Carbohydrate metabolism

Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
Carbohydrates are central to many essential metabolic pathways. Plants synthesize carbohydrates from carbon dioxide and water through photosynthesis, allowing them to store energy absorbed from the sunlight internally. When animals and fungi consume plants, they use cellular respiration to break down these stored carbohydrates to make energy available to cells. Both animals and plants temporarily store the released energy in the form of high-energy molecules, such as ATP, for use in various cellular processes.
Humans can consume a variety of carbohydrates, digestion breaks down complex carbohydrates into a few simple monomers (monosaccharides) for metabolism: glucose, fructose, mannose and galactose. Glucose is distributed to cells in the tissues, where it is broken down or stored as glycogen. In aerobic respiration, glucose and oxygen are metabolized to release energy, with carbon dioxide and water as endproducts. Most of the fructose and galactose travel to the liver, where they can be converted to glucose and fat.
Some simple carbohydrates have their own enzymatic oxidation pathways, as do only a few of the more complex carbohydrates. The disaccharide lactose, for instance, requires the enzyme lactase to be broken into its monosaccharide components, glucose and galactose.
Metabolic pathways.
Glycolysis.
Glycolysis is the process of breaking down a glucose molecule into two pyruvate molecules, while storing energy released during this process as ATP and NADH. Nearly all organisms that break down glucose utilize glycolysis. Glucose regulation and product use are the primary categories in which these pathways differ between organisms. In some tissues and organisms, glycolysis is the sole method of energy production. This pathway is common to both anaerobic and aerobic respiration.
Glycolysis consists of ten steps, split into two phases. During the first phase, it requires the breakdown of two ATP molecules. During the second phase, chemical energy from the intermediates is transferred into ATP and NADH. The breakdown of one molecule of glucose results in two molecules of pyruvate, which can be further oxidized to access more energy in later processes.
Glycolysis can be regulated at different steps of the process through feedback regulation. The step that is regulated the most is the third step. This regulation is to ensure that the body is not over-producing pyruvate molecules. The regulation also allows for the storage of glucose molecules into fatty acids. There are various enzymes that are used throughout glycolysis. The enzymes upregulate, downregulate, and feedback regulate the process.
Gluconeogenesis.
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms.[1] In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) - used by humans and many other animals to maintain blood glucose levels, avoiding low levels (hypoglycemia).[2] In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.[3] In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.
In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to pyruvate or intermediates of glycolysis (see figure). For the breakdown of proteins, these substrates include glucogenic amino acids (although not ketogenic amino acids); from breakdown of lipids (such as triglycerides), they include glycerol, odd-chain fatty acids (although not even-chain fatty acids, see below); and from other parts of metabolism they include lactate from the Cori cycle. Under conditions of prolonged fasting, acetone derived from ketone bodies can also serve as a substrate, providing a pathway from fatty acids to glucose.[4] Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting.[5]
The gluconeogenesis pathway is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the pathway leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from fatty acid catabolism via beta oxidation.[6]
Glycogenolysis.
Glycogenolysis refers to the breakdown of glycogen. In the liver, muscles, and the kidney, this process occurs to provide glucose when necessary. A single glucose molecule is cleaved from a branch of glycogen, and is transformed into glucose-1-phosphate during this process. This molecule can then be converted to glucose-6-phosphate, an intermediate in the glycolysis pathway.
Glucose-6-phosphate can then progress through glycolysis. Glycolysis only requires the input of one molecule of ATP when the glucose originates in glycogen. Alternatively, glucose-6-phosphate can be converted back into glucose in the liver and the kidneys, allowing it to raise blood glucose levels if necessary.
Glucagon in the liver stimulates glycogenolysis when the blood glucose is lowered, known as hypoglycemia. The glycogen in the liver can function as a backup source of glucose between meals. Liver glycogen mainly serves the central nervous system. Adrenaline stimulates the breakdown of glycogen in the skeletal muscle during exercise. In the muscles, glycogen ensures a rapidly accessible energy source for movement.
Glycogenesis.
Glycogenesis refers to the process of synthesizing glycogen. In humans, glucose can be converted to glycogen via this process. Glycogen is a highly branched structure, consisting of the core protein Glycogenin, surrounded by branches of glucose units, linked together. The branching of glycogen increases its solubility, and allows for a higher number of glucose molecules to be accessible for breakdown at the same time. Glycogenesis occurs primarily in the liver, skeletal muscles, and kidney. The Glycogenesis pathway consumes energy, like most synthetic pathways, because an ATP and a UTP are consumed for each molecule of glucose introduced.
Pentose phosphate pathway.
The pentose phosphate pathway is an alternative method of oxidizing glucose. It occurs in the liver, adipose tissue, adrenal cortex, testis, milk glands, phagocyte cells, and red blood cells. It produces products that are used in other cell processes, while reducing NADP to NADPH. This pathway is regulated through changes in the activity of glucose-6-phosphate dehydrogenase.
Fructose metabolism.
Fructose must undergo certain extra steps in order to enter the glycolysis pathway. Enzymes located in certain tissues can add a phosphate group to fructose. This phosphorylation creates fructose-6-phosphate, an intermediate in the glycolysis pathway that can be broken down directly in those tissues. This pathway occurs in the muscles, adipose tissue, and kidney. In the liver, enzymes produce fructose-1-phosphate, which enters the glycolysis pathway and is later cleaved into glyceraldehyde and dihydroxyacetone phosphate.
Galactose metabolism.
Lactose, or milk sugar, consists of one molecule of glucose and one molecule of galactose. After separation from glucose, galactose travels to the liver for conversion to glucose. Galactokinase uses one molecule of ATP to phosphorylate galactose. The phosphorylated galactose is then converted to glucose-1-phosphate, and then eventually glucose-6-phosphate, which can be broken down in glycolysis.
Energy production.
Many steps of carbohydrate metabolism allow the cells to access energy and store it more transiently in ATP. The cofactors NAD+ and FAD are sometimes reduced during this process to form NADH and FADH2, which drive the creation of ATP in other processes. A molecule of NADH can produce 1.5–2.5 molecules of ATP, whereas a molecule of FADH2 yields 1.5 molecules of ATP.
Typically, the complete breakdown of one molecule of glucose by aerobic respiration (i.e. involving both glycolysis and the citric-acid cycle) is usually about 30–32 molecules of ATP. Oxidation of one gram of carbohydrate yields approximately 4 kcal of energy.
Hormonal regulation.
Glucoregulation is the maintenance of steady levels of glucose in the body.
Hormones released from the pancreas regulate the overall metabolism of glucose. Insulin and glucagon are the primary hormones involved in maintaining a steady level of glucose in the blood, and the release of each is controlled by the amount of nutrients currently available. The amount of insulin released in the blood and sensitivity of the cells to the insulin both determine the amount of glucose that cells break down. Increased levels of glucagon activates the enzymes that catalyze glycogenolysis, and inhibits the enzymes that catalyze glycogenesis. Conversely, glycogenesis is enhanced and glycogenolysis inhibited when there are high levels of insulin in the blood.
The level of circulatory glucose (known informally as "blood sugar"), as well as the detection of nutrients in the Duodenum is the most important factor determining the amount of glucagon or insulin produced. The release of glucagon is precipitated by low levels of blood glucose, whereas high levels of blood glucose stimulates cells to produce insulin. Because the level of circulatory glucose is largely determined by the intake of dietary carbohydrates, diet controls major aspects of metabolism via insulin. In humans, insulin is made by beta cells in the pancreas, fat is stored in adipose tissue cells, and glycogen is both stored and released as needed by liver cells. Regardless of insulin levels, no glucose is released to the blood from internal glycogen stores from muscle cells.
Carbohydrates as storage.
Carbohydrates are typically stored as long polymers of glucose molecules with glycosidic bonds for structural support (e.g. chitin, cellulose) or for energy storage (e.g. glycogen, starch). However, the strong affinity of most carbohydrates for water makes storage of large quantities of carbohydrates inefficient due to the large molecular weight of the solvated water-carbohydrate complex. In most organisms, excess carbohydrates are regularly catabolised to form acetyl-CoA, which is a feed stock for the fatty acid synthesis pathway; fatty acids, triglycerides, and other lipids are commonly used for long-term energy storage. The hydrophobic character of lipids makes them a much more compact form of energy storage than hydrophilic carbohydrates. Gluconeogenesis permits glucose to be synthesized from various sources, including lipids.
In some animals (such as termites) and some microorganisms (such as protists and bacteria), cellulose can be disassembled during digestion and absorbed as glucose.


