Transcript Document

• EPIM
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Strategies for Engineered Negligible Senescence - Cancer-causing nuclear
mutations/epimutations—OncoSENS
1
For the purposes of SENS, the effect of
mutations and epimutations that
really matters is cancer, this is
because if even one cell turns into a
cancer cell it might spread and
become deadly
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DNA repair - Frequencies of epimutations in DNA repair genes
1
Deficiencies in DNA repair enzymes are
occasionally caused by a newly arising
somatic mutation in a DNA repair gene,
but are much more frequently caused
by epigenetic alterations that reduce or
silence expression of DNA repair genes
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Heparin sulfate - Epimerisation and 2-O-sulfation
1
Epimerisation is catalysed by one enzyme,
the GlcA C5 epimerase or heparosan-Nsulfate-glucuronate 5-epimerase (). This
enzyme epimerises GlcA to iduronic acid
(IdoA). Substrate recognition requires that
the GlcN residue linked to the nonreducing side of a potential GlcA target be
N-sulfated. Uronosyl-2-O-sulfotransferase
(2OST) sulfates the resulting IdoA
residues.
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Epimutation
1
In biology, and specifically genetics,
'epigenetics' is the study of heritable
changes in gene activity that are not
caused by changes in the DNA
sequence; it also can be used to
describe the study of stable, long-term
alterations in the transcriptional
potential of a cell that are not
necessarily heritable
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Epimutation
The term also refers to the changes
themselves: functionally relevant changes
to the genome that do not involve a
change in the nucleotide sequence
1
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Epimutation
1
One example of an epigenetic change
in eukaryotic biology is the process of
cellular differentiation
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Epimutation
In 2011, it was demonstrated that the
methylation of messenger RNA|mRNA
plays a critical role in human energy
balance (biology)|energy homeostasis.
The obesity-associated FTO gene is
shown to be able to demethylate N6methyladenosine in RNA. This
discovery launched the subfield of RNA
epigenetics.
1
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Epimutation - Mechanisms
1
Several types of epigenetic inheritance
systems may play a role in what has
become known as cell memory, note
however that not all of these are
universally accepted to be examples of
epigenetics.
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Epimutation - MicroRNAs
1
MicroRNAs (miRNAs) are members of noncoding RNAs that range in size from 17 to 25
nucleotides
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Epimutation - MicroRNAs
It appears that about 60% of human
protein coding genes are regulated by
miRNAs.Friedman RC, Farh KK, Burge
CB, Bartel DP (2009)
1
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Epimutation - sRNAs
1
Bacterial small RNA|sRNAs are small
(50-250 nucleotides), highlystructured, non-coding RNA
fragments found in bacteria
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Epimutation - Prions
Prions are
Infection|infectious
forms of proteins
1
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Epimutation - Prions
1
Fungal prions are considered by some to
be epigenetic because the infectious
phenotype caused by the prion can be
inherited without modification of the
genome
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Epimutation - Structural inheritance systems
In ciliates such as Tetrahymena and
Paramecium, genetically identical cells show
heritable differences in the patterns of ciliary
rows on their cell surface. Experimentally
altered patterns can be transmitted to
daughter cells. It seems existing structures
act as templates for new structures. The
mechanisms of such inheritance are unclear,
but reasons exist to assume that multicellular
organisms also use existing cell structures to
assemble new ones.
1
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Epimutation - Development
1
Somatic epigenetic inheritance through
epigenetic modifications, particularly
through DNA methylation and chromatin
remodeling, is very important in the
development of multicellular eukaryotic
organisms
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Epimutation - Development
Epigenetics can be divided into
predetermined and probabilistic epigenesis.
Predetermined epigenesis is a unidirectional
movement from structural development in
DNA to the functional maturation of the
protein. Predetermined here means that
development is scripted and predictable.
Probabilistic epigenesis on the other hand is
a bidirectional structure-function development
with experiences and external molding
development.
