James Cudworth (colonist)

General James Cudworth (; 1612 – 1682) was one of the most important men in Plymouth Colony. He served as Deputy to the Plymouth General Court (1649), Commander of militia in King Philip's War (1675–8), Assistant Governor (1656–8, 1674–80) and Deputy Governor (1681–2) of Plymouth Colony, and Commissioner to the New England Confederation (four times, 1655–81).
Family background.
The Rev. Dr Ralph Cudworth (1572/3–1624).
James Cudworth was the eldest son of The Rev. Dr Ralph Cudworth, who was a student at, and graduate and Fellow of, Emmanuel College, Cambridge. In 1606, Dr Cudworth was instituted as Vicar of Coggeshall, Essex (at the presentation of Robert, 3rd Lord Rich (later 1st Earl of Warwick)), to replace Thomas Stoughton (who, having been active in the Conference of Reformed Ministers at Dedham, Essex, had been deprived by High Commission for nonconformism). Dr Cudworth resigned his Fellowship (c.1610) to accept the Rectoriate of Aller, Somerset, England (which was in the presentation of Emmanuel College).
At the Parish Church of St. Mary Newington, Southwark (1611), Ralph Cudworth married Mary Machell ("c".1582–1634), who had been a nurse to Henry, Prince of Wales (1593/4–1612), eldest son of James I. It appears likely that Mary was a granddaughter of John Machell (d.1558), clothworker, Alderman and Sheriff of London (1555–56). A pedigree tradition, reinforced by a more recent claim, argued that she was the daughter of Mathew Machell of Shacklewell, Hackney, Middlesex (John Machell's second son by his second marriage) and his wife Mary Lewknor (who obtained a licence to marry in 1568). Mary Lewknor was one of the daughters of Edward Lewknor and his wife Dorothy Wroth (sister of the Edwardian courtier Sir Thomas Wroth (c.1518–73)). It is also contended that Mary Machell was the daughter of Mathew Machell's elder brother, John, by his second wife Ursula Hynde (daughter of Francis Hynde of Madingley Hall, Cambridge, and his wife Jane Verney). Despite extended debate, it is not absolutely certain which Machell (John or Matthew) was father of Mary, but these are the likely candidates.
Ralph and Mary Cudworth had three sons and at least two (possibly three) daughters, before Dr Cudworth died at Aller (1624). James Cudworth was baptized there (2 August 1612), followed by Elizabeth (1615), Ralph (1617), Mary (1619) and John (1622), and probably Jane (c. 1624).
The Rev. Dr John Stoughton (d.1639).
Dr Cudworth was succeeded, as Rector, by The Rev. Dr John Stoughton (son of Thomas Stoughton of Coggeshall), who was also a student, graduate, and Fellow of Emmanuel College. Stoughton later married Ralph's widow, Mary (Machell) Cudworth ("c".1582–1634). Dr Stoughton, an influential clergyman and preacher, took on the education of his stepchildren and, following the death of Mary their mother (Summer 1634), remarried to Jane Browne (daughter of John Browne of Frampton, Dorset).
John Browne was closely associated with John White of Dorchester, Dorset, Dr Stoughton, and others, in the promotion of religious emigration and colonization in New England: Dr Stoughton's brother, Thomas, sailed in the "Mary and John" (1630) to found Dorchester, Boston in Massachusetts Bay Colony (later becoming a freeman: 18 May 1631), and was followed (1632) by his brother, Israel Stoughton, (who was admitted freeman: November 5, 1633). Mary Machell's cousins, Sir Nathaniel Rich and his sister Margaret, Lady Wroth, wife of Sir Thomas Wroth (1584–1672) of Petherton Park, Somerset, near Aller (whose father, Richard Rich (d.1598), was the acknowledged illegitimate son and substantial legatee of Richard, 1st Lord Rich), were also highly active in the promotion of colonial enterprise in the Americas. Lady Wroth had been present at Dr Cudworth's deathbed (1624) and, at the time of her father's death (1598), their minister at Leigh, Essex (England), had been William Noyes (whose son, James Noyes, and nephew, Thomas Parker, migrated (1634) and had important roles in the settlement and ministry of Newbury, Essex County, Massachusetts Bay Colony). As a member of the Rich family, she and they were generally associated with the interests, influence and patronage of the Lords Rich (later Earls of Warwick).
Dr Stoughton was invited by John Winthrop and John Wilson to take up his ministry in New England (1632), but elected to remain in old England and accepted a preaching appointment at St Mary Aldermanbury, London. His correspondence with Sir Thomas Wroth was intercepted by government agents and was the subject of an official inquiry (in which both men escaped serious consequences). Dr Stoughton (d. 1639) and his widow, Jane Browne Stoughton (d. 1658), raised two daughters (Jane, and another who died in infancy). Jane Browne Stoughton also left a son and daughter by her first marriage (to the clergyman Walter Newburgh).
Dr Stoughton sent his younger stepson, Ralph Cudworth (1617–88), to study at Emmanuel College, Cambridge, where, by the 1650s, he had become Master of Christ's College, married Damaris Cradock Andrewes (daughter of Mathew Cradock, first Governor of the Massachusetts Bay Company), become a leading figure among the Cambridge Platonists, and was consulted by John Thurloe. James Cudworth's youngest brother, John Cudworth (1622–75) of London and Bentley, Suffolk, became an Alderman of London, and was Master of the Worshipful Company of Girdlers (1667–68).
Career.
Settlement in Scituate, Plymouth Colony, Massachusetts (1634–8).
Having married Mary Parker (c.1606–c.1673/81) at Northam, Devon, England (February 1, 1633/4), James and his new bride migrated to New England (1634), where they initially settled at Scituate (in Plymouth Colony, Massachusetts). In December 1634, he wrote to his stepfather (in response to a letter of exhortation received from Dr Stoughton), thanking him for the thorough religious education which he had given him. He mentioned that he had planted, successfully, a crop of corn (which yielded 60 bushels). Scituate's population amounted to 60 residents, and Cudworth's house (as the largest) was used for local religious meetings. He listed the pastors and teachers in the various settlements, noting (with approval) the arrival of John Lothropp, who landed at Boston in the "Griffin" (September 18, 1634) together with Anne Hutchinson and Zechariah Symmes (whom Cudworth calls "my cosson", and first went as teacher to Charlestown). James Cudworth and Timothy Hatherly (the founder of Scituate, who had emigrated in 1632) top the list of those who had prepared the way for Lothropp at Scituate, where he arrived (27 September 1634). Cudworth also reported the forthcoming marriage of Dr Stoughton's brother, Thomas, at Dorchester. The letter survives among the British State Papers and was presumably among those seized from Dr Stoughton for scrutiny soon afterwards (since certain suggestive passages are underscored).
Cudworth was admitted as a freeman of Plymouth Colony (January 1, 1634/5). Brethren of Scituate who were members of the Plymouth church had been dismissed (23 November 1634) in the expectation that they would form their own congregation and, a covenant being joined, Cudworth (and his wife) were registered as members of the Scituate church (January 18, 1634/5). John Lothropp (who, in England, had been deprived of his ministry for dissent) accepted formal appointment as their minister (January 19, 1634/5). Lothropp's record shows that "My sonn Fuller and my daughter Jane, and Edward Foster and Lettice Handford, marr[ie]d att Mr Cudworths by Captaine Standige Aprill 8 ye 4th day of the weeke 1635", which traces Cudworth's connection with Myles Standish back to the first year of his life in America. Cudworth's first children were born at Scituate: James (3 May 1635), Mary (1637), and Jonathan (1638; who died in infancy).
In October 1636, the Plymouth General Court appointed William Brewster, James Cudworth, and several other prominent citizens to a special committee which was to join with the Governor (and Assistant Governors) in reviewing all laws, with proposed changes to laws being presented at the next court meeting.
Removal to Barnstable, Plymouth Colony (1638–46).
The removal of some part of the Scituate population to a new plantation at Barnstable was advocated to the Governor, Thomas Prence (then in his second term), in two letters by John Lothropp (1638–39). The causes appear to have included a split in the Scituate congregation concerning Lothropp's views on baptism. James Cudworth and his family were among those who removed to Barnstable (taking with them their crops from Scituate). They arrived (October 11, 1639), and were listed there (1640) as amongst the first settlers. Their younger children, Israel (1641), Joanna (1643), an unbaptized male child (d.1644), and Jonathan (who survived) were born (or baptized) at Barnstable.
Deputy to Plymouth General Court (1649), Assistant Governor (1656–8), and Commissioner (1657).
Cudworth retained his interests in Scituate, and was listed (1643) for both locations as among the men "Able To Bear Arms". He was in Scituate (1646), and (as the progress of the English Civil War led to Charles I's execution (1649), the Interregnum, and the declaration of the Commonwealth of England as a Republic), Cudworth became a Deputy to Plymouth General Court (from 1649), and later Captain of the Scituate Militia (1652). During this time, the sovereignty of the English Parliament, and the authority of the puritan Oliver Cromwell, as Lord Protector (1653–8), enlarged the expectations of the puritan colonial legislature.
Both Captain James Cudworth and his friend Timothy Hatherly were appointed as supervisors of the last will and testament (7 March 1655/56) of Myles Standish (d.1656) of Duxbury, Massachusetts, and Cudworth was also a witness to this will. Standish was a "Mayflower" colonist of 1620, had been Plymouth Militia's first Captain (1621–56), and was a leading figure in Plymouth Colony (he died on October 3, 1656). In 1657, James Cudworth and Thomas Prence became the two Plymouth Commissioners (of eight, in all, from the four colonies) of the United Colonies of New England (or New England Confederation), (an alliance for the strengthening of the Puritan colonies and their defense against the Native Americans). Cudworth served as Assistant Governor (1656–8), during a time which saw the end of William Bradford's last term of office (June 3, 1657) and the commencement of the third and lengthy administration of Thomas Prence (1657–73).
Stand against persecution (1657–73).