Eric Westhof

Éric Westhof is a French biochemist born in Uccle (Belgium) on July 25, 1948. He is a member of the Academie des sciences, head of Education and Training (DEF) and a member of the Board of Directors of the "La Main à la pâte" Foundation. He is professor emeritus of structural biochemistry at the University of Strasbourg at the Institute of Molecular and Cellular Biology.
Biography.
After obtaining a bachelor's degree in physical sciences from the University of Liège, he carried out research work at the Regensburg Universität (Germany) on a EURATOM grant with a view to obtaining a doctorate from the University of Liège in 1974. He then became a research associate (on a Fulbright-Hays fellowship) at the University of Wisconsin until 1977 in Professor M. Sundaralingam's laboratory. Thanks to an EMBO grant, he then established himself in 1981 at the Institute of Molecular and Cellular Biology of the Centre national de la recherche scientifique (IBMC-CRNS), affiliated with the Université Louis Pasteur (ULP-Strasbourg) in France. In 1984, he obtained a position as a research fellow (CR1) and has been a professor of structural biochemistry since 1988. From 2005 to 2016, he was director of the CNRS Research Unit "Architecture and Reactivity of RNA" at the Institute of Molecular and Cellular Biology (IBMC), where he was director from 2006 to 2016. From 2003 to 2007 he was chairman of the Research Commission of the Faculty of Life Sciences of Louis Pasteur University, where he was an elected member of the Scientific Council from 2002-2006. He was then elected vice president research and doctoral training (2007-2008). Together with Alain Beretz, he is involved in the merger of the three Strasbourg universities and becomes vice-president research and doctoral training at the University of Strasbourg between 2009 and 2012.
Eric Westhof is executive editor of "RNA" journal (CSHP), "Nucleic Acids Research" (OUP), and the "Journal of Molecular Recognition" (Wiley).
Research area.
His research area concerns the structural biology of nucleic acids (stereochemistry, topology, modelling and bioinformatics) and especially ribonucleic acid molecules (RNA). He has developed computer tools dedicated to crystallographic refinement and computer manipulation of nucleic acids. These have led to excellent three-dimensional RNA structures. For more than a decade, these tools have been used by nucleic acid crystallographers in many countries.  At a time when only the structure of the transfer RNA was known, he and François Michel proposed a three-dimensional model of the structure of the core of group I autocatalytic introns.  Ten years later, crystallography confirms the architecture of the model, thus offering a vast field of new applications in structural biology. Folding of other ribozymes (hepatitis delta virus, ribonuclease P, hairpin ribozyme) has also been proposed. Several years after these publications, independent crystal structures have shown the accuracy of the architecture of the folds and interactions responsible for self-assembly. His expertise in RNA structure modeling has led him to collaborate with several groups. Thus, with F. Eckstein and T. Tuschl, the first model of the hammer-headed ribozyme was produced on the basis of fluorescence data. With Dr. Kochoyan, the first models of RNA aptamers modelled from nuclear magnetic resonance data were presented. With W. Filipowicz and F. Kolb, a DICER double-stranded RNA binding and cleavage model explaining the maturation of microRNAs has been published.
Analysis of crystallographic structures and comparisons with theoretical models then made it possible to establish predictive rules for RNA folding. With Neocles Leontis, Eric Westhof proposed an ontology of pairs between nucleic acid bases that allows automatic annotation of crystal structures and bioinformatic research of structured regions in RNA sequences; This structural bioinformatics work by the RNA has made it possible to identify a set of constraints in sequence allowing architectural models of RNA. This set of rules and constraints, which can be read from sequence alignments and manipulated by computer, allows them to deduce RNA architectures, which is essential for our understanding of the function and structural evolution of RNAs.
Eric Westhof has extended his physico-chemical, structural and dynamic studies of RNAs to functional and evolutionary aspects, as well as to the prediction of strong and specific molecular interactions with molecules of therapeutic interest. The crystallographic structures of many complexes between aminoglycoside antibiotics and the site A of the 30S particle of eubacterial ribosomes clearly show the origin of the binding specificity and resistance induced by these aminoglycosides. Recently, with Marat and Gula Yusupov and their collaborators, a detailed understanding of decoding errors due to tautomeric forms of the pairs between G and U has been demonstrated. In parallel with Henri Grosjean, a new representation of the genetic code anchored in ribosome structures related to messenger RNA and transfer RNA and integrating the very numerous observations on the effects of changes in transfer RNAs is of great interest.
Other articles based on the analysis of crystallographic and bioinformatic structures have generated a large number of citations. In 1984, Eric Westhof and Marc van Regenmortel's team demonstrated a correlation that proved to be central in immunochemistry: antigen epitopes generally have greater mobility than the less immunogenic regions of proteins. With Pascal Auffinger, the importance and specificity of halogen atom-mediated bonds in biological macromolecules and nucleic acids was established. Finally, with the Genolevures consortium, they annotated the non-coding RNAs of yeasts in addition to the coding genes and compared them between yeasts.
Nucleic acid base pairs.
The natural bases of nucleic acids form a great variety of base pairs with at least two hydrogen bonds between them. These hydrogen bonds can occur between atoms belonging to any of the three edges of the nucleic acid edges. The possible combinations lead to a classification in twelve main families, with the Watson-Crick family being one of them. In a given family, some of the base pairs are isosteric between them, meaning that the positions and the distances between the C1’ carbon atoms are very similar. The isostericity of Watson-Crick pairs between the complementary bases forms the basis of RNA helices and of the resulting RNA secondary structure (covariation). In addition, several defined suites of non-Watson-Crick base pairs assemble into RNA modules that form recurrent, rather regular, building blocks of the tertiary architecture of folded RNAs. RNA modules are intrinsic to RNA architecture are therefore disconnected from a biological function specifically attached to a RNA sequence. RNA modules occur in all kingdoms of life and in structured RNAs with diverse functions. Because of chemical and geometrical constraints, isostericity between non-Watson-Crick pairs is restricted and this leads to higher sequence conservation with coevolution (neutral networks) in RNA modules with, consequently, greater difficulties in extracting 3D information from sequence analysis.
Tautomerism and recognition of nucleic acid base pairs.
Nucleic acid helices are recognized in several biological processes like during nucleic acid replication or ribosomal translational decoding. In polymerases and the ribosomal decoding site, the recognition occurs on the minor groove sides of the helical fragments. With or without the use of alternative conformations, protonated or tautomeric forms of the bases, some base pairs with Watson-Crick-like geometries can form and be stabilized. Several of these pairs with Watson-Crick-like geometries extend the concept of isostericity beyond the number of isosteric pairs formed between complementary bases. These observations set therefore limits and constraints to geometric selection in molecular recognition of complementary Watson-Crick pairs for fidelity in replication and translation processes.
Ribosomal decoding fidelity and efficiency.
The basic principles of mRNA decoding are conserved among all extant life forms. We present an integrative view all the complex interaction networks between mRNA, tRNA, and rRNA : the intrinsic stability of codon-anticodon trimers, the spatial conformation of the anticodon stem-loop of tRNA, the presence of modified nucleotides, the occurrence of non-Watson-Crick pairs in the codon-anticodon helix and the interactions with bases of rRNA at the decoding site. We derive an information-rich, alternative representation of the genetic code table. The new organization of the 64 codons is circular with an asymmetric distribution of codons that leads to a clear segregation between GC-rich 4-codon boxes and AU-rich 2:2-codon and 3:1-codon boxes. The advantage of integrating data in this circular decoding system is that all tRNA sequence variations can be visualized, within an internal structural and energy framework, for each organism and anticodon. Within this new representation, the multiplicity and complexity of nucleotide modifications, especially at positions 34 and 37 of the anticodon loop, segregate meaningfully and correlate well with the necessity to stabilize AU-rich codon-anticodon pairs and to avoid miscoding in split codon boxes. This structure-based network of interactions results in an energetically uniform decoding of all tRNAs that can adapt to the cellular constraints. The evolution and expansion of the genetic code is viewed as originally based on GC content with the progressive introduction of A/U together with tRNA modifications and the modification enzymes. This allows for a great diversity of codon usage depending on GC content of the genome and on the number and types of tRNAs. The representation should help the engineering of the genetic code to non-natural amino acids.
In summary, in order to maximize the diversity in codon usage without increasing the numberf different tRNAs (for decoding the 61 sense codons), cells developed sophisticated arrays of tRNA modifications that are anchored in cellular metabolic enzymatic pathways. The genetic code is not translated universally and several differences exist between organisms and in the three kingdoms of life. In each organism, there is a very strong connectivity between the elements responsible for the reliability and efficiency of the decoding process of the genetic code. The multiplicity of these highly interconnected elements and the integration of the various biological information flows ultimately allow for the maintenance of subtle cellular homeostasis and place the processes of translation at the center of cellular activities.


GyrA RNA motif

The "gyrA" RNA motif is a conserved RNA structure identified by bioinformatics. The RNAs are present in multiple species of bacteria within the order Pseudomonadales. This order contains the genus "Pseudomonas", which includes the opportunistic human pathogen "Pseudomonas aeruginosa" and "Pseudomonas syringae", a plant pathogen.
"gyrA" RNAs are always found in the presumed 5' untranslated regions of "gyrA" genes, which encodes a protein forming a subunit of a DNA gyrase. Resistance to the antibiotic ciprofloxacin in "Pseudomonas" is often achieved via mutations in the "gyrA" gene. Because of its positioning, the "gyrA" RNA motif was hypothesized to be a cis-regulatory element acting up the downstream "gyrA" genes. However, "gyrA" was previously regarded as a gene whose level of expression is consistent in a wide variety of growth conditions.


Medusa (comics)