1
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Epimutation - Medicine
1
Epigenetics has many and varied
potential medical applications as it
tends to be multidimensional in
nature
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Epimutation - Evolution
Epigenetics can impact
evolution when epigenetic
changes are heritable
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Epimutation - Evolution
Two important ways in which
epigenetic inheritance can be different
from traditional genetic inheritance,
with important consequences for
evolution, are that rates of epimutation
can be much faster than rates of
mutation and the epimutations are
more easily reversible
1
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Epimutation - Genomic imprinting and related disorders
1
Some human disorders are associated
with genomic imprinting, a
phenomenon in mammals where the
father and mother contribute different
epigenetic patterns for specific
genomic loci in their germ cells
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Epimutation - Variant histones H2A in cancer
1
The histone variants of the H2A family are
highly conserved in mammals, playing
critical roles in regulating many nuclear
processes by altering chromatin structure
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Epimutation - Cancer treatment
Current research has shown that
epigenetic pharmaceuticals could be
a putative replacement or adjuvant
therapy for currently accepted
treatment methods such as radiation
therapy|radiation and chemotherapy,
or could enhance the effects of these
current treatments
1
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Epimutation - Cancer treatment
1
Drug development has focused mainly on
histone acetyltransferase (HAT) and
histone deacetylase (HDAC), and has
included the introduction to the market of
the new pharmaceutical vorinostat, an
HDAC inhibitor. HDAC has been shown to
play an integral role in the progression of
oral squamous cancer.
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Epimutation - Cancer treatment
1
Current front-runner candidates for
new drug targets are Histone
methyltransferase|histone lysine
methyltransferases (KMT) and protein
arginine methyltransferases (PRMT).
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Epimutation - Twin studies
1
Recent studies involving both dizygotic
and monozygotic twins have produced
some evidence of epigenetic influence in
humans.
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Epimutation - Twin studies
1
Direct comparisons between identical
twins constitute the ideal
experimental model for testing
environmental epigenetics, because
DNA sequence differences that would
be abundant in a singleton-based
study do not interfere with the
analysis
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Epimutation - Twin studies
One of the first high-throughput
studies of epigenetic differences
between monozygotic twins focused in
comparing global and locus-specific
changes in DNA methylation and
histone modifications in a sample of
40 monozygotic twin pairs.Fraga MF,
Ballestar E, Paz MF et al (2005)
Epigenetic differences arise during
the lifetime of monozygotic twins
1
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Epimutation - Twin studies
A more recent study, where 114
monozygotic twins and 80 dizygotic
twins were analyzed for the DNA
methylation status of around 6000
unique genomic regions, concluded
that epigenetic similarity at the time
of blastocyst splitting may also
contribute to phenotypic similarities
in monozygotic co-twins
1
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Epimetheus (mythology)
1
While Prometheus is characterized as ingenious and
clever, Epimetheus is depicted as foolish.
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Epimetheus (mythology) - Mythology
1
According to Plato's use of the old myth in
his Protagoras (dialogue)|Protagoras
(320d–322a), the twin Titans were
entrusted with distributing the traits among
the newly created animals. Epimetheus
was responsible for giving a positive trait
to every animal, but when it was time to
give man a positive trait, lacking foresight
he found that there was nothing left.Leo
Strauss, Natural Right and History, p. 117.
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Epimetheus (mythology) - Mythology
1
Prometheus decided that mankind's
attributes would be the civilizing arts
and fire, which he stole from Zeus.
Prometheus later stood trial for his
crime. In the context of Plato's
dialogue, Epimetheus, the being in
whom thought follows production,
represents nature in the sense of
materialism, according to which
thought comes later than thoughtless
bodies and their thoughtless
motions.Leo Strauss, Natural Right
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Epimetheus (mythology) - Mythology
1
According to Hesiod, who related the
tale twice (Theogony, 527ff; Works and
Days 57ff), Epimetheus was the one
who accepted the gift of Pandora from
the gods. Their marriage may be
inferred (and was by later authors),
but it is not made explicit in either
text.