In September 1657, the Commissioners issued a letter, to the authorities of Rhode Island, demanding the suppression of the Quakers; of all the Commissioners, Cudworth alone refused to sign. In December (tenth month, Old Style) 1658, he wrote a long letter (to a person in England), in which he provided details of the brutally harsh and (as he considered) illegal laws and punishments meted out to the Quakers (and others) who the Puritan monopoly in the colonial legislature wished to purge. He reported that this "Antichristian Persecuting Spirit" had been at work during the previous two years (during his magistracy), and that he had often had to object to such proceedings (though in a respectful manner). His objections had given rise to a petition against him (signed by 19 people, who complained that he had entertained Quakers at his house). This, he admitted, he had done to acquaint himself with Quaker principles (rather than to condemn them out of prejudice); and he found that he disagreed with the Quakers on various matters, and told the court, which heard the petition (presided over by Thomas Prence), that he was no Quaker: but that, just "as I was no Quaker, so I will be no Persecutor".
When the Act of Court was read before the people at Scituate (and before the Scituate Military Company (of which he was head)), there was a great disturbance against him, which he brought under control by making a speech. Consequently, a fresh petition was brought (signed by 54 hands), to which the court answered respectfully that Cudworth was a very useful and accomplished person, and that the only point against him was his association with Quakers (One or other of these petitions from "sundry persons from the towne of Scituate" was noted in the General Court (March 2, 1657/58)). In consequence of this, he and his friend Hatherly had been removed from the Bench at the previous election, and Cudworth himself was relieved of his military command (with Lt James Torrey and Ensign John Williams subsequently ordered to assume command of the company).
The persecutions to which Cudworth referred were (he stated) fuelled by the actions of the Boston legislature (then led by John Endecott). Cudworth's uncle, Israel Stoughton (d.1644), had worked with Endecott during the period of the Antinomian Controversy surrounding Anne Hutchinson, but had returned to England. Israel's son, William Stoughton (later involved in the Salem witch trials) was, during the 1650s, also resident in England. It was the voyage from England of the "Speedwell" in 1656 (which brought eight Quakers who were immediately imprisoned and expelled), and of the "Woodhouse" in 1657, and the subsequent renewal of their attempts to enter the Massachusetts Bay Colony from Rhode Island or Barbados, which now aroused the Puritan hostility. The treatment of Quakers (such as Christopher Holder, who was flogged, imprisoned, and had an ear cut-off) under Boston laws (and their law of banishment on pain of death), whipped up similar fervor elsewhere in the United Colonies in imitation: laws were emended retrospectively so that even minor actions of dissent and, of course, the Quaker refusal to take oaths were punishable by cumulative fines and imprisonments resulting in the eprivation of livelihood. Cudworth noted the strong influence of Quakerism upon the people of Sandwich, in Barnstable County.
At the time of the petitions against Cudworth (March 1657/58), the Rhode Island Assembly (upholding their principle of freedom of consciences) rebuked the United Colonies Commissioners for their demand concerning preventing the admission of Quakers, and warned that any subsequent civil troubles should be referred to "The Supream Authority of England". Cudworth's letter, written weeks after the death of Oliver Cromwell (September 3, 1658), naming the relevant members of the legislature and accusing them of arbitrary legislation outside the principles of English law, may reflect this intention. For disobedience to their laws, the Boston authorities executed: William Robinson and Marmaduke Stephenson (October 1659), Mary Dyer (1 June 1660), and William Leddra (March 1661).
In 1659, James Cudworth was sent, by Scituate, as a Deputy to the Plymouth General Court, but was not approved by the Court. Charged with disaffection to authority (on the evidence of a copy of his letter), he was ordered to appear before the Court (March 1660) on a bond of £500, and was sentenced (6 June 1660) to be disfranchised of his freedom of Plymouth Colony, having been found a "manifest opposer of the laws of government". In October 1660, he was questioned concerning a letter of reply received from John Browne of Frampton. In the light of the information which reached England, a lengthy indictment of the persecutions against Quakers in New England was published in London by George Bishop, entitled "New-England Judged" (1661), with a supplement describing the sufferings of the martyrs, and a full second part was published in 1667. The first volume (1661) of Bishop's work included the first publication of Cudworth's letter: it was this, therefore, which may have been influential in causing Charles II (following the Restoration of the English Monarchy (1660)), to issue "The King's Missive" (9 September 1661), which required that any Quakers held by them under sentence of death or other corporeal punishment should forthwith not be proceeded against, but should be returned (at once) to England where the charges against them might be considered according to English law.
Before this, in March 1660/61, Cudworth's elder daughter, Mary, had married the Quaker, Robert Whitcomb, and had been fined for disorderly marriage and for choosing each other without parental consent. They were, however, permitted to marry in orderly fashion (the principal objection being to Mr Henry Hobson, who had derided their authority by the counterfeit solemnization). In 1665, Cudworth's eldest son, James, also married a Quaker, Mary Howland, and they were fined for fornication (Cudworth's consent or otherwise is not noted).
Rehabilitation (1673), Assistant Governor (1674–80), and Deputy Governor (1681–2).
It was not until the death of the Governor of Plymouth Colony, Thomas Prence (March 29, 1673), and the election of his long-serving Assistant, Josiah Winslow (son of the Pilgrim Edward Winslow) as Governor, that Cudworth was officially rehabilitated. In June 1666, a majority of the Scituate militia had elected Cudworth as their commander, but this choice was nullified on account of his support for Quakers and his writing against the rulers. The Court remarked, "As to Mr. Cudworth it is directly against the advice of this court, and as to Mr. Pierce he is a stranger to us, therefore Sergeant Daman [i.e. John Damon] is directed to take command till further orders." Governor Winslow adopted a more lenient policy towards the Quakers and, among his first actions, released Cudworth and Robinson from prison (where they had been held as sympathizers). Colony records show that "Captain Cudworth, by a full and clear vote, is accepted and reestablished in the association and body of this Commonwealth." (July 4, 1673). On the same day he was appointed magistrate for Scituate, with powers to solemnize marriages, to grant subpoenas for witnesses, and to administer oaths to witnesses.
Cudworth was also chosen by the Court to lead a military expedition against the Dutch at New York (1673). However, in declining this invitation, he addressed a very thoughtful letter to Governor Winslow, objecting that his wife (then aged 67) who was in poor health would be unlikely to survive during his absence, and that he lacked the capabilities demanded by such an undertaking. He was ready to serve King and Country, but wondered why the General Court should choose him over others better qualified. He contended that the "voice of the people" was not always the "voice of God", and that he did not feel that God called him to the present task. He emphasised that he was not motivated, in his refusal, by discontent arising from any former difference: he explained that he had formerly bent his mind and thoughts to military work and other public concerns, but was discharged from them: "and therein I took "vox populi" to be "vox Dei", and that God did thereby call and design me to sit still and be sequestered from all publick transactions, which condition suits me so well that I have received more satisfaction and contentment therein, than ever I did in sustaining any publick place."
Cudworth was chosen again as Assistant Governor (1674–80), was appointed to take charge of the Plymouth Colony military forces (1675) and, during that summer, was in charge of one-hundred Plymouth men and two-hundred Massachusetts (Bay Colony) men. In December 1675, Governor Winslow became commander-in-chief of the United Colonies forces, and planned a campaign of attacks against the Indians during King Philip's War (1675–76). Cudworth, now promoted to the rank of Major, took Winslow's place as commander of all Plymouth forces, and marched to the relief of Swansea with Major Thomas Savage (June 1675). Major Cudworth was appointed, with two others (Cornet Robert Stetson and Isaac Chittenden), by the Plymouth War Council as press masters (December 6) to obtain enough fit and able Scituate men for an expedition against the Native Americans. On December 30, the council further ordered that any person pressed into the colony's service who refused to serve would pay a fine (and if his financial reseources were insufficient, he would be sent to prison for a term not to exceed six months).
Cudworth served as Deputy Governor (1681–2), and became an official agent for Plymouth Colony. In this capacity he was charged with a mission to travel to England to obtain a new charter (by which the colony was to incorporate part of Narragansett territory). He made his last will and testament in New England (dated at Scituate, September 15, 1681), which, since it does not mention his wife, suggests that she may have died (some time after 1673). In his will, he named his sons, James, Israel, and Jonathan; his elder daughter Mary's four children (Israel, Robert, James, and Mary Whitcomb); and his younger daughter, Joanna Jones. The will also (impossibly) left two-thirds of his lands to his eldest son, James, and one-third each to Israel and Jonathan (he may have intended that two-fourths should go to the eldest and one fourth each to the others, but this is differently explained in another source).
Death (1682) and Memorial.
James Cudworth is said to have made his journey to England, and to have died, of smallpox, in London. An inventory of his possessions (which included books worth almost £8), was compiled (June 20, 1682), and his last will and testament was proved (July 7, 1682). His burial place remains unknown (and it is possible that his body was disposed of informally owing to the nature of his illness). His wife, Mary Parker Cudworth (d. c. 1673–81), was presumably buried in Scituate (though both the date and place are unknown). A memorial stone, in his honor, was erected in the Men of Kent Cemetery in Scituate, Massachusetts, which reads:
A Memorial to Gen. James Cudworth. We Honor Him as a Lover of Religious Freedom, a Brave and Able Commander and a True Patriot
Marriage and Children.
James Cudworth married Mary Parker (c.1606–c.1673/81) at Northam, Devon, England (February 1, 1633/4), and their children were:


Membrane bound polyribosome

In cell biology, membrane bound polyribosomes are attached to a cell's endoplasmic reticulum. When certain proteins are synthesized by a ribosome they can become "membrane-bound". The newly produced polypeptide chains are inserted directly into the endoplasmic reticulum by the ribosome and are then transported to their destinations. Bound ribosomes usually produce proteins that are used within the cell membrane or are expelled from the cell via "exocytosis".


Heterochromatin

Heterochromatin is a tightly packed form of DNA or "condensed DNA", which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed, however according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.
Constitutive heterochromatin can affect the genes near itself (e.g. position-effect variegation). It is usually repetitive and forms structural functions such as centromeres or telomeres, in addition to acting as an attractor for other gene-expression or repression signals.
Facultative heterochromatin is the result of genes that are silenced through a mechanism such as histone deacetylation or Piwi-interacting RNA (piRNA) through RNAi. It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active.
Heterochromatin has been associated with the di- and tri -methylation of H3K9 in certain portions of the genome. H3K9me3-related methyltransferases appear to have a pivotal role in modifying heterochromatin during lineage commitment at the onset of organogenesis and in maintaining lineage fidelity.
Note that the informal diagram shown here may be in error as to the location of heterochromatin. An inactivated X-chromosome (a.k.a. Barr body) migrates to the nuclear membrane alone, leaving the active X and other chromosomes within the nucleoplasm (away from the membrane in general). Other heterochromatin appear as particles separate from the membrane, "Heterochromatin appears as small, darkly staining, irregular particles scattered throughout the nucleus ...".
Structure.
Chromatin is found in two varieties: euchromatin and heterochromatin. Originally, the two forms were distinguished cytologically by how intensely they get stained – the euchromatin is less intense, while heterochromatin stains intensely, indicating tighter packing. Heterochromatin is usually localized to the periphery of the nucleus.
Despite this early dichotomy, recent evidence in both animals and plants has suggested that there are more than two distinct heterochromatin states, and it may in fact exist in four or five 'states', each marked by different combinations of epigenetic marks.
Heterochromatin mainly consists of genetically inactive satellite sequences, and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both centromeres and telomeres are heterochromatic, as is the Barr body of the second, inactivated X-chromosome in a female.
Function.
Heterochromatin has been associated with several functions, from gene regulation to the protection of chromosome integrity; some of these roles can be attributed to the dense packing of DNA, which makes it less accessible to protein factors that usually bind DNA or its associated factors. For example, naked double-stranded DNA ends would usually be interpreted by the cell as damaged or viral DNA, triggering cell cycle arrest, DNA repair or destruction of the fragment, such as by endonucleases in bacteria.
Some regions of chromatin are very densely packed with fibers that display a condition comparable to that of the chromosome at mitosis. Heterochromatin is generally clonally inherited; when a cell divides, the two daughter cells typically contain heterochromatin within the same regions of DNA, resulting in epigenetic inheritance. Variations cause heterochromatin to encroach on adjacent genes or recede from genes at the extremes of domains. Transcribable material may be repressed by being positioned (in "cis") at these boundary domains. This gives rise to expression levels that vary from cell to cell, which may be demonstrated by position-effect variegation. Insulator sequences may act as a barrier in rare cases where constitutive heterochromatin and highly active genes are juxtaposed (e.g. the 5'HS4 insulator upstream of the chicken β-globin locus, and loci in two "Saccharomyces" spp.).
Constitutive heterochromatin.
All cells of a given species package the same regions of DNA in constitutive heterochromatin, and thus in all cells, any genes contained within the constitutive heterochromatin will be poorly expressed. For example, all human chromosomes 1, 9, 16, and the Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.
Facultative heterochromatin.
The regions of DNA packaged in facultative heterochromatin will not be consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within are poorly expressed) may be packaged in euchromatin in another cell (and the genes within are no longer silenced). However, the formation of facultative heterochromatin is regulated, and is often associated with morphogenesis or differentiation. An example of facultative heterochromatin is X chromosome inactivation in female mammals: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed.
Among the molecular components that appear to regulate the spreading of heterochromatin are the Polycomb-group proteins and non-coding genes such as Xist. The mechanism for such spreading is still a matter of controversy. The polycomb repressive complexes PRC1 and PRC2 regulate chromatin compaction and gene expression and have a fundamental role in developmental processes. PRC-mediated epigenetic aberrations are linked to genome instability and malignancy and play a role in the DNA damage response, DNA repair and in the fidelity of replication.
Yeast heterochromatin.
"Saccharomyces cerevisiae", or budding yeast, is a model eukaryote and its heterochromatin has been defined thoroughly. Although most of its genome can be characterized as euchromatin, "S. cerevisiae" has regions of DNA that are transcribed very poorly. These loci are the so-called silent mating type loci (HML and HMR), the rDNA (encoding ribosomal RNA), and the sub-telomeric regions.
Fission yeast ("Schizosaccharomyces pombe") uses another mechanism for heterochromatin formation at its centromeres. Gene silencing at this location depends on components of the RNAi pathway. Double-stranded RNA is believed to result in silencing of the region through a series of steps.
In the fission yeast "Schizosaccharomyces pombe", two RNAi complexes, the RITS complex and the RNA-directed RNA polymerase complex (RDRC), are part of an RNAi machinery involved in the initiation, propagation and maintenance of heterochromatin assembly. These two complexes localize in a siRNA-dependent manner on chromosomes, at the site of heterochromatin assembly. RNA polymerase II synthesizes a transcript that serves as a platform to recruit RITS, RDRC and possibly other complexes required for heterochromatin assembly. Both RNAi and an exosome-dependent RNA degradation process contribute to heterochromatic gene silencing. These mechanisms of "Schizosaccharomyces pombe" may occur in other eukaryotes. A large RNA structure called RevCen has also been implicated in the production of siRNAs to mediate heterochromatin formation in some fission yeast.


Jeotgalicoccus psychrophilus

Jeotgalicoccus psychrophilus is a gram-positive bacterium. It is psychrophilic, it growth between 4 and 34 °C. To this also refers the selected species name. The cells are coccoid.


Bangalore Bio-Cluster

The Bangalore Bio-Cluster, now known as the "Bangalore Life Science Cluster" in short BLiSC, is an informal name for a group of three biological science research and development institutions in Bangalore, India. The three research institutions include:
BLiSC is a unique hub of excellence in biological research in India. Its creation aims at developing best practices for inter-institutional collaborations across the nation.


Membrane models

Before the emergence of electron microscopy in the 1950s, scientists did not know the structure of a cell membrane or what its components were; biologists and other researchers used indirect evidence to identify membranes before they could actually be visualized. Specifically, it was through the models of Overton, Langmuir, Gorter and Grendel, and Davson and Danielli, that it was deduced that membranes have lipids, proteins, and a bilayer. The advent of the electron microscope, the findings of J. David Robertson, the proposal of Singer and Nicolson, and additional work of Unwin and Henderson all contributed to the development of the modern membrane model. However, understanding of past membrane models elucidates present-day perception of membrane characteristics. Following intense experimental research, the membrane models of the preceding century gave way to the "fluid mosaic model" that is accepted today.
Gorter and Grendel's membrane theory (1920).
Evert Gorter and François Grendel (Dutch physiologists) approached the discovery of our present model of the plasma membrane structure as a lipid bi-layer. They simply hypothesized that if the plasma membrane is a "bi-layer", then the surface area of the mono-layer of lipids measured would be double the surface area of the plasma membrane. To examine their hypothesis, they performed an experiment in which they extracted lipids from a known number of red blood cells ("erythrocytes") of different mammalian sources, such as humans, goats, sheep, etc. and then spreading the lipids as a mono-layer in a Langmuir-Blodgett trough. They measured the total surface area of the plasma membrane of red blood cells, and using Langmuir's method, they measured the area of the mono-layer of lipids. In comparing the two, they calculated an estimated ratio of 2:1 Mono-layer of lipids:Plasma membrane. This supported their hypothesis, which led to the conclusion that cell membranes are composed of two apposing molecular layers. The two scientists proposed a structure for this bi-layer, with the polar hydrophilic heads facing outwards towards the aqueous environment and the hydrophobic tails facing inwards away from the aqueous surroundings on both sides of the membrane. Although they arrived at the right conclusions, some of the experimental data were incorrect such as the miscalculation of the area and pressure of the lipid mono-layer and the incompleteness of lipid extraction. They also failed to describe membrane function, and had false assumptions such as that of plasma membranes consisting of mostly lipids. However, on the whole, this envisioning of the lipid bi-layer structure became the basic underlying assumption for each successive refinement in modern understanding of membrane function.
The Davson and Danielli model with backup from Robertson (1940–1960).
Following the proposal of Gorter and Grendel, doubts inevitably arose over the veracity of having just a simple lipid bi-layer as a membrane. For instance, their model could not provide answers to questions on surface tension, permeability, and the electric resistance of membranes. Therefore, physiologist Hugh Davson and biologist James Danielli suggested that membranes indeed do have proteins. According to them, the existence of these "membrane proteins" explained that which couldn't be answered by the Gorter-Grendel model.
In 1935, Davson and Danielli proposed that biological membranes are made up of lipid bi-layers that are coated on both sides with thin sheets of protein and they simplified their model into the "pauci-molecular" theory. This theory declared that all biological membranes have a "lipoid" center surrounded by mono-layers of lipid that are covered by protein mono-layers. In short, their model was illustrated as a "sandwich" of protein-lipid-protein. The Davson-Danielli model threw new light on the understanding of cell membranes, by stressing the important role played by proteins in biological membranes.
By the 1950s, cell biologists verified the existence of plasma membranes through the use of electron microscopy (which accounted for higher resolutions). J. David Robertson used this method to propose the unit membrane model. Basically, he suggested that all cellular membranes share a similar underlying structure, the unit membrane. Using heavy metal staining, Robertson's proposal also seemed to agree instantaneously with the Davson-Danielli model. According to the trilaminar pattern of the cellular membrane viewed by Robertson, he suggested that the membranes consist of a lipid bi-layer covered on both surfaces with thin sheets of proteins. This suggestion was a great boost to the proposal of Davson and Danielli. However, even with Robertson's substantiation, the Davson-Danielli model had serious complications, a major one being that the proteins studied were mainly globular and couldn't therefore fit into the model's claim of thin protein sheets. These difficulties with the model stimulated new research in membrane organization and paved the way for the fluid mosaic model, which was proposed in 1972.
Singer and Nicolson's fluid mosaic model (1972).
In 1972, S. Jonathan Singer and Garth Nicolson developed new ideas for membrane structure. Their proposal was the "fluid mosaic model", which is the dominant model now. It has two key features—a mosaic of proteins embedded in the membrane, and the membrane being a fluid bi-layer of lipids. The lipid bi-layer suggestion agrees with previous models but views proteins as globular entities embedded in the layer instead of thin sheets on the surface.
According to the model, membrane proteins are in three classes based on how they are linked to the lipid bi-layer:
As for the fluid nature of the membrane, the lipid components are capable of moving parallel to the membrane surface and are in constant motion. Many proteins are also capable of that motion within the membrane. However, some are restricted in their mobility due to them being anchored to structural elements such as the cytoskeleton on either side of the membrane.
In general, this model explains most of the criticisms of the Davson–Danielli model. It eliminated the need to accommodate membrane proteins in thin surface layers, proposed that the variability in the protein/lipid ratios of different membranes simply means that different membranes vary in the amount of protein they contain, and showed how the exposure of lipid-head groups at the membrane surface is compatible with their sensitivity to phospholipase digestion. Also, the fluidity of the lipid bi-layers and the intermingling of their components within the membrane make it easy to visualize the mobility of both lipids and proteins.
Henderson and Unwin's membrane theory.
Henderson and Unwin have studied the purple membrane by electron microscopy, using a method for determining the projected structures of unstained crystalline specimens. By applying the method to tilted specimens, and using the principles put forward by DeRosier and Klug for the combination of such two-dimensional views, they obtained a 3-dimensional map of the membrane at 7 Å resolution. The map reveals the location of the protein and lipid components, the arrangement of the polypeptide chains within each protein molecule, and the relationship of the protein molecules in the lattice.
High-resolution micrographs of crystalline arrays of membrane proteins, taken at a low dose of electrons to minimize radiation damage, have been exploited to determine the three-dimensional structure by a Fourier transform.
Recent studies on negatively stained rat hepatocyte Gap™ junctions subjected to 3-dimensional Fourier reconstructions (of low-dose electron micrographs) indicate that the six protein sub-units are arranged in a cylinder slightly tilted tangentially, enclosing a channel 2 nm wide at the extracellular region. The dimensions of the channel within the membrane were narrower but could not be resolved (Unwin and Zampighi, 1980). A small radical movement of the sub-units at the cytoplasmic ends could reduce the sub-unit inclination tangential to six-fold axis and close the channel.
Further details of the molecular organization should emerge as more methods of preparation become available, so that high-resolution 3-dimensional images comparable to the purple membranes are obtained. By using ingenious procedures for the analysis of periodic arrays of biological macromolecules, in which data from low-dose electron images and diffraction patterns were combined, Henderson and Unwin (1975) reconstructed a three-dimensional image of purple membranes at 0.7 nm resolution. Glucose embedding was employed to alleviate dehydration damage and low doses (< 0.5 e/A*) to reduce the irradiation damage. The electron micrographs of unstained membranes were recorded such that the only source of contrast was a weak phase contrast induced by defocusing.
In their experiment, Unwin and Henderson found that protein extends to both sides of the lipid bi-layer and is composed of seven α-helices packed about 1–1.2 nm apart, 3.5–4.0 nm in length, running perpendicular to the plane of membrane. The molecules are organized around a 3-fold axis with a 2 nm-wide space at the center that is filled with lipids. This elegant work represents the most significant step forward thus far, as it has for the first time provided us with the structure of an integral membrane protein in situ.
The availability of the amino acid sequence, together with information about the electron scattering density from the work of Henderson and Unwin, has stimulated model-building efforts (Engleman et al., 1980) to fit the bacteriorhodopsin sequence information into a series of α-helical segments.


