Rapamycin & AGing -- LL-37 -- L. Reuteri -- CRISPRs -- Translational Fidelity- C. Diff
randall
http://news.biocompare.com/News/NewsStory/300647/NewsStory.html
Recovery Act Funding Seeks To Help Understand Basic Secrets Of Aging
The National Institute on Aging (NIA), part of the National Institutes
of Health, today announced two major awards to advance exciting areas
of basic research on aging. Grants for studies to determine the
potential healthy aging effects of rapamycin, a compound involved in
regulating cell growth, and to understand the causes of protein
misfolding — when a protein is either not formed correctly or damaged
afterwards — that lead to age-related disease are made possible
through American Recovery and Reinvestment Act funding. These grants
are part of the $5 billion that President Obama announced Sept. 30 on
the National Institutes of Health campus.
"This is a remarkable time in aging research. Our knowledge about the
basic biology of aging has grown rapidly in recent years, and the
studies supported with Recovery Act funds provide a wonderful
opportunity to build on what we know in some key areas," said NIA
Director Richard J. Hodes, M.D. "These studies, at the cellular level,
will increase our understanding of some of the basic biological
processes that occur with passage of time."
Study in Mice to Determine Possible Healthy Effects of Rapamycin
NIA has awarded $5.2 million over the next two years to the University
of Texas Health Science Center in San Antonio to determine the effects
of rapamycin on the health of mice.
"In a recent study, a team of researchers reported that rapamycin
extended the median and maximal lifespan of mice, when the drug was
fed to the mice beginning in middle age. With Recovery Act funding, we
can more quickly follow up on these exciting and provocative
findings," said Felipe Sierra, Ph.D., director of NIA's Division of
Aging Biology.
Rapamycin — an inhibitor of the mTOR pathway that helps to regulate
cell growth and proliferation and that is used to help suppress the
immune system in people undergoing organ transplant — is one of many
compounds being studied for effects that might be similar to those of
calorie restriction. Calorie restriction, very low calorie but
nutritious diets that have been tested in laboratory animals and on a
limited basis in humans, has been found to have variety of positive
effects on health and longevity. Despite these findings, calorie
restriction may not be practical or safe for most people.
The study, led by Arlan Richardson, Ph.D., will seek answers to three
questions:
1.How does rapamycin affect models of age-related human diseases in
mice?
2.How does rapamycin affect normal physiology?
3.By what mechanisms does rapamycin work?
"Under normal circumstances, it took over 10 years of research to
demonstrate that caloric restriction retarded age-related diseases and
increased healthspan. However, Recovery Act funding will allow us to
determine in two years if rapamycin can retard or reduce age-related
diseases and improve quality of life in mice," said Richardson.
The team will test rapamycin's effects on multiple models of
Alzheimer's disease, atherosclerosis, cardiovascular disease,
Parkinson's disease, kidney disease and cancer. In addition,
investigators will look at rapamycin's effects on the physiology and
behavior of healthy mice, focusing special attention on the response
to infection, metabolism, movement and cardiac function.
Study to Develop New Technologies to Monitor Protein Folding
NIA has awarded $1 million to Northwestern University in Evanston,
Ill., and the Salk Institute in La Jolla, Calif., and $1 million to
The Scripps Research Institute in La Jolla, to develop new
technologies — biosensors — that will monitor aging and age-related
disease by focusing on protein folding.
The proper folding of proteins in cells, or proteostasis, is important
for health. Like a three-dimensional puzzle, sections of a protein
naturally fold into shapes and then arrange themselves to align to
each other to produce the final active protein. A protein's function
in the body depends on these folding patterns. If a protein is formed
incorrectly or becomes damaged and then misfolds, it disrupts the
pattern. As a consequence, the protein does not perform its normal
function or cannot be properly disposed of by cellular machinery.
These problems and consequences on cellular proteostasis may lead to
disease.