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Epimetheus (mythology) - Mythology
1
In later myths, the daughter of Epimetheus
and Pandora was Pyrrha, who married
Deucalion and was one of the two who
survived the Deluge (mythology)|deluge.
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Epimetheus (mythology) - In modern culture
1
Carl Schmitt, in his book Ex captivitate salus
describes himself as a Christian Epimetheus.
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Epimetheus (mythology) - In modern culture
1
Les Amis, in his book Commemorating Epimetheus
(2009), reinstates the value of Epimetheus
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Self-refuting idea - Epimenides paradox
1
The first notable self-refuting idea is the
Epimenides paradox, a statement
attributed to Epimenides, a Cretan
philosopher, that All Cretans are liars. If
interpreted as meaning no Cretan ever
speaks the truth, this cannot be true if
uttered by a Cretan.
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Self-refuting idea - Epimenides paradox
1
A more common example is the selfrefuting statement I am lying
(because the first statement allows the
possibility some Cretans do not speak
the truth, the speaker being one of
them). The second statement has no
third alternative—the speaker's
statement is either true or false.
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Galactose epimerase deficiency
'Galactose epimerase deficiency', also
known as 'GALE deficiency',
'Galactosemia III' and 'UDP-galactose-4epimerase deficiency', is a rare,
autosome|autosomal dominance
(genetics)|recessive form of galactosemia
associated with a deficiency of the enzyme
galactose epimerase.
1
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Galactose epimerase deficiency - Genetics
1
Galactose epimerase deficiency is an
autosomal recessive disorder, which
means the defective gene is located on
an autosome, and two copies of the
defective gene - one from each parent
- are required to inherit the disorder.
The parents of an individual with an
autosomal recessive disorder both
carry one copy of the defective gene,
but usually do not experience any
signs or symptoms of the disorder.
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Galactose epimerase deficiency - Genetic basis
Various human GALE mutations
resulting in Type III galactosemia
have been identified. Functional
analysis of these mutant GALE
isoforms suggests that reduced
catalytic efficiency and increased
likelihood of proteolytic digestion act
causatively in Type III galactosemia.
1
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Galactose epimerase deficiency - Biochemical basis
GALE deficiency inhibits UDP-glucose
regeneration, preventing the formation of
glucose-1-phosphate and leading to the
accumulation of galactose and galactose1-phosphate
1
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Galactose epimerase deficiency - Biochemical basis
Blockage of the Leloir pathway by
GALE deficiency or dysfunction
activates alternate pathways of glucose
metabolism and leads to galactitol and
galactonate formation
1
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Galactose epimerase deficiency - Symptoms
Symptoms of congenital Type III
Galactosemia are apparent from birth, but
vary in severity depending on whether the
peripheral or generalized disease form is
present. Symptoms may include:
1
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Galactose epimerase deficiency - Symptoms
1
* Dysmorphic features
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Galactose epimerase deficiency - Symptoms
1
* Sensorineural hearing
loss
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Galactose epimerase deficiency - Symptoms
* Depletion of
cerebellar Purkinje
cells
1
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Galactose epimerase deficiency - Symptoms
1
* Ovarian failure (POI) and
hypertrophic hypergonadism
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Galactose epimerase deficiency - Symptoms
Studies of Type III galactosemia
symptoms are mostly descriptive, and
precise pathogenic mechanisms
remain unknown. This is largely due
to a lack of functional animal models
of classic galactosemia. The recent
development of a Drosophila
melanogaster GALE mutant exhibiting
galactosemic symptoms may yield a
promising future animal model.
1
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Galactose epimerase deficiency - Detection and treatment
1
Screening for elevated galactose levels
may detect GALE deficiency or
dysfunction in infants, and mutation
studies for GALE are clinically available
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Cefepime
1
A 2007 meta-analysis suggested when
data of trials were combined,
Mortality rate|mortality was
increased in patients treated with
cefepime compared with other βlactam antibiotics
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Cefepime - Clinical use
1
Cefepime is usually reserved to treat
moderate to severe nosocomial
pneumonia, infections caused by
multiple drug-resistant
microorganisms (e.g. Pseudomonas
aeruginosa) and empirical treatment
of febrile neutropenia.