Medusa (Medusalith Amaquelin-Boltagon) is a fictional character appearing in American comic books published by Marvel Comics. Her name and aspects of her character are derived from Greek mythology as her hair has prehensile attributes like that of Medusa the Gorgon's hair. This character has psychokinetic control over her hair, a power she obtained through Terrigenesis. Due to this, she is able to expand it to double its normal length, pick locks with it, remotely lift objects (both animate and inanimate), and she often uses it as a rope to contain objects and people.
Serinda Swan portrayed Medusa in the character's live-action debut in the 2017 television series "Inhumans".
Publication history.
Medusa first appeared in "Fantastic Four" #36 (1965), and was created by Stan Lee and Jack Kirby. She appears first in flashback, then in costume as part of the fledgling "Frightful Four". She appears in #38, 41, 42, 43, 44-48 and in various subplot glimpses from #49-62. The Inhumans also appear in "Fantastic Four" # 82-83, with Medusa. They are granted their first new adventure in "Fantastic Four Annual" #5, and a solo series in the split-book "Amazing Adventures" (volume 2) #1-10. The first four installments are written and drawn by Jack Kirby. The second four installments are written by Roy Thomas and illustrated by Neal Adams. That storyline flows into the ongoing "Kree-Skrull War" in the "Avengers" title #94-97.
Medusa has also figured prominently in the 12 part maxi-series "The Inhumans" written by Paul Jenkins and illustrated by Jae Lee in the 1990s.
Medusa appears in the new series "FF" by Matt Fraction and Mike Allred, which debuted in November 2012.
Beginning in May 2015, Medusa appeared as one of the main characters in "A-Force", an all-female Avengers spin-off being launched by G. Willow Wilson, Marguerite Bennett, and Jorge Molina during Marvel's "Secret Wars" crossover.
In 2017, Medusa appears in an early adventure with the Frightful Four, published as Avengers 1.1- 5.1 This five issue mini-series is positioned between "Avengers" (vol. 1) #16 & 17, as a side story when the evil team thinks they have killed the Fantastic Four (in "Fantastic Four" #38) but no one knows it. They publicly attack Captain America and his new team of replacements after their press conference to earn some "street cred". They are publicly beaten in a rematch in issue 4.1 but Medusa presumably flees before the team's final cameo in 5.1 where they are preparing a grave for her as a "traitor".
Fictional character biography.
Medusa belongs to the race of Inhumans, a species of prehistoric earthlings mutated by the Terrigen Mists produced deep under the Inhuman city-state of Attilan, presently located in the oxygen-rich Blue Area of the Moon. Crystal (who later became the wife of the Avenger Quicksilver) is Medusa's younger sister. Considered a member of Attilan's Royal Family, Medusa's parents chose to expose her to the Terrigen Mists when she was a child.
During her adolescent years Medusa would often visit her distant cousin Black Bolt during his confinement, and she learned to communicate with him through body language. During the course of these visits, the two fell in love and became engaged. She attended Black Bolt's release from his isolation cell at the age of eighteen, and witnessed the first confrontation between Black Bolt and his insane brother Maximus the Mad. Maximus also claims to be in love with Medusa, and has made frequent attempts to usurp both the throne of Attilan as well as his brother's bride-to-be. It was in Maximus' first successful attempt to take the throne that Medusa was knocked off a sky-sled by the Trikon and afflicted with amnesia. She left Attilan, and wandered Europe as a thief.
Still suffering from amnesia, Medusa joined super-villain team the Frightful Four and battled the Fantastic Four on three separate occasions.
She was then pursued by Gorgon on behalf of Maximus. Eventually Medusa regained her senses and rejoined forces with the Inhumans Royal Family on the run. She was reunited with Black Bolt, who had been searching for her, and returned to Attilan. However, she became trapped in Atillan by the "negative zone" barrier created by Maximus. She was eventually freed from the barrier at great cost by Black Bolt, and left the Great Refuge to visit the outside world as an adventurer. It was some time before the disastrous effects of worldly pollution on the Inhumans was known. She engages Spider-Man in his own title for an issue, being manipulated by the manufacturer/promoter of a line of shampoo products. She also has been re-abducted by the Frightful Four in an attempt to manipulate her. The Fantastic Four became friends and allies and aided the Inhumans on several occasions, such as during the frequent power struggles between Black Bolt and the deranged Maximus.
Medusa has been known to join the Fantastic Four as a full team member for brief periods of time. She became a temporary replacement for Susan Richards, known as the Invisible Girl at that time, when on family leave, caring for her comatose son Franklin Richards. Through her relations with the Fantastic Four, Medusa and Black Bolt have sought to achieve an understanding and peace between the races of Earth and Attilan. Nevertheless, the Inhumans have been forced to relocate their home of Attilan several times due to continued human hostility.
Black Bolt would eventually become the king of the Inhumans upon the death of his parents. Medusa oversaw the moving of Attilan to the Blue Area of the Moon. Alongside the Inhuman Royal Family, she battled the Avengers under Maximus's mind control. Medusa and Black Bolt were then married and Medusa was made queen, becoming both royal consort and royal interpreter. When Medusa became pregnant, Attilan's Genetics Council argued that the pregnancy should be terminated due to the possibility of the child inheriting Maximus' insanity coupled with Black Bolt's immense and destructive power. Medusa defied the Council and fled to Earth to avoid the compulsory abortion and live anonymously in the desert until the child was born, a son named Ahura. Black Bolt reconciled with Medusa and the pair returned to Attilan and turned their infant son over to the Genetics Council. Following these events Ahura was not mentioned or seen in the Marvel Universe for several years.
Later, alongside the Inhumans and the original X-Factor, she battled Apocalypse. Alongside the Inhumans and Avengers, she also battled the Brethren.
Royalty.
Medusa's primary role among the Inhumans is as interpreter for her liege and husband, the silent but commanding Black Bolt. As such she is an experienced state figure within the quasi-feudal system of the Inhumans' government, and is used to speaking with awareness of regal issues of protocol and comportment. This imperial attitude is usually tempered by her strong sense of morality and fairness.
Medusa is featured in the six issue series "Beyond!". She is kidnapped along with other famous and infamous superhumans to the artificial planet known as Battleworld. After witnessing Venom apparently murder Spider-Man - although it is later revealed to be the Space Phantom - Spider-Man apparently mistaking her for Mary Jane as he compliments her hair in his 'last moments', she passes royal judgement that he must undergo fifty lashes. She supersedes the authority of the Avenger's representative, Janet Van Dyne, and uses the control over her hair to create a whipping motion so fast that it produces miniature sonic booms, which Venom is especially vulnerable to. While Hank Pym tries to dissuade Medusa from continuing the punishment, Venom is able to stab Medusa through the thigh. Later on in the issue, Medusa saves the team during the sudden crash landing of their space vessel by absorbing the majority of the impact with her hair. As stated by Wasp, Medusa is the team's primary short-range offense. Eventually the team triumphs over the Beyonder and returns to Earth. At the end of the series, Medusa can be seen alongside Black Bolt attending the funeral of her "Beyond!" teammate Gravity. She gives Gravity's parents a precious statue, the highest honor amongst the Inhumans, in commemoration of Gravity's sacrifice.
In "I Heart Marvel", Medusa stars and narrates in a one-shot vignette appearing in issue #3 of the "Marvel Ai" edition. Titled "Silence of the Heart", the story explores the relationship between Medusa and Black Bolt. Medusa explains that her husband's silence is a burden that she also bears. Black Bolt makes an appearance at this point and the two are shown to make love as Medusa contemplates her longing to hear a moan, whisper, or laugh from him.
The title "Son of M" focuses on Pietro Maximoff following the events of "House of M". After attempting to commit suicide, a dying Pietro is brought to Attilan by Crystal. While Gorgon protests, Medusa grants Pietro asylum in Attilan until he is fully recovered. Once healed, a depowered Pietro tries to convince Black Bolt and Medusa to allow him access to the Terrigen Mists, but Medusa firmly states that Terrigenesis is a process forbidden to outsiders and that such a process upon a human could result in drastic mutations. Pietro manages to expose himself to the Mists regardless, and receives new powers before collecting both the Terrigen Crystals and his daughter, Luna, and returning to Earth. The crystals eventually end up in the possession of a black-ops sector of the United States government. The sector's subsequent refusal to return the crystals sparks a declaration of war between the Inhumans and the United States.
During this title it is made reference that Black Bolt and Medusa are childless. Upon discovery that Luna has been taken to Earth by Pietro, Medusa advises Crystal that perhaps it is right that Pietro should spend time with his daughter. Crystal remarks that if Medusa had children of her own she might be able to understand how she felt over the matter. It is not apparent whether this is an example of Ahura's existence being retconned from the Marvel Universe, or if this is meant to be a sarcastic comment in reference to Ahura's supposed confinement.
The events of "Silent War" immediately follow the events of "Son of M". The Silent War series reveals a growing rift between Medusa and Black Bolt as the two disagree on his decision to declare war against the United States for failing to relinquish the Terrigen Crystals. Medusa finds herself no longer able to interpret her husband's wishes as she used to. While Medusa is issuing Black Bolt's war declarations to the Inhumans council he becomes frustrated and snaps his fingers to silence her, indicating that she wasn't relating what he intended. Medusa later confides to Black Bolt that he had never treated her that way before, as if she were a dog, and Black Bolt responds apologetically.
Their son, Ahura, also reappears in this series as a mentally unstable adolescent. Medusa argues that Black Bolt seems not to care that their son is being kept in isolation, and advises him that despite his orders she has gone to visit Ahura in his cell on more than one occasion. Black Bolt is angered by this and becomes physically aggressive with Medusa, grabbing her face and mouth to silence her. In her growing confusion with her husband's actions, Medusa finds herself drawn to Maximus against her will and would visit him often in his prison cell. It is revealed by Luna, Crystal's daughter, that Maximus had somehow implanted a "darkness" into Medusa's mind that was affecting her actions. Later on, Medusa and Maximus share a kiss as a distraught Black Bolt watches from the shadows. Medusa's thoughts at the time, however, reveal that she is not in control of her actions and that she only loves Black Bolt. The end of Silent War is left a cliffhanger with Black Bolt confined in prison, Ahura released, and Medusa now at Maximus' side as he assumes the throne of the Inhumans.
Due to inconsistencies with other Marvel titles featuring Black Bolt during this time, it is unclear when, and if, "Silent War" takes place in relation to The Illuminati, World War Hulk, and Secret Invasion storylines.
Medusa appears alongside Black Bolt in issue #1 of the "World War Hulk" series. Medusa is seen with Black Bolt when Hulk attacks Attilan. She warns Hulk not to pursue a fight with her husband, as Black Bolt has defeated Hulk in past battles. The fight begins and Medusa is not shown to interfere or assist. Black Bolt is subsequently defeated by Hulk, though the battle is not shown beyond Black Bolt's opening attack and it is made unclear as to how Hulk managed to win the fight.
It was revealed in "" that Black Bolt had been replaced by a Skrull impostor for an unknown amount of time. The impostor revealed himself to the Illuminati and was killed. Both the sudden rift between Medusa and Black Bolt apparent in "Silent War" and Black Bolt's later defeat at the hands of Hulk in "World War Hulk" could be attributed to this development, for it is uncertain just when Black Bolt might have been replaced by his Skrull duplicate.
When the "Secret Invasion" begins, the Inhumans part of the story, by "Heroes" writer Joe Pokaski, digs into how the Inhuman Royal Family deals with the news that the Black Bolt they knew was a Skrull impostor. Medusa is shown fighting a Skrull that not only possesses her powers, but also possesses the powers of Mister Fantastic. Medusa heads into Kree space to get Ronan the Accuser to help look for the Skrull ship containing Black Bolt and her son. She succeeds in rescuing her family and returning to Attilan.