Arrakis Therapeutics

Arrakis Therapeutics is a Waltham, Massachusetts-based biotechnology company developing drugs for neurological disorders and other diseases. The company was co-founded in 2015 by CEO Michael Gilman, a former Biogen executive who co-founded and led Padlock Therapeutics (bought out by Bristol-Myers Squibb in 2016) and Stromedix (acquired by Biogen Idec in 2012).
Named after the desert world in Frank Herbert’s science fiction classic "Dune", Arrakis will use small-molecule medicinal chemistry to target RNA. While there are already approved drugs based on RNA-targeting molecules, they have been found by accident whereas Arrakis intends to take a systematic approach, Gilman says. The company claims a bioinformatic tool will allow its scientists to identify sites on RNA that can bind small molecules, while another set of chemical biology tools will allow researchers to validate the molecules’ efficacy and selectivity. In addition to neurology, Arrakis will also target cancer and rare genetic diseases.
In February 2017, Arrakis received a $38.5 million Series A round from investors including pharmaceutical giants Celgene and Pfizer.


Phosphoric monoester hydrolases

Phosphoric monoester hydrolases (or phosphomonoesterases) are enzymes that catalyse the hydrolysis of O-P bonds by nucleophilic attack of phosphorus by cysteine residues or coordinated metal ions.
They are categorized with the EC number 3.1.3.
Examples include:


James Inglese

James Inglese is an American biochemist, the director of the Assay Development and Screening Technology laboratory at the National Center for Advancing Translational Sciences, a Center within the National Institutes of Health. His specialty is small molecule high throughput screening. Inglese’s laboratory develops methods and strategies in molecular pharmacology with drug discovery applications. The work of his research group and collaborators focuses on genetic and infectious disease-associated biology.
Biography.
Inglese received his BS in Chemistry from the Rensselaer Polytechnic Institute in 1984 and a Ph.D. in Organic Chemistry from the Pennsylvania State University in 1989, where he conducted research under Stephen J. Benkovic on inhibitor design, synthesis and mechanism studies for the reduced folate-requiring enzymes. He pursued postdoctoral studies on G protein-coupled receptors (GPCRs) with Robert J. Lefkowitz at the Duke University School of Medicine. During this time studied the emerging family of G protein-coupled receptor kinases (GRKs), discovering several lipid post-translational modifications regulating GRK function and GPCR interaction..
Research.
During the following 10 years, Inglese led research groups in the private sector. At the combinatorial chemistry biotech, Pharmacopeia Inc., he developed methods to enable the company's electrophoretic tag-encoded libraries, pioneering the development of technologies such as micro plate laser scanning cytometry for high throughput screening (HTS) . Subsequently, at the Merck Research Laboratories, he directed HTS assay development for the analysis of chemical libraries in the company’s drug discovery efforts.
Inglese co-founded the NIH’s Chemical Genomics Center (NCGC) in 2004. This came at a time when the academic community was divided with regard to the role of academics in drug development, with many thinking that this should be solely the domain of the pharmaceutical industry
. He helped bring new technology and methods to drug development within the NIH . As Deputy Director of the NCGC, he led the development of the Quantitative High Throughput Screening (qHTS) platform in 2006. This pioneered a new approach to HTS that normally relies on a single concentration of a test compound and has been cited over 500 times according to Scopus and Web of Science.
Inglese has overseen the use of qHTS in numerous collaborative chemical probe discovery projects a. According to Scopus, as of August 2020, Inglese has published 180 documents that have been cited over 12,400 times. Sixteen publications have been cited more than 200 times, while 35 have been cited 100 times or more.
In 2009, his group's mechanistic studies of PTC124 (Ataluren), then in clinical trials for subclasses of cystic fibrosis and muscular dystrophy, revealed that the precursor discovery and subsequent development may have been guided by a confounding artifact of the reporter gene assay used in its identification and medicinal chemistry optimization . This led Inglese to design a new class of HTS reporter using the concept from physics of a coincidence circuit: by joining two biochemically distinct reporters, separated by a P2A ribosome skipping site, one can distinguish between compounds that act at the level of reporter expression, which will affect both reporters, from compounds that directly affect the activity of one or the other reporter.
Complementing the laboratory’s bioassay program, Inglese explores screening strategies to assess pharmacological activity, for example, from secondary metabolites contained in natural product extracts or novel chemical scaffolds derived from synthetic chemistry methodology research . His team’s recent efforts have explored topologically expansive mRNA-encoded peptide libraries using a modified mRNA display to identify inhibitors of infectious disease molecular targets .
Profesional activities.
Inglese founded the journal "ASSAY and Drug Development Technologies", serving as Editor-in-Chief from 2002 to 2014, and was Editor-in-Chief of the "Methods in Enzymology" volume 414 on Measuring Biological Responses with Automated Microscopy.


Camfetamine

Camfetamine (N-methyl-3-phenyl-norbornan-2-amine) is a stimulant drug closely related to the appetite suppressant fencamfamine, being its N-methyl homologue. It has been sold as a designer drug following the banning of mephedrone and related substituted cathinone derivatives in many countries, and reportedly has slightly stronger stimulant effects than fencamfamine, but with correspondingly more severe side effects.


RH-34

RH-34 is a compound which acts as a potent and selective partial agonist for the 5-HT2A serotonin receptor subtype. It was derived by structural modification of the selective 5-HT2A antagonist ketanserin, with the 4-(p-fluorobenzoyl)piperidine moiety replaced by the "N"-(2-methoxybenzyl) pharmacophore found in such potent 5-HT2A agonists as NBOMe-2C-B and NBOMe-2C-I. This alteration was found to retain 5-HT2A affinity and selectivity, but reversed activity from an antagonist to a moderate efficacy partial agonist.
Legal status.
RH-34 is a controlled substance in Hungary and Brazil.


Indian hedgehog (protein)

Indian hedgehog homolog (Drosophila), also known as IHH, is a protein which in humans is encoded by the "IHH" gene. This cell signaling protein is in the hedgehog signaling pathway. The several mammalian variants of the "Drosophila" hedgehog gene (which was the first named) have been named after the various species of hedgehog; the Indian hedgehog is honored by this one. The gene is not specific to Indian hedgehogs.
Function.
The Indian hedgehog protein is one of three proteins in the mammalian hedgehog family, the others being desert hedgehog (DHH) and sonic hedgehog (SHH). It is involved in chondrocyte differentiation, proliferation and maturation especially during endochondral ossification. It regulates its effects by feedback control of parathyroid hormone-related peptide (PTHrP).


Tetraloop

Tetraloops are a type of four-base hairpin loop motifs in RNA secondary structure that cap many double helices. There are many variants of the tetraloop. The published ones include ANYA,
CUYG,
GNRA,
UNAC
and UNCG.
Three types of tetraloops are common in ribosomal RNA: GNRA, UNCG and CUUG, in which the N could be either uracil, adenine, cytosine, or guanine, and the R is either guanine or adenine. These three sequences form stable and conserved tetraloops that play an important role in structural stability and biological function of 16S rRNA.


Ribosyldihydronicotinamide dehydrogenase (quinone)

In enzymology, a ribosyldihydronicotinamide dehydrogenase (quinone) () is an enzyme that catalyzes the chemical reaction
Thus, the two substrates of this enzyme are 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide and quinone, whereas its two products are 1-(beta-D-ribofuranosyl)nicotinamide and hydroquinone.
This enzyme belongs to the family of oxidoreductases, specifically those acting on diphenols and related substances as donor with other acceptors. The systematic name of this enzyme class is 1-(beta-D-ribofuranosyl)-1,4-dihydronicotinamide:quinone oxidoreductase. Other names in common use include NRH:quinone oxidoreductase 2, NQO2, NQO2, NAD(P)H:quinone oxidoreductase-2 (misleading), QR2, quinone reductase 2, N-ribosyldihydronicotinamide dehydrogenase (quinone), and NAD(P)H:quinone oxidoreductase2 (misleading).