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Cefepime - Clinical use
Cefepime has good activity against
important pathogens including
Pseudomonas aeruginosa,
Staphylococcus aureus, and multiple
drug-resistant Streptococcus
pneumoniae. A particular strength is its
activity against Enterobacteriaceae.
Whereas other cephalosporins are
degraded by many plasmid- and
chromosome-mediated beta-lactamases,
cefepime is stable and is a front-line
agent when infection with
1
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Cefepime - Spectrum of bacterial susceptibility
Cefepime is a broad-spectrum
cephalosporin antibiotic and has been
used to treat bacteria responsible for
causing pneumonia and infections of
the skin and urinary tract. Some of
these bacteria include Pseudomonas,
Escherichia, and Streptoccus species.
The following represents MIC
susceptibility data for a few medically
significant microorganisms.
1
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Cefepime - Spectrum of bacterial susceptibility
* Pseudomonas
aeruginosa: 0.06 - 256
μg/ml
1
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Cefepime - Spectrum of bacterial susceptibility
1
* Streptococcus pneumoniae:
≤0.007 - 8 μg/ml
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Cefepime - Spectrum of bacterial susceptibility
http://www.tokue.com/Assets/MIC/Cefepime.pdf
1
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Cefepime - Chemistry
1
The combination of the syn-configuration
of the methoxyimino Moiety
(chemistry)|moiety and the aminothiazolyl
moiety confers extra stability to beta
lactamase|beta;-lactamase enzymes
produced by many bacteria. The Nmethylpyrrolidine moiety increases
penetration into Gram-negative bacteria.
These factors increase the activity of
cefepime against otherwise resistant
organisms including Pseudomonas
aeruginosa and Staphylococcus aureus.
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Epimenides
1
Plutarch writes that Epimenides purified
Athens after the pollution brought by the
Alcmeonidae, and that the seer's expertise
in sacrifices and reform of funeral
practices were of great help to Solon in his
reform of the Athenian state
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Epimenides
1
Epimenides was also said to
have prophesied at Sparta on
military matters.
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Epimenides
Epimenides is also reckoned with
Melampus and Onomacritus as one of the
founders of Orphism (religion)|Orphism.
1
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Epimenides - Works
1
Several prose and poetic works, now lost,
were attributed to Epimenides, including a
theogony, an epic poem on the
Argonauts|Argonautic expedition, prose
works on purifications and sacrifices, a
cosmogony, oracles, a work on the laws of
Crete, and a treatise on Minos and
Rhadymanthus.
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Epimenides - Cretica
1
Epimenides' Cretica (Κρητικά) is quoted
twice in the New Testament. Its only
source is a 9th-century Syriac commentary
by Isho'dad of Merv on the Acts of the
Apostles, discovered, edited and
translated (into Greek) by Prof. J. Rendel
Harris in a series of articles in the
Expositor (Oct. 1906, 305–17;
[http://books.google.com/books?id=facQA
AAAYAAJpg=PA336#v=onepageqf=false
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Epimenides - Cretica
In the poem, Minos
addresses Zeus thus:
1
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Epimenides - Cretica
1
The lie of the Cretans is that Zeus was
mortal; Epimenides considered Zeus
immortal. Cretans, always liars, with
the same theological intent as
Epimenides, also appears in the Hymn
to Zeus of Callimachus. The fourth
line is quoted (with a reference to one
of your own poets) in Acts of the
Apostles, s:Bible (King
James)/Acts#17:28|chapter 17, verse
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Epimenides - Cretica
The second line is quoted, with a veiled
attribution (a prophet of their own), in the
Epistle to Titus, s:Bible (King
James)/Titus#1:12|chapter 1, verse 12, to
warn Titus about the Cretans. The prophet
in Titus 1:12 is identified by Clement of
Alexandria as Epimenides (Stromata,
[http://www.newadvent.org/fathers/02101.h
tm i. 14]). In this passage, Clement
mentions that some say Epimenides
1
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Epimenides - Cretica
Chrysostom
([http://www.newadvent.org/fathers/23083.
htm Homily 3 on Titus]) gives an
alternative fragment:
1
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Epimenides - Cretica
1
:For even a tomb, King, of
you
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Epimenides - Cretica
1
:They made, who never
died, but ever shall be.