During the "War of Kings" storyline, Medusa was with the Inhumans when they went into space and forged an alliance with the Kree and was also there when Havok, Lilandra Neramani, and the rest of Havok's Starjammers requested asylum from Vulcan and his forces. When Maximus speaks out, Medusa pushes him aside. After Ronan is wounded in battle with Vulcan's forces, Medusa states to the Shi'ar that they had made a big mistake and vows that they will pay for this. Medusa does a broadcast on Black Bolt's behalf and tells the citizens of the Kree Empire that they have suffered an unprovoked assault by the forces of the Shi'ar. The shield that once protected their star system has fallen. During a discussion with the other members of the Inhuman Royal Family, Medusa states that Shi'ar blood will spill in the next fight while trying to keep the Kree in line. Medusa and Black Bolt approve of Maximus' idea to create a mechanism to help them in their fight against the Shi'ar. Medusa ends up devastated when the T-Bomb goes off with Black Bolt and Vulcan still where the T-Bomb was. While weeping in Crystal's arms, Medusa declared that they have won.
During the "Dark Reign" storyline, Medusa was seen when Quicksilver appears in Attilan and present them with the Xerogen Crystals following the defeat of Unspoken. Medusa then absolves him of his crimes and restores his citizenship.
During the "Realm of Kings" storyline, Medusa ends up taking control of the Inhumans following Black Bolt's death. Devos the Devastator arrives and ends up inciting a riot in the Alpha Primitives. The Mighty Avengers arrive and help to quell the riots incited by Devos the Devastator. Henry Pym learns from Medusa about what happened to Black Bolt and expresses his sorrow for her loss as he too had lost Wasp. Medusa and the rest of the Inhumans deal with Dr. Vere and Zarek when they plot to overthrow the Inhuman Royal Family.
She takes her husband's place in the Illuminati when Iron Man reassembles the team in response to the Hood's attempts to acquire the Infinity Gems, although in the end Steve Rogers takes 'custody' of Black Bolt's gem at the conclusion of the crisis.
As part of the "Marvel NOW!" event, Medusa becomes a member of the Future Foundation when the Fantastic Four take a time-traveling trip.
During the "Civil War II" storyline, Medusa and Crystal introduce the Inhuman Ulysses to Captain Marvel, War Machine, and Black Panther. Medusa later catches Iron Man infiltrating New Attilan to claim Ulysses and fails to reason with him. After Iron Man defeats Medusa, Crystal, and Karnak and makes off with Ulysses, Medusa leads some Inhumans to Stark Tower to confront Iron Man which led the Avengers, the Ultimates, S.H.I.E.L.D., and other superheroes to intervene. Medusa was present when Ulysses projected his latest vision of a rampaging Hulk standing over the corpses of the superheroes.
During the "Inhumans vs. X-Men" storyline, Beast overhears Medusa telling the rest of the Inhuman Royal Family that they to be prepared just in case the X-Men lose patience in their truce and attack them. As the X-Men take action against the Inhumans, Medusa sends Iso and Inferno to find out what happened to Black Bolt and Crystal as she prepares for battle. Medusa then fights the time-displaced Beast in the lab of the original Beast as she effectively calls off the truce. As she gets the upper hand, Nightcrawler teleports in and takes her away. Despite the subsequent escalation of the conflict, when Medusa learns that the X-Men only attacked now because the Terrigenesis cloud was about to reach the point where it would make the whole planet toxic to mutants, she resolves the situation by destroying the cloud, preventing any further Inhumans from manifesting their powers, feeling that the future of her species is not worth the present loss of mutant life that would result. She also abdicates her throne to Iso.
In the aftermath, she along with her sister, Crystal, Black Bolt, Flint, Gorgon and Swain, are guided by Noh-Varr to the former Kree throne-world of Hala where he has stated they may discover the origins of Terrigen and in so doing offer a future to their doomed people, however, things are not well for the former Queen as she runs her hand through her powerful hair only to pull a large clump out with it, forcing her to announce to her crew that she is dying. It is soon apparent that Medusa's decision to destroy the Terrigen Cloud is the reason that is afflicting Medusa. She did what she had to in order to save the Mutant race, but in doing so she had doomed the future of her people. Because Medusa had pressed the button, that act had the consequence of gradually draining the life energies from her. Akin to dying of a broken heart, Medusa had acted to end a cultural heritage that had lasted millennia and her body has essentially chosen to end with it. Her only hope now is to find the secrets of the Terrigen and bring a new source of it back to their people, so she too can be revitalized. When the Inhumans obtain the Primagen from the Progenitors' World Farm and Gorgon buys his fellow Inhumans time to get away, Maximus takes a sample of the Primagen and has a vision where the Progenitors attack Earth in retaliation for the theft of the Primagen. While on the Astral Plane with Black Bolt, Medusa and Black Bolt agreed to continue as partners and not lovers. When Medusa takes the Primagen, it restores her hair and health while also causing a backlash in the attacking Progenitor to destroy the approaching Progenitors causing the Ordinator-Class Progenitors that saw the attack from the World Farm to spare Earth from their invasion.
During the "Death of the Inhumans" storyline, Medusa is seen with the Inhuman Royal Family when they find the dead bodies of the Universal Inhumans. When an explosive trap starts to go off, Medusa managed to make it out alive. Medusa and the Inhuman Royal Family later mourn the fallen Inhumans following Vox's attack on New Arctilan. After Black Bolt was taken captive by the Kree, Medusa and the surviving Inhuman Royal Family members try to recruit Beta Ray Bill in their fight against Vox and the Kree. The Inhuman Royal Family are finally taking the battle to the Kree and arrive just in time to save Black Bolt from Vox. Medusa is present when it is discovered that Vox is not a Super-Inhuman and is just a Kree programming. When the Inhuman Royal Family and Beta Ray Bill take the battle to the Kree, Medusa and Karnak fight a Vox-controlled Crystal and Lockjaw. After Black Bolt's sonic scream is used on the Vox-controlled Inhumans enough to free Crystal and Lockjaw and cause the Kree to retreat, Medusa is pleased that Crystal and Lockjaw are freed from Vox's control. Black Bolt emerges from the room as Medusa orders Lockjaw to take them away from the Kree base. When Crystal asks where they should go, Black Bolt uses his sign language to say "home." Lockjaw then teleports them away.
Medusa and Black Bolt once again become lovers later on.
Powers and abilities.
Medusa possesses a long, thick head of red hair; thanks to her exposure to the mutagenic Terrigen Mist, every strand of her hair has great tensile strength, modulus of elasticity, and sheer resistance far surpassing human hair. She possesses the psychokinetic ability to animate her hair for a number of feats, including elongating it to almost twice its normal length (Medusa's hair is approximately in length when relaxed), and using her hair to lift and move heavy weights (up to 1.6 tons); a portion of her hair must be used to anchor the rest at these greater weights, so that more than her scalp/skull is used as a brace.
Medusa can control the movement of her hair as if it were countless thin appendages growing from her head. A psionic field permeates her mutagenically altered hair-cells, causing mutual attraction across the gaps between strands. These relatively small forces operate in conjunction to develop larger forces. Through concentration, she can psionically move her hair in any manner imaginable. She can snap the length of it through the air like a whip (the tip of which moves faster than the speed of sound), or rotate it in a fan-like manner. She can bind persons or objects with it as if it were rope, or use it to lift objects which weigh more than she could lift with her arms. Her scalp, skull, and neck do not support the weight of an object that she lifts: It is held aloft by the psionic force coursing through the hair. Medusa can also perform delicate manipulations with her hair such as lock picking or threading a needle, and such complex acts of coordination as typing or shuffling a deck of cards. Although she has no nerve endings in her hair, she can "feel" sensations on all parts of her hair by a form of mental feedback from her psionic field.
Medusa is an accomplished thief, using her hair. Medusa is also able to retain some degree of control over her hair after it has been cut or otherwise severed from her scalp. She presumably has the typical enhanced physical abilities granted by the genetically superior Inhuman physiology. She is also highly skilled at interpreting the gestures and body language of Black Bolt, and has a fluency in a special sign language used to communicate with Black Bolt.
Like all Inhumans, Medusa's immune system is weaker than that of an average human. However, due to her frequent ventures into the outside world, Medusa's immune system has been strengthened so much that it is no longer as weak as that of her fellow Inhumans. As such she has attained a resistance to the pollutants of the outside world, which enabled her to join the Fantastic Four (as well as be a former member of the Frightful Four) in the first place.
Other versions.
Earth X.
In the alternate future of "Earth X", Medusa's hair volume has drastically increased. She has lost Black Bolt and fears the emotional loss of her son, Ahura. She is the acting ruler and Queen of the Inhumans. Many of her remaining friends and allies have mutated due to the incidents on Earth. As a way to tie together some of the powerful factions remaining on Earth, Captain Britain proposes to her. Their story continues into the mini-series "Paradise X", where convenience has turned into love. However, the status of their relationship and their political positions is thrown into turmoil when Captain Britain's presumed lost wife Meggan is brought back to life.
Heroes Reborn.
In "Heroes Reborn", Medusa's home city of Attilan plays host to the Fantastic Four. As in other realities, she speaks for her husband, Black Bolt. The Four are asked to help the Inhumans stop the plans of Maximus the Mad, who seeks out and plans to control the Terrigen Mists. The group at first does not understand the request, which leads to a battle. Medusa proves herself a capable fighter, helping to keep the battle at a stalemate.
In this universe Galactus is worshipped, and the Royal Council pay reverence to him and his team of heralds in the form of finely crafted statues throughout Attilan.
Marvel 1602.
Medusa appears in the "Marvel 1602" miniseries: "1602: Fantastick Four" as a member of the "Four Who Are Frightful", and the Wizard's lover. She has snakes for hair and must also wear a veil, to prevent her gaze turning men to stone. While her introduction describes her as "inhuman," Medusa's origins are not mentioned. She appears to be a native French speaker (hence, "Madame" Medusa).
Mutant X.
In "Mutant X", after the Beyonder/Goblin Queen and the vampire Dracula lay waste to the Earth's heroes in an attempt to conquer the Multiverse, a team of Inhumans, Medusa included, and Eternals attack from above. They battle in the heart of Washington D.C. Dracula easily slays the entire group.
Marvel Zombies 3.
In "Marvel Zombies 3" #2 she along with the Inhuman Royal Family are shown to be zombies have visited a zombie Kingpin to ask for food which they get. In the next issue Machine Man blows up and obliterates her rotting head.
Ultimate Marvel.
A version of Medusa appears in the "Ultimate Marvel" series, first appearing in the Ultimate Fantastic Four issue "Annual 1: Inhuman". She is still the queen of the Inhumans and wife to their leader, Black Bolt. As with her namesake, in this universe her skin is green in color and she has actual snakes for hair. It is not stated whether her newly serpentine hair restricts or enhances her abilities in any way. Along with Crystal, the Inhuman Gorgon is female and also Medusa's sister. Black Bolt's brother, Maximus, does not display any romantic feelings for Medusa in this universe.
Unlike other versions, Ultimate Medusa is against all associations with the Fantastic Four and believes that the two races of Inhumans and humans can never co-mingle in peace. She also exhibits an extreme degree of loyalty towards her people, stating that there can be no greater honor than to put aside one's individual happiness for the welfare of Attilan. Despite these sentiments, she expresses regret over her husband's inability to vocalize his feelings. When Black Bolt does feel the need to safely speak, he vocalizes regret over Crystal's actions.


