ⟩ ⟨ v n , v 2 ⟩ ⋯ ⟨ v n , v n ⟩ ] {\displaystyle v=-{\frac {1}{G\left(v_{1},v_{2},\ldots ,v_{n}\right)}}\det {\begin{bmatrix}0&c_{1}&c_{2}&\cdots &c_{n}\\v_{1}&\left\langle v_{1},v_{1}\right\rangle &\left\langle v_{1},v_{2}\right\rangle &\cdots &\left\langle v_{1},v_{n}\right\rangle \\v_{2}&\left\langle v_{2},v_{1}\right\rangle &\left\langle v_{2},v_{2}\right\rangle &\cdots &\left\langle v_{2},v_{n}\right\rangle \\\vdots &\vdots &\vdots &\ddots &\vdots \\v_{n}&\left\langle v_{n},v_{1}\right\rangle &\left\langle v_{n},v_{2}\right\rangle &\cdots &\left\langle v_{n},v_{n}\right\rangle \end{bmatrix}}} The Gram determinant can also be expressed in terms of the exterior product of vectors by | G ( v 1 , … , v n ) | = ‖ v 1 ∧ ⋯ ∧ v n ‖ 2 . {\displaystyle {\bigl |}G(v_{1},\dots ,v_{n}){\bigr |}=\|v_{1}\wedge \cdots \wedge v_{n}\|^{2}.} The Gram determinant therefore supplies an inner product for the space ⋀ n ( V ) {\displaystyle {\textstyle \bigwedge }^{\!n}(V)} . If an orthonormal basis ei, i = 1, 2, ..., n on V {\displaystyle V} is given, the vectors e i 1 ∧ ⋯ ∧ e i n , i 1 < ⋯ < i n , {\displaystyle e_{i_{1}}\wedge \cdots \wedge e_{i_{n}},\quad i_{1}<\cdots
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{
"page_id": 987959,
"source": null,
"title": "Gram matrix"
}
|
<i_{n},} will constitute an orthonormal basis of n-dimensional volumes on the space ⋀ n ( V ) {\displaystyle {\textstyle \bigwedge }^{\!n}(V)} . Then the Gram determinant | G ( v 1 , … , v n ) | {\displaystyle {\bigl |}G(v_{1},\dots ,v_{n}){\bigr |}} amounts to an n-dimensional Pythagorean Theorem for the volume of the parallelotope formed by the vectors v 1 ∧ ⋯ ∧ v n {\displaystyle v_{1}\wedge \cdots \wedge v_{n}} in terms of its projections onto the basis volumes e i 1 ∧ ⋯ ∧ e i n {\displaystyle e_{i_{1}}\wedge \cdots \wedge e_{i_{n}}} . When the vectors v 1 , … , v n ∈ R m {\displaystyle v_{1},\ldots ,v_{n}\in \mathbb {R} ^{m}} are defined from the positions of points p 1 , … , p n {\displaystyle p_{1},\ldots ,p_{n}} relative to some reference point p n + 1 {\displaystyle p_{n+1}} , ( v 1 , v 2 , … , v n ) = ( p 1 − p n + 1 , p 2 − p n + 1 , … , p n − p n + 1 ) , {\displaystyle (v_{1},v_{2},\ldots ,v_{n})=(p_{1}-p_{n+1},p_{2}-p_{n+1},\ldots ,p_{n}-p_{n+1})\,,} then the Gram determinant can be written as the difference of two Gram determinants, | G ( v 1 , … , v n ) | = | G ( ( p 1 , 1 ) , … , ( p n + 1 , 1 ) ) | − | G ( p 1 , … , p n + 1 ) | , {\displaystyle {\bigl |}G(v_{1},\dots ,v_{n}){\bigr |}={\bigl |}G((p_{1},1),\dots ,(p_{n+1},1)){\bigr |}-{\bigl |}G(p_{1},\dots ,p_{n+1}){\bigr |}\,,} where each ( p j , 1 ) {\displaystyle (p_{j},1)} is the corresponding point p j {\displaystyle p_{j}} supplemented with the coordinate value of 1 for an ( m + 1 ) {\displaystyle (m+1)} -st
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{