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Epimenides - Epimenides paradox
1
In the Middle Ages, many forms of the liar
paradox were studied under the heading
of insolubilia, but these were not
associated with Epimenides.
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Planetary nomenclature - Epimetheus (moon)|Epimetheus
1
People from myth of
Castor and Pollux
(twins)
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Isomerase - Racemases, epimerases
1
Isomerization at one chiral carbon of
several yields epimers, which differ
from one another in absolute
configuration at just one chiral carbon
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Isomerase - Epimerization
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An example of epimerization is found
in the Calvin cycle when D-ribulose-5phosphate is converted into Dxylulose-5-phosphate by ribulosephosphate 3-epimerase
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Centipede - Anamorphy vs. epimorphy
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Centipedes grow their
legs at different points
in their development
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Centipede - Anamorphy vs. epimorphy
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The Craterostigmomorpha only have one
phase of anamorphis, with embryos
having 12 pairs, and moultees 15.
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Centipede - Anamorphy vs. epimorphy
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The clade Epimorpha, consisting of orders
Geophilomorpha and Scolopendromorpha,
exhibits epimorphy: all pairs of legs are
developed in the embryonic stages, and
offspring do not develop more legs
between moults
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Epimer
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In stereochemistry, 'epimer' refers to one
of a pair of
Stereoisomerism|stereoisomers. The two
isomers differ in configuration at only one
stereogenic center. All other stereocenters
in the molecules, if any, are the same in
each.
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Epimer
Doxorubicin and
epirubicin are two
closely related drugs
and epimers.
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Epimer - Examples
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The two molecules pictured are both
epimers and anomers (as indicated by
the 'α'-glucose and 'β' designation).
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Epimer - Examples
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These two molecules are epimers but,
because not mirror images of each
other, are also not enantiomers
(enantiomers have the same name but
differ in 'D' and 'L' classification)
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Epimer - Examples
Other closely related compounds are epiinositol and inositol and lipoxin and epilipoxin.
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Epimer - Epimerisation
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Epimerisation is a chemical process
where an epimer is transformed into
its chiral counterpart. It can happen in
condensed tannins depolymerisation
reactions. Epimerisation can be
spontaneous (generally a slow
process), or catalyzed by enzymes,
e.g. the epimerization between the
sugars N-acetylglucosamine and Nacetylmannosamine, which is
catalyzed by RENBP|Renin-Binding
Protein.
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Lobry-de Bruyn-van Ekenstein transformation - Epimerization
The carbon atom at which the initial
deprotonation takes place is a
stereocenter. If, for example, D-glucose
(an Aldose) rearranges to D-fructose, the
ketose, the stereochemical configuration is
lost in the enol form. In the chemical
reaction the enol can be protonated from
two faces, resulting in the backformation of
glucose or the formation of the epimer
mannose|D-mannose. The final product is
a mix of D-glucose, D-fructose and Dmannose.
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Methylmalonyl CoA epimerase - Role in Fatty Acid Catabolism
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Methylmalonyl CoA epimerase then
catalyzes the rearrangement of (R)methylmalonyl-CoA to the (S) form in a
reaction that uses a vitamin B12
cofactor (biochemistry)|cofactor and a
resonance-stabilized carbanion
Reactive intermediate|intermediate
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Methylmalonyl CoA epimerase - Reaction Mechanism
Acting as a Enzyme catalysis|general
base, the enzyme abstracts a proton from
the β-carbon of (R)-methylmalonyl-CoA.