Spliceman

Spliceman is an online genomic identification tool used to predict the likelihood that a mutation within a DNA sequence is linked with genetic disease. It was created in 2011 by a Brown University lab, and has been used in several studies to identify disease-causing mutant alleles.
Context.
Numerous sources cite that approximately one-third of disease-causing mutations affect RNA splicing. Such mutations frequently affect Exonic splicing enhancers, regions of pre-mRNA that recruit the spliceosome to remove intron sequences and aid in the formation mature mRNA. Spliceman Co-Authors Kian Huat Lim and William Fairbrother write that "Spliceman takes a set of DNA sequences with point mutations and computes how likely these single nucleotide variants alter splicing phenotypes."
The tool takes advantage of findings in 2011 on positional distribution analysis within DNA sequences. Each hexamer of DNA base pairs has a positional distribution near splice sites where it is most likely to occur. Point mutations that change one hexamer to another with large changes in positional distributions were shown to be more likely to cause splicing mutations than mutations with small changes to positional distributions.
Spliceman was created to apply those findings by predicting the likelihood of splicing mutations based on the distances in positional distributions between RNA sequences. Users enter a DNA sequence as input to the program with an indicated mutation. Spliceman isolates the changed hexamers and computes the L1-distance between the frequencies of each hexamer appearing at each location near the splice site to measure the differences in their positional distributions. They distances are then assigned percentile ranks to estimate the likelihood of a splicing mutation.
Applications.
The Spliceman tool has applications in personalized genomic medicine. It has been used in several studies to identify disease-causing mutant alleles. Its applications so far include aid in the location of mutations related to neural tube defects, pustular psoriasis, chronic ear infection, hypercholesterolemia, and several other genetic illnesses.
The Spliceman tool is available for free online on the website for the Fairbrother Lab.
A second version of the tool, Spliceman 2.0, has been developed to accept inputs in a wider array of file formats. This makes the tool more compatible with other tools that handle variants. It can handle many more variations than its precursor due to its ability to accept files of larger sizes. Spliceman 2.0 outputs a report that includes more data and visualization of those data.


Globules of fat

In human cell biology globules of fat are the individual pieces of intracellular fat inside cell types other than adipocytes (fat cells). Intercellular fat is bound in the globular form by phospholipid membranes, which are hydrophobic. This means that fat globules are insoluble in water.
In simpler terms: a vacuole or droplet of triglyceride or some other blood lipid, which is located inside a cell that is not an adipocyte (fat cell), as opposed to fat cells in between other cells in an organ. Lipids and any lipid digestive derivatives must be transported in the globular form within the cell, blood and tissue spaces due to its insolubility.
Globules of fat are emulsified in the stomach into small droplets by bile salts during food digestion, speeding up the rate of digestion by the enzyme lipase later on. Bile salts possess detergent properties that allow them to emulsify fat globules into smaller emulsion droplets, and then into even smaller micelles. This increases the surface area for lipid-hydrolyzing enzymes to act on the fats.
Micelles are roughly 200 times smaller than emulsion droplets, allowing them to facilitate transport monoglycerides and fatty acids across the surface of the enterocyte, where absorption occurs.
Milk fat is another form of intracellular fat found in the mammary glands of female mammals. In this form, fat globules or droplets are formed through the synthesis of phosphatidylcholine to regulate globule formation.


Family Records Centre

The Family Records Centre (FRC) provided access to family history research sources mainly for England and Wales. It was administered jointly by the General Register Office (GRO) and The National Archives.
It opened in March 1997 and was fully operational by the following month. It was situated at 1 Myddelton Street, Clerkenwell, London, close to the London Metropolitan Archives. It closed in 2008.
Throughout the FRC, there was free access to a wide range of family history material, databases and internet websites. Staff were always available to provide help and advice on family history research and there were regular one-to-one family history surgeries and computer skills tutorials. Talks on family history topics took place every week and other events, including exhibitions and conferences, were organised. There were good facilities for customers with special needs, and there was a small bookshop next to the entrance on the ground floor and a refreshment area with vending machines and lockers for personal belongings in the basement.
Its main resources were indexes to civil registration of births, marriages and deaths on the ground floor (provided by the GRO), and the Victorian census returns on the first floor (provided by The National Archives).
Births, Marriages & Deaths Indexes.
The births, marriages and deaths indexes were in large, heavy, hardcover books (red covers for births, green for marriages and black for deaths) in three sections respectively, with each section arranged in date order. Using the details from an index, a copy (certificate) of the corresponding birth, marriage or death entry could be applied for at the cashiers' section on the same floor. Other indexes at the FRC included some births, marriages and deaths of British nationals which took place abroad, indexes of legal adoptions in England & Wales from 1927 onwards, and various indexes of war deaths in the armed forces in both World Wars.
The births, marriages and deaths indexes were originally at Somerset House until the 1970s. In the early 1980s, the births and marriages indexes were at St Catherine's House, at the northeast corner of the intersection of Kingsway and Aldwych, and the deaths indexes were at Alexandra House, farther up Kingsway. After more space was made available at St Catherine's House, the deaths indexes were moved from Alexandra House. Finally, they were all moved to the FRC in 1997.
Census returns for England and Wales.
The 1841 to 1901 census returns for England and Wales could be consulted at the FRC and were accessed mainly online by searching for individuals by name. The 1841 to 1891 census returns were also available on microfilm, while the 1901 census was also available on microfiche. A selection of street indexes and other search aids were also available.
Before the FRC opened, the census microfilms were at the Public Record Office (now part of the National Archives) in Chancery Lane for some years, after having been moved from the Land Registry building, Portugal Street, London, where they had been since the mid-1970s.
Other microfilm resources.
Other microfilm resources available included wills and administrations from the Prerogative Court of Canterbury up to 1858, which could also be searched online, death duty registers, from 1796 to 1858, and many nonconformist registers (mainly pre-1837).
Demise.
On 21 June 2006, it was announced that the National Archives' staff and residual services at the FRC would be relocating to the National Archives at Kew by the end of 2008. Official press releases were vague about plans for the births, marriages and deaths indexes housed on the ground floor. During October 2007 the index volumes in question were progressively removed from public access to a closed archive in Christchurch, Dorset.
The closure date was later brought forward to early 2008.
The ground floor (GRO section) of the FRC closed on 27 October 2007 and the rest of the FRC closed on 15 March 2008.


Rhaphidozoum

Rhaphidozoum is a radiolarian genus reported in the subfamily Sphaerozoidae. The genus contains bioluminescent species. It is a genus of colonial radiolarians (as opposed to solitary).
Species.
The following species are recognized:


Mepindolol

Mepindolol (Betagon) is a non-selective beta blocker. It is used to treat glaucoma.


Tailless tenrec

The tailless tenrec ("Tenrec ecaudatus"), also known as the common tenrec, is a species of mammal in the family Tenrecidae. It is the only member of the genus Tenrec. Native to Madagascar, it is also found in the Comoros, Mauritius, Réunion, and Seychelles, where it has been introduced. Its natural habitats are subtropical or tropical dry forest, subtropical or tropical moist lowland forest, subtropical or tropical moist montane forest, dry savanna, moist savanna, subtropical or tropical dry shrubland, subtropical or tropical moist shrubland, subtropical or tropical high-altitude shrubland, subtropical or tropical dry lowland grassland, subtropical or tropical high-altitude grassland, arable land, pastureland, plantations, rural gardens, and urban areas.
The tailless tenrec is the largest species of the tenrec family, Tenrecidae. It is 26 to 39 cm (10 to 15½ in) in length and weighs up to . It has medium-sized, coarse grey to reddish-grey fur and long, sharp spines along its body. It not only eats small invertebrates and animals such as frogs and mice, it also eats leaves. If threatened, this tenrec will scream, erect its spiny hairs to a crest, jump, buck and bite. It shelters in a nest of grass and leaves under a rock, log or bush by day. It gives birth to a litter of as many as 32 young, with an average litter between 15-20 after a gestation of 50–60 days; when young, they have a black-and-white striped appearance. Despite being sometimes known as the tailless tenrec, they have a small tail 1 to 1.5 cm (⅜ to ½ in) in length.
The tenrec is the first known tropical mammal found to hibernate for long stretches without arousal periods, up to nine months at a time. The Tailless tenrec is a host of the Acanthocephalan intestinal parasite "Promoniliformis ovocristatus".


Lina Nilsson (scientist)

Lina Nilsson is an American biomedical engineer known for her work in technology and entrepreneurship. She was named one of MIT Technology Reviews 35 Innovators Under 35 and has been interviewed or profiled by Fortune and the White House's Office of Science and Technology Policy. She has been published in The New York Times, The Washington Post, Science, Make Magazine, and various scientific journals.
Early life and education.
Nilsson received a B.S. in Chemical Engineering from the Illinois Institute of Technology, followed by a M.S. in Biomedical Engineering from the University of Washington. As a PhD candidate at the University of Washington, she applied for and was awarded a Bonderman Travel Fellowship, which "gives students eight months to “come to know the world in new ways.”" She visited biology labs in Asia and South America, where she saw researchers hindered by lack of access to proper laboratory equipment. Nilsson has a Dr.Sc. from the Swiss Federal Institute of Technology, where she received the ETH Medal for an outstanding doctoral thesis.
Career.
Nilsson moved to the University of California, Berkeley, where she worked as a postdoc and was named the Innovation Director at the Blum Center for Developing Economies. Drawing from her Bonderman Fellow experiences, she cofounded Tekla Labs there to develop high quality, open-source lab equipment that scientists could build themselves. In 2013, MIT Technology Review selected her as one of its 35 Innovators Under 35 for work at the Blum Center and Tekla Labs, and along with the others named, she appeared at the magazine's Emtech conference.
From 2015 to 2017, Nilsson worked at Enlitic as first the Head of Market Development, then the Vice President of Strategy and Operations, and then the Chief Operating Officer. She now works at Recursion Pharmaceuticals.
Nilsson's areas of interest include technological innovation, access to laboratory equipment for low-income students, and retention and recruitment of women to engineering. In interviews, she has spoken on the importance of socially conscious engineering courses and emphasizing humanitarian end goals to attract more women to the profession. On the topic of expanding infrastructure and access, she states that equipment and resource access is the "new horizon for democratizing science, beyond open data and open knowledge movements (such as open access science journals)."


Disaccharidase

Disaccharidases are glycoside hydrolases, enzymes that break down certain types of sugars called disaccharides into simpler sugars called monosaccharides. In the human body, disaccharidases are made mostly in an area of the small intestine's wall called the brush border, making them members of the group of "brush border enzymes".
A genetic defect in one of these enzymes will cause a disaccharide intolerance, such as lactose intolerance or sucrose intolerance.
Examples of disaccharidases.
For a thorough scientific overview of small-intestinal disaccharidases, one can consult chapter 75 of OMMBID. For more online resources and references, see inborn error of metabolism.