"Scientists already know that proper protein folding may be affected
by age. Protein misfolding inhibits the body's ability to respond to
environmental and/or physiological stresses and cues and could lead to
age-related diseases like Alzheimer's or Parkinson's. This Recovery
Act funding provides an opportunity to better understand the role of
proteostasis and the aging environment in which protein misfolding
occurs," said NIA's Sierra.
The Recovery Act funding will also support the development of the
Proteostasis Aging Sensor Consortium (PASC) comprised of five
investigators, representing leaders in the fields of protein folding,
human cell biology and aging. The highly complementary skill sets of
these investigators will create synergy to implement these new
technologies within the time frame of the Recovery Act funding.
The researchers from Northwestern University led by Richard Morimoto,
Ph.D., and from the Salk Institute led by Andrew Dillin, Ph.D., will
develop new tools to detect protein misfolding first in a worm model
and then in mammalian tissue culture cells. Researchers from The
Scripps Research Institute led by William Balch, Ph.D., Jeffery Kelly,
Ph.D., and Rockland Wiseman Ph.D., will use some of the tools
developed by the Northwestern and Salk teams as well as their own to
test protein misfolding in different compartments of mammalian cells
in culture and in mice. The five investigators established the PASC to
coordinate collaboration in the design, test and use of all the tools
designed to follow protein folding and misfolding in cells.
"Aging is highly complex, involving multiple and variable metabolic
and biochemical parameters. These studies could lead to first-in-class
biosensors that would detect key features of the aging environment and
its response to stress and disease," said Richard Morimoto, Ph.D.,
principal investigator and professor of biochemistry, molecular
biology and cell biology at Northwestern University. "Ultimately,
biosensors aim to enable researchers to monitor disease progression
and the response to therapeutic intervention in real time."
The NIA leads the federal effort supporting and conducting research on
aging and the medical, social and behavioral issues of older people.
For more information on research and aging, go to www.nia.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical
Research Agency — includes 27 Institutes and Centers and is a
component of the U.S. Department of Health and Human Services. It is
the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates the
causes, treatments, and cures for both common and rare diseases. For
more information about NIH and its programs, visit www.nih.gov.
<sniP>
Can we get some low dose rapamycin? Add some low dose FAE's (fumaric
acid esters)
and toss in some low dose naltrexone (LDN) and we have a JRS..psor.
cocktail.
mTOR
http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin
Symbols FRAP1; FLJ44809; FRAP; FRAP2; MTOR; RAFT1; RAPT1
http://en.wikipedia.org/wiki/Mammalian_target_of_rapamycin#Aging
It's hypothesized that some dietary regimes, like caloric restriction
and methionine restriction, cause lifespan extension by decreasing
mTor activity.[27]
The drug rapamycin, an inhibitor of the mTOR pathway, has shown
increased longevity in mouse experiments
<sniP>
www.ncbi.nlm.nih.gov/pubmed/14608357
RUNX1 -- distal peak of association is in RAPTOR (p150 target of
rapamycin (TOR)-scaffold protein containing WD-repeats).
<sniP>
More rapamycin look alikes:
Sirolimus -- aka- rapamycin (Rapa Nui or Easter Island dirt)
http://en.wikipedia.org/wiki/Sirolimus
Everolimus (derivative of sirolimus)
http://en.wikipedia.org/wiki/Everolimus
Similar with tacrolimus (Japanese dirt bacteria)
http://en.wikipedia.org/wiki/Tacrolimus
---------
mTOR and Rapamycin is particulary interesting for psoriatics besides
the fact you can gain additional year's of LIFE.
88 hits in our Psor newsgroup for keyword: rapamycin
http://groups.google.com/group/alt.support.skin-diseases.psoriasis/search?hl=en&group=alt.support.skin-diseases.psoriasis&q=rapamycin
The first in that bunch:
3052 hits for :: rapamycin + mtor [pubmed]
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=mtor+rapamycin&log$=activity
Boring.
But adding the kicker resveratrol [returns 7 hits]
http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=DetailsSearch&term=mtor+rapamycin+resveratrol&log$=activity
Why shouldn't i have a glass of red wine with my easter island dirt
bacterium?