Aulosphaera

Aulosphaera is a genus of Cercozoa. The genus contains bioluminescent species. It one of two known bioluminescent phaeodarean genera (formerly thought to be radiolarians), the other being "Tuscaridium". The described bioluminescent species is "Aulosphaera triodon" Haeckel, 1887.
Species.
The following species are known (incomplete list):


MRNA surveillance

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.
Overview.
The translation of messenger RNA transcripts into proteins is a vital part of the central dogma of molecular biology. mRNA molecules are, however, prone to a host of fidelity errors which can cause errors in translation of mRNA into quality proteins. RNA surveillance mechanisms are methods cells use to assure the quality and fidelity of the mRNA molecules. This is generally achieved through marking aberrant mRNA molecule for degradation by various endogenous nucleases.
mRNA surveillance has been documented in bacteria and yeast. In eukaryotes, these mechanisms are known to function in both the nucleus and cytoplasm. Fidelity checks of mRNA molecules in the nucleus results in the degradation of improperly processed transcripts before export into the cytoplasm. Transcripts are subject to further surveillance once in the cytoplasm. Cytoplasmic surveillance mechanisms assess mRNA transcripts for the absence of or presence of premature stop codons.
Three surveillance mechanisms are currently known to function within cells: the nonsense-mediated mRNA decay pathway (NMD); the nonstop mediated mRNA decay pathways (NSD); and the no-go mediated mRNA decay pathway (NGD).
Nonsense-mediated mRNA decay.
Overview.
Nonsense-mediated decay is involved in detection and decay of mRNA transcripts which contain premature termination codons (PTCs). PTCs can arise in cells through various mechanisms: germline mutations in DNA; somatic mutations in DNA; errors in transcription; or errors in post transcriptional mRNA processing. Failure to recognize and decay these mRNA transcripts can result in the production of truncated proteins which may be harmful to the organism. By causing decay of C-terminally truncated polypeptides, the NMD mechanism can protect cells against deleterious dominant-negative, and gain of function effects. PTCs have been implicated in approximately 30% of all inherited diseases; as such, the NMD pathway plays a vital role in assuring overall survival and fitness of an organism.
A surveillance complex consisting of various proteins (eRF1, eRF3, Upf1, Upf2 and Upf3) is assembled and scans the mRNA for premature stop codons. The assembly of this complex is triggered by premature translation termination. If a premature stop codon is detected then the mRNA transcript is signalled for degradation – the coupling of detection with degradation occurs.
Seven smg genes (smg1-7) and three UPF genes (Upf1-3) have been identified in "Saccharomyces cerevisiae" and "Caenorhabditis elegans" as essential trans-acting factors contributing to NMD activity. All of these genes are conserved in "Drosophila melanogaster" and further mammals where they also play critical roles in NMD. Throughout eukaryotes there are three components which are conserved in the process of NMD. These are the Upf1/SMG-2, Upf2/SMG-3 and Upf3/SMG-4 complexes. Upf1/SMG-2 is a phosphoprotein in multicellular organisms and is thought to contribute to NMD via its phosphorylation activity. However, the exact interactions of the proteins and their roles in NMD are currently disputed.
Mechanism in mammals.
A premature stop codon must be recognized as different from a normal stop codon so that only the former triggers a NMD response. It has been observed that the ability of a nonsense codon to cause mRNA degradation depends on its relative location to the downstream sequence element and associated proteins. Studies have demonstrated that nucleotides more than 50–54 nucleotides upstream of the last exon-exon junction can target mRNA for decay. Those downstream from this region are unable to do so. Thus, nonsense codons lie more than 50-54 nucleotides upstream from the last exon boundary whereas natural stop codons are located within terminal exons. Exon junction complexes (EJCs) mark the exon-exon boundaries. EJCs are multiprotein complexes that assemble during splicing at a position about 20–24 nucleotides upstream from the splice junction. It is this EJC that provides position information needed to discriminate premature stop codons from natural stop codons. Recognition of PTCs appears to be dependent on the definitions of the exon-exon junctions. This suggests involvement of the spliceosome in mammalian NMD. Research has investigated the possibility of spliceosome involvement in mammalian NMD and has determined this is a likely possibility. Furthermore, it has been observed that NMD mechanisms are not activated by nonsense transcripts that are generated from genes that naturally do not contain introns (e.g., Histone H4, Hsp70, melanocortin-4-receptor).
When the ribosome reaches a PTC the translation factors eRF1 and eRF3 interact with retained EJC complexes though a multiprotein bridge. The interactions of UPF1 with the terminating complex and with UPF2/UPF3 of the retained EJCs are critical. It is these interactions which target the mRNA for rapid decay by endogenous nucleases
Mechanism in invertebrates.
Studies involving organisms such as "S. cerevisiae", "D.melanogaster" and "C. elegans" have shown that PTC recognition involving invertebrate organisms does not involve exon-exon boundaries. These studies suggest that invertebrate NMD occurs independently of splicing. As a result, EJCs which are responsible for marking exon-exon boundaries are not required in invertebrate NMD. Several models have been proposed to explain how PTCs are distinguished from normal stop codons in invertebrates. One of these suggests that there may be a downstream sequence element which functions similar to the exon junctions in mammals. A second model proposes that a widely present feature in mRNA, such as a 3' poly-A tail, might provide the positional information required for recognition. Another model, dubbed the "faux 3'UTR model", suggests that premature translation termination may be distinguished from normal termination because of intrinsic features that may allow it to recognize its presence in an inappropriate environment. These mechanisms, however, have yet to be conclusively demonstrated.
Mechanism in plants.
There are two mechanisms of PTC recognition in plants: according to its distance from the EJC (like in vertebrates) or from the poly-A tail. The NMD mechanism in plants induces the decay of mRNAs containing a 3’UTR longer than 300 nucleotides, that is why the proportion of mRNAs with longer 3'UTRs is much lower in plants than in vertebrates.
NMD avoidance.
mRNAs with nonsense mutations are generally thought to be targeted for decay via the NMD pathways. The presence of this premature stop codon about 50-54 nucleotides 5' to the exon junction appears to be the trigger for rapid decay; however, it has been observed that some mRNA molecules with a premature stop codon are able to avoid detection and decay. In general, these mRNA molecules possess the stop codon very early in the reading frame (i.e. the PTC is AUG-proximal). This appears to be a contradiction to the current accepted model of NMD as this position is significantly 5' of the exon-exon junction.
This has been demonstrated in β-globulin. β-globulin mRNAs containing a nonsense mutation early in the first exon of the gene are more stable than NMD sensitive mRNA molecules. The exact mechanism of detection avoidance is currently not known. It has been suggested that the poly-A binding protein (PABP) appears to play a role in this stability. It has been demonstrated in other studies that the presence of this protein near AUG-proximal PTCs appears to promote the stability of these otherwise NMD sensitive mRNAs. It has been observed that this protective effect is not limited only to the β-globulin promoter. This suggests that this NMD avoidance mechanism may be prevalent in other tissue types for a variety of genes. The current model of NMD may need to be revisited upon further studies.
Nonstop mediated mRNA decay.
Overview.
Nonstop mediated decay (NSD) is involved in the detection and decay of mRNA transcripts which lack a stop codon. These mRNA transcripts can arise from many different mechanisms such as premature 3' adenylation or cryptic polyadenylation signals within the coding region of a gene. This lack of a stop codon results a significant issue for cells. Ribosomes translating the mRNA eventually translate into the 3'poly-A tail region of transcripts and stalls. As a result, it cannot eject the mRNA. Ribosomes thus may become sequestered associated with the nonstop mRNA and would not be available to translate other mRNA molecules into proteins. Nonstop mediated decay resolves this problem by both freeing the stalled ribosomes and marking the nonstop mRNA for degradation in the cell by nucleases. Nonstop mediated decay consists of two distinct pathways which likely act in concert to decay nonstop mRNA.
Ski7 pathway.
This pathway is active when Ski7 protein is available in the cell. The Ski7 protein is thought to bind to the empty A site of the ribosome. This binding allows the ribosome to eject the stuck nonstop mRNA molecule – this even frees the ribosome and allows it to translate other transcripts. The Ski7 is now associated with the nonstop mRNA and it is this association which targets the nonstop mRNA for recognition by the cytosolic exosome. The Ski7-exosome complex rapidly deadenylates the mRNA molecule which allows the exosome to decay the transcript in a 3' to 5' fashion.
Non-Ski7 pathway.
A second type of NSD has been observed in yeast. In this mechanism, the absence of Ski7 results in the loss of poly-A tail binding PABP proteins by the action of the translation ribosome. The removal of these PABP proteins then results in the loss of the protective 5'm7G cap. The loss of the cap results in rapid degradation of the transcript by an endogenous 5'-3' exonuclease such as XrnI.
No-Go decay.
No-Go decay (NGD) is the most recently discovered surveillance mechanism. As such, it is not currently well understood. While authentic targets of NGD are poorly understood, they appear to consist largely of mRNA transcripts on which ribosomes have stalled during translation. This stall can be caused by a variety of factors including strong secondary structures, which may physically block the translational machinery from moving down the transcript. Dom34/Hbs1 likely binds near the A site of stalled ribosomes and may facilitate recycling of complexes. In some cases, the transcript is also cleaved in an endonucleolytic fashion near the stall site; however the identity of the responsible endonuclease remains contentious. The fragmented mRNA molecules are then fully degraded by the exosome in a 3' to 5' fashion and by Xrn1 in a 5' to 3' fashion.
It is not currently known how this process releases the mRNA from the ribosomes, however, Hbs1 is closely related to the Ski7 protein which plays a clear role in ribosome release in Ski7 mediated NSD. It is postulated that Hbs1 may play a similar role in NGD.
Evolution.
It is possible to determine the evolutionary history of these mechanisms by observing the conservation of key proteins implicated in each mechanism. For example: Dom34/Hbs1 are associated with NGD; Ski7 is associated with NSD; and the eRF proteins are associated with NMD. To this end, extensive BLAST searches have been performed to determine the prevalence of the proteins in various types of organisms. It has been determined that NGD Hbs1 and NMD eRF3 are found only in eukaryotes. However, the NGD Dom34 is universal in eukaryotes and archaea. This suggests that NGD appears to have been the first evolved mRNA surveillance mechanism. The NSD Ski7 protein appears to be restricted strictly to yeast species which suggest that NSD is the most recently evolved surveillance mechanism. This by default leaves NMD as the second evolved surveillance mechanism.