This results in the formation of a carbanion
intermediate in which the α-carbon is
stabilized by resonance. The enzyme
then acts as a general acid to protonate
the β-carbon, resulting in the formation of
(S)-methylmalonyl-CoA.
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Epimetheus (moon)
'Epimetheus' is an inner satellite of
Saturn. It is also known as 'SaturnXI'. It is
named after the mythological Epimetheus
(mythology)|Epimetheus, brother of
Prometheus.
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Epimetheus (moon) - Discovery
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Epimetheus occupies essentially the same
orbit as the moon Janus (moon)|Janus.
Astronomers assumed that there was only
one body in that orbit, and accordingly had
difficulty determining their orbital
characteristics. Observations were
photographic and spaced widely apart in
time, so that while the presence of two
objects was not obvious, the observations
were difficult to reconcile with a
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Epimetheus (moon) - Discovery
Audouin Dollfus observed a moon on
December 15, 1966, which he proposed to
be named Janus. On December 18,
Richard Walker (astronomer)|Richard
Walker made a similar observation which
is now credited as the discovery of
Epimetheus. However, at the time, it was
believed that there was only one moon,
unofficially known as Janus, in the given
orbit.
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Epimetheus (moon) - Discovery
Twelve years later, in October 1978,
Stephen M. Larson and John W.
Fountain realised that the 1966
observations were best explained by
two distinct objects (Janus and
Epimetheus) sharing very similar
orbits. This was confirmed in 1980 by
Voyager 1, and so Larson and Fountain
officially share the discovery of
Epimetheus with Walker.
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Epimetheus (moon) - Discovery
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Epimetheus received its name in 1983.
The name Janus was approved by the
International Astronomical Union|IAU
at the same time, although the name
had been used informally since
Dollfus proposed it shortly after the
1966 discovery.
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Epimetheus (moon) - Orbital relationship between Epimetheus and Janus
The exchange takes place about once
every four years; the last close
approaches occurred on January 21,
2006, and in 2010, when Janus's orbital
radius increased by ~20km, while
Epimetheus's decreased by ~80km;
Janus's orbit is less affected because it is
four times more massive than Epimetheus
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Epimetheus (moon) - Orbital relationship between Epimetheus and Janus
1
The orbital relationship between Janus
and Epimetheus can be understood in
terms of the Three-body
problem#Circular restricted three-body
problem|circular restricted three-body
problem, as a case in which the two
moons (the third body being Saturn)
are similar in size to each other.
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Epimetheus (moon) - Physical characteristics
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From its very low density and relatively
high albedo, it seems likely that
Epimetheus is a very porous icy body
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Epimetheus (moon) - Physical characteristics
1
The south pole shows what might be
the remains of a large impact crater
covering most of this face of the moon,
and which could be responsible for the
somewhat flattened shape of the
southern part of Epimetheus.
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Epimetheus (moon) - Physical characteristics
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There appear to be two terrain types:
darker, smoother areas, and brighter,
slightly more yellowish, fractured
terrain. One interpretation is that the
darker material evidently moves
down slopes, and probably has a lower
ice content than the brighter material,
which appears more like bedrock.
Nonetheless, materials in both
terrains are likely to be rich in water
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Epimetheus (moon) - Ring
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A Rings of Saturn#Janus/Epimetheus
Ring|faint dust ring is present around
the region occupied by the orbits of
Epimetheus and Janus, as revealed by
images taken in forward-scattered
light by the Cassini–Huygens|Cassini
spacecraft in 2006. The ring has a
radial extent of about 5000km. Its
source are particles blasted off their
surfaces by meteoroid impacts, which
then form a diffuse ring around their
orbital paths.
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Epistle to Titus - Epimenides paradox
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One of the secular peculiarities of the
Epistle to Titus is the inclusion of text
which has become known as the
Epimenides paradox. According to the
World English Bible translation, Titus
1:12–13 reads (in part) One of them, a
prophet of their own, said, 'Cretans
are always liars, evil beasts, and idle
gluttons.' This testimony is true. The
statement by a member of a group that
all members are liars is now a famous
logic problem.
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