This is an even better cocktail then LDN + FAE's + low dose rapamycin?
PerhaPs, i can find resveratrol grown in Rapa nui dirt?
This abstract calls for rapamycin with NAC and taurine to attenuate
psoriasis/mTOR
www.ncbi.nlm.nih.gov/pubmed/18463678
=============
Topical bacteria explained by Dr. Gallo (UCSD) atopy dermatological
researcher (think LL-37 or LL37).
http://www.medicalnewstoday.com/articles/171988.php
Skin's Healthy Balance Maintained By Surface Bacteria
On the skin's surface, bacteria are abundant, diverse and constant,
but inflammation is undesirable. Research at the University of
California, San Diego School of Medicine now shows that the normal
bacteria living on the skin surface trigger a pathway that prevents
excessive inflammation after injury.
"These germs are actually good for us," said Richard L. ___Gallo__,
MD, PhD, professor of medicine and pediatrics, chief of UCSD's
Division of Dermatology and the Dermatology section of the Veterans
Affairs San Diego Healthcare System.
The study, published in the advance on-line edition of Nature Medicine
on November 22, was done in mice and in human cell cultures, primarily
performed by post-doctoral fellow Yu Ping Lai .
"The exciting implications of Dr. Lai's work is that it provides a
molecular basis to understand the 'hygiene hypothesis' and has
uncovered elements of the wound repair response that were previously
unknown. This may help us devise new therapeutic approaches for
inflammatory skin diseases," said Gallo.
The so-called "hygiene hypothesis," first introduced in the late
1980s, suggests that a lack of early childhood exposure to infectious
agents and microorganisms increases an individuals susceptibility to
disease by changing how the immune system reacts to such "bacterial
invaders." The hypothesis was first developed to explain why allergies
like hay fever and eczema were less common in children from large
families, who were presumably exposed to more infectious agents than
others. It is also used to explain the higher incidence of allergic
diseases in industrialized countries.
The skin's normal microflora - the microscopic and usually harmless
bacteria that live on the skin - includes certain staphylococcal
bacterial species that will induce an inflammatory response when they
are introduced below the skin's surface, but do not initiate
inflammation when present on the epidermis, or outer layer of skin.
In this study, Lai, Gallo and colleagues reveal a previously unknown
mechanism by which a product of staphylococci inhibits skin
inflammation. Such inhibition is mediated by a molecule called
staphylococcal lipoteichoic acid (LTA) which acts on keratinocytes -
the primary cell types found on the epidermis.
The researchers also found that Toll-like receptor 3 (TLR3) activation
is required for normal inflammation after skin injury.
"Keratinocytes require TLR3 to mount a normal inflammatory response to
injury, and this response is kept from becoming too aggressive by
staphylococcal LTA," said Gallo. "To our knowledge, these findings
show for the first time that the skin epithelium requires TLR3 for
normal inflammation after wounding and that the microflora helps to
modulate this response."
<sniP>
Dr. Gallo is hot:
www.ncbi.nlm.nih.gov/pubmed/19894716
[...]
These results support carpeting or toroidal pore mechanisms of
membrane disruption by LL-37 and demonstrate that the combination of
tryptophan mutants and sensitive spectroscopic tools may provide
important molecular clues about antimicrobial action.
PMID: 19894716
www.ncbi.nlm.nih.gov/pubmed/19781786
Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the
septic response to LPS.
Muto J, Yamasaki K, Taylor KR, __Gallo RL__.
Division of Dermatology, University of California, San Diego and VA
San Diego Health Care System, San Diego, CA 92161, USA.