Robert M. Nerem

Robert M. Nerem, often referred to as Bob Nerem, a member of the U. S. National Academy of Engineering and the Institute of Medicine, held the Parker H. Petit Distinguished Chair for Engineering in Medicine and Institute Professor Emeritus at the Georgia Institute of Technology where he was an Emeritus Professor until his death.
Biography.
Nerem was born on July 20, 1937 and died March 7, 2020. He received his B.S. from the University of Oklahoma in 1959, his M.Sc. from The Ohio State University in 1961 and his Ph.D. from the same university in 1964. He joined the faculty at Ohio State in the Department of Aeronautical and Astronautical Engineering, being promoted to Professor in 1972 and serving from 1975-1979 as Associate Dean for Research in the Graduate School. From 1979 to 1986 he was Professor and Chairman of the Department of Mechanical Engineering at the University of Houston.
Career.
Nerem joined Georgia Tech in 1987 as the Parker H. Petit Distinguished Chair for Engineering in Medicine. He also was associate Director of the NSF Science and Technology Center for the Emergent Behavior of Integrated Cellular Systems, Director of the Georgia Tech/Emory Center (GTEC) for Regenerative Medicine and from 1995 to 2009 was the Founding Director of the Parker H. Petit Institute for Bioengineering and Bioscience, an interdisciplinary organization for biochemistry, bioengineering, and biology .
He was Technical Editor of the ASME Journal of Biomechanical Engineering from 1988 to 1997.
Leadership.
He was President of the International Federation of Medical and Biological Engineering from 1988 to 1991, of the International Union for Physical and Engineering Sciences in Medicine from 1991 to 1994, and of the Tissue Engineering Society International (now the Tissue Engineering and Regenerative Medicine International Society) from 2002 to 2004. He was Chairman of the U.S. National Committee on Biomechanics (1988–91), and is a Fellow and was the founding President (1992-1994) of the American Institute of Medical and Biological Engineering He was a part-time Senior Advisor for Bioengineering in the National Institute for Biomedical Imaging and Bioengineering at the National Institutes of Health (2003-2006).
Research and publications.
His research interests included biomechanics, cardiovascular devices, cellular engineering, vascular biology, and tissue engineering and regenerative medicine. He is the author of more than 200 publications in refereed articles and 84 publications in book chapters and non-refereed articles, and of two patents.
Nerem's work on "Molecular cloning and characterization of the constitutive bovine aortic endothelial cell nitric oxide synthesis" was published in 1992 in the Journal of Clinical Investigation and has been cited by 671 works in refereed articles. This article details the relationship between endothelial cell nitric oxide synthase (NOS) and vascular homeostasis.
He is also most notable for his research on "The elongation and orientation of cultured endothelial cells in response to shear stress", which was published in 1985 in the Journal of Biomedical Engineering and has been cited by 512 papers in refereed articles. A complete list of Professor Nerem's published work can be found on his Google Scholar Citations page.
His most notable works published from 2007 - 2013 include "Human Mesenchymal Stem Cells Form Multicellular Structures in Response to Applied Cyclic Strain" published in 2009 in the Annals of Biomedical Engineering; "Bone Marrow Derived Mesenchymal Stem Cells Promote Angiogenic Processes in a Time and Dose Dependent Manner InVitro" published in 2009 in the Journal of Tissue Engineering Part A; "A Tissue Engineering Approach to Progenitor Cell Delivery Results in Significant Cell Engraftment and Improved Myocardial Remodeling," published in 2007 in Stem Cells; "Fluid Shear Stress Promotes an Endothelial Phenotype During Early Differentiation of Embryonic Stem Cells," published in 2010 in the Journal of Tissue Engineering Part A; and lastly, "Discovery of Shear- and Side-specific mRNAs and miRNAs in Human Aortic Valvular Cells," published in 2010 in AJP Heart and Circulatory Physiology
Awards.
He is a Fellow of the American Association for the Advancement of Science; of the Council of Arteriosclerosis, American Heart Association the American Physical Society, and the American Society of Mechanical Engineers
In 1989 he received the H.R. Lissner Award from ASME and in 2002 the Pierre Galletti Award from AIMBE.
In 1988 he was elected to the National Academy of Engineering (NAE), and he served on its Council from 1998 to 2004). In 1992 he was elected to the Institute of Medicine of the National Academy of Sciences and in 1998 a Fellow of the American Academy of Arts and Sciences. In 1994, he was elected a Foreign Member of the Polish Academy of Sciences and in 1998 he was made an Honorary Fellow of the Institution of Mechanical Engineers in the United Kingdom. In 2004 he was elected an honorary foreign member of the Japan Society for Medical and Biological Engineering, and in 2006 a Foreign Member of the Swedish Royal Academy of Engineering Sciences. In 2008 he was selected by NAE for the Founders Award.
He holds honorary doctorates from the University of Paris, Imperial College London, and Illinois Institute of Technology.


Befunolol

Befunolol (INN) is a beta blocker with intrinsic sympathomimetic activity used in the management of open-angle glaucoma. It also acts as a β adrenoreceptor partial agonist. Befunolol was introduced in Japan in 1983 by Kakenyaku Kako Co. under the trade name Bentos.


Coelenteramide

Coelenteramide is the oxidized product, or oxyluciferin, of the bioluminescent reactions in many marine organisms that use coelenterazine. It was first isolated as a blue fluorescent protein from "Aequorea victoria" after the animals were stimulated to emit light. Under basic conditions, the compound will break down further into coelenteramine and 4-hydroxyphenylacetic acid.
It is an aminopyrazine.


A-967079

A-967079 is a drug which acts as a potent and selective antagonist for the TRPA1 receptor. It has analgesic and antiinflammatory effects and is used in scientific research, but has not been developed for medical use.


Mycena tintinnabulum

Mycena tintinnabulum is a European species of agaric fungus in the family Mycenaceae. The mycelium, but not the fruit body, is bioluminescent.


Beta-adrenergic agonist

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.
Function.
Activation of β1 receptors induces positive inotropic, chronotropic output of the cardiac muscle, leading to increased heart rate and blood pressure, secretion of ghrelin from the stomach, and renin release from the kidneys.
Activation of β2 receptors induces smooth muscle relaxation in the lungs, gastrointestinal tract, uterus, and various blood vessels. Increased heart rate and heart muscle contraction are associated with the β1 receptors; however, β2 cause vasodilation in the myocardium.
β3 receptors are mainly located in adipose tissue. Activation of the β3 receptors induces the metabolism of lipids.
Medical uses.
Indications of administration for β agonists include:
Side effects.
Although minor compared to those of epinephrine, beta agonists usually have mild to moderate adverse effects, which include anxiety, hypertension, increased heart rate, and insomnia. Other side effects include headaches and essential tremor. Hypoglycemia was also reported due to increased secretion of insulin in the body from activation of β2 receptors.
In 2013, zilpaterol, a β agonist sold by Merck, was temporarily withdrawn due to signs of sickness in some cattle that were fed the drug.
Receptor selectivity.
Most agonists of the beta receptors are selective for one or more beta-adrenoreceptors. For example, patients with low heart rate are given beta agonist treatments that are more "cardio-selective" such as dobutamine, which increases the force of contraction of the heart muscle. Patients who are suffering from a chronic inflammatory lung diseases such as asthma or COPD may be treated with medication targeted to induce more smooth muscle relaxation in the lungs and less contraction of the heart, including first-generation drugs like salbutamol (albuterol) and later-generation medications in the same class.
β3 agonists are currently under clinical research and are thought to increase the breakdown of lipids in obese patients.
β1 agonists.
β1 agonists stimulate adenylyl cyclase activity and opening of calcium channel (cardiac stimulants; used to treat cardiogenic shock, acute heart failure, bradyarrhythmias). Selected examples are:
β2 agonists.
β2 agonists stimulate adenylyl cyclase activity and closing of calcium channel (smooth muscle relaxants; used to treat asthma and COPD). Selected examples are:
Undetermined/unsorted.
These agents are also listed as agonists by MeSH.


Mir-24 microRNA precursor family

The miR-24 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give a mature ~22 nucleotide product. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. miR-24 is conserved in various species, and is clustered with miR-23 and miR-27, on human chromosome 9 and 19. Recently, miR-24 has been shown to suppress expression of two crucial cell cycle control genes, E2F2 and Myc in hematopoietic differentiation and also to promote keratinocyte differentiation by repressing actin-cytoskeleton regulators PAK4, Tsk5 and ArhGAP19.