CC (cat)

CC, for "CopyCat" "or" "Carbon Copy" (December 22, 2001 – March 3, 2020), was a brown tabby and white domestic shorthair and the first cloned pet. She was cloned by scientists at Texas A&M University in conjunction with Genetic Savings & Clone Inc. CC's surrogate mother was a tabby, but her genetic donor, Rainbow, was a calico domestic shorthair. The difference in hair coloration between CC and Rainbow is due to X-inactivation and epigenetic re-programming, which normally occurs in a fertilized embryo before implantation.
In September 2006, CC gave birth to four kittens. The litter was fathered naturally by another lab cat named Smokey. It included two males named Tim and Zip and one female named Tess. Another kitten (a female) was stillborn. This incident was the first time a cloned pet gave birth. Throughout her life, CC appeared to be free of the cloning-related health problems that have arisen in some other animal clones. "CC has always been a perfectly normal cat and her kittens are just that way, too," says Shirley Kraemer, CC's owner. "We’ve been monitoring their health and all of them are fine, just like CC has been for the past five years."
In 2004, Genetic Savings and Clone produced the first commercially cloned pet, a Maine Coon cat named "Little Nicky" who was cloned from a 17 year old deceased pet cat.
On March 3, 2020, CC died at 18 in College Station, Texas.


Missyplicity

The Missyplicity Project was a project devoted to cloning Joan Hawthorne and John Sperling's dog, a border collie and husky mix. Missy died on July 6, 2002 at the age of 15 years.
History.
In 1997, news that Dolly the sheep had been cloned inspired the couple to find out whether their dog Missy could also be cloned. In 1998, a multimillion-dollar project was launched to clone Missy, trading as "Genetic Savings & Clone". Missy died in 2002 before efforts to clone her had succeeded, but her DNA was gene banked for future cloning efforts.
One of the key scientists on the Missyplicity Project and Genetic Savings & Clone was Dr. Taeyoung Shin, who was born and completed his Ph.D. in South Korea before moving to the United States. After both The Missyplicity Project and GSC proved unable to clone dogs, Dr. Shin's Ph.D. thesis advisor, Dr. Hwang Woo-Suk, led a team of research scientists at Seoul National University in a major dog cloning effort. This project was designed to overcome the specific obstacles encountered by both the Missyplicity and GSC teams.
In 2005, Dr. Hwang and his team successfully cloned the world's first dog, which they named Snuppy. In 2007, Lou Hawthorne, former CEO of GSC and current CEO of BioArts International, was introduced to Dr. Hwang and his team by Dr. Shin of BioArts, and asked if they would clone Missy. They agreed and Missy's conserved cells were flown to the Sooam Biotech Research Foundation outside of Seoul.
The scientists at Sooam, led by Dr. Hwang, used Missy's cells to successfully produce three Missy clones. After 10 years of research and effort, the quest to clone Missy had finally succeeded. Three identical clones of Missy were returned to the original owners. The clones are named Mira (after a Korean myth of an all-powerful benevolent dragon), Chingu (which means "friend" in Korean) and Sarang ("love").
Mira, born December 5, 2007, was the world's first clone of a family dog and bore a striking physical and behavioral resemblance to the original Missy. Chingu and Sarang were born on February 15 and 19. They were flown to the United States on April 18, where they joined their genetic sister Mira.
Related projects.
The news of the project to clone Missy spread quickly, and many people contacted Hawthorne and Sperling wanting to gene bank and clone their own pets. In response to this demand, several members of the Missyplicity Project founded Genetic Savings & Clone (GSC) in February 2000.
Operation CopyCat was a branch of the Missyplicity Project that concentrated on cloning cats, after the discovery that dog genes are harder to copy than cat genes. Operation CopyCat announced that on December 22, 2001, CopyCat was born of the Missyplicity Project. She was called CC for short, and was born at the Texas A&M, College of Veterinary Medicine.
BioArts and Sooam decided to partner to offer a limited number of cloning spots to the public through a program called "Best Friends Again" in 2008. In 2009, Lou Hawthorne the CEO of BioArts announced he was withdrawing from the program due to the small market, unethical competition, weak intellectual property protection, unscalable bioethics and unpredictable results. However Sooam Biotech continued developing proprietary techniques based on a licence from ViaGen's subsidiary Start Licensing (which owns the original Dolly patent) and continued creating cloned dogs for owners whose dogs had died, charging $100,000 a time. Sooam Biotech was reported to have cloned 700 dogs by 2015, a cloning success rate of 40% and to be producing 500 cloned embryos of various species a day in 2016.
References.
Hossein MS, Jeong YW, Park SW, Kim JJ, Lee E, Ko KH, Kim HS, Kim YW, Hyun SH, Shin T, Hawthorne L, Hwang WS.Cloning missy: obtaining multiple offspring of a specific canine genotype by somatic cell nuclear transfer. Cloning Stem Cells. 2009 Mar;11(1):123-30. doi: 10.1089/clo.2008.0029.


Neamblysomus

Neamblysomus is a genus of golden moles containing two species:


Eqbal Dauqan

Eqbal Mohammed Abdu Dauqan (born 1980) is a Yemeni-Malaysian biochemist known for her studies of nutrition, advocacy for refugees, and support of women scientists in her home country of Yemen and adopted country of Malaysia.
She earned her bachelor's degree in biological chemistry in 2002 and a master's degree in organic chemistry in 2008, both from Taiz University in Yemen. She earned her Ph.D. in biochemistry in 2012 at the National University of Malaysia under a scholarship from the Organization for Women in Science for the Developing World, and remained there as a postdoctoral researcher. In 2014, Dauqan received the Elsevier Foundation Award for Early Career Scientists in the Developing World for her work on antioxidants in vegetable oils.
She became a professor and Head of the Department of Medical Laboratories Sciences at Al Saeed University in Taiz, Yemen. She earned acclaim for her popular writing. In 2015, after her university was bombed and members of her family killed as part of the Yemeni Civil War, she returned to the National University of Malaysia as an assistant professor in chemical science and food technology, sponsored by the Institute of International Education's Scholar Rescue Fund. She is now activity mentoring junior scholars who work in critical environments.
In 2019, she was elected to the Global Young Academy.


FOX reagent

The FOX reagent, or ferrous oxidation−xylenol orange, is used to measure levels of hydrogen peroxide in biological systems. The reagent is incubated with the sample and absorbance of the product form after a series of oxidation reactions is then measured at a wavelength of 560 nm. The reagent itself is an aqueous solution of ferrous ammonium sulfate, sorbitol, sulfuric acid and xylenol orange.
Use as an assay.
As an example for one of its uses, the FOX reagent can be an effective assay for the detections of lipid hydroperoxides (LOOHs) in plant tissues from different fruits and vegetables. The FOX assay relies on the oxidation of Fe2+ to Fe3+ in acidic conditions. After this initial oxidation, the xylenol orange within the assay is also oxidized to produce the product that has the 560 nm absorbance via colorimetric determination. The method itself is practical because of its relative cheapness and because the FOX reagent is not influenced by environmental factors, such as oxygen or light levels. The assay would also allow for the immediate detection of any amount of LOOHs.
With the sensing of LOOHs, the FOX reagent only senses the first products of fatty acid oxidation, and is quite useful prior to the processing of fruits and vegetables. This sensitiveness of the reagent couples well with the rapid detection of the assay. This is advantageous over other assays in which more advanced oxidation would need to proceed in order to be detected by the reagents used for the chosen assay. Recent uses of the assay involve modifications in which the assay can be used to detect the enzyme 5-lipoxygenase, which can be found in insect and human cells. Modifying the assay can also aid in the detection of protein, as well as lipid, hydroperoxide in human cells. Aside from its use in vegetation, the FOX assay has also been used to detect the LOOHs present within animal tissue. Specifically, it can be used in order to detect fatty acid oxidation in poultry, such as cooked and uncooked chicken. Since lipid oxidation in chicken tissue may result in the build up of toxins and the loss of flavor, early detection via the FOX assay would allow proper evaluation of the quality of meat produced.