"page_id": 987959,
"source": null,
"title": "Gram matrix"
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|
dimension. Note that in the common case that n = m, the second term on the right-hand side will be zero. == Constructing an orthonormal basis == Given a set of linearly independent vectors { v i } {\displaystyle \{v_{i}\}} with Gram matrix G {\displaystyle G} defined by G i j := ⟨ v i , v j ⟩ {\displaystyle G_{ij}:=\langle v_{i},v_{j}\rangle } , one can construct an orthonormal basis u i := ∑ j ( G − 1 / 2 ) j i v j . {\displaystyle u_{i}:=\sum _{j}{\bigl (}G^{-1/2}{\bigr )}_{ji}v_{j}.} In matrix notation, U = V G − 1 / 2 {\displaystyle U=VG^{-1/2}} , where U {\displaystyle U} has orthonormal basis vectors { u i } {\displaystyle \{u_{i}\}} and the matrix V {\displaystyle V} is composed of the given column vectors { v i } {\displaystyle \{v_{i}\}} . The matrix G − 1 / 2 {\displaystyle G^{-1/2}} is guaranteed to exist. Indeed, G {\displaystyle G} is Hermitian, and so can be decomposed as G = U D U † {\displaystyle G=UDU^{\dagger }} with U {\displaystyle U} a unitary matrix and D {\displaystyle D} a real diagonal matrix. Additionally, the v i {\displaystyle v_{i}} are linearly independent if and only if G {\displaystyle G} is positive definite, which implies that the diagonal entries of D {\displaystyle D} are positive. G − 1 / 2 {\displaystyle G^{-1/2}} is therefore uniquely defined by G − 1 / 2 := U D − 1 / 2 U † {\displaystyle G^{-1/2}:=UD^{-1/2}U^{\dagger }} . One can check that these new vectors are orthonormal: ⟨ u i , u j ⟩ = ∑ i ′ ∑ j ′ ⟨ ( G − 1 / 2 ) i ′ i v i ′ , ( G − 1 / 2 ) j ′ j v j
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{
"page_id": 987959,
"source": null,
"title": "Gram matrix"
}
|
′ ⟩ = ∑ i ′ ∑ j ′ ( G − 1 / 2 ) i i ′ G i ′ j ′ ( G − 1 / 2 ) j ′ j = ( G − 1 / 2 G G − 1 / 2 ) i j = δ i j {\displaystyle {\begin{aligned}\langle u_{i},u_{j}\rangle &=\sum _{i'}\sum _{j'}{\Bigl \langle }{\bigl (}G^{-1/2}{\bigr )}_{i'i}v_{i'},{\bigl (}G^{-1/2}{\bigr )}_{j'j}v_{j'}{\Bigr \rangle }\\[10mu]&=\sum _{i'}\sum _{j'}{\bigl (}G^{-1/2}{\bigr )}_{ii'}G_{i'j'}{\bigl (}G^{-1/2}{\bigr )}_{j'j}\\[8mu]&={\bigl (}G^{-1/2}GG^{-1/2}{\bigr )}_{ij}=\delta _{ij}\end{aligned}}} where we used ( G − 1 / 2 ) † = G − 1 / 2 {\displaystyle {\bigl (}G^{-1/2}{\bigr )}^{\dagger }=G^{-1/2}} . == See also == Controllability Gramian Observability Gramian == References == Horn, Roger A.; Johnson, Charles R. (2013). Matrix Analysis (2nd ed.). Cambridge University Press. ISBN 978-0-521-54823-6. == External links == "Gram matrix", Encyclopedia of Mathematics, EMS Press, 2001 [1994] Volumes of parallelograms by Frank Jones
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{
"page_id": 987959,
"source": null,
"title": "Gram matrix"
}
|
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