Fragments of hyaluronan released after injury bind and activate TLR4
in a complex with CD44. Here we investigated if the recognition of
hyaluronan by CD44 and TLR4 alters lipopolysaccaride (LPS)
responsiveness and thus could alter the septic response. In contrast
to mice injected with LPS, mice exposed to hyaluronan prior to LPS had
greatly decreased serum IL-6 and TNFalpha and were protected from
symptoms of sepsis. The protective effect of HA was not seen in Cd44
(-/-) mice. Consistent with our findings in vivo, addition of
hyaluronan to macrophages before LPS exposure significantly decreased
the release of IL-6 and TNFalpha and this effect was not seen in
macrophages from Cd44(-/-) mice. Investigation of the mechanism
responsible for inhibition of LPS activation showed hyaluronan
treatment resulted in an increase in peritoneal macrophage A20 mRNA
expression, and that this was significantly reduced in macrophages
from Cd44(-/-) mice and Tlr4(-/-) mice. Suppression of the A20
response with siRNA inhibited the ability of hyaluronan to protect
against the cytokine response to LPS. Therefore, our results show that
hyaluronan acts through TLR4, CD44 and A20 to stimulate a unique
cellular response that can protect against the septic response to LPS.
PMID: 19781786
====================
http://news.biocompare.com/News/NewsStory/300859/NewsStory.html
A Sticky Solution For Identifying Effective Probiotics
Scientists have crystallised a protein that may help gut bacteria bind
to the gastrointestinal tract. The protein could be used by probiotic
producers to identify strains that are likely to be of real benefit to
people.
"Probiotics need to interact with cells lining the gut to have a
beneficial effect, and if they attach to surfaces in the gut they are
more likely to stick around long enough to exert their activity," says
Dr Nathalie Juge from the Institute of Food Research. IFR is an
Institute of the Biotechnology and Biological Sciences Research
Council, which funded the research.
The gut is the largest immune system organ in the body. The cells
lining the gut are covered in a protective layer of mucus that is
continuously renewed by specialised cells. As well as protecting the
gut lining, mucus provides an attachment site for beneficial bacteria
that help maintain normal gut function.
Mucus adhesion has been well studied for pathogenic bacteria, but
precisely what enables commensal (our gut bacteria) bacteria to stick
is not known. In a paper published in the Journal of Biological
Chemistry, IFR and University of East Anglia scientists have obtained
the first crystal structure of a mucus-binding protein.
The protein was obtained from a strain of Lactobacillus reuteri, a
lactic acid bacterium naturally found in the gastrointestinal tract.
Lactic acid bacteria are the most common microorganisms used as
probiotics.
These mucus-binding proteins are more abundant in lactic acid bacteria
than other types and particularly in strains that inhabit the gut. The
presence of the proteins may contribute to the ability of lactic acid
bacteria to interact with the host.
The team of scientists found that these mucus-binding proteins also
recognise human immunoglobulin proteins. These are an integral part of
the immune system. Mucus-binding proteins may therefore also play a
wider role in gut health as a site of attachment for bacteria.
"The strain-specificity of these proteins demonstrates the need for
the careful molecular design and selection of probiotics," says Dr
Juge. "This also opens new avenues of research to study the
fundamental roles bacteria play in the gastrointestinal tract."
<sniP>
LAB - L reuteri
http://en.wikipedia.org/wiki/Lactobacillus_reuteri#L._reuteri_as_an_anti-microbial_agent
========================
No more GIT (gastro intestinal track) hunches once we know it all?
http://news.biocompare.com/News/NewsStory/300995/NewsStory.html
Researchers Discover Biological Basis Of 'bacterial Immune System'
Athens, Ga. – Bacteria don't have easy lives. In addition to mammalian
immune systems that besiege the bugs, they have natural enemies called
bacteriophages, viruses that kill half the bacteria on Earth every two
days.
Still, bacteria and another class of microorganisms called archaea
(first discovered in extreme environments such as deep-sea volcanic
vents) manage just fine, thank you, in part because they have a built-
in defense system that helps protect them from many viruses and other
invaders.
A team of scientists led by researchers at the University of Georgia
has now discovered how this bacterial defense system works, and it
could lead to new classes of targeted antibiotics, new tools to study
gene function in microorganisms and more stable bacterial cultures
used by food and biotechnology industries to make products such as
yogurt and cheese.
The research was published today in the journal Cell.