Biophoton

Biophotons (from the Greek βίος meaning "life" and φῶς meaning "light") are photons of light in the ultraviolet and low visible light range that are produced by a biological system. They are non-thermal in origin, and the emission of biophotons is technically a type of bioluminescence, though bioluminescence is generally reserved for higher luminance luciferin/luciferase systems. The term "biophoton" used in this narrow sense should not be confused with the broader field of biophotonics, which studies the general interaction of light with biological systems.
Biological tissues typically produce an observed radiant emittance in the visible and ultraviolet frequencies ranging from 10−17 to 10−23 W/cm2 (approx 1-1000 photons/cm2/second). This low level of light has a much weaker intensity than the visible light produced by bioluminescence, but biophotons are detectable above the background of thermal radiation that is emitted by tissues at their normal temperature.
While detection of biophotons has been reported by several groups, hypotheses that such biophotons indicate the state of biological tissues and facilitate a form of cellular communication are still under investigation, Alexander Gurwitsch, who discovered the existence of biophotons, was awarded the Stalin Prize in 1941 for his work.
Detection and measurement.
Biophotons may be detected with photomultipliers or by means of an ultra low noise CCD camera to produce an image, using an exposure time of typically 15 minutes for plant materials. Photomultiplier tubes have been used to measure biophoton emissions from fish eggs, and some applications have measured biophotons from animals and humans. Electron Multiplying CCD (EM-CCD) optimized for the detection of ultraweak light have also been used to detect the bioluminescence produced by yeast cells at the onset of their growth.
The typical observed radiant emittance of biological tissues in the visible and ultraviolet frequencies ranges from 10−17 to 10−23 W/cm2 with a photon count from a few to nearly 1000 photons per cm2 in the range of 200 nm to 800 nm.
Proposed physical mechanisms.
Chemi-excitation via oxidative stress by reactive oxygen species and/or catalysis by enzymes (i.e., peroxidase, lipoxygenase) is a common event in the biomolecular milieu. Such reactions can lead to the formation of triplet excited species, which release photons upon returning to a lower energy level in a process analogous to phosphorescence. That this process is a contributing factor to spontaneous biophoton emission has been indicated by studies demonstrating that biophoton emission can be increased by depleting assayed tissue of antioxidants or by addition of carbonyl derivatizing agents. Further support is provided by studies indicating that emission can be increased by addition of reactive oxygen species.
Plants.
Imaging of biophotons from leaves has been used as a method for assaying R gene responses. These genes and their associated proteins are responsible for pathogen recognition and activation of defense signaling networks leading to the hypersensitive response, which is one of the mechanisms of the resistance of plants to pathogen infection. It involves the generation of reactive oxygen species (ROS), which have crucial roles in signal transduction or as toxic agents leading to cell death.
Biophotons have been also observed in the roots of stressed plants. In healthy cells, the concentration of ROS is minimized by a system of biological antioxidants. However, heat shock and other stresses changes the equilibrium between oxidative stress and antioxidant activity, for example, the rapid rise in temperature induces biophoton emission by ROS.
Hypothesized involvement in cellular communication.
In the 1920s, the Russian embryologist Alexander Gurwitsch reported "ultraweak" photon emissions from living tissues in the UV-range of the spectrum. He named them "mitogenetic rays" because his experiments convinced him that they had a stimulating effect on cell division.
In the 1970s Fritz-Albert Popp and his research group at the University of Marburg (Germany) showed that the spectral distribution of the emission fell over a wide range of wavelengths, from 200 to 750 nm. Popp's work on the biophoton emission's statistical properties, namely the claims on its coherence, was criticised for lack of scientific rigour.
One biophoton mechanism focuses on injured cells that are under higher levels of oxidative stress, which is one source of light, and can be deemed to constitute a "distress signal" or background chemical process, but this mechanism is yet to be demonstrated. The difficulty of teasing out the effects of any supposed biophotons amid the other numerous chemical interactions between cells makes it difficult to devise a testable hypothesis. A 2010 review article discusses various published theories on this kind of signaling.
The hypothesis of cellular communication by biophotons was highly criticised for failing to explain how could cells detect photonic signals several orders of magnitude weaker than the natural background illumination.


Maria Menshikova

Princess Maria Alexandrovna Menshikova (26 December 1711 – 1729) was a daughter of Aleksandr Danilovich Menshikov, the favourite of Peter I of Russia.
Life.
She was the eldest daughter and first child of Prince Aleksandr Danilovich Menshikov and Daria Mikhailovna Arsenieva.
Thanks to her father's influence in the Russian court, she was engaged to Grand Duke Peter of Russia, a grandson of Peter the Great. Though they never married their engagement was announced and a dowry discussed. This proposal brought about the disgrace of her father who was subsequently exiled to Siberia.
After following her father into exile, she died of smallpox in Berezovo at age seventeen.


Louis Joseph, Duke of Guise

Louis Joseph de Lorraine "Duke of Guise" and Duke of Angoulême, (7 August 1650 – 30 July 1671) was the only son of Louis, Duke of Joyeuse and Marie Françoise de Valois, the only daughter of Louis-Emmanuel d'Angoulême, Count of Alès, Governor of Provence and son of Charles de Valois Duke of Angoulême, a bastard of Charles IX of France.
Biography.
He was born at the Hôtel de Guise, present Hôtel de Soubise.
His mother having been confined to the abbey of Essay for "imbecility" (that is, mental illness), Louis Joseph was raised by his aunt and legal guardian, Marie de Lorraine, known as ""Mademoiselle de Guise"." Upon the death of his uncle Henry II, Duke of Guise, Louis Joseph succeeded him as head of the House of Guise. Mlle de Guise promptly ordered extensive renovations to the family's stately residence, known as the "Hôtel de Guise."
In October 1663, the young duke and his aunt were received in great pomp in his duchy of Joinville. He received an excellent education, under the guidance of Mlle de Guise's protégé, Philippe Goibaut, and his skills as a horseman were honed by François Roger de Gaignières, his "écuyer".
On 15 June 1667, the young Duke married Élisabeth Marguerite d'Orléans, duchesse d'Alençon, daughter of Gaston, Duke of Orléans, at Saint-Germain-en-Laye. As she was a "petite-fille de France", the marriage was considered a "coup" for the House of Guise, for the bridegroom was a mere "prince étranger": Saint-Simon noted that she was a stickler for receiving the honours due her rank, even at the expense of her husband's dignity at the court of Louis XIV, inasmuch as he "was only entitled to a folding stool." Mademoiselle de Guise carefully trained her nephew to receive Italian nobles and ambassadors who were passing through Paris, and it doubtlessly was in order to add additional luster to the couple's little court that Mlle de Guise invited Marc-Antoine Charpentier to move into an apartment at the Hôtel de Guise and compose for the young couple's chapel.
The couple had one son:
The young Duke was winning the approval of Louis XIV and was given the honor of being at the King's side in military reviews. Then disaster struck. Returning from a visit to the court of Charles II, king of England, he fell ill with smallpox on 18 July 1671, and died twelve days later.
The music for his funeral was composed by Marc-Antoine Charpentier. His body was carried to Joinville to be buried near his ancestors, and his heart was buried at the abbey of Montmartre.


Scintillons

Marine dinoflagellates at night can emit blue light by bioluminescence, a process also called “the phosphorescence of the seas”. Light production in these single celled organisms is produced by small structures in the cytoplasm called scintillons. Among bioluminescent organisms, only dinoflagellates have scintillons.
In the dinoflagellates, the biochemical reaction that produces light involves a luciferase-catalysed oxidation of a linear tetrapyrrole called luciferin.  The dinoflagellate "Lingulodinium polyedra" (previously called "Gonyaulax polyedra") also contains a second protein called luciferin binding protein (LBP) that has been proposed to protect luciferin from non-luminescent oxidation. Luciferin is released from LBP by a decrease in pH, and the same decreased pH also activates the luciferase. Light production in the dinoflagellates occurs in bioluminescent organelles called scintillons and can be stimulated by agitation of the surrounding seawater.
The name scintillon was first used to describe cytoplasmic particles isolated from a bioluminescent species of dinoflagellate that were able to produce a flash of light in response to a decrease in pH. Scintillons were first observed in "L. polyedra" by fluorescence microscopy, where they appear as small blue dots close to the cell surface. This blue fluorescence is due to the presence of the bioluminescence reaction substrate, a naturally fluorescent molecule called luciferin. When light production is stimulated by addition of dilute acid to the cells under the microscope, the site of light production corresponds to the location of the scintillons. Furthermore, the natural luciferin fluorescence is reduced after the light producing reaction.
Cells observed under the electron microscope after a technique involving rapid freezing of the cells followed by substitution of water with a polymer (Fast-freeze Fixation/Freeze Substitution) contain a large number of electron dense bodies around the cell periphery. These structures correspond in size and location to the fluorescent bodies confirmed to be scintillons by their light emission, and they show colocalization of anti-luciferase and anti-LBP labeling meaning both bioluminescence proteins are found in the structures. Scintillons appear as cytoplasmic drops hanging in the vacuolar space, as they are almost completely surrounded by the vacuolar membrane. This structure led to the proposal that a voltage gated proton channel in the vacuolar membrane could allow an action potential to be propagated along the vacuolar membrane. This would in turn let protons enter into the cytoplasm around all the scintillons in the cells virtually simultaneously producing an intense but brief flash of light. Voltage gated proton channels were subsequently identified in a dinoflagellate confirming their predicted existence
Scintillons have been extensively purified from "L. polyedra" by centrifugation, and these purified scintillon preparations contain luciferase and luciferin binding protein as the only detectable protein components. The amount of luciferase, LBP and luciferin all vary over the course of a daily (circadian) period, as do the number of scintillons in the cell. These observations suggest that the circadian control of bioluminescence involves a daily synthesis and degradation of luciferase and LBP. When synthesized, these two proteins aggregate together and migrate to the vacuole membrane where LBP binds luciferin and the scintillons acquires an ability to produce light upon stimulation.
Scintillons are not identical in different species. Scintillons isolated from dinoflagellates belonging to the genus "Pyrocystis" such as "P. lunula" (previously "Dissodinium lunula") or "P. noctiluca" are less dense than those of "L. polyedra" and do not contain LBP. Little is known about the structure or composition of scintillons in species other than "L. polyedra".


Agon (comics)


Transposase-2 RNA motif

The Transposase-2 RNA motif is a conserved RNA structure that was discovered by bioinformatics.
These RNAs are usually located nearby to genes that encode transposases, which are the main component of transposons. Many kinds of transposon are found adjacent to inverted repeats, which could be mistaken for simple RNA secondary structures. Therefore Transposase-2 RNAs could reflect this side effect of transposon replication, and not encode a separate RNA. However, the consistency of the RNA's alignment (e.g., all RNAs have the complete secondary structure, with no truncations) is not typical of transposon-associated repeats. Assuming that Transposase-2 RNAs do function as RNAs, they might function as cis-regulatory elements to regulate the transposase genes, or they might operate in "trans" as small RNAs that participate in the transposon's biology in some other way.
Transposase-2 motif RNAs are found in two different bacterial phyla: Actinobacteria and Firmicutes.
Although their presence in two phyla could suggest that they are highly diverged, and have a very old origin, in view of their association with transposons, it is fairly likely that the widespread distribution of these RNAs is a result of relatively recent horizontal gene transfer.


C-sis internal ribosome entry site (IRES)

The c-sis internal ribosome entry site (IRES) is a RNA element found in the 5' UTR of the PDGF beta chain gene. The internal ribosome entry site contains three modules that can individually mediate internal ribosome entry. However, the full length sequence is required for maximal IRES activity. It is thought that the three IRES elements are somehow responsive to cellular changes and act to regulate the level of translation.


UxuA RNA motif

The "uxuA" RNA motif is a conserved RNA structure that was discovered by bioinformatics.
"uxuA" motif RNAs are found in the bacterial genus "Vibrio".
"uxuA" RNAs occur upstream of genes that encode mannonate dehydratase, which functions as part of the catabolism of glucuronate. This gene association could suggest that "uxuA" RNAs operate as cis-regulatory elements to control expression of the mannonate dehydratase genes. However, since the RNAs are found in relatively closely related organisms, it is possible that the apparent gene association arose by chance. Therefore, "uxuA" RNAs might also function in "trans" as small RNAs.