Zinc protoporphyrin

Zinc protoporphyrin (ZPP) is a compound found in red blood cells when heme production is inhibited by lead and/or by lack of iron. Instead of incorporating a ferrous ion, to form heme, protoporphyrin IX, the immediate precursor of heme, incorporates a zinc ion, forming ZPP. The reaction to insert a ferrous ion into protoporphyrin IX is catalyzed by the enzyme ferrochelatase.
Clinical utility.
Measurement of zinc protoporphyrin in red cells has been used as a "screening" test for lead poisoning.
and for iron deficiency.
There are a number of specific clinical situations in which this measurement has been found to be useful.
Zinc protoporphyrin levels can be elevated as the result of a number of conditions, for instance:
The virtue of elevated ZPP testing as a "screen" is that all of these conditions can be considered worth discovering.
The fluorescent properties of ZPP in intact red cells allows the ZPP/heme molar ratio to be measured quickly, at low cost, and in a small sample volume.
More recently, ZnPP is finding a new use as a drug in combined cancer therapies.
History.
Porphyrin compounds containing zinc have been known since the 1930s. They became of more than academic interest with the discovery, in 1974, that ZPP was the major non-heme porphyrin formed in red cells as the result of lead poisoning or iron deficiency.
It was already known at this time that non-heme Protoporphyrin IX levels were elevated in these conditions, but prior investigators had used acidic extraction methods in their assays that converted ZPP to unbound Protoporphyrin IX.
The early literature is sometimes confusing, and results are hard to compare without detailed examination of the measurement methods and the conversion factors used to report the results. Reports may refer to free erythrocyte protoporphyrin (FEP) or erythrocyte protoporphyrin (EP or EPP). ZPP is also abbreviated ZP and ZnPP. Current practice is tending to measure and report the molar ratio of ZPP to heme (μmole/mole).
For cancer therapy.
ZnPP is finding a new use in cancer therapies. Research into the field of nanotechnology is finding a use for many compounds which show different and often more favorable properties at the nanoscale. ZnPP is one such compound that can effectively aid in the treatment of multiple types of cancer in laboratory experiments. The clinical application of the nanomaterial ZnPP will only come through continued research and more definitive results.
The chemical group that ZnPP belongs to is similar to free heme which is a natural substrate of heme oxygenase. ZnPP is known as a competitive inhibitor of heme oxygenase. Heme oxygenase is a cytoprotective enzyme that copes with oxidative stress on a cell and shows higher expression in cancerous tissues. ZnPP suppression of heme oxygenase reduces cell viability of cancer cells and increases cytotoxicity in cancer cells. ZnPP works in combination with anticancer drugs to increase cytotoxicity greatly in some cases; results in one study have shown a five-fold increase in treatment efficacy. ZnPP has been shown to have a major role in inhibiting tumor growth especially solid tumors. Tumors from brain cancer, colon cancer, prostate cancer, renal cell cancer, oral squamous cell cancer, and leukemia all show a susceptibility to ZnPP due to increase expression of heme oxygenase. The inhibition of heme oxygenase leads to an increase of reactive oxidative species in the cell which sensitizes the cells to chemotherapeutic agents. Increased reactive oxidative species can cause apoptosis in cancer cells and reduce drug resistance when exposed to ZnPP due to loss of the heme oxygenase coping mechanism. The combination of these two therapies is highly effective in treating cancer in experiments thus far, and is a possible new method for overcoming drug resistance. The reduced coping ability of tissues treated with ZnPP also increases radiosensitivity. Cells treated with ZnPP and radiation as opposed to simply one of the two are less viable and more likely to stay in G1 phase of the cell cycle, rather than progress to the G2 phase. ZnPP and radiation combination therapy shows more apoptosis than the same amount of radiation displaying that ZnPP puts stress on cancerous tissue. ZnPP have been injected in a number of trials on solid tumors, but can be utilized more broadly when effectively delivered to cancer cells and not healthy cells. A targeted delivery system is needed to fully exploit the uses of ZnPP as a therapeutic agent and heme oxygenase inhibitor due to the potential side effects of free ZnPP on healthy tissue. Reducing the anti-oxidant capability of healthy cells can reduce effects that would have been favorable. However ZnPP have been encapsulated in nanoparticles with specialized coating for drug delivery inside the body. ZnPP did not show any reduce inhibitory potential on heme oxygenase when loaded into nanoparticles. Similarly ZnPP loaded into nanoparticles has a higher cytotoxicity than free ZnPP after two days due to a more favorable release rate as well as better biodistribution and internalization. The possible negative effects on major organs were not seen and blood distribution is more desirable in ZnPP loaded nanoparticles than free ZnPP. The specific inhibition of heme oxygenase using nanoparticles with encapsulated ZnPP reduces side effects and is likely the future method of administering ZnPP treatment.


Omphalotus mangensis

Omphalotus mangensis is a species of agaric fungus in the family Marasmiaceae. Found in China, the fruit bodies of the fungus are bioluminescent.


Sequence (biology)

A sequence in biology is the one-dimensional ordering of monomers, covalently linked within a biopolymer; it is also referred to as the primary structure of a biological macromolecule. While it can refer to many different molecules, the term sequence is most often used to refer to a DNA sequence.


Mid-Continent Public Library

Mid-Continent Public Library, officially known as Consolidated Library District #3, is a consolidated public library system serving Clay, Platte, and Jackson Counties in Missouri, with headquarters in Independence, Missouri.
Mid-Continent Public Library is the largest public library system in the U.S. state of Missouri by number of volumes and size of budget. Its collection ranks among the 100 largest libraries in America, which includes university, public, and private collections, and is among the nation's 20 largest public library systems. (Note: The Kansas City Public Library is a separate library system with facilities primarily serving Kansas City in Jackson County, Missouri.)
On May 8, 2014, the Mid-Continent Public Library received the National Medal for Museum and Library Service during a ceremony at the White House in Washington D.C. The medal is the country's highest honor awarded by the Institute of Museum and Library Services.
Background.
Mid-Continent Public Library's roots go back to the Independence Public Library, formed by the Independence Library Association in 1892 and the creation of the Citizens Improvement Association Library (later the Carnegie Library) in Excelsior Springs in the 1890s.
After World War II, Clay, Platte and Jackson counties formed countywide library systems. They began collaborating in the early 1960s, and on November 10, 1965 Clay and Jackson formed the Mid-Continent Public Library Service as a joint administrative body, though each library retained separate governing boards and budgets.
Even though they remained separate, their combined resources allowed them to merge administrative costs. Gaining the name Mid-Continent Public Library in 1968, the library system was well on its way to achieving its goal. Separating library services from school districts enabled them to expand library services to rural areas, which presently did not have services.
Platte County joined the group in 1968. In 1978, seven years after the state legislature passed a law allowing for consolidated multi-county library systems, the Clay and Jackson libraries officially merged to form Consolidated Library District No. 3. Platte County joined a year later.
A notable librarian, James A. Leathers, was influential in the creation of a regional library system and became the first Director of Mid-Continent Public Library Service. His focus was to provide education, information, and recreation to the public. His desire was for the library to serve all individuals regardless of age, and he aimed to provide services for the young as well as the elderly.
The library system is overseen by a Library Board of twelve members, four appointed by County Commissioners in each of the service region's three counties. It currently has 31 branches in the Kansas City Metropolitan Area of Missouri located in Kansas City, Independence, Liberty, Gladstone, Lee's Summit, Grandview, Blue Springs, Grain Valley, and other cities. It also hosts two installations at community centers in partnership with the Kansas City Parks and Recreation Department that provide automated library services and public Internet access.
In 1994, the Mid-Continent Public Library began to see advances in technology. It made improvement with circulation, intra-library loan, and online catalogs. In 1995, dial-up Internet access was provided for catalog use. In 1996, the full access to Internet was provided. In 2001, WorldCat was added to the online databases.
In fiscal 2008-2009, the collection held 3,544,072 items. Total annual circulation was 9,183,005 items, and it filled 1,773,586 intra- and interlibrary loans. Branch libraries served 4,673,737 visitors. Total attendance at live programming events for adults and families and for children was 318,639 patrons. The system has 466,344 registered borrowers.
Annual circulation for the year exceeded one-half million items for each of the Mid-Continent Library's five busiest branches: Liberty, Lee's Summit, Colbern Road, North Independence, and Blue Springs South.
The system has one of the nation's largest Summer Reading Programs, which was completed by 106,846 patrons in fiscal 2009. It is known for its array of services, including more than 250 online learning tools and research databases with remote access, downloadable audiobooks, and Library-by-Mail for homebound patrons. Library branches offer self-checkout machines and self-service hold pick-ups, and LCD flat-panel monitors on every on-site public access computer. Most branches also offer free wi-fi access. The library system collaborates and partners with local foundations.
Midwest Genealogy Center.
On 21 June 2008, Mid-Continent Public Library inaugurated the Midwest Genealogy Center in Independence, Missouri. It is the largest stand-alone public genealogy research facility in America.
The building houses a unique collection of records in almost completely open stacks. It holds 80,000 family history books, 100,000 local history items, 565,000 rolls of microfilm, and 7,000 maps. It also contains all available U.S. federal population census records and federal indexes, Civil War histories, immigration and naturalization records, ship passenger lists, Native American records, biographical archives, manuscripts pertaining to the American slave trade and the Antebellum South, Papers of the St. Louis Fur Trade, and a large variety of state records for Missouri and other states such as state censuses, tax records, penitentiary records, military service records, compiled records of Missouri Union and Confederate Army soldiers, approximately 50 Missouri newspapers, local newspaper indexes to obituaries and weddings, and genealogical periodicals. The center also has 10,000 volumes available for circulation in the “Genealogy from the Heartland Collection” created from donations by the American Family Records Association (AFRA), Missouri State Genealogical Association (MoSGA), Heart of America Genealogical Society (HAGS), Gann Family Association, and patron contributions.
The center's equipment includes microfilm reader-printers, self-digitization stations, and free access to important research databases. It offers many advanced services, including free wireless Internet access and digital video conferencing capabilities for viewing national broadcasts relevant to genealogists and family historians.
The Midwest Genealogy Center is open seven days per week. Groups and tours are welcomed by appointment.