"Understanding how bacteria defend themselves gives us important
information that can be used to weaken bacteria that are harmful and
strengthen bacteria that are helpful," said Michael Terns, a professor
of biochemistry and molecular biology in UGA's Franklin College of
Arts and Sciences. "We also hope to exploit this knowledge to develop
new tools to speed research on microorganisms."
Other authors on the Cell paper include Rebecca Terns, a senior
research scientist in biochemistry and molecular biology at UGA; Caryn
Hale, a graduate student in the Terns lab at UGA; Lance Wells, an
assistant professor of biochemistry and molecular biology and Georgia
Cancer Coalition Scholar at UGA and his graduate student Peng Zhao;
and research associate Sara Olson, assistant professor Michael Duff
and associate professor Brenton Graveley of the University of
Connecticut Health Center.
The system, whose mechanism of action was uncovered in the Terns lab
(Michael and Rebecca Terns are a husband-wife team), involves a
"dynamic duo" made up of a bacterial RNA that recognizes and
physically attaches itself to a viral target molecule, and partner
proteins that cut up the target, thereby "silencing" the would-be cell
killer.
The invader surveillance component of the dynamic duo (an RNA with a
viral recognition sequence) comes from sites in the genomes of
bacteria and archaea, known technically as "clustered regularly
interspaced short palindromic repeats" or more familiarly called
CRISPRs. (A palindrome is a word or sentence that reads the same
forward and backward.) CRISPR RNAs don't work alone in fighting
invaders, though.
Their partners in invader defense are Cas proteins that arise from a
suite of genes called "CRISPR-associated" or Cas genes. Together, they
form the "CRISPR-Cas system," and the new paper describes this dynamic
duo and how they protect bacteria from viruses.
"You can look at one as a police dog that tracks down and latches onto
an invader, and the other as a police officer that follows along and
`silences' the offender," said Rebecca Terns. "It functions like our
own immune system, constantly watching for and neutralizing intruders.
But the surveillance is done by tiny CRISPR RNAs rather than
antibodies."
What the team discovered was that a particular complex of CRISPR RNAs
and a subset of the Cas proteins termed the RAMP module recognizes and
destroys invader RNAs that it encounters.
"This work has uncovered intriguing parallels between the bacterial
CRISPR-Cas system and the human immune system, suggesting a novel way
to target disease-causing bacteria," said Laurie Tompkins, Ph.D., who
oversees genetic mechanisms grants at the National Institutes of
Health's National Institute of General Medical Sciences. "It may be
possible to turn CRISPR-Cas into a suicide machine, killing pathogenic
bacteria by an attack on their own molecules, similar to the self-
destruction seen in human autoimmune diseases."
Understanding how the system silences invaders opens up opportunities
to exploit it. So far, CRISPRs have been found in about half of the
bacterial genomes that have been mapped or sequenced and in nearly all
sequenced archaeal genomes. Such pervasiveness indicates that an
ability to manipulate the CRISPR-Cas system could yield a broad range
of applications. For example, using the knowledge that they have
obtained in this work, the Terns now envision being able to design new
CRISPR RNAs that will take advantage of the system to selectively
cleave target RNAs in bacterial cells.
"These could target viruses that wipe out cultures of bacteria used by
industry to produce enzymes," said Michael Terns, "or could target the
gene products of the bacteria themselves. With this set of Cas
proteins, we now know how to cut a target RNA at the site we choose."
"Believe it or not, we have only recently recognized that these
microorganisms have a heritable immune system [because it is so
different from our own]," added Rebecca Terns.
Remarkably, scientists are already in a position to begin to
capitalize on their rapidly growing knowledge of this bacterial immune
system.
<sniP>
----
2009 Nov 25;139(5):945-56.
RNA-Guided RNA Cleavage by a CRISPR RNA-Cas Protein Complex.
Hale CR, Zhao P, Olson S, Duff MO, Graveley BR, Wells L, Terns RM,
Terns MP.
Departments of Biochemistry and Molecular Biology, University of
Georgia, Athens, GA 30602, USA.