Bromopride

Bromopride (INN) is a dopamine antagonist with prokinetic properties widely used as an antiemetic, closely related to metoclopramide. It is not available in the United States.
Bromopride appears to be safe and effective for use in pregnancy.
Indications.
Bromopride is indicated in the treatment of nausea and vomiting, including postoperative nausea and vomiting (PONV); gastroesophageal reflux disease (GERD/GORD); and as preparation for endoscopy and radiographic studies of the gastrointestinal tract. The manufacturer also claims it is valuable in, among other indications, hiccups and gastrointestinal adverse effects of radiation therapy.
Adverse effects.
Bromopride is generally well tolerated; the most common adverse effects of its use are somnolence and fatigue. Bromopride may rarely cause extrapyramidal symptoms and, as with metoclopramide, may increase prolactin levels.
Chemistry.
Bromopride is a substituted benzamide, closely related to metoclopramide. It is identical to metoclopramide except for the presence of a bromine atom where metoclopramide has a chlorine substituent.
Availability.
Bromopride is not available in the United States or the United Kingdom. It is marketed in Brazil by Sanofi-Synthélabo under the trade name "Digesan", by LIBBS under the name Plamet, and as a generic drug.


Jaffe reaction

The Jaffe reaction is a colorimetric method used in clinical chemistry to determine creatinine levels in blood and urine. In 1886, Max Jaffe (1841–1911) wrote about its basic principles in the paper "Über den Niederschlag, welchen Pikrinsäure in normalem Harn erzeugt und über eine neue Reaction des Kreatinins" in which he described the properties of creatinine and picric acid in an alkaline solution. The color change that occurred was directly proportional to the concentration of creatinine, however he also noted that several other organic compounds induced similar reactions. In the early 20th century, Otto Folin adapted Jaffe's research into a clinical procedure. The Jaffe reaction, despite its nonspecificity for creatinine, is still widely employed as the method of choice for creatinine testing due to its speed, adaptability in automated analysis, and cost-effectiveness, and is the oldest methodology continued to be used in the medical laboratory. It is this nonspecificity that has motivated the development of new reference methods for creatinine analysis into the 21st century.
Max Jaffe.
Max Jaffe was a distinguished 19th-century German biochemist, pathologist, pharmacologist, and professor. He was born on July 25, 1841, in what was formerly Grünberg, Silesia and is now Zielona Góra, Poland. While attending medical school at the University of Berlin, he studied under Ludwig Traube and Wilhelm Kühne. Afterward, he worked as an assistant in a medical clinic in Königsberg. There, he co-authored a paper on putrid sputum with Ernst Viktor von Leyden that led to the discovery of certain characteristic putrid processes in the lungs. After earning his degree in internal medicine, he served in the Franco-Prussian War and was decorated with the Iron Cross Second Class. The title of "Extraordinary Professor of Medicinal Chemistry" was awarded to him in 1872 and the following year he became the first "Ordinary Professor of Pharmacology" at the University of Königsberg. He was promoted to director of the "Laboratory for Medical Chemistry and Experimental Pharmacology" in 1878 and became a member of the "Deutsche Akademie der Naturforscher Leopoldina" in 1882. Aside from studying creatinine, he is also known for discovering urobilin and urobilinogen in urine and found that these compounds originated in bile. He died on October 26, 1911 in Berlin and is buried in the Weißensee Cemetery.
"...eine neue Reaktion des Kreatinins".
Creatinine was first synthesized "in vitro" by Ivan Horbaczewski in 1885. One year later, Jaffe's research was published in the paper "Über den Niederschlag, welchen Pikrinsäre in normalem Harn erzeugt und über eine neue Reaction des Kreatinins". Jaffe had noticed that, when mixed in a sodium hydroxide (NaOH) solution, picric acid and creatinine formed a reddish-orange color and needle-like crystal precipitate. By using zinc chloride in a process known as the "Neubauer reaction", and then performing the Weyl's test, a colorimetric reaction using sodium nitroprusside (SNP), he determined that the precipitated compound was a double salt of the solution. Although he found the amount of precipitate directly proportional to the creatinine concentration, he also noted that the reaction was highly nonspecific and could be observed with many other organic compounds.
Clinical applications.
Although Jaffe's name is synonymous with clinical creatinine testing, his paper only described the principle behind what would later become the enduring method. It was Otto Folin (1867–1934), a Harvard biochemist, who adapted Jaffe's research—abandoning the standard Neubauer reaction of the time—and published several papers using the Jaffe reaction to analyze creatinine levels in both blood and urine. Folin began using the picric acid procedure in 1901 and included it in his 1916 "Lab Manual of Biological Chemistry". During his career, Folin modified and improved several quantitative colorimetric procedures, the first of which was for creatinine. He took advantage of technology available at the time, using a Duboscq colorimeter for measurement precision, and is credited for introducing colorimetry into modern biochemical analysis.
Folin's research did not focus on creatinine as a renal function indicator. Since the precursors of creatinine are synthesized in the liver, at this point in history, creatinine was considered indicative of liver function. It was not until 1926 that Poul Kristian Brandt Rehberg suggested creatinine was a significant marker for renal function.
Interfering chromogens.
The nonspecificity of Jaffe's reaction causes falsely elevated creatinine results in the presence of protein, glucose, acetoacetate, ascorbic acid, guanidine, acetone, cephalosporins, aminoglycosides (mainly streptomycin), ketone bodies, α-keto acids, and other organic compounds. Ammonium is also an interferent; if the sample is plasma, care needs to be taken that ammonium heparin has not been used as an anticoagulant. Nonspecificity is markedly decreased in urine samples since urine creatinine levels are much higher than blood and it generally does not contain significant levels of interfering chromogens.
The Jaffe reaction's nonspecificity remains an important issue. Diabetes patients are a high-risk population to develop chronic kidney disease (CKD) and, therefore, interferences from glucose and acetoacetate are of particular importance.
Artifacts such as hemolysis, lipemia, and icteremia can also affect accuracy. Hemolysis releases Jaffe-reacting chromogens and therefore will falsely increase results. Lipemia and icteremia can inhibit optical readings and falsely decrease values. The procedure has been developed over time with the intention to minimize these interferents.
From Neubauer to SRM 967.
Before Jaffe, Neubauer described a similar precipitation reaction by mixing creatinine with zinc chloride (ZnCl2) and performing a Weyl's test—the addition of SNP to NaOH and then incubating with acetic acid (CH3CO2H) to develop a color change. Until Folin developed Jaffe's reaction into a clinical procedure, Neubauer's method was how creatinine was measured. As Folin's method evolved, various techniques were implemented to remove Jaffe-reacting substances, mostly protein, from the sample and increase specificity. By the 1950s, precipitated aluminum silicate, called Lloyd's reagent, was being used to remove protein from serum, further improving accuracy. Fuller's earth was also used for protein-binding, but the reference method until the 1980s was adsorption with Lloyd's reagent. New concerns arose due to non-standardization of procedures; different labs were reading results at different endpoints. This problem was resolved with the advent of automated analyzers in the 1960s and 1970s, which introduced a kinetic reading of results rather than a specific endpoint. Kinetic Jaffe methods involve mixing serum with alkaline picrate and reading the rate of change in absorption spectrophotometrically at 520 nm. This not only standardized the procedure, but also removed the need for sample deproteinization. It also introduced two new problems—analyzers used an algorithmic compensation to correct for pseudochromogens, and calibrations were not yet standardized between instruments.
The 1980s saw several new technologies that promised to change the way creatinine testing was done. Enzymatic and ion-exchange methods provided better accuracy but had other drawbacks. Enzymatic methods reduced some interferences but other new ones were discovered. High-performance liquid chromatography, HPLC, was more sensitive and specific, and had become the new reference method endorsed by the American Association for Clinical Chemistry. HPLC addressed the shortcomings of Jaffe-based methods, but was labor-intensive, expensive, and therefore impractical for routine analysis of the most frequently ordered renal analyte in medical labs. Simple, easily automated and cost-effective, Jaffe-based methods have persisted into the 21st century, despite their imperfections.
By 2006, isotope dilution mass spectrometry (IDMS) became the reference method. To improve the accuracy in creatinine testing, new standards were developed by the National Institute of Standards and Technology (NIST). The College of American Pathologists (CAP) and the National Kidney Disease Education Program (NKDEP) collaborated with NIST to develop a new control reference called "standard reference material 967" (SRM 967). SRM 967 aims to standardize calibration of creatinine testing, including Jaffe methods. Use of both IDMS and SRM 967 are currently recommended by the National Institutes of Health.


Actino-pnp RNA motif

The Actino-"pnp" RNA motif is a conserved structure found in actinobacteria that is apparently in the 5' untranslated regions of genes predicted to encode exoribonucleases. The RNA element's function is likely analogous to an RNA structure found upstream of polynucleotide phosphorylase genes in "E. coli" and related enterobacteria. In this latter system, the polynucleotide phosphorlyase gene regulates its own expression levels by a feedback mechanism that involves its activity upon the RNA structure. However, the "E. coli" RNA appears to be structurally unrelated to the Actino-"pnp" motif.


Yunnanin A

Yunnanin A is a biologically active cyclic peptide.


Methylation induced premeiotically

In molecular biology, methylation induced premeiotically (MIP) is a process by which cytosines within repeated DNA sequences are "de novo" methylated prior to the sexual cycle. This process was first described in the ascomycete "Ascobolus immersens". MIP is dependent upon the gene "masc1" which encodes a cytosine methyltransferase-like protein.
At least one major function of the process appears to be genome defense. Related functions have been found in other fungi, including "Neurospora" and "Aspergillus" species.


Opine dehydrogenase

In enzymology, an opine dehydrogenase () is an enzyme that catalyzes the chemical reaction
The 3 substrates of this enzyme are (2S)-2-{[1-(R)-carboxyethyl]amino}pentanoate, NAD+, and H2O, whereas its 4 products are L-2-aminopentanoic acid, pyruvate, NADH, and H+.
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is (2S)-2-{[1-(R)-carboxyethyl]amino}pentanoate:NAD+ oxidoreductase (L-aminopentanoate-forming). Other names in common use include (2S)-2-{[1-(R)-carboxyethyl]amino}pentanoate dehydrogenase (NAD+, and L-aminopentanoate-forming).