ImClone Systems

ImClone Systems Incorporated was a biopharmaceutical company dedicated to developing biologic medicines in the area of oncology. It was founded in 1984 and had its corporate headquarters in Bridgewater, New Jersey, and its research headquarters in New York City. On October 6, 2008, it accepted a $6.5 billion acquisition offer from Eli Lilly and Company, and became a fully-owned subsidiary of Eli Lilly and Company on November 24, 2008. Prior to the acquisition, it was traded on the NASDAQ stock exchange under the symbol IMCL. Imclone lost its separate identity in 2014 when its former ImClone research and manufacturing sites were renamed "Eli Lilly and Company".
Insider trading scandal.
ImClone's stock price dropped sharply at the end of 2001 when its drug Erbitux, an experimental monoclonal antibody, failed to get the expected Food and Drug Administration (FDA) approval. It was later revealed by the U.S. Securities and Exchange Commission that numerous executives sold their stock before the announcement of the decision after the close of trading on December 28.
Its founder, Samuel D. Waksal, was arrested in 2002 on insider trading charges for informing friends and family to sell their stock, and attempting to sell his own. His daughter, Aliza Waksal, sold $2.5 million in shares on December 27. His father, Jack Waksal, sold $8.1 million in shares over the 27th and 28th. Company executives had done the same. John B. Landes, the general counsel, sold $2.5 million in shares on December 6. Ronald A. Martell, the vice president for marketing and sales, sold $2.1 million in shares on December 11. Four other executives sold shares in the following weeks as well. Later, Samuel Waksal pleaded guilty to various charges, including securities fraud, and on June 10, 2003, was sentenced to seven years and three months in prison.
Martha Stewart, the founder of Martha Stewart Living Omnimedia (Waksal had dated Stewart's daughter) also became embroiled in the scandal after it emerged that she sold about $230,000 in ImClone shares on December 27, just a day before the announcement of FDA decision. Although Stewart maintained her innocence, she was found guilty and sentenced on July 16, 2004, to five months in prison, five months of home confinement, and two years probation for lying about a stock sale, conspiracy, and obstruction of justice.
Ultimately a new clinical trial and FDA filing prepared by Imclone's partner Merck KGaA ("German Merck," not to be confused with the US company of similar name) resulted in an FDA approval of Erbitux in 2004 for use in colon cancer.
A Congressional hearing on improprieties at ImClone, held in October 2002, unveiled a culture of corruption dating back to 1986. This was the year that ImClone CEO Waksal first forged the signature of the company's general counsel John Landes (one of the three original employees of the company) for financial gain. Nonetheless, Landes defended Waksal's illegal actions at the hearings before the Subcommittee on Oversight and Investigations, portraying the forgery as "a good-faith misunderstanding," to which Representative James Greenwood replied "My children know better than that, Mr. Landes." Further questioning about this and subsequent forgeries on Waksal's part revealed that neither Landes, the chief legal officer of the company, nor the company's outside directors reported Waksal's actions to proper authorities or made any moves to have Waksal removed as CEO. Instead, testimony revealed that they initiated their own internal investigation, which was never concluded. The decades-long tolerance for Waksal's fraud, starting from the company's earliest days, provoked Representative Peter Deutsch to refer to the ongoing misconduct as "wacky."
The FDA's February 2004 announcement of approval for use of Erbitux for treatment of colorectal cancer reported that conclusions were drawn from a trial involving 329 patients, of which 10.8% responded when Erbitux was used by itself, delaying tumor growth by 1.5 months. When used in conjunction with a standard chemotherapy treatment, irinotecan, 22.9% of patients responded and tumor growth was delayed by approximately 4.1 months.
In September 2001, Bristol-Myers Squibb committed $2 billion (including a $1 billion up-front cash payment) for less than 20% of ImClone due to what was called at the time the drug's "blockbuster" potential.
In January 2006, the company was put up for sale but failed to find any buyers, likely due to the fact that Erbitux by that time faced significant competition in the medical marketplace. ImClone directors withdrew the sale of the company in mid-2006.
In April 2007, The Wall Street Journal reported that "Bristol-Myers Squibb Co. and ImClone Systems Inc. said their cancer drug, Erbitux, failed to significantly prolong the lives of people with pancreatic cancer in a new study, marking yet another setback in the drug industry's efforts to find a better treatment for this deadly disease."
Compassionate use controversy.
The FDA approved the aforementioned colorectal cancer drug, Erbitux, on February 12, 2004. In May 2001, while ImClone was still seeking approval for the drug (then known as IMC-C225), the CBS news program "60 Minutes" aired a story about two cancer patients' struggles to obtain "compassionate use" of the drug. One ultimately succeeded; the other failed despite repeated pleas to ImClone officials. It was alleged in the story that ImClone was arbitrary in who received the drug and had no written criteria for compassionate use.
Carl Icahn acquisition.
On October 25, 2006, a group led by billionaire investor Carl Icahn acquired a majority of stock thereby giving him control of the board. Within hours of the announcement, interim CEO Joseph Fischer resigned, and Icahn announced that other members of the Board of Directors would not be re-elected.
Yeda/Aventis/Imclone patent dispute.
Yeda Research and Development, a company set up to commercialize and market the products of research at the Weizmann Institute of Science in Israel, challenged the Aventis-owned patent, licensed by Imclone, for the use of anti-Epidermal growth factor receptor antibodies in combination with chemotherapy, to slow the growth of certain tumors. This is the so-called '866' patent, which was filed in 1989 by Rhone-Poulenc-Rorer, issued in 2001, and on which Joseph Schlessinger was listed as first-named inventor.
Joseph Schlessinger's former colleagues at the Weizmann Institute, in particular Michael Sela, claimed to have come up with this concept alongside Schlessinger when they worked together there years earlier, and Yeda challenged the Aventis patent in the United States. Schlessinger testified in court that the idea of combining the anti-EGFR antibody that his lab had developed with chemotherapy in cancer treatment was his own idea. However, the Weizmann Institute scientists provided extensive documentation that they had been developing this idea using an antibody against EGFR that Schlessinger's laboratory had developed and generated, and that he had given them for these studies. Schlessinger claims to have initiated the idea of this use in combination therapy, but had not documented his research and ideas as thoroughly, leaving him forced to rely on his recollections of the events that led to the patent filing some 17 years before Yeda mounted their challenge.
The court ruled that Yeda are the sole owners of the disputed patent in the U.S., while Yeda and Sanofi-Aventis co-own the 866 Patent's foreign counterparts. Following the ruling, ImClone and Sanofi-Aventis agreed to settle the dispute with Yeda, for $120 million, with each company paying Yeda $60 million. In return, ImClone were also granted a worldwide license to technology covered by the 866 Patent, and agreed to pay a small royalty on Erbitux sales to Yeda.
Takeover offer from Bristol-Myers Squibb, and subsequent bidding showdown.
On July 31, 2008, Bristol-Myers Squibb offered to take over ImClone for $60 a share cash. The offer was made by letter addressed to ImClone's chairman of the board, Carl Icahn.
On September 10, 2008, an undisclosed company and CEO offered to take over ImClone for $70 a share, financing approach was not disclosed. The offer was conditional on the results of a due diligence review of ImClone's business and technology by the undisclosed party, to be completed September 28, 2008.
On September 23, 2008, Bristol-Myers Squibb upped its offer to take over ImClone to $62 a share. In addition, Bristol threatened to take the offer to the share holders for a proxy battle with the intention of replacing the current Board of Directors headed by Carl Icahn.
On October 6, 2008, ImClone agreed to be acquired by Eli Lilly for $6.5 billion ($70/share). On November 24, 2008, ImClone was formally acquired by Eli Lilly, with all NASDAQ IMCL shares tendered for $6.5 billion ($70/share). ImClone is now a fully owned subsidiary of Eli Lilly and Company. In 2014 a drug developed by ImClone, tumor angiogenesis inhibitor Cyramza, was approved by the FDA for gastric cancer. Lilly acquired the drug through its purchase of ImClone.


Journal of Biotechnology

Journal of Biotechnology is a peer-reviewed scientific journal covering research ranging from genetic and molecular biological positions to biochemical, chemical, or bioprocess engineering aspects as well as research on the computer application of new software concepts which are directly relevant to biotechnology.
Abstracting and indexing.
The journal is abstracted and indexed in BIOSIS, Cambridge Scientific Abstracts, Chemical Abstracts, Current Contents/Agriculture, Biology & Environmental Sciences, EMBASE, EMBiology, MEDLINE, and Scopus.


Estanislao

Estanislao ( – 1838) was an indigenous "alcalde" of Mission San José and a member and leader of the Lakisamni tribe of the Yokuts people of northern California. He is famous for leading bands of armed Native Americans in revolt against the Mexican government and Mission establishments.
Early life.
Estanislao was born with the Yokuts name Cucunuchi c. 1798 on the banks of the Río de Laquisimes (present-day Stanislaus River, Modesto, California). According to records at Mission San José, mission padres visited the Laquisimes area in 1821 and insisted that Cucunuchi return to the mission along with his wife, daughter, and mother to receive a formal Christian education. His younger brother Canocee had already visited the mission in 1820 and been baptized with the name "Orencio". Cucunuchi and his family journeyed to the mission on September 24, 1821, but his father did not go. He was soon baptized with the name "Estanislao" (Spanish for Stanislaus) after his arrival at Mission San José.
Life at the mission.
Estanislao was the "alcalde" of the community before he left the mission with about 400 followers in 1827. Juan Bojorques describes Estanislao in his "Recuerdos sobre la historia de California" (1887) as "about six feet tall, his skin was more white than bronze, he was very muscular like a horse". Juan Bautista Alvarado also mentions Estanislao's literacy in "History of California" (1876), he writes: "Estanislao was able to read and write and stood out among the leaders of other Central California Indian tribes".
The group began raiding the Missions San José, Santa Clara, and Santa Cruz and Mexican settlers in the area around the Laquisimas River (now the Stanislaus River; during the later Mexican era, this river was called "Rio Estanislao"). Estanislao was joined by Chumash Indians led by Pacomio and by other Yokuts until at one time his army had 4,000 men. Estanislao educated his men in battle techniques he had learned from Spanish and Mexican soldiers. These techniques, including trenches, palisades, and an early form of guerilla warfare were essential to initial success on the battlefield. His raids were characterized as sudden, usually involving a trap, and ending with no loss of life, and he would sometimes use his sword to carve his initial, "S," authenticating his handiwork (Estanislao is therefore thought to have been one of the inspirations for the fictional character Zorro).
The Franciscan friars and Mexican settlers pleaded for help from the Mexican army. Finally, Governor Echeandía called the army into action. Three expeditions from the Presidio of San Francisco and the Presidio of Monterey failed to subdue the band. A fourth, larger force led by General Mariano Guadalupe Vallejo finally ousted Estanislao and his people from the Laquisimas River in the Spring of 1829. Commander Ignacio Martínez wrote to Vallejo with orders concerning the rebels, "They are extremely insolent ..., seducing the other [Indians] to accompany them in their evil and diabolical schemes, openly insulting our troops and ridiculing them and their weapons... The objective will be to administer a total defeat to the Indians..., leaving them completely crushed." Both Vallejo and Estanislao were accused of brutality and atrocities by their forces in the battle. During the aftermath of the battle, six Indians were captures, including a man named Matias. Four of them were brutally executed, one of whom died from 73 arrows and a gunshot to the head. The governor ordered an investigation into the extrajudicial killings which found soldier Joaquin Alverado guilty. He was sentenced to five years of additional military service.
Estanislao returned briefly to the Mission San Jose on May 31, 1829 to ask Father Narciso Duran for forgiveness for his men and himself. Father Duran successfully petitioned Governor José María de Echeandía to pardon Estanislao. The pardon was granted for Estanislao and his men on October 7, 1829.
There are multiple theories concerning the later years of his life. Estanislao returned to the Laquisimas River to lead his people. Yoscolo, a Yokut Indian from the Mission Santa Clara, joined Estanislao's group in 1831. Yoscolo brought several hundred Indians with him from the Mission Santa Clara. Yoscolo and Estanislao led many raids against Mexican settlers. Yoscolo was different from Estanislao and did not mind killing Mexican settlers if he had to. Yoscolo sometimes wore a mask during his raids (another link to the fictional character Zorro).
During the spring of 1833, malaria was introduced into the San Joaquin Valley by Canadian beaver trappers from the Hudson's Bay Company. More than 20,000 California natives died from malaria that spring, including Yokuts, Chumash, Miwok and others.
Later life.
On August 24, 1834, Estanislao returned to the Mission San Jose and prospered there while teaching others the Yokuts language and culture. He remained at the Mission until his death, possibly from smallpox, on July 31, 1838. The Stanislaus River, Stanislaus County, and the failed Mormon settlement Stanislaus City (now Ripon) were named in his honor.