Compelling evidence indicates that the CRISPR-Cas system protects
prokaryotes from viruses and other potential genome invaders. This
adaptive prokaryotic immune system arises from the clustered regularly
interspaced short palindromic repeats (CRISPRs) found in prokaryotic
genomes, which harbor short invader-derived sequences, and the CRISPR-
associated (Cas) protein-coding genes. Here, we have identified a
CRISPR-Cas effector complex that is comprised of small invader-
targeting RNAs from the CRISPR loci (termed prokaryotic silencing (psi)
RNAs) and the RAMP module (or Cmr) Cas proteins. The psiRNA-Cmr
protein complexes cleave complementary target RNAs at a fixed distance
from the 3' end of the integral psiRNAs. In Pyrococcus furiosus,
psiRNAs occur in two size forms that share a common 5' sequence tag
but have distinct 3' ends that direct cleavage of a given target RNA
at two distinct sites. Our results indicate that prokaryotes possess a
unique RNA silencing system that functions by homology-dependent
cleavage of invader RNAs.
PMID: 19945378
===========
http://news.biocompare.com/News/NewsStory/300994/NewsStory.html
Cells Defend Themselves From Viruses, Bacteria With Armor Of Protein
Errors
When cells are confronted with an invading virus or bacteria or
exposed to an irritating chemical, they protect themselves by going
off their DNA recipe and inserting the wrong amino acid into new
proteins to defend them against damage, scientists have discovered.
These "regulated errors" comprise a novel non-genetic mechanism by
which cells can rapidly make important proteins more resistant to
attack when stressed, said Tao Pan, Professor of Biochemistry and
Molecular Biology at the University of Chicago. A team of 18
scientists from the University of Chicago and the National Institute
of Allergy and Infectious Disease led by Pan and Jonathan Yewdell
published the findings Thursday in the journal Nature.
"This mechanism allows every protein to get some protection," Pan
said. "The genetic code is considered untouchable, but this is a non-
genetic strategy used in cells to create a bodyguard for proteins."
Proteins are constructed through a process called translation where
cellular elements use the genetic code to guide the assembly of
building blocks called amino acids into the correct sequence. First, a
copy of the DNA, called messenger RNA, is made and transferred to a
cellular structure called a ribosome. Transfer RNAs (tRNA), one for
each of the 20 amino acids used in building proteins, read the
messenger RNA code and bring the proper amino acids to the ribosome,
where they are bonded together to form a complete protein.
Each tRNA can be attached to only one of 20 amino acids, a specificity
that prevents errors during the construction of proteins. In
artificial laboratory preparations, scientists have observed that only
one out of every 10,000 amino acids is placed into a protein
incorrectly, and thus protein errors were thought to be exceptionally
rare.
But Jeffrey Goodenbour, University of Chicago graduate student and co-
lead author along with Nir Netzer of the NIAID, decided to look at how
often tRNA errors, called misacylations, occurred in live cells. After
developing a novel technique for measuring these errors, published for
the first time in this paper, the authors were surprised to find a
much higher error rate in those cells for the amino acid methionine.
As high as one out of every 100 methionines was incorrectly placed in
proteins, they found.
When the cells were stressed by exposure to a virus, bacteria or a
toxic chemical such as hydrogen peroxide, that error rate went even
higher, as up to 10 percent of methionines placed into new proteins
were different from what the gene specified.
[is this why in the rapamycin links above they say methionine
restriction increases longevity?]
"That was 1,000 times more than the textbook says should be there,"
Pan said.
Further experiments revealed that it was always the same amino acid,
methionine, placed incorrectly into new proteins. Methionine is one of
only two amino acids to carry sulfur atoms on its side chains, a
feature that allows it to neutralize dangerous molecules called
reactive oxygen species (ROS) that form inside an infected or stressed
cell. ROS can damage proteins through a chemical process called
oxidation, but methionine can be oxidized (and restored through a
process called reduction) without being permanently damaged.
"The idea is that methionine can protect you from having oxidation of
the active site of protein, which would ultimately completely block
function of the protein," Goodenbour said. "You end up reducing the
total reactive oxygen species load in the cell. It's a very
interesting mechanism."
Cells normally put methionines near important parts of a protein to
protect those segments from being damaged by reactive oxygen species.
When the cell is under stress, and the amount of ROS increases, the
number of methionine "errors" is ramped up tenfold, allowing new
proteins to be even more resistant to attack.
"Think of a boxing match," Pan said. "If you put methionine close to
active site, the reactive oxygen species has to get past it to get to
the active site residues for oxidization. You've put something right
in front of it so a protein can take a hit. If you have a lot of
methionines, to knock this protein out will take many, many hits. So
this is a strategy used in cells to create a bodyguard for a protein."
A remaining puzzle is to determine why extra protective methionines
are not encoded as part of the DNA in the first place, instead of
being left to the post-genetic random placement described in this
paper. Pan suggests that random placement of the amino acids makes
proteins even more resistant to attack, since no two are created
alike.
"This sounds chaotic and doesn't make a lot of sense according to the
textbook," Pan said. "But this way the cells can always ensure that a
subset of these proteins is somewhat less sensitive to the extra hits.
I think that's the most important part of this - to make every protein
molecule different - and you cannot do this genetically."
<snip>
----
2009 Nov 26;462(7272):522-6.
Innate immune and chemically triggered oxidative stress modifies
translational fidelity.
Netzer N, Goodenbour JM, David A, Dittmar KA, Jones RB, Schneider JR,
Boone D, Eves EM, Rosner MR, Gibbs JS, Embry A, Dolan B, Das S,
Hickman HD, Berglund P, Bennink JR, Yewdell JW, Pan T.
Laboratory of Viral Diseases, National Institute of Allergy and
Infectious Diseases, Bethesda, Maryland 20892, USA.
Translational fidelity, essential for protein and cell function,
requires accurate transfer RNA (tRNA) aminoacylation. Purified
aminoacyl-tRNA synthetases exhibit a fidelity of one error per 10,000
to 100,000 couplings. The accuracy of tRNA aminoacylation in vivo is
uncertain, however, and might be considerably lower. Here we show that
in mammalian cells, approximately 1% of methionine (Met) residues used
in protein synthesis are aminoacylated to non-methionyl-tRNAs.
Remarkably, Met-misacylation increases up to tenfold upon exposing
cells to live or non-infectious viruses, toll-like receptor ligands or
chemically induced oxidative stress. Met is misacylated to specific
non-methionyl-tRNA families, and these Met-misacylated tRNAs are used
in translation. Met-misacylation is blocked by an inhibitor of
cellular oxidases, implicating reactive oxygen species (ROS) as the
misacylation trigger. Among six amino acids tested, tRNA misacylation
occurs exclusively with Met. As Met residues are known to protect
proteins against ROS-mediated damage, we propose that Met-misacylation
functions adaptively to increase Met incorporation into proteins to
protect cells against oxidative stress. In demonstrating an unexpected
conditional aspect of decoding mRNA, our findings illustrate the
importance of considering alternative iterations of the genetic code.
PMID: 19940929
====================
http://www.medicalnewstoday.com/articles/172329.php
Clostridium difficile, also known as C. difficile, or C. diff, is a
bacterium which infects and can make humans ill, as well as other
animals. Symptoms can range from diarrhea to serious and potentially
fatal inflammation of the colon.
<sniP>
============
http://www.medicalnewstoday.com/articles/172319.php
Leprosy targetted for elimination by WHO
=====
randall
JRStern
wrote:
>Can we get some low dose rapamycin? Add some low dose FAE's (fumaric
>acid esters)
>and toss in some low dose naltrexone (LDN) and we have a JRS..psor.
>cocktail.
Just give me $700,000,000,000 and I'll make my own cocktails.
J.
P.
As psoriasis is age related, this may help. Wonder if I can go back to
being 18 again